Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)=[CH:6][CH:7]=1.Br[C:26]1[N:30]2[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[N:34][C:29]2=[N:28][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:26]3[N:30]4[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:36])[CH3:37])=[N:34][C:29]4=[N:28][CH:27]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccc(F)cc3C#N)c2)OC1(C)C
Product: CC(C)(O)c1cnn2c(-c3cccc(-c4ccc(F)cc4C#N)c3)cnc2n1

Procedure:
4- Fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)-propan-2-ol in 32% yield using a similar procedure to that described in Example C, step f, to give a yellow solid: mp 175° C.; 1H NMR (360 MHz, CDCl3) δ 1.71 (6H, s), 3.25 (1H, br s), 7.41-7.67 (5H, m), 8.01 (1H, m), 8.24 (1H, s), 8.31 (1H, s), 8.78 (1H, s); MS (ES+) m/z 374 [M+H]+. Anal. Found: C, 67.38; H, 4.27; N, 18.51%. Required for C21H16FN5O: C, 67.55; H, 4.32; N, 18.76%.
Reaction SMILES: [C:1]1([C:7]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[OH:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[C:1]1([C:7]2[C:16]([C:17]([F:19])([F:20])[F:18])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[O:21][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1c(-c2ccccc2)c(C(F)(F)F)cc2ccccc12
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2c(-c3ccccc3)c(C(F)(F)F)cc3ccccc23)cc1
Yield: 36 %

Procedure:
2-Phenyl-3-(trifluoromethyl)-1-naphthalenol (182) (0.19 g, 0.66 mmol) and 4-fluorobenzaldehyde was heated with Cs2CO3 in DMSO at 100° C. to give 92 mg (36%) of the title compound (183) as alight brown solid. 1H NMR (400 MHz, CDCl3): δ 6.67 (d, J=8.8 Hz, 2H), 7.14 (d, J=6.9 Hz, 2H), 7.18-7.27 (m, 3H), 7.58-7.70 (m, 4H), 7.89 (d, J=8.2 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 8.27 (s, 1H), 9.82 (s, 1H). LCMS (ESI): m/z 415 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[NH:12][C:13](=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:11])[C:3]=1[NH:12][C:13](=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:15]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1OC1CCCC1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cc(N)cc2Cl)cc1OC1CCCC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide (1.5 g; that is prepared as described in Example 8) in glacial acetic acid (22 mL) is treated with iron pin dust (1.3 g) and the mixture is heated with stirring at 90° C. for 1 hour. The reaction mixture is cooled, basified to pH 8 by treatment with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate (2×150 mL). The combined organic extract is dried over magnesium sulfate and concentrated in vacuo, to give a white solid. This solid is subjected to flash chromatography, eluting with a mixture of ethyl acetate and pentane (1:1 v/v), to give N-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxybenzamide (0.8 g), m.p. 170-172° C. [Elemental analysis: C,54.8; H,5.04; N,6.5; Cl,17.4%; calculated: C,57.7; H,5.1; N,7.1; Cl,17.9%].
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C#N)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-cyanophenylboronic acid. The title compound was obtained in 45% yield as yellow foam. MS (m/e): 507.4 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11]1([CH3:18])[C:15]([CH3:17])([CH3:16])[O:14][BH:13][O:12]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[B:13]1[O:14][C:15]([CH3:17])([CH3:16])[C:11]([CH3:18])([CH3:10])[O:12]1
Reactant: Cc1cc(N)ccc1Br
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1cc(N)ccc1B1OC(C)(C)C(C)(C)O1
Temperature: 95 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
To an oven-dried round bottom flask fitted with a stir bar was added 4-bromo-3-methylaniline (5.7 gm, 31 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.3 mL, 92 mmol, Aldrich Chemical Company), and PdCl2(PPh3)2 (2.2 gm, 3.1 mmol, Strem Chemicals Inc, Newburyport, Mass.). The flask was sealed with a rubber septum, purged with Argon, and then charged with dry dioxane (100 mL) and triethylamine (26 mL). The reaction mixture was stirred vigorously at 95° C. for 16 h. After cooling to rt, the dioxane was removed in vacuo and the residue was partitioned between EtOAc (200 mL) and water (100 mL). The organic layer was washed with saturated NaHCO3 (2×75 mL), brine (50 mL), and was dried over MgSO4. Removal of the solvents in vacuo followed by flash chromatography of the residue yielded the product (3.3 gm, 46%) as a tan oil. 1H-NMR (CDCl3; 400 MHz): δ 7.61–7.64 (m, 1H), 6.48–6.58 (m, 2H), 3.60–3.90, (br s, 2H), 2.49 (s, 3H), 1.34 (s, 12H). ESI-MS (m/z): Calcd. for C13H20BNO2: 234.1 (M+H); found: 234.2
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]2[N:50]3[C:45]([CH:46]=[N:47][C:48](O)=[N:49]3)=[CH:44][CH:43]=2)[CH:37]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:48]2[N:47]=[CH:46][C:45]3=[CH:44][CH:43]=[C:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([S:33](=[O:35])(=[O:34])[NH:32][C:28]([CH3:29])([CH3:31])[CH3:30])[CH:37]=4)[N:50]3[N:49]=2)=[CH:23][CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(N)cc2)C1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CN(C(=O)OC(C)(C)C)CCN5C(=O)OC(C)(C)C)cc4)nn23)c1

Procedure:
Analogous to Example 1510b, 2-(4-Amino-phenyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.180 g, 0.477 mmol) and N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (149 mg, 0.429 mmol) were reacted to afford 2-{4-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazine-1,4-dicarboxylic acid di-tert-butyl ester, which was treated with 10% TFA in dichloromethane overnight. Conc. and purification by HPLC afforded N-tert-Butyl-3-[2-(4-piperazin-2-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide as the TFA salt (162 mg, 61%). LCMS (HPLC): 0.8 min, m/z=506 (M+H); 1H-NMR (DMSO-d6): 9.81 (s, 1H), 9.44 (br s, 3H), 9.09 (s, 1H), 8.57 (s, 1H), 8.34 (d, 1H, J=8.0 Hz), 7.87 (m, 3H), 7.74 (m, 1H), 7.62 (s, 1H), 7.48 (d, 2H, J=8.5 Hz), 7.24 (d, 1H, J=4.8 Hz), 7.05 (d, 1H, J=4.8 Hz), 4.46 (m, 1H), 3.59 (m, 3H), 3.27 (m, 3H), 1.11 (s, 9H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[NH:26][N:25]=[C:24]([CH:27]4[CH2:29][CH2:28]4)[CH:23]=3)[C:18]([OH:30])=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[CH:27]1([C:24]2[CH:23]=[C:22]([NH:21][C:19]3[C:18]([OH:30])=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:20]=3)[NH:26][N:25]=2)[CH2:29][CH2:28]1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ncc(O)c(Nc3cc(C4CC4)n[nH]3)n2)c1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2ncc(O)c(Nc3cc(C4CC4)n[nH]3)n2)c1
Reaction time: 0.5 h
Yield: 101.3 %

Procedure:
To a solution of N-tert-butyl-3-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-5-hydroxypyrimidin-2-yl)benzenesulfonamide (Compound 102) (25 mg, 0.053 mmol, 1.0 equiv.) in CH2Cl2 (5 mL) was added BCl3 (1.5 mL, 1.48 mmol, 28.0 equiv.) at room temperature. The mixture was stirred for 0.5 hours, then, concentrated. The residue was recrystallized with methanol and isopropyl ether to give 3-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-5-hydroxypyrimidin-2-yl)benzenesulfonamide (Compound 99) (20 mg, 92%). LC-MS (m/z)=373.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.83 (m, 2H), 0.92-0.99 (m, 2H), 1.87-1.99 (m, 1H), 6.47 (s, 1H), 7.47 (s, 2H), 7.76 (dd, J=8.0 Hz, 8.0 Hz, 1H), 7.95-7.98 (m, 2H), 7.76 (d, J=8.0 Hz, 1H), 8.67 (s, 1H), 9.88 (bs, 1H), 11.54 (bs, 1H).
Reaction SMILES: Cl[Si:2]([CH3:22])([CH3:21])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4]1.CCN(CC)CC.[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CCCCCC>[CH:30]1([NH:36][Si:2]([CH3:22])([CH3:21])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:4]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C[Si](C)(Cl)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Reactant: NC1CCCCC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: C[Si](C)(NC1CCCCC1)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Reaction time: 24 h
Yield: 94.5 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-3-phenyl-s-indacen-1-yl) silane (3.8523 g, 0.01182 moles) was stirred in hexane (100 mL) as NEt3 (1.5136 g, 0.01496 moles) and cyclohexylamine (1.2107 g, 0.01221 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (4.3313 g, 94.5 percent).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:27])=[CH:21][CH:20]=1)#[N:2].[OH-:36].[Na+].Cl>CS(C)=O.O>[F:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([C:1]([NH2:2])=[O:36])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:24][CH:23]=2)=[O:27])=[CH:34][CH:33]=1
Reactant: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C#N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C(N)=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
The N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea (360 mg, 0.762 mmol) obtained in Example 10 was dissolved in dimethylsulfoxide (4.5 ml), and then 5N aqueous sodium hydroxide (1.5 ml) was added and the mixture was heated at 80° C. while stirring for 60 minutes. The reaction solution was cooled in an ice water bath, 2N hydrochloric acid (3.75 ml) was added for neutralization, and then the mixture was diluted with water (21 ml) and the precipitated crude crystals were filtered out. These were suspended in ethanol (20 ml) and subjected to sonication, and upon filtering out the crystals they were dried under reduced pressure to obtain the title compound (214 mg, 0.436 mmol, 57.3%) as gray crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14](=O)([O:21]C1C=CC([N+]([O-])=O)=CC=1)[O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18]>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])=[O:21])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CNC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Brc1ccc(N2CCNCC2)cc1
Solvent: ClCCCl
Product: CNC(=O)COC(=O)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 65 °C

Procedure:
1.17 g (4.85 mmol) of 1-(4-bromophenyl)piperazine are added to a solution of 1.47 g (4 mmol) of 2-(methyl-amino)-2-oxoethyl 4-nitrophenyl carbonate, obtained in step 2.1., in 18 ml of 1,2-dichloroethane. This reaction mixture is heated at 65° C. for 2.25 hours. The mixture is allowed to cool to room temperature and it is then concentrated under reduced pressure. The oily yellow residue is taken up in dichloromethane and washed successively with sodium hydroxide (1N), water, aqueous 5% citric acid solution, water and then brine. This organic phase is dried over sodium sulfate and is concentrated under reduced pressure. After washing with diisopropyl ether, 1.3 g of product are obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=[C:14]([C:13]([F:12])([F:25])[F:26])[CH:15]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Br)ccc1O
Yield: 88.5 %

Procedure:
Using 5-bromosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:29]([O-])=O)=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>[Pd].O1CCOCC1>[NH2:29][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:33][CH:32]=2)=[CH:19][C:18]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(OCc3ccccc3)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2)ccc1N
Yield: 98.6 %

Procedure:
By using 3.32 g of t-butyl N-[5-(4-benzyloxyphenoxy)-2-nitrophenyl]-N-methylcarbamate, 0.39 g of 10% palladium on carbon, 100 ml of methanol and 100 ml of 1,4-dioxane, reaction and purification were carried out in a similar manner to that described in Reference Example 7, whereby 2.40 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[CH2:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7](=[CH:22][N:23]([CH3:25])[CH3:24])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: O=C1CCN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1CN=C(c2ccccc2)c2cc(Cl)ccc2C1=O

Procedure:
The mixture of 2.2 g of 8-chloro-1-phenyl-3,4-dihydro-2-benzazepin-5-one and 15 ml of dimethylformamide-dimethylacetal is refluxed for one hour and the excessive reagent removed under reduced pressure at a temperature not exceeding 135°. The residue is crystallized from diethyl ether, to yield the 8-chloro-4-dimethylaminomethylidene-1-phenyl-3,4-dihydro-2-benzazepin-5-one; m.p. 179°-180°.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[CH2:16]([NH2:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:24][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCc1ccccc1
Reactant: CN(C)CCCOc1ccccc1C=O
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1ccccc1C=NCCc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
A solution of 32.5 g of 2-(3-dimethylaminopropoxy)-benzaldehyde and 18.9 g of phenethylamine in 150 ml of toluene is heated at reflux for one hour. After 30 minutes, 1 mole equivalent of water is collected in a Dean-Stark trap. After cooling to approximately 50° C, the solvent is removed using a rotary evaporator and the oily residue is distilled to give 36.2 g of the title compound, boiling point 165°-167° C at 0.05 mm of Hg.
Reaction SMILES: [N:1]([C:4]([CH3:33])([CH3:32])[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]=[C:10]([N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[S:22](=[O:31])(=[O:30])[CH2:21][CH2:20]2)[CH:9]=1)=[O:6])=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[O:31]=[S:22]1(=[O:30])[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH2:25][N:19]([C:10]2[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]([CH3:33])([CH3:32])[NH2:1])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=2)[CH2:20][CH2:21]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C(C)(C)N=[N+]=[N-])c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C(C)(C)N)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution 2-azido-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropanamide (160 mg, 0.345 mmol) in ethyl acetate (25 mL) was added 10% palladium on carbon (100 mg), the flask was degassed and refilled with hydrogen (repeated for three times). After being stirred at room temperature overnight under a hydrogen atmosphere, the resulting mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford 110 mg of the title compound (yield was 73%). MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CDCl3) δ ppm 11.05 (s, 1 H), 8.30 (s, 1 H), 8.02 (dd, J=0.8, 7.6 Hz, 1 H), 7.89 (d, J=7.2 Hz, 1 H), 7.59 (d, J=8.8 Hz, 1 H), 7.53 (t, J=7.6 Hz, 1 H), 7.37 (m, 3 H), 5.17 (s, 2 H), 4.6 (brs., 2 H), 3.56 (s, 2 H), 2.48 (s, 3 H), 1.56 (s, 6 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[C:8]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][CH:13]=1)(=[O:10])[CH3:9].Cl>N1C=CC=CC=1>[CH3:7][C:4]1[S:3][C:2]([NH:1][S:16]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:6][N:5]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
2-Amino-5-methyl-1,3,4-thiadiazole (250 mg, 2.19 mmol) was suspended in pyridine (0.5 mL). N-Acetylsulfanilyl chloride (410 mg, 1.75 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3N HCl and the mixture extracted with ethyl acetate. The organic extracts were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous Na2SO4, filtered, and volatiles evaporated. The residue was crystallized from MeOH to give the product (491 mg, 1.6 mmol, 97%) as a solid, mp 239-240° C.; 1H NMR (500 MHz, DMSO) δ 2.07 (3, s), 2.44 (3, s), 7.74 (4, s), 10.82 (1, s), 13.85 (1, s); 13C NMR (125 MHz, DMSO) δ 16.1, 24.1, 118.6, 126.9, 135.7, 142.8, 154.3, 167.7, 168.9; MS (ESI+, m/z) Calculated for C11H13N4O3S2 313.0. found 313.0 (M+H)+; HRMS (FAB+, m/z) Calculated for C11H13N4O3S2 313.0429. found 313.0428 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([CH:16]2[CH2:18][CH2:17]2)[N:3]=1.[NH2:19][CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].C([O-])(O)=O.[Na+].O1CCOCC1>O>[CH:16]1([C:4]2[N:3]=[C:2]([NH:19][CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:22])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[N:5]=2)[CH2:18][CH2:17]1
Reactant: Clc1cc(-c2ccc(Cl)c(Cl)c2)nc(C2CC2)n1
Reactant: NC[C@H](O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O[C@@H](CNc1cc(-c2ccc(Cl)c(Cl)c2)nc(C2CC2)n1)c1ccccc1
Yield: 81.9 %

Procedure:
A mixture of 4-chloro-2-cyclopropyl-6-(3,4-dichloro-phenyl)-pyrimidine (108 mg, 0.364 mmol), (R)-(−)-2-amino-1-phenylethanol (67.2 mg, 0.490 mmol), and NaHCO3 (190.1 mg, 2.26 mmol) and 1,4-dioxane was refluxed for 48 h. The mixture was poured into water and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound as a white solid (119.4 mg, 82%). MS (ESI): mass calcd. for C21H19Cl2N3O, 399.09; m/z found, 400.1 [M+H]+. 1H NMR (CD3OD): 8.13-8.05 (m, 1H), 7.85-7.79 (m, 1H), 7.64-7.58 (m, 1H), 7.45-7.31 (m, 4H), 7.30-7.23 (m, 1H), 6.68-6.59 (m, 1H), 4.93-4.85 (m, 1H), 3.81-3.65 (m, 1H), 3.56-3.48 (m, 1H), 2.16-2.01 (m, 1H), 1.16-1.09 (m, 2H), 1.02-0.94 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([O:1][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:3]=1[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1c(O)cccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#Cc1c(OCc2ccccc2)cccc1[N+](=O)[O-]
Yield: 32.3 %

Procedure:
To a solution of 2-hydroxy-6-nitrobenzonitrile (Example 115) (1.0 g, 6.09 mmol) and Cs2CO3 (2.16 g, 6.64 mmol) in acetone (14 mL) was added benzyl bromide (1.16 g, 6.76 mmol). The reaction was refluxed under N2 for 1.5 hours, then filtered and the filtrate concentrated. The residue was purified by flash chromatography 3:2 Hexane:EtOAc to provide 2-nitro-6-(benzyloxy)benzonitrile (500 mg, 32%). 1H NMR (400 MHz, MeOD) δ 5.40 (s, 2H), 7.34-7.45 (m, 3H), 7.53 (m, 2H), 7.69 (dd, J=8.6, 0.8 Hz, 1H), 7.82 (t, J=8.4 Hz, 1H), 7.91 (t, J=8.2, 0.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[CH2:11]OS(C)(=O)=O)[CH:5]=[CH:4][N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C>COCCOC>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:11][C:10]2[CH:17]=[CH:18][CH:19]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:29][C@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CS(=O)(=O)OCc1cccc(-c2ccnc(Cl)n2)c1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: C[C@@H]1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 53 %

Procedure:
Intermediate 125 Methanesulfonic acid 3-(2-chloro-pyrimidin-4-yl)-benzyl ester (0.70 g) and Intermediate 127 2-(R)-Methyl-piperazine-1-carboxylic acid tert-butyl ester (0.61 g) with diisopropylethylamine (0.70 mL) in ethylene glycol dimethyl ether (20 mL) was refluxed for 3 hours, cooled to room temperature, evaporated under reduced pressure and the residue was dissolved in dichloromethane, washed with water (3×), brine, dried over dried over Na2SO4, chromatographed on silica gel (dichloromethane:methanol=98:2) to give 0.50 g of oily product with yield 53%. LC-MS showed the product had the expected M+H+ of 403. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (s, 1H) 8.0 (s, 1H) 7.9 (d, 1H) 7.6 (d, 1H) 7.5 (m, 2H) 4.2 (S, 1 h) 3.8 (d, 1H) 3.4 (m, 2H) 3.0 (m, 1H) 2.7 (d, 1H), 2.6 (d, 1H) 2.1 (m, 2H) 1.4 (s, 9H) 1.2 (d, 3H).