Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:31][CH2:32][CH3:33])[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([O:23]C(OC(C)(C)C)=O)[C:16](=O)[O:17]C(C)(C)C)[C:6]=2[C:5]([CH3:34])=[C:4]([CH3:35])[N:3]=1.Cl.O1CCOC[CH2:38]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:31][CH2:32][CH3:33])[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([OH:23])[C:16](=[O:17])[CH3:38])[C:6]=2[C:5]([CH3:34])=[C:4]([CH3:35])[N:3]=1
Reactant: C1COCCO1
Reactant: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCN(O)C(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The preparation of tert-butyl 4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl[(tert-butoxycarbonyl)oxy]carbamate is described in Parts A-F of Example 14. A solution of 4M hydrochloric acid in dioxane (1.8 mL, 7.2 mmol, 20 eq) is added to a solution of tert-butyl 4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl[(tert-butoxycarbonyl)oxy]carbamate (175 mg, 0.36 mmol, 1.0 eq) in dichloromethane (4 mL) and stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting crude material was dissolved in 1-methyl-2-pyrrolidinone (NMP) (4 mL) and cooled to −8° C. Triethylamine (0.500 mL, 10 eq) and acetic anhydride (0.034 mL, 0.36 mmol) were sequentially added dropwise to the reaction mixture and stirred for 1 hour. The crude reaction mixture was concentrated reduced pressure at 70° C. The residue was partitioned between saturated aqueous sodium carbonate and chloroform and the phases were separated. The aqueous phase was back-extracted with chloroform and the combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude material. The material was purified by column chromatography on a BIOTAGE HORIZON High-Performance Flash Chromatography instrument (silica gel, eluting with 10-50% CMA in chloroform) and trituration with chloroform/ethyl acetate. The resulting material was filtered and washed with ethyl acetate and dried under high vacuum to afford 0.025 g of N-[4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N-hydroxyacetamide as a white powder, mp 164.0-166.0° C. MS (APCI) m/z 334 (M)+; Anal. Calcd for C17H27N5O2.0.05CHCl3 C, 60.34; H, 8.03; N, 20.64. Found: C, 60.05; H, 7.97; N, 20.43.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:7][N:6]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[C:5]2=[O:24])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:29]>C1COCC1.CCOC(C)=O>[CH:1]1([N:4]2[C:8]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:7][N:6]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH2:29])=[O:21])=[CH:22][CH:23]=3)[C:5]2=[O:24])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(N2CC3(CCCCCC3)N(C3CC3)C2=O)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(N2CC3(CCCCCC3)N(C3CC3)C2=O)cc1
Reaction time: 2 h
Yield: 19.1 %

Procedure:
A solution of 76 mg (2.1 mmol) 4-(1-Cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid ethyl ester in 2 ml THF/Methanol 1.1 was treated with 0.5 ml of 1N LiOH. After stirring for 3 h the reaction mixture was acidified with 1N HCL, taken up in EtOAc and washed with water to give 65.5 mg of pure 4-(1-cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid MS (API): 327.5 (M−H). A solution of 47 mg (1.3 mmol) 4-(1-cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid and 27 mg (0.16 mmol) of 1,1-carbonyl diimidazole in 1 ml of THF was stirred under reflux for 1 h, then 32 mg (0.4 mmol) of Ammonium acetate was added and the stirring under reflux was continued for another 2 h. The reaction mixture was taken up in EtOAc and washed with 1N HCL and water. The crude product was crystallized in Ether/Heptan to give 25 mg of pure 4-(1-Cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzamide. MS (ESI): 328.4 (MH+).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[Cl:32][C:33]1[CH:41]=[C:40]2[C:36]([C:37]([Sn](CCCC)(CCCC)CCCC)=[N:38][NH:39]2)=[CH:35][CH:34]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:37]4[C:36]5[C:40](=[CH:41][C:33]([Cl:32])=[CH:34][CH:35]=5)[NH:39][N:38]=4)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (190 mg, 0.37 mmol) and 6-chloro-3-tributylstannyl-1H-indazole (crude form step 1, 619 mg, 0.70 mmol) were dissolved in DMF (3.4 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol) and copper(I) iodide (15 mg, 0.079 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath for 3 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-3% MeOH) then triturated with diethyl ether/ethyl acetate to afford 159 mg (73%) of 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light brown powder.
Reaction SMILES: CO[C@@H]1[C@@H](O[N+]([O-])=O)C[C@H](C(OC)=O)C1.[F:16][CH:17]1[CH:21]([O:22][N+:23]([O-:25])=[O:24])[CH2:20][CH:19]([C:26]([O:28]C)=[O:27])[CH2:18]1>>[F:16][CH:17]1[CH:21]([O:22][N+:23]([O-:25])=[O:24])[CH2:20][CH:19]([C:26]([OH:28])=[O:27])[CH2:18]1
Reactant: COC(=O)C1CC(F)C(O[N+](=O)[O-])C1
Agent: COC(=O)[C@@H]1C[C@H](OC)[C@@H](O[N+](=O)[O-])C1
Product: O=C(O)C1CC(F)C(O[N+](=O)[O-])C1

Procedure:
The title compound was prepared by following step D for example 1, except that the reagent (+)-methyl (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate was replaced by methyl (1RS,3RS,4RS)-3-fluoro-4-(nitrooxy)cyclopentanecarboxylate. 1H NMR (500 MHz, CDCl3) δ 2.13-2.52 (m, 1H), 2.30-2.52 (m, 2H), 2.61-2.69 (m, 1H), 3.16 (m, 1H), 5.10 (m, 1H), 5.47 (m, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH2:14])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:15](=S)=[S:16].C(O)C.[K+].[Br-]>O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]3[NH:13][C:15]([SH:16])=[N:14][C:9]=3[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCNCC2)cc1N
Reactant: S=C=S
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Sc1nc2cc(N3CCNCC3)ccc2[nH]1
Yield: 84.3 %

Procedure:
5-(Piperazin-1-yl)-2-mercapto-1H-benzimidazole (7.9 g, 85%) was prepared by an analogous procedure to that described in preparation 1 (step 5) using the diamine (8.0 g, 0.04 mol) (obtained in step 2 above), carbon disulfide (3.6 g, 0.048 mol), ethanol (40 nmL) and water (4 nmL). mp 260-261° C.; IR (KBr) 3350, 1498 cm-1 ; 1H NMR (DMSO-d6) δ 2.40 (s, 1H, SH), 3.00 (t, J=4.4 Hz, 4H, N(CH2)2), 3.50 (brs, 1H, NH), 4.42 (t, J=4.5 Hz, 4H, N(CH2)2), 6.68 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H) ; Mass (m/z) 234 (M+.).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:17][C:16]([CH2:19][NH:20]C(=O)C(F)(F)F)([CH3:18])[CH2:15]4)[CH:12]=3)[C:7](=[O:28])[C:6]([C:29]([OH:31])=[O:30])=[CH:5]2)[CH2:3][CH2:2]1.C(O)C>[OH-].[Na+]>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:17][C:16]([CH2:19][NH2:20])([CH3:18])[CH2:15]4)[CH:12]=3)[C:7](=[O:28])[C:6]([C:29]([OH:31])=[O:30])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1(CNC(=O)C(F)(F)F)CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(CN)CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
A solution of 1.05 g (2.38 mmoles) of 1-cyclopropyl-6-fluoro-7-(3-trifluoroacetamidomethyl)-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Example 30), in 15 ml of 1N sodium hydroxide and 6 ml of ethanol is heated to reflux for 3 hours, and evaporated under vacuum. Acetic acid is added, the product is filtered and washed with water, and 0.7 g (85%) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-aminomethyl-3-methyl-1-azetidinyl)-3-quinolinecarboxylic acid, melting at 274°-9° C., are obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1.[OH-].[Li+]>C1COCC1.CO>[F:14][C:2]([F:1])([F:13])[C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1csc(C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1csc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Ethyl 2-(trifluoromethyl)thiazole-4-carboxylate (400 mg, 1.176 mmol) was dissolved in THF/methanol mixture (9:1) and 1M lithium hydroxide (3.55 ml, 3.55 mmol) was added slowly. The reaction mixture was stirred at RT for 1 hour, pH was adjusted to 2 and the reaction mixture was extracted three times with ethyl acetate. Ethyl acetate phases were combined, dried and evaporated to dryness. Yield 93%. m/z [197.1+1]
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:34](#[N:36])[CH3:35]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:35]4[CH:34]=[N:36][C:2]([NH2:7])=[N:3][CH:4]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[N:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1

Procedure:
5-Chloro-2-((4-methylsulfonylpiperazin-1-yl)methyl)-7-morpholinothiazolo[5,4-d]pyrimidine, 5-pyrimidine-2-amine boronic acid (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate (3 eq) and acetonitrile. The solution was microwaved at 130° C. for 8 minutes. The solvents were removed and the resulting residue was purified by reverse phase silica gel chromatography to give 122.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)[C:3]=1[NH2:35].S1C=CC=C1.C([O-])(=O)C.[K+].[H][H]>C(O)C.[Pd].CO>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:22]2[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=[C:18]2[NH:17][CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:4]3[C:3]([NH2:35])=[CH:2][N:7]=[CH:6][N:5]=3)[CH2:12][CH2:13]2)=[CH:29][CH:28]=1
Reactant: Nc1c(Cl)ncnc1NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: c1ccsc1
Solvent: CO
Product: Nc1cncnc1NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Yield: 72.4 %

Procedure:
A mixture of 1.5 parts of 6-chloro-N4 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-4,5-pyrimidinediamine, 3 parts of a solution of thiophene in ethanol 4%, 1 part of potassium acetate and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 1 part of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The solid residue was taken up in water. The solution was treated with ammonia. The product was extracted with trichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone, yielding 1 part (72.4%) of N4 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-4,5-pyrimidinediamine; mp. 207.7° C. (intermediate 165).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16](C)[CH:15]=[CH:14][C:13]=1[C:19]1C=NN(C)C=1)=[O:11].CC1C=CC=C([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)C=1C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19])=[O:11]
Reactant: Cc1cccc(-n2nccn2)c1C(=O)O
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1cccc(-n2nccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 2-methyl-6-(2H-1,2,3-triazol-2-yl)benzoic acid. ESI-MS m/z: 314 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28]C(=O)C)[CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][C:14]2=[O:15])[CH2:9][CH2:8]1)=[O:6].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:8][CH2:9][CH:10]([N:13]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][C:14]2=[O:15])[CH2:11][CH2:12]1)=[O:6]
Reactant: COc1cc(OC(C)=O)ccc1C(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(O)ccc1C(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
1-[1-(2-Methoxy-4-acetyloxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.4 g) and sodium hydroxide (0.5 g) are dissolved in methanol (20 ml) and the mixture is stirred at room temperature for 1 hour. The solvent is concentrated and water is added to the residue, then the mixture is extracted with chloroform, dried with magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to give 1-[1-(2-methoxy-4-hydroxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.3 g).
Reaction SMILES: [O:1]1CCOC[CH2:2]1.[C:7]([O:11][C:12](=[O:38])[NH:13][C:14]1[C:15]([O:36][CH3:37])=[N:16][N:17]2[C:21]([C:22]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH2:30][O:31][CH3:32])=[CH:24][C:23]=3[O:33][CH3:34])=[C:20](Br)[S:19][C:18]=12)([CH3:10])([CH3:9])[CH3:8].C[Zn]C>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CCCCCCC.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:38])[NH:13][C:14]1[C:15]([O:36][CH3:37])=[N:16][N:17]2[C:21]([C:22]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH2:30][O:31][CH3:32])=[CH:24][C:23]=3[O:33][CH3:34])=[C:20]([O:1][CH3:2])[S:19][C:18]=12)([CH3:10])([CH3:9])[CH3:8]
Reactant: COCc1cc(OC)c(-c2c(Br)sc3c(NC(=O)OC(C)(C)C)c(OC)nn23)c(OC)c1
Reactant: C1COCCO1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C[Zn]C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COCc1cc(OC)c(-c2c(OC)sc3c(NC(=O)OC(C)(C)C)c(OC)nn23)c(OC)c1
Temperature: 60 °C

Procedure:
To a dioxane (15 mL) solution of tert-butyl{2-bromo-3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxypyrazolo[5,1-b][1,3]thiazol-7-yl}carbamate (323 mg, 0.612 mmol) were added 2M dimethyl zinc (0.612 mL, 1.22 mmol) and bis(tri-tert-butylphosphine)palladium(0) (15.6 mg, 0.031 mmol), and the mixture was heated at 60° C. for one hour. After the reaction was completed, the solvent was directly distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=1/1) to obtain the title compound (205 mg, 0.442 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][NH2:18])[CH3:2].C(N(CC)CC)C.[C:27]([C:29]1[CH:30]=[CH:31][C:32]([O:39][CH3:40])=[C:33]([S:35](Cl)(=[O:37])=[O:36])[CH:34]=1)#[N:28]>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][NH:18][S:35]([C:33]1[CH:34]=[C:29]([C:27]#[N:28])[CH:30]=[CH:31][C:32]=1[O:39][CH3:40])(=[O:37])=[O:36])[CH3:2]
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCN
Reactant: COc1ccc(C#N)cc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.5 %

Procedure:
To a stirred solution of 326 mg of ethyl[2-(2-amino-ethyl)-5-isopropylphenoxy]acetate hydorochloride and 0.452 mL of triethylamine in a mixture of 10 mL of tetrahydrofuran and 5 mL of water was added 238 mg of 5-cyano-2-methoxybenzene-sulfonyl chloride under ice-cooling, and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added 30 mL of water, and the mixture was extracted with 120 mL of ethyl acetate. The organic layer was washed with 100 mL of water, and 100 mL of brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 343 mg of ethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]3[C:15](=[O:18])[NH:16][CH2:17][C:13]=3[CH:12]=[C:11]([NH:19][C@@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]3[NH:26]C(=O)OC(C)(C)C)[N:10]=2)=[CH:4][C:3]=1[CH3:34].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:11]1[N:10]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:34])[CH:4]=2)[C:14]2[C:15](=[O:18])[NH:16][CH2:17][C:13]=2[CH:12]=1
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)cc3c2C(=O)NC3)ccc1F
Yield: 2.6 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(4-(4-fluoro-3-methylphenylamino)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (50.0 mg, 0.106 mmol) and TFA (1 mL, 12.98 mmol) in DCM (0.5 mL) was stirred at RT for 1 hr. The resulting mixture was concentrated and the residue was purified by preparative HPLC to give the title compound as a white solid (1 mg, 2.54%). 1H NMR (500 MHz, CD3OD) δ ppm 1.14-1.95 (m, 8 H), 2.28 (s, 3 H), 3.73 (br s, 1 H), 4.30 (s, 2H), 4.38 (s, 1 H), 6.17 (s, 1 H), 7.00 (t, J=9.03 Hz, 1 H), 7.41-7.54 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:31])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.Cl[CH:34]([F:36])[F:35]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:34]([F:36])[F:35])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: FC(F)Cl
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(OC(F)(F)F)cc1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared by the method of Preparation 10c using [2-ethyl-8-fluoro-4-oxo-3-(4-trifluoromethoxybenzyl)-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[CH3:8][O:9][C:10](=[O:29])[C@H:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[N:12]1[CH2:17][CH:16](O)[C:15]2[S:19][CH:20]=[CH:21][C:14]=2[CH2:13]1.C(=O)(O)[O-].[Na+]>C(#N)C.C1(C)C=CC=CC=1.O>[CH3:8][O:9][C:10]([C@@H:11]([N:12]1[CH2:13][C:14]2[CH:21]=[CH:20][S:19][C:15]=2[CH2:16][CH2:17]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])=[O:29]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1Cc2ccsc2C(O)C1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of sodium iodide in acetonitrile is added chlorotrimethylsilane. The mixture is stirred at room temperature under nitrogen for 30 minutes. A solution of (αS,7RS)-methyl-α-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate (9) (23.4 g, 69.3 mmol) in toluene and acetonitrile is added to the mixture at 0–5° C. After the addition is complete the mixture is warmed to room temperature and stirred for 2 hours. Water is then added to the mixture at 0–5° C. The mixture is then warmed again to room temperature and stirred for an additional 4 hours. The reaction mixture is then basified with aqueous sodium bicarbonate solution. The organic layer is then washed with aqueous sodium thiosulfate solution, followed by water, then brine. The organic layer is then dried, filtered and concentrated to provide clopidogrel free base as an oil product (21.4 g). 1H-NMR (CDCl3, ppm) 7.7 (1H, dd), 7.35 (1H, m), 7.2–7.35 (2H, m), 7.2 (1H, d), 6.68 (1H, dd), 4.95 (1H, s) 3.5–4.0 (2H, m), 3.75 (3H, s), 2.9 (4H, s); chiral HPLC 99:1 enantiomeric ratio.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[I:25]I>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([I:25])=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cn[nH]c3c2)CC1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(I)n[nH]c3c2)CC1
Reaction time: 16 h
Yield: 38 %

Procedure:
A stirred solution of 6-[4-(t-butoxycarbonyl)piperazin-1-yl]-1H-indazole (7.20 g, 23.8 mmol) in N,N-dimethylformamide at 0° C. is treated with powdered potassium hydroxide (5.40 g, 95.4 mmol) followed by the dropwise addition of a solution of iodine (10.9 g, 42.9 mmol) in N,N-dimethylformamide, stirred at ambient temperatures for 16 h, diluted with ethyl acetate and quenched with 10% aqueous sodium metabisulfite solution. The phases are separated. The aqueous phase is extracted with ethyl acetate. The extracts are combined with the organic phase, washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude material is purified by flash chromatography (silica gel, 30:70 ethyl acetate/hexanes) to afford the title compound as a yellow solid, 3.4 g (38% yield) identified by NMR and mass spectral analyses.