Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([S:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH:6]([CH3:8])[CH3:7])C>CO.[OH-].[Na+]>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([S:9][CH:5]([CH:6]([CH3:8])[CH3:7])[C:4]([OH:18])=[O:3])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(Sc1ccc(OC)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(SC(C(=O)O)C(C)C)cc1

Procedure:
2-(4Methoxy-phenylsulfanyl)-3-methyl-butyric acid was prepared starting from 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester (5.8 g, 21.6 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 1. Yield 5.0 g, 99%. Low melting solid. MS: 242 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[O:7][CH2:8][CH:9]([N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])[CH:5]2[O:4][CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:28][S:29]([O:1][CH:2]1[CH2:3][O:4][CH:5]2[CH:9]([N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])[CH2:8][O:7][CH:6]12)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1C1COC2C(O)COC21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
Under a N2 atmosphere, to a solution of 2-(6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)isoindoline-1,3-dione (2.35 g, 8.54 mmol) in dichloromethane (40 mL) were added triethylamine (1.30 g, 12.8 mmol) and N,N-dimethylpyridin-4-amine (209.2 mg, 1.7 mmol) and the mixture was cooled to 0° C. and then methanesulfonyl chloride (0.8 mL, 10.0 mmol) was added to the mixture. The resulting mixture was stirred at 0° C. for 30 min, then moved to room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with 1M HCl (100 mL), water (100 mL) and brine (100 mL). The separated organic phase was dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/200) to give the title compound as a white solid (2.35 g, 77.9%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:12][OH:13])[CH2:2][CH:3]=[CH2:4].[CH2:14]([O:17][C:18]1([CH3:47])[CH2:23][CH2:22][N:21]([C:24]2[N:29]3[N:30]=[C:31]([CH2:33]I)[CH:32]=[C:28]3[N:27]=[C:26]([CH3:35])[C:25]=2[C@H:36]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:20][CH2:19]1)[CH:15]=[CH2:16].[H-].[Na+]>CN(C=O)C>[CH2:14]([O:17][C:18]1([CH3:47])[CH2:19][CH2:20][N:21]([C:24]2[N:29]3[N:30]=[C:31]([CH2:33][O:13][CH2:12][C:6]4[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=4[CH2:1][CH2:2][CH:3]=[CH2:4])[CH:32]=[C:28]3[N:27]=[C:26]([CH3:35])[C:25]=2[C@H:36]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:22][CH2:23]1)[CH:15]=[CH2:16]
Reactant: C=CCCc1cc(F)ccc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCc1cc(F)ccc1COCc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
A mixture of (2-(but-3-en-1-yl)-4-fluorophenyl)methanol (43.8 mg, 0.243 mmol) and (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (142 mg, 0.243 mmol) in DMF (5 mL) at 0° C. was added NaH (9.72 mg, 0.243 mmol) and the reaction was stirred at 0° C. for 3 h. It was then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 20% EtOAc/hexane to isolate (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-(but-3-en-1-yl)-4-fluorobenzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.079 mmol, 32.3% yield) as an oil. LCMS (M+1)=637.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.Cl[CH:10]([C:15](=O)[CH2:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11]([C:10]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:8][C:15]=1[CH2:16][CH3:17])=[O:12]
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: Nc1nccnc1Cl
Product: CCc1nc2c(Cl)nccn2c1C(=O)OC
Temperature: 170 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
3-Chloro-2-aminopyrazine (2.1 g, 16.2 mmol) and methyl 2-chloro-3-oxopentanoate (6.7 mL, 48.6 mmol) were mixed, and heated under stirring at 170° C. for 2 hours. After being allowed to cool, the unnecessary materials were filtered off and washed with ethyl acetate, and then filtrates were combined and evaporated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (0.99 g) as white crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](=O)[CH2:13]Br)[N:7]=1)=[O:5])C.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[C:22]([NH2:24])=[S:23])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:22]2[S:23][CH:13]=[C:12]([C:8]3[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:11]=[CH:10][N:9]=3)[N:24]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[CH3:17]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1ccnc(C(=O)CBr)n1
Product: CCOc1ccc(-c2nc(-c3nccc(C(=O)O)n3)cs2)cc1OCC

Procedure:
4-Ethoxycarbonyl-2-(α-bromoacetyl)pyrimidine and 3,4-diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(4-carboxy-2-pyrimidyl)thiazole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([NH2:8])[CH:7]=1.[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([NH:8][C:20](=[O:21])[CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1N
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1NC(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A mixture of 5-chloro-2-methyl-4-nitrophenylamine (0.475 g, 2.55 mmol) and phenylacetyl chloride (0.394 g, 2.55 mmol) in toluene (10 mL) was heated under reflux for 4 h, then cooled to room temperature. A solid crystallized from the reaction mixture upon cooling, and was isolated by vacuum filtration and dried to provide the title compound as a yellow solid (0.330 g, 43%).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1>O>[F:1][CH:2]([F:5])[CH2:3][NH:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([Cl:6])=[CH:8][CH:9]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: FC(F)CCl
Solvent: O
Product: FC(F)CNCc1ccc(Cl)cc1
Yield: 61 %

Procedure:
An amount of 22.4 g (207 mmol) of 2,2-difluoro-1-chloroethane and 10 g (69 mmol) of 4-chlorobenzylamine are heated in an autoclave at an internal temperature of 120° C. for 16 hours. Subsequently, 50 g of water are added and the aqueous phase is separated. The aqueous phase is again extracted with 2,2-difluoro-1-chloroethane and the combined organic phases are distilled as described in Example 1.1. Here also, the 4-chlorobenzylamine hydrochloride which is present in the aqueous phase can be converted back into free 4-chlorobenzylamine by addition of sodium hydroxide solution. After distillation, 4.25 g of 2,2-difluoro-N-(4-chlorobenzyl)ethanamine are obtained, which corresponds to a yield of 61%, based on reacted 4-chlorobenzylamine
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[NH3:27].C(OCC)C>O1CCOCC1>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH2:27])=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)cc2)s1
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(N)(=O)=O)cc2)s1

Procedure:
4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (3a) (3.8 g, 11.5 mmol) is dissolved in dioxane (50 ml) with stirring. Sodium carbonate (2.45 g, 23 mmol) is added followed by a solution of ammonia in dioxane (50 ml, 0.75 M). After stirring for 2 hours at room temperature diethyl ether (120 ml) is added and the solid precipitate is removed by filtration. The solid is stirred in tetrahydrofuran (200 ml) and the mixture is then filtered through Celite™ filter material to remove inorganic material. Removal of the solvent affords N-[4-methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH:13]=[C:12]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[OH-].[Na+]>CO>[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][O:16][C:14]1[CH:15]=[C:10]([N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:6][C:7]([OH:9])=[O:8])[CH:11]=[C:12]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:13]=1)([OH:23])=[O:22]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(N(CC(=O)O)CC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)O)cc(N(CC(=O)O)CC(=O)O)c1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
A solution of 2.0 g (3.3 mmol) of N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]glycine and 2.8 ml (16.5 mmol) of 6N NaOH in 100 ml of methanol was stirred at reflux under argon for 16 hours. After cooling to room temperature, the precipitated sodium salt was removed by filtration, dissolved in 300 ml of water and the mixture was acidified with 4 ml of 6NHCl. The product was extracted with ethyl acetate and the dried extract wasconcentrated at reduced pressure to a solid which was recrystallized from acetone-hexane to give 1.8 g (92% yield, mp 126°-128°) of N-[3-(4-carboxybutoxy)-5-(octadecyloxy)phenyl]-N-(carboxymethyl)glycine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Br)=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH:13]([OH:15])[CH3:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:11][CH2:12][CH:13]([OH:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(O)CN
Reactant: Clc1ccc(CCBr)cc1
Product: CC(O)CNCCc1ccc(Cl)cc1

Procedure:
In Stage 2, 2-(4′-chlorophenyl)ethyl bromide was reacted with 1-amino-2-propanol to form the secondary amine, 1-[2-(4-chloro-phenyl)-ethylamino]-propan-2-ol. 1-[2-(4-Chloro-phenyl)-ethylamino]-propan-2-ol was separated from excess 1-amino-2-propanol and water soluble byproducts by extraction into toluene and removing water from the toluene containing 1-[2-(4-Chloro-phenyl)-ethylamino]-propan-2-ol by azetropic distillation and can be used directly into the next step without further purification and without isolation.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([CH3:36])([CH3:35])[CH2:6][C:7]1[N:8]=[C:9]([C:18](=[O:34])[CH:19]([F:33])[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1>O1CCCC1>[CH3:4][C:5]([CH3:36])([CH3:35])[CH2:6][C:7]1[N:8]=[C:9]([C:18]([OH:34])([CH3:1])[CH:19]([F:33])[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[N:10]([S:12]([N:15]([CH3:16])[CH3:17])(=[O:14])=[O:13])[CH:11]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)C(F)c1ccc(-c2ccc(F)cn2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)C(F)c1ccc(-c2ccc(F)cn2)cc1
Temperature: 25 °C

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (ca. 15 μL, 0.04 mmol) was added to a 0° C. solution of 4-(2,2-dimethylpropyl)-2-{fluoro[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (10 mg, 0.02 mmol) in tetrahydrofuran (3 mL). After warming slowly to ambient temperature, the reaction was quenched with a few drops of water and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-{2-fluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20].C(=O)(O)O>ClCCl>[C:18]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)c1csc(N)n1
Agent: O=C(O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1csc(NC(=O)C(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold mixture of ethyl 2-amino-1,3-thiazole-4-carboxylate (2 g) prepared in a similar manner according to Step 1 of the following Production Example 7, pyridine (1.3 ml) and dichloromethane (20 ml) was added isobutyryl chloride (0.91 ml) and stirred for 30 minutes. To the mixture was added saturated aqueous hydrogen bicarbonate (30 ml), and the organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed with ethyl acetate to give ethyl 2-(isobutyrylamino)-1,3-thiazole-4-carboxylate (1.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH3:37])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Reactant: C=O
Product: CN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-fluoro-1-methylpiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 273) and formaldehyde following General Procedure R.
Reaction SMILES: Cl.C([O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH:14]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C=C.[H][H]>C(O)C.[Pt](=O)=O>[ClH:12].[C:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][CH:14]([C:7]2[CH:8]=[C:9]([Cl:13])[CH:10]=[C:11]([Cl:12])[C:6]=2[OH:5])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:22][CH:23]=1)(=[NH:28])[NH2:29]
Reactant: C=CCOc1c(Cl)cc(Cl)cc1C(Nc1ccc(C(=N)N)cc1)C(=O)OCC
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(Nc1ccc(C(=N)N)cc1)c1cc(Cl)cc(Cl)c1O
Yield: 197.2 %

Procedure:
A solution of 300 mg of ethyl (RS)-(2-allyloxy-3,5-dichloro-phenyl)-(4-carbamimidoyl-phenylamino)-acetate hydrochloride (1:1) (see Example 293.3) in 5 ml of ethanol was treated with hydrogen in ther presence of a catalytic amount of platinum dioxide for 45 minutes while stirring. The reaction mixture was suction filtered over Speedex. The filtrate was concentrated and gave 270 mg of ethyl (RS)-(4-carbamimidoyl-phenylamino)-(3,5-dichloro-2-hydroxy-phenyl)-acetate hydrochloride (1:1); MS (ISP) m/z 382/384 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:16].[NH3:17]>C(O)C.C(Cl)(Cl)Cl>[ClH:16].[CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]([NH2:17])=[NH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: N#Cc1cccc(Cc2ccccc2)c1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: N=C(N)c1cccc(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
3-Benzylbenzonitrile (83.45 g.; prepared as described by C. R. Hauser, W. Q. Beard and F. N. Jones, J. Org. Chem., 1961, 26, 4790) was dissolved in a mixture of anhydrous ethanol (52 ml.) and anhydrous chloroform (390 ml.). The solution was saturated with anhydrous hydrogen chloride at 0° C. and kept at 0° C. for 3 days. The solvent was evaporated in vacuo and the residue triturated with anhydrous diethyl ether. The solid obtained (78 g.) was treated with saturated anhydrous ethanolic ammonia (600 ml.), and the mixture maintained at 0° C. for 3 days. A small amount of ammonium chloride was filtered off and the filtrate was evaporated in vacuo. The gummy residue was triturated with anhydrous diethyl ether to give a solid, which was filtered off and extracted with hot water. The extract was filtered and evaporated to dryness in vacuo. The resulting residue was recrystallised from a mixture of ethanol and diethyl ether (with the aid of charcoal) to give 3-benzylbenzamidine hydrochloride (30.1 g.), m.p. 170°-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:13])=[O:12])[C@@H:7]([C:25](=[O:35])[NH:26][O:27]CC2C=CC=CC=2)[CH2:6]1)=[O:4].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)(=[O:13])=[O:12])[C@@H:7]([C:25](=[O:35])[NH:26][OH:27])[CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1CCN(S(=O)(=O)CCCOc2ccc(F)cc2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1CCN(S(=O)(=O)CCCOc2ccc(F)cc2)[C@@H](C(=O)NO)C1
Yield: 98.9 %

Procedure:
A mixture of (2R,4R)-2-benzyloxycarbamoyl-1-[3-(4-fluorophenoxy)-propane-1-sulfonyl]-piperidine-4-carboxylic acid methyl ester (800 mg, 1.57 mmol) and 200 mg of 5% palladium on barium sulfate in 15 mL of methanol was shaken in a Parr apparatus under a 40 psi hydrogen gas atmosphere for 2 hours. The catalyst was removed by passage of the mixture through a 0.45 μm nylon filter and the filtrate was concentrated to give 650 mg of (2R,4R)-1-[3-(4-fluorophenoxy)-propane-1-sulfonyl]-2-hydroxycarbamoyl-piperidine-4-carboxylic acid methyl ester as a white foam: MS (atmospheric pressure chemical ionization) acidic mode, 417 (M−1); 1H NMR (400 MHz, CDCl3) δ 6.94-6.97 (m, 2 H), 6.80-6.83 (m, 2 H), 4.56 (s, 1 H), 4.03 (t, 2 H, J=5.3 Hz), 3.83 (d, 1 H, J=12.9 Hz), 3.68 (s, 3 H), 3.15-3.28 (m, 3 H), 2.76 (t, 1 H, J=11.5 Hz), 2.54 (d, 1 H, J=13.5 Hz), 2.26 (d, 2 H, J=5.9 Hz), 2.02 (m, 1 H, J=13.0 Hz), 1.73-1.78 (m, 1 H), 1.56-1.62 (m, 1 H).
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[N:10][C:9]=2[O:14]C)=[CH:5][CH:4]=1)[CH3:2].C(Cl)(Cl)Cl>CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[C:9](=[O:14])[NH:10][N:11]=[CH:12][CH:13]=2)=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCc1ccc(Cc2ccnnc2OC)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Cc2ccn[nH]c2=O)cc1
Temperature: 60 °C
Reaction time: 25 h
Yield: 68.7 %

Procedure:
To a mixture of 4-(4-ethylbenzyl)-3-methoxy-pyridazine (2.11 g, 9.24 mmol) and chloroform (20 ml), trimethylsilyliodo (1.45 ml, 10.2 mmol) was added and this reaction mixture was stirred at 60° C. for 25 hours. After cooling to room temperature, the reaction mixture was diluted with methanol and concentrated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the titled compound (1.36 g, 69%) as a yellow powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].[Br:16]Br>C(O)(=O)C>[Br:16][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[N:6][CH:7]=[CH:8][CH:9]=2
Reactant: BrBr
Reactant: c1cnc2cccnc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1cnc2cccnc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
To a stirred mixture of 1,5-naphthyridine (C-1) (50.0 g, 384 mmol, 1.0 eq) and sodium acetate (62.9 g, 768 mmol, 2.0 eq) in acetic acid (300 mL) at 80° C., a solution of bromine (67.5 g, 422 mmol, 1.1 eq) in acetic acid (80 mL) was added dropwise while keeping the reaction temperature at 80° C. to 90° C. After stirring for 2 h at 80° C., the reaction was complete based on TLC analysis. The resulting mixture was cooled to RT and then filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0-30% ethyl acetate-petroether) to afford the desired product 3-bromo-1,5-naphthyridine (C-2) (36.5 g, 45% yield) as a pale yellow solid. 1H NMR (300 MHz, CDCl3-d6) δ: 8.97 (m, 2H), 8.57 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 7.65 (m, 1H); ESI-MS m/z: 208.96 [M+H]+.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([N:20]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C@@H:22]3[CH2:29][NH:30][CH2:31][CH2:32][C@@H:21]23)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:1]([CH2:9][CH2:10][C:11]([N:30]1[CH2:31][CH2:32][C@H:21]2[N:20]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C@@H:22]2[CH2:29]1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(N2c3ccccc3[C@@H]3CNCC[C@H]32)cc1
Reactant: O=C(O)CCC(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(CCC(=O)N1CC[C@@H]2[C@@H](C1)c1ccccc1N2c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To the suspension arising from the admixture of 865 mg. (4.20 mmole) of dicyclohexylcarboiimide and 748 mg. (4.20 mmole) of 3-benzoylpropionic acid in 30 ml. of dichloromethane at 0° C. was added 1.0 g. (4.0 mmole) of dl-trans-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole in 10 ml. of the same solvent. The resulting mixture was stirred and allowed to warm to room temperature over 2 hours. After cooling again to 0° C. the reaction mixture was filtered, washed with dichloromethane and the filtrates evaporated to obtain a residue of dl-trans-2-[(3-benzoyl)propionyl]-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole which was used without purification in the next step.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=1[CH3:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[CH3:13][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:15]=[C:16]([NH2:18])[S:17][CH:2]=2)=[C:6]([CH3:14])[CH:7]=1
Reactant: NC(N)=S
Reactant: COc1cc(C)c(C(=O)CBr)c(C)c1
Solvent: CCO
Product: COc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 74.9 %

Procedure:
A mixture of 2-bromo-1-(4-methoxy-2,6-dimethylphenyl)ethanone (8.65 g, 33.6 mmol) and thiourea (2.56 g, 33.6 mmol) in 95% EtOH (48 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (50 mL). The solids were filtered and dried under vacuum to give 4-(4-methoxy-2,6-dimethylphenyl)thiazol-2-amine (5.9 g) as white solids in 66% yield: 1H NMR (500 MHz, CDCl3) δ 6.61 (s, 2 H), 6.27(s, 1 H), 4.91 (bs, 2 H), 3.79 (s, 3 H), 2.15 (s, 6 H).