Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.O.[Cl:9][C:10]1[S:14][C:13]([C:15]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[C:20](=[O:44])[N:21]([CH2:28][C:29]2[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=2)[CH2:32][NH:33]C(=O)OC(C)(C)C)[C:22]3=[O:27])=[O:16])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[NH2:33][CH2:32][C:31]1[CH:30]=[C:29]([CH:43]=[CH:42][CH:41]=1)[CH2:28][N:21]1[C:20](=[O:44])[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[NH:17][C:15]([C:13]2[S:14][C:10]([Cl:9])=[CH:11][CH:12]=2)=[O:16])[C:22]1=[O:27]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40 ml of a mixture of TFA and water (9:1) are added dropwise to an ice-cooled mixture of 3.95 g (7.5 mmol) of tert-butyl 3-[(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzylcarbamate in 40 ml of chloroform. Ice-cooling is removed and the solution is stirred at room temperature for 2 h and then concentrated. The residue is taken up in dichloromethane/methanol (98:2) and the mixture is washed with sat. sodium bicarbonate solution, dried over magnesium sulfate and concentrated. Yield: 3.22 g (97.8% of theory);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[N+:16]([O-])=O.[H][H]>CO>[NH2:16][C:3]1[CH:4]=[CH:5][C:6]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(S(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Solvent: CO
Product: Nc1ccc(S(=O)c2ccccc2)cc1N

Procedure:
5.4 G. of 2-amino-4-phenylsulfinyl-1-nitrobenzene is hydrogenated at 1 atmosphere pressure in 500 ml. methanol in the presence of 5 g. 5% palladized carbon, until the theoretical uptake of hydrogen has occurred. The catalyst is removed by filtration and the filtrate stripped under vacuum. The residue is recrystallized from methanol-benzene, yielding 1,2-diamino-4-phenylsulfinylbenzene.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11].O>ClCCl.C(O)=O>[CH:1]([NH:8][C@@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:14]([OH:16])=[O:15])=[O:3]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC=O)C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of acetic anhydride (18 ml) in dichloromethane (15 ml) was added drop wise to a cooled (0° C.) solution of L-tert-leucine (5 g) in formic acid (50 ml). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 3 h. Water (25 ml) was added. The mixture was stirred for another 30 min, concentrated in vacuo and co-evaporated twice with toluene. The remaining residue was triturated with diethyl ether. The solids were collected and dried in vacuo (50° C.).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23](=[O:28])[CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23]([OH:28])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:24]2)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ccccn1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
n-Butyl lithium (2.5 M, 2.4 mL, 6.0 mmol) was added dropwise to a solution of 2-bromopyridine (0.57 mL, 6.0 mmol) in THF (10 mL) at −78° C. under nitrogen and stirred for 30 minutes. A solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.3 g, 5.78 mmol) in THF (10 mL) was added dropwise and the mixture stirred at −78° C. for 1 hour. The reaction mixture was warmed to room temperature then saturated aqueous sodium hydrogen carbonate and ethyl acetate were added, the organics separated, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 20-50% ethyl acetate/pentane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.62 g). LCMS m/z 305.3 [M+H]+. R.T.=2.50 min (Analytical Method 3).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.CC([O-])(C)C.[K+].C1COCC1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O>[CH2:21]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2[nH]nnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(Cn2nnc3ccccc32)cc1
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of benzotriazole (1.2 g, 10.1 mmol) in DMF (40 mL) at r.t. was added a solution of 1M KOtBu in THF (11 mL, 11 mmol). After stirring for 30 min., benzyl bromide (2.0 g, 11.6 mmol) was added. The mixture was further stirred for 1 h, diluted with H2O, and extracted with EtOAc. The EtOAc extract was washed with H2O (3×), dried (MgSO4) and concentrated. The residue was stirred with hexane containing small amount of Et2O to give 1.2 g (57%) of the title compound as a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.[N+]([CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O-])=O>CCO>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:22]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:13][C:12]=3[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Solvent: CCO
Product: COc1ccc(Cn2cc(-c3ccccc3)c3c2CCNC3)cc1

Procedure:
The title compound (0.19 g) was prepared from 1.51 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 1.0 mL of 4-methoxybenzylamine, and 1.13 g of (2-nitro-vinyl)-benzene, using EtOH as the solvent and omitting SiO2. MS (ESI): exact mass calculated for C21H22N2O, 318.17; found, m/z 319.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.30 (m, 4H), 7.20-7.15 (m, 1H), 7.14-7.11 (m, 2H), 7.08 (s, 1H), 6.90-6.87 (m, 2H), 5.05 (s, 2H), 4.34 (s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.88 (t, J=6.3 Hz, 2H).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[K+].[K+].[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][CH:20]([NH2:29])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=2[CH3:28])[CH:15]=[C:16]([CH3:18])[CH:17]=1.ClCCl>C(Cl)(Cl)Cl.O>[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][CH:20]([N:29]=[C:1]=[S:2])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=2[CH3:28])[CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(C)cc(CC(N)c2cccc(C)c2C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)cc(CC(N=C=S)c2cccc(C)c2C)c1

Procedure:
A solution of thiophosgene (39.5 g) in 200 ml of chloroform was treated with a solution of potassium carbonate (99 g) in water (200 ml) at room temperature. To this mixture was added a solution of 2-(3,5-dimethylphenyl)-1-(2,3-dimethylphenyl)-ethylamine (72.5 g) in chloroform (600 ml) with vigorous stirring. After completion of the reaction the mixture was poured into dichloromethane (500 ml) and washed three times with water, dried over sodium sulphate and the solvent evaporated in vacuo. This yielded the title compound [2-(3,5-Dimethyl-phenyl)-1-(2,3-dimethyl-phenyl)-ethyl]-isothiocyanate in form of a yellow oil (81.9 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:24](O)([CH3:27])([CH3:26])[CH3:25].C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:9]
Reactant: COC(=O)CCCCC(=O)O
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCCCC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of adipic acid monomethyl ester (4.8 g, 30 mmol) in DMF (30 mL), was added CDI (4.9 g, 30 mmol), and the resulting mixture was stirred under N2 at 40° C. for 1 hour. t-Butanol (4.4 g, 60 mmol) and DBU (4.6 g, 30 mmol) were added, and stirring proceeded at 40° C. for 70 hours. The mixture was poured into ether (100 mL), and this mixture was washed with 10% aq. HOAc (100 mL), 10% aq. K2CO3 (100 mL), and water (3×100 mL), dried (MgSO4), and evaporated, providing 5.1 g of hexanedioic acid tert-butyl ester methyl ester, in 78% yield; 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.59-1.67 (m, 4H), 2.21-2.26 (m, 2H), 3.67 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[S:13][CH:14]=[C:15]([CH3:16])[C:3]=12.[Cl-].[CH2:18]=[N+:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.O.C(=O)(O)[O-].[Na+]>C(#N)C>[OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[S:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:15]([CH3:16])[C:3]=12
Reactant: CCOC(=O)c1cnc2scc(C)c2c1O
Reactant: C=[N+]1CCOCC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnc2sc(CN3CCOCC3)c(C)c2c1O
Temperature: 60 °C
Yield: 96.6 %

Procedure:
A suspension of ethyl 4-hydroxy-3-methylthieno[2,3-b]pyridine-5-carboxylate (Preparation 26, 0.92 g) and 4-methylenemorpholin-4-ium chloride (1.57 g) in acetonitrile (40 mL) is heated to 60° C. for 4 h. The resulting suspension is allowed to cool to room temperature, poured into water, and adjusted to neutral pH with saturated aq. sodium bicarbonate. The solution is extracted with CH2Cl2 (3×100 mL). The combined organic layers are washed with brine (25 mL), dried (Na2SO4), and concentrated to afford 1.26 g of the title compound as a yellow solid. Physical characteristics. M.p. 182-185° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.64, 4.37, 3.70, 3.38, 2.51, 2.47, 1.35; MS (ESI−) m/z 335 (M-H). Anal. Found. C, 56.93; H, 6.10; N, 8.26; S, 9.34.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].Br[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.ClCCl>CCOCC>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]#[C:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9])[CH:12]=1
Reactant: C#CCCCCCCO
Reactant: Brc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: OCCCCCCC#Cc1cccnc1
Yield: 91 %

Procedure:
A mixture of 34.6 g of 7-octyn-1-ol 26.4 mL of 3-bromopyridine, 115 mL of triethylamine and 350 mL of dichloromethane was stirred and flushed with argon. To the mixture was added 3.85 g of bis triphenylphosphine palladium II chloride and 0.365 g of cuprous iodide and then the mixture was refluxed overnight. The cooled reaction mixture was diluted with ether and the solids were filtered, washed well with ether, and then discarded. The filtrates were extracted repeatedly with 1N hydrochloric acid and the combined aqueous layers were made strongly basic with excess sodium hydroxide. The mixture was extracted with dichloromethane, dried over sodium sulfate and evaporated to provide 51 g (91%) of crude 8-(3-pyridinyl)-7-octyn-1-ol. Catalytic hydrogenation in 1000 mL of ethanol using 5 g of 10% palladium on carbon provided, after distillation, 36 g (72%) of 3-pyridineoctanol, bp 145°-152° C. (0.3 mm). Analysis Calculated for C13H21NO: C, 75.32; H, 10.21; N, 6.76. Found: C, 75.13; H, 10.21; N, 6.66.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](B(O)O)=[CH:19][CH:18]=1>>[F:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][CH:18]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(F)c2ccccc12
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)c2ccccc12

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 4-fluoronaphthalene-1-boronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H13FN4, 329. Found, 329.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:47][CH3:48])=[C:13]([NH:16][C:17]3[N:30]4[C:21](=[N:22][C:23]5[C:28]([C:29]4=[O:31])=[C:27]([F:32])[C:26]([F:33])=[CH:25][CH:24]=5)[C:20]4[CH:34]=[CH:35][N:36]([S:37]([C:40]5[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=5)(=[O:39])=[O:38])[C:19]=4[N:18]=3)[CH:14]=2)C[CH2:8][CH2:7]1)=[O:5].[OH-].[NH4+:51].[CH2:52]1[CH2:56]OC[CH2:53]1>C(OCC)(=O)C>[CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:47][CH3:48])=[C:13]([NH:16][C:17]3[N:30]=[C:21]([NH:22][C:23]4[C:28]([C:29]([NH:51][CH:52]([CH3:56])[CH3:53])=[O:31])=[C:27]([F:32])[C:26]([F:33])=[CH:25][CH:24]=4)[C:20]4[CH:34]=[CH:35][N:36]([S:37]([C:40]5[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=5)(=[O:39])=[O:38])[C:19]=4[N:18]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: C1CCOC1
Reactant: [NH4+]
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4ccc(F)c(F)c4c(=O)n13)N(C(=O)CN(C)C)CCC2
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(=O)NC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-8,9-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (270 mg, 0.393 mmol) in THF (5 mL) was added ammonium hydroxide (27% aqueous) (100 mL, large excess). The resulting mixture was let stir at rt for 16 h at which time it was diluted with ethyl acetate and washed with water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure. The residue was purified via chromatography on SiO2 and afforded 6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-(1-methylethyl)benzamide (110 mg, 0.156 mmol) as a yellow solid. (ESIMS (M+H)+=705)
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:11]2[C:6](=[CH:7][C:8]([C:25]3[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:9][CH:10]=2)[N:5]=1.[O:35]([CH:37]([CH3:39])[CH3:38])[Na]>C(O)(C)C>[CH:37]([O:35][CH2:3][C:4]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:11]2[C:6](=[CH:7][C:8]([C:25]3[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:9][CH:10]=2)[N:5]=1)([CH3:39])[CH3:38]
Reactant: CC(C)O[Na]
Reactant: FC(F)(F)c1ccc(Nc2nc(CCl)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)OCc1nc(Nc2ccc(C(F)(F)F)cc2)c2ccc(-c3ncccc3C(F)(F)F)cc2n1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a suspension of [2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine hydrochloride (1.9 g, 0.0037 mol) in dry isopropanol (100 mL), add 20 equivalents of NaO-i-Pr (prepared from Na and isopropanol). Stir the pale yellow mixture at 60° C. for 5 hours, cool and evaporate the solvent under reduced pressure. Partition the residue between ethyl acetate and water and wash the organic layer with water (1×). Dry the organic layer (Na2SO4) and concentrate to give [2-isopropoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine as a foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23](Cl)=[O:24]>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:23](=[O:24])[CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Br:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1Br
Reactant: CCOC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)Cc2ccccc2Br)c[nH]1
Temperature: 0 °C
Yield: 54.9 %

Procedure:
Ethylpyrrole-2-carboxylate (1.9428 g, 13.96 mmol) in a minimal amount (˜5 mL) of dichloroethane was added to an ice cooled stirring mixture of aluminum chloride (4.0458 g, 30.34 mmol) and 2-bromophenylacetyl chloride (6.7116 g, 28.74 mmol) in dichloroethane (44 mL, 0.66 M) under N2. The ice bath was removed, and the reaction was stirred at room temperature for 2 h. 19.2977 g (2.6 mMol/g) Polyamine resin HL (200-400 mesh) and dichloroethane (20 mL) were added, and the reaction was stirred for ˜100 min. The reaction was then filtered through a glass-fritted funnel directly into ice water. The resin was rinsed with CH2Cl2, then the organic layers were removed, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 80:20 to 60:40 Hexanes: EtOAc) to obtain 2.5751 g (54.9%) 63 as a white solid. Note: A small amount of CH2Cl2 was required to solubilize the crude product before placement on the silica column. 1H (CDCl3, 400 MHz): δ 10.32 (1H, broad s), 7.57-7.53 (2H, m), 7.38-7.37 (1H, m), 7.29-7.21 (2H, m), 7.13-7.07 (1H, m), 4.35 (2H, q, J=7.2 Hz), 4.25 (2H, s), 1.36 (3H, t, J=7.2 Hz) ppm. 13C (CDCl3, 100 MHz): δ 191.78, 161.04, 134.91, 132.62, 131.66, 128.59, 127.40, 126.95, 126.25, 124.98, 124.17, 114.88, 60.92, 46.56, 14.26 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.26; CH2 carbons: 60.92, 46.56; CH carbons: 132.62, 131.66, 128.59, 127.40, 126.95, 114.88 ppm. HPLC: 10.078 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([O:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])C>O1CCCC1.C1(C)C=CC=CC=1.[Cl-].[NH4+]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:12](=[O:11])[C:13]([F:16])([F:15])[F:14])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Br)cn1)C(F)(F)F
Reaction time: 0.29 h
Yield: 68.8 %

Procedure:
To a stirred solution of 2,5-Dibromo-pyridine (4 g, 6.87 mmol) in dry tetrahydrofuran (30 mL) and dry toluene (40 mL) is added drop wise n-Butyl litihum (1.62 g, 25.31 mmol) at −78° C. After stirring for 15-20 minutes, added trifluoro-acetic acid ethyl ester (3.56 g, 25.31 mmol) at −78° C. then stirred at −78° C. for another 30 minutes. The reaction mixture is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting in 20% ethyl acetate in hexane to afford the title compound (1.2 g). 1HNMR (400 MHz, DMSO-d6) δ: 7.72 (d, J=8.32 Hz, 1H), 7.85-7.88 (dd, J1=8.32 Hz, J2=2.44 Hz 1H), 8.52 (d, J=2.36 Hz, 1H). LC-MS (m/z): [M+H]=255.8.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[CH2:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([N+]([O-])=O)=[CH:22][CH:23]=2)[C:18]([CH3:28])=[N:17]1)[CH3:15].C([O-])=O.[NH4+]>CO.[Pd]>[CH2:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=3)=[CH:22][CH:23]=2)[C:18]([CH3:28])=[N:17]1)[CH3:15]
Reactant: CCn1nc(C)c2cc([N+](=O)[O-])ccc21
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCn1nc(C)c2cc(NCCc3ccc(C(F)(F)F)nc3)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A solution of (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (849 mg, 4.14 mmol, prepared as per example 47, step 1) and 1-ethyl-3-methyl-5-nitro-1H-indazole (700 mg, 3.76 mmol) in MeOH (10 mL) was treated with ammonium formate (5 eq.) and 10% Pd/C (140 mg) and stirred at 80° C. for 2 h. Filtration, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (794 mg, 61%) as a light yellow oil. MS m/e: 349.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18](Cl)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][S:32][C:33]1[N:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[CH:36]=[CH:35][N:34]=1>O1CCOCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18]([C:35]2[CH:36]=[CH:37][N:38]=[C:33]([S:32][CH3:31])[N:34]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Oc2nc(Cl)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(Oc2nc(-c3ccnc(SC)n3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 50.2 %

Procedure:
To a teflon-lined septum-sealed Schlenk tube, a mixture of Compound 1e (213 mg; 0.49 mmol), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine (Compound 7a) (305 mg; 0.735 mmol) and tetrakis-(triphenylphosphine)palladium(0) (57 mg; 0.049 mmol) in dioxane (1.0 mL) was irradiated in a Microwave reactor at 150° C. for 30 min. The resultant mixture was diluted with EtOAc, and washed with saturated NH4Cl(aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 7b (129 mg; 50% yield). 1H-NMR (400 MHz, CDCl3): δ 8.48-8.50 (m, 1H), 8.08-8.12 (m, 1H), 7.54-7.57 (m, 1H), 7.16-7.23 (m, 2H), 6.96-7.01 (m, 2H), 6.27 (br. s, 0.7H), 5.18 (br, 0.3H), 4.25-4.36 (m, 1H), 3.88 (s, 3H), 3.24-3.59 (m, 4H), 2.68 (s, 3H), 1.79-2.16 (m, 4H), 1.44-1.54 (m, 9H); MS: m/z 525.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH2:30])[CH:24]=1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH:19][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:30][CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[CH:8]=2)[N:3]=1
Reactant: COc1cccc(CN)c1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: NCc1cccnc1
Product: COc1cccc(CNc2ccc3cc(NCc4cccnc4)ccc3n2)c1

Procedure:
The title compound, MS: m/e=371.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 3-methoxybenzylamine and 3-picolylamine.