Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[H][H]>C(O)C>[NH2:1][CH:2]1[CH2:10][CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: [H][H]
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CCO
Product: NC1CCCC(C(=O)O)C1
Reaction time: 192 h
Yield: 57.2 %

Procedure:
A mixture of 3-aminobenzoic acid (66.12 g, 0.48 mol) and 10% palladiumon-carbon (13.2 g) in 30% aqueous ethanol (1200 mL) was placed in a 4 L stainless steel high-pressure reactor and reduced at 50° C. and 500 psi of hydrogen for 30 h. The mixture was filtered through Celite and the filter cake was washed with ethanol. The solvent was evaporated, boiling ethanol (1 L) was added and the mixture was allowed to stand for 8 days at room temperature. The mixture was filtered and the product was washed with ethanol and then dried in a vacuum oven at 50° C., to give 3-aminocyclohexanecarboxylic acid (39.30 g, 57%) as a white solid.
Reaction SMILES: [CH2:1]([Sn:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([CH:21]([CH2:24][CH3:25])[CH2:22][OH:23])[CH3:20]>>[CH2:1]([Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([O:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:19][CH3:20])[O:18][Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Reactant: CCC(CC)CO
Product: CCCCCCCC[Sn](CCCCCCCC)(OCC(CC)CC)O[Sn](CCCCCCCC)(CCCCCCCC)OCC(CC)CC
Reaction time: 0.67 h
Yield: 99 %

Procedure:
700 g (1.94 mol) of dioctyltin oxide (made by Sankyo Organic Chemicals Co., Ltd., Japan) and 1600 g (15.7 mol) of 2-ethyl-1-butanol (made by Chisso Corporation, Japan) were put into a 3000 mL flask. The flask containing the mixture, which was a white slurry, was attached to an evaporator (R-144, made by Sibata, Japan) having a temperature regulator-equipped oil bath (OBH-24, made by Masuda Corporation, Japan), a vacuum pump (G-50A, made by Ulvac, Japan) and a vacuum controller (VC-10S, made by Okano Works Ltd., Japan) connected thereto. The outlet of a purge valve of the evaporator was connected to a line for nitrogen gas flowing at normal pressure. The purge valve of the evaporator was closed, and the pressure in the system was reduced, and then the purge valve was gradually opened, so as to pass nitrogen into the system, and thus return the system to normal pressure. The oil bath temperature was set to 157° C., and the flask was immersed in the oil bath and rotation of the evaporator was commenced. With the purge valve of the evaporator left open, rotational stirring and heating were carried out for approximately 40 minutes at normal pressure, and then the purge valve was closed, and the pressure in the system was gradually reduced, and water-containing 2-ethyl-1-butanol was distilled off with the pressure in the system at from 84 to 65 kPa. This state was maintained for 7 hours, and then the pressure in the system was further reduced, and excess 2-ethyl-1-butanol was distilled off. Once distillate stopped coming off, the flask was lifted out from the oil bath. The reaction liquid was a transparent liquid. After lifting the flask out from the oil bath, the purge valve was gradually opened, so as to return the pressure in the system to normal pressure. 883 g of reaction liquid was obtained in the flask. According to 119Sn—, 1H—, and 13C-NMR analysis results, the product 1,1,3,3-tetraoctyl-1,3-bis(2-ethylbutyloxy)-distannoxane was obtained at a yield of 99% based on the dioctyltin oxide. The same procedure was carried out so as to produce 1,1,3,3-tetraoctyl-1,3-bis(2-ethylbutyloxy)-distannoxane to be used in the following step B.
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CC=CC=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.O>C(#N)C>[CH2:1]([NH:17][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCCCCCCCCCCCCCCN
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCNC(=O)c1cccnc1
Reaction time: 3 h
Yield: 82.4 %

Procedure:
30.7 g of cetylamine and 33.2 g of pyridine were dispersed in 200 ml of acetonitrile, and 25 g of nicotinic acid chloride hydrochloride was added thereto under cooling with water. After reacting for 3 hours at 55° C., 800 ml of water was added thereto. The thus formed crystals were collected by filtration. Recrystallization from 500 ml of ethanol yielded 36.3 g of the end product. m.p. 85°-87° C.
Reaction SMILES: I[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[Cl:21][C:22]1[C:27](B(O)O)=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:21][C:22]1[C:27]([C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: O=c1c(I)cc(-c2ccccn2)cn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(-c2cccnc2Cl)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
3-Iodo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one (200 mg) synthesized by the same method as mentioned in Referential Example 6, 130 mg of 2-chloro-3-pyridyl boronic acid and 250 mg of cesium carbonate were suspended in 10 ml of dimethylformamide, 40 mg of tetrakistriphenylphosphine palladium were added and the mixture was stirred at 100° C. in a nitrogen atmosphere for 3 hours. After allowing to cool, the reaction solution was poured into water, the mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo and the residue was purified by a silica gel column chromatography (hexane-ethyl acetate system) to give 143 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[N:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=1)(=[O:7])[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CCN(CC)c1ccc(Nc2nc(Cl)ccc2C(N)=O)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(Nc2nc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccc2C(N)=O)cc1
Temperature: 100 °C
Yield: 55.8 %

Procedure:
A mixture of 6-chloro-2-(4-(diethylamino)phenylamino)nicotinamide (1.669 g, 5.24 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (1.573 g, 7.85 mmol), and DIEA (1.829 mL, 10.47 mmol) in N-methyl-2-pyrrolidinone (10 mL) was heated at 100° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with satd. NaHCO3, water, and concentrated. The resulting residue was purified by MPLC (ISCO, hexane/ethyl acetate, 80 g silica gel column) to give 1.41 g (R)-tert-butyl 1-(5-carbamoyl-6-(4-(diethylamino)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate as a yellow solid. LCMS: (M+H)+=483.3.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Cl:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20]>>[Cl-:16].[OH:21][CH:18]([CH2:19][OH:20])[CH2:17][N+:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:1])[CH3:15]
Reactant: CCCCCCCCCCCCN(C)C
Reactant: OCC(O)CCl
Product: CCCCCCCCCCCC[N+](C)(C)CC(O)CO
Product: [Cl-]
Temperature: 30 °C
Reaction time: 2 h

Procedure:
In a 2 L reactor system 638.06 g of dimethyldodecyl amine (97.6%, 2.92 moles) is added to 603.91 g distilled water. The solution is heated to 30° C. and 21.21 g sodium hydroxide (50%) is added. Over 30 minutes 353.49 g 3-chloro-1,2-dihydroxypropane (99.3%, 3.18 moles) is added while the reaction solution is being mixed with a mechanical stirrer. The reaction solution is mixed at 30° C. for 90 minutes and then the temperature is gradually increased to 40° C. over 45 minutes. The temperature is then increased over the next hour to 55° C. The solution turned from a semi-opaque white to clear. The solution is held at 55° C. for two hours; after one hour the solution is getting more viscous so 135.48 g distilled water is added. The solution is allowed to cool to room temperature and stirred overnight. The solution had become too viscous for the stirrer to operate so 150.59 g distilled water is added and the temperature is increased to 45° C. The solution is allowed to cool to room temperature and 46.59 g trimethylamine (43.6%) is added and mixed for two hours. The solution is allowed to stand without mixing or heating for 60 hours. The solution is then heated to 40° C. and the pH is adjusted to 10 and purged with nitrogen until the residual trimethylamine hydrochloride is less than 20 ppm. The pH is then decreased to 6.5 with concentrated hydrochloric acid. The isolated product has the following structure:
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:53][C:54]1[CH:59]=[C:58]([CH3:60])[CH:57]=[CH:56][C:55]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:65]2[CH2:66][CH2:67][CH:62]([NH:61][C:55]3[CH:56]=[CH:57][C:58]([CH3:60])=[CH:59][C:54]=3[CH3:53])[CH2:63][CH2:64]2)=[O:12])=[CH:5][CH:6]=1
Reactant: Cc1ccc(NC2CCNCC2)c(C)c1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC2CCN(C(=O)CC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c(C)c1
Reaction time: 8 h
Yield: 44 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.101 g, 0.00039 mole) in DMF (3 mL) was added DIPEA (0.233 g, 0.0018 mole), HOBt (0.053 g, 0.00039 mole) and EDCI.HCl (0.138 g, 0.000721 mole). After 2 minutes (2,4-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00036 mole was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (1% methanol in chloroform) afforded 0.07 g (44%) of N-biphenyl-4-yl-3-[4-(2,4-dimethyl-phenylamino)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 442.24 (M+1)+, 98.89%, 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 7.8-7.6 (m, 6H), 7.5 (t, 2H), 7.4 (t, 3H), 6.8 (d, 2H), 6.6 (d, 1H), 4.3 (dd, 2H), 3.9 (d, 1H), 3.7 (s, 2H), 3.5 (bs, 1H), 3.2 (t, 1H), 2.7 (m, 1H), 2.2 (s, 3H), 2.1 (s, 3H), 1.9 (t, 2H), 1.5 (t, 1H), 1.3 (d, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=2)=[N:7][CH:8]=1.[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C(C)=CC=CC=1>[Cl-:1].[F:16][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][P+:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][N:7]=2)[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: Fc1ccc(-c2ccc(CCl)cn2)cc1F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Fc1ccc(-c2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Product: [Cl-]
Reaction time: 24 h
Yield: 49.8 %

Procedure:
A mixture of 0.46 g of 5-chloromethyl-2-(3,4-difluorophenyl)pyridine, 0.6 g of triphenylphosphine and 10 ml of xylene was heated to boiling for 24 hours. After cooling the precipitate was filtered off, washed with toluene and dried. There was obtained 0.48 g of colourless [2-(3,4-difluorophenyl)-5-pyridyl]methyltriphenylphosphonium chloride, m.p. 259°-260.5° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].N1C=CC=CC=1.C[Si](C)(C)[N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]>C1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:23]([N:22]1[CH2:26][CH2:25][CH2:24][C:1]1=[O:2])=[O:27]
Reactant: O=C(Cl)Cl
Reactant: COc1ccccc1O
Reactant: C[Si](C)(C)N1CCCC1=O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1ccccc1OC(=O)N1CCCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of phosgen (6.27 g, 63.3 mmol) in anhydrous benzene (30 ml) was dropwise added under ice-cooling a solution of 2-methoxyphenol (7.86 g, 63.3 mmol) and purified pyridine (5.00 g, 63.3 mmol) in anhydrous benzene (20 ml). The mixture was stirred overnight at room temperature. From a reaction solution were separated white precipitates by filtration, and a filtrate was evaporated under reduced pressure to give a colorless oily material. The oily material was dissolved in anhydrous benzene (20 ml), to which was added a solution of 1-trimethylsilyl-2-pyrrolidinone (9.66 g, 63.3 mmol) in anhydrous benzene (10 ml). The mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated under reduced pressure to dryness to give a solid material. The desired product was separated using column chromatography on silica gel (eluted with benzene-acetone 20:1→1:1).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7](O)(=[O:11])[CH:8]([CH3:10])[OH:9].C(O)(C)C>O>[C:7]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:11])[CH:8]([CH3:10])[OH:9]
Reactant: CN(C)CCO
Reactant: CC(O)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: CC(O)C(=O)OCCN(C)C

Procedure:
A dimethylethanolamine lactate was prepared by mixing 13.3 parts of dimethylethanolamine and 18.0 parts of lactic acid (85 percent solution in water). The mixture was held at 40° C. to 60° C. for a short time and there was then added 7.2 parts of isopropanol. The final composition comprised 75 percent solids and contained 7.1 percent water.
Reaction SMILES: CC(C)([O-])C.[K+].F[C:8]1[C:9]([C:14]([OH:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[CH:17]1([OH:21])[CH2:20][CH2:19][CH2:18]1>>[CH:17]1([O:21][C:8]2[C:9]([C:14]([OH:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1ncccc1F
Reactant: OC1CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)c1ncccc1OC1CCC1
Reaction time: 18 h
Yield: 100 %

Procedure:
Potassium tert-butoxide (358 mg, 3.19 mmol) was suspended in cyclobutanol (0.5 mL), 3-fluoropyridine-2-carboxylic acid (150 mg, 1.06 mmol) was added and the reaction was stirred at 100 C for 18 h. The mixture was evaporated under vacuum to afford the title compound (100% conversion assumed), which was used in the next step without further purification. Method C HPLC-MS: MH+ requires m/z=194. Found: m/z=194, Rt=0.83 min (100%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:27]=[CH:26][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][NH:21][C@@H:20]([CH:23]([CH3:25])[CH3:24])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C(N(CC)CC)C.[C:35]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)#[N:36]>C(Cl)Cl>[C:35]([C:37]1[CH:38]=[CH:39][C:40]([S:43]([N:21]2[CH2:22][C:16]3[C:17](=[N:18][CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:27][CH:26]=4)=[O:13])[CH:15]=3)[C@@H:20]2[CH:23]([CH3:24])[CH3:25])(=[O:45])=[O:44])=[CH:41][CH:42]=1)#[N:36]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(S(=O)(=O)c2ccc(C#N)cc2)[C@H]3C(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.8 %

Procedure:
To a solution of (S)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (6.9 mg, 17.8 μmol) in CH2Cl2 (600 μL) was added triethylamine (5.0 μL, 36.6 μmol) and 4-cyanobenzenesulfonyl chloride (5.4 mg, 26.8 μmol). The mixture was stirred at rt for 15 h, at which point it was quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with EtOAc (10 mL), then the organic phase was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to yield 4.9 mg of (S)-6-((4-cyanophenyl)sulfonyl)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide as an HCl salt (13, 46%). LC-MS tR=0.84 min in 1 min chromatography, MS (ESI) m/z 553.5 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 8.85 (d, J=2.0 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H), 8.03 (dd, J=2.0 Hz, 8.8 Hz, 2H), 7.86 (m, 4H), 7.60 (d, J=8.4 Hz, 2H), 4.93 (m, 2H), 4.73 (dt, J=1.2 Hz, 16.4 Hz, 1H), 4.66 (s, 2H), 3.19 (q, J=7.6 Hz, 2H), 2.41-2.32 (m, 1H), 1.20 (t, J=7.6 Hz, 3H), 1.00 (d, J=7.2 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[F:16])[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[F:16])[CH2:7][Br:18])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=C(C)Oc1cc(F)ccc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(CBr)Oc1cc(F)ccc1F
Temperature: 105 °C
Yield: 87.2 %

Procedure:
A solution of 3-(2,5-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.35 g, 5.57 mmol) in carbon tetrachloride (30.9 mL) was treated with N-bromosuccinimide (1.09 g, 6.13 mmol) and benzoyl peroxide (108 mg, 0.44 mmol). The reaction was then heated to reflux (105° C.) for 5 h. At this time, the reaction was cooled to 25° C. and then was placed in the refrigerator overnight. At this time, the reaction was removed from the refrigerator. The resulting precipitate was removed by filtration and was rinsed with carbon tetrachloride (25 mL). The filtrate was concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2% ethyl acetate/hexanes) afforded impure 4-bromo-3-(2,5-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.56 g, 87%) as a clear oil. The material was used without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH2:30](O)[CH2:31][CH2:32]C>>[N:23]1([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH2:15][CH2:30][CH2:31][CH3:32])=[O:13])=[CH:7][CH:6]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: C1CCCNCC1
Reactant: CCCCO
Product: CCCCOC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCCCC3)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol, 1.00 equiv), azepane (470 mg, 4.75 mmol, 10.00 equiv), butan-1-ol (2 mL). The resulting solution was stirred for overnight at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 150 mg (crude) of butyl 3-(azepan-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>>[F:27][C:26]([F:29])([F:28])[CH2:25][O:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:38]4[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.55) (0.273 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.19 g, 68%). MS (ISP) 560.2 [(M+H)+]; mp 250° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1[C:19]2([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:18]1>O1CCCC1.[Cu]I>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:18][C:19]1([OH:17])[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]c1ccccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccccc2OCc2ccccc2)CC1

Procedure:
(2-(Benzyloxy)phenyl)magnesium bromide (33.8 mL, 1M) was added to a solution of EXAMPLE 263A (6.0 g) and CuI (1.07 g) in tetrahydrofuran (220 mL) at 0° C. over 10 minutes. The reaction was quenched with pH 7 buffer (20 mL), extracted twice with ether, and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was chromatographed on silica gel using 2-20% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].C[Al](C)C.[OH:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16].Cl>C1(C)C=CC=CC=1.CCCCCC>[CH2:2]([NH:4][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([OH:9])[CH3:18])[CH3:3]
Reactant: CC(O)CCCCC(=O)O
Reactant: CCN
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCNC(=O)CCCCC(C)O
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 81.9 %

Procedure:
A stirred suspension of dry ethylamine hydrochloride (3.26 g, 0.04 mol) in toluene, under nitrogen, was cooled in an ice bath and treated during 40 minutes with 20 ml of a 2.0M solution of trimethylaluminum in hexane. The mixture was kept at 0° for 10 minutes and at ambient temperature for 2.5 hours. A portion of the resulting solution (46.8 ml) was added, under nitrogen, during 15 minutes to a solution of the product from Step I (2.0 g, 0.016 mol) in toluene (100 ml). This mixture was warmed at 80° C. for 3 hours, cooled and added continuously to dilute HCl. The product was extracted with ethyl acetate. The extracts were dried (MgSO4) and concentrated to give 2.27 g of N-ethyl-6-hydroxyheptanamide.