Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][C:20]([NH2:23])=[N:19]2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.Cl[C:25]1[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]2[CH2:37][C:36]([CH3:39])([CH3:38])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]2)=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+].CCOCC>O1CCOCC1.O.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>[NH2:23][C:20]1[CH:21]=[CH:22][N:18]([C:5]2[CH:6]=[CH:7][C:8]([C:25]3[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]4[CH2:37][C:36]([CH3:38])([CH3:39])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]4)=[CH:27][CH:26]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:19]=1
Reactant: COc1cc(-n2ccc(N)n2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-n2ccc(N)n2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 100 °C

Procedure:
A degassed reaction mixture of 1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-3-amine (474 mg, 1.505 mmol), 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Intermediate 1-1 (370 mg, 1.308 mmol) tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.065 mmol) and 1 M NaHCO3 (330 mg, 3.92 mmol) in 1,4-dioxane (7 mL) and water (2.3 mL) was heated at 100° C. for 14 h. After cooling to RT, the mixture was filtered through celite, washed with EtOAc, and the filtrate was concentrated. The residue was suspended in MeOH, acidified to pH 2-3 using 1 M aqueous HCl and loaded on a 10 g SCX column. The column was washed with MeOH, then eluted with 2 N NH3 in MeOH. The collected fractions were concentrated to give a light brown oil, which was treated with ether and concentrated to give 570 mg of 6-(4-(3-amino-1H-pyrazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C(=O)([O-])[O-].[K+].[K+].I[CH2:33][CH3:34]>CC(=O)CC>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([O:22][CH2:33][CH3:34])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCI
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 64.7 %

Procedure:
3.0 g (9 millimoles) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzoic acid, 4 g (30 millimoles) of potassium carbonate and 2.9 g (18.9 millimoles) of iodoethane in 27 ml of butan-2-one were refluxed until conversion was complete (monitored by thin layer chromatography). When the mixture had cooled, the solid was filtered off, the filtrate was evaporated down and the residue was recrystallized from methanol to give 2.1 g (65%) of the title compound of melting point 137°-138° C.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][C:12]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:14]=2)[C:9](=[O:20])[C:8]2[CH:7]=[C:6]([S:21](Cl)(=[O:23])=[O:22])[CH:5]=[CH:4][C:3]1=2.[CH3:25][CH:26]1[CH2:31][CH:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>C1COCC1>[CH3:25][CH:26]1[CH2:31][CH:30]([CH3:32])[CH2:29][N:28]([S:16]([C:12]2[CH:13]=[CH:14][C:15]3[N:2]([CH3:1])[C:3]4[C:8](=[CH:7][C:6]([S:21]([N:2]5[CH2:15][CH:10]([CH3:11])[CH2:9][CH:8]([CH3:7])[CH2:3]5)(=[O:23])=[O:22])=[CH:5][CH:4]=4)[C:9](=[O:20])[C:10]=3[CH:11]=2)(=[O:18])=[O:17])[CH2:27]1
Reactant: CC1CNCC(C)C1
Reactant: Cn1c2ccc(S(=O)(=O)Cl)cc2c(=O)c2cc(S(=O)(=O)Cl)ccc21
Solvent: C1CCOC1
Product: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=O)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 10-methyl-9-oxo-9,10-dihydroacridine-2,7-disulfonyl dichloride from Example 7 (810 mg, 2 mmole) in THF (20 mL) was added 3,5-dimethylpiperidine (2 mL, 15 mmole) and the reaction mixture was stirred at room temperature for 6 hours. Solvent was evaporated and the residue was treated with 1 N HCl (50 mL) and stirred for 10 minutes. Yellow product was collected by filtration, washed with water and methanol and dried. Crude material was crystallized from chloroform-ethanol to provide 900 mg (80%) of yellow 11-4. MS 560 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:15]=3[CH:28]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1.O>[CH3:27][C:24]([O:23][C:21]([N:17]1[CH2:16][C:15]2[CH:28]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=3)[CH:12]=[CH:13][C:14]=2[O:20][CH2:19][CH2:18]1)=[O:22])([CH3:25])[CH3:26]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)O)cc3)cc2C1
Temperature: 60 °C
Yield: 84.3 %

Procedure:
To a slurry of 1,1-dimethylethyl 7-{4-[(methyloxy)carbonyl]phenyl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (9.8 g, 26 mmol) in tetrahydrofuran (40 mL) was added a solution of lithium hydroxide (3.1 g, 130 mmol) in water (15 mL). The resulting mixture was heated at 60° C. for 18 h then partitioned between ethyl acetate (100 mL) and 1M hydrochloric acid (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel column chromatography (5% methanol in dichloromethane) provided 4-(4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoic acid (8.1 g, 85% yield). MS (EI) for C21H23NO5: 370 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([S:19][CH3:20])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:28]([F:33])([F:32])C([O-])=O.[Na+]>C(#N)C.C(Cl)(Cl)Cl>[F:32][CH:28]([F:33])[O:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([S:19][CH3:20])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CSc1ncc(C#N)c(-c2cnc3c(O)cccn23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CSc1ncc(C#N)c(-c2cnc3c(OC(F)F)cccn23)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
20 mg of the 4-(8-hydroxyimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [158-1] was dissolved in 1 mL of acetonitrile, then 20 mg of potassium carbonate and 13 mg of sodium chlorodifluoroacetate were added, and stirred overnight at 90° C. After cooling the reaction mixture back to room temperature, diluted in 100 mL of chloroform, and washed with water and dried over anhydrous magnesium sulfate. The insolubles were filtered, then the filtrate was concentrated under reduced pressure and purified by preparative thin-layer chromatography, to obtain 15 mg of 4-[8-(difluoromethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(methylthio)pyrimidine-5-carbonitrile [161-1] as a light brown solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])[C:47]1=[O:59])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cc1ccccc1CN1CCN([C@H](C(=O)O)C(C)(C)C)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2C)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 65A (0.023 g, 0.076 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.189 mmol) and the mixture was stirred at 25° C. for 2 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.013 g, 42% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.89 (m, 9 H), 1.46 (m, 2 H), 2.29 (s, 3 H), 2.38 (m, 1 H), 2.76 (m, 5 H), 3.22 (m, 2 H), 3.53 (m, 4 H), 3.84 (d, J=9.93 Hz, 1 H), 3.95 (m, 1 H), 4.02 (s, 1 H), 4.18 (m, 2 H), 4.41 (m, 2 H), 6.88 (d, J=9.56 Hz, 1 H), 7.04 (m, 5 H), 7.21 (m, 6 H), 7.32 (m, 1 H), 7.53 (d, J=9.56 Hz, 1 H), 7.89 (m, 5 H), 8.65 (d, J=4.04 Hz, 1 H).
Reaction SMILES: [CH3:1][NH2:2].[C:3]1(=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5](=[O:13])[O:4]1>C1COCC1>[CH3:1][NH:2][C:5](=[O:13])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[C:3]([OH:4])=[O:14]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccccc1C(=O)O
Temperature: 25 °C

Procedure:
To 20 ml of 2.0 M methylamine in THF is added 1.62 g (10 mmol) of isochroman-1,3-dione at 0° C. The mixture is stirred at 25° C. for 45 m and concentrated to dryness. The residue is stirred in 40 ml of 0.3 N HCl. The white solid is filtered off, washed with water, and dried to give 1.74 g (90%); 1H NMR (DMSO-d6) δ 7.80 (s, 1H), 7.81 (s, 1H), 7.40 (m, 3H), 3.83 (s, 2H), 2.57 (s, 3H); MS (ES−) m/z 192.1 (M−H)−1.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([O-:19])=[O:18].CS(O)(=O)=O.C>C(O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:24]([C:23]4[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: C
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc([N+](=O)[O-])cc3)nc(=O)c1-2
Reaction time: 6 h
Yield: 16.7 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0 g, 9 mmol) , 4-nitrobenzaldehyde (2.04 g, 13.5 mmol), methanesulfonic acid (0.25 ml) and xylenes (50 ml) was heated at reflux overnight, followed by an additional 6 hours. Ethanol (200 ml) was added to the reaction mixture, which was then refluxed and then treated with DARCO®. The reaction mixture was filtered, concentrated to 100 ml and then cooled. Yellow needles formed, which were collected by filtration and washed with ether to afford 0.53 g (17%) of 1-cyclopentyl-3-ethyl-6-(4-nitrophenyl)pyrazolo [3,4-d]pyrimidin-4-one, m.p. 321°-323° C. (dec.).
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH2:3][C@H:4]([NH:21][C:22]1[N:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:7][CH:6]=1.O1CCCC1.[OH-].[Li+]>CO>[CH3:1][CH:2]([CH3:38])[CH2:3][C@H:4]([NH:21][C:22]1[N:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:24][CH:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N[C@@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cn3)cc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C[C@H](Nc1ccc(C(=O)NCCC(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
A mixture of (S)-ethyl N-({6-[(3-methyl-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}butyl)amino]pyridin-3-yl}carbonyl)-beta-alaninate (60.9 g, 115 mmol) was dissolved in methanol (230 ml) and tetrahydrofuran (115 ml) and treated with aqueous lithium hydroxide (115 ml, 0.230 mol, 2.0M). The reaction was heated to 50° C. for 30 minutes. The solution was concentrated in vacuo, and the resulting residue was diluted with water (approximately 500 ml). The mixture was then acidified with aqueous 1.0M hydrochloric acid (230 ml, to approximately pH 4.0). The precipitated solid was collected by filtration and washed with water (2×100 ml). Air was pulled through the filter cake over 12 hours to affect drying of the product. The crude solid was transferred into a 2-liter flask with a stirbar and the solid was suspended in ethyl acetate (approximately 1.5 L). Sodium sulfate (approximately 500 g) was added and the mixture was stirred vigorously for a further 1 hour. The cloudy mixture was filtered through a plug of celite, resulting in a clear solution. The solution was concentrated in vacuo and the remaining solid was suspended in diethyl ether (1 L) and concentrated in vacuo (the process was repeated twice). The resulting solid was pulverized with a mortar and pestel, and dried in a vacuum oven for 12 hours at 60° C. The final product (50.1 g, 87%) was obtained as a off-white solid. 1H NMR (400 MHz, DMSO-d6, δ): 9.01 (s, 1H), 8.39 (d, J=1.2 Hz, 1H), 8.26 (dd, J=8.4, 2.0 Hz, 2H), 8.15 (d, J=8.4 Hz, 1H), 8.10 (d, J=8.2 Hz, 2H), 7.84 (d, J=6.7 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 6.66 (br. s., 1H), 5.15 (br. s., 1H), 3.33-3.43 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.74-1.86 (m, 1H), 1.62-1.72 (m, 1H), 1.51-1.62 (m, 1H), 0.95 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H). MS (M+1): 501.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[N:11][C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH:27]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH2:27][NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[N:11][C:10]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CSc1nc(-c2ccncc2)nn1-c1ccc(N)cc1
Reactant: Cc1ccsc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CSc1nc(-c2ccncc2)nn1-c1ccc(NCc2sccc2C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred solution of 1-(4-aminophenyl)-5-methylthio-3-(4-pyridyl)-1H-1,2,4-triazole (Example 1) (100 mg, 0.35 mmol) and 3-methylthiophene-2-carboxaldehyde (44 mg, 0.35 mmol) in 5% acetic acid in MeOH (4 mL) at room temperature was treated with sodium cyanoborohydride (55 mg, 0.88 mmol) and the reaction mixture was further stirred at room temperature for 48 h. The reaction mixture was concentrated, diluted with EtOAc, washed with NaHCO3 solution, brine and dried (MgSO4). The residue obtained on concentration was flash chromatographed on silica gel and eluted with a gradient of dichloromethane/acetone (9/1 to 3/1). The title compound was obtained as a white solid (85 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:27])[N:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[ClH:29]>O1CCOCC1>[ClH:29].[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:27])[N:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cccn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2cccn(C)c2=O)cc1

Procedure:
A solution of N-[(1,1-dimethylethoxyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (60 mg, 0.155 mmol) in 4 N HCl in dioxane (4 mL) was stirred for 2 hr and was concentrated. The residue was triturated with several portions of ether to give 4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (55 mg, quant) as a white powder. LRMS-Electrospray: m/z positive ion 573 (2M+H) 328 (M+H+CH3CN) 319 (M+H+CH30H) 287 (M+H). HRMS: Obs. Mass 287.1396. Calcd. Mass 287.1396 (M+H)
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH2:7][CH2:8][N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:51]1[N:52]=[N:53][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:55][CH:56]=1>CN(C=O)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:6]2[C:5]3[CH:19]=[CH:20][C:2]([C:51]4[N:52]=[N:53][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:55][CH:56]=4)=[CH:3][C:4]=3[CH2:10][N:9]([CH3:11])[CH2:8][CH2:7]2)=[CH:13][CH:14]=1
Reactant: CN1CCN(c2ccc(F)cc2)c2ccc(Br)cc2C1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CN1CCN(c2ccc(F)cc2)c2ccc(-c3ccc(C(F)(F)F)nn3)cc2C1
Temperature: 65 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A round bottomed flask was charged with 7-bromo-1-(4-fluorophenyl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (75 mg, 0.22 mmol) from step A above, bis(pinacolato)diboron (62 mg, 0.25 mmol) and potassium acetate (66 mg, 0.67 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (16 mg, 0.02 mmol) in DMF (1 mL). The mixture was refilled with nitrogen three times and then stirred at 65° C. overnight. The mixture was cooled to room temperature. Cesium carbonate (219 mg, 0.67 mmol), 3-chloro-6-trifluoromethylpyridazine (49 mg, 0.67 mmol), and water (0.5 mL) were added. The mixture was refilled with nitrogen three times and then stirred at 60° C. for 3 hours. After cooling, the mixture was partitioned between methylene chloride and water. The aqueous phase was extracted with methylene chloride (3×20 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (100:0 to 10:1 methylene chloride/methanol) to yield the desired 1-(4-fluorophenyl)-4-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (71 mg, 79%) as a grey solid
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:11][C:12]([CH2:14]Br)=[CH2:13]>CO>[CH3:7][O:6][C:4](=[O:5])[CH:3]([CH2:14][C:12]([Br:11])=[CH2:13])[C:2]([O:9][CH3:10])=[O:8]
Reactant: C=C(Br)CBr
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: CO
Product: C=C(Br)CC(C(=O)OC)C(=O)OC
Reaction time: 0.75 h
Yield: 66.1 %

Procedure:
To a flask under nitrogen was added MeOH (67 mL), and sodium metal (1.15 g, 0.05 g atom) was added in portions over 30 min. To the resulting solution dimethyl malonate (13.2 g, 0.1 mol) in MeOH (10 mL) was added from a dropping funnel over 30 min. The solution was cooled to 0°, and 2,3-dibromopropene (12 g, 0.05 mol) in MeOH (15 mL) was added over 40 min. After a further 45 min at 0°, the pH of the mixture was neutral to litmus paper. The reaction medium was then concentrated under reduced pressure and the residue was dissolved in EtOAc (100 mL) and the resulting solution washed with distilled H2O (100 mL). The aqueous phase was re-extracted with Et2O (100 mL) and the combined organic phases were washed with brine, dried (MgSO4), concentrated under reduced pressure and purified by distillation (82°-84°/1 Torr) to give the title compound as a colorless liquid (8.3 g, 66% yield): 1H NMR (400 MHz, CDCl3) δ5.69 (m, 1H, olefinic), 5.48 (d, J=1.9 Hz, 1H, olefinic), 3.81 (t, J=7.63 Hz, 1H), 3.75 (s, 6H), 3.02 (dd, J=0.95, 7.63 Hz, 2H); 13CNMR (100 MHz, CDCl3) δ8 168.30, 129.18, 119.68, 52.59, 50.28, 40.36.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH:12]=O)(=[O:3])[CH3:2].[C:14](Br)(Br)([Br:16])[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCCC>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH:12]=[C:14]([Br:16])[Br:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C)ccc1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC(=O)Oc1cc(C)ccc1C=C(Br)Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a stirred mixture of 2-formyl-5-methylphenyl acetate (12.8 g, 71.8 mmol), carbon tetrabromide (47.6 g, 144 mmol), and 150 mL of DCM at 0° C. (translucent clear/yellow solution) under nitrogen was added a solution of triphenylphosphine (75 g, 287 mmol) in 140 mL of DCM dropwise over 15 min. A clear orange solution results initially. After 1 hr a purplish suspension results. The reaction was stirred for 2 hr at RT. After 2 hr 100 mL of heptane was added. The mixture was filtered to remove solids and the collected filtrate was concentrated under reduced pressure to give a dark brown gum. This was dissolved in minimal DCM and filtered through a silica gel plug which was flushed with 70% Heptane/30% EtOAc. The combined washes from the silica plug were concentrated under reduced pressure to give a yellow oil, 2-(2,2-dibromovinyl)-5-methylphenyl acetate (16.7 g). 1H NMR (400 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.31 (s, 3H), 7.01 (s, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.54 (d, J=8.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[N:21][C:22]([NH:25][C:9](=[O:11])[CH2:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([CH3:12])[CH:4]=2)=[CH:23][CH:24]=1
Reactant: Nc1ccc(-c2ccccn2)cn1
Reactant: Cc1cc(CC(=O)O)cnc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)Nc2ccc(-c3ccccn3)cn2)cnc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(6-chloro-5-methylpyridin-3-yl)acetic acid 74-4 (57 mg, 0.31 mmol), 2,3′-bipyridin-6′-amine 124-1 (51 mg, 0.30 mmol), 1,3-dicyclohexylcarbodiimide (75 mg, 0.36 mmol) and 4-(dimethylamino)pyridine (6 mg, 0.06 mmol) in DMF (1.2 mL) was stirred at room temperature for 10 hours. The reaction mixture was filtered through celite, washed and diluted with ethyl acetate (30 ml) and extracted with water 930 ml×2). The organic phase was dried over Na2SO4 and concentrated by evaporation. The residue was subjected to silica gel column chromatography with ethyl acetate as eluent to give N-(2,3′-bipyridin-6′-yl)-2-(6-chloro-5-methylpyridin-3-yl)acetamide 124-2 as white solid.