Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].[O-:14][Mn](=O)(=O)=O.[K+].Cl>CC#N.O>[I:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]([OH:14])=[O:5]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(I)c(C=O)cc1OC
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(I)c(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a stirred solution of 2-iodo-4,5-dimethoxybenzaldehyde (1.0 g, 3.42 mmol) in CH3CN (25 mL) was added a solution of KMnO4 (0.76 g, 4.79 mmol) in water (15 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. After the reaction was complete, the pH was adjusted to <7 with 1N HCl. The mixture was extracted with DCM and the organic layers combined, washed with brine, dried over sodium sulfate, and evaporated to give 2-Iodo-4,5-dimethoxybenzoic acid (0.89 g, 85%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[O:15][CH2:16][CH3:17])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:16]([O:15]/[C:9](=[CH:8]\[C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][CH3:24])[CH:27]=2)=[CH:3][CH:4]=1)/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:17]
Reactant: CCOC(=O)/C(=C/c1ccc(Br)cc1)OCC
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)cc1)OCC
Yield: 89.4 %

Procedure:
To a solution of 10.8 g (36.1 mmol) of ethyl (Z)-3-(4-bromophenyl)-2-ethoxyacrylate, 108 mL (217 mmol) in 120 mL of toluene, aqueous 2 M sodium carbonate solution and 1.5 g (1.8 mmol) of dichloro[11′-bis(diphenylphosphino)ferrocene]palladium are added. The reaction medium is stirred and 9.25 g (39.7 mmol) of methyl[3-(4,4,5,5-tetramethyl[1.3.2]dioxaborolan-2-yl)phenyl]amine are then added. After stirring at 80° C. for 2 hours, the reaction medium is hydrolyzed and diluted with ethyl acetate. After separation of the phases by settling, the ethyl acetate phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 90/10 and then 80/20 heptane/ethyl acetate mixture. 10.5 g (94%) of ethyl (Z)-2-ethoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate are obtained in the form of a yellow oil. After taking up the product in pentane, 9.5 g (85%) of ethyl (Z)-2-ethoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate are obtained in the form of a pale yellow solid with a melting point of 52° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:27]1[CH:31]=[CH:30][N:29]=[C:28]1[CH2:32][C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[CH2:41]O)=[CH:35][CH:34]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:26][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:41]/[CH:40]=[CH:39]/[C:36]2[CH:35]=[CH:34][C:33]([CH2:32][C:28]3[NH:29][CH:30]=[CH:31][N:27]=3)=[CH:38][CH:37]=2)=[O:9])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21]
Reactant: OC/C=C/c1ccc(Cc2ncc[nH]2)cc1
Reactant: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CC1=C(C(=O)OC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Temperature: 25 °C

Procedure:
360 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-isopropyloxycarbonyl-4-(3- nitrophenyl)pyridine -3carboxylic acid together with 215 mg (1 mM) of (E)-3-{4-(1-imidazolylmethyl)phenyl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 541 mg (97.2%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[O:15]1[CH2:29][CH:16]1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CC(C)=O>CO>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[OH:15][CH:16]([CH2:29][NH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)NCCN)cc1
Reactant: COC(=O)c1ccccc1OCC1CO1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1OCC(O)CNCCNS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 2.15 g of N-(2-aminoethyl)-p-toluenesulfonamide (0.1 mole) and 2.08 g of methyl 2-(2,3-epoxypropoxy)benzoate (0.01 mole) in 100 ml of methanol was stored at 25° C. for 4 hours. The methanol was then removed under reduced pressure, leaving an oil (NMR indicated only mono-alkylated product). The oil was then dissolved in 50 ml of methanol and an equimolar quantity of oxalic acid was added to the solution. 50 Ml of acetone was added, and the product crystallized upon refrigeration. The product was recrystallized from acetone/methanol (1:1) to yield 1.4 g of product which had a melting point of 165°-166° C. The elemental analysis (CHN) and NMR spectrum were consistent with the assigned structure.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[CH3:14][C:15]1[C:20]([C:21]#[CH:22])=[CH:19][CH:18]=[CH:17][N:16]=1.CC1C=C(C=C(N2C=C(C3C=NC=CC=3)N=N2)C=1C)C(O)=O>>[CH3:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:1]1[CH:22]=[C:21]([C:20]2[C:15]([CH3:14])=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=[N:2]1
Reactant: C#Cc1cccnc1C
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Agent: Cc1cc(C(=O)O)cc(-n2cc(-c3cccnc3)nn2)c1C
Product: Cc1ccc(C(=O)O)cc1-n1cc(-c2cccnc2C)nn1

Procedure:
4-Methyl-3-[4-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid (5:3 mixture with 4-methyl-3-[5-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid) was prepared from 3-azido-4-methyl benzoic acid and 2-methyl-3-ethynyl pyridine in the same manner as 3,4-dimethyl-5-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid (Example 8).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[CH2:13](I)[CH3:14]>CN(C=O)C>[CH2:13]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)[CH3:14]
Reactant: CCI
Reactant: Oc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
Sodium hydride (60% in mineral oil, 1.65 g, 41 mmol) was added to a solution of 6-hydroxyindole (5.0 g, 38 mmol) in anhydrous DMF (25 mL) at −20° C. under N2. The resulting dark green solution was allowed to warm up to room temperature and stirred for 10 min. Ethyl iodide (3.3 mL, 6.4 g, 41 mmol) was added, and the resulting solution was stirred at room temperature for 1 h. The mixture was poured into ice-water (150 mL), and extracted with EtOAc (3×200 mL). The organic solution was dried (MgSO4) and concentrated at reduced pressure. The residue was purified by flash chromatography (SiO2, 5% then 15% EtOAc/hexanes) to give the title compound (4.5 g, 75%) as a white solid. 1H NMR (CDCl3) δ 7.98 (br. s, 1H), 7.50 (m, 1H), 7.10 (m, 1H), 6.90 (m, 1H), 6.80 (m, 1H), 6.45 (m, 1H), 4.10 (q, J=6.5 Hz, 2H), 1.45 (t, J=6.5 Hz, 3H).
Reaction SMILES: C(C1C=C2C(=CC=1)N=C(C(OCC)=O)NC2=O)#N.[CH3:19][C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([O:32]CC)=O)=[N:24][C:23]=2[S:22][CH:21]=1.NCC1C=C(C=CC=1)N.[NH2:44][CH2:45][C:46]1[CH:47]=[C:48]([CH2:52][NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[CH:49]=[CH:50][CH:51]=1>>[CH3:19][C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([NH:44][CH2:45][C:46]3[CH:47]=[C:48]([CH2:52][NH:53][C:54](=[O:60])[O:55][C:56]([CH3:58])([CH3:57])[CH3:59])[CH:49]=[CH:50][CH:51]=3)=[O:32])=[N:24][C:23]=2[S:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Reactant: CCOC(=O)c1nc2scc(C)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccc(C#N)cc2c(=O)[nH]1
Agent: NCc1cccc(N)c1
Product: Cc1csc2nc(C(=O)NCc3cccc(CNC(=O)OC(C)(C)C)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Reference Example 45, and using, instead of ethyl 6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxylate, ethyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained according to the method described in U.S. Pat. No. 4,054,656 and using, instead of 3-(aminomethyl)aniline, 1,1-dimethylethyl {[3-(aminomethyl)phenyl]methyl}carbamate, the title compound was obtained as a white powder (2.11 g, 82%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]([OH:12])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=O)[CH3:24])=[CH:18][CH:17]=1.CC1C=CC(CCC(=O)C)=CC=1>>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH:11][CH2:10][CH:9]([OH:12])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)=[CH:18][CH:17]=1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)Cc1ccc(C)cc1
Agent: CC(=O)CCc1ccc(C)cc1
Product: Cc1ccc(CCCNCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 3, replacing 2-(3-chlorophenyl)-2-hydroxy ethanamine by 2-(3-trifluoromethylphenyl)-2-hydroxyethanamine, and 4-methylphenylacetone by 4-(4-methylphenyl)butan-2-one. The chromatographed material was recrystallised from hexane to give the title compound mp 52°-55° as a 44:56 ratio of diastereoisomers.
Reaction SMILES: C1COCC1.[C:6]1([C@H:16]([N:18]([CH2:26][C@@H:27]2[C@@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][NH:29][CH2:28]2)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[CH:38]1[N:42]=[CH:41][N:40]([C:43](N2C=NC=C2)=[O:44])[CH:39]=1>C(N(CC)CC)C>[N:40]1([C:43]([N:29]2[CH2:30][C@H:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:27]([CH2:26][N:18]([C@@H:16]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)[CH3:17])[C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH2:28]2)=[O:44])[CH:39]=[CH:38][N:42]=[CH:41]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)n2ccnc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 107.4 %

Procedure:
A 10 ml THF solution of 940 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate was mixed with 0.3 ml of triethylamine and 3.54 g of CDI and stirred at room temperature for 2Hours. The reaction solution was concentrated under a reduced pressure and diluted with ethyl acetate. This was washed with 1 M hydrochloric acid and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. By evaporating the solvent under a reduced pressure, 1.23 g of tert-butyl {[(3R,4S)-1-(1H-imidazol-1-ylcarbonyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate was obtained as a pale yellow amorphous substance. EP: 525.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:20]([O:22]C)=[O:21])[CH:13]=[CH:12]1.CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:31]>C1COCC1>[OH:31][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:3][C:2](=[O:1])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:20]([OH:22])=[O:21])[CH:13]=[CH:12]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COC(=O)c1cccc2ccn(Cc3nc4ccccc4o3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Cn1ccc2cccc(C(=O)O)c21)Nc1ccccc1O
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To methyl 1-(1,3-benzoxazol-2-ylmethyl)-1H-indole-7-carboxylate (0.22 g), methanol (2.0 mL), and THF (2.0 mL) was added a 1 M aqueous sodium hydroxide solution (1.0 mL), followed by stirring at 70° C. for 14 hours. The reaction mixture was ice-cooled, a 10% aqueous citric acid solution (5.0 mL) was added thereto, and the precipitated solid was collected by filtration, and washed with water and diethyl ether/hexane (1/1) to obtain 1-{2-[(2-hydroxyphenyl)amino]-2-oxo ethyl}-1H-indole-7-carboxylic acid (0.18 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]1[N:7]2[CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=1.[OH-].[Na+]>C(O)C.O>[OH2:16].[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]1[N:7]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=1
Reactant: CCOC(=O)c1cn2c(ccc3c(Cl)cccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c(ccc3c(Cl)cccc32)n1

Procedure:
100 mg of ethyl 6-chloroimidazo-[1,2-a]-quinoline-2-carboxylate were suspended in a mixture of 4.5 ml of ethanol and 2 ml of water and then 0.5 ml of N sodium hydroxide solution was added. The mixture was heated on a steam bath for 4 hours and the resulting solution was filtered then acidified with 0.5 ml of N hydrochloric acid and cooled to give colorless crystals of 6-chloroimidazo-[1,2-a]-quinoline-2-carboxylic acid monohydrate melting at 288°-289° C.
Reaction SMILES: C(O)C.Cl[C:5]1[C:10]([Cl:11])=[N:9][CH:8]=[CH:7][N:6]=1.Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14]>C(N(CC)CC)C>[Cl:11][C:10]1[C:5]([NH:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:19])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: CCOC(=O)CN
Reactant: Clc1nccnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNc1nccnc1Cl
Yield: 14.6 %

Procedure:
To an ethanol solution (10 mL) of 2,3-dichloropyrazine (1.0 g), glycine ethyl ester hydrochloride (940 mg) and triethylamine (1.9 mL) were added and the mixture was irradiated with microwave (150° C., 10 min). The reaction mixture was concentrated under reduced pressure. To the resulting residue, a saturated aqueous sodium bicarbonate solution was added and the product was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (hexane: ethyl acetate=10:1) to give 212 mg (15% yield) of the desired product.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:22][N:23]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:44][CH:43]=2)[N:36]=1)[C:24]1[CH:34]=[CH:33][C:27]2[N:28]([CH3:32])[C:29]([NH2:31])=[N:30][C:26]=2[CH:25]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:32][N:28]1[C:27]2[CH:33]=[CH:34][C:24]([N:23]([CH3:22])[C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]4[CH:43]=[CH:44][C:45]([CH2:48][S:49]([CH3:52])(=[O:50])=[O:51])=[CH:46][CH:47]=4)[N:36]=3)=[CH:25][C:26]=2[N:30]=[C:29]1[NH:31][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: CN(c1ccc2c(c1)nc(N)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(c1ccc2c(c1)nc(NC(=O)c1ccccc1)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzoic acid (51 mg, 0.402 mmol) in N,N-dimethylformamide (2 ml) was added 1,1′-carbonyldiimidazole (65.2 mg, 0.400 mmol). The mixture was stirred for 30 minutes at room temperature and then a solution of N5,1-dimethyl-N5-[2-({4-[(methylsulfonyl)methyl]phenyl}amino)pyrimidin-4-yl]-1H-benzimidazole-2,5-diamine (88 mg, 0.201 mmol) and triethylamine (0.03 ml, 0.201 mmol) in N,N-dimethylformamide (2 ml) was added. The reaction mixture was stirred for 16 h, quenched with saturated sodium bicarbonate solution (30 ml) and the product then precipitated. The crude product was filtered, washed with water, diethyl ether and air dried to give the desired product without further purification. 1H NMR (400 MHz, d6-DMSO) δ 12.82 (s, 1H), 9.28 (s, 1H), 8.28 (d, J=7.3 Hz, 2H), 7.89 (d, J=6.1 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.4 Hz, 1H), 7.51-7.44 (m, 4H), 7.25-7.20 (m, 3H), 5.79 (d, J=5.9 Hz, 1H), 4.34 (s, 2H), 3.77 (s, 3H), 3.47 (s, 3H), 2.84 (s, 3H). MS (ESI) m/z=542 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C@H:5]1[C@H:12]2[C@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C:7]([CH2:15][O:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6]1)[OH:4].[Cl:36][C:37]1[C:42](Cl)=[N:41][CH:40]=[CH:39][N:38]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:36][C:37]1[C:42]([NH:1][CH2:2][C@H:3]([C@H:5]2[C@H:12]3[C@H:8]([O:9][C:10]([CH3:13])([CH3:14])[O:11]3)[C:7]([CH2:15][O:16][C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:6]2)[OH:4])=[N:41][CH:40]=[CH:39][N:38]=1
Reactant: Clc1nccnc1Cl
Reactant: CC1(C)O[C@H]2[C@H]([C@H](O)CN)C=C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)O[C@H]2[C@H]([C@H](O)CNc3nccnc3Cl)C=C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
(S)-2-amino-1-((3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (1-5) (2 g, 3.82 mmol, 1.0 eq) was dissolved in DMF (15.3 mL). 2,3-Dichloropyrazine (1.20 g, 7.63 mmol, 2 equiv) was added followed by triethylamine (2.13 mL, 15.3 mmol, 4 equiv). The reaction was stirred 20 hours at 60° C. Over a period of 52 hours 2,3-dichloropyrazine (299 mg, 1.91 mmol, 0.5 equiv) was added every 3 hours. The reaction was concentrated and purified via flash chromatography on silica gel column (ethyl acetate/hexanes) to yield (S)-2-(3-chloropyrazin-2-ylamino)-1-((3aS,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (1-6) as a white foam. 1H NMR (500 MHz, CDCl3) δ 7.91 (d, 1H, J=1.5 Hz), 7.62 (d, 1H, J=1.5 Hz), 7.21-7.48 (m, 15H), 5.84 (2 s, 1H), 5.62 (m, 1H), 4.97 (t, 1H, J=6 Hz), 4.60-4.77 (2 d, 1H, J=7 Hz), 3.95 (d, 1H, J=14 Hz), 3.75 (m, 2H), 3.31 (m, 1H), 2.57-2.88 (m, 2H), 1.36 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:15])[CH2:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[NH:48][C:47]([C@@H:49]4[CH2:53][CH2:52][CH2:51][N:50]4[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[N:46][CH:45]=3)=[CH:40][CH:39]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:57]([O:56][C:54]([N:50]1[CH2:51][CH2:52][CH2:53][C@H:49]1[C:47]1[NH:48][C:44]([C:41]2[CH:42]=[CH:43][C:38]([C:7]3[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C@@H:16]4[CH2:20][CH2:19][CH2:18][N:17]4[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:15])[CH2:9][CH:8]=3)=[CH:39][CH:40]=2)=[CH:45][N:46]=1)=[O:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1CC=C(c2ccc(-c3cnc([C@@H]4CCCN4C(=O)OC(C)(C)C)[nH]3)cc2)CC1
Temperature: 80 °C
Yield: 92.9 %

Procedure:
To a solution of (25)-tert-butyl 2-(4-(trifluoromethylsulfonyloxy)cyclohex-3-enyl carbamoyl)pyrrolidine-1-carboxylate (2) (1.65 g, 3.73 mmol) and (5)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (3) (1.95 g, 4.44 mmol) in THF (19 mL), Pd(PPh3)2Cl2 (130 mg, 0.185 mmol) and aqueous Na2CO3 (2M, 7.5 mL, 15 mmol) were added under N2 protection at rt. The reaction mixture was heated at 80° C. overnight, and cooled to rt. The mixture was then filtered through a CELITE™ pad and washed with ethyl acetate. The combined organic phases were concentrated to provide the crude product, which was purified by silica gel column chromatography (n-hexane/ethyl acetate, 1:2) to afford (2S)-tert-butyl 2-(4-(4-(2-((5)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)cyclohex-3-enylcarbamoyl)pyrrolidine-1-carboxylate (4) (2.1 g, 93% yield).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[H-].[Na+].Cl[C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1.O>O1CCCC1>[CH2:1]([O:6][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-penten-1-ol (640 mg, 7.5 mmol) and sodium hydride (260 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:13]([O:15][CH3:24])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=Cc2ccc(OC)c(OC)c2)C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(=Cc1ccc(OC)c(OC)c1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
3-(3,4-dimethoxyphenyl)-2-(4-methoxyphenyl)prop-2-enoic acid (2 g, 6.37 mmol) was dissolved in dimethyl formamide (DMF) (4 mL) and added potassium carbonate (K2CO3) (2.28 g, 16.6 mmol) followed by methyl iodide (CH3I) (0.48 mL, 7.64 mmol) drop wise. The reaction mixture was stirred for 2 hours at room temperature (RT) and the reaction was monitored by TLC. Upon the completion of reaction, K2CO3 was filtered and cold water (100 mL) was added to the filtrate. The resulting precipitate was filtered to get pale yellow solid (2 g, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C:23]2([C:26](O)=[O:27])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:26]([C:23]3([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:25][CH2:24]3)=[O:27])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: O=C(N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)C1(c2ccccc2)CC1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 1-phenylcyclopropanecarboxylic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.46-7.37 (m, 4H), 7.33 (dt, J=7.5, 11.5, 4H), 7.28-7.22 (m, 2H), 6.22 (d, J=7.3, 1H), 4.31 (dd, J=6.7, 12.7, 1H), 3.56 (d, J=13.2, 1H), 3.40 (d, J=13.2, 1H), 2.81 (dd, J=2.1, 8.9, 1H), 2.39-2.18 (m, J=7.3, 12.5, 18.1, 4H), 2.13 (dd, J=7.3, 8.9, 1H), 1.99 (dt, J=5.6, 11.0, 1H), 1.75 (q, J=3.6, 2H), 1.67-1.58 (m, J=8.3, 16.6, 1H), 1.38-1.22 (m, 2H), 1.01 (q, J=3.6, 2H); MS (ESI+) m/z 361 (M+H)+.