Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[N:7]([C:10]2[S:11][C:12]([C:16]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:6]=[N:5]1.[H-].[Na+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1>O1CCCC1.C(OCC)(=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][CH2:2][CH2:3][N:4]2[C:8](=[O:9])[N:7]([C:10]3[S:11][C:12]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[O:17])=[C:13]([CH3:15])[N:14]=3)[CH:6]=[N:5]2)=[CH:31][CH:32]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1nc(-n2cnn(CCO)c2=O)sc1C(=O)NCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-n2cnn(CCOCc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To the solution of 2-(1-(2-hydroxyethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.11 g, 0.31 mmol) in anhydrous tetrahydrofuran was added sodium hydride (60% in mineral oil, 0.015 g, 0.35 mmol) at 0° C. The reaction mixture was stirred for 30 minutes, followed by the addition of 1-(bromomethyl)-4-fluorobenzene (0.04 mL, 0.31 mmol). The resulting mixture was stirred at ambient temperature for 17 hours, diluted with ethyl acetate and washed with water and brine. The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate to afford the title compound as a white solid in 46% yield (0.06 g): mp 235-236° C. (ethyl acetate): 1H NMR (300 MHz, DMSO-d6) δ 9.14 (br s, 1H), 9.11-9.06 (m, 1H), 8.95 (t, J=5.5 Hz, 1H), 8.73 (s, 1H), 8.56-8.48 (m, 1H), 8.15-8.08 (m, 1H), 7.65-7.56 (m, 2H), 7.32-7.22 (m, 2H), 5.81 (s, 2H), 4.57 (d, J=5.5 Hz, 2H), 3.79 (t, J=5.4 Hz, 2H), 3.64 (t, J=5.4 Hz, 2H), 2.54 (s, 3H): 13C NMR (75 MHz, DMSO-d6) δ 162.0, 161.4, 152.6, 152.1, 150.6, 145.1, 143.8, 143.7, 141.1, 131.9, 131.9, 131.0, 128.7, 121.9, 116.6, 62.9, 58.6, 48.3, 40.7, 17.5: MS (ES+) m/z 469.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Cl[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: Clc1ccc(Cl)nc1
Product: COc1ccc(CC2c3cc(Oc4ccc(Cl)cn4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2,5-dichloro-pyridine
Reaction SMILES: C([O:5][C:6](=[O:31])[CH:7]([C:9]([C:11]1[C:12]([O:29][CH3:30])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:10])[NH2:8])(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[F:28][C:25]1[CH:26]=[CH:27][C:22](/[CH:21]=[CH:20]/[C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([C:9]([CH:7]([NH2:8])[C:6]([OH:31])=[O:5])=[O:10])[C:12]=3[O:29][CH3:30])[NH:16][N:15]=2)=[CH:23][CH:24]=1
Reactant: COc1c(C(=O)C(N)C(=O)OC(C)(C)C)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1c(C(=O)C(N)C(=O)O)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
472 mg of {3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonyl}-aminoacetic acid tert-butyl ester was dissolved in 5 mL of dichloromethane, 2.5 mL of trifluoroacetic acid was added, and stirred overnight at room temperature. The reaction solution was added with water, and extracted with a mixed solution of ethyl acetate:tetrahydrofuran=1:1. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give 384 mg of the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[NH:10]C(=O)O[C:7](=[O:12])[C:6]=2[CH:13]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[NH2:10][C:5]1[C:4]([CH3:14])=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([NH:18][CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)N
Reactant: Cc1cc(Br)cc2c(=O)oc(=O)[nH]c12
Solvent: c1ccncc1
Product: Cc1cc(Br)cc(C(=O)NC(C)C)c1N
Yield: 118.7 %

Procedure:
To a suspension of the benzoxazinedione of Step E, (4.0 g, 15.56 mmol) in pyridine (20 mL) was added isopropylamine (1.2 g, 20.23 mmol) and the reaction was heated to reflux for 2 hours. The reaction was then cooled, concentrated from toluene on a rotary evaporator and then dried under vacuum to afford a solid (5.01 g).
Reaction SMILES: [F:1][CH2:2][CH:3]([NH2:9])[CH2:4][CH2:5]C(O)=O.S(=O)(=O)(O)O.[NH:15]=[N+]=[N-].C(=O)=O.C(Cl)(Cl)[Cl:22]>O>[ClH:22].[ClH:22].[F:1][CH2:2][CH:3]([NH2:9])[CH2:4][CH2:5][NH2:15]
Reactant: ClC(Cl)Cl
Reactant: [N-]=[N+]=N
Reactant: NC(CF)CCC(=O)O
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cl
Product: NCCC(N)CF
Temperature: 25 °C
Yield: 53 %

Procedure:
To a solution of 5-fluoro-4-amino-pentanoic acid (6.75 g, 50 mmoles) in conc. sulfuric acid (49 g, 0.5 moles) is added a solution of hydrazoic acid in chloroform (1.14 N, 44 mL) at 40° C. with vigorous stirring. Heating and stirring are continued until the end of carbon dioxide evolution (6 hours). The reaction mixture is poured into water (500 mL), heated to boiling and the sulfate is precipitated with barium chloride (105 g in 400 mL of water). After cooling to room temperature, barium sulfate is removed by filtration (celite) and the excess barium ions are precipitated by dropwise addition of 2 N sulfuric acid until no further precipitation occurs. After filtration (celite), evaporation gives a solid residue which is recrystallized from methanol/acetone to give 1-fluoro-2,4-diaminobutane dihydrochloride (2HCl, 4.7 g, 53%) as white, slightly hygroscopic crystals, Mp 135° C.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([C:19]([O:21]CC)=[O:20])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].C(O)=O.CS(O)(=O)=O>O>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1
Agent: CS(=O)(=O)O
Solvent: O=CO
Solvent: O
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(C(=O)O)nn12
Reaction time: 1 h

Procedure:
5.8 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-carbethoxy-s-triazolo[4,3-b]pyridazine were heated under reflux with 18.3 ml. 90% aqueous formic acid and 2.75 ml. methane-sulfonic acid for 3 hours at a bath temperature of 130° C. 80 ml. water were then added thereto and the precipitated crystals were filtered off with suction, after having stood for 1 hour, and washed with water. There were thus obtained 4.85 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-carboxy-s-triazolo[4,3-b]pyridazine, which has a melting point of 257° - 260° C. 1 g. of the product was recrystallized from 15 ml. dioxan with the addition of charcoal, to give 0.6 g. of pure product which melts, with foaming up, at 260° - 262° C.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([NH2:34])[CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]([N:18]1[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])C.O.[OH-].[Li+]>O1CCCC1.CO.O>[NH2:34][CH:5]([CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]([N:18]1[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(N)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CC(N)C(=O)O

Procedure:
To a solution of 2-amino-3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propionic acid ethyl ester (0.033 g, 0.065 mmol) in tetrahydrofuran, methanol and water (1 ml each) was added lithium hydroxide hydrate (0.014 g, 0.33 mmol). After 3 hours the reaction was concentrated in vacuo and the title compound was isolated by chromatography on silica gel (0.031 g, LRMS 478.5).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]([NH:33][NH2:34])=[O:32])=[CH:28][CH:29]=2)[CH:24]=[N:23]1.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[F:14][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([NH:34][NH:33][C:31]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[NH:22][N:23]=[CH:24]3)=[O:32])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Reactant: NNC(=O)c1ccc2[nH]ncc2c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCc1cccc(C(F)(F)F)c1)NNC(=O)c1ccc2[nH]ncc2c1
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To a solution of 3-[3-(trifluoromethyl)phenyl]propionic acid (437 mg, 2.00 mmol) and N,N-dimethylformamide (1 drop) in tetrahydrofuran (4 mL) was added oxalyl chloride (0.183 mL, 2.10 mmol) at room temperature, and the resulting mixture was stirred for 30 min. The reaction mixture was added dropwise to a mixture of 1H-indazole-5-carbohydrazide (352 mg, 2.00 mmol), tetrahydrofuran (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) at room temperature, and the resulting mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethanol to give the title compound (383 mg, yield 51%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[CH3:9])[CH3:18]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1cccc(C)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(C)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 3′-methylacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) was heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract was concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, was isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether. The purified oil solidified on standing at room tempera-ture.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:13]=[CH:12][C:8]([NH:9][CH2:10][CH3:11])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)#[N:4].[Cl:17][C:18]1[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=1.O>O1CCCC1>[Cl:17][C:18]1[S:22][C:21]([S:23]([N:9]([C:8]2[CH:12]=[CH:13][C:5]([C:3]#[N:4])=[CH:6][C:7]=2[N+:14]([O-:16])=[O:15])[CH2:10][CH3:11])(=[O:25])=[O:24])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCNc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(c1ccc(C#N)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in tetrahydrofuran (THF) (3.0 ml), 4-cyano-N-ethyl-2-nitroaniline (0.38 g (1.99 mmol)) was added with stirring at room temperature. To the mixture, upon stirring for 15 minutes at room temperature and after the solution had turned deep purple, 5-chloro-2-thiophenesulfonyl chloride (0.55 g (2.53 mmol)) was added and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.22 g (30%) of the title compound as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13](OC)([O:16]C)[CH2:14]Br.[H-].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]#[N:10])[CH2:14][C:13](=[O:16])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(CBr)(CBr)OC
Reactant: N#CCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2cccc(Br)c2)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 3-bromophenylacetonitrile (7.55 g, 38.5 mmol) and 1,3-dibromo-2,2-dimethyoxypropane (10.09 g, 38.5 mmol) in dry DMSO (100 ml) was added in two portions sodium hydride (3.23 g of 60% dispersion in oil, 81 mmol) while the mixture was cooled in a water bath. The mixture was stirred at RT for 10 minutes, and heated at 60° C. in an oil bath for 6 hours. The reaction was diluted with water and extracted with EtOAc. The organic layer was separated, washed with water and the solvent removed. The residual red oil was eluted through a short pad of silica, eluent 10% EtOAc/Hexane. The resulting ketal was dissolved in acetone (100 ml) and 1N aqueous HCl (10 ml) and heated at reflux for 6 hours under a nitrogen atmosphere. The solvent was removed and the residue was neutralized by treatment with aqueous NaHCO3 and extracted with EtOAc. The solvent was removed and the residue was chromatographed (SiO2, eluent 10% EtOAc in hexane) to give a yellow oil which solidified on drying under vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1>>[CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:19]3[N:24]=[C:23]([NH:25][C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=4[C:28](=[O:29])[NH:30][CH3:31])[C:22]([Cl:36])=[CH:21][N:20]=3)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCOc2cc(N)ccc21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCOC(=O)N1CCCOc2cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc21

Procedure:
3-[5-Chloro-4-(2-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a yellow foam (102 mg, 52%). LCMS (m/e) 497 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.14-11.00 (m, 1H), 8.70-8.36 (m, 1H), 8.12 (s, 1H), 7.57-6.96 (m, 7H), 6.48-6.38 (m, 1H), 4.33-4.03 (m, 4H), 3.88-3.60 (m, 2H), 3.03 (d, 3H, J=4.4 Hz), 2.15-2.00 (m, 2H), 1.42-1.12 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:14]1([C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: C1CCNC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](C(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (20.0 g) obtained in Reference Example 1(2) is dissolved in chloroform (200 ml), and thereto are added pyrrolidine (9.2 g), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (24.7 g) and triethylamine (13.6 g) under ice-cooling. The mixture is then stirred at room temperature for 17 hours. Ice-water is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine successively, and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform, followed by chloroform/methanol=20/1) to give methyl trans-4-(pyrrolidin-1-ylcarbonyl)-cyclohexanecarboxylate (11.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:17]1([CH:14]2[C:15]3[C:10](=[N:9][C:8]4[C:3]([C:2]=3[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:11][CH2:12][CH2:13]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNC1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3ccccc13)CCCC2N1CCCC1

Procedure:
9-Amino-1,2,3,4-tetrahydroacridin-1-ol (5.36 g) was refluxed overnight in 250 ml of toluene that contained pyrrolidine (7.10 g) and p-toluenesulfonic acid monohydrate (9.5 g). At the end of this time the reaction mixture was washed with an aqueous K2CO3 solution and then the organic phase was concentrated. The residue obtained in this manner was purified by flash chromatography (5% Et3N, toluene) to give, after recrystallization from benzene/pentane, 2.91 g, m.p. 201°-203°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][CH2:30][C@H:29]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:28]2)=[CH:23][CH:22]=1)=O)(C)(C)C.[ClH:37]>ClCCl.C(OCC)(=O)C>[ClH:37].[ClH:37].[ClH:37].[ClH:37].[N:32]1([C@H:29]2[CH2:30][CH2:31][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C@H:9]4[CH2:10][NH:11][CH2:12][CH2:13][NH:8]4)=[CH:26][CH:25]=3)[CH2:28]2)[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CC[C@H](N4CCCC4)C3)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1cc(N2CC[C@H](N3CCCC3)C2)ccc1[C@H]1CNCCN1
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of (S)-1,4-di(t-butoxycarbonyl)-2-(4-((S)-3-(pyrrolidin-1-yl) pyrrolidin-1-yl)phenyl)piperazine (479 mg, 0.957 mmol) in dichloromethane (4 mL) was added 4 N hydrogen chloride in ethyl acetate (4 mL) at room temperature. After stirring for 3 h, the resulting precipitate was collected and dried in vacuo to afford (S)-2-(4-((S)-3-(pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)piperazine tetrahydrochloride (370 mg, 87%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5](Br)[C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[S:23])=[CH:20][CH:19]=1>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[N:24]=[C:22]([C:21]3[CH:25]=[CH:26][C:18]([OH:17])=[CH:19][CH:20]=3)[S:23][C:5]=2[CH2:4][C:3]([O:2][CH3:1])=[O:16])=[CH:8][CH:9]=1
Reactant: COC(=O)CC(Br)C(=O)c1ccc(Cl)cc1
Reactant: NC(=S)c1ccc(O)cc1
Product: COC(=O)Cc1sc(-c2ccc(O)cc2)nc1-c1ccc(Cl)cc1

Procedure:
By a process analogous to Example 2, methyl-3-bromo-3-(4-chlorobenzoyl)propionate and 4-hydroxy-thiobenzamide are reacted to give methyl 4-(4-chlorophenyl)-2-(4-hydroxyphenyl)thiazole-5-acetate. This compound is hydrolysed using 2 N sodium hydroxide to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:4]=2[CH:3]=1.Cl.[CH3:15]O>>[CH3:15][O:12][C:11]([C:9]1[CH:8]=[CH:7][C:5]2[S:6][C:2]([CH3:1])=[CH:3][C:4]=2[CH:10]=1)=[O:13]
Reactant: Cc1cc2cc(C(=O)O)ccc2s1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2sc(C)cc2c1

Procedure:
A solution of 2-methylbenzo[b]thiophene-5-carboxylic acid (17.4 g) in methanol (250 ml) was saturated with hydrogen chloride and then heated under reflux for 30 minutes. The solid which crystallised out on cooling was filtered off and dried to give 2-methylbenzo[b]thiophene-5-carboxylic acid methyl ester (16.7 g), m.p. 97°-98°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[CH:9]1[CH:14]=[CH:13][C:12]([O:15][P:16](Cl)(Cl)=[O:17])=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.[C:29]([O:43][CH3:44])(=[O:42])[CH2:30][CH2:31][NH:32][C:33](=[O:41])[C@@H:34]([C:36]([CH2:39][OH:40])([CH3:38])[CH3:37])[OH:35].CN1C=CN=C1>ClCCl.CO>[OH:35][C@H:34]([C:36]([CH3:38])([CH3:37])[CH2:39][O:40][P:16]([NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])([O:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)=[O:17])[C:33]([NH:32][CH2:31][CH2:30][C:29]([O:43][CH3:44])=[O:42])=[O:41]
Reactant: COC(=O)CCNC(=O)[C@H](O)C(C)(C)CO
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(N[C@@H](C)C(=O)OC)Oc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
L-alanine methyl ester hydrochloride (1.35 g, 9.65 mmol) was suspended in dichloromethane (20 mL) and treated with phenyl phosphodichloridate (1.51 mL, 10.15 mmol) at −78° C. under an atmosphere of argon. Diisopropylethylamine (2.6 mL, 20.27 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 1 hr. The mixture was chilled to −5° C. and methyl pantothenate (1.6 mL, 20.27 mmol) was added dropwise in dichloromethane. N-methylimidazole (1.6 mL, 20.27 mmol) was added, and after stirring at −5° C. for 30 mins and room temperature for 1 hour, 2 mL of methanol was added. The mixture was washed sequentially with water (30 mL), 5% citric acid (30 mL), and brine (10 mL). The organic phase was dried (Na2SO4) and the solvent was removed under reduced pressure. Purification was achieved with a 1:1 mixture of EtOAc:hexane to afford the product as a clear colorless oil. (1.1 g, 24% yield). HPLC showed the product, as a 1:1 mixture of disastereomers, having a purity of 97%. 1H NMR (300 MHz, CDCl3): δ 1.11 (s, 3H, CH3), 1.27, 1.39 and 1.40 (2 Ss, 3H, CH3), 1.41 (overlapping d, 3H, J=1.2 Hz, CHCH3), 3.55 (m, 2H, CH2), 3.60 (m, 1H, CH2), 3.63 (m, 1H, CH), 3.66 and 3.68 (2 Ss, 3H, COCH3), 3.70 and 3.74 (2 Ss, 3H, COCH3), 3.78 (m, 1H CH), 4.03 (m, 1H, CH), 4.17 (m, 1H, CH), 7.16 and 7.35 and 7.40 (2 Ms, 5H, Ph). Expected Mol. Wt. 474.18, Observed Mol. Wt. 475.03 (M+H+].