Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12](=[O:29])[CH2:13][N:14]([C:24](=[O:28])[C@H:25]([CH3:27])[NH2:26])[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)([CH3:10])([CH3:9])[CH3:8].C([O-])(=O)C.[Na+].C(O)(=O)C.O=[C:40]([CH2:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(O)C.[Ni]>[C:7]([O:11][C:12](=[O:29])[CH2:13][N:14]([C:24](=[O:28])[C@H:25]([CH3:27])[NH:26][CH:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)([CH3:8])([CH3:10])[CH3:9]
Reactant: C[C@H](N)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Yield: 91.8 %

Procedure:
L-Alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate (21 g) is dissolved in 200 ml of ethanol. To the solution 4.1 g of sodium acetate, 10 ml of acetic acid, 25 g of ethyl 2-oxo-4-phenylbutyrate and 25 g of molecular sieve 3A are added in sequence. Thereafter, 30 g of Raney nickel suspended in 100 ml of ethanol is added with ethanol, and catalytic reduction is carried out under ordinary temperature and ordinary pressure. When the absorption of hydrogen has cased, the supernatant is separated by decantation, and the precipitate is washed two or three times with ethanol. The supernatant and the washings are combined and concentrated under reduced pressure. The residue is dissolved in 500 ml of ethyl acetate, and the solution is washed with aqueous sodium hydrogen carbonate and filtered with 30 g of diatomaceous earth. The ethyl acetate layer is separated from the filtrate, washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to give 24 g of N-(1-ethoxycarbonyl- 3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine tert-butyl ester as a slightly yellow, viscous oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=2)[NH:12][C:11]=1[C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pt](=O)=O>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=2)[NH:12][C:11]=1[C:22]1[CH:23]=[C:24]([CH3:29])[CH:25]=[C:26]([CH3:28])[CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCNC(=O)OC(C)(C)C)c1
Agent: O=[Pt]=O
Solvent: CO
Product: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCNC(=O)OC(C)(C)C)c1
Reaction time: 4 h
Yield: 91.2 %

Procedure:
{2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]-ethyl}-carbamic acid tert-butyl ester (0.4 g) was dissolved in methanol (25 mL) and platinum (IV) oxide (40 mg) added. The mixture was placed on a Parr hydrogenation apparatus and hydrogenated at 45psi for 4 h; by this time the starting material had been consumed and converted into one product. The catalyst was removed by filtration and the filtrates evaporated under reduced pressure using a rotary evaporator and the final traces of solvent removed by using a high vacuum overnight. The amine (338 mg) was obtained as a powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](=O)[CH3:8].C([O-])(=O)C.[NH4+:14]>CO.C([BH3-])#N.[Na+]>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[CH3:8]
Reactant: [NH4+]
Reactant: CC(=O)c1cnccn1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cnccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 749 %

Procedure:
To a solution of 1-pyrazin-2-yl-ethanone (2.0 g, 15.85 mmol) and ammonium acetate (19.337 g, 158.5 mmol) in methanol (50 mL) was added sodium cyanoborohydride (0.7 g, 11.1 mmol) in one portion. The reaction mixture was stirred overnight at room temperature. After removal of methanol, water (20 mL) was added to the residue and the resulting solution was basified by addition of sodium hydroxide to pH=13. The aqueous solution was extracted with dicholromethane and the combined organic phase was dried over sodium sulfate. Removal of the solvent under reduced pressure afforded 14.62 g of 1-pyrazin-2-yl-ethylamine, yield: 75%. MS (M+H)=124.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([CH2:48][NH:49][S:50]([CH2:53][CH:54]([CH3:56])[CH3:55])(=[O:52])=[O:51])=[N:33][C:34]=2[NH:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CO>[CH2:27]([NH:26][C:24]([C@@H:13]1[C@@H:14]([OH:15])[C@@H:10]([OH:9])[C@H:11]([N:29]2[CH:37]=[N:36][C:35]3[C:30]2=[N:31][C:32]([CH2:48][NH:49][S:50]([CH2:53][CH:54]([CH3:55])[CH3:56])(=[O:52])=[O:51])=[N:33][C:34]=3[NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[O:12]1)=[O:25])[CH3:28]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4ccc(OC)cc4)nc(CNS(=O)(=O)CC(C)C)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4ccc(OC)cc4)nc(CNS(=O)(=O)CC(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.7 %

Procedure:
A solution of (2R,3R,4S,5S)-4-(benzoyloxy)-5-[(ethylamino)carbonyl]-2-{2-{[(isobutylsulfonyl)amino]methyl}-6-[(4-methoxybenzyl)amino]-9H-purin-9-yl}tetrahydro-3-furanyl benzoate (Preparation 22) (40 mg, 0.05 mmol) in methanol (2 ml) was treated with potassium carbonate (28 mg, 0.20 mmol). The mixture was stirred at room temperature for 20 minutes after which time a precipitate had formed. Dichloromethane (10 ml) was added to the mixture to dissolve the precipitate. The mixture was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (95:5 by volume) to afford the title compound as a white solid (21 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.NN>[Ni].CO.C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Cl)c2cccnc12
Yield: 98 %

Procedure:
In the similar fashion using route 6 general procedure 14, 5-chloro-8-nitroquinoline (Intermediate 25) (500 mg, 2.40 mmol), Raney nickel (100 mg, 20% wt), hydrazine hydrate (0.5 ml, 9.62 mmol) and MeOH/THF (10 ml, 4:1), gave the title compound (420 mg, 98%) which was used in the next step without purification.
Reaction SMILES: CO[C:3](=[O:21])[CH2:4][CH2:5][C:6]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(O)(=O)C.C1(C)C=CC=CC=1>O1CCCC1>[CH3:12][O:11][C:9]([CH:8]1[CH2:7][C:6]([C:19]#[N:20])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:5][CH2:4][C:3]1=[O:21])=[O:10]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C1CC(C#N)(c2ccccc2)CCC1=O
Temperature: 25 °C

Procedure:
4-cyano-4-phenylheptanedioic acid dimethyl ester (14.45 g, 0.05 mole) was dissolved in dry tetrahydrofuran (350 ml). Sodium tert-butylate (9.6 g, 0.1 mole) was then added in portions. During this addition the reaction mixture turned an orange colour. The reaction mixture was then boiled under reflux for 5 hours. During the boiling a beige-coloured pasty suspension was formed. The reaction mixture was cooled to room temperature overnight. 2.5N acetic acid (170 ml) was slowly added dropwise to the reaction mixture while cooling with ice. Toluene (100 ml) was then added to the reaction mixture. The organic phase was separated and washed with saturated sodium hydrogen carbonate solution (3×70 ml), water (3×50 ml) and sodium chloride solution (1×70 ml). After drying over Na2SO4, the solvent was distilled off on a rotary evaporator and the residue was recrystallised from methanol. The desired product was obtained in a yield of 10.7 g (83%) as a yellow solid with a melting point of 75°-80° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C:4](=[O:30])[CH2:3]1)[C@:16]1([CH3:17])[C:11](=[C:12]([CH2:22]SC2C=CC=CC=2)[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3>[Ni]>[OH:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C:4](=[O:30])[CH2:3]1)[C@:16]1([CH3:17])[C:11](=[C:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3
Reactant: C[C@]12CCC(=O)C(CSc3ccccc3)=C1CC[C@H]1[C@@H]3[C@@H](O)CC(=O)[C@@]3(C)CC[C@@H]12
Agent: [Ni]
Product: CC1=C2CC[C@H]3[C@@H]4[C@@H](O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Yield: 64.4 %

Procedure:
Analogously to Example 6(b), 10.0 g of 15α-hydroxy-4-(phenylthiomethyl)androst-4ene-3,17-dione is treated with Raney nickel, thus isolating 4.8 g of 15α-hydroxy-4-methylandrost-4ene-3,17-dione as a foam.
Reaction SMILES: F[CH2:2][C:3](O)([C:8]([F:15])([F:14])[C:9]([F:13])([F:12])[CH2:10][CH3:11])C(F)(F)F.CCC(=O)C(=O)CC>>[F:12][C:9]([F:13])([C:8]([F:15])([F:14])[CH2:3][CH3:2])[CH2:10][CH3:11]
Reactant: CCC(F)(F)C(F)(F)C(O)(CF)C(F)(F)F
Agent: CCC(=O)C(=O)CC
Product: CCC(F)(F)C(F)(F)CC

Procedure:
As another example, 2-fluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-hexanol may be prepared by fluorinating commercially available 3,4-hexanedione to form 3,3,4,4-tetrafluorohexane which may then be dehydrogenated to form 3,3,4,4-tetrafluoro-1-hexene. CF3 may then be added to the 3,3,4,4-tetrafluoro-1-hexene to form 2-trifluoromethyl-1,3,3,4,4-pentafluorohexane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-hexene. The 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-hexene may then be reacted with sulfuric acid and then water to form 2-fluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-hexanol.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([C@H:25]([CH3:28])[CH2:26][CH3:27])[C:17]([NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18].[CH:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]2[N:37]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:38]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[C:32]=12)=O>ClCCCl>[CH:20]1([NH:19][C:17](=[O:18])[C@H:16]([NH:15][CH2:29][C:31]2[CH:36]=[CH:35][N:34]=[C:33]3[N:37]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:38]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[C:32]=23)[C@H:25]([CH3:28])[CH2:26][CH3:27])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC[C@@H](C)[C@@H](N)C(=O)NC1CCCC1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@@H](C)[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium triacetoxyborohydride (104 mg, 0.493 mmol) and (2R,3R)-2-amino-N-cyclopentyl-3-methylpentanamide (48.9 mg, 0.246 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. To this mixture was added 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (75 mg, 0.246 mmol). The reaction mixture was stirred at room temperature for 1 h and was subsequently concentrated to afford the title compound as a crude intermediate. [M+H] calc'd for C26H38N4O5, 487; found, 487.7.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][CH2:28][NH2:29])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:32])[CH3:31])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Solvent: c1ccncc1
Product: CC(=O)NCCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propylamine (25 mg, 0.06 mmol) in pyridine (1 mL) at room temperature is added acetic anhydride (500 μL, 5.3 mmol). The mixture is stirred for 2 h, concentrated in vacuo, and the residue chromatographed on SiO2 (89% dichloromethane 10% methanol 1% concentrated ammonium hydroxide) to yield the title compound, 12 mg (47%), as a light brown solid
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:18](=[O:20])[CH3:19])=[CH:22][CH:23]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: CC(=O)c1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-acetyl-phenylboronic acid to give 1-{4-[3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-phenyl}-ethanone. LC-MS m/e 329(MH+).
Reaction SMILES: [Cl-].[C:2]1([PH+:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:21].[Na+].[OH2:23]>>[Br-:21].[O:23]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[CH:7][P+:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Na+]
Product: C(=C1CCCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution consisting of 2.1 parts of triphenylphosphonium chloride in 50 parts of water is added with stirring to 2 parts of sodium bromide. At the end of about 5 minutes an additional 4 parts of sodium bromide is added the mixture is stirred until precipitation is complete. The precipitate is isolated by filtration, thus affording [(tetrahydro-2H-pyran-2-ylidene)-methyl]triphenylphosphonium bromide. This product is characterized by 60-MHz nuclear magnetic resonance peaks in CDCl3 (deuterated chloroform) at 107 cps (multiplet), 170 cps (multiplet), 228 cps (multiplet), 329 cps (doublet, J≃18 cps) in addition to the aromatic protons, by microanalytic determination of bromide.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:19]=1)N.C(O)(C(F)(F)F)=O>C(OCC)(=O)C>[N:24]1([C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:16]3[C:4](=[O:15])[C:5]([N:10]4[CH:14]=[CH:13][N:12]=[N:11]4)=[CH:6][NH:7]3)[CH:19]=2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Reactant: NNc1cc(N2CCOCC2)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCOCC2)ncn1
Temperature: 5 °C
Yield: 61.5 %

Procedure:
1.9 g (8.8 mmol) of the compound from Example 3A and 1.9 g (9.7 mmol) of the compound from Example 16A are initially introduced into 25 ml ethyl acetate and 504 mg (4.4 mmol) TFA are added at RT. The mixture is stirred under reflux for 16 h, then cooled to 5° C. and subsequently stirred for a further 2 h. The solid formed is filtered off, washed with ethyl acetate and dried first in air and thereafter under a high vacuum. 1.7 g of product are obtained.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[CH3:20])C.[OH-].[Na+]>C1COCC1>[CH3:20][C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[C:12](=[O:11])[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(C)cc1C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)CC#N)c(C)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.6 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 12 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5 gms. of 2,4-dimethyl-benzoic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids and then extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered. The organic layer is concentrated in vacuo and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-(2,4-dimethyl-phenyl)-3-oxo-propionitrile in the amount of2.0011 gms.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:3].F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.CNC.[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH:45]=[N:46][C:47]([N:50]2[C:58]3[C:53](=[CH:54][CH:55]=[C:56]([C:59](O)=[O:60])[CH:57]=3)[C:52]([S:62]([CH3:64])=[O:63])=[CH:51]2)=[N:48][CH:49]=1>ClCCl>[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH:49]=[N:48][C:47]([N:50]2[C:58]3[C:53](=[CH:54][CH:55]=[C:56]([C:59]([N:2]([CH3:3])[CH3:1])=[O:60])[CH:57]=3)[C:52]([S:62]([CH3:64])=[O:63])=[CH:51]2)=[N:46][CH:45]=1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
HATU (158 mg, 0.41 mmol), diisopropylethylamine (0.32 ml, 0.41 mmol) and dimethylamine (2M in THF) (0.95 mL, 1.89 mmol) were added to an ice-cooled suspension of 51e) (150 mg, 0.38 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with dichloromethane (40 mL) and washed with saturated ammonium chloride solution (2×30 mL), saturated sodium hydrogen carbonate solution (2×30 mL), water (30 mL), and brine (30 mL). The organic phase was dried over sodium sulfate and evaporated. The remnant was purified by column chromatography [100-200 mesh silica; 2% methanol in dichloromethane]. White solid. Yield: 62 mg (38% of theory). LC-MS (method 5): Rt=2.99 min; m/z [M+H]+=423.2
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26](B(O)O)[CH:27]=1>>[C:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[CH:26][C:25]=3[O:31][CH3:32])=[CH:3][C:4]=2[C:17]([F:20])([F:19])[F:18])(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)cc1C(F)(F)F
Reactant: COc1ccc(F)cc1B(O)O
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(C(F)(F)F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-fluoro-2-methoxybenzene boronic acid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1.[H-].[Na+]>>[CH2:11]([O:10][C:8]([C:7]1[C:2]([N:34]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[C:3]2[C:15]([CH3:16])=[N:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]2=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccc2)c1Cl
Reactant: COc1ccc(S(=O)(=O)NCc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccc2)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Following the procedure of Example 38, the product of Example 43 is reacted with (4-methoxybenzenesulfonyl)(3-pyridinylmethyl) amine and sodium hydride to provide ethyl-4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 148°-150° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]#[N:12])[CH:8]=[CH:9][CH:10]=1.C(=O)(O)[O-:14].[K+].OO.O>CO.C(=O)([O-])[O-].[K+].[K+]>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:11]([NH2:12])=[O:14]
Reactant: N#Cc1cccc(CCCBr)c1
Reactant: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc(CCCBr)c1
Reaction time: 0.75 h
Yield: 298.9 %

Procedure:
To 15.2 g (0.067 mole) of 3-(3-bromopropyl)cyanobenzene (the product of step (c)) in 55 ml methanol, 2.2 g potassium bicarbonate was added; to that mixture, 15.2 ml of 30% hydrogen peroxide was added dropwise. The reaction mixture was stirred for about 45 minutes. Then, 113 mg potassium carbonate was added and the resulting mixture was stirred overnight. Water (about 35 ml) was added to the reaction mixture and the resulting solution put in a freezer for about 50 minutes. The solid was collected by filtration and dried overnight to give 15.9 g of the above-identified product as a solid, melting point 109° C.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1.CCN(CC)CC.O>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[N:13][CH:14]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
Pivaloyl chloride (85 mL, 0.69 mol) was added to a solution of 5-bromopyridin-2-amine (100 g, 0.58 mol) and Et3N (120 mL, 0.87 mmoL) in CH2Cl2 at −78° C. The temperature was allowed to warm to room temperature and the stirring was continued overnight. The reaction mixture was poured into water, extracted with CH2Cl2, dried over MgSO4, evaporated in vacuo and purified by silica gel column chromatography (10% EtOAc in petroleum ether) to afford N-(5-bromopyridin-2-yl)pivalamide (130 g, 87% yield). 1H NMR (CDCl3, 400 MHz) δ 8.28 (d, J=2.0 Hz, 1H), 8.17 (d, J=9.2 Hz, 1H), 7.99 (br s, 1H), 7.77 (dd, J=9.2 and 2.0, 1H), 1.28 (s, 9H).
Reaction SMILES: [F:1][C:2]([C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:16]=[CH:17][CH:18]=1)([F:12])[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O.[OH-].[NH4+]>C(Cl)Cl>[CH3:33][S:34]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:14]=1)([F:1])[F:12])(=[O:36])=[O:35]
Reactant: O=C1CNC(=O)N1c1cccc(C(F)(F)COCCCCCCO)c1
Reactant: CS(=O)(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCCCCCOCC(F)(F)c1cccc(N2C(=O)CNC2=O)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Intermediate 62 (1.94 g, 5.45 mmol) was disolved in methylene chloride (15 mL) and triethylamine (1.21 mL, 8.72 mmol) was then added. The mixture was cooled to 0° C. and a solution of methanesulfonyl chloride (0.680 mL, 8.72 mmol) in methylene chloride (5 mL) was slowly added at the same temperature. The mixture was stirred at room temperature for 16 hours. The crude reaction was cooled to 0° C. and then 50% solution water/ammonium hydroxide (40 mL) was added. The organic layer was washed with water (2×40 mL), brine (1×40 mL), dried (Na2SO4) and concentrated. The title compound was obtained (2.4 g, 100%) as oil.