Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S([CH2:11][C@H:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15](=[O:24])[CH2:14][CH2:13]2)(=O)=O)=CC=1.[I-:25].[Na+].CC(C)=O>C1CCCCC1>[I:25][CH2:11][C@H:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:24])[CH2:14][CH2:13]1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2Cc2ccccc2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: O=C1CC[C@@H](CI)N1Cc1ccccc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A mixture of (S)-5-[[(4-methylphenyl)sulfonyl]methyl]-1-(phenylmethyl)-2-pyrrolidinone (244.5 g, 0.68 mol), sodium iodide (305 g, 2.03 mol), and 3 L of acetone was refluxed and stirred overnight. The suspension was cooled to 10° C. and was filtered. The salts were rinsed with three 250-mL portions of acetone, and the acetone washes and filtrate were concentrated on a rotary evaporator to a thick slurry. Methylene chloride (1.5 L) was added and the white precipitate was filtered off and washed with methylene chloride. The filtrate was dried over magnesium sulfate (MgSO4), filtered through a pad of silica gel, and concentrated on a rotary evaporator to give 196.8 g (92% yield) of (S)-5-iodomethyl-1-(phenylmethyl)-2-pyrrolidinone as an off-white solid, mp 92°-94° C. (cyclohexane). 1 h NMR (CDCl3) δ 1.7-2.75 (m, 4 H, CH2), 3.18-3.28 (m, 2 H, CH2I), 3.42 (m, 1 H, NCH), 3.98 and 4.05 (AB, 2 H, Jgem =15 Hz, CH2Ph), 7.20 (m, 5 H, phenyl). [α]25D =+12.11 (c 0.35, methanol). Anal. Calcd for C12H14NOI: C, 45.73; H, 4.48; N, 4.44. Found: C, 45.58; H, 4.35; N, 4.22.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:18])([CH3:17])[CH:15]=O)[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1.[CH3:30][C:31]1([CH3:39])[O:38][CH:34]2[CH2:35][NH:36][CH2:37][CH:33]2[O:32]1>CO.C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:15])([CH3:17])[CH2:18][N:36]3[CH2:37][CH:33]4[O:32][C:31]([CH3:39])([CH3:30])[O:38][CH:34]4[CH2:35]3)[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1
Reactant: CC1(C)OC2CNCC2O1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)C=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C(C)(C)CN3CC4OC(C)(C)OC4C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 61.8 %

Procedure:
The title compound was prepared by the procedure of Example 138, step (i) using 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1,1-dimethyl-2-oxo-ethyl)-phenyl]-amide (as prepared in Example 138, step (h), 60.0 mg, 0.154 mmol) and 2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole (Couturier, M. et at, Organic Process Research & Development, 2002, 6, 42-48, 132 mg, 0.924 mmol). Silica gel chromatography (1-3% MeOH/DCM) afforded the title compound (49.3 mg, 63%) as a white solid. 1H-NMR (1:1 CD3OD; 400 MHz): 8.13 (d, 1H, J=8.6 Hz), 7.98 (s, 1H), 7.32 (dd, 1H, J=8.6, 2.3 Hz), 7.21 (d, 1H, J=2.3 Hz), 5.73 (m, 1H), 4.48 (m, 2H), 2.70 (d, 2H, J=11.4 Hz), 2.59 (s, 2H), 2.31 (m, 2H), 2.08 (m, 2H), 1.98-2.04 (m, 2H), 1.59 (t, 2H, J=6.3 Hz), 1.44 (s, 3H), 1.34 (s, 6H), 1.23 (s, 3H), 1.09 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C30H39N5O3, 518.3 (M+H). found 518.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[NH:4][C:3]1=[O:17].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([N:4]1[C@@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][N:2]([CH3:1])[C:3]1=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CN1C[C@H](C(=O)OCc2ccccc2)NC1=O
Solvent: O
Product: CN1C[C@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1=O
Reaction time: 1 h
Yield: 32.3 %

Procedure:
To the solution of (R)-benzyl 1-methyl-2-oxo-imidazolidine-4-carboxylate (1000 mg, 4.27 mmol) in 11 ml of DMF sodium hydride (129 mg, 5.12 mmol) was added, resulting in a slightly exothermic reaction (temperature rise to about 27° C.) and formation of a turbid solution. After stiffing for 1 h at room temperature (bromomethyl)benzene (0.609 ml, 876 mg, 5.12 mmol) was added resulting again in a slightly exothermic reaction (temperature rise to about 29° C.). After stirring overnight the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed successively with a 10% citric acid solution, twice with saturated NaHCO3 solution and brine, dried over Na2SO4 and the solvent was then removed under reduced pressure. Column chromatography on silica gel using dichloromethane and dichloromethane/methanol 98/2 gave (R)-benzyl 3-benzyl-1-methyl-2-oxoimidazolidine-4-carboxylate (425 mg, 1.38 mmol, yield: 31%, ESI-MS [M+H]+=325.1), which was converted into to the corresponding carboxylate by stiffing overnight at room temperature in a mixture of 2.7 ml of THF and 1.44 mL of 2N NaOH. Water was added to the reaction mixture followed by extraction with MTBE. The aqueous layer subsequently was acidified to pH 3 using 2M HCl, and extracted three times with dichloromethane. The combined organic layers were then washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The title compound was obtained as colorless oil which solidified by standing over time (245 mg, yield: 75%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]([OH:18])([CH3:17])[CH3:16]>>[CH:15]([O:18][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH3:17])[CH3:16]
Reactant: CC(C)O
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
According to the procedure described for the synthesis of example 4, step c, the title compound has been synthesized from 2-chloro-5-methanesulfonyl-benzoic acid and isopropanol. MS (m/e): 257.0 (M−H, 100%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.C(O)CCC>O1CCOCC1>[CH:14]1([C:12]2[CH:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:17][C:18]4[CH:19]=[C:20]([S:24]([NH2:27])(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=4)[N:7]=3)[NH:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCCCO
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1
Temperature: 95 °C
Reaction time: 8 h
Yield: 3.2 %

Procedure:
The mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (150 mg, 0.64 mmol, 1.0 equiv.), 3-aminobenzenesulfonamide (329 mg, 1.91 mmol, 3.0 equiv.), butan-1-ol (1 mL) and dioxane (0.5 mL) was stirred at 95° C. for 8 h. Then, the reaction mixture was cooled to room temperature and filtered. The residue was crystallized with methane/water/isopropyl ether to afford Compound 82 (7.7 mg, 3%). LC-MS (m/z): 372.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.62-0.63 (m, 2H), 0.88-0.92 (m, 2H), 1.82-1.86 (m, 1H), 6.06 (bs, 1H), 6.49 (bs, 1H), 7.39 (s, 2H), 7.52 (d, J=1.8 Hz, 2H), 7.97 (s, 3H), 10.02 (s, 1H), 10.45 (bs, 1H), 12.27 (bs, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].Br[CH2:17][C:18]#[N:19]>CC(C)=O>[C:18]([CH2:17][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH3:7])#[N:19]
Reactant: N#CCBr
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1OCC#N
Yield: 84.2 %

Procedure:
Potassium carbonate (24 g) was added to a solution of of 2-methoxy phenol (18.94 g, 0.152 mol) in acetone (500 ml) at room temperature. A solution of bromoacetonitrile (17.43 g, 0.145 mol) in acetone (500 ml) was then added and the resulting suspension was heated at reflux for 10 h. The reaction vessel was then cooled and the solution was concentrated under reduced pressure and taken up into water (150 ml). Chloroform (250 ml) was added and the two layers separated. The organic phase was washed with brine (100 ml) and 10% aqueous NaOH (100 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure to give the product (19.91 g, 80%) as an oil. 1H NMR (CDCl3, 250 MHz) 7.0 (4H m), 4.8 (2H, s), 3.9 (3H, s).
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)[C:3]([OH:5])=[O:4].Cl.[CH3:18][CH2:19]O>>[NH2:1][C@H:2]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)[C:3]([O:5][CH2:18][CH3:19])=[O:4]
Reactant: CCO
Reactant: N[C@H](Cc1ccc2c(c1)CCCC2)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@H](N)Cc1ccc2c(c1)CCCC2

Procedure:
A mixture of 3.7 g (14.5 mmol) (R)-2-amino-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionic acid and 150 mL EtOH was combined with 50 mL ethanolic HCl with stirring. The reaction mixture was stirred for 2 h, evaporated down under reduced pressure and the residue was taken up in DCM. The organic solution washed with 15% K2CO3 solution, dried and evaporated down under reduced pressure.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[N:15]=2)=[CH:10][C:9]=1[OH:20].[CH2:21]([O:23][C:24]([C:26]1[C:27]2[S:35][CH:34]=[C:33]([CH2:36]Br)[C:28]=2[C:29]([Cl:32])=[N:30][CH:31]=1)=[O:25])[CH3:22]>O1CCCC1.CN(C)C=O>[CH2:21]([O:23][C:24]([C:26]1[C:27]2[S:35][CH:34]=[C:33]([CH2:36][O:20][C:9]3[CH:10]=[C:11]([C:14]4[O:18][N:17]=[C:16]([CH3:19])[N:15]=4)[CH:12]=[CH:13][C:8]=3[CH3:7])[C:28]=2[C:29]([Cl:32])=[N:30][CH:31]=1)=[O:25])[CH3:22]
Reactant: Cc1noc(-c2ccc(C)c(O)c2)n1
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nc(C)no4)ccc3C)csc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of cesium carbonate (1.02 g, 3.13 mmol), 2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenol (0.42 g, 2.20 mmol) (from Example 52 supra) in tetrahydrofuran/N,N-dimethylformamide (5:2, 21 mL) was heated at 70° C. for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.68 g, 2.04 mmol) (from Example 1 supra) was added. Heating was continued for 1 hour. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (2×). The combined organic phase washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with 5-10% ethyl acetate in dichloromethane to give 4-chloro-3-[2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.51 g, 57%).
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:26]([OH:35])[C@@H:27]([C@H:29]([C@@H:31](CO)[OH:32])[OH:30])[OH:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C@@H:26]([C@H:27]([C@@H:29]([CH2:31][OH:32])[OH:30])[OH:28])[OH:35])=[O:7]
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=CCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)CO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 100 °C
Reaction time: 24 h
Yield: 11 %

Procedure:
1.0 g (2.8 mmol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise to a solution of 0.86 g (2.8 mmol) of xylitol and 0.78 g (5.7 mmol) of potassium carbonate in dry N,N-dimethylformamide (2.5 mL) at 80° C. After the reaction mixture was stirred at 100° C. for 24 hours, the potassium carbonate was separated by filtration. The resulting solution was diluted with t-butylmethylether, and washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over magnesium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain 146 mg of the title compound (12% yield) as a colorless viscous product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][O:25][C:26](Cl)=[O:27]>>[CH3:24][O:25][C:26](=[O:27])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: COC(=O)Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OC)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid methyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.96 mmol) and methylchloroformate (89 μl, 1.16 mmol). The title compound was obtained as white powder (200 mg, 56%).
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([CH3:10])[N:5]1[CH2:11][CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]1[O:23][C:24]2[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:15].I[CH:33]([CH3:35])[CH3:34]>CN(C)C=O>[CH3:10][C@H:6]1[CH2:7][CH2:8][CH2:9][C@@H:4]([CH3:3])[N:5]1[CH2:11][CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]1[O:23][C:24]2[CH:30]=[C:29]([O:31][CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:15]
Reactant: CC(C)I
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccc(O)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2nc(N3CCCC[C@H]3C(=O)NCCN3[C@H](C)CCC[C@@H]3C)oc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydride as a 60% dispersion in oil (6 mg) was added to a solution of (2S)-N-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-1-(6-hydroxy-1,3-benzoxazol-2-yl)-2-piperidinecarboxamide (54.5 mg) [see Preparation 39] in dimethylformamide (2 ml) at 0° C. After 5 minutes 2-iodopropane (0.014 ml) were added. The reaction mixture was stirred at room temperature for 4 hours, after which time sodium hydride (3 mg) followed by 2-iodopropane (0.007 ml) was added. The mixture was stirred for a further 18 hours, after which time the solvent was removed and the residue partitioned between water and diethyl ether. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 97:3.5:0.5, by volume, dichloromethane/methanol/0.88 aqueous ammonia solution to afford (2S)-N-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-1-(6-isopropoxy-1,3-benzoxazol-2-yl)-2-piperidinecarboxamide (24 mg) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:22]([N:29]1[C:33](=[O:34])[C:32](=[C:35]2[N:39]([CH3:40])[C:38]3[CH:41]=[C:42]([O:45][CH2:46][CH2:47][O:48][CH3:49])[CH:43]=[CH:44][C:37]=3[S:36]2)[S:31][CH2+:30]1SC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:8]([C:4]1[CH:3]=[C:2]([N:1]=[C:30]2[N:29]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:33](=[O:34])[C:32](=[C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[C:42]([O:45][CH2:46][CH2:47][O:48][CH3:49])[CH:43]=[CH:44][C:37]=4[S:36]3)[S:31]2)[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: COCCOc1ccc2c(c1)N(C)C(=C1S[CH2+](SC)N(Cc3ccccc3)C1=O)S2
Reactant: CC(=O)c1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: COCCOc1ccc2c(c1)N(C)C(=C1SC(=Nc3cccc(C(C)=O)c3)N(Cc3ccccc3)C1=O)S2

Procedure:
The title compound was synthesized in a manner similar to that described in Example 146 by condensing 3′-aminoacetophenone with 3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate. 1H-NMR (CDCl3): δ 7.75 (1H, d), 7.60-7.64 (3H, m), 7.28-7.50 (6H, m), 7.24 (1H, d), 6.85 (1H, m), 5.21 (2H, s), 4.18 (2H, m), 3.80 (2H, m), 3.70 (3H, s), 3.48 (3H, s), 2.65 (3H, s); MS(ESI): 546 (MH+).
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[NH:13][CH:14]=[C:15]([C:17](=O)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)=[O:11]>FC(F)(F)C(O)=O>[CH3:8][O:9][C:10]([C:12]1[NH:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)=[O:11]
Reactant: COC(=O)c1cc(C(=O)Cc2ccccc2)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(CCc2ccccc2)c[nH]1
Reaction time: 8 h
Yield: 50.3 %

Procedure:
Triethylsilane (0.323 mL, 2.03 mmol) was added to a stirring, room temperature solution of methyl-4-phenylacetyl-1H-pyrrole-2-carboxylate (0.1593 g, 0.655 mmol) in trifluoroacetic acid (TFA) (1.47 mL, 0.45 M) under N2. After stirring overnight, the reaction was complete by HPLC. The TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 95:5 Hexanes: EtOAc) to obtain pure 27 (0.0755 g, 50.3%): 1H (CDCl3, 400 MHz): δ 9.17 (1H, broad s), 7.32-7.25 (2H, m), 7.23-7.17 (3H, m), 6.80 (1H, s), 6.69 (1H, s), 3.85 (3H, s), 2.93-2.85 (2H, m), 2.84-2.75 (2H, m) ppm. 13C (CDCl3, 100 MHz): δ 161.97, 142.15, 128.70, 128.55, 126.13, 125.96, 122.40, 121.26, 115.28, 51.67, 37.57, 28.92 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 51.67; CH2 carbons: 37.57, 28.92; CH carbons: 128.70, 128.55, 126.13, 121.26, 115.28 ppm. HPLC: 10.033 min. (Starting material: 8.751 min.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[C:17]1[N:22]=[C:21]2[N:23]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[O:34][CH2:33][CH2:32][C:31]=4[CH:35]=3)[N:24]=[N:25][C:20]2=[N:19][CH:18]=1.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:17]2[N:22]=[C:21]3[N:23]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]5[O:34][CH2:33][CH2:32][C:31]=5[CH:35]=4)[N:24]=[N:25][C:20]3=[N:19][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Brc1cnc2nnn(Cc3ccc4c(c3)CCO4)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cnc3nnn(Cc4ccc5c(c4)CCO5)c3n2)C1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
To a solution of (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (37 mg, 0.165 mmoL) in anhydrous DMF (2 mL) was added NaH (60% in oil, 7 mg, 0.18 mmol). The solution was stirred at 23° C. for 15 minutes. 6-Bromo-1-(2,3-dihydro-benzofuran-5-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (50 mg, 0.15 mmol) was added and the reaction solution was microwaved at 100° C. for 30 min. Water (10 mL) was added and the aqueous layer was extracted with EtOAc (3×10 mL). The combined extracts were dried with Na2SO4, and concentrated to provide {(R)-1-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (67 mg, 99% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[C:11]([NH2:14])[C:10]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]([CH:27]=O)=O>CO>[CH2:1]([N:8]1[C:12]2=[N:13][CH:25]=[CH:27][N:14]=[C:11]2[C:10]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1c(-c2ccc3ccccc3c2)nn(Cc2ccccc2)c1N
Reactant: O=CC=O
Solvent: CO
Product: c1ccc(Cn2nc(-c3ccc4ccccc4c3)c3nccnc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
190 mg of 2-benzyl-5-(naphthalen-2-yl)-2H-pyrazole-3,4-diamine was dissolved in 10 mL of methanol, added with 100 μl of 40% glyoxal aqueous solution, and stirred at room temperature for 5 hours. The reaction solution was partitioned between water and ethyl acetate, and the organic layer was extracted and washed with water. The organic layer was dried over magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5), to afford 180 mg of the title compound as a pale yellow powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].ClC(Cl)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>>[C:19]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 80 °C

Procedure:
An ice-cooled solution of 5 grams of acetanilide and 15 g. of aluminum chloride in 75 ml. of dichloroethane is treated with 5 g. of benzoyl chloride in portions. The mixture is then heated at 80° C for 3 hours, decomposed with ice and dilute hydrochloric acid and the resulting solid isolated by suction filtration and recrystallized from ethanol:water to give p-benzoylacetanilide.
Reaction SMILES: [C:1]([CH2:4][C:5]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)([OH:3])=[O:2].O.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O>C1(C)C=CC=CC=1>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:22][C:21]([CH2:20][C:5]1([CH2:4][C:1]([O:3][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])=[O:2])[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:23]
Reactant: CCCC1CCC(C2CCC(CC(=O)O)(CC(=O)O)CC2)CC1
Reactant: OCCCCCCBr
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1CCC(C2CCC(CC(=O)OCCCCCCBr)(CC(=O)OCCCCCCBr)CC2)CC1

Procedure:
10.0 g (30.8 mmol) of (4-carboxymethyl-4′-propylbicyclohexyl-4-yl)acetic acid are heated on a water separator for 6 h together with 15.0 g (80.4 mmol) of 6-bromo-1-hexanol and 0.50 g (2.90 mmol) of paratoluenesulfonic acid monohydrate in 150 ml of toluene. After cooling, the reaction mixture is subjected to absorptive filtration (SiO2, toluene), and the filtrate is concentrated to dryness. The crude product obtained in this way is used directly for the next reaction.
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34](=[O:48])[C@@H:35]1[CH2:39][C@@H:38]([OH:40])[CH2:37][N:36]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>O1CCCC1.C(O)=O>[CH3:32][O:33][C:34](=[O:48])[C@@H:35]1[CH2:39][C@H:38]([O:40][CH:3]=[O:4])[CH2:37][N:36]1[C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)[C@@H]1C[C@H](OC=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.67 h

Procedure:
Diethyl azodicarboxylate (2.2 mL) was added to a cold (−15° C.) stirred solution of triphenyl phosphine (3.67 g) in tetrahydrofuran (40 mL). After stirring at 0° C. for 100 min, a solution of N-tert-butoxycarbonyl-trans-4-hydroxy-L-proline methyl ester (2.29 g) in tetrahydrofuran (20 mL) and formic acid (2.20 mL) were added. The mixture was stirred at room temperature for 14 hr, the solvent was removed and coevaporated several times with toluene in vacuo. The residue was diluted with toluene and precipitated solids were removed by filtration which was washed with toluene. The combined organic layers were evaporated in vacuo and the residue was purified by silica gel column chromatography (chloroform then chloroform:methanol=15:1, v/v) to give the title compound (4.07 g) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.39-1.50 (m, 9H), 2.25-2.34 (m, 1H), 2.43-2.60 (m, 1H), 3.54-3.67 (m, 1H), 3.72-3.83 (m, 1H), 3.75 (s, 3H), 4.37-4.55 (m, 1H), 5.35-4.41 (m, 1H), and 7.97 (s, 1H).