Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([O:31][C:32]([N:34]([CH2:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:46][NH:47][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:48][CH:49]=1)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CN)cc1)C1CCCCC1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC(C)(C)OC(=O)N(Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C1CCCCC1
Yield: 75.9 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.71 mmol) and 4-[N-(tert-butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzylamine (335 mg, 1.05 mmol). Purify by chromatography on silica gel (150 g) eluting with hexane/EtOAc (1:0 to 9:1 gradient) to obtain 6-{-4-[N-(tert-butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzylamino}-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (320 mg, 76%). MS (ES+) m/z: 494 (M-Boc+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])(=[O:18])=[O:17])[CH:12]=[N:13][CH:14]=2)O1.Cl[C:29]1[CH:30]=[CH:31][C:32]2[N:33]=[CH:34][N:35]=[C:36]([O:39][CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[C:37]=2[N:38]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[O:43]1[CH2:42][CH2:41][CH:40]([O:39][C:36]2[C:37]3[N:38]=[C:29]([C:9]4[CH:10]=[C:11]([NH:15][S:16]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])(=[O:17])=[O:18])[CH:12]=[N:13][CH:14]=4)[CH:30]=[CH:31][C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:45][CH2:44]1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 108 %

Procedure:
A mixture of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluoro benzenesulfonamide (0.110 g, 0.278 mmol) (Intermediate 4), 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 1) (0.081 g, 0.305 mmol), 1 N aq. sodium bicarbonate (0.555 ml, 0.555 mmol) and PdCl2(dppf)-CH2Cl2Adduct (23.0 mg, 2.80 μmol) in dioxane (2.78 ml) was subjected to microwave irradiation for 1 hour at 110° C. The reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=2:1) to give N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.15 g, 18%) as a yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 1.78-1.98 (2H, m), 2.12-2.26 (2H, m), 3.55-3.72 (2H, m), 3.90-4.05 (2H, m), 5.58-5.72 (1H, m), 7.20-7.42 (1H, m), 7.48-7.62 (2H, m), 7.90-8.05 (1H, m), 8.36-8.52 (2H, m), 8.58 (1H, d, J=8.2 Hz), 8.86 (1H, s), 9.13 (1H, s), 11.29 (1H, br s). m/z=500.1 [M+1]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]1[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C@@H:20]2[C@H:18]1[CH2:19]2)=[O:16])([CH3:13])([CH3:12])[CH3:11].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=1)=[O:29]>C(#N)C>[C@@H:18]12[CH2:19][C@@H:20]1[CH2:21][C@@H:22]([C:23]([O:25][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=1)=[O:29])=[O:24])[N:17]2[C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:16]
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCC(=O)c1cccc(Br)c1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
DIPEA (2.79 mL, 16.0 mmol) was added to a stirring slurry of (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (2.00 g, 8.80 mmol) and 2-bromo-1-(3-bromophenyl)ethanone (2.22 g, 8.00 mmol) in acetonitrile (25 mL) (the solution became clear and amber colored) and the reaction mixture was stirred overnight. The reaction was concentrated and purified via BIOTAGE® (80 g SiO2, 10-25% EtOAc/hexanes) to yield (1R,3S,5R)-3-(2-(3-bromophenyl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (3.37 g, 7.94 mmol) as a viscous light yellow oil. LC-MS retention time 1.853 min; m/z 423 and 425.98 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a waters XTERRA® MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (d, J=1.8 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.38 (dd, J=8.0, 7.8 Hz, 1H), 5.58-5.10 (m, 2H), 4.23 (br s, 1H), 3.62-3.39 (m, 1H), 2.58 (dt, J=13.3, 6.5 Hz, 1H), 2.46 (dd, J=13.3, 9.5 Hz, 1H), 1.73-1.51 (m, 1H), 1.47 (s, 9H), 0.85 (br s, 1H), 0.51 (s, 1H).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:9]=[CH:8][N:7]=1)[CH3:5])=[N+]=[N-]>CCO.[Pd]>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([CH:4]([NH2:1])[CH3:5])[N:11]=2)=[CH:14][CH:15]=1
Reactant: CC(N=[N+]=[N-])c1nccc(Oc2ccc(F)cc2)n1
Agent: [Pd]
Solvent: CCO
Product: CC(N)c1nccc(Oc2ccc(F)cc2)n1
Reaction time: 2 h
Yield: 69.5 %

Procedure:
2-(1-azidoethyl)-4-(4-fluorophenoxy)pyrimidine (120 mg, 0.463 mmol) was dissolved in 2 mL neat EtOH. 24.6 mg (0.023 mmol) of 10% Palladium on carbon catalyst was added. With vigorous stirring, the reaction vial was evacuated and purged 3 times with H2. The reaction vessel was fitted with an H2 balloon and stirred for 2 h. The mixture was filtered through Celite and concentrated in vacuo to give 75 mg (69%) 1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanamine as a brown oil. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.7 Hz, 1H), 7.13-6.92 (m, 4H), 6.59 (d, J=5.7 Hz, 1H), 4.00 (q, J=6.8 Hz, 1H), 1.34-1.30 (m, 3H). Anal. RP-HPLC tR=1.18 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 234.2 (M+H)+.
Reaction SMILES: [CH:1]1([CH:6]=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([Mg]Br)#[CH:9]>O1CCCC1>[CH:1]1([CH:6]([OH:7])[C:8]#[CH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#C[Mg]Br
Reactant: O=CC1CCCC1
Solvent: C1CCOC1
Product: C#CC(O)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of 0.87 ml of cyclopentanecarboxaldehyde (8.15 mmol; Aldrich) in 10 ml of tetrahydrofuran is added to 18 ml of a commercially available 0.5 M solution of ethynylmagnesium bromide in tetrahydrofuran (10 mmol, Aldrich) cooled beforehand to 0° C. The mixture is then stirred for 2 hours at ambient temperature and a saturated solution of NH4Claq is added. The mixture is extracted with ethyl acetate and the organic phases are then combined, washed with a saturated solution of NaClaq, dried over sodium sulphate, filtered, and concentrated under vacuum. 0.931 g of (±)-1-cyclopentylprop-2-yn-1-ol is obtained in the form of a light brown oil with a yield of 92%.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:4][C:3]2[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=2[F:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Nc1cc(F)ccc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(F)ccc2F)cc1
Reaction time: 48 h
Yield: 76.1 %

Procedure:
A stirred mixture of 15.0 g (0.116 mole) of 2,5-difluoroaniline and 24.4 g (0.128 mole) of 4-methylphenylsulfonyl chloride in 50 ml of pyridine was heated at reflux for approximately 18 hours. The reaction mixture was cooled and poured into 500 ml of 6N hydrochloric acid. This acidic mixture was allowed to stand at room temperature for two days. A precipitate formed and was collected by filtration. The filter cake was washed with dilute hydrochloric acid and was dried under reduced pressure to yield 25.0 g of N-(4-methylphenylsulfonyl)-2,5-difluoroaniline. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([OH:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C1C=CC=CC=1.C(O)=O.C=O>C(O)C>[CH3:1][NH:8][CH2:9][CH2:10][C:11]([OH:26])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OC(CCNCc1ccccc1)(COc1ccccc1)c1ccccc1
Agent: C=O
Solvent: O=CO
Solvent: CCO
Product: CNCCC(O)(COc1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 62.4 %

Procedure:
45 g (0.13 mole) of N-benzyl-3-hydroxy-3-phenyl-4-phenoxybutylamine prepared as described in (c) were dissolved in 400 ml of ethanol, and 7.8 g of formic acid and 20 g of 35% strength formaldehyde solution were added in succession at the boiling point. After 3 hours, the alcohol was distilled off, 200 ml of 2N sodium hydroxide solution were added to the residue and the mixture was extracted with 3 times 2 ml of ether. The solution was dried and then evaporated down, the residue was taken up in 250 ml of acetic acid and the solution was hydrogenated in a shaken flask, using 5 g of palladium on carbon as the catalyst. When absorption of hydrogen was complete, the mixture was filtered, the filtrate was evaporated down, 2N sodium hydroxide solution was added and the mixture was extracted with 3 times 200 ml of ether. After the solvent had been distilled off, the product solidified. 22 g (65%) of N-methyl-3-hydroxy-3-phenyl-4-phenoxybutylamine of melting point 98°-99° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:3]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([N:16]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[S:17]([CH3:20])(=[O:19])=[O:18])[C:3]=1[CH3:21]
Reactant: COC(=O)CBr
Reactant: COc1nc2cc(Cl)c(C)c(NS(C)(=O)=O)c2nc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CN(c1c(C)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A mixture of N-(7-chloro-2,3-dimethoxy-6-methylquinoxalin-5-yl)methanesulphonamide (694 mg, 2.09 mmol), potassium carbonate (347 mg, 2.51 mmol) and acetone (21 ml) was heated at reflux for 10 minutes and was then allowed to cool to room temperature. Methyl bromoacetate (396 μl, 640 mg, 4.19 mmol) was added and the mixture was heated at reflux for 18 hours. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed twice with water and then brine and then dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane to give N-(7-chloro-2,3-dimethoxy-6-methylquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide as a white solid (407 mg, 48%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.[NH2:43][C@@H:44]1[CH2:49][CH2:48][C@H:47]([OH:50])[CH2:46][CH2:45]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:43][C@H:44]5[CH2:49][CH2:48][C@@H:47]([OH:50])[CH2:46][CH2:45]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: N[C@H]1CC[C@@H](O)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@H]2CC[C@@H](O)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.08 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.13 mL (0.72 mmole) of ethyldiisopropyl amine and 0.030 g (0.20 mmole) of cis-4-amino-cyclohexanol hydrochloride in 2.0 mL of dimethylformamide was added 0.085 g (0.2 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.066 g of cis-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-hydroxy-cyclohexyl)-3-methoxy-benzamide (I-68) as a white solid.
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([N+:38]([O-:40])=[O:39])[CH:32]=2)=[CH:16][CH:15]=1>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:6]/[N:7]([CH3:9])[CH3:8])=[C:33]([N+:38]([O-:40])=[O:39])[CH:32]=2)=[CH:16][CH:15]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
tert-butoxybis(dimethylamino)methane (0.50 mL, 2.30 mmol) was added to a solution of 3-(4-chlorophenyl)-2-(4-methyl-3-nitrophenyl)quinazolin-4(3H)-one (0.300 g, 0.76 mmol) in DMF (20 mL). Stirring at 50° C. for 3 hours and concentrating in vacuo afforded (E)-3-(4-chlorophenyl)-2-(4-(2-(dimethylamino)vinyl)-3-nitrophenyl)quinazolin-4(3H)-one (0.340 g, 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([NH:5][CH:6]([C:10](=[O:13])[CH2:11][CH3:12])[CH2:7][CH:8]=[CH2:9])=O.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH2:7]([C:6]1[N:5]=[C:3]([C:2]([CH3:15])([CH3:14])[CH3:1])[O:13][C:10]=1[CH2:11][CH3:12])[CH:8]=[CH2:9]
Reactant: C=CCC(NC(=O)C(C)(C)C)C(=O)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C=CCc1nc(C(C)(C)C)oc1CC
Reaction time: 4 h

Procedure:
2.10 g of the above prepared 2,2-dimethyl-N-(1-propionyl-but-3-enyl)-propionamide (9.94 mmol) were treated with 16.74 ml of trifluoroacetic acid (219 mmol) and 8.29 ml of trifluoroacetic anhydride (6 eq.) and kept for 4 h at 50°, when TLC indicated the disappearance of starting material. The reaction mixture was then poured onto crashed ice/Na2CO3, the aqueous layer (pH ˜8), extracted twice with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=95/5) delivered 1.29 g of the title compound as yellowish liquid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]3/[C:13](=[C:23](/[CH3:26])\[C:24]#[N:25])/[C:14]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=4[O:16][CH2:17][C:11]=3[CH:10]=2)=[C:6]([CH2:29][O:30][CH3:31])[N:5]=[C:4]([CH3:32])[N:3]=1.CO.[CH3:35][NH:36][CH3:37]>>[CH3:35][N:36]([CH3:37])[C:2]1[C:7]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]3/[C:13](=[C:23](/[CH3:26])\[C:24]#[N:25])/[C:14]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=4[O:16][CH2:17][C:11]=3[CH:10]=2)=[C:6]([CH2:29][O:30][CH3:31])[N:5]=[C:4]([CH3:32])[N:3]=1
Reactant: COCc1nc(C)nc(Cl)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Reactant: CNC
Solvent: CO
Product: COCc1nc(C)nc(N(C)C)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 57.4 %

Procedure:
[step 4] Using (E)-2-(8-{[4-chloro-6-(methoxymethyl)-2-methylpyrimidin-5-yl]methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (164 mg, 0.365 mmol) obtained in step 3 and 2 mol/L dimethylamine methanol solution (1.28 mL, 2.55 mmol), and in the same manner as in Reference Example 13G, step 4, the title compound (96 mg, 56%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.C[N:34](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:34])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(Cc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(=O)O)s4)c3c2)CC1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
To a mixture of 0.048 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid, 0.046 g (0.12 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1), 0.008 g (0.15 mmole) of ammonium chloride and 1 mL of dimethylformamide was added 0.052 mL of diisopropylethylamine. The mixture was stirred at ambient temperature for 1 hour, filtered and then purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 10:90-90:10) to give 0.027 g of 4-(3-chloro-phenyl)-2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.2) as a white solid. MH+/Z=467
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=3[F:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.[ClH:43]>C(Cl)Cl>[ClH:43].[NH2:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:21])[C:13]4[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=4[F:20])[C:4]=23)[CH2:23]1
Reactant: Cc1ccc(F)c(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)c1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](N)C4)c23)c1
Yield: 61 %

Procedure:
A solution of (R)-tert-butyl 1-(5-bromo-3-(2-fluoro-5-methylbenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (120 mg, 0.22 mmol) in DCM (3 mL) was treated with TFA followed by 1M HCl as described in Example 62, Step C, to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-fluoro-5-methylbenzamide hydrochloride (0.070 g, 61% yield). 1H NMR (400 MHz, D2O) δ 8.17 (s, 1H), 7.50-7.48 (m, 1H), 7.45 (s, 1H), 7.33-7.30 (m, 1H), 7.09-7.04 (m, 1H), 3.50-3.48 (m, 1H), 3.31-3.29 (m, 2H), 3.18-3.13 (m, 1H), 3.06-3.03 (m, 1H), 1.86-1.82 (m, 1H), 1.68-1.64 (m, 1H), 1.43-1.41 (m, 2H); LCMS (APCI+) m/z 446, 448 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]=[C:13]1[O:17][C:15](=O)[CH2:14]1.C(OC(=O)C)(=O)C>CC(C)=O>[CH3:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:15]([CH2:14][C:13](=[O:17])[CH3:12])=[N:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: C=C1CC(=O)O1
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: CC(=O)Cc1nc2cccc(C)c2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of 2-amino-6-methylbenzoic acid (20 g, 0.132 mol) in acetone (100 mL), diketene (15.3 mL, 0.198 mol) was added dropwise at room temperature, and the mixture was stirred overnight at room temperature. The reaction solvent and excess diketene were concentrated and evaporated under reduced pressure, and tetrachloride (80 mL) were added to the residue, and subsequently acetic anhydride (27 g, 0.265 mol) was added thereto, and the mixture was heated under reflux for 3 hours. The reaction solvent and excess acetic anhydride were concentrated and evaporated under reduced pressure, and the resulting powder was collected, and washed with diethylether to give crude 5-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (13.75 g, 48% yield). A solution of the compound (12.99 g, 0.06 mol) and 2-hydrazinopyridine (7.18 g, 0.066 mol) in ethanol (100 mL) was heated under reflux for 1 hour. The reaction solution was allowed to cool to room temperature, the reaction solvent was concentrated and evaporated under reduced pressure. A solution of the residue in phosphorous oxychloride (45.8 g, 0.3 mol) was heated and stirred at 100° C. for 1 hour. The reaction solution was allowed to cool to room temperature, and the solvent was concentrated and evaporated under reduced pressure, and the residue was poured into iced water. A sodium hydroxide solution was added to the mixture to become basic, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate:methanol=98:2) to give the title compound (4.4 g, 24% yield)
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.C([NH:15][C@H:16]([C:21](O)=[O:22])[C@H:17]([CH2:19][CH3:20])[CH3:18])(OC(C)(C)C)=O.Cl>>[ClH:1].[NH2:15][C@@H:16]([CH:17]([CH3:18])[CH2:19][CH3:20])[C:21]([N:5]1[CH2:6][C:3]([F:7])([F:2])[CH2:4]1)=[O:22]
Reactant: FC1(F)CNC1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CCC(C)[C@H](N)C(=O)N1CC(F)(F)C1

Procedure:
(S)-2-amino-1-(3,3-difluoro-azetidin-1-yl)-3-methyl-pentan-1-one hydrochloride was prepared by coupling 3,3-difluoro-azetidine hydrochloride (WO 0047582) with Boc-(L)-isoleucine followed by HCl deprotection as analogously described in Example 1 (mp 195° C. dec.).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:20]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH2:17][CH2:18][CH3:19])[CH:10]=3)[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCCCc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1cc(CCCN2CCN(c3ccccc3)CC2)n(-c2ccccc2)n1

Procedure:
100 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-butyl-1H-pyrazol-5-yl)propanal (80 mg, 0.312 mmol), 1-phenylpiperazine (0.047 mL, 0.312 mmol), DIPEA (0.081 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).