Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=O)OC(C)(C)C.[Cl:15]C1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CO.CS(C)=O>[ClH:15].[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:8]([NH:7][C@H:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[NH2:1])=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Temperature: 140 °C

Procedure:
A microwave vial was charged with tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 1.0 g, 4.99 mmol), 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 0.997 g, 5.49 mmol), DIPEA (2.62 ml, 14.98 mmol) and DMSO (16.6 ml). The reaction was heated with microwave irradiation at 140° C. for 2 hours and then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. This was then purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford a cream solid to which was then added methanol (10 ml) and HCl in 1,4-dioxane (4M, 6.24 ml, 24.97 mmol) and the reaction was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo and azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]=[O:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([Si:41]([CH3:55])([CH3:54])[O:42][CH2:43][C@@H:44]1[CH2:53][N:52]2[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]2)[CH2:46][NH:45]1)([CH3:40])[CH3:39].[Cl-].[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[C@H:44]([CH2:43][O:42][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:54])[CH3:55])[CH2:53][N:52]4[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]4)[CH2:46]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]=[O:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1C=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1-c1ccccc1C=O
Temperature: 90 °C
Yield: 18 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-formyl phenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D59, 106 mg, 0.201 mmol),), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 72 mg, 0.251 mmol) were dissolved in toluene (2 mL). Bis tritertbutylphosphine palladium (27 mg, 0.052 mmol), followed by hexadecyltrimethylammoium chloride (30 μL, 25% aq sol), and finally sodium hydroxide solution (0.25 mL, 50% aq sol) were added. The mixture was degassed for 5 minutes before heating at 90° C. for 2 hours. Reaction cooled to R.T., diluted with EtOAc, washed with sat NaHCO3 solution, dried (MgSO4). Filtered. Solvent evaporated. Residue purified eluting with 0-50% EtOAc/Pent. Solvent evaporated under reduced pressure to afford a pale yellow solid in 18% yield.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:26])[CH2:13][CH2:14][C:15](=[O:25])[N:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17])=[O:6])C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH2:3].[CH2:18]([N:16]([CH3:17])[C:15]([CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:5](=[O:6])[C:4]([OH:27])=[O:3])=[O:26])=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(=O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)C(=O)O
Reaction time: 1 h
Yield: 150.4 %

Procedure:
A mixture of 2-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-2-oxoacetic acid ethyl ester (626 mg), potassium carbonate (277 mg), methanol (7 ml) and water (4 ml) was stirred for 1 hr. at room temperature. Water was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried and evaporated to give the title compound (458 mg) having the following physical data:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[CH3:6][NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1>Cl>[CH3:6][NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:5][CH2:4][CH2:3][NH2:2])[N:12]=1
Reactant: CNc1nc(CCl)cs1
Reactant: NCCS
Agent: Cl
Product: CNc1nc(CSCCN)cs1
Yield: 35 %

Procedure:
Cysteamine hydrochloride (2.8 g; 24.6 mmoles) and 2-methylamino-4-chloromethylthiazole (4.0 g; 24.6 mmoles) [prepared from N-methylthiourea and 1,3-dichloro-2-propane] were dissolved in 20 ml of concentrated hydrochloric acid and the solution was heated at an oil bath temperature of 100°. After 30 hours of heating, the reaction mixture was evaporated under reduced pressure and the residue made basic with 40% aqueous NaOH solution. The aqueous phase was extracted with methyl acetate, dried, filtered and evaporated to give 1.75 g of the title compound as an oil which was used without further purification in Step B.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[C:9]([OH:13])(=[O:12])[CH2:10][CH3:11].C([O-])(=O)CC.[K+]>>[CH3:11][CH:10]1[CH2:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:13][C:9]1=[O:12]
Reactant: C=CCCCCCC
Reactant: CCC(=O)O
Agent: CCC(=O)[O-]
Agent: [K+]
Product: CCCCCCC1CC(C)C(=O)O1

Procedure:
Octene-1 in an amount of 2.24 g. and 11.65 g. of manganic acetate, Mn(C2H3O2)3.2H2O, (comprising two equivalents of Mn+3 based on titration value), were refluxed under nitrogen in 200 ml. propionic acid containing 20 g. potassium propionate. In less than an hour a good yield of alphamethyl-gamma-n-hexyl-butyrolactone was obtained.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][N:3]2[C:4]3=[N:9][C:8]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[CH:7][C:6](=[O:16])[N:5]3[CH2:17][C@@:2]2([CH3:1])[C:18]([F:21])([F:19])[F:20])[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(CCBr)c1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cccc(CCN2c3nc(N4CCOCC4)cc(=O)n3C[C@@]2(C)C(F)(F)F)c1

Procedure:
The product is prepared according to the procedure described in stage k of Example 1, using 100 mg of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (Example 1j) and 85 mg of 1-(2-bromoethyl)-3-methoxybenzene, replacing the sodium hydride with 214 mg of caesium carbonate. After purification by preparative HPLC/MS (method C), 65 mg of (2S)-1-[2-(3-methoxyphenyl)ethyl]-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: [F:1][CH:2]([F:15])[C@@H:3]1[C@@H:12]([OH:13])[C@H:11]([OH:14])[C@H:6]2[NH:7][C:8](=[S:10])[O:9][C@H:5]2[CH2:4]1.[CH3:16]I.[OH-].[Na+]>CCO>[F:15][CH:2]([F:1])[C@@H:3]1[C@@H:12]([OH:13])[C@H:11]([OH:14])[C@H:6]2[N:7]=[C:8]([S:10][CH3:16])[O:9][C@H:5]2[CH2:4]1
Reactant: CI
Reactant: O[C@H]1[C@H](O)[C@@H](C(F)F)C[C@@H]2OC(=S)N[C@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of (3aR,4R,5R,6S,7aS)-6-(difluoromethyl)-4,5-dihydroxyhexahydrobenzo[d]oxazole-2(3H)-thione (233 mg, 0.97 mmol) in EtOH (5 mL) was added MeI (277 mg, 1.95 mmol) and 5 N NaOH (0.21 mL, 1.1 mmol). The mixture was stirred at room temperature for 2 h. The solvents were evaporated to give the crude product. This was purified by SiO2 column, eluted with 3%-5% MeOH in DCM to give (3aR,4R,5R,6S,7aS)-6-(difluoromethyl)-2-(methylthio)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole-4,5-diol (218 mg, 88%) as a pale yellow solid. MS m/z 254.1 (M+1, 100%); 1H NMR (400 MHz, MeOD) δ 6.16 (td, J=56.8 Hz, 1.8 Hz, 1H), 4.79-4.83 (m, 1H), 3.85 (t, J=7.6 Hz, 1H), 3.39 (t, J=9.0 Hz, 1H), 3.28 (t, J=7.9 Hz, 1H), 2.48 (s, 3H), 2.27 (dt, J=14.7 Hz, 3.6 Hz, 1H), 1.91-2.10 (m, 2H).
Reaction SMILES: [OH-].[Li+:2].C([O:5][C:6](=[O:27])[CH2:7][C:8]1[N:9]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:12]=1)C>O1CCOCC1>[Li+:2].[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:9]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:12]=[C:8]2[CH2:7][C:6]([O-:27])=[O:5])=[CH:25][CH:24]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C([O-])Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.1 mL 1M aqueous lithiumhydroxide solution was added to 300 mg (1,4-bis-(4-fluoro-phenyl)-1H-imidazol-2-yl)-acetic acid ethyl ester in 10 mL dioxane. The reaction was stirred 2 h at RT and evaporated to give 270 mg desired product. Rt: 1.09 min (method B), (M+H)+: 315
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:27])[N:12]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26])[C:13]2=[O:18])=[O:6])=[N+]=[N-].[H][H].[ClH:30]>CO.[Pd]>[ClH:30].[NH2:1][CH2:4][C:5]([NH:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:27])[N:12]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26])[C:13]2=[O:18])=[O:6]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 84 %

Procedure:
A mixture of 2-azido-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}acetamide (1.2 g, 3.24 mmol), and 10% Pd/C (0.15 g) in 4N HCl (20 ml) and CH3OH (50 ml) was hydrogenated in Parr shake apparatus, under 50 psi of hydrogen for 3 hours. The mixture was then filtered through celite and the filtrate was concentrated to a solid residue. The solid was slurried in ethanol (20 ml) and the suspension filtered to give 2-amino-N-{[2-(2,6-dioxo(3-piperidyl)) 1,3-dioxoisoindolin-4-yl]methyl}acetamide hydrochloride (0.86 g, 84%) as a white solid: mp 270-272° C.; 1H NMR (DMSO-d6) 6 d 11.16 (s, 1H), 9.28 (t, J=5.7 Hz, 1H), 8.33 (s, 3H), 7.83 (s, 3H), 5.20-5.13 (dd, J=5.3 and 12.5 Hz, 1H), 4.81 (d, J=5.7 Hz, 2H), 3.69 (s, 2H), 2.92-2.87 (m, 1H), 2.65-2.51 (m, 2H), 2.09-2.05 (m, 1H); 13C NMR (DMSO-d6) 5 d 172.76, 169.80, 167.44, 166.91, 166.52, 138.24, 134.74, 133.53, 131.51, 127.17, 122.08, 48.89, 37.89, 30.94, 21.99; Anal. Calcd. For C16H17N4O5Cl: C, 50.47; H, 4.50; N, 14.71; Cl, 9.31. Found: C, 50.39; H, 4.61; N, 14.42; Cl, 9.25.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]S(C)(=O)=O)=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[C:17]([CH3:20])[C:16]([CH3:21])=[N:15]1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[C:17]([CH3:20])[C:16]([CH3:21])=[N:15]1
Reactant: Cc1nn(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)c(C)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(-c2cc(O)c(Cl)cc2F)c(C)c1C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A mixture of 1-(2-fluoro-4-chloro-5-methylsulfonyloxyphenyl)- 3,4,5-trimethylpyrazole (33.3 g), 2N aqueous sodium hydroxide (100 ml) and ethanol (50 ml) was stirred at 40° C. for 30 minutes. After cooling, the reaction mixture was acidified with aqueous hydrochloric acid and then extracted wth toluene. The toluene layer thus obtained was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (24.2 g) as a pale yellow crystalline solid. Recrystallization of this solid from a mixture of n-hexane/ethyl acetate yielded a white crystalline solid. m.p. 158°-160° C.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[Cl:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[CH2:16]([O:18][C:19]([C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1)=[O:20])[CH3:17]>C1C=CC=CC=1>[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]([C:9]([C:8]2[C:7]([Cl:6])=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:24][CH:25]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.6 %

Procedure:
A solution of tin (IV) chloride (3.72 g, 5 mmol) in benzene (10 mL) was added dropwise to a mixture of 2-chloronicotinoyl chloride (2.02 g, 11 mmol) and 1H-pyrrole-2-carboxylic acid ethyl ester (0.73 g; prepared as discussed below) in dry benzene (12 mL) at 0° C. The reaction was allowed to warm up slowly to room temperature and stirred 4 hours. The reaction was concentrated, the residue was dissolved in ethyl acetate and washed with brine, dried and concentrated to give 1.53 g of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid ethyl ester as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH3:18])=[N:12][NH:13]2.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:33])[N:22]=1.Cl>O>[NH2:33][C:23]1[N:22]=[C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:10]=3[C:11]([CH3:18])=[N:12][NH:13]4)=[C:2]([F:1])[CH:3]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=1
Reactant: Cc1n[nH]c2cccc(Oc3ccc(N)cc3F)c12
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Agent: Cl
Solvent: O
Product: Cc1n[nH]c2cccc(Oc3ccc(Nc4cc(-c5ccncc5)nc(N)n4)cc3F)c12

Procedure:
60 mg (0.23 mmol) of 3-fluoro-4-[(3-methyl-1H-indazol-4-yl)oxy]phenylamine (from example III) and 48 mg (0.23 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) are suspended in 4 ml of water, and 0.02 ml of concentrated hydrochloric acid is added. The reaction mixture is heated at reflux overnight, resulting in the formation of a brown precipitate. This is filtered off, washed repeatedly with water and dried under high vacuum. This gives 65 mg (65% of theory) of the product as a brown solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[Br:14][CH2:15][Si:16](Cl)([CH3:18])[CH3:17].O>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH:15]([Br:14])[SiH:16]([CH3:18])[CH3:17])=[CH:8][CH:9]=1
Reactant: C[Si](C)(Cl)CBr
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C[SiH](C)C(Br)c1ccc(Br)cc1
Reaction time: 1.5 h
Yield: 57.8 %

Procedure:
A solution of n-butyllithium (2.5M, 53 mL, 0.133 mole) was added dropwise over 30 minutes under argon to a solution of 1,4-dibromobenzene (30.0 g, 0.127 mole) in dry THF (575 mL) at -78° C. After stirring for 1.5 h, bromomethylchlorodimethylsilane (25.0 g, 0.133 mole) was added to the reaction mixture through a canula and the solution was stirred for 1.5 h at -78° C. The reaction was poured into water (325 mL) and extracted with ether. The combined extracts were washed with water and brine, and then dried (Na2SO4) and concentrated in vacuo to an oil. The oil was distilled (Kugelrohr, 110°-125° C., 0.05 mm Hg) to afford the compound as a clear, colorless oil (22.6 g, 58%). 1H NMR (400 MHz, CDCl3) 7.45 (dd, 4H), 2.60 (s, 2H), 0.45 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1>C1COCC1.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: NC(=O)c1cc(-c2cccc(CO)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2cccc(C=O)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of 5-[3-(hydroxymethyl)phenyl]-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (250 mg, 0.477 mmol) in THF (60 mL) was added MnO2 (1.3 g, 14.30 mmol). The reaction mixture was stirred at room temperature overnight and filtered through a pad of celite after that. The filtrate was collected and concentrated at reduced pressure to give the crude product (150 mg, 60%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[CH2:10]1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:20][C:16]1[CH:15]=[C:14]([C:11]2[CH2:10][CH:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[O:13][N:12]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cccc(C2=NOC(c3c(Cl)cccc3Cl)C2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(C2=NOC(c3c(Cl)cccc3Cl)C2)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Iron powder (99 mg, 1.78 mmol) was added into a suspension of (±)-5-(2,6-dichlorophenyl)-3-(3-nitrophenyl)-2-isoxazoline (100 mg, 0.297 mmol) in ethanol/water (2/1) under nitrogen. The mixture was stirred for 10 min, followed by the addition of ammonium chloride (32 mg, 0.594 mmol). The reaction was stirred for 20 min at room temperature, followed by heating at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature and filtered through a plug of Celite. The filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate to provide the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][C:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([C:46]([O:48][CH3:49])=[O:47])[CH2:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:57][C:54]1[CH:53]=[CH:52][C:51]([CH2:50][C:42]2([C:46]([O:48][CH3:49])=[O:47])[CH2:43][CH2:44][CH2:45][CH:40]([NH:39][C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=[C:8]4[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[O:19])[CH2:41]2)=[CH:56][CH:55]=1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: COC(=O)C1(Cc2ccc(F)cc2)CCCC(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(Cc2ccc(F)cc2)CCCC(NC(=O)c2ccc3c(c2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 85.2 %

Procedure:
In a flask, 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (567 mg, 1.15 mmol), methyl 3-amino-1-(4-fluorobenzyl)cyclohexanecarboxylate (1.09 mmol), and HATU (622 mg, 1.64 mmol) was dissolved in dimethylformamide (3 mL). The reaction mixture was stirred for 2 minutes at room temperature. Diisopropylethylamine (0.95 mL, 5.45 mmol) was added to the reaction. The reaction was allowed to stir for an additional 1 hr. Upon completion, the reaction was quenched with water (5 mL). The water layer was extracted with ethyl acetate (20 mL) three times. The organic fractions were combined, dried with sodium sulfate, and concentrated to yield the crude product. The crude compound was purified using flash chromatography (0-100% ethyl acetate in hexane gradient) to give the title compound (690 mg).
Reaction SMILES: C([Mg]Cl)(C)C.[Br:6][C:7]1[C:8]([F:14])=[N:9][CH:10]=[CH:11][C:12]=1I.[CH:15]1([CH2:18][NH:19][C:20]2[C:25](I)=[CH:24][N:23]=[C:22]([NH2:27])[N:21]=2)[CH2:17][CH2:16]1>CCOCC.C1COCC1.[Cl-].[Zn+2].[Cl-].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>[Br:6][C:7]1[C:8]([F:14])=[N:9][CH:10]=[CH:11][C:12]=1[C:25]1[C:20]([NH:19][CH2:18][CH:15]2[CH2:16][CH2:17]2)=[N:21][C:22]([NH2:27])=[N:23][CH:24]=1
Reactant: Fc1nccc(I)c1Br
Reactant: Nc1ncc(I)c(NCC2CC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccnc(F)c2Br)c(NCC2CC2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
Isopropylmagnesium chloride, 2 M solution in THF (0.814 mL, 1.63 mmol) was added dropwise over 15 minutes to a degassed solution of 3-bromo-2-fluoro-4-iodopyridine (0.468 g, 1.55 mmol) in Et2O (0.150 mL) and THF (0.850) cooled at −78° C. The solution was stirred for 0.5 h. Zinc chloride, 1.0 M solution in diethyl ether (0.776 mL, 0.776 mmol) was then added dropwise to the reaction over 10 minutes. The reaction was allowed to reach room temperature. The reaction warmed to room temperature within 15 min. A solution of compound 238 (0.150 g, 0.517 mmol) and tetrakis(triphenylphosphine)palladium (0.0418 g, 0.0362 mmol) in THF (0.50 mL) was added to the reaction. The reaction was equipped with a reflux condenser and stirred in a 60° C. oil bath. After 2 h the reaction was removed from heat and allowed to stand overnight. Saturated NH4Cl (0.5 mL) and 12% 2-propanol in CH2Cl2 (2 mL) were added. The organics were sequestered and the aqueous was extracted with 12% 2-propanol in CH2Cl2 (4×4 mL). The combined organics were washed with brine, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography (elution 3% methanol in DCM with 0.175% NH4OH additive) afforded compound 240 (0.140 g, 80.1% yield). 1H NMR (500 MHz, CDCl3) δ ppm 0.22 (d, J=4.40 Hz, 2 H) 0.46-0.59 (m, 2 H) 0.96-1.07 (m, 1 H) 3.21-3.36 (m, 2 H) 4.51 (br. s., 1 H) 5.11 (br. s., 2 H) 7.16 (d, J=4.89 Hz, 1 H) 7.69 (s, 1 H) 8.22 (d, J=4.89 Hz, 1 H) ppm.