Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]1([N:13]2[C:17]([NH2:18])=[C:16]([C:19]#[N:20])[CH:15]=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>N1C=CC=CC=1>[C:7]1([N:13]2[C:17]([NH:18][C:1]([CH2:2][CH2:3][CH3:4])=[O:5])=[C:16]([C:19]#[N:20])[CH:15]=[N:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1cnn(-c2ccccc2)c1N
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1c(C#N)cnn1-c1ccccc1
Temperature: 50 °C
Yield: 50 %

Procedure:
6.8 ml (66 mmol) of butyryl chloride were added to a solution of 5.52 g (30 mmol) of 1-phenyl-4-cyano-5-aminopyrazole [known from J. Org. Chem. 21 (1956), 1240] in 70 ml of pyridine. The mixture was heated for 15 hours at 50° C. and then poured into 500 ml of 5% strength by weight aqueous hydrochloric acid. The product was extracted from the aqueous phase with methylene chloride and then isolated in a conventional manner. Yield: 50%.
Reaction SMILES: ClN1C(=O)CCC1=O.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.[CH3:20][S:21][CH3:22]>ClCCl>[CH3:20][S:21]([CH3:22])=[N:15][C:14]1[CH:16]=[CH:17][C:11]([C:10]([F:18])([F:19])[F:9])=[CH:12][CH:13]=1
Reactant: CSC
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CS(C)=Nc1ccc(C(F)(F)F)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A solution of N-chlorosuccinimide (12-43 g, 93.1 mmol) in ˜170 mL of dichloromethane was added to a mixture of 4-(trifluoromethyl) aniline (15 g, 93.1 mmol) and dimethyl sulfide (6.35 g, 102 mmol) in 230 mL of dichloromethane at −5-0° C. After the addition was complete, the mixture was stirred at 0-5° C. for 1 h, and N-chlorosuccinimide (0.02 g, 4.64 mmol) was added. After a further 30 minutes, the mixture was washed with 500 mL of 1N sodium hydroxide.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:20]([O:22]CC3C=CC([N+]([O-])=O)=CC=3)=[O:21])=[C:8]([C:11]3[N+:12]4[C:13](=[CH:16][N:17]([CH3:19])[CH:18]=4)[S:14][CH:15]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:20]([O-:22])=[O:21])=[C:8]([C:11]3[N+:12]4[C:13](=[CH:16][N:17]([CH3:19])[CH:18]=4)[S:14][CH:15]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3csc4cn(C)c[n+]34)[C@H](C)[C@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3csc4cn(C)c[n+]34)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 19.1 %

Procedure:
To a solution of 60.5 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-3-yl)-1-carbapen-2-em-3-carboxylate in 1.8 ml of THF and 1.8 ml of {fraction (1/15)} M phosphate buffer (pH 6.8) was added 71 mg of 10% Pd-C. The reactor was purged with hydrogen, and the reaction mixture was stirred at room temperature for 3.5 hours. The catalyst was collected by filtration through Celite, and washed with water. The filtrate was washed with 20 ml of ethyl acetate, and purified by column chromatography on DIAION HP-20 and on COSMOSEAL40C18-PREP (water:methanol=20:1) to give 8.3 mg of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:18]=[CH:17]3)[C@@H:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].C([O:33][CH2:34][C:35](Cl)=[O:36])(=O)C>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[C@@H:10]([NH:12][C:34](=[O:33])[CH2:35][OH:36])[CH3:11])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Product: CCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CO)cc1

Procedure:
Prepared as described in Example 5 using (1R,2S)-1-(4-ethylphenyl)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}propan-2-amine (20 mg, 50 μmol) and 2-chloro-2-oxoethyl acetate (21 mg, 150 μmol). Yield 21 mg (91%).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][NH:5][C:6]([C:8]1[C:13]([OH:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:10][N:9]=1)=[O:7].[OH-].[Na+].Cl>C1COCC1>[Cl:21][C:17]1[CH:16]=[C:15]([C:11]2[CH:12]=[C:13]([OH:14])[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:22])=[O:2])=[O:7])=[N:9][CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CNC(=O)c1ncc(-c2cccc(Cl)c2)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ncc(-c2cccc(Cl)c2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of {[5-(3-chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester, 6, (0.163 g, 0.509 mmol) in THF (5 mL) is added 1M NaOH (1.5 ml, 1.27 mmol) and the reaction mixture stirred at room temperature for 1 hour. The solution is acidified using 1M HCl (3 mL), the solvent removed under reduced pressure and the resulting solid suspended in CHCl3:iso-propanol (1:1), filtered and the filtrate dried (MgSO4), filtered and re-concentrated under reduced pressure. The crude material is triturated with a small amount of MeOH to afford 0.10 g (64% yield) of the desired product as a colorless solid. 1H NMR (400 MHz, MeOD) δ ppm 8.31 (1H, d, J=1.8 Hz), 7.47 (2H, d, J=1.8 Hz), 7.30-7.65 (4H, m), 4.07 (2H, s). HPLC-MS: m/z 307 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([NH:16][CH3:17])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:14][NH:16][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CNC(=O)C1(c2ccc(Cl)cc2)CCCCC1
Agent: Cl
Product: CNCC1(c2ccc(Cl)cc2)CCCCC1
Yield: 121.6 %

Procedure:
The title compound was synthesized from 1-(4-chlorophenyl)-N-methylcyclohexanecarboxamide (278 mg, 1.11 mmol) using General Procedure E, followed by HCl salt formation to give pure (1-(4-chlorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride as an off-white solid (185 mg, 70%). HPLC Rt=8.38 min; 1H NMR (400 mHz, MeOH-d4) 7.39 (s, 4H), 3.10 (s, 2H), 2.52 (s, 3H), 2.19-2.16 (m, 2H), 1.65-1.49 (m, 6H), 1.37-1.30 (m, 4H); LC-MS 7.49 min, (M+1)+0 238 @ 7.63 min.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:11]([P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[CH2:12])=[CH2:10])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O.O.O.O.O.O.O.O.O.[S-2:30].[Na+].[Na+]>C(O)C>[CH2:16]([O:15][P:13]([CH:11]1[CH:9]([P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][S:30][CH2:12]1)([O:18][CH2:19][CH3:20])=[O:14])[CH3:17]
Reactant: [S-2]
Reactant: C=C(C(=C)P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(OCC)C1CSCC1P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.3 %

Procedure:
In ethanol, 2.02 g (6.19 mmols) of 2,3-bis(diethoxyphosphoryl)-1,3-butadiene was dissolved, to which 1.63 g (6.81 mmols) of commercially available sodium sulfide nonahydrate was added, followed by stirring at room temperature for 3 days. After completion of the reaction, the reaction mixture was dried over anhydrous sodium sulfate for 1 hour. Ethyl acetate was added to and the resulting mixture was charged into a silica gel column to dissolve out the specified substance with ethyl acetate. Thereafter, the solvent was removed, and the resulting crude product was purified with a silica gel column (ethyl acetate:chloroform=1:2) to obtain the specified substance in the form of a yellow oil at a yield of 1.88 g (yield: 84.3%).
Reaction SMILES: [O-]CC.[Na+].C(O)C.[CH2:8]([CH:15](C(C)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:24]N1C(=O)CCC1=O>>[Br:24][C:14]1[C:9]([CH2:8][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1Br
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To a 2 L 4-necked round bottom flask that was equipped with an overhead stirrer, an addition funnel, a condenser and a temperature-probe, was added the solution of sodium ethoxide/ethanol (21% wt. %, 161.8 g) at 20-25° C. under nitrogen. Ethyl 2-benzylacetoacetate (103.1 g, 0.454 mole) was added dropwise. The resulting solution was stirred at 20-25° C. for 30 minutes. The reaction mixture was then cooled to −35° C. with a dry ice/acetone bath. N-Bromosuccinimide (NBS; 97.95 g, 0.545 mole) was added portion-wise over 30 minutes. After the addition was over, the reaction mixture was stirred at −35° C. for 1 hr before warming up to 20-25° C. and it was stirred for an additional 2 hrs. The reaction was then quenched with water (400 mL) and ethyl acetate (600 mL) was added. The layers were separated and the product was extracted from aqueous layer with ethyl acetate (400 mL×3). The combined organic layers was washed with saturated sodium bicarbonate twice (400 mL×2), water twice (400 mL×2) and brine (500 mL). After the removal of solvent, the product (crude, 132 g) was distilled under reduced pressure. Ethyl 2-bromo-3-benzenepropanoate (97.7 g) was obtained at yield 83.7%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH2:43])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:44]([CH2:46]N)[OH:45]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH:43][CH2:46][CH2:44][OH:45])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(N)=O)cc1
Reactant: NCCO
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(=O)NCCO)cc1
Reaction time: 3 h
Yield: 21 %

Procedure:
A portion of the crude intermediate of example 58 above, (25 mg, 0.03 mmol) was added to a solution of ethanolamine in ethanol (1M, 10 mL). The resulting solution was stirred for 3 h before evaporation of the solvent. The residue was purified by preparative HPLC to yield 15 mg, 21% of the desired material.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[C:7]([N:12]2[C:16]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([C:24]#[N:25])[CH:18]=3)=[CH:15][C:14]([C:26]([O:28]CC)=[O:27])=[N:13]2)[CH:8]=[CH:9][C:10]=1[F:11].Cl>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([N:12]2[C:16]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([C:24]#[N:25])[CH:18]=3)=[CH:15][C:14]([C:26]([OH:28])=[O:27])=[N:13]2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
12.0 ml of water and 741 mg (30.1 mmol) of lithium hydroxide are added to 1.20 g (3.10 mmol) of the carboxylic ester of Example 128A in 36.0 ml of THF. The mixture is stirred at RT for 6 h and a 1N aqueous hydrogen chloride solution is subsequently added to the reaction solution. The mixture is extracted with dichloromethane and the combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. 1.10 g (95% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[N+:12]([C:10]1[C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=[C:3]([CH:11]=1)[CH:2]=[O:1])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C=O)cc1O
Solvent: CC(=O)O
Product: COc1c(O)cc(C=O)cc1[N+](=O)[O-]
Temperature: 27.5 °C
Yield: 65 %

Procedure:
Isovanillin (500 gm) and acetic acid (1750 ml) were cooled to −5 to 0° C. To this solution, nitric acid (750 ml) was charged slowly at −5 to 0° C. with stirring. The temperature of the reaction mass was slowly raised to 25-30° C. and maintained for 12 hours. The reaction mass was quenched into ice water (4 kg), the solids filtered and washed with water (2 lt). The solids were stirred with a 1% sodium bicarbonate solution (1 lt), filtered and dried at 45-50° C. The solid was dissolved in 6 volumes of ethyl acetate, ethyl acetate was distilled off up to half the volume and 3 volumes of n-Hexane were charged slowly at 45-50° C. The reaction mass was cooled slowly to 0-5° C., maintained for 1 hour, the solids filtered, washed with 0.5 volumes of 1:1 mixture of ethyl acetate:n-Hexane and dried at 45-50° C. to yield the title compound (423 gm, 65% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=1)([O-:3])=[O:2].[BH4-].[Na+]>CCO>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([OH:16])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1C1=CC(O)CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 3-(3-nitropyridin-4-yl)cyclohex-2-enone (1.0 equiv.) was added EtOH (1.1 M) and CeCl3-7H2O (1.3 equiv.). The reaction was cooled to 0° C., then NaBH4 (1.3 equiv.) was added in portions. Stirred for 2 h at 0° C., then quenched by adding water, concentrated to remove the EtOH, added EtOAc, extracted the organics, dried with brine, then Na2SO4, and concentrated to yield 3-(3-nitropyridin-4-yl)cyclohex-2-enol (99%). LC/MS=221.1 (M+H), LC=2.24 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:21])[S:10][CH2:11][CH2:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:6][CH:7]=1.[BH4-].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:21])[S:10][CH2:11][CH2:12][CH:13]([OH:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:6][CH:7]=1
Reactant: O=C(CCSC(=S)Nc1ccc(Cl)cn1)c1ccccc1
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OC(CCSC(=S)Nc1ccc(Cl)cn1)c1ccccc1
Reaction time: 20 h
Yield: 34.8 %

Procedure:
The procedure of Example 3 is followed, but a suspension of 3-oxo-3-phenylpropyl 5-chloropyrid-2-yldithiocarbamate (28.0 g) in methanol (840 cc) and a solution of potassium borohydride (9.0 g) in distilled water (120 cc) are used as the starting materials at a maximum of 30° C. The reaction is allowed to proceed for 20 hours at between 20° and 25° C. Unreacted starting material (5.5 g) is filtered off from the reaction mixture. The filtrate is evaporated to dryness. The residue (20.0 g) is dissolved in chloroform (200 cc). The solution is chromatographed on silica (0.063-0.2 mm, 400 g) contained in a column of diameter 5 cm. Elution is carried out with chloroform (2 liters), this eluate being discarded, and then with chloroform (4.5 liters). The eluate which is collected is evaporated to dryness under reduced pressure (20 mm Hg) at 45° C. The chromatographed product (14.4 g) is recrystallised from acetonitrile (40 cc). 3-Hydroxy-3-phenylpropyl 5-chloropyrid-2-yldithiocarbamate (9.8 g), which melts at 91° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH:19]([NH:22][C:23]([C@H:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[NH2:30])=[O:24])([CH3:21])[CH3:20]>CC(N(C)C)=O>[CH:19]([NH:22][C:23]([C@H:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[NH:30][C:3]1[C:2]([CH3:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)=[O:24])([CH3:21])[CH3:20]
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CC(C)NC(=O)[C@H]1CCC[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cnc(Cl)nc1N[C@@H]1CCC[C@@H]1C(=O)NC(C)C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1 g (6.1 mmol, 1 eq) 5-methyl-2,4-dichloropyrimidine (prepared analogously to A-1a) are dissolved in 3 mL DMA and then 5.3 mL (30.5 mmol, 5 eq) Hünig base are added dropwise. 1.03 g (6.1 mmol, 1 eq) (1S,2R)-2-aminocyclopentanecarboxylic acid isopropylamide are added and the reaction mixture is stirred for 1 h at 70° C. HPLC monitoring shows that the reaction is total and only one regioisomer is formed. The reaction mixture is combined with RP gel, the volatile constituents are eliminated in vacuo, the product is purified by column chromatography through an RP phase and isolated (from water/MeCN (+0.2% HCOOH in each case) from 82/18 to 60/40 in 15 min). Corresponding product fractions are combined, freed from the solvent by freeze-drying and 956 mg of C-1d are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:14])(=[O:13])[C:5]2[CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=[CH:18][C:4]=2[NH:3]1>[OH-].[Na+].O1CCCC1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:14])(=[O:13])[C:5]2[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C(=O)N2

Procedure:
Stir at room temperature 795 mg of the ester of Example 26 in a mixture of 50 ml of 10% aqueous sodium hydroxide and 50 ml of tetrahydrofuran for 3 hours. Separate the layers and extract the organic layer with 10% aqueous sodium hydroxide. Wash the combined aqueous layers with ether and acidify with acetic acid. Separate the precipitate by filtration, wash with water and dry in order to obtain the title product (m.p. 337°-340° C. with subsequent dec.).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([C@:14]34[CH2:22][NH:21][CH2:20][C@H:19]3[CH2:18][S:17][C:16]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15]4)[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:21]2[CH2:20][C@@H:19]3[C@@:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([C:7]5[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=5)[CH:9]=4)([N:15]=[C:16]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[S:17][CH2:18]3)[CH2:22]2)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(-c4cccnc4F)c3)CNC[C@H]2CS1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(-c4cccnc4F)c3)CN(c3ccc(F)cc3)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl(±)-{(4aR*,7aS*)-7a-[3-(2-fluoropyridin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl}carbamate obtained in Preparation Example 18-(9) (72 mg) was mixed with 4-fluorobenzeneboronic acid (24.7 mg), copper (II)acetate (6.1 mg), triethylamine (93.2 μL, specific gravity: 0.73 g/cm3) and molecular sieves 4 A (powder) (57.6 mg) in dichloromethane (3 mL), and the mixture was stirred under a nitrogen atmosphere at room temperature for 11 hours and 30 minutes. 4-Fluorobenzeneboronic acid (23.5 mg) and copper (II) acetate (12 mg) were further added. The atmosphere was changed to an open system, followed by further stirring. After 23 hours and 45 minutes, the reaction suspension was purified by NH-silica gel column chromatography. The resulting product was purified again by pTLC to obtain the title compound (15 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:45])[S:35]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:37])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:45])[S:35]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)(=[O:36])=[O:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)S(=O)(=O)Cc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(N(C)S(=O)(=O)Cc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-6-(N-phenylmethanesulphonyl-methylamino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=O)[CH2:12][CH2:13][C:3]1=2.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[N:16][OH:17])[CH2:12][CH2:13][C:3]1=2
Reactant: Cn1c2c(c3ccccc31)C(=O)CC2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c2c(c3ccccc31)C(=NO)CC2
Yield: 92 %

Procedure:
3,4-Dihydro-4-methylcyclopent[b]indol-1(2H)-one (1.7 g) and hydroxylamine hydrochloride (1.925 g) in pyridine were heated at 60° for 18 h and cooled. The reaction mixture was evaporated in vacuo to a residue to which was added 8% sodium bicarbonate (150 ml). Extraction with ethyl acetate (300 ml) produced a suspension in the organic layer; this layer and associated solid was separated from the aqueous layer. The aqueous layer was re-extracted with ethyl acetate (250 ml). The combined organic extracts (and suspended solid) were evaporated to a residue, boiled with a mixture of ethanol (150 ml) and methanol (150 ml) and cooled to ca. 50°. The residue was adsorbed from this solution on to FCC silica and applied to an FCC column. Elution with ethyl acetate/3-10% methanol provided the title compound (1.69 g), m.p. 219°-224° (decomp.).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:7])([CH2:5][OH:6])[CH3:4].C1(C=CC(O)=CC=1)O.C[O-].[Na+].[C:19](OC)(=[O:23])[C:20]([CH3:22])=[CH2:21]>C1(C)C=CC=CC=1>[C:19]([O:1][CH2:2][C:3]([CH3:7])([CH3:4])[CH2:5][OH:6])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=C(C)C(=O)OC
Reactant: CC(C)(CO)CO
Agent: C[O-]
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCC(C)(C)CO
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
To a 2-L flask was charged neopentyl glycol (208.3 g, 2.0 moles), toluene (250 mL), hydroquinone (0.5 g) and sodium methoxide (25% in methanol, 8 g). The mixture was heated to 60-65° C. and methyl methacrylate (120 g, 1.2 moles) was added dropwise over 1 hour. The reaction was held at 70° C. for one hour under moderate vacuum to remove methanol and low boilers. Reaction was worked up by washing with 2×250 mL water and 1×100 mL saturated sodium chloride solution at 70° C. Toluene was evaporated and the resulting crude product (166 g) distilled to provide 3-hydroxy-2,2-dimethylpropyl methacrylate of 97% GC assay. To a 300 mL flask was charged 3-hydroxy-2,2-dimethylpropyl methacrylate (11.5 g, 0.064 moles), methylene chloride (20 g), DMAP (0.01 g), hydroquinone (0.05 g) and the mixture cooled to 0-5° C. To this was added dropwise diketene (5.4 g) at <3° C. Reaction allowed to warm to room temperature and stir overnight. Reaction cooled to 0-5° C. and additional diketene (2 g) added to complete reaction. Once reaction was complete, the dichloromethane was removed at 60° C. with house vacuum. Crude product distilled via Kugelrohr distillation to provide desired product of 92.6% assay with 1.6% starting material remaining (GC assay).