Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O(CC1S[CH:14]2[CH:11](C(=O)[N:13]2[C:16](=C(O)C)[C:17]([O-:19])=O)N=1)C1C=CC=CC=1.CS(Cl)(=O)=O.[O:29]([CH2:36][C:37]1[S:43][CH:42]2[CH:39]([C:40](=[O:65])[N:41]2[C:44](=[C:58](OS(C)(=O)=O)[CH3:59])[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=2)=[O:46])[N:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1CCOCC1>O1CCCC1.C(N(CC)CC)C>[O:29]([CH2:36][C:37]1[S:43][CH:42]2[CH:39]([C:40](=[O:65])[N:41]2[C:44](=[C:58]([N:13]2[CH2:16][CH2:17][O:19][CH2:11][CH2:14]2)[CH3:59])[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=2)=[O:46])[N:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(O)=C(C(=O)[O-])N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 1.5 h

Procedure:
One dissolves p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl -α-(1-hydroxyethylidene)acetate (940 mg) in tetrahydrofuran (14 ml), adds triethylamine (0.61 ml) and methanesulfonyl chloride (0.172 ml), and stirs for 1 hour ε+ -15° to -20° C. To the produced solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, one adds morpholine (0.209 ml), stirs for 1.5 hours at -15° to -20° C., and for 2 hours at 0° C., to give a solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -15° C., adds pyridine (0.174 ml) followed by after 5 minutes a solution of bromine in carbon tetrachloride (1 mole/liter: 2.1 ml), stirs for 15 minutes at the same temperature, pours into water (50 ml), and extracts with ethyl acetate (50 ml). The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give residue (1.7 g). Purification of the residue by chromatography over silica gel containing 10% water gives from the fractions eluted with a mixture of benzene and ethyl acetate (2:1) p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-bromo-1-morpholinoethylidine)acetate (1.109 g; Yield: 89.7%) and p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-bromo-1-morpholinoethyl)-α-methanesulfonylacetate (85 mg; Yield: 7.7%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][CH:22]([CH3:25])[CH2:23][OH:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:21][CH:22]([CH3:25])[CH2:23][OH:24])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Reactant: CC(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CO)NC(=O)c1cccc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.30 mmol) was reacted with 2-aminopropan-1-ol (CAS 78-91-1) (0.05 mL, 0.6 mmol), HATU (141 mg, 0.36 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(1-hydroxypropan-2-yl)benzamide 17. LC/MS (ESI+): m/z 323 (M+H). 1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.61 (t, J=13.5 Hz, 1H), 8.57-8.48 (m, 1H), 8.43 (s, 1H), 8.29 (d, J=7.9 Hz, 1H), 8.19 (dd, J=8.8, 3.1 Hz, 1H), 8.05 (d, J=30.8 Hz, 2H), 7.97 (d, J=7.7 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 4.76 (s, 1H), 4.18-4.00 (m, 1H), 3.52 (dd, J=10.5, 5.7 Hz, 1H), 3.46-3.35 (m, 1H), 1.19 (d, J=6.7 Hz, 3H).
Reaction SMILES: F[C:2](F)([C:10]([F:13])([F:12])[F:11])[CH:3]=[C:4](I)[CH:5]([OH:8])[CH2:6][CH3:7].[OH2:15].Cl.[NH2:17]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:11][C:10]([F:13])([F:12])[C:2]1[O:15][N:17]=[C:4]([CH:5]([OH:8])[CH2:6][CH3:7])[CH:3]=1
Reactant: NO
Reactant: CCC(O)C(I)=CC(F)(F)C(F)(F)F
Reactant: O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCC(O)c1cc(C(F)(F)F)on1

Procedure:
9.01 g of 6,6,7,7,7-pentafluoro-4-iodo-4-heptene-3-ol was dissolved in 70 ml of ethanol, and 30 ml of water, 3.81 g of hydroxylamine hydrochloride and 7.51 g of potassium carbonate were then added. The mixture was stirred and heated under reflux for 24 hours. The reaction mixture was concentrated under reduced pressure. After water was added, the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.63 g of 1-(5-trifluoromethyl-isoxazol-3-yl)propanol.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([CH3:21])[CH:9]=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:5]1)(=O)C.[OH-].[K+]>CCO.O>[C:24]([CH2:23][CH2:22][CH:6]1[C:7]2[C:12](=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])[C:10]([CH3:20])=[CH:9][C:8]=2[CH3:21])[NH:4][CH2:5]1)([OH:26])=[O:25]
Reactant: CCOC(=O)CCC1CN(C(C)=O)c2c(NC(=O)C(C)(C)C)c(C)cc(C)c21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(c1NC(=O)C(C)(C)C)NCC2CCC(=O)O
Yield: 70.4 %

Procedure:
N-[1-Acetyl-3-(2-ethoxycarbonylethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (2.6 g) was dissolved in EtOH (40 ml), and a solution of KOH (1.3 g) in water (10 ml) was added, which was followed by refluxing for 20 hr. EtOH was evaporated under reduced pressure, and the mixture was adjusted to pH 5 with 2N hydrochloric acid and extracted with CHCl3 (100 ml). The CHCl3 layer was washed with water and dried over anhydrous sodium sulfate, CHCl3 was evaporated under reduced pressure to give 1.5 g of N-[3-(2-carboxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide. 1H-NMR (CDCl3) δ
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:30]=[CH:29][C:17]([O:18][CH:19]3[CH2:24][CH2:23][CH:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]3)=[CH:16][CH:15]=2)=[O:13])=[N:8][N:7]=1.O.[OH-].[Li+]>C1COCC1.CO>[F:34][C:32]1[CH:31]=[C:4]([CH:3]=[C:2]([F:1])[CH:33]=1)[CH2:5][C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:30]=[CH:29][C:17]([O:18][C@@H:19]3[CH2:20][CH2:21][C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]3)=[CH:16][CH:15]=2)=[O:13])=[N:8][N:7]=1
Reactant: COC(=O)C1CCC(Oc2ccc(C(=O)Nc3nnc(Cc4cc(F)cc(F)c4)s3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1nnc(Cc2cc(F)cc(F)c2)s1)c1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)cc1
Reaction time: 16 h
Yield: 78.2 %

Procedure:
1.5 g of methyl 4-{4-[5-(3,5-difluorobenzyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenoxy}-cyclohexanecarboxylate (3.08 mmol, 1 eq.) are dissolved in 20 mL of a 1/1 mixture of THF/methanol. 0.258 g of lithium hydroxide monohydrate (6.15 mmol; 2 eq.) is added with stirring. After 16 hours at room temperature, the reaction medium is evaporated, diluted with water, and aqueous 6% sulfur dioxide solution is added. The precipitate is filtered off and washed with water. The residue is then triturated and filtered in ethyl acetate and ethanol. 1.14 g of cis-4-{4-[5-(3,5-difluorobenzyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenoxy}cyclohexanecarboxylic acid are obtained.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([S:19][CH:20]([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:23]C(OC(Cl)C)=O>ClC(Cl)C>[ClH:23].[CH:20]([S:19][C:17]1[CH:16]=[CH:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1)([CH3:22])[CH3:21]
Reactant: CC(C)Sc1ccc2c(n1)OCCN(Cc1ccccc1)C2
Reactant: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: CC(C)Sc1ccc2c(n1)OCCNC2
Product: Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of the compound obtained in step 2 (0.24 g) in dichloroethane (5 mL) was added 1-chloroethyl chloroformate (0.090 mL), and the resulting mixture was stirred at 90° C. for 2 hr. The solvent was evaporated under reduced pressure, and methanol (5 mL) was added. The mixture was stirred at 80° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was crystallized from ethanol-diisopropyl ether, and the obtained solid was purified by preparative HPLC. To the obtained residue was added 4N hydrogen chloride/ethyl acetate, and the resulting mixture was recrystallized from ethanol-diisopropyl ether to give the title compound (0.11 g, 56%) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9]CC=C)=[CH:5][CH:4]=1)#[N:2].C(OCC)C.[C:18]1(OC2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1>>[CH2:23]([C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[OH:9])[CH:18]=[CH2:19]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: C=CCOc1ccc(C#N)cc1
Solvent: CCOCC
Product: C=CCc1cc(C#N)ccc1O
Temperature: 25 °C

Procedure:
A solution of allyl 4-cyanophenyl ether (12 g) in diphenylether (20 ml) was heated at 260° C. for 30 minutes. The reaction mixture was cooled to ambient temperature, diethyl ether was added and the mixture was extracted with 1M aqueous sodium hydroxide solution. The aqueous phase was separated, acidified with 2M aqueous hydrochloric acid solution and extracted with diethyl ether. The organic phase was separated, dried (MgSO4) and evaporated to give 2-allyl-4-cyanophenol as a solid (11.4 g), m.p. 70° C.; microanalysis, found: C, 73.7; H, 5.6; N, 9.2%; C10H9NO. 0.25H2O requires: C, 73.4; H, 5.8; N, 8.6%; NMR: 3.2-3.5(2H,d), 5.0-5.1(2H,m), 5.85-6.05(1H,m), 6.9-7.0(1H,d), 7.4-7.5(2H,m) and 10.6(1H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1.Br[CH2:31][CH:32]1[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:31][CH:32]3[CH2:34][CH2:33]3)[C:11](=[O:21])[C@H:10]([CH2:23][C:24]3[CH:28]=[C:27]([CH3:29])[O:26][N:25]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(CBr)no1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: BrCC1CC1
Product: Cc1cc(C[C@@H]2C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N(CC3CC3)C2=O)no1

Procedure:
The title compound was prepared from (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E),3-(bromomethyl)-5-methylisoxazole, and (bromomethyl)cylopropane as described in Example 60.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH:2]=[CH2:3].[C:8](=[S:10])=S.C[OH:12]>C(OCC)C>[CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH:2]=[CH2:3].[CH2:1]([N:4]([CH2:5][CH2:6][CH3:7])[C:8](=[S:10])[OH:12])[CH:2]=[CH2:3]
Reactant: S=C=S
Reactant: CO
Agent: C=CCNCCC
Solvent: CCOCC
Product: C=CCN(CCC)C(O)=S
Reaction time: 0.25 h

Procedure:
A quantity of N-Allyl-n-propylamine (12.7 g of a 35% solution in methanol, 0.042 mole) was dissolved in 50 ml of ethyl ether, plus 1.52 g of carbon disulfide (0.02 mole) was charged into a beaker and the reaction mixture in the beaker was allowed to let stand for approximately 15 minutes, after which time the volatiles were stripped off, leaving behind 3.7 g of a solid residue, which was identified by conventional instrumental techniques as being the subject compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccncc1
Product: Cc1c2n(c3c(-c4ccncc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (60 mg, 77%), MS (ISP) m/z=312.5 [(M+H)+], mp 295° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available pyridine-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [F:1][S:2]([F:15])([F:14])([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18](=[O:25])[CH2:19][C:20](=O)[CH:21](Br)[CH3:22].[CH2:26](OC(=O)C)C>CC(C)=O>[CH2:16]([O:17][C:18](=[O:25])[CH2:19][C:20]1[N:9]=[C:7]([C:6]2[CH:5]=[CH:4][C:3]([S:2]([F:12])([F:13])([F:14])([F:15])[F:1])=[CH:11][CH:10]=2)[S:8][C:21]=1[CH3:22])[CH3:26]
Reactant: NC(=S)c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)Cc1nc(-c2ccc(S(F)(F)(F)(F)F)cc2)sc1C

Procedure:
0 g 4-Pentafluorosulfanyl-thiobenzamide and 9.93 g 4-bromo-3-oxo-pentanoic acid methyl ester were dissolved in 30 ml acetone and refluxed for one hour. The cooled reaction mixture was diluted by adding 250 ml ethylacetate and washed three times with saturated NaHCO3 solution. The organic layer was dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography with the eluent n-heptane:ethyl acetate=5:1 to provide 4.5 g [5-Methyl-2-(4-pentafluorosulfanyl-phenyl)-thiazol-4-yl]-acetic acid ethyl ester as an oil which solidified upon standing.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50 mmol) in CH3OH (100 mL) was added NaBH4 (5.7 g, 150 mmol) portionwise carefully and the mixture was stirred at rt for 3 h. The reaction was quenched by carefully pouring into ice-water (100 mL) and organic solvent was removed under reduced pressure. The aqueous phase was neutralized to pH=7 with 1N HCl and extracted with DCM/MeOH (5×60 mL, v/v=10/1). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product (9.8 g, 97%) as a white solid. [LCMS: Rt=1.36 min, m/z 146.1 (M-Bu+H)]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[C:16]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[CH:25]1[C:12]2=[N:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:15]=3[N:11]2[CH2:10][CH2:9][CH2:8][N:7]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:35]
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCNC(=O)OC(C)(C)C)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc3n(c12)CCCN(C(=O)OC(C)(C)C)C3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a stirred solution of tert-butyl(3-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propyl)carbamate (Reference example 228, 500 mg, 0.959 mmol) and triphenylphosphine (377 mg, 1.44 mmol) in tetrahydrofuran (30 mL) was added a solution of diethyl azodicarboxylate in toluene (40%, 0.655 mL, 1.44 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h, concentrated in vacuo, and purified by column chromatography on silica gel eluting with a 10-20% ethyl acetate/n-hexane gradient mixture to give a colorless amorphous solid (138 mg, 0.274 mmol, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](C(S)C(OCC)=O)=[S:10])=[CH:4][CH:3]=1.[NH:18]([C:20]([O:22][CH3:23])=[O:21])[NH2:19]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:19][NH:18][C:20]([O:22][CH3:23])=[O:21])=[S:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(S)C(=S)Cc1ccc(Cl)cc1
Reactant: COC(=O)NN
Solvent: ClCCl
Product: COC(=O)NNC(=S)Cc1ccc(Cl)cc1

Procedure:
A mixture of 130 g of 2-[2-(4-chlorophenyl)-1-thioxoethyl]thioglycolic acid, ethyl ester, 45 g of methyl hydrazinocarboxylate and 500 ml of dichloromethane was heated at reflux for 4 hours, then concentrated in vacuo. The residue was taken up in 1.2 liters of ether and extracted with three 500 ml portions of 0.5N sodium hydroxide. The alkaline extracts were combined, washed with ether and acidified with 6N hydrochloric acid to pH 4. The solution was extracted three times with a mixture of ether and dichloromethane. The organic phases were combined and concentrated. The residual oil was concentrated at 70°-75° C. for one hour at 0.1 mmHg. The residue was crystallized from acetone-methylcyclohexane and then from toluene, giving the desired product as ivory colored crystals, mp 147.5°-148° C. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90 MHz: 3.80 (s, 3H, OCH3); 4.03 (s, 2H, CH2CS); 7.31 (bs, 4H, C6H4); 8.60 (bs, 1H, NH); 9.90 (bs, 1H, NH).
Reaction SMILES: [C:1](OC1C=CC(C2C=CC=CC=2)=CC=1)(=[O:4])[C:2]#[CH:3].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C#C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C>[C:19]1([NH:18][C:1](=[O:4])[C:2]#[CH:3])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Reactant: Nc1ccccc1
Agent: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: C#CC(=O)Nc1ccccc1
Yield: 87 %

Procedure:
The compound 20 was prepared according to the method described for compound 1 employing aniline (1 g, 0.01 mol), propargylic acid (0.76 g, 0.01 mol), DCC (2.2 g, 0.01) and DMAP (8.6 mg, 0.07 mmol) to give brown solid compound 20 (1.35 g, 87%). 1H NMR (300 MHz, CD2Cl2) δ 2.93 (s, 1H), 7.15 (t, J=6.9 Hz, 1H), 7.33 (t, J=7.5 Hz, 2H), 7.52 (t, J=7.4 Hz, 2H), 7.79 (br s, 1H).
Reaction SMILES: C([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=O)CCC.C[C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32].O1CCOC[CH2:38]1>>[CH3:38][C:7]1[C:6]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:30]=2)=[CH:15][C:14]2[C:9](=[C:10]([CH2:17][O:18][C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: C1COCCO1
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(COC(=O)c3ccc(OC)cc3)cccc2c1Cl
Product: COc1ccc(C(=O)OCc2cccc3cc(Nc4ccccc4)c(C)nc23)cc1
Yield: 90 %

Procedure:
A solution of 3-butyryl-4-chloro-8-(4-methoxybenzoyloxymethyl)-quinoline 3.3 g, 8.3 mmol) and 2-methylaniline (1.33 ml, 12.4 mmol) in 1,4-dioxan (30 ml) was heated at reflux for 2 hours, then the dioxan evaporated and the product converted to free base. Recyrstallization from ethanol gave 3-butyryl-4-(2-methylphenylamino-8-(4-methoxybenzoyloxymethyl)-quinoline (3.5 g, 90%), m.p. 135°-137°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[CH3:43][N:44]1[CH2:48][CH2:47][CH2:46][C@H:45]1[C:49](O)=[O:50]>CS(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C@@H:6]([NH:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[O:26])=[C:21]([CH3:32])[CH:20]=3)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([C@@H:45]3[CH2:46][CH2:47][CH2:48][N:44]3[CH3:43])=[O:50])=[N:8][C:9]=2[CH:15]=1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)[C@@H]2CCCN2C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1d from N-[(1S)-5-amino-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, PFTU, diisopropylethylamine, and (S)-1-methylpyrrolidine-2-carboxylic acid in dimethylsulfoxide. HPLC-MS results: retention time: 2.03 minutes; C31H39ClN6O3 (579.15); mass spectrum: (M−H)−=578.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1([S:13]([CH2:16]Cl)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1.C(O)(=O)C>O1CCCC1>[CH3:18][O:19][C:20]1[N:21]=[C:22]([CH2:16][S:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:15])=[O:14])[C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: O=S(=O)(CCl)c1ccccc1
Reactant: COc1ccc([N+](=O)[O-])cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2ccccc2)n1
Yield: 80 %

Procedure:
A 1M KOt-Bu solution in tetrahydrofuran (50 mL, 50 mmol) is cooled to −40° C., treated portion-wise with a solution of chloromethyl phenyl sulfone (4.39 g, 23.0 mmol) and then with a solution of 2-methoxy-5-nitropyridine (3.55 g, 23.0 mmol) in tetrahydrofuran, stirred for 45 min at −40° C., treated with glacial acetic acid (3.0 g, 50 mmol) and filtered. The filtercake is air-dried to give the title compound as a tan solid, 5.70 g (80% yield), mp 147-149° C., identified by mass spectral and HNMR analyses.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([OH:19])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:20](I)([CH3:22])[CH3:21].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH:20]([CH3:22])[CH3:21])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(C)I
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reaction time: 0.25 h

Procedure:
0.23 g (7.8 mmol) of an 80% suspension of sodium hydride in mineral oil was washed with anhydrous pentane to remove the mineral oil and then suspended in 50 ml of anhydrous dimethylformamide. A solution of 2.0 g (6.5 mmol) of 3-chloro-2-(4-chloro-3-hydroxyphenyl)5-trifluoromethylpyridine in 50 ml of anhydrous dimethylformamide was added dropwise to this suspension at 0° C. After the addition is complete, the mixture was stirred for 15 minutes and then 1.3 g (7.8 mmol) of isopropyl iodide were slowly added dropwise. The mixture was then stirred at 20°-25° C. for about 15 h and subsequently poured into 400 ml of water and extracted three times with methyl tert-butyl ether. The combined organic phases were washed with water, dried over sodium sulfate and evaporated under reduced pressure. Yield: 1.9 g (83%) of a colorless oil.