Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[CH3:13][C:14]1([CH3:27])[C:18]2([CH2:22][S:23](Cl)(=[O:25])=[O:24])[C:19]([CH2:21][CH:15]1[CH2:16][CH2:17]2)=[O:20]>C(Cl)Cl.C(N(CC)CC)C>[CH:4]1([CH2:3][CH2:2][NH:1][S:23]([CH2:22][C:18]23[C:14]([CH3:13])([CH3:27])[CH:15]([CH2:16][CH2:17]2)[CH2:21][C:19]3=[O:20])(=[O:25])=[O:24])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: NCCC1CCc2ccccc21
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CCC1(CS(=O)(=O)NCCC1CCc3ccccc31)C(=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indene (2 ml), 1.99 g, 17.2 mmol) was dissolved in dry THF (2 ml) and stirred at -78° under nitrogen. n-Butyllithium (6.87 ml of a 2.5M solution in hexane: 17.2 mmol) was added, and the solution was then warmed to ambient temperature, stirred for 15 minutes, recooled to -78°, and added via syringe to a solution of chloroacetonitrile (1.09 ml, 1.30 g, 17.2 mmol) in THF (2 ml) stirred at -78°. After completion of the addition, the solution was diluted with ether (200 ml) and washed with 1M HCl followed by saturated sodium bicarbonate solution. The ether layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 10% EtOAc in hexane and the product fractions evaporated in vacuo to give 3-cyanomethylindene. 3-Cyanomethylindene (310 mg, 2.0 mmol) was dissolved in a 10% solution of conc. ammonium hydroxide in absolute ethanol. 5% Rhodium/alumina catalyst (60 mg) was added and the mixture was shaken under an atmosphere of hydrogen (40 psi) overnight. The mixture was filtered, and the filtrate was evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 93:7:0.7 CH2Cl2 :MeOH:NH4OH, and the product fractions were combined and evaporated to dryness in vacuo to provide 1-(2-aminoethyl)indane. 1-(2-Aminoethyl)indane (47 mg, 0.292 mmol) and (+)-10-camphorsulfonyl chloride (73 mg, 0.29 mmol) were combined in CH2Cl2 (2 ml), treated with triethylamine (2 drops), and stirred at ambient temperature overnight. The mixture was evaporated to dryness in vacuo and the residue chromatographed on a silica gel column eluted in with 20% EtOAc in hexane. The product fractions were combined and evaporated to dryness in vacuo. The resulting oil was dried in vacuo at ambient temperature for 3 hours to provide the title compound as a solid: (mp 52°-70°).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[Br:16][C:7]1[CH:6]=[C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C#N)cc1Br
Reaction time: 2 h
Yield: 41 %

Procedure:
A solution of 5.2 g (27 mmol) of 4'-methyl-1,1'-biphenyl-2-nitrile (Step B) in 60 mL of methylene chloride at 0° C. was treated with 6.7 g of silver trifluoroacetate (30 mmol). When all the silver trifluoroacetate was dissolved, 1.6 mL of bromine was added dropwise (4.95 g, 31 mmol) with vigorous stirring. After two hours, the reaction mixture was filtered and the solid washed with methylene chloride. The combined organic layers were washed once with dilute (<1 N) aqueous sodium hydroxide and once with brine. The organic layer was removed, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica, eluting with 10% etherexane to give 3 g (41%) of product. 1H NMR (200 MHz, CDCl3): δ 2.46 (s, 3H), 7.2-7.8 (m, 7H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:19][CH2:20]Cl)[C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]=1[CH3:16].[NH:22]1[C:26]([NH2:27])=[CH:25][CH:24]=[N:23]1>>[CH3:13][C:11]1([CH3:14])[CH2:10][C:9]2[C:15]([CH3:16])=[C:5]([N:4]3[CH2:19][CH2:20][N:27]([C:26]4[CH:25]=[CH:24][NH:23][N:22]=4)[CH2:2][CH2:3]3)[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]=2[O:12]1
Reactant: Nc1ccn[nH]1
Reactant: Cc1c(C)c(N(CCCl)CCCl)c(C)c2c1OC(C)(C)C2
Product: Cc1c(C)c(N2CCN(c3cc[nH]n3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 13.5 %

Procedure:
By using N,N-bis(2-chloroethyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (165 mg, 0.50 mmol) synthesized in Reference Example 146 and 1H-pyrazole-5-amine (59 mg, 0.60 mmol), the reaction was carried out in the same manner as Example 117 to obtain 23 mg of the title compound as a colorless solid (yield 12%).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:34][CH2:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: NCC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: NCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 44.8 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 100 mg of 3-(aminomethyl)azetidine dihydrochloride, and 200 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 25 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 42 mg of the title compound as a colorless powder.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:20])([CH:17]([CH3:19])[CH3:18])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].[CH3:21][N:22]=[C:23]=[O:24]>CN(C=O)C.C1COCC1>[CH3:20][C:3]([NH:2][C:23]([NH:22][CH3:21])=[O:24])([C:4](=[O:5])[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:17]([CH3:18])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(C)(N)C(C)C)cc1
Reactant: CN=C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A solution of 2-amino-2,3-dimethyl-N-(p-tolylsulfonyl)butyramide hydrochloride (5 g, 15.58 mmols) dissolved in 50 mL of DMF under nitrogen is cooledto -30° C. Then 10 mL of methyl isocyanate in 10 mL of THF is added at such a rate that temperature is maintained at -30° C., and the reaction mixture is allowed to stir for two hours at -30° C. and then for 16 hours at room temperature.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20](Cl)=[O:21])[CH:15]=1.CCOC(C)=O>C1COCC1>[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH3:3])=[CH:5]2)=[O:21])[CH:15]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cn(C(=O)c2cc(Cl)ncn2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 120 mg (3.00 mmol) sodium hydride (60% in mineral oil) were added batchwise to 380 mg (2.90 mmol) 3-methylindole in 15 mL THF and the mixture was stirred for 30 min at RT. 500 mg (2.83 mmol) 6-chloropyrimidine-4-carboxylic acid chloride were added batchwise and then the reaction mixture was stirred for 2 h at RT. Then 50 mL EtOAc were added and the mixture was washed with 50 mL saturated sodium hydrogen carbonate solution (1×), 30 mL water and with 50 mL 1 M hydrochloric acid. The organic phase was dried on sodium sulphate, filtered and then evaporated down i. vac. The product was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]1[C:11]([C:12]2[CH:26]=[CH:25][C:15]3[N:16]=[C:17]([C:19]4[O:20][C:21]([NH2:24])=[CH:22][CH:23]=4)[NH:18][C:14]=3[CH:13]=2)=[N:10][NH:9][C:8](=[O:27])[CH2:7]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:5][CH:6]1[C:11]([C:12]2[CH:26]=[CH:25][C:15]3[N:16]=[C:17]([C:19]4[O:20][C:21]([NH:24][C:1](=[O:3])[CH3:2])=[CH:22][CH:23]=4)[NH:18][C:14]=3[CH:13]=2)=[N:10][NH:9][C:8](=[O:27])[CH2:7]1
Reactant: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(N)o3)[nH]c2c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(-c2nc3ccc(C4=NNC(=O)CC4C)cc3[nH]2)o1
Reaction time: 3 h

Procedure:
0.3 ml of acetyl chloride in 3 ml of chloroform is added to a solution of 309 mg of 5-methyl-6-[2-(5-amino-2-furyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one and 0.2 ml of triethylamine in 10 ml of chloroform, and the mixture is boiled for 3 hours. The usual working up is carried out, and 5-methyl-6-[2-(5-acetamido-2-furyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one is obtained.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].I[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[CH2:20]([O:19][C:17]([C:16]1[CH:22]=[CH:23][C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:14][CH:15]=1)=[O:18])[CH3:21]
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#CC2(O)CN3CCC2CC3)cc1
Temperature: 65 °C
Yield: 46.4 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (604 mg), ethyl 4-iodobenzoate (1.1 g), bis(triphenylphosphine)-palladium (II) chloride (140 mg), copper (I) iodide (70 mg) and anhydrous triethylamine (4 ml) and anhydrous dimethylformamide (8 ml) was stirred under an atmosphere of argon. The reaction mixture was heated at 65° C. for 18 hours. The reaction mixture was cooled and the triethylamine and dimethylformamide removed by evaporation. To the residue was added 2M sodium hydroxide (25 ml) and the mixture extracted with dichloromethane. The organic phase was washed with water, saturated brine and dried (MgSO4). Evaporation gave a solid which was crystallised from acetonitrile to give 3-[2-(4-ethoxycarbonylphenyl)ethynyl]-3-hydroxyquinuclidine (553 mg) as a colourless solid, m.p. 176°-177° C.; microanalysis, found: C, 72.2; H, 7.3; N, 4.8%; C18H21NO3 requires: C, 72.2; H, 7.07; N, 4.68%; NMR (DMSO-d6): 1.32(3H, t), 1.49-2.01(5H, m), 2.68(4H, t), 2.78-3.14(2H, d of d), 4.32(2H, q), 5.66(1H, br.s), 7.49-7.58(2H, d) and 7.90-7.98(2H, d); m/Z 300 (M+H).
Reaction SMILES: [CH:1]([CH:4]1[N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7][N:6]2[C:17]3[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=[C:5]12)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:17]3[CH:23]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[CH:20][C:18]=3[N:19]=[C:5]12)([CH3:3])[CH3:2]
Reactant: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1NCCn2c1nc1ccc(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.3 %

Procedure:
To a solution of tert-butyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (20 mg, 0.05 mmol) in CH2Cl2 (1 mL) was added TFA (0.3 mL) under N2. The mixture was stirred at rt for 1 h. The mixture was concentrated to afford 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (20 mg, TFA salt, 100% yield) as a yellow solid, which was used for the next step without further purification. LC-MS m/z 352.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:15][C:16]1[N:17]=[C:18]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[NH2:26])[S:19][CH:20]=1>>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:26][C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:18]3[S:19][CH:20]=[C:16]([CH3:15])[N:17]=3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)Cc1cccc2cnccc12
Reactant: Cc1csc(-c2sccc2N)n1
Product: Cc1csc(-c2sccc2NC(=O)Cc2cccc3cnccc23)n1

Procedure:
2-(Isoquinolin-5-yl)-N-(2-(4-methylthiazol-2-yl)thiophen-3-yl)acetamide was prepared from 2-(isoquinolin-5-yl)acetic acid (63 mg, 0.341 mmol) and 2-(4-methylthiazol-2-yl)thiophen-3-amine (67 mg, 0.341 mmol) according to protocol A. Retention time (min)=3.130, method [7], MS (ESI) 366.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 11.55 (s, 1H), 9.64 (s, 1H), 8.60 (d, J=6.8 Hz, 1H), 8.39 (d, J=6.6 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.05-8.08 (m, 2H), 7.88-7.91 (m, 1H), 7.24 (d, J=5.5 Hz, 1H), 6.74 (s, 1H), 4.31 (s, 2H), 2.45 (s, 3H).
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])[CH:3]=O.[NH2:14][C:15]([NH2:17])=[O:16].COC1C=CC=CC=1N>C(O)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][C:2]1[O:16][C:15]([NH2:17])=[N:14][CH:3]=1
Reactant: NC(N)=O
Reactant: COc1ccccc1CC(Cl)C=O
Solvent: CCO
Solvent: COc1ccccc1N
Product: COc1ccccc1Cc1cnc(N)o1

Procedure:
A mixture of 2-chloro-3-(2-methoxylphenyl)-propionaldehyde (10 g, crude from above) and urea (9.6 g, 0.16 mol) was dissolved in ethanol (250 mL) and then heated to reflux overnight. The solvent was evaporated to dryness. The residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10% aqueous solution, 100 mL) and water (50 mL). The organic layer was extracted three times with hydrochloric acid (5% aqueous solution, 250 mL). The combined aqueous layers were adjusted to pH 9 to 10 with a 10% aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300 mL). The organic layer was separated, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by silica gel column chromatography to yield the yellow-red solid product. (0.72 g, 0.35% from 2-methoxyaniline). ESI-MS m/z calc. 204.1. found 205.1 (M+1)+ 1H NMR (CDCl3) δ 7.26-7.20 (m, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.91-6.86 (m, 2H), 6.35 (s, 1H), 4.49 (bs, 2H), 3.85 (s, 2H), 3.82 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[NH2:17].CCN(CC)CC>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:17][CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]1)=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: NC1Cc2ccccc2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1Cc2ccccc2C1)C(F)(F)F
Temperature: 25 °C
Yield: 82 %

Procedure:
Under N2 at −75° C., trifluoroacetic acid was added to a stirring solution of 2,3-dihydro-1H-inden-2-amine (HCl salt, 8.0 g, 47.2 mmol), Et3N (14.9 ml, 106.7 mmol) and THF (160 ml). After the solution was allowed to warm up to rt, it was partitioned between H2O and DCM. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was triturated with hexanes:Et2O (1:1) to obtain the product as a white solid (8.9 g, 82% yield). 1H-NMR (400 MHz, CDCl3) δ 7.28-7.20 (m, 4H), 6.50 (s, 1H), 4.81-4.74 (m, 1H), 3.38 (dd, J=16.4, 7.1 Hz, 2H), 2.89 (dd, J=16.3, 4.2 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:41]1[CH:66]=[CH:65][C:44]2[NH:45][C:46]([C@@H:48]3[CH2:52][C@H:51]([CH3:53])[CH2:50][N:49]3[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[N:47][C:43]=2[CH:42]=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:41]4[CH:66]=[CH:65][C:44]5[NH:45][C:46]([C@@H:48]6[CH2:52][C@H:51]([CH3:53])[CH2:50][N:49]6[C:54](=[O:64])[C@@H:55]([NH:59][C:60]([O:61][CH3:62])=[O:63])[CH:56]([CH3:57])[CH3:58])=[N:47][C:43]=5[CH:42]=4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[N:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(I)ccc2[nH]1)C(C)C
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)n5)cc4)cc3)ccc2[nH]1)C(C)C
Temperature: 80 °C
Yield: 37.9 %

Procedure:
To a suspension of (2S,4S)-4-methyl-2-{4-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (138 mg, 0.2606 mmol), methyl ((S)-1-((2S,4S)-2-(5-iodo-1H-benzo[d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (126.2 mg, 0.2606 mmol), Pd(DPPF)(Cl)2.CH2Cl2 (21.3 mg, 0.02606 mmol) in 2-propanol (1.4 mL) is added 1M aqueous NaHCO3 (1.3 mL, 1.3 mmol). The reaction mixture is heated at 80° C. for 19 hours, cooled to RT, and extracted with dichloromethane (2×10 mL). The organic layer is dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (50 to 100% EtOAc in hexanes) to give (2S,4S)-2-[4-(4′-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-1H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (75 mg, 38%). HPLC: Waters symmetry shield RP18 3.5 μm 4.6 mm×50 mm, solvent A: 0.01% TFA in acetonitrile, solvent B: 0.01% TFA in water, gradient: 15:85 A:B to 90:10 A:B over 10 minutes, RT=4.87 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Cl[CH2:31][CH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:35].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH2:32][CH2:33][C:34]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[O:35])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: O=C(CCCCl)N1CCOCC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCCC(=O)N5CCOCC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (41 mg, 0.1 mmol), 4-chloro-1-morpholinobutan-1-one (29 mg, 0.15 mmol) and DIEA (0.1 mL, 0.58 mmol) in NMP (1 mL) was stirred at 80° C. After 10 h, additional 4-chloro-1-morpholinobutan-1-one (51 mg) was added, and the reaction continued overnight. The crude product was purified by RP-HPLC to give 4-(4-(4-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)-1-morpholinobutan-1-one as a white powder; ESMS m/z 571.3.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:14])=[C:5]2[OH:24].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:13]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[OH:24])=[CH:3][C:2]([NH:1][S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=2)(=[O:35])=[O:34])=[CH:11][C:10]=3[F:12])=[O:14])=[CH:18][CH:19]=1
Reactant: Nc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(F)c3ncc(C(=O)NCc4ccc(Cl)cc4)c(O)c3c2)cc1
Reaction time: 2 h

Procedure:
To a flask containing 6-amino-N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide from Example No. 186 (0.06 g) and pyridine (1.5 mL) is added 4-methoxyphenylsulfonyl chloride (0.04 g). The reaction mixture is stirred for 2 hours then concentrated under reduced pressure. The residue is triturated with toluene (2×) and dried in vacuo. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% MeOH:CH2Cl2 to 6% MeOH:CH2Cl2. The product-containing fractions are evaporated to give 0.04 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([Cl:11])[C:3]=12.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1cnc2[nH]cnc(Cl)c1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(Cl)c2c(Cl)ncnc21
Reaction time: 0.33 h

Procedure:
To a solution of 4,5-dichloro-1H-pyrrolo[2,3-d]pyrimidine D39 (1 g) in DMF (20 ml) at 0° C. was added sodium hydride (60% w/w in mineral oil, 255 mg, 6.4 mmol) and the mixture stirred for 20 mins. Phenylsulfonyl chloride (1.31 g, 7.4 mmol) was the added dropwise and the reaction mixture was kept in a cool bath for 15 hours. The mixture was poured into water (40 ml), and the precipitate was filtered, washed with water and Et2O, dried in a vacuum to give the desired product D40 in 1.62 g as an ashen solid. LCMS [MH+] 329.9@1.77 min (5 min run)
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.Cl[CH2:30][C:31]#[N:32].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:31]([CH2:30][N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:27])[F:28])=[CH:10][CH:11]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17]1)#[N:32]
Reactant: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Reactant: N#CCCl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 70 °C

Procedure:
A mixture of 2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 1 (16 g, 0.052 mole), chloroacetonitrile (8 g, 0.10 mole) and sodium bicarbonate (17 g, 0.20 mole) in DMF (125 ml) was warmed at 70° C. for 2.5 hours. The mixture was concentrated to an oil which was stirred with water and extracted with ethyl acetate. The organic extracts were washed twice with water and dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to an oil (18 g) which solidified upon triturating with petroleum ether to a solid (16.5 g, 92%, m.p. 125°-129° C. A sample was recrystallized from the hexanes to yield 3-cyanomethyl-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, m.p. 134°-135° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][C:14]([CH3:19])([CH2:17][OH:18])[CH2:15][OH:16]>>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([O:16][CH2:15][C:14]([CH3:19])([CH3:13])[CH2:17][OH:18])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C)(CO)CO
Product: CC(C)(CO)COc1ccc(N)cc1C#N
Yield: 59.7 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 2 using 2-chloro-5-nitrobenzonitrile (10 g) and 2,2-dimethyl-1,3-propanediol (5.7 g), the title compound (7.2 g) was obtained. melting point: 194-196° C.