Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@@H:29]([CH3:34])[C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:34][C@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[C:30](=[O:32])[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCNC1
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)N1CCCC1
Yield: 51.6 %

Procedure:
Using the same procedure as in Example 26, methyl (2S)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) was reacted with pyrrolidine (0.46 ml, 5.5 mmol) to give the title compound as a beige solid (140 mg, 50%), except that the mixture was heated at 55° C. for 20 hours and purified by chromatography on silica gel (eluant: 4% methanol in DCM); NMR Spectrum 1.60 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.49-3.30 (m, 3H), 3.76 (m, 1H), 5.62 (q, 1H), 5.77 (s, 2H), 6.95 (d, 1H), 7.28 (m, 2H), 7.35 (d, 1H), 7.74-7.68 (m, 3H), 7.82 (dd, 1H), 8.15 (s, 1H), 8.53 (m, 3H), 11.08 (br s, 1H); Mass spectrum MH+ 494.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[S:4][C:3]=1[C:12](=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(O[N:25]=O)CC(C)C>C(O)(=O)C.O1CCOCC1>[C:14]([C:13]1[N:25]=[N:1][C:2]2[C:10]3[CH:9]=[CH:8][C:7]([CH3:11])=[N:6][C:5]=3[S:4][C:3]=2[C:12]=1[OH:18])([O:16][CH3:17])=[O:15]
Reactant: CC(C)CCON=O
Reactant: COC(=O)CC(=O)c1sc2nc(C)ccc2c1N
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1nnc2c(sc3nc(C)ccc32)c1O
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of 6 g (0.022 mol) of 3-amino-2-carbomethoxyacetyl-6-methyl-thieno[2,3-b]pyridine in 1.8 ml acetic acid and 180 ml dioxane was slowly added 4.8 g (4.2 ml, 0.041 mol) of isoamylnitrite and stirring continued for 24 hours. It was then poured on ice-water, filtered and washed with water. The crude product was crystallized from DMSO/H2O to give 4.0 g (64%) of 3-carbomethoxy-4-hydroxy-7-methylpyrido[3',2':4,5]-thieno[3,2-c]pyridazine; m.p., 265°-268° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]2([CH3:17])[CH3:16])(=O)[CH3:2].[Cl-].[OH:19][NH3+:20].Cl>N1C=CC=CC=1>[N:20](=[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]2([CH3:17])[CH3:16])[CH3:2])[OH:19]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: [NH3+]O
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Product: CC(=NO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 100.3 %

Procedure:
15 g (65 millimoles) of 6-acetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene and 6.5 g (91 millimoles) of hydroxylammonium chloride in 100 ml of pyridine were heated for 1 hour at 80° C. After cooling, the mixture was poured onto water and acidified with 2N hydrochloric acid. The precipitated crystals were filtered off under suction, washed with water and dried. 16 g of 6-[1-hydroximinoethyl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene were obtained in this manner. 5 g (20 millimoles) thereof and 5 g (20 millimoles) of terephthalic monomethyl ester chloride were combined and were stirred for 6 hours at 120° C. After cooling, the solidified material was dissolved with about 60 ml of methanol. The supernatant methanol phase was decanted and the solid residue was recrystallized twice from chloroform/methanol. 2.5 g of the title compound of melting point 207°-208° C. were obtained in this manner.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15](=[O:17])[CH3:16])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.ClCCl.C(OCC)(=[O:23])C>>[CH:2]12[O:23][CH:3]1[CH2:4][CH2:5][CH2:6][CH:1]2[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)Nc1ccccc1OC1C=CCCC1
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1OC1CCCC2OC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of N-[2-(2-cyclohexen-1-yloxy)phenyl]acetamide (76 mg, 329 μmol, 1.0 equiv.) in dichloromethane (5 ml) m-chlorobenzoic acid (85 proz.; 121 mg, 559 μmol, 1.7 equiv.) was added at 0° C. Stirring was continued overnight while the reaction mixture was allowed to warm up slowly to room temperature. The heterogenous mixture was diluted with ethyl acetate and washed with sat. sodium sulfite, 5% sodium hydroxide and brine. Drying over sodium sulfate, evaporation of the solvent and flash chromatography on silica gel provided 59 mg (73%) of the title compound as a mixture of the diastereoisomers (ratio A:B=trans:cis=5:3 [1H-NMR]).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:43]([C:45]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:56][N:55]([C:57]([N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)=[O:58])[CH2:54][CH:53]([C:65]3[S:66][CH:67]=[C:68]([C:70]([OH:72])=O)[N:69]=3)[CH2:52]2)=[CH:47][CH:46]=1)[CH3:44].[NH2:73][C:74]1[CH:79]=[CH:78][N:77]=[CH:76][CH:75]=1>C1COCC1>[CH2:43]([C:45]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:56][N:55]([C:57]([N:59]3[CH2:60][CH2:61][O:62][CH2:63][CH2:64]3)=[O:58])[CH2:54][CH:53]([C:65]3[S:66][CH:67]=[C:68]([C:70]([NH:73][C:74]4[CH:79]=[CH:78][N:77]=[CH:76][CH:75]=4)=[O:72])[N:69]=3)[CH2:52]2)=[CH:47][CH:46]=1)[CH3:44]
Reactant: CCc1ccc(C2CC(c3nc(C(=O)O)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: Nc1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1ccc(C2CC(c3nc(C(=O)Nc4ccncc4)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 14.9 %

Procedure:
145 mg (0.279 mmol) of PYBOP and 169 mg (1.304 mmol) of N,N-diisopropylethylamine were added to a mixture of 80 mg (0.186 mmol) of the compound from Example 143A in 0.5 ml of THF. The reaction mixture was stirred at room temperature for 40 minutes. 21 mg (0.223 mmol) of 4-aminopyridine were then added, and stirring of the mixture at RT was continued overnight. For work-up, the solvent was evaporated and the residue was taken up in ethyl acetate. The organic phase was washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. Diastereomer separation of the cis/trans isomer mixture according to Method 12C gave 14 mg of the title compound (cis isomer) and 23 mg of the trans isomer.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([F:26])([F:25])[F:24])[CH:8]=2)[N:3]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[CH2:27]([N:29]([CH2:30][CH3:31])[C:2]1[C:11]([C:12]2[N:16]=[N:15][NH:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([F:24])([F:26])[F:25])[CH:8]=2)[N:3]=1)[CH3:28]
Reactant: CCNCC
Reactant: FC(F)(F)c1ccc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Product: CCN(CC)c1nc2ccc(C(F)(F)F)cc2c(-c2ccccc2)c1-c1nn[nH]n1

Procedure:
The title compound was prepared in analogy to example 102 step C from 2-chloro-4-phenyl-3-(1H-tetrazol-5-yl)-6-trifluoromethyl-quinoline (prepared as described in example 102 step B) and diethylamine. Light yellow solid. MS (ESI): 413.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>O1CCCC1.C(N(CC)CC)C>[CH3:40][C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1
Yield: 90.2 %

Procedure:
To a suspension of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (2 g, 0.005 mol) in 20 ml of tetrahydrofuran and 0.5 ml of triethylamine is added a solution of p-toluenesulfonyl chloride (0.95 g, 0.005 mol) in 10 ml of tetrahydrofuran dropwise over a 15 minute period, under nitrogen. After complete addition, the resultant solution is stirred at room temperature for 1 hour. This is quenched in cold water and extracted with methylene chloride (2×, 50 ml). The methylene chloride solution is washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to a yellow solid. This, after re-crystallization from methanol, gives 2.5 g (90%) of white crystalline 1-[(4-methylphenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine with melting point 215°-217° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Nc1cnc2ccccc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-amino-4-chloroquinoline (20.0 g, 112 mmol) in dichloromethane (125 mL) was cooled to 0° C. Triethylamine (47.0 mL, 0.336 mol) was added followed by a solution of acetyl chloride (16.0 mL, 0.224 mol) in dichloromethane (45 mL), which was added dropwise. The reaction was stirred overnight at room temperature. An analysis by LC/MS indicated the presence of starting material, and additional acetyl chloride (4 mL, 56 mmol) was added. The reaction was stirred for four hours at room temperature. Saturated aqueous sodium bicarbonate (100 mL) was added, and the mixture was stirred for three days. The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide N-(4-chloroquinolin-3-yl)acetamide as a dark red solid.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14](=O)[CH3:15])[CH:10]=[CH:11][CH:12]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][OH:29])[CH:22]=1)[CH2:19][NH2:20]>>[C:1]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][OH:29])[CH:22]=2)[CH3:15])[CH:10]=[CH:11][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1cccc(CC(C)=O)c1
Reactant: NCC(O)c1ccc(O)c(CO)c1
Product: COC(=O)COc1cccc(CC(C)NCC(O)c2ccc(O)c(CO)c2)c1

Procedure:
The compound was prepared as in Example 1 from 1-(3-carbomethoxymethoxyphenyl) propan-2-one (1.82 g) and 2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl) ethanamine (1.5 g) and crystallised from benzene m.p. 60°-64° as a 42:58 mixture of diastereoisomers.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([N+]([O-])=O)=[O:27]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 75.9 %

Procedure:
3.0 g of 1-(2-chloroethyl)-3-n-propyl-3-L-arabinopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.5 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-L-arabinopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH3:16][C:17]([NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH:33]1[CH2:35][O:34]1)([CH3:22])[C:18]([O:20][CH3:21])=[O:19]>C1(C)C=CC=CC=1.CO>[CH3:21][O:20][C:18](=[O:19])[C:17]([NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH:33]([OH:34])[CH2:35][N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[CH:12]=[CH:13][C:14]([F:15])=[C:2]([F:1])[CH:3]=2)[CH2:7][CH2:8]1)([CH3:16])[CH3:22]
Reactant: Fc1ccc(OC2CCNCC2)cc1F
Reactant: COC(=O)C(C)(C)NC(=O)c1ccccc1OCC1CO1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1ccccc1OCC(O)CN1CCC(Oc2ccc(F)c(F)c2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A toluene solution of 4-(3,4-difluorophenoxy)piperidine (0.03 ml, 0.5 M) was mixed with a toluene solution of methyl 2-methyl-2-{[2-(2-oxiranylmethoxy)benzoyl]amino}-propanoate (0.03 ml, 0.5 M). The mixture was diluted with 0.20 ml toluene and 0.05 ml methanol. The reaction mixture was stirred overnight at 100° C. in sealed vials. The product were concentrated in vacuo and used without any purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:24]([OH:26])=[O:25]>>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:21]([F:20])=[C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1F
Reactant: CCCCCCCC(C)C(=O)c1ccc(O)cc1F
Product: CCCCCCCCOc1ccc(C(=O)O)c(-c2ccc(C(=O)C(C)CCCCCCC)c(F)c2)c1F

Procedure:
The same procedure as in Example 20 was repeated, except that (+)-3-fluoro-4-(2-methylnonanoyl) phenol was used instead of (+)-3-fluoro-4-(2-methylnonanoyl) phenol in Example 20 and 3-fluoro-4-octyloxy benzoic acid was used instead of 3-fluoro-4-heptyloxybenzoic acid in Example 20, to obtain an objective compound having the aforementioned physical and chemical properties.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:12][C:13]2[O:14][C:15]3[C:21]([CH2:22][CH:23]=[O:24])=[CH:20][C:19]([Cl:25])=[CH:18][C:16]=3[N:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.O>C(O)C>[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:12][C:13]2[O:14][C:15]3[C:21]([CH2:22][CH2:23][OH:24])=[CH:20][C:19]([Cl:25])=[CH:18][C:16]=3[N:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1ccc(Cc2nc3cc(Cl)cc(CC=O)c3o2)cc1OC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cc2nc3cc(Cl)cc(CCO)c3o2)cc1OC1CCCC1
Reaction time: 1 h
Yield: 109.5 %

Procedure:
Sodium borohydride 0.05 g, 0.0013 mol) was added to a stirred solution of 2-(3-cyclopentyloxy-4-methoxybenzyl)-5-chlorobenzoxazole-7-ethanal (1.0 g, 0.0025 mol) in 10 ml ethanol. Stirring was continued for 1 hour. Water (15 ml) was added and the reaction mixture was extracted with 2×50 ml ethyl acetate. The ethyl acetate layer was washed once with water (50 ml), dried and evaporated to give 1.1 g of pale yellow crystals. A small sample of this solid was recrystallized from a blend of ether-hexane to give the title compound as a white solid, mp 74-76° C.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C(OCC)C>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)N(NS(=O)(=O)c1ccccc1)C(=O)c1ccccc1
Reaction time: 2 h

Procedure:
N'-t-butyl-N'-benzoylhydrazine (0.4 g) was stirred in pyridine (3 ml) at room temperature. Benzenesulfonyl chloride (0.5 g) was added slowly, dropwise and stirred for 2 hours, diluted with diethyl ether (20 ml) and washed several times with a 10% HCl solution and then water. The organic layer was dried over magnesium sulfate, filtered and the solvent rotavapped off to afford a white solid in good yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:31])([F:30])[F:32])[CH:22]=2)=[O:28])=[CH:7][CH:6]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Product: O=C(Nc1ccc(Sc2ccc3ccccc3n2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
2-(4-Aminophenylthio)quinoline (3.9 moles, 1.0 g) and 4-chloro-3-trifluoromethylphenylisocyanate (3.9 moles, 0.85 g) were reacted according to procedure A to yield the title compound, 0.8 g, 43%. Mass Spec (FD) 463. Calculated for C23H15ClF3N3OS: C, 58.29; H, 3.19; N, 8.87. Found: C, 58.56; H, 3.43; N, 9.02. M Pt 194°-195 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[NH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][N:19]([C:25](=[O:26])[N:24]([CH3:28])[CH3:23])[N:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cn[nH]c1-2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C(=O)n1cc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 0.33 g of 8-chloro-6-(2-chlorophenyl) 1H,4H-pyrazolo[4,3-d](2)benzazepine in 10 ml of methylene chloride, the mixture of 0.16 g of dimethylcarbamoyl chloride and 0.15 g of pyridine is added and the whole stirred for 2 hours at room temperature. The mixture is diluted with methylene chloride, washed with ice-cold aqueous sodium carbonate, dried and evaporated under reduced pressure. The residue is chromatographed on silica gel and eluted with benzene-methanol(95:5), to yield the 8-chloro-6-(2-chlorophenyl)-2-dimethylcarbamoyl-2H,4H-pyrazolo[4,3-d](2)benzazepine melting at 175°-176°.
Reaction SMILES: [ClH:1].O1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([C@H:35]2[N:39](C(OC(C)(C)C)=O)[C:38]([CH3:48])([CH3:47])[CH2:37][CH2:36]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][C@@H:30]([OH:34])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])=[C:11]([F:49])[CH:10]=1>C(Cl)Cl>[ClH:8].[ClH:1].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([C@@H:35]2[CH2:36][CH2:37][C:38]([CH3:48])([CH3:47])[NH:39]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][C@@H:30]([OH:34])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])=[C:11]([F:49])[CH:10]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4F)[C@@H]4CCC(C)(C)N4)CC3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
4N HCl in dioxane (3 mL, 0.191 mmol) was added to a solution of (S)-tert-butyl 5-((S)-1-(4-chloro-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.115 g, 0.191 mmol) in dry DCM (30 mL) and stirred at room temperature for 2 hours. The reaction was concentrated to dryness to reveal (S)-2-(4-chloro-2-fluorophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)ethanone dihydrochloride (0.093 g, 0.162 mmol, 84.7% yield). HPLC, 220 nM=1.93 minutes, 100% purity. LC/MS=2.22 minutes, (APCI+) m/z=502 [M+H]+. 1H NMR (400 MHz, D2O) 8.38 (s, 1H), 7.27 (d, J=10.54 Hz, 1H), 7.21-7.15 (m, 2H), 5.22 (t, J=7.81 Hz, 1H), 4.43 (d, J=8.98 Hz, 1H), 4.19 (dd, J1=8.59 Hz, J2=14.8 Hz, 1H), 4.15-4.05 (m, 1H), 3.87-3.75 (m, 2H), 3.74-3.46 (m, 5H), 3.42 (q, J=7.03 Hz, 2H), 3.39-3.25 (m, 2H), 2.19 (dd, J1=7.08 Hz, J2=13.27 Hz, 1H), 2.07-1.97 (m, 1H), 1.90-1.72 (m, 4H), 1.36 (s, 3H), 1.31 (s, 3H), 1.04 (t, J=7.03 Hz, 2H), 0.97 (d, J=7.03 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([NH:40][CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:39])=[CH:36][C:35]=1[O:49][CH3:50]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:48]=[CH:47][C:37]([C:38]([NH:40][CH:41]5[CH2:42][CH2:43][O:44][CH2:45][CH2:46]5)=[O:39])=[CH:36][C:35]=4[O:49][CH3:50])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NC2CCOCC2)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Yield: 43.8 %

Procedure:
A mixture of 0.0605 g (0.20 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0571 g (0.30 mmole) of toluenesulfonic acid monohydrate, 0.0501 g (0.20 mmole) of 4-amino-3-methoxy-N-(tetrahydro-2H-pyran-4-yl) benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 19.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile-methanol to give 0.0452 g 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-7).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=O)[CH3:2].Cl.[NH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26]>N1C=CC=CC=1>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[C:1](=[N:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:2]
Reactant: COC(=O)Cc1ccccc1CON
Reactant: CC(=O)c1ccc2ccccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)Cc1ccccc1CON=C(C)c1ccc2ccccc2c1
Temperature: 90 °C
Yield: 105.7 %

Procedure:
2'-acetonaphthone (1.02 g) and the title compound of Step C (1.39 g) were dissolved in 40 mL of pyridine. The solution was heated to 90° C. for 3 h, and then was cooled to room temperature overnight. The pyridine was removed in vacuo and the residue was taken up in 40 mL of 1N HCl solution and extracted with ethyl acetate (3×50 mL) The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield 2.2 g (about 100% yield) of the title compound of Step D as an amber oil. 1H NMR (CDCl3): δ 7.99 (d,1H), 7.86 (m,4H), 7.48 (m,3H), 7.31 (m,3H), 5.33 (s,2H), 3.85 (s,2H), 3.68 (s,3H), 2.34 (s,3H).