Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:32]=[C:33]([NH2:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:33]1[N:38]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:30][N:32]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)C(N)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Product: CC(C)(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
85 mg (0.20 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]-piperidine-3-carboxylic acid (Example 108A) and 35 mg (0.3 mmol) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 2. Yield: 61 mg (60% of theory).
Reaction SMILES: [N:1]1[C:8]([F:9])=[N:7][C:5](F)=[N:4][C:2]=1[F:3].[NH2:10][C:11]1[C:12]([OH:45])=[C:13]([N:21]=[N:22][C:23]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:24][NH:25][C:26]2[CH:31]=[C:30]([S:32]([OH:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:27]=2[C:36]([OH:38])=[O:37])[CH:14]=[C:15]([S:17]([OH:20])(=[O:19])=[O:18])[CH:16]=1.P([O-])([O-])(O)=O.[Na+].[Na+].[OH-].[Na+]>>[F:9][C:8]1[N:1]=[C:2]([F:3])[N:4]=[C:5]([NH:10][C:11]2[C:12]([OH:45])=[C:13]([N:21]=[N:22][C:23]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[N:24][NH:25][C:26]3[CH:31]=[C:30]([S:32]([OH:35])(=[O:33])=[O:34])[CH:29]=[CH:28][C:27]=3[C:36]([OH:38])=[O:37])[CH:14]=[C:15]([S:17]([OH:20])(=[O:19])=[O:18])[CH:16]=2)[N:7]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: Nc1cc(S(=O)(=O)O)cc(N=NC(=NNc2cc(S(=O)(=O)O)ccc2C(=O)O)c2ccccc2)c1O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(S(=O)(=O)O)cc1NN=C(N=Nc1cc(S(=O)(=O)O)cc(Nc2nc(F)nc(F)n2)c1O)c1ccccc1

Procedure:
14 parts of cyanuric fluoride are added dropwise to a neutral solution of 60 parts of the copper complex of 5-amino-3-[3-phenyl-5-(2-carboxy-5-sulfophenyl)-1-formazano]-4-hydroxy-benzenesulfonic acid and 5 parts of disodium hydrogen phosphate in 500 parts of at a temperature below 2° C., the pH being kept constant by addition of sodium hydroxide solution. A solution of 5-[4,6-difluoro-1,3,5-triazin-2-ylamino]-3-[3-phenyl-5-(2-carboxy-5-sulfophenyl)-1-formazano]4-hydroxybenzenesulfonic acid is obtained.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH:23]5[CH2:26][O:25][CH2:24]5)[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:27][C@H:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1>>[CH3:27][C@@H:28]1[NH:29][CH2:30][CH2:31][N:32]([C:2]2[N:7]=[C:6]([N:8]3[C:16]4[CH:15]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[C:21]([CH:23]6[CH2:26][O:25][CH2:24]6)[CH:22]=5)[N:13]=[CH:12][C:11]=4[CH:10]=[N:9]3)[CH:5]=[CH:4][CH:3]=2)[CH2:33]1
Reactant: C[C@H]1CNCCN1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncc(C5COC5)c4)cc32)n1
Product: C[C@H]1CN(c2cccc(-n3ncc4cnc(-c5cncc(C6COC6)c5)cc43)n2)CCN1
Yield: 24 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 1-(6-fluoropyridin-2-yl)-6-(5-(oxetan-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine and (S)-2-methylpiperazine, 113 was obtained as an off-white solid (26.3 mg, 24%). 1H NMR (400 MHz, DMSO) δ 9.39-9.28 (m, 1H), 9.20-9.11 (d, J=2.1 Hz, 1H), 9.11-9.02 (s, 1H), 8.72-8.61 (m, 2H), 8.60-8.53 (t, J=2.1 Hz, 1H), 7.84-7.67 (t, J=8.1 Hz, 1H), 7.32-7.18 (d, J=7.7 Hz, 1H), 6.87-6.76 (d, J=8.5 Hz, 1H), 5.08-4.98 (dd, J=8.2, 6.2 Hz, 2H), 4.76-4.68 (t, J=6.3 Hz, 2H), 4.48-4.35 (m, 1H), 4.28-4.13 (dd, J=20.9, 11.0 Hz, 2H), 3.06-2.88 (ddd, J=19.7, 14.7, 7.1 Hz, 2H), 2.87-2.73 (m, 2H), 2.60-2.53 (m, 1H), 2.39-2.31 (d, J=7.7 Hz, 1H), 1.09-0.99 (dd, J=14.9, 6.2 Hz, 3H); MS (ESI) m/z: 428.2 [M+H]+
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:29]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]=[N:27][N:26]=2)=[CH:15][CH:14]=1>>[CH2:1]([C:4]1[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:29]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:28]=[N:27][N:26]=3)=[CH:17][CH:18]=2)[C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1ccc(C=O)[nH]1
Product: CCCc1ccc(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 78 %

Procedure:
This compound was prepared using the same procedure as in Example 1. 3.9 g of 5-n-propyl-2-pyrrolaldehyde (0.031 moles) and 15 g of 4′-bromomethyl-2-(1-triphenylmethyltetrazol-5-yl)-biphenyl (0.031 moles) yield 15 g of product which are used in the subsequent step. Formula: C41H35N5O (m.w. 613.76). Yield 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][C:13]([CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1)=[O:14].[H][H]>C(OCC)(=O)C.[Ni]>[NH2:9][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:12][C:13]([CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1)=[O:14]
Reactant: [H][H]
Reactant: O=C(Nc1c(Cl)cc(O)cc1[N+](=O)[O-])C1CCOC1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cc(O)cc(Cl)c1NC(=O)C1CCOC1

Procedure:
0.60 g (2.09 mmol) N-(2-chloro-4-hydroxy-6-nitrophenyl)tetrahydrofuran-3-carboxamide were placed in 10 mL ethyl acetate and hydrogenated under a hydrogen atmosphere and with the addition of 0.20 g Raney nickel at RT and a hydrogen pressure of 3 bar until all the hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down i.vac.
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]#[N:23])[CH:18]=[CH:19][CH:20]=1.[C:31]([O:35][CH2:36]C)(=[O:34])[CH:32]=C>>[CH3:36][O:35][C:31](=[O:34])[CH2:32][C:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:22]#[N:23])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: C=CC(=O)OCC
Reactant: COc1cccc(C(C#N)Cc2ccccc2)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: COC(=O)CC(C#N)(Cc1ccccc1)c1cccc(OC)c1
Temperature: 25 °C

Procedure:
Benzyl trimethylammonium hydroxide (40% in MeOH, 100 μl, 0.22 mmol) was added to a stirred mixture of 2-(3-methoxyphenyl)-3-phenylpropanenitrile (1 g, 4.2 mmol) and ethyl acrylate (0.51 g, 5.1 mmol). After the initial exothermic reaction had subsided the mixture was refluxed for 4 h, cooled to room temperature and extracted three times with DCM. The combined organic layers were washed with water, dried, filtered and evaporated to obtain a pale yellow oil m(CR)=1.06 g that was purified by flash chromatography on 12 g SiO2 using 20% EtOAc in cyclohexane affording 594 mg of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].O.[N-:30]=[N+:31]=[N-:32].[Na+]>S(Cl)(Cl)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([N:30]=[N+:31]=[N-:32])=[O:6]
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: [N-]=[N+]=NC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (105 mg, 269 μmol) was dissolved in thionyl chloride (5 mL) and was stirred at 65° C. for 1 h. The reaction mixture was concentrated before it was dissolved in DCM (3 mL); to this was added tetrabutylammonium bromide (8 mg, 27 μmol), water (269 μl, 269 μmol), and sodium azide (21.0 mg, 323 μmol) at 0° C. before it was stirred for 2 h. The reaction mixture was diluted with 75 mL of DCM, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoyl azide. MS (ESI) m/z: Calculated: 415.1; Observed: 416.0 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>ClCCl>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22])[CH3:19]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 22.9 %

Procedure:
To a solution of 10.0 mg (0.0437 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole in 3.0 mL dichloromethane were added 6.2 mg (0.0874 mMol) ethyl isocyanate. The reaction was mixed for 48 hours and to it were then added 0.15 gm (0.0874 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the filtrate washed with 1N hydrochloric acid. The aqueous phase was washed several times with dichloromethane and was then made basic with dilute aqueous sodium hydroxide. The aqueous phase was then extracted several times with an equal volume of dichloromethane. These organic extracts were dried over sodium sulfate and then concentrated under reduced pressure to give 3.0 mg (23%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:10]2[C:13]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]>CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:10]2[C:13]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:14][CH2:15][CH2:16]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C#N)cc2C1C1(c2ccccn2)CCC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(CN)cc2C1C1(c2ccccn2)CCC1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
tert-Butyl 7-cyano-1-[1-(pyridin-2-yl)cyclobutyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (169 mg, 0.434 mmol) was dissolved in methanol (15 mL) under an atmosphere of nitrogen. Raney nickel (100 mg) was added and the reaction mixture stirred at room temperature under an atmosphere of hydrogen for 9 hours. The catalyst was removed by filtration. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography (silica, dichloromethane, methanol). Yield: 103 mg (0.262 mmol, 60%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH2:3][CH2:2]1>[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH:3]=[CH:2]1
Reactant: c1cnc2c(c1)SCC2
Agent: [Pd]
Product: c1cnc2ccsc2c1
Temperature: 25 °C

Procedure:
The dihydrothienopyridine (5; 3.0 g) and a catalytic amount of palladium on carbon (5% by weight, 0.15 g) were combined neat in a flask with a magnetic stir bar. A sand bath was equilibrated to 220°-250° C. and the reaction, stirring under a nitrogen atmosphere, was set in the sand bath until TLC examination indicated consumption of starting material (typically 20-40 min). The crude reaction mixture was allowed to cool to room temperature and was purified by flash chromatography in 5% ethanol/chloroform yielding 1.34 g (45%) of compound 4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([C:28](=[O:31])[CH2:29]Cl)[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[NH:33]1[CH:37]=[CH:36][CH:35]=[N:34]1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:28](=[O:31])[CH2:29][N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CCl)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)Cn2cccn2)c1

Procedure:
Prepared according to the procedure described in Example 37, Step 2, using the following starting materials: (2′-{[(2-chloro-acetyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and pyrazole.
Reaction SMILES: [CH3:1][C:2]([S:22]([CH3:25])(=[O:24])=[O:23])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[CH:10]=[N:9]1)[C:3](O)=[O:4].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH:49]1[O:54][NH2:55]>CS(C)=O.CCOC(C)=O.O>[CH3:1][C:2]([S:22]([CH3:25])(=[O:24])=[O:23])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([B:13]2[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14]2)[CH:10]=[N:9]1)[C:3]([NH:55][O:54][CH:49]1[CH2:50][CH2:51][CH2:52][CH2:53][O:48]1)=[O:4]
Reactant: NOC1CCCCO1
Reactant: CC1(C)OB(c2cnn(CCC(C)(C(=O)O)S(C)(=O)=O)c2)OC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)OB(c2cnn(CCC(C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To a solution of (2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanoic acid (7.0 g, 0.019 mol) in DMSO (300 mL) was added HOBT (3.24 g, 0.024 mol). The reaction solution was stirred at room temperature for 20 min, EDCI.HCl (4.6 g, 0.024 mol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (2.5 g, 0.021 mol) were added at room temperature and the reaction mixture was stirred at room temperature overnight. Water (200 mL) and EtOAc (200 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL×3). The organic layers were combined and washed with H2O (50 mL), brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel eluting with MeOH/DCM (0-10% gradient) to give a 2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanamide (4.7 g, 52%). LC-MS M+H+472.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C@H:14]([C:19]([O:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:17][CH:16]([CH3:18])[CH2:15][C@H:14]([NH:13][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:19]([O:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:20]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
4-Nitrobenzoyl chloride (0.60 g, 3.9 mmol) in DCM (2 ml) was added dropwise over 10 min to a solution of cyclopentyl L-leucinate (0.70 g, 3.5 mmol) and diisopropylethylamine (0.94 ml, 5.3 mmol) in DCM (10 ml) at −5° C. under an atmosphere of nitrogen. On completion of the addition, the reaction mixture was allowed to warm to RT and stirred for a further 30 min. The reaction mixture was poured on to sat. aq. NaHCO3 and the aqueous layer was extracted with DCM. The organic extracts were combined, washed with brine, dried over MgSO4 and evaporated under reduced pressure afford the title compound as an oily solid (1.2 g, 87%). m/z 347.1 [M+H]+.
Reaction SMILES: I[C:2]1[C:10]([N+]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.[OH:23][CH2:24][CH2:25][CH:26]=[CH:27]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.O.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>[OH:23][CH2:24][CH2:25][CH:26]=[CH:27][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[CH:15][C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5](=[O:14])[NH:6]2
Reactant: OCCC=CB(O)O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc[nH]c1C=C1C(=O)Nc2cccc(C=CCCO)c21

Procedure:
To a stirred solution of (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 2) in dimethoxyethane (5 mL) was added 4-hydroxy-1-butenyl-boronic acid (48 mg, 0.418 mmol) (from Example 68 above), tetrakis(triphenylphosphine)palladium(0) (39 mg, 0.034 mmol) (Aldrich) and 2M Na2CO3 solution in H2O (0.34 mL). The reaction mixture was stirred at 850C overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Hex:EtOAc=5:1) to provide 1,3-dihydro-4-(4-hydroxy-but-1-enyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-indol-2-one as a yellow solid. (Yield 21 mg, 50%).
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=[O:20].O>C(#N)C.O>[CH3:16][C:7]1([OH:20])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10](=[O:11])[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]1
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O
Solvent: CC#N
Product: CC1(O)C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Temperature: 0 °C

Procedure:
To a solution of 5.0 g of 2,6-di-t-butyl-p-cresol in 90 ml of acetonitrile/water (5/1) was added 10.5 g of bistrifluoroacetoxyiodobenzene with stirring at 0° C. After stirring for 30 minutes, 90 ml of water was added and the reaction solution was extracted three times with 50 ml of dichloromethane and washed four times with 60 ml of water. Organic layers were dried over anhydrous sodium sulfate, then concentrated under reduced pressure and the precipitating crystal was filtered to give a crude crystal, which was recrystallized from hexane to give 4-methyl-4-hydroxy-2,6-di-t-butylcyclohexa-2,5-diene-1-one as a pale yellow solid. The yield was 3.0 g (55%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH3:33])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[C:21]1[N:26]=[C:25]([CH2:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH:24]=[CH:23][CH:22]=1.[CH3:34][CH2:35][O:36][CH:37]=[C:38]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>O1CCCC1>[CH2:35]([O:36][CH:37]([CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH:27]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([C:14]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=2[CH3:33])[N:26]=1)[C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH3:34]
Reactant: CCCC(=O)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC(=O)C(c1cccc(-c2c(C)cc(C)cc2C)n1)C(OCC)C(C(=O)OCC)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl amine (0.16 mL, 1.13 mmol) was dissolved in tetrahydrofuran (2 mL). n-Butyllithium (2.5M, 0.45 mL, 1.13 mmol) was added at 0° C. and the reaction stirred for 0.5 h. The solution was cooled to −78° C. and 1-(6-mesityl-pyridin-2-yl)-pentan-2-one (0.29 g, 1.0 mmol) was added. After 0.5 h, ethyl ethoxymethylene malonate (0.21 mL, 1.0 mmol) was added and the reaction was warmed to room temperature. The solution was quenched with water, extracted with ethyl acetate, dried, and concentrated. Flash chromatography (10%-20% ethyl acetate/hexanes) gave the title compound as a mixture of two isomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](Cl)[N:9]2[N:13]=[CH:14][CH:15]=[C:8]2[N:7]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+]>[Pd].C(OCC)(=O)C.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]2[N:13]=[CH:14][CH:15]=[C:8]2[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)n2nccc2n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1ccn2nccc2n1
Yield: 77.9 %

Procedure:
A suspension of 7-chloro-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester (15.0 g), sodium acetate (6.54 g), and 10% palladium on carbon (665 mg) in ethyl acetate-ethanol (1-1.50 mL) was stirred under a hydrogen atmosphere. After the completion of the reaction, the reactant was filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, aqueous baking soda, and brine, dried with sodium sulfate, and concentrated in vacuo. The yellow residue was recrystallized to yield a light yellow needle crystal (9.9 g, 78%). mp:114-115° C.
Reaction SMILES: [I-].[Na+].Cl[Si](CC)(CC)CC.S(=O)(=O)(O)O.[CH3:16][O:17][C:18](=[O:37])[C@H:19]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[N:20]1[CH2:25][CH:24](O)[C:23]2[S:27][CH:28]=[CH:29][C:22]=2[CH2:21]1.C(=O)(O)[O-].[Na+]>C(#N)C.CN(C=O)C>[CH3:16][O:17][C:18]([C@@H:19]([N:20]1[CH2:21][C:22]2[CH:29]=[CH:28][S:27][C:23]=2[CH2:24][CH2:25]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])=[O:37]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1Cc2ccsc2C(O)C1
Agent: CC[Si](Cl)(CC)CC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of sodium iodide in acetonitrile, and in N,N,dimethylformamide is added chlorotriethylsilane. The mixture is stirred at room temperature under nitrogen for 1 hour. (αS,7RS)-methyl-α-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate bisulfate salt (30.2 g, 69.3 mmol) is added to the mixture at 0–5° C. After the addition is complete the mixture is warmed to room temperature and stirred for 12 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 oily product (20.1 g). The product obtained was found to be identical to the product obtained in Example 1 by 1H-NMR.