Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][C:7]1[C:12](=[O:13])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[N:20]=[CH:21][CH:22]=[CH:23][C:9]=2[N:8]=1)([O-])=O.C(O)(=O)C>C(O)C.[Fe]>[NH2:1][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][C:7]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]2[N:20]=[CH:21][CH:22]=[CH:23][C:9]=2[N:8]=1
Reactant: O=c1c(Cc2ccccc2[N+](=O)[O-])nc2cccnc2n1-c1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccccc1Cc1nc2cccnc2n(-c2ccccc2)c1=O
Yield: 9.4 %

Procedure:
The mixture of 2-(2-nitrobenzyl)-3-oxo-4-phenyl-3,4-dihydropyrido[2,3-b]pyrazine (1.39 g), iron (2.17 g) and acetic acid (1.16 g) in ethanol (15 ml) was refluxed for 3 hours. The reaction mixture was cooled and filtered. To the filtrate was added saturated sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layer was dried and evaporated. The crude product was purified by silica column chromatography to obtain 2-(2-aminobenzyl)-3-oxo-4-phenyl-3,4-dihydropyrido[2,3-b]pyrazine (120 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].[CH:11]1(B(O)O)[CH2:13][CH2:12]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:11]1([C:2]2[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=2[CH3:8])[CH2:13][CH2:12]1
Reactant: Cc1nc(C#N)ccc1Br
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc(C#N)ccc1C1CC1
Temperature: 110 °C
Reaction time: 12 h
Yield: 75.9 %

Procedure:
5-Bromo-6-methyl-pyridine-2-carbonitrile (0.5 g, 2.5 mmol), cyclopropylboronic acid (CAN:411235-57-9, 0.36 g, 4 mmol), Pd2(dba)3 (CAN:411235-57-9, 0.1 g, 0.2 mmol), xantphos (CAN:161265-03-8, 0.15 g, 0.26 mmol) and Cs2CO3 (1.1 g, 3 mmol) were suspended in 1,4-dioxane (30 mL) under a nitrogen atmosphere. The mixture was stirred for 12 h at 110° C., filtered, concentrated under reduced pressure and purified by column chromatography (silica gel, 5 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (0.3 g, 75%) as yellow solid; MS (D): m/e=159.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[I-].[K+].[F:10][C:11]1[CH:48]=[CH:47][C:14]([C:15]([C:17]2[N:26]=[C:25](C3C(C(C)C)=C(S([O-])(=O)=O)C(C(C)C)=CC=3C(C)C)[C:24]3[C:19](=[CH:20][C:21]([CH3:46])=[CH:22][CH:23]=3)[N:18]=2)=[O:16])=[CH:13][CH:12]=1.O>CC(N(C)C)=O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([C:17]2[N:26]=[C:25]([NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[C:24]3[C:19](=[CH:20][C:21]([CH3:46])=[CH:22][CH:23]=3)[N:18]=2)=[O:16])=[CH:47][CH:48]=1
Reactant: Cc1ccc2c(-c3c(C(C)C)cc(C(C)C)c(S(=O)(=O)[O-])c3C(C)C)nc(C(=O)c3ccc(F)cc3)nc2c1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc2c(Nc3cc(C)[nH]n3)nc(C(=O)c3ccc(F)cc3)nc2c1
Yield: 14.4 %

Procedure:
A solution of 5-methyl-1H-pyrazol-3-amine (225 mg, 2.31 mmol), potassium iodide (188 mg, 0.088 mmol), and 2-(4-fluorobenzoyl)-7-methylquinazolin-4-yl-2,4,6-triisopropylbenzenesulfonate (380 mg, 0.69 mmol) in DMA (2 mL) was stirred at 50° C. for 6 h, then water was added and the solution was filtered. The solid was then dried and triturated with acetonitrile to give (4-fluorophenyl)(7-methyl-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (36 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 2.50 (s, 3H), 6.53 (s, 1H), 7.38 (t, 2H), 7.51 (d, 2H), 7.66 (s, 1H), 8.08 (m, 2H), 8.62 (d, 1H), 10.57 (s, 1H), 12.18 (s, 1H); LC-MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[Na].C(=O)([O-])O.[C:16]([NH:24][C:25]1[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:26]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>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.C1(C)C=CC=CC=1.C(O)C>[C:16]([NH:24][C:25]1[CH:37]=[C:36]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:35]=[CH:34][C:26]=1[C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: OB(O)c1ccccc1F
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: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2F)cc1NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
56 mg of 2-fluorophenylboronic acid, 0.10 g of sodium, hydrogen carbonate, 0.6 mL of ethanol, 0.3 mL of wafer and 23 mg of tetrakis(triphenylphosphine)palladium(0) were added to 2.1 mL of toluene solution containing 0.15 g of tert-butyl 2-(benzamido)-4-bromobenzoate, and the resulting mixture was heated to reflux for 2 hours, lifter the reaction mixture was cooled to room temperature, 17 mg of 2-fluorophenylboronic acid and 23 mg of tetrakis(triphenylphosphine )palladium(0) were added and she resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, toluene and a saturated sodium hydrogen carbonate aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=10:1] to obtain tert-butyl 2-(benzamido)-4-(2-fluorophenyl)benzoate.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:23]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:19][CH2:18]1
Reactant: CC1(C)OB(c2cc(C(F)(F)F)ccc2OCC2CC2)OC1(C)C
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-Cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c9) the title compound is obtained as off-white solid.
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][C:11]2([N:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]4[CH2:26][CH2:25]4)=[C:20]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[N:19]=3)=[O:17])[CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:16]([N:15]3[C:11]4([CH2:35][CH2:36][NH:8][CH2:9][CH2:10]4)[CH2:12][CH2:13][CH2:14]3)=[O:17])=[N:19][C:20]=2[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN2C(=O)c2ccc(C3CC3)c(Cc3ccc(F)cc3)n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1)N1CCCC12CCNCC2
Yield: 92.4 %

Procedure:
A solution of tert-butyl 1-(5-cyclopropyl-6-(4-fluorobenzyl)picolinoyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (Example 111, 19 mg, 38.5 μmol) and 2,2,2-trifluoroacetic acid (43.9 mg, 29.5 μL, 385 μmol) in DCM (0.4 mL) was stirred for 12 h at ambient temperature. The reaction mixture was poured onto 20 mL saturated aqueous NaHCO3 solution/ice and extracted with EtOAc (2×20 mL). The combined extracts were washed with ice-water/brine (20 mL), dried over Na2SO4 and brought to dryness to give the title compound (14 mg, 92%) as colorless oil; MS (EI): m/e=394.5 [MH+].
Reaction SMILES: [BH4-].[Na+].S(=O)(=O)(O)O.[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH:10]=[C:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21].N>O.C1COCC1>[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH2:10][CH:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: N
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
In a 250 mL round bottom flask dry THF (94 mL) was taken. It was cooled to −10° C. and NaBH4 (2.38 g) was added. After that sulfuric acid (6.0 g) was added dropwise at −5 to 0° C. over a period of 15-30 min. Separately, 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (5.0 g) was mixed in a solvent mixture of THF (12.5 mL) and water (1.7 mL) and added into the reaction mixture, keeping the temperature between −2 to 0. It was stirred for 1 h at −2 to 0° C. Reaction mixture was poured into cold water. It was basified by adding aq. ammonia solution. Product was extracted in ethyl acetate. The organic layer was collected. It was washed with water and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-4.8 g, % Y-95.6%, % Purity by HPLC-90.8%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[CH:17][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1nccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (10 g, 33.4 mmol, 1 eq) in 1,4-dioxane (160 mL) add a 4 M solution of hydrochloric acid in 1,4-dioxane (80 mL, 0.3 mol, 10 eq) and stir under nitrogen at room temperature overnight. Dilute with DCM (600 mL) then basify with 50% aqueous sodium hydroxide. Add water (100 mL), separate the layers and extract the aqueous twice with DCM (200 mL). Combine the organic extracts, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter, and concentrate to give 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as a viscous oil which solidifies on standing (6.39 g, 96%). MS (ES): m/z=199.1, 201.1 [M+H]+.
Reaction SMILES: [NH:1]([C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:23][C:24]([NH2:26])=[O:25])=[C:9]([CH3:22])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)N>C(O)C.[Ni]>[NH2:1][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:23][C:24]([NH2:26])=[O:25])=[C:9]([CH3:22])[N:10]2[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1c(CC(N)=O)c2c(OCC(=O)NN)cccc2n1Cc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: Cc1c(CC(N)=O)c2c(OCC(N)=O)cccc2n1Cc1ccccc1
Yield: 11.3 %

Procedure:
A mixture of 230mg (0.63 mmol) of 4-(2-hydrazino-2-oxoethoxy)-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide and 300 mg of Raney Ni in 40 mL of ethanol was heated to maintain reflux for 4 hours. The mixture was cooled the EtOH poured off the catalyst, and the catalyst washed twice with methylene chloride. The combined solvents were filtered, concentrated and the residue chromatographed on silica gel and on eluting with 10% MeOH/EtOAc, 25 mg (11% yield) of 4-(2-amino-2-oxoethoxy)-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide were obtained. This material melted at 190-207° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:12][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Br)ccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a solution of 5-bromo-2-methyl-benzoic acid (9.9 g, 46 mmol) in DMF (100 mL) was added K2CO3 (7.6 g, 55 mmol) and CH3I (20 g, 140 mmol) slowly. After stirring at room temperature for 4 h, the solvent was removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed under vacuum to afford 5-bromo-2-methylbenzoic acid methyl ester (8.6 g, 82%), which was used in next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.1, 1H), 7.50 (dd, J=8.1, 2.1, 1H), 7.12 (d, J=8.1, 1H), 3.89 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N+:19]([O-])=O)[CH:10]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:14]=2)[NH2:19])[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(Cc2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
Add Pd/C (10%, 200 mg) to the solution of 1-methyl-4-(3-nitro-5-(trifluoromethyl)benzyl)piperazine (812 mg, 2.68 mmol) in methanol (15 mL), flush with H2, stir under hydrogen atmosphere for 16 hrs at room temperature. Filter and concentrate the filtrate to give the crude product (732 mg, 100%). MS: (M+1): 273.0.
Reaction SMILES: [OH-].[K+].[CH3:3]N(N=O)C(N)=O.[Cl:10][C:11]1[N:12]=[CH:13][N:14]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:15]=1[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27][C:28]2[CH:33]=[C:32]([CH2:34][CH:35]=[CH2:36])[CH:31]=[C:30]([C:37]#[N:38])[CH:29]=2)[C:21]=1[F:39])=[O:17]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:10][C:11]1[N:12]=[CH:13][N:14]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:15]=1[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27][C:28]2[CH:33]=[C:32]([CH2:34][CH:35]3[CH2:3][CH2:36]3)[CH:31]=[C:30]([C:37]#[N:38])[CH:29]=2)[C:21]=1[F:39])=[O:17]
Reactant: CN(N=O)C(N)=O
Reactant: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(CC3CC3)c2)c1F
Temperature: 0 °C

Procedure:
To a mixture of 30% aqueous KOH (11 mL) and diethyl ether (11 mL) was added N-methyl-N-nitrosourea (0.097 g, 0.938 mmol) in one portion with stirring and cooling at 0° C. and the reaction mixture was maintained at this temperature for 20 min. The organic phase was isolated, dried over KOH pellets and added dropwise to a solution of 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(2-propen-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.054 g, 0.094 mmol) and palladium(II) acetate (2.106 mg, 9.38 μmol) in diethyl ether (11.00 mL) with stirring and cooling at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then allowed to warm to room temperature and stirred overnight at which time LC-MS indicated complete conversion to desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1.C(O)(=O)C>C1COCC1.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2ccccn2)nc(N2CCOCC2)n1
Reaction time: 0.17 h
Yield: 13.3 %

Procedure:
To 0.224 g (2.38 mmol) of 2-aminopyridine in THF (3 mL) was added 2.5 mL of lithium bis(trimethylsilyl)amide (1 M solution in THF) and the mixture was stirred for 10 min. A solution of 0.204 g (0.56 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (4 mL) was added and the mixture was stirred for 1 hr. The resulting mixture was neutralized with acetic acid, diluted with water and extracted with EtOAc. The organic layer was washed with water and aqueous NH3, and dried. After removal of the solvent, the residue was purified by chromatography on alumina, eluting with CH2Cl2/EtOAc (1:5) to give an orange powder. Recrystallization from EtOH/CH2Cl2 gave 31.5 mg (13% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(2-pyridinyl)-1,3,5-triazin-2-amine: mp 230-232° C.; 1H NMR (CDCl3) δ 8.41-8.37 (m, 2H), 8.20 (d, J=8.4 Hz, 1H), 8.12 (br s, 1H), 7.91-7.89 (m, 1H), 7.75 (td, J=7.5, 1.8 Hz, 1H), 7.60 (t, JHF=53.5 Hz, 1H), 7.45-7.39 (m, 2H), 7.05 (ddd, J=7.3, 4.9, 0.9 Hz, 1H), 3.96-3.94 (m, 4H), 3.85-3.82 (m, 4H); HRMS (FAB+) MNa+ Calcd. for C20H18F2N8NaO: m/z 447.1466. Found: m/z 447.1464.
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:23]1([C:26]([N:20]2[CH2:21][CH2:22][CH:17]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C@@H:11]5[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]5[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH2:18][CH2:19]2)=[O:27])[CH2:25][CH2:24]1
Reactant: O=C(O)C1CC1
Reactant: O=C1N[C@@H]2CCCC[C@H]2N1C1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CC1)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To the solution of (3aR,7aR)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one, 0.25 mmol) in dry DMF (3 mL) was added cyclopropanecarboxylic acid (26 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SO4. The crude product was purified with high pH prep-LCMS to provide the title compound (48 mg, 51%) as white powder. 1H NMR (400 MHz, METHANOL-D4): δ ppm 0.61-0.81 (m, 4H), 1.16-1.43 (m, 6H), 1.50-1.67 (m, 2H), 1.68-1.98 (m, 8H), 2.13-2.29 (m, 3H), 2.44-2.62 (m, 2H), 2.80-3.10 (m, 5H), 3.48-3.66 (m, 1H), 4.31 (d, J=13.28 Hz, 1H), 4.47 (d, J=13.28 Hz, 1H). MS (M+1): 375.2
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:43])[N:9]=[C:10](SC)[C:11]([C:28]1[C:29]([F:40])=[C:30]2[C:35](=[C:36]([O:38][CH3:39])[CH:37]=1)[O:34][CH2:33][CH2:32][CH2:31]2)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=2)=[CH:15][CH:14]=1.[CH2:44]([O:46][C:47]([C:49]1[S:53][CH:52]=[N:51][C:50]=1[NH:54][NH2:55])=[O:48])[CH3:45]>C(N(CC)CC)C>[CH2:44]([O:46][C:47]([C:49]1[S:53][CH:52]=[N:51][C:50]=1[N:54]1[C:8](=[O:43])[NH:9][C:10]([CH:11]([C:28]2[C:29]([F:40])=[C:30]3[C:35](=[C:36]([O:38][CH3:39])[CH:37]=2)[O:34][CH2:33][CH2:32][CH2:31]3)[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=3)=[CH:15][CH:14]=2)=[N:55]1)=[O:48])[CH3:45]
Reactant: CCOC(=O)c1scnc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C(F)(F)F)n2)cc1)c1cc(OC)c2c(c1F)CCCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2cc(OC)c3c(c2F)CCCO3)[nH]c1=O
Temperature: 85 °C
Reaction time: 20 h
Yield: 56.6 %

Procedure:
To 4 ml of a DMF solution containing 111 mg of [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (189a)), 37 mg of 4-hydrazinothiazole-5-carboxylic acid ethyl ester (Example (185c)) and 0.031 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 20 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was dissolved in 4 ml of methanol and 0.032 ml of acetic acid, and then 83 mg of sodium cyanotrihydroborate was added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (74 mg).
Reaction SMILES: Cl.Cl.C([C:10]1[C:11]([Cl:21])=[N:12][C:13]2[CH2:14][CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[CH3:20])C1C=CC=CC=1.CO>C(Cl)Cl.[Cl-].[Na+].O.ClCCCl>[ClH:21].[Cl:21][C:11]1[CH:10]=[C:19]([CH3:20])[C:18]2[CH2:17][NH:16][CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: Cc1c(Cc2ccccc2)c(Cl)nc2c1CNCC2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Cl)nc2c1CNCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 179.4 %

Procedure:
To a suspension of crude benzyl-2-chloro-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine dihydrochloride (8.00 g, 23.1 mmol) in DCM (100 mL), 2 M Na2CO3aq (50 mL) was added. The mixture was stirred for 20 min, and then diluted with brine. The products were extracted twice with DCM, and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give crude (6.14 g). A solution of the residue and ACEC1 (5.05 mL, 46.3 mmol) in DCE (100 mL) was allowed to stir at 70° C. for 1.5 h under nitrogen. MeOH (50 mL) was added and the mixture was stirred at the same temperature for 1 h. The mixture was cooled to rt and concentrated. The residue was triturated with MeOH (10 mL) and EtOAc (400 mL), and the white solid was collected on a funnel, washed with EtOAc (200 mL), and dried under reduced pressure to give 2-chloro-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (4.54 g): 1H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (br s, 2 H), 7.33 (s, 1 H), 4.21-4.24 (app t, 2 H), 3.41-3.43 (m, 2 H), 3.05 (t, J=6.57 Hz, 2 H), 2.24 (s, 3 H); MS (ESI+) m/z 183.44 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1.[SH:20][CH:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3]([S:20][CH:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CCC(S)C(C)=O
Reactant: NS(=O)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(Sc1nc(Nc2ccc(S(N)(=O)=O)nc2)ncc1Br)C(C)=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
73 mg (0.2 mmol) of 5-(5-bromo-4-chloro-pyrimidin-2-ylamino)-pyridine-2-sulfonic acid amide and 32 mg (0.27 mmol) of 3-mercapto-2-pentanone are dissolved in 4 ml of DMF p.a. After 0.038 ml (0.27 mmol) of triethylamine is added, it is allowed to stir for 2 hours at room temperature and for 3 hours at 50° C. After concentration by evaporation, it is flashed with dichloromethane/MeOH (9:1).