Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:27])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20](OC)=[O:21].CC(C[AlH]CC(C)C)C>O1CCCC1.C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:27])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:20][OH:21])[CH:24]=[CH:25][CH:26]=1
Reactant: COCCOc1nc(N)c2nc(Br)n(Cc3cccc(C(=O)OC)c3)c2n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCCOc1nc(N)c2nc(Br)n(Cc3cccc(CO)c3)c2n1
Temperature: 0 °C
Yield: 1213.6 %

Procedure:
To a solution of Compound (5) (3.35 g, 7.67 mmol) in THF (“tetrahydrofuran”) (20 mL) cooled to 0° C. was added a 1 M solution of DIBAL-H (34.5 mL, 34.52 mmol) in toluene. The reaction temperature was maintained at 0° C. for 2 h but little progress in the reaction was observed. Additional equivalents (7.6 mL) of DIBAL-H were added at 2 and 4 hours respectively. The DIBAL-H reagent was quenched with 1N HCl, and the quenched reaction mixture was extracted with dichloromethane (3×50 mL) and dried over Na2SO3. Evaporation of the solvent gave 38 g (70%) of Compound (6) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 3.42 (s, 3H), 3.74 (t, J=5.1, 9.9 Hz, 2H), 4.49 (t, J=4.8, 10.2 Hz, 2H), 4.67 (s, 2H), 5.29 (s, 2H), 7.29 (m, 3H), 7.39 (s, 1H). LCMS: m/z for C16H18BrN5O3++H observed 408.1 and 410.0 at 1.85 minutes of a 3.5 minute run, eluting 5-95% CH3CN in H2O (C18 column).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N:13]#[C:14][NH2:15].Cl.CO>O1CCOCC1.C(Cl)Cl>[OH:12][C:4]1[CH:3]=[C:2]([NH:1][C:14]([NH2:15])=[NH:13])[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=1
Reactant: N#CN
Reactant: Nc1cc(O)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: N=C(N)Nc1cc(O)cc(C(F)(F)F)c1

Procedure:
A solution of 3-Amino-5-trifluoromethyl-phenol (0.21 g, 1.19 mmol), cyanamide (0.5 g, 1.19 mmol), 4N HCl in dioxane (2.975 ml, 1.199 mmol) in dioxane (10 ml) was heated in a sealed tube at 80° C. overnight resulting in complete conversion to product by TLC (10% MeOH:CH2Cl2). The reaction was partitioned between ethyl acetate/saturated NH4Cl solution and extracted. Some product remained in the aqueous phase after multiple extractions. The crude product (0.65 g, 0.297 mmol) was sufficiently pure by LC/MS to use directly for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12](=O)[NH:11][N:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:12]1[C:13]2[C:18](=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:10][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2n[nH]c(=O)c3ccc(C)cc23)cc1
Product: COc1ccc(-c2nnc(Cl)c3ccc(C)cc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(4-methoxyphenyl)-6-methyl-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:25])[CH2:23][OH:24])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34].CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:17]=[CH:18][C:19]([CH:22]([NH:25][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:30]([O:29][CH3:28])[CH:31]=2)[CH2:23][OH:24])=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(N)CO)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)NC(CO)c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To a stirred solution of 299 (88 mg, 0.24 mmol) in dry DCM (2 mL) at −20° C. was added 3,4-dimethoxybenzoyl chloride (50 mg, 0.25 mmol) followed by Et3N (37 μL, 126 mmol). The reaction mixture was allowed to warm up to room temperature then was stirred for 48 h. A solution of sat. NH4Cl was added, followed by DCM and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/DCM: 4/96) to afford title compound 300 (91 mg, 0.17 mmol, 71% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.65-7.58 (m, 1H), 7.46 (m, 7H), 6.80 (d, J=8.1 Hz, 1H), 5.20-5.10 (m, 1H), 3.95-3.78 (m, 2H), 3.88 (s, 3H) 3.84 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[I:17]N1C(=O)CCC1=O>>[I:17][C:5]1[N:6]=[C:2]([CH3:1])[NH:3][C:4]=1[C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1
Reactant: Cc1ncc(-c2ccc(S(C)(=O)=O)cc2)[nH]1
Reactant: O=C1CCC(=O)N1I
Product: Cc1nc(I)c(-c2ccc(S(C)(=O)=O)cc2)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product of Step 2 (750 mg, 3.2 mmol) in 10 mL of CFI3CN was added N-iodosuccinimide (710 mg, 3.2 mmol). The mixture was stirred at 25° C. for 1 h, cooled to −20° C. The precipitate was collected by filtration, washed with cold Et2O and dried to give 4-iodo-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-imidazole. LCMS: [M+1]+=362.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11](C(OC)=O)[C:12]([O:14]C)=[O:13].S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Yield: 80 %

Procedure:
Dimethyl 2-(2-chloro-4-nitrophenyl)malonate (96 mmol) was suspended in acetic acid (175 mL). Conc. sulfuric acid (3.5 mL) was added and the mixture was stirred at 80° C. over night. Water (30 mL) was added and the mixture was stirred at 100° C. for 2 h. after which conc. sulfuric acid (1 mL) was added. The mixture was stirred at room temperature over night. The formed precipitate was filtered off and washed with water. The remaining solid was dried under reduced pressure to give 2-(2-chloro-4-nitrophenyl)acetic acid as a solid (80%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.[NH4+].[OH-]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH3:24])=[O:33])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)c1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
The product of Step 3 (2.55 g) in CH2Cl2 (30 mL) was cooled to 0° C. and treated with mCPBA (60%, 2.16 g) and stirred for 1 h. The reaction mixture was treated with ice (20 g), saturated NH4OH solution (20 mL) and stirred for 10 minutes. The organic layer was separated and the aqueous layer re-extracted with CH2Cl2 (2×30 mL). The combined organic portions were dried over MgSO4, filtered and evaporated to give a gum. Silica gel chromatography, eluting with EtOAc/CH2Cl2 mixtures, gave 1-benzyloxycarbonyl-4-(2-methylsulfinylphenyl)piperidine (0.5 g).
Reaction SMILES: [NH2:1][OH:2].[C:3]12([CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]1)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2>>[OH:2][N:1]=[C:11]([OH:12])[CH2:10][C:3]1([CH2:15][C:14]([OH:13])=[O:16])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NO
Reactant: O=C1CC2(CCCCCC2)CC(=O)O1
Product: O=C(O)CC1(CC(O)=NO)CCCCCC1

Procedure:
In a manner analogous to that described in Example 1, by the reaction of hydroxylamine with 1,1-cycloheptane-diacetic anhydride, there was obtained 1,1-cycloheptane-diacetic acid N-hydroxylimide (m.p. 90°-100° C.) which, by acylation with benzene-sulphonyl chloride, was converted into benzene-sulphonyloxy-1,1-cycloheptane, diacetic acid imide (m.p. 130°-133° C.).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][N:16]([CH2:27][CH:28]=O)[C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:30]([CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][NH:44][CH3:45])=[N+:31]=[N-:32].C(O)(=O)C>C1COCC1.C(OCC)(=O)C>[N:30]([CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][N:44]([CH3:45])[CH2:28][CH2:27][N:16]([CH3:15])[C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[N+:31]=[N-:32]
Reactant: CN(CC=O)C(=O)OCc1ccccc1
Reactant: CNCCOCCOCCOCCN=[N+]=[N-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CCOCCOCCOCCN=[N+]=[N-])CCN(C)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 58.4 %

Procedure:
Sodium triacetoxyborohydride (3.55 g, 16.8 mmol) was added portionwise at room temperature to benzyl methyl(2-oxoethyl)carbamate (2.68 g, 12.9 mmol), 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-N-methylethanamine 222c (3.00 g, 12.9 mmol), and acetic acid (2 equiv.) in THF (20 mL). The mixture was stirred for 2 hours, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried (Mg2SO4) and evaporated. The residue was purified by Combiflash purification system (ethyl acetate/dichloromethane) to give product as an oil (3.19 g, 58%); MS (ES, m/z): 424 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:13]=1[CH2:14][N:15]1[CH2:19][C@H:18]([C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[C@@H:17]([CH2:25][OH:26])[CH2:16]1.CCOCC>C(Cl)Cl>[Cl:11][C:12]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:13]=1[CH2:14][N:15]1[CH2:19][C@H:18]([C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[C@@H:17]([CH:25]=[O:26])[CH2:16]1
Reactant: OC[C@H]1CN(Cc2ccc(Cl)cc2Cl)C[C@@H]1c1ccsc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C[C@H]1CN(Cc2ccc(Cl)cc2Cl)C[C@@H]1c1ccsc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a solution of 0.31 mL (3.6 mmol) of oxalyl chloride in 20 mL of CH2Cl2 at −78° C. was added 0.51 mL (7.2 mmol) of DMSO and the reaction mixture was stirred. After 10 min., a solution of 0.49 g (1.8 mmol) of 1-(2,4-dichlorobenzyl)-3-(R)-hydroxymethyl-4-(S)-(3-thienyl)pyrrolidine in 20 mL of CH2Cl2 was then added. After stirring for 10 min. at −78° C., the reaction was allowed to warm to rt. The reaction mixture was poured into ether and extracted twice with sat'd NaHCO3 solution and once with sat'd NaCl solution. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated to give 0.49 g of the title compound. Mass Spectrum (ESI) m/e=340 (M+1 35Cl, 35Cl), 342 (M+1 35Cl, 37Cl), and 344 (M+1 37Cl, 37Cl).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=O>>[F:14][C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(F)ccc1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(F)ccc3O)CC2)nc[nH]1

Procedure:
6-[4-(5-Fluoro-2-hydroxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-fluoro-2-hydroxybenzaldehyde (available from Aldrich). 1H NMR (400 MHz, DMSO-d6) δ 2.45-2.48 (m, 4H), 3.43-3.49 (m, 4H), 3.57 (s, 2H), 5.28 (s, 1H), 6.73-6.80 (m, 1H), 6.89-6.94 (m, 1H), 6.99-7.02 (m, 1H), 7.89 (s, 1H), 9.90 (br s, 1H), 11.64 (br s, 1H). Mass spectrum (ES) MH+=305.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@H:11]([C@@H:12](O)[C:13](=[O:36])[C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:10]1)(C(C)(C)C)(C)C.C(N(S(F)(F)[F:44])CC)C>C(Cl)Cl>[OH:8][C@@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@H:11]([C@@H:12]([F:44])[C:13](=[O:36])[C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:10]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)[C@H](O)[C@@H]4C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)[C@H](F)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 31.6 %

Procedure:
A solution of methyl 3α-tert-butyldimethylsilyloxy-6α-hydroxy-7-keto-5β-cholanoate (2.4 g, 4.49 mmoles) in methylene chloride (50 ml) was added dropwise in one hour to a solution of diethylamino-sulfur-trifluoride (2.72 ml, 20.0 mmoles) in methylene chloride (50 ml) and the mixture was left to react overnight under argon atmosphere, with magnetic stirring. The reaction mixture was washed with water (1×30 ml), subsequently with a sodium bicarbonate saturated solution (2×20 ml), finally with brine (1×30 ml). The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue (2.0 g) was subjected to flash chromatography on silica, eluting with methylene chloride, to obtain 0.6 g of a pure product (32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12])[CH:6]([C:24](O)=[O:25])[CH:5]2[C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1[F:34].C(N1CC[O:40][CH2:39][CH2:38]1)C.ClC(OCC)=O.[NH3:49]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:7]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)(=[O:12])=[O:13])[CH:6]([O:40][CH2:39][CH3:38])[C:24]([NH2:49])=[O:25])=[C:4]([CH2:5][C:27]2[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=2[F:33])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccc(Cl)cc3C(c3c(F)cccc3F)C2C(=O)O)cc1OC
Reactant: CCN1CCOCC1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(C(N)=O)N(c1ccc(Cl)cc1Cc1c(F)cccc1F)S(=O)(=O)c1ccc(OC)c(OC)c1
Yield: 99.6 %

Procedure:
To 0.34 g of 5-chloro-3-(2,6-difluorophenyl)-1-[(3,4-dimethoxyphenyl)sulfonyl]indoline-2-carboxylic acid in 10 ml of tetrahydrofuran are successively added, at 0° C., 90 μl of N-ethylmorpholine and 68 μl of ethyl chloroformate, the mixture is left at this temperature for 30 minutes, and 0.5 ml of 6M aqueous ammonia solution is introduced. The reaction medium is concentrated and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a dichloromethane/methanol mixture (100% dichloromethane to 98% dichloromethane/2% methanol) to give 0.256 g of product (99.6% HPLC purity).
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=1)[CH2:3][C:4]#[N:5].[BH4-].[Na+].Cl>O1CCCC1>[OH:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=1)[CH2:3][C:4]#[N:5]
Reactant: N#CCC(=O)CCc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(O)CCc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 5.5 grams (0.022 mole) of 3-oxo-5-(3-phenylphenyl)pentanenitrile and 0.5 gram (0.013 mole) of sodium borohydride in 75 mL of tetrahydrofuran was heated at reflux for four hours. After this time the reaction mixture was allowed to cool to ambient temperature where it stood for about 16 hours. The reaction mixture was then poured into 300 mL of aqueous 1N hydrochloric acid. The mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. NMR analysis of the residual oil indicated that it was impure. The oil was dissolved in 20:1 methylene chloride and ethyl acetate, and the solution was passed through a column of silica gel. The eluate was concentrated under reduced pressure, yielding 3.8 grams of 3-hydroxy-5-(3-phenyl-phenyl)pentanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](C)=[C:5]([C:18]([O:20][CH3:21])=[O:19])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH2:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH3:1][C:2]12[CH2:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:5]([C:18]([O:20][CH3:21])=[O:19])([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]1[C:8]([O:10][CH3:11])=[O:9])[CH:4]=[N:3]2
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1
Reactant: C=Cc1ccccc1
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)C1C(c2ccccc2)C2(C(=O)OC)C=NC1(C)CC2c1ccccc1
Reaction time: 3 h

Procedure:
To 0.45 g (1.5 mmol) dimethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (1) in 25 ml CHCl3 under N2 and cooled to 0°-10° in an ice bath there was added 3.12 g (30.0 mmol) of commercially obtained styrene (4) followed by 0.64 g (4.5 mmol) boron trifluoride etherate added dropwise via syringe. The resulting solution was stirred at 0°-10° for 3 hours and then at room temperature for 16 hours.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][NH:17][C:16](=S)[C@H:15]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:25][CH2:24]2)=[O:22])[CH2:14][CH2:13]1>CO>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][NH:17][C:16](=[N:2][NH2:3])[C@H:15]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:25][CH2:24]2)=[O:22])[CH2:14][CH2:13]1
Reactant: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: NN
Solvent: CO
Solvent: O
Product: NN=C1NC[C@H](c2cccc(F)c2F)CC[C@H]1NC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
Hydrazine monohydrate (1.46 mL, 30.1 mmol) was added to a solution of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (502 mg, 1.00 mmol) in methanol (20 mL). After 30 min, the reaction was concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give the title compound (515 mg). MS 499.1 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][C:11]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:12]=3[C:13]([O:15]C(C)(C)C)=[O:14])=[CH:6][C:5]=2[CH3:25])[CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][C:11]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:12]=3[C:13]([OH:15])=[O:14])=[CH:6][C:5]=2[CH3:25])[CH2:2][CH2:3]1
Reactant: Cc1ccc(Nc2cnc(C3CC3)c(C)c2)c(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2cnc(C3CC3)c(C)c2)c(C(=O)O)c1

Procedure:
A solution of tert-butyl 2-(6-cyclopropyl-5-methylpyridin-3-ylamino)-5-methylbenzoate (1.52 mmol, 0.514 g) in TFA (5 ml) was stirred at room temperature for 30 minutes. The solvent was reduced under reduced pressure and the crude mixture was purified by reverse phase chromatography using a 30% to 100% (Water-ACN) gradient and affording 0.150 g (35% of yield) of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]([N+:20]([O-])=O)[C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]>[Pd].CO>[NH2:20][C:12]1[C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=[C:10]([CH2:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH:11]=1
Reactant: COC(=O)c1ncc(Cc2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ncc(Cc2ccc(F)c(F)c2)cc1N
Reaction time: 2 h

Procedure:
A mixture of methyl 5-[(3,4-difluorophenyl)methyl]-3-nitro-2-pyridinecarboxylate (1.67 g, 5.42 mmol), 10% Pd-C (1.67 g) and MeOH (170 ml) was reduced under hydrogen for 2 h. The product was filtered through Celite, concentrated in vacuo and purified by chromatography on silica gel, eluting with 50-75% EtOAc/hexanes. The product was triturated with EtOAc to afford an off-white solid collected by filtration. 1H NMR (d6-DMSO) δ 7.77 (1H, s), 7.39-7.30 (2H, m), 7.08-7.05 (1H, m), 6.92 (1H, s), 6.62 (2H, s), 3.88 (2H, s), 3.76 (3H, s); HRMS calcd for C14H12F2N2O2+H+: 279.0945. Found 279.0938.
Reaction SMILES: Cl[C:2]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.O.[NH2:28][NH2:29]>N1C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][C:23]([CH3:25])=[CH:22][C:21]=3[CH3:26])[NH:29][N:28]=2)[CH:7]=[C:8]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:9]=1[OH:16])([CH3:14])([CH3:15])[CH3:13]
Reactant: Cc1cc(C)c(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Cl)n1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(C)c2c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n[nH]c2n1
Yield: 90.1 %

Procedure:
A mixture of 18.3 g of 4-(2-chloro-4,6-dimethylnicotinoyl)-2,6-di-tertiary butylphenol, 11 g of hydrazine hydrate and 100 ml of pyridine is reacted and the product is treated in a similar manner as Example 1 to give 15.5 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-4,6-dimethyl-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 257°-258° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH:1]1([C:7]2[C:8]([CH3:13])=[N+:9]([O-:22])[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ncccc1C1CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(C2CCCCC2)ccc[n+]1[O-]
Yield: 112.4 %

Procedure:
A solution of 3-cyclohexyl-2-methylpyridine (170 mg, 1.0 mmol), in CH2Cl2 (5 mL) was treated with MCPBA (0.33 g, 1.9 mmol) for 18 hours. The solution was then washed with saturated NaHCO3 solution (5 mL), the phases separated, and the aqueous extracted with CH2Cl2 (2×10 mL). The combined organic phases were then dried (Na2SO4), filtered, and concentrated to afford crude 3-cyclohexyl-2-methylpyridine N-oxide as a white solid (0.215 g) which was used immediately in the next reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[Cl:27])[C:17]([NH2:20])=[N:18][N:19]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:28]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1>>[NH:39]1[CH:38]=[C:37]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:16]([C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=6[Cl:27])[C:17]([NH2:20])=[N:18][N:19]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:28]=2)[CH:41]=[N:40]1
Reactant: Nc1nnc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n1-c1ccccc1Cl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Nc1nnc(-c2cc3c(s2)-c2ccc(-c4cn[nH]c4)cc2OCC3)n1-c1ccccc1Cl

Procedure:
Following the procedure in Example 93, 5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-(2-chlorophenyl)-4H-1,2,4-triazol-3-amine was coupled with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give 307. MS (ESI) 461.1