Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][NH:33][C:32](=[O:36])[CH2:31]2)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:32](=[O:36])[CH2:31]2)=[CH:37][CH:38]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CN(CCc2ccc(F)cc2)CCN1
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 33.5 %

Procedure:
tert-Butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (1.6 g, 4.4 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (0.96 g, 4.3 mmol) were reacted according to Example 2 (step f) to provide the title compound (730 mg, 33%) as a yellow powder: ESI MS m/z 507 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH3:11])[C:8]([OH:10])=O)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][N:27]([C:8](=[O:10])[CH:7]([N:6]4[C:2]([CH3:1])=[N:3][C:4]([C:12]([F:15])([F:14])[F:13])=[N:5]4)[CH3:11])[C:26]=3[CH:25]=[N:24]2)=[CH:21][CH:22]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1nc(C(F)(F)F)nn1C(C)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)nn1C(C)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of 2-[5-methyl-3-(trifluoromethyl)-1,2,4-triazol-1-yl]propanoic acid (0.051 g, 0.23 mmol) and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.050 g, 0.23 mmol) in DMF (1 mL) were added Hunig's base (0.059 g, 0.46 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU) (0.096 g, 0.25 mmol). The mixture was stirred at room temperature for 1 hour and then partitioned between water (4 mL) and ethyl acetate (6 mL). The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (0.029 g, 0.069 mmol, 30%). 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.44 (ddd, J=10.4, 5.2, 2.8 Hz, 2H), 7.21-7.10 (m, 2H), 5.61 (q, J=7.1 Hz, 1H); 3.77 (ddd, J=12.6, 7.5, 3.0 Hz, 1H), 3.52 (ddd, J=12.5, 8.4, 3.0 Hz, 1H), 2.82 (td, J=6.4, 2.4 Hz, 2H), 2.52 (s, 3H), 2.10-1.80 (m, 5H); MS: (ES) m/z calculated for C19H18ClF3N6O [M+H]+ 423.1, found 422.9.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([O:26]C3C=CC=CC=3)=O)=[CH:19][CH:18]=2)[C:7]2[CH:33]=[CH:34][CH:35]=[CH:36][C:6]1=2)=[O:4].[C:37]1([CH2:43][CH2:44][NH2:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:45][CH2:44][CH2:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:26])=[CH:21][CH:22]=2)[C:7]2[CH:33]=[CH:34][CH:35]=[CH:36][C:6]1=2)=[O:4]
Reactant: NCCc1ccccc1
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CCl)c3ccccc32)cc1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccccc1)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CCl)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
To a solution of (3aR*,10aS*)-4-(chloroacetyl)-9-[4-(phenoxycarbonylamino)benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (151 mg, 0.3 mmol) in DMF (1.5 mL) was added 2-phenylethylamine (38 μl, 0.3 mmol) and the mixture was stirred at room temperature for 4 hours. This reaction mixture was diluted with ethyl acetate and washed with 2 portions of water and, then, with saturated aqueous NaCl solution. This solution was dried over NaSO4 and concentrated under reduced pressure and the residue was crystallized from ethanol-diethyl ether to provide 62 mg (yield 39%) of the title compound. m.p. 224°-226° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=1.[Br:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)=[N:22][CH:23]=1>>[Br:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[O:16])[CH2:26]2)=[N:22][CH:23]=1
Reactant: Brc1cnc(N[C@@H]2CCCNC2)nc1
Reactant: O=C(O)c1ccccc1-c1ccccc1F
Product: O=C(c1ccccc1-c1ccccc1F)N1CCC[C@@H](Nc2ncc(Br)cn2)C1

Procedure:
prepared by reaction of 2′-fluoro-biphenyl-2-carboxylic acid with (R)-(5-bromo-pyrimidin-2-yl)-piperidine-3-yl-amine.
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([NH:13][C:14](=[O:16])[CH3:15])[CH2:8][C:7](=[O:17])[C:6]=2[C:5]([O:18][CH3:19])=[C:4]([N+:20]([O-])=O)[CH:3]=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[NH2:20][C:4]1[CH:3]=[CH:2][C:12]2[CH2:11][CH2:10][C@H:9]([NH:13][C:14](=[O:16])[CH3:15])[CH2:8][C:7](=[O:17])[C:6]=2[C:5]=1[O:18][CH3:19]
Reactant: COc1c([N+](=O)[O-])cc(Cl)c2c1C(=O)C[C@@H](NC(C)=O)CC2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1c(N)ccc2c1C(=O)C[C@@H](NC(C)=O)CC2
Yield: 133.4 %

Procedure:
632 g) N—((S)-4-Chloro-1-methoxy-2-nitro-9-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetamide (100 mg, 0.3 mmol), 20% Pd(OH)2/C (30 mg) and Methanol (20 mL) were placed under a blanket of Hydrogen at atmospheric pressure. After 24 h the reaction mixture was filtered and the filtrate concentrated under reduced pressure to yield 105 mg (100%) of N—((S)-2-Amino-1-methoxy-9-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetamide; hydrochloride. TLC: 5:1 CH2Cl2:MeOH Rf 0.5 homogeneous; (SM A: Rf 0.55); 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J=8.09 Hz, 1H), 7.01 (m, 1H), 6.86 (d, J=8.09 Hz, 1H), 3.95 (m, 1H), 3.66 (s, 3H), 3.5 (bs, water+NH2), 2.79-2.64 (m, 4H), 1.95-1.85 (m, 1H), 1.78 (s, 3H), 1.7-1.6 (m, 1H).
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:41]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:42])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)C3CCCCC3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure J using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and cyclohexanecarbonyl chloride as a colorless oil (86%). 1H NMR (CDCl3, 300 MHz) δ 7.70 (d, J=2.3 Hz, 1H), 7.43 (m, 4H), 7.15 (m, 4H), 7.04 (dd, J=8.7, 2.3 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 4.86 (s, 2H), 2.63 (t, J=7.7 Hz, 2H), 2.10 (m, 1H), 1.76 (s, 6H), 1.75-1.56 (m, 10H), 1.42-0.97 (m, 4H), 0.94 (t, J=7.4 Hz, 3H). M+ (ESI): 550.8. HPLC, Rt: 6.45 min (Purity: 100%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=[O:8].Cl.[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>>[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([NH:1][C@H:2]3[CH2:6][CH2:5][CH2:4][C@H:3]3[C:7]([OH:9])=[O:8])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: N[C@H]1CCC[C@H]1C(=O)O
Agent: Cl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Yield: 84.2 %

Procedure:
According to the procedure of Example 10, Step 1, the reaction of 322.9 mg (2.5 mmol) of cis-2-amino-1-cyclopentane-carboxylic acid with 960.7 mg of 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride provided 927.7 mg of cis-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid in 84% yield. MS: 441.1 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([F:31])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([O:39][C:40](=O)[NH:41][CH:42]2[CH2:44][CH2:43]2)C=CC=CC=1>CS(C)=O>[CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:40]([NH:41][CH:42]2[CH2:44][CH2:43]2)=[O:39])=[C:26]([F:31])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CC1)Oc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1NC(=O)OCc1ccccc1
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(F)c3)c2cc1NC(=O)OCc1ccccc1
Yield: 9.2 %

Procedure:
[4-(4-Amino-3-fluorophenoxy)-7-methoxyquinolin-6-yl]carbamic acid benzyl ester (100 mg) and cyclopropylcarbamic acid phenyl ester (64 mg) were heated and stirred in dimethylsulfoxide (0.7 ml) at 85° C. for 5 hours and 40 minutes, in the same manner as Example 224, to obtain the title compound (11 mg) as a solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[O:12]C.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[O:20]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[OH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(C(F)(F)F)ccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Oc1cc(C(F)(F)F)ccc1Oc1ccccc1
Temperature: 130 °C
Reaction time: 17 h
Yield: 51.8 %

Procedure:
A mixture of 4-fluoro-3-methoxybenzotrifluoride (5.26 g, 28.9 mmol), phenol (2.71 g, 28.8 mmol) and 325 mesh potassium carbonate (4.79 g, 34.7 mmol) in dry DMSO (50 mL) is heated to 130° C. and stirred for 17 hours under N2. The reaction is filtered, and the filtrate is acidified with 1 N HCl. The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 15/1 hexanes/ethyl acetate to afford 3.79 g (49%) of the title compound (Rf=0.47 (4/1 hexanes/EtOAc) that is contaminated with starting 4-fluoro-3-methoxybenzotrifluoride.
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[N:6][N:7]=1.[N:15]1([CH2:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)[NH2:21])[CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:19][C@@H:20]([NH:21][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[N:6][N:7]=2)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:30])([F:31])[F:32])[CH:23]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: N[C@H](CN1CCC1)c1ccc(F)c(C(F)(F)F)c1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(N[C@H](CN3CCC3)c3ccc(F)c(C(F)(F)F)c3)nnnc12

Procedure:
Compound 12 was prepared following general synthesis scheme 7 wherein 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide was reacted with (S)-2-(azetidin-1-yl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid. LC-MS [435 (M+1)].
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1)=O)C1C=CC=CC=1>[Pd].C(O)C>[NH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1
Reactant: O=C(NCCCc1ccc(CO)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NCCCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Palladium on carbon (5%, 0.15 g) was added to a solution of 4-(3-benzyloxycarbonylaminopropyl)benzylalcohol (1.00 g), which is the product of Reference example 50(a) in ethanol (20 ml). The mixture was stirred under an atmosphere of hydrogen at ambient temperature for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated to afford 4-(3-aminopropyl)benzylalcohol as a gum. In a similar manner to that described in Example 5, a reaction was carried out using 4-(3-aminopropyl)benzylalcohol, 4-pyridine-2-ylbenzoic acid (668 mg) and carbonyidiimidazole (650 mg) and the reaction mixture was treated to afford the desired compound (0.74 g) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][CH3:13])=[CH:3]1.CCN(CC)CC.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]([CH3:13])[C:21](=[O:24])[CH:22]=[CH2:23])=[CH:3]1
Reactant: C=CC(=O)Cl
Reactant: CNCc1cn(C)c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1cn(C)c2ccccc12
Reaction time: 1 h

Procedure:
To a stirred solution of 1-methyl-3-(methylaminomethyl)-1H-indole (1.0 g, 5.7 mmole) and Et3N (0.8 mL, 5.7 mmole) in CH2Cl2 (50 mL) at 0° C. was added acryloyl chloride (0.47 mL, 5.8 mmole) in one portion. After stirring for 1 h the reaction was washed with cold H2O and brine, then was dried (MgSO4) and concentrated under vacuum. This material was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:28][CH3:29])[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:30]>CO.ClCCl.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>[CH2:28]([C:13]1[N:14]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:17]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:30])[C:11]=2[N:12]=1)[CH3:29]
Reactant: CCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Reactant: N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2-ethyl-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinoline (2.624 g, 6.451 mmol), 7 N ammonia in methanol (40 mL), and tetrakis(triphenylphosphine)palladium(0) were combined in a pressure vessel and heated at 120° C. for 16 hours. An analysis by HPLC indicated that the reaction was incomplete. The volatiles were removed under reduced pressure, and the residue was dissolved in chloroform. The solution was washed sequentially with aqueous potassium carbonate, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The resulting dark yellow solid was added to a pressure vessel with 7 N ammonia in methanol (60 mL), and the reaction was sealed and heated at 150° C. for 18 hours. The volatiles were removed under reduced pressure, and the residue was stirred with 0.5 N potassium hydroxide in methanol for 30 minutes. The resulting solid was isolated by filtration, diluted with dichloromethane, purified by column chromatography on silica gel (eluting with 5% to 10% CMA in chloroform), triturated with diethyl ether and filtered, and recrystallized from acetonitrile after a hot filtration. The crystals were isolated by filtration, washed with diethyl ether, and dried to provide 0.139 g of 2-ethyl-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 232.0-233.0° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[O:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: OC1CCOCC1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Temperature: 70 °C
Yield: 86 %

Procedure:
2,4-Dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), tetrahydro-2H-pyran-4-ol (1.05 equiv), sodium tert-butoxide (1.05 equiv) and 1,4-dioxane (0.56 M) were combined and heated at 70° C. for 5 h. The reaction mixture was concentrated and extracted with ethyl acetate/H2O. The organic layers were combined, evaporated under reduced pressure and purified by silica-gel chromatography (0-50% hexane:ethyl acetate over 800 mL) followed by 5-15% (DCM:MeOH over 800 mL). Pure fractions were combined, evaporated under reduced pressure and dried under high vacuum to give the title compound (86% yield) as a yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.57 (s, 1H), 5.62-5.70 (m, 1H), 5.59 (s, 2H), 4.11-4.19 (m, 2H), 3.74-3.82 (m, 2H), 3.62 (d, J=8.20 Hz, 2H), 2.15-2.24 (m, 2H), 1.91-2.01 (m, 2H), 0.90-0.98 (m, 2H), 0.00 (s, 9H); MS (ESI) m/z 510.2 [M+1]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:11]3[CH2:12][CH2:13][C:14]2=[C:15]([C:19]#[N:20])[C:16]([OH:18])=[O:17])[CH2:6]1)(=[O:3])[CH3:2].O1CCCC1.[OH-].[Na+].[H][H]>[Pd].C(O)C>[C:1]([O:4][C@H:5]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([C:19]#[N:20])[C:16]([OH:18])=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=C(C#N)C(=O)O)CC[C@@H]32)C1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C#N)C(=O)O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
37 g. of the ethyl ester of 3β-acetoxy-20-cyano-5,17(20)-pregnadiene-21-oic acid is mixed in 450 ml. of tetrahydrofuran and 150 ml. of ethanol with 2.5 g. of 10% palladium-charcoal catalyst and 2 ml. of N/10 sodium hydroxide solution and hydrogenated under normal pressure with hydrogen at room temperature. The reaction mixture is worked up as set forth in Example 1(b), thus obtaining the ethyl ester of 3β-acetoxy-20-cyano-5-pregnene-21-oic acid (34 g.), m.p. 170° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH:10](O)=O>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][CH:10]=[N:9][C:4]=2[CH:3]=1
Reactant: O=CO
Reactant: Nc1cnc(Cl)cc1N
Product: Clc1cc2nc[nH]c2cn1
Yield: 82 %

Procedure:
A mixture of 6-chloropyridine-3,4-diamine (4.00 g, 27.86 mmol) in formic acid (20.0 mL) was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure to give a brown oil, which was partitioned between EtOAc (300 mL) and a sat'd aq NaHCO3 (100 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (6% to 9% MeOH) to afford 3.5 g (82%) of 6-chloro-3H-imidazo[4,5-c]pyridine as white solid, MS (ESI): m/z=154.1 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:15])([C:11]([F:14])([F:13])[F:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O>[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:15])([F:1])[C:11]([F:12])([F:13])[F:14])(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCC(F)(F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCC(F)(F)C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
3.0 g of 8,8,9,9,9-pentafluorononan-1-ol are dissolved in 26 ml of abs. pyridine, 3.1 g of p-toluenesulphonyl chloride are added at 0° C. and the mixture is stirred in the cold for 1.5 hours. The reaction mixture is then added to water, extracted 3 times with ether, dried over magnesium sulphate and concentrated in vacuo. Preparative column chromatography on silica gel using a hexane-ethyl acetate gradient leads to 4.1 g of 8,8,9,9,9-pentafluorononyl tosylate as a clear oil.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].S(OC(C#C)C)([C:16]1[CH:22]=CC(C)=[CH:18][CH:17]=1)(=O)=O>CN(C=O)C>[C:1]1(=[O:11])[N:5]([CH:17]([C:16]#[CH:22])[CH3:18])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: C#CC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: C#CC(C)N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of potassium phthalimide (0.275 mole; 5.1 g) in DMF (20 ml), 2-tosyloxy-3-butyne (0.25 mole) is added and allowed to react for 3 hours at 70° C. After cooling, the reaction mixture is extracted with chloroform and the chloroform layer is washed and dried. Removal of the chloroform, in vacuo, yields crude 2-phthalimido-3-butyne.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:7]=1.[Cl:17][C:18]1[CH:31]=[CH:30][C:29]2[CH:28]3[CH2:32][C:21]([CH2:33][N:34]4[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]4)([C:22]4[C:27]3=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:20]=2[CH:19]=1>>[Si:10]([O:9][CH2:8][C:6]1[CH:7]=[C:2]([C:37]2([OH:40])[CH2:38][CH2:39][N:34]([CH2:33][C:21]34[CH2:32][CH:28]([C:29]5[CH:30]=[CH:31][C:18]([Cl:17])=[CH:19][C:20]=53)[C:27]3[C:22]4=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:35][CH2:36]2)[CH:3]=[N:4][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(Br)c1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Product: CC(C)(C)[Si](C)(C)OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)c1
Yield: 51 %

Procedure:
Using a procedure similar to that described in example 1 except employing 3-bromo-5-(tert-butyldimethylsilyl)oxymethylpyridine (described in example 69b) and 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 1m), the title compound was formed in 51% yield as an oil. TLC analysis (Rf 0.20, 25% ethyl acetate in hexane). MS (CI, CH4) m/z 561 (M+1,100), 563 (40), 589 (M+29,20), 545 (26), 429 (26)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH2:25]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,4-dimethoxyaniline were reacted to yield N2-(3,4-dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 20.98 min.; purity: 74%; MS (m/e): 399 (MH+).