Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][N:3]=1.O.O.Cl[Sn]Cl.Cl.[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][N:3]=1
Reactant: Cc1noc2c(C)cc([N+](=O)[O-])cc12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1noc2c(C)cc(N)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a suspension of 3,7-dimethyl-5-nitrobenzo[d]isoxazole (Step 46.5) (50 mg, 0.260 mmol) in acetic acid (1.5 mL) was added dropwise a solution of SnCl2.2H2O (176 mg, 0.781 mmol) in HCl conc (0.316 mL, 10.41 mmol) and the resulting mixture was stirred at RT overnight. The reaction was poured into a cold 4N NaOH solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 0-55%) to afford the title product (25 mg, 0.153 mmol, 59% yield) as beige solid. tR: 0.57 min (LC-MS 2); ESI-MS: 163 [M+H]+; Rf=0.23 (hexane/EtOAc 1:1).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[F:7][C:8]1[CH:20]=[C:19](F)[C:18]([F:22])=[CH:17][C:9]=1[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11].O>CS(C)=O.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:2]([O:4][C:19]1[C:18]([F:22])=[CH:17][C:9]([C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])=[C:8]([F:7])[CH:20]=1)([CH3:5])([CH3:3])[CH3:1]
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Reactant: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)Oc1cc(F)c(C(=O)NS(C)(=O)=O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
Potassium tert-butoxide (1.46 g, 13.0 mmol) was added to a solution of 2,4,5-trifluoro-N-(methylsulfonyl)benzamide (Preparation 108, 1.5 g, 5.924 mmol) in DMSO (10 mL) and stirred at room temperature. After 3 hours, potassium tert-butoxide (140 mg, 1.3 mmol) was further added and stirred for 18 hours more. The reaction mixture was diluted with EtOAc and 10% aqueous citric acid solution. The pH of the water layer was acidic. The organic layer was washed with more 10% aqueous citric acid and brine, then dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as a cream solid (1.76 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]3[CH2:11][CH2:12][NH:13][CH2:14][CH:5]3[C:4]=2[CH:3]=1.Br[CH2:16][CH2:17][CH2:18][C:19]#[N:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:19]([CH2:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[CH:5]2[CH2:14]1)#[N:20]
Reactant: N#CCCCBr
Reactant: Cc1ccc2c(c1)C1CNCCC1N2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C1CN(CCCC#N)CCC1N2

Procedure:
In toluene (60 ml) are dissolved 8-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (5.7 g), γ-bromobutyronitrile (4.5 g) and triethylamine (4.6 g), and the mixture is refluxed for 5 hours. After cooling, the reaction mixture is washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The resulting residue is treated with ethanolic hydrogen chloride in the same manner as described in Example 1 (1) to give the dihydrochloride of the titled compound (5.5 g), m.p. 160° - 165°C (recrystallized from aqueous ethanol).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)[C:17]([OH:19])=O)[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:33][C:34]1[N:35]=[CH:36][C:37]([CH:40]([OH:42])[CH3:41])=[N:38][CH:39]=1.[OH-].[Na+].Cl>ClCCl.CN(C=O)C.O.N1C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][CH:21]3[CH2:22][CH2:23][O:26][CH2:24][CH2:25]3)[C:17]([NH:33][C:34]3[CH:39]=[N:38][C:37]([CH:40]([OH:42])[CH3:41])=[CH:36][N:35]=3)=[O:19])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH2:2][CH2:3]1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Reactant: CC(O)c1cnc(N)cn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(O)c1cnc(NC(=O)[C@H](CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)cn1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propionic acid (200 mg) in dichloromethane (10 mL) were sequentially added a solution of oxalyl chloride in 0.5 M dichloromethane (1.3 mL) and DMF (16 μL) under ice-cooling, followed by stirring for 30 minutes under ice-cooling. Thereafter, 1-(5-aminopyrazin-2-yl)ethanol (81 mg) and pyridine (0.09 mL) were added thereto under ice-cooling, followed by stirring for 3 hours. To the reaction mixture was added water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. To a solution of the oily substance obtained by concentration in methanol (4 mL) was added 1 M aqueous sodium hydroxide solution (1 mL) at room temperature, followed by stirring at room temperature for 1 hour. To the reaction mixture was added 1 M hydrochloric acid to adjust the pH to 3, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (wetting with hexane:ethyl acetate=1:1, chloroform:methanol=1:0-10:1) to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(1-hydroxyethyl)pyrazin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamide (170 mg) as a white amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[NH:15][CH2:14][CH:13]2[C:23]([O:25][CH3:26])=[O:24])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:27][C:28]1[CH:32]=[CH:31][N:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[C:35]([Cl:42])[CH:34]=2)[N:29]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:37]([C:36]3[CH:40]=[CH:41][C:33]([N:30]4[CH:31]=[CH:32][C:28]([CH3:27])=[N:29]4)=[CH:34][C:35]=3[Cl:42])=[O:38])[CH2:14][CH:13]2[C:23]([O:25][CH3:26])=[O:24])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1ccn(-c2ccc(C(=O)Cl)c(Cl)c2)n1
Reactant: COC(=O)C1CNc2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)C1CN(C(=O)c2ccc(-n3ccc(C)n3)cc2Cl)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
As described in Example 65, methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate was reacted with 4-(3-methyl-1-pyrazolyl)-2-chlorobenzoyl chloride to give methyl 4-(4-methoxybenzenesulfonyl)-1-[2-chloro-4-(3-methyl-1-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as a white solid. Anal. for C29H27ClN4O6S: Calc'd: C, 58.3; H, 4.6; N, 9.4. Found: C,58.2; H, 4.9; N, 8.9.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][C:8]=23)[CH:6]=1.C1COCC1.C([Li])CCC.CCCCCC.[CH:40]1([CH:46]=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH:40]1([CH:46]([C:2]2[CH:3]=[N:4][N:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][C:8]=34)[CH:6]=2)[OH:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-n3cc(Br)cn3)ccnc21
Reactant: O=CC1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-n3cc(C(O)C4CCCCC4)cn3)ccnc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-(4-bromo-1H-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (50.0 mg, 0.000127 mol) in THF (2.0 mL, 0.025 mol) under a nitrogen atmosphere was cooled to −78° C. and 1.6 M n-butyllithium in hexane (0.10 mL, 0.00016 mol) was added slowly. The mixture was stirred for 15 min and then treated with cyclohexanecarboxaldehyde (25.0 μL, 0.000208 mol). After 20 min at −78° C., the reaction was partitioned between water and EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the cyclohexyl[1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]methanol as a crude residue, LC/MS (M+H)+: 427.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][N:42](C(OC(C)(C)C)=O)[CH:43]=2)O1.C([O-])([O-])=O.[K+].[K+].Cl>O1CCOCC1.O.CO.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>[NH:41]1[CH:40]=[C:39]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[C:19]([S:22]([NH:25][C:26]4[S:30][N:29]=[CH:28][N:27]=4)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]2=3)[CH:43]=[N:42]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1-c1cn[nH]c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
A microwave vial was charged with INTERMEDIATE D (0.100 g, 0.192 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (Sigma-Aldrich, St. Louis, Mo., 0.113 g, 0.384 mmol), tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol), and K2CO3 (0.133 g, 0.959 mmol). The solids were diluted with dioxane (1.279 mL) and water (0.639 mL), and the reaction was heated under microwave irradiation at 100° C. for 30 minutes. The reaction mixture was lyophilized overnight and the material was then taken up in methanol, and acidified with HCl (1N) (3.84 mL, 3.84 mmol). The mixture was concentrated onto silica gel, and purified via silica gwel MPLC (Biotage Isolera One; PuriFlash HP, 15μ, 25 g), eluting with 0 to 100% ethyl acetate in heptane to yield slightly impure material. The material was loaded onto a 500 mg SCX column and the product was eluted (with impurity) in the ammonia wash. The resulting material was then purified by reverse-phase preparative HPLC (Column: Phenomenex 150×30 mm, 5 micron, C18 column; 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min) to provide 4-(2-(1H-pyrazol-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.022 g, 0.043 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.47 (m, J=12.80 Hz, 2H) 4.28-4.37 (m, 2H) 6.25 (d, J=8.51 Hz, 1 H) 7.08 (dd, J=8.56, 2.20 Hz, 1 H) 7.14 (d, J=2.15 Hz, 1 H) 7.59-7.64 (m, 1 H) 7.65-7.70 (m, 1 H) 7.96 (s, 2 H) 8.02 (d, J=1.37 Hz, 1 H) 8.43 (s, 1 H). m/z (ESI) 509.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:34]=[CH:33][C:26]([C:27](N(OC)C)=[O:28])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[CH3:35][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:34]=[CH:33][C:26]([C:27](=[O:28])[CH3:35])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 4-(3-acetyl-6-bromo-1-oxo-4-phenyl-1H-isoquinolin-2-ylmethyl)-N-methoxy-N-methylbenzamide (330 mg) in tetrahydrofuran (10 ml) was added methyl magnesium bromide (3M tetrahydrofuran solution, 0.64 ml) under ice-cooling and the mixture was stirred for 2 hrs. under ice-cooling. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=19/1→7/3) to give the title compound (259 mg, 87%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[N:3]=1.Cl.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(O)C.O1CCOCC1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=3[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[N:3]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(Br)cc2)nc(N)n1
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a stirred suspension of 4-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-2-yl-amine (0.054 g, 0.20 mmol) in ethanol (7.5 ml) was added a solution of hydrogen chloride in dioxane (4.0 M, 0.025 ml) followed by 4-bromoaniline (0.069 g, 0.40 mmol). After heating under reflux for 45 minutes, volatiles were removed under reduced pressure. The residue was treated with 1.0 M hydrochloric acid (10 ml) and stirred for 30 minutes. Filtration provided the hydrochloride salt of the title compound (0.08 g, 90% yield). 1H NMR (DMSO-d6) δ 3.90 (s, 3H, CH3), 6.71 (s, 1H, Ar), 7.30 (d, 1H, J=9.0 Hz, Ar), 7.57-7.59 (m, 2H, Ar), 7.65 (dd, 1H, J=9.0 Hz, J=2.4 Hz, Ar), 7.70 (d, 1H, J=2.4 Hz, Ar), 7.80-7.86 (m, 2H, Ar), 11.08 (s, 1H, NH).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[CH2:33](N(CC)CC)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH3:33])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: O=C(c1nc2c(s1)CNCC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: CCN(CC)CC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In dichloromethane (10 ml), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (400 mg) was suspended, followed by the addition of triethylamine (0.22 ml) and acetic acid (0.05 ml). The resulting mixture was stirred at room temperature for 5 minutes. To the reaction mixture, a 30% aqueous solution (0.08 ml) of formaldehyde and sodium triacetoxyborohydride (264 mg) were added. The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue. The resulting mixture was washed with water and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was dissolved in a saturated hydrochloride solution in ethanol (1 ml), followed by concentration under reduced pressure. The residue thus obtained was crystallized from hexane and ethyl acetate, whereby the title compound (298 mg, 71%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH:14]=[C:13]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: COc1cccc(S)c1
Product: COc1cccc(Sc2nc(Nc3cc(C)[nH]n3)cc3cc(OC)ccc23)c1

Procedure:
Similar procedure as described in example 305 was used, starting from 3-methoxy-benzenethiol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-methoxy-phenylsulfanyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 393 (MH+).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=4)=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[CH3:63][C:64]([O:67][C:68]([N:70]1[CH2:75][CH2:74][CH:73]([NH2:76])[CH2:72][CH2:71]1)=[O:69])([CH3:66])[CH3:65]>ClCCl.CN(C)C=O>[C:64]([O:67][C:68]([N:70]1[CH2:75][CH2:74][CH:73]([NH:76][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]3[N:19]=[CH:18][C:9]4[N:10]([CH3:17])[C:11](=[O:16])[C:12]([F:14])([F:15])[CH2:13][N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:8]=4[N:21]=3)=[CH:24][CH:25]=2)[CH2:72][CH2:71]1)=[O:69])([CH3:63])([CH3:65])[CH3:66]
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc21
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
A mixture of 0.10 g (0.23 mmole) of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-256), 0.093 g (0.92 mmole) of triethylamine, 0.133 g (0.35 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.070 g (0.35 mmole) of 4-amino-1-piperidinecarboxylic acid 1,1-dimethylethyl ester was added. The mixture was stirred for 3 hours, then taken up in 50 mL of dichloromethane and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.095 g of 4-[4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-259).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.CN1CCOCC1.[CH3:43][C:44]1([CH3:52])[O:48][CH:47]([CH2:49][O:50][NH2:51])[CH2:46][O:45]1>C(OCC)(=O)C.O1CCCC1>[CH3:43][C:44]1([CH3:52])[O:48][CH:47]([CH2:49][O:50][NH:51][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=2[NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[CH2:46][O:45]1
Reactant: CC1(C)OCC(CON)O1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC1(C)OCC(CONC(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)O1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a stirring solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (4.52 g, 11.5 mmol) in freshly distilled tetrahydrofuran (20 mL) at −15° C. was added diphenylphosphinic chloride (2.85 mL, 14.95 mmol). The resultant reaction mixture was stirred for 30 minutes at −15° C. N-Methylmorpholine (1.26 mL, 11.5 mmol) was added and stirring was continued for 90 minutes at −15° C. The reaction was then charged with O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (2.03 g, 13.8 mmol) and allowed to stir at −15° C. for 30 minutes. N-methylmorpholine (1.9 mL, 17.25 mmol) was added and the reaction was allowed to warm to room temperature. After 17 hours, the mixture was diluted with ethyl acetate and partitioned twice with saturated NaHCO3 solution, then twice with water, and twice with saturated brine solution. Organic layers were collected, dried over sodium sulfate, filtered and concentrated in vacuo. The afforded residue was purified by silica column chromatography in 3:1 hexanes/ethyl acetate. The corresponding fractions were collected, dried in vacuo, and crystallized from ethyl acetate/hexanes affording N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (4.12 g, 68.6%) as light brown solid: m.p.=114-115° C.; 1NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.62 (s, 1H), 7.53-7.55 (m, 1H), 7.31-7.37 (m, 2H), 7.17 (dd, 1H, J=16.9, 9.3), 6.60-6.65 (m, 1H), 4.22 (t, 1H, J=6.1), 3.96 (t, 1H, J=8.3), 3.76-3.77 (m, 2H), 3.63 (t, 1H, J=4.9), 1.26 (s, 3H), 1.21 (s, 3H); MS(APCI+)=522.9; Anal. calcd/found for C19H18F3IN2O4: C, 43.70/43.88; H, 3.47/3.43; N, 5.36/5.20; F, 10.91/10.87.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[C:18]([CH3:20])[N:17]([CH3:21])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=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>[C:22]([N:6]1[C:5]2[CH:26]=[CH:27][C:2]([C:32]3[CH:33]=[N:34][C:29]([NH2:28])=[N:30][CH:31]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]=[C:18]([CH3:20])[N:17]([CH3:21])[N:16]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)nn1C
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)nn1C
Temperature: 110 °C
Yield: 76 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-[2-(1,5-dimethyl-1H-[1,2,4]triazol-3-yl)-phenyl]-1H-benzimidazole (38 mg, 0.09 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (24 mg, 0.109 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.01 mmol) and 2 M aqueous Na2CO3 (0.2 mL, 0.4 mmol). The reaction mixture is heated under Argon at 110° C. for 3 hours. The residue is diluted with EtOAc (20 mL), washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-10% MeOH/CH2Cl2 as the eluent to afford the title compound (30 mg, 76%) as an off-white solid. LCMS (ESMS): m/z 439.72 (M++1).