Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[Na].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1
Reactant: CC(=O)c1ccc(F)cn1
Agent: [Na]
Solvent: CO
Solvent: O
Product: CC(O)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
1-(5-Fluoropyridin-2-yl)ethanone (Method 1; 11.3 g, (75% pure), 60.9 mmol) in MeOH was added sodium boronhydride (2.30 g, 60.9 mmol) potion wise at 0° C. After adding, the reaction was warmed to room temperature and stirred at room temperature for 1 hour. Water (10 ml) was added and the solution was extracted with ether (2×50 ml). The combined organic layers were dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (ether) to give the title compound as a clear oil (7.5 g, 87%). 1H NMR (400 MHz) 8.46 (d, J=3.2 Hz, 1H), 7.69 (ddd, J=3.2, 3.2 and 3.2 Hz, 1H), 7.55 (m, 1H), 5.44 (d, J=4.4 Hz, 111), 4.73 (m, 1H), 1.34 (d, J=6.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.BrC1SC=CC=1C1C=CC=CC=1.[CH2:25]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[CH3:26].CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:7]1([C:5]2[CH:6]=[C:2]([N:33]3[CH2:32][CH2:31][N:30]([C:28]([O:27][CH2:25][CH3:26])=[O:29])[CH2:35][CH2:34]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: Brc1cc(-c2ccccc2)cs1
Agent: [Pd]
Agent: Brc1sccc1-c1ccccc1
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(c2cc(-c3ccccc3)cs2)CC1
Temperature: 100 °C
Reaction time: 48 h
Yield: 4.61 %

Procedure:
A solution of the mixture of 2-bromo-4-phenylthiophene and 2-bromo-3-phenylthiophene (6.00 g, 25.0 mmol), 1-ethoxycarbonylpiperazine (3.96 g, 25.0 mmol), sodium tert-butoxide (3.48 g, 36.2 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (468 mg, 0.750 mmol) and tris(dibenzylideneacetone)dipalladium (0) (544 mg, 0.594 mmol) in toluene (50 ml) was stirred at 100° C. for 48 hours. Insolubles were filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain ethyl 4-(4-phenyl-2-thienyl)piperazine-1-carboxylate (365 mg, 4.61%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:28]=[C:29]([NH2:33])[CH:30]([CH3:32])[CH3:31]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:24]3[O:26][N:33]=[C:29]([CH:30]([CH3:32])[CH3:31])[N:28]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)C(N)=NO
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C
Product: Cc1ccc(C2CC(c3nc(C(C)C)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1C

Procedure:
80 mg (0.222 mmol) of the compound from Example 128A and 35 mg (0.333 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([OH:18])=O)[CH:9]=2)=[CH:4][C:3]=1[F:19].S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].Cl.[NH2:30][C:31]1([C:39]([O:41][CH3:42])=[O:40])[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([NH:30][C:31]3([C:39]([O:41][CH3:42])=[O:40])[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33][CH2:32]3)=[O:18])[CH:9]=2)=[CH:4][C:3]=1[F:19]
Reactant: COC(=O)C1(N)CCC(F)(F)CC1
Reactant: Cc1ccc(-c2ccc(Cl)c(F)c2)cc1CC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)c(F)c3)ccc2C)CCC(F)(F)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6.06 g (21.7 mmol) of the compound from Example 1A were dissolved in 7.5 ml (103 mmol) of thionyl chloride. The reaction mixture was stirred at 80° C. for 1 h and then concentrated. The residue was dissolved in 30 ml of acetonitrile. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to 5.00 g (21.8 mmol) of the compound from Example 4A. The phases were separated, the aqueous phase was extracted repeatedly with ethyl acetate and the combined organic phases were dried over sodium sulphate, filtered and concentrated. 140 ml of acetonitrile and 8.76 g (63.4 mmol) of potassium carbonate were added to the residue. With ice-cooling, the solution of the acid chloride was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was then added to ice-water and extracted repeatedly with dichloromethane, and the combined organic phases were washed repeatedly with 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated. This gave 8.22 g (83% of theory) of the title compound, which were converted without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].OO.S([O-])([O-])(=[O:29])=S.[Na+].[Na+].C(O)C.O>C(O)C.[O-2].[O-2].[O-2].[O-2].[O-2].[V+5].[V+5]>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:29])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=S([O-])([O-])=S
Agent: [V+5]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 381 %

Procedure:
2-[[3-Methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylthio]benzimidazole (monohydrate) (20.0 g) was dissolved in ethanol (150 ml), to which was added dropwise at about 20° C. a solution of vanadium pentaoxide (30 mg) in a mixture of 35% aqueous solution of hydrogen peroxide (6.14 g) and ethanol (6 ml), and allowed to react at 18°-22° for about 2.5 hours. After completion of the reaction an aqueous solution of sodium thiosulfate (2 g/60 ml) was added to the reaction mixture, which was stirred by ice-cooling for about 1 hour. The crystals were collected by filtration and washed with an ice-cooled mixture of ethanol-water (1:1). The crystals thus obtained were treated with a mixture of ethanol-water (9:1, 100 ml), heated (70°-80° C.) and stirred so that the crystals were dissolved, then the insoluble matters were removed by hot filtration. The filtrate was ice-cooled for crystallization, and the crystals were collected by filtration, washed with ice-cooled ethanol-water mixture (8:2) and dried in vacuo, to give white needles of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylsulfinyl]benzimidazole (17.8 g). (yield: 89.5%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH:18]([OH:20])[CH3:19])[CH:11]=[CH:10]1.N1C=CN=C1>O1CCCC1>[Si:1]([O:20][CH:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[NH:9][CH:10]=[CH:11]2)[CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)c1cccc2cc[nH]c12
Temperature: 20 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
Add tert-butyldimethylsilyl chloride (16.4 g, 108 mmol) in anhydrous tetrahydro-furan (100 ml) to 1-(indol-7-yl)ethan-1-ol (10.7 g, 66.4 mmol) and imidazole (11.8 g, 173 mmol) in anhydrous tetrahydrofuran (100 ml). Stir at 20° C. for 2 hours. Dilute with hexanes (400 ml). Wash with 0.25 M aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. Dry over magnesium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with hexane containing 10-25% ethyl acetate to provide the desired compound (16 g, 87%) as a colorless oil.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]2)[CH2:10][CH2:9]1.CCN(CC)CC.Cl[C:36]([O:38][CH2:39][C:40]#[CH:41])=[O:37]>C(Cl)Cl>[CH2:39]([O:38][C:36]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]2[CH2:20][CH2:19][CH:18]([C:21](=[O:22])[NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:37])[C:40]#[CH:41]
Reactant: CC(C)CNC(=O)C1CCN(C2CCCNCC2)CC1
Reactant: C#CCOC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCOC(=O)N1CCCC(N2CCC(C(=O)NCC(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
1-(azepan-4-yl)-N-(2-methylpropyl)piperidine-4-carboxamide TFA salt (0.15 g, 0.38 mmol) was dissolved in DCM (8 mL) at rt. NEt3 (0.16 mL, 1.14 mmol) and propargyl chloroformate (0.06 mL, 0.57 mmol) were added and the reaction mixture was stirred at rt for 2 h under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol.), organic layer washed with sat. NaCl sol. and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 Å, 12 mL per min, gradient 0% to 10% MeOH in DCM]) to give prop-2-yn-1-yl-4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate (0.04 g, 31%) as a yellow gum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([Cu])#[N:12].[NH4+].[OH-]>CN1CCCC1=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[N:12])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cc(F)ccc1Br
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1cc(F)ccc1C#N
Temperature: 180 °C
Reaction time: 5.5 h
Yield: 78.4 %

Procedure:
To a solution of intermediate 126, 1-bromo-4-fluoro-2-methoxybenzene (9.0 g) in N-methylpyrrolidone (100 mL, Sure Seal; Aldrich) was added CuCN (6.6 g, 73.7 mmol, 1.8 eq.; Aldrich), and the mixture stirred at 180° C. under anhydrous nitrogen for 5.5 hrs. After cooling, 14% aqueous NH4OH (330 mL) was added and stirring continued for 45 min at room temperature. The mixture was extracted with ether (100 mL×3), and the combined extracts washed sequentially with dilute aqueous NH4OH, dilute HCl and brine, then dried (MgSO4), and concentrated to provide the title compound (5.2 g, Yield 85% in 2 steps) as a white solid: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.91 (3H, s, OMe), 6.69 (1H, dd, J=2.3 Hz, J=10.5 Hz, Ar—H), 6.72 (1H, dt, J=2.5 Hz, J=J=8.0 Hz, Ar—H), 7.55 (1H, dd, J=6.5 Hz, J=8.5 Hz, Ar—H); 13C NMR (CDCl3, 125.8 Hz) δ ppm: 56.49, 98.16, 100.06, 100.27, 108.31, 108.50, 115.83 135.37, 135.46, 163.25, 163.34 165.47, 167.50. An analytical sample was obtained by trituration with ether: Anal. calcd for C8H6FNO: C, 63.57; H, 4.00; N, 9.26; found: C, 63.36; H, 3.91; N, 9.16.
Reaction SMILES: C=O.[CH:3]1([N:6]2[C:10]3[C:11]([O:29][C@@H:30]([C@@H:32]4[CH2:36][C:35](=[O:37])[NH:34][CH2:33]4)[CH3:31])=[N:12][C:13]([C:15]4[CH:23]=[C:22]5[C:18]([C:19]6([CH2:28][NH:27][CH2:26]6)[C:20](=[O:25])[N:21]5[CH3:24])=[CH:17][CH:16]=4)=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:5][CH2:4]1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.C(OCC)(=O)C>[CH:3]1([N:6]2[C:10]3[C:11]([O:29][C@@H:30]([C@@H:32]4[CH2:36][C:35](=[O:37])[NH:34][CH2:33]4)[CH3:31])=[N:12][C:13]([C:15]4[CH:23]=[C:22]5[C:18]([C:19]6([CH2:26][N:27]([CH3:38])[CH2:28]6)[C:20](=[O:25])[N:21]5[CH3:24])=[CH:17][CH:16]=4)=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:5][CH2:4]1
Reactant: C[C@@H](Oc1nc(-c2ccc3c(c2)N(C)C(=O)C32CNC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)N(C)C(=O)C32CN(C)C2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Formaldehyde in water (37%, 0.07 mL, 0.89 mmol) was added to a mixture of 6′-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1′-methylspiro[azetidine-3,3′-indolin]-2′-one 3.85 (42 mg, 0.089 mmol) in 1,2-dichloroethane (1.5 mL). After 15 min, sodium triacetoxyborohydride (78 mg, 0.37 mmol) was added and mixture stirred at room temperature overnight. The reaction mixture was then diluted with water and ethyl acetate. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel column chromatography (0-20% methanol in dichloromethane) to afford 6′-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1,1′-dimethylspiro[azetidine-3,3′-indolin]-2′-one 3.86.
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14](N)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].S(O)(O)(=O)=O.Cl[C:26]1[NH:27][CH2:28][CH2:29][N:30]=1>C(O)(C)C>[CH:1]([O:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:26]3[NH:30][CH2:29][CH2:28][N:27]=3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCc1ccc(Cc2ccc(N)cc2)cc1
Reactant: ClC1=NCCN1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)OCc1ccc(Cc2ccc(C3=NCCN3)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 4-(4-isopropoxymethylbenzyl)-phenylamine (400 mg, 1.57 mmol) in isopropanol (4.8 mL) at 20° C. under argon atmosphere was added 2-chloro-2-imidazoline sulfate (382 mg, 1.88 mmol). The mixture was heated to 80° C. and stirred for 3 hours. The solvent was evaporated in vacuo, and water and 10% sodium hydroxide was added to pH 11-12. The basic aqueous phase was extracted with dichloromethane (3×20 mL), and the combined organic layers were washed with water, dried (Na2SO4), and evaporated in vacuo. The crude product was purified by flash chromatography, washed with 0.07M potassium carbonate, and concentrated to give pure 2-[4-(4-isopropoxymethyl-benzyl)-phenyl]-imidazoline (463 mg, 91%) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[O:15]1CCOCC1>>[CH:1]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)=[O:15]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1cnc(SC)nc1C
Product: CCOC(=O)c1cnc(SC)nc1C=O

Procedure:
A solution of ethyl 4-methyl-2-(methylthio)pyrimidine-5-carboxylate in dioxane (330 mg, 1.56 mmol) was treated with SeO2 (220 mg, 2.0 mmol) at 100° C. for 3 days. After cooling, the reaction mixture was concentrated and the residue was purified by flash chromatography (20% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 227 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:14][CH3:15])[NH:11]2)=[C:7]([NH2:16])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C.CCOC(C)=O>[CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:14][CH3:15])[N:11]2[CH2:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:7]([NH2:16])[N:6]=1
Reactant: BrCC1CCOCC1
Reactant: CCC(C)COc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(C)COc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 35.6 %

Procedure:
To a solution of 2-[(2-methylbutyl)oxy]-8-methoxy-9H-purin-6-amine (109 mg) in dry DMF (1.86 mL) was added potassium carbonate (165 mg) and the mixture was stirred at 60° C. for 90 mins. The mixture was cooled to room temperature and 4-(bromomethyl)tetrahydro-2H-pyran (59 mg) was added. The reaction was stirred at 50° C. overnight and was cooled to room temperature. The mixture was taken up in EtOAc (15 mL) and washed with water (2×10 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give a yellow viscous oil. The material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to afford the title compound as a yellow oil (41 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:12]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C=O)C.O>[Cl:11][C:10]1[C:3]2[C:2]([NH:23][CH:21]([C:18]3[CH:19]=[CH:20][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=3)[CH3:22])=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1
Reactant: Clc1csc2ncnc(Cl)c12
Reactant: CC(C)c1ccc(C(C)N)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(C)Nc2ncnc3scc(Cl)c23)cc1
Yield: 87.2 %

Procedure:
A mixture of 4,5-dichlorothieno[2,3-d]pyrimidine (prepared as taught in EP 447,891) (775 mg, 3.8 mmol), 1-(4-isopropylphenyl)ethanamine (compound 95) (734 mg, 4.5 mmol), and triethylamine (767 mg, 7.6 mmol) in DMF (20 mL) was allowed to react for 24 hours at 20° C. The reaction mixture was diluted with water and extracted thrice with Et2O. The organic portions were combined, washed with brine, and dried (Na2SO4). The mixture was filtered through silica gel, and the solvent was removed in vacuo. The residue was purified by flash chromatography (15 percent Et2O in pentane), yielding 1.1 g of oil.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([N:23]2[CH2:29][CH:28]3[CH2:30][CH2:31][CH:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:22])[C:3]1=[O:32].[C:33](N1C=CN=C1)([N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1)=[O:34].C(OCC)(=O)C>O>[CH:25]12[CH2:31][CH2:30][CH:28]([CH2:27][CH2:26]1)[CH2:29][N:23]([C:21]([CH2:20][N:4]1[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])=[N:8][CH:2]([NH:1][C:33]([N:35]3[CH:39]=[CH:38][N:37]=[CH:36]3)=[O:34])[C:3]1=[O:32])=[O:22])[CH2:24]2
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CN1C(=O)C(NC(=O)n2ccnc2)N=C(c2ccccc2F)c2ccccc21)N1CC2CCC(CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl]carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.2 g) and carbonyldiimidazole (895 mg) was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction mixture, and organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The amorphous powder was washed with isopropyl ether to afford (3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-3-(imidazol-1-yl) carbonylamino-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.43 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:27])[C:5]([C:9]2[N:10]=[N:11][C:12]([N:15]([CH3:26])[CH:16]3[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]3)=[CH:13][CH:14]=2)=[C:6]([OH:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][N:39](C(OC(C)(C)C)=O)[CH:40]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O.O1CCOCC1>[F:27][C:4]1[C:5]([C:9]2[N:10]=[N:11][C:12]([N:15]([CH3:26])[CH:16]3[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]3)=[CH:13][CH:14]=2)=[C:6]([OH:8])[CH:7]=[C:2]([C:36]2[CH:37]=[N:38][NH:39][CH:40]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN(c1ccc(-c2c(O)cc(Cl)cc2F)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CN(c1ccc(-c2c(O)cc(-c3cn[nH]c3)cc2F)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 130 °C
Reaction time: 2 h
Yield: 13.5 %

Procedure:
5-Chloro-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol (Example 40-6, 0.32 g, 0.82 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.00 g, 3.40 mmol), and Cs2CO3 (5.52 g, 26.0 mmol) were added to a microwave vial. XPhos Precatalyst (60 mg, 0.08 mmol) was then added to the mixture followed by dioxane (5 mL) and water (0.9 mL). The reaction mixture was sealed and stirred at 130° C. for 2 h in a Biotage® Initiator microwave reactor. The reaction mixture was filtered through celite and the filter cake was washed with methanol. The filtrate was concentrated in vacuo. The crude product was purified via reverse phase preparative HPLC (10 to 45% acetonitrile in water, 0.1% trifluoroacetic acid as modifier). The appropriate fractions containing product were free based by catch and release using SiliaBond Propylsulphonic Acid® (4 eq, methanol as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo and the resulting solid was dissolved in MeOH. SiliaMetS® DMT (6 eq.) was added and the mixture was shaken for 18 h. The solid was filtered and the filtrate was concentrated in vacuo. The resulting solid was suspended in CH3CN/H2O (6/2 mL). 1 M HCl aqueous (3 equivalents) was added and volatiles were concentrated in vacuo to provide the hydrochloride salt of 3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol as a yellow solid (47 mg). LCMS Rt=0.48 min [Method Q]; [M+H]: 425.3; 1H NMR (400 MHz, MeOD) δ 8.25-8.32 (m, 1H), 8.14 (s, 2H), 8.04 (d, J=10.0 Hz, 1H), 7.19 (dd, J=11.5, 1.5 Hz, 1H), 7.11 (s, 1H), 5.10 (bs, 1H), 3.19 (s, 3H), 1.91-2.24 (m, 4H), 1.66 (s, 6H), 1.57 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[C:4]([F:11])[CH:3]=1.[NH3:12].[BH4-].[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:12])[CH3:9])=[C:4]([F:11])[CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1F
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(N)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
To a solution of 1-(4-bromo-2-fluorophenyl)ethanone (2.0 g, 9.2 mmol) in methanol (50 mL) was added ammonia (7 N in methanol, 8.0 mL, 55 mmol) and titanium(IV) isopropoxide (5.4 mL, 18 mmol). The reaction mixture was stirred at room temperature for 18 h, cooled to 0° C. and sodium borohydride (520 mg, 14 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 20 min, quenched with 2 M ammonium hydroxide and filtered. The reaction mixture was extracted with methylene chloride and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford the desired product (1.2 g, 63%) as an oil: ESI MS m/z 219 [C8H9BrFN+H]+.