Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]3)O1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[NH2:11][C:7]1[C:6]2[C:2]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]4)=[CH:3][S:4][C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: Nc1nccc2scc(Br)c12
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3csc4ccnc(N)c34)ccc21
Temperature: 25 °C
Yield: 115.8 %

Procedure:
To a 250 mL round bottom flask was added 3-bromothieno[3,2-c]pyridin-4-amine (2.65 g, 11.59 mmol), 1,1-dimethylethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate (5 g, 14.48 mmol), 1,4-Dioxane (50 mL) and 2M potassium carbonate (21.72 mL, 43.4 mmol). The reaction was capped and flushed with N2 then PdCl2(dppf)-CH2Cl2 adduct (0.591 g, 0.724 mmol) was added. The reaction was then refluxed overnight under an inert atmosphere. The reaction mixture was cooled to room temperature and then filtered through a silica plug. Then diluted with 150 mL H2O and extracted with ethyl acetate (3×150 mL). The organics were combined and dried over Na2SO4 and then concentrated to a black residue. This was then purified via normal phase chromatography (50-100% EtOAc/Hexanes). Product fractions were combined and concentrated to afford 1,1-dimethylethyl 5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (5.19 g, 13.42 mmol, 93% yield) as an off white solid. LC/MS (ES) m/z=368.2 [M+H]+
Reaction SMILES: [CH3:1][CH:2]([OH:8])[CH2:3][CH2:4][CH:5]([OH:7])[CH3:6].[O-]CCCC.[K+].[Cl:15][C:16]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>O1CCCC1>[Cl:15][C:16]1[CH:23]=[C:22]([O:7][CH:5]([CH3:6])[CH2:4][CH2:3][CH:2]([OH:8])[CH3:1])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(O)CCC(C)O
Agent: CCCC[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(O)CCC(C)Oc1ccc(C#N)c(Cl)c1
Yield: 46.6 %

Procedure:
To a solution of 2,5-hexanediol (28 mg, 0.240 mmol) in tetrahydrofuran was added an excess of potassium butoxide. The admixture was stirred, briefly, and 2-chloro-4-fluoro-benzonitrile (37 mg, 0.240 mmol) was added. The admixture was stirred at room temperature for 72 hours. Purification by reverse phase high pressure chromatography eluting with a solvent gradient (15% of 0.1% formic acid/CH3CN in 0.1% formic acid/water to 100% of 0.1% formic acid/water) provided 28.4 mg of 2-chloro-4-(4-hydroxy-1-methyl-pentyloxy)-benzonitrile. 1H NMR (CDCl3) δ 7.50 (d, 1H), 6.95 (m, 1H), 6.79 (br d, 1H), 4.43 (m, 1H), 3.79 (m, 1H), 1.89-1.40 (m, 4H), 1.30 (d, 3H), 1.17 (d, 3H); MS m/z 253.
Reaction SMILES: O1CCOCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:15][N:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=[N:17]1.Br[C:31]1[N:36]=[C:35]([NH2:37])[CH:34]=[C:33]([CH3:38])[CH:32]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:38][C:33]1[CH:32]=[C:31]([C:20]2[N:16]([CH3:15])[N:17]=[CH:18][CH:19]=2)[N:36]=[C:35]([NH2:37])[CH:34]=1
Reactant: Cc1cc(N)nc(Br)c1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(N)nc(-c2ccnn2C)c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Dioxane (2.12 mL), water (0.24 mL), tribasic potassium phosphate (300 mg, 1.41 mmol), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (120 mg, 0.58 mmol) were added to 6-bromo-4-methylpyridin-2-amine (88 mg, 0.47 mmol) in a scintillation vial. The vial was purged with argon 3 times before PdCl2(dppf)-CH2Cl2 adduct (34 mg, 0.047 mmol) was added. The vial was purged 3 times with argon, sealed, and heated to 100° C. After 1.5 hours, the reaction was cooled to room temperature, filtered through CELITE (washed with dichloromethane), and diluted with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-70% acetone/hexanes, linear gradient) to afford 4-methyl-6-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine. MS ESI calc'd. for C10H13N4 [M+H]+ 189. found 189. 1H NMR (500 MHz, CDCl3) δ 7.46 (s, 1H), 6.77 (s, 1H), 6.48 (d, J=1.8 Hz, 1H), 6.30 (s, 1H), 4.15 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2.[CH:15](=O)[CH2:16][CH2:17][CH3:18]>[Pd].C(O)C>[CH2:15]([CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([O:4][CH3:3])[CH:6]=2)[C:10]1=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CCCC=O
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC1Cc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
Potassium hydroxide (0.44 g, 85% weight pure, 6.67 mmol) and 10% palladium on activated carbon (0.42 g) were added to a mixture of 5-methoxy-1-indanone (5.0 g, 30.8 mmol) and butyraldehyde (3.3 mL, 37 mmol) in ethanol (30 mL). The resulting mixture was stirred under an atmosphere of hydrogen at room temperature for 2 hours. The mixture was filtered and the filtrate evaporated under vacuum. The residue was partitioned between EtOAc (200 mL) and water (200 mL) containing 2N HCl (5 mL). The organic phase was washed with brine (100 mL), dried over MgSO4, filtered, and evaporated under vacuum to afford crude 2-butyl-5-methoxy-1-indanone (7.0 g) as an oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11](N(OC)C)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=[O:12]
Reactant: CON(C)C(=O)c1n[nH]c2ccc(I)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1n[nH]c2ccc(I)cc12
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a solution of 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (500 mg, 1.51 mmol), from Synthetic Preparation 6, in THF (10 mL) at 0° C. was added lithium aluminum hydride (61 mg, 1.66 mmol). After 30 min, the reaction was quenched by the slow addition of EtOAc followed by 0.4N NaHSO4, and extracted. The organic layer was washed with brine, dried, and concentrated. The crude product was purified by flash chromatography to give 5-iodo-1H-indazole-3-carboxaldehyde (240 mg, 58.2%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:32]>>[Cl:32][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: CCCc1ccc(CO)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCc1ccc(CCl)cc1

Procedure:
(4-Propylphenyl)methanol (4.93 g) synthesized in Reference Example 36 was dissolved in carbon tetrachloride (65 mL), triphenylphosphine (9.5 g) was added thereto, and the mixture was heated under reflux for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in hexane. The insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane) to give the title compound (2.24 g) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.OS(O)(=O)=O.[C:20](=O)([O-])O.[Na+]>CO>[O:1]=[C:2]1[C:11]2[C:10]([C:12]([O:14][CH3:20])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cccc2c1C(=O)CCC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc2c1C(=O)CCC2

Procedure:
A solution of 3.466 g of 8-oxo-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid in 30 ml of methanol is admixed with 1.850 ml of conc. H2SO4 and the reaction solution is subsequently heated to reflux over 18 hours. The reaction solution is subsequently cooled and poured onto 200 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with 2×200 ml of ethyl acetate. The combined organic phases are washed with 150 ml of saturated aqueous sodium hydrogencarbonate solution and 150 ml of water, dried over sodium sulphate and concentrated. The crude product is obtained as a brown oil and is used without further purification. Rt=3.42
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([Cl:27])=[C:20]([N:22]([CH3:26])[C:23](=[O:25])[CH3:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[Cl:27][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:5]=[C:4]([CH3:7])[C:3]([C:8]#[N:9])=[C:2]3[N:1]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:26])[C:23](=[O:25])[CH3:24]
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1Cl
Reactant: Cc1n[nH]c(N)c1C#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C#N)c(C)nn23)ccc1Cl
Yield: 72.6 %

Procedure:
A mixture of 0.055 g (0.43 mmol) of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.120 g (0.43 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-chloro-phenyl]-N-methyl-acetamide in 12 mL of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 106 mg of N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 73%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([Cl:13])[CH:5]=[C:4]([CH3:14])[N:3]=1.[OH-].[Na+].OS(O)(=O)=O>O.CO>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:13])[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Cl)c(C(=O)O)c(Cl)n1
Yield: 65.7 %

Procedure:
A solution of commercially available (Maybridge) ethyl 2,4-dichloro-6-methylpyridine-3-carboxylate (1.0 g, 4.3 mmol) and NaOH (342 mg, 8.6 mmol) in water (1.7 mL) and MeOH (1.5 mL) was heated to 80° C. for 4 h. The mixture was acidified using 50% H2SO4 and then filtered. The solid collected was washed with cold water and dried to give of 2,4-dichloro-6- methylpyridine-3-carboxylic acid (582 mg, 66%): LCMS RT: 0.70 min, MH+: 206.2.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.Cl.Cl.[C@@H:25]12[NH:32][C@@H:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]([N:33]1[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[C:34]1[CH3:42])[CH2:26]2.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:42][C:34]1[N:33]([CH:27]2[CH2:28][C@H:29]3[N:32]([CH2:2][CH2:3][C:4]4([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]4)[C@H:25]([CH2:31][CH2:30]3)[CH2:26]2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2
Reactant: CC(C)(C)OC(=O)N1CCOC(CC=O)(c2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of tert-butyl 2-(2-oxoethyl)-2-phenylmorpholine-4-carboxylate (226.1 mg, 0.74 mmol), 1-[(1R,5S)8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazole dihydrochloride (272.7 mg, 0.74 mmol) and diisopropylethylamine (0.27 mL, 1.48 mmol) in 3 mL CH2Cl2 was added sodium triacetoxyborohydride (235.4 mg, 1.11 mmol) and the reaction mixture was stirred for 2 h at room temperature. After evaporation, the residue was chromatographed (5% (2M NH3/MeOH) in CHCl3) to provide tert-butyl 2-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholine-4-carboxylate (329.9 mg, 84%) as an off-white foam: 1H NMR (400 MHz, CDCl3), δ 7.65 (m, 1H), 7.49-7.40 (br., 2H), 7.39-7.34 (m, 2H), 7.31 (m, 1H), 7.27 (m, 1H), 7.19-7.11 (m, 2H), 4.75-4.16 (m, 2H), 3.76-3.47 (m, 3H), 3.40-3.13 (m, 4H), 2.58 (s, 3H), 2.46-2.32 (m, 2H), 2.17-1.82 (m 8H), 1.63 (m, 2H), 1.53-1.40 (br., 9H); ESI-MS 531 (M+H), 553 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]2[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=[C:27]2[NH:35][CH:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][N:44]=[C:45]=[S:46])[CH2:38][CH2:37]2)=[CH:21][CH:20]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:45]([NH:44][CH2:43][CH2:42][N:39]2[CH2:40][CH2:41][CH:36]([NH:35][C:27]3[N:26]([CH2:25][C:22]4[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=3)[CH2:37][CH2:38]2)=[S:46])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1ccccc1NCc1ccc(Cl)c(Cl)c1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCNC(=S)Nc4ccccc4NCc4ccc(Cl)c(Cl)c4)CC3)nc3ccccc32)cc1
Yield: 78.9 %

Procedure:
A mixture of 20 parts of N-[(3,4-dichlorophenyl)methyl]-1,2-benzenediamine, 33 parts of 1-[(4-fluorophenyl)methyl]-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 450 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 40 parts (78.9%) of N-[2-[[(3,4-dichlorophenyl)methyl]amino]phenyl]-N'-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiourea (199).
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([C:23]1[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:25][NH:26][CH:27]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:23]2[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:25][NH:26][CH:27]=2)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: CCOC(=O)c1n[nH]cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1n[nH]cc1CN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
4-Benzhydryloxypiperidine (1.0 g, 3.7 mmol) synthesized in Production Example 1, ethyl 4-formylpyrazole-3-carboxylate (630 mg, 3.7 mmol), and dichloromethane (30 mL) were fed to the system, and the atmosphere of the system was replaced with argon gas, and the system was cooled by ice. At 0° C., sodium triacetoxyborohydride (1.2 g, 5.6 mmol) was added thereto, and the mixture was heated to a room temperature. After the disappearance of the raw material was confirmed by TLC, the reaction mixture was quenched with a saturated sodium hydrogen carbonate solution. The reaction mixture was separated into a water layer and an organic layer, and the water layer was extracted with dichloromethane again. The extract was combined to the organic layer. The combined organic layer was dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (1.3 g, 83%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:21](I)[CH3:22].C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([O:17][CH2:21][CH3:22])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CCI
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 2 h
Yield: 61.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.015 g, 0.043 mmol) in dichloromethane (1 mL) was treated with ethyl iodide (0.016 g, 0.102 mmol), DBU (0.016 g, 0.102 mmol) and stirred 2 hours at 20 C. The product mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 0.010 g of a clear oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1.[CH3:27][C:28]1[N:29]=[CH:30][S:31][C:32]=1[CH2:33][CH2:34]O>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:34][CH2:33][C:32]3[S:31][CH:30]=[N:29][C:28]=3[CH3:27])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1
Reactant: Cc1ncsc1CCO
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCc2scnc2C)cc1OC

Procedure:
The title compound was prepared using the method of example 89 step (vii), using the product of example 89 step (vi) (150 mg) and 2-(4-methylthiazol-5-yl)ethanol (60 mg) to give the title compound as a gum, 10 mg.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:15])[F:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:14])[F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f60) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](Cl)(=[O:25])[CH3:24]>>[C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH:15][C:23](=[O:25])[CH3:24])[N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Product: CC(=O)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 330 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and acetylchloride.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[CH:3][N:2]=1.[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:38])[F:37])[N:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>CS(C)=O.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C:12]([NH:35][CH2:34][C:33]2[C:28]([N:25]3[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]3)=[N:29][C:30]([C:36]([F:39])([F:37])[F:38])=[CH:31][CH:32]=2)=[O:20])=[CH:3][N:2]=1
Reactant: O=C(Nc1cncc2ccccc12)Oc1ccccc1
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CN)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)Nc2cncc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.1 %

Procedure:
Phenyl isoquinolin-4-ylcarbamate (72 mg, 0.27 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (78 mg, 0.29 mmol) was dissolved in dimethyl sulfoxide. Then triethylamine (0.08 mL, 0.54 mmol) was added to it. The mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give the desired 1-(isoquinolin-4-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (example compound 18) (60 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[C:12]3=2)[C:7]1=[O:23].[H-].[Na+].[CH3:30]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]3[CH2:19][CH2:18][N:17]([CH3:30])[C:16](=[O:20])[C:12]3=2)[C:7]1=[O:23]
Reactant: CI
Reactant: O=C1NCCn2c1c1c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 9-(3-chloro-4-fluorobenzyl)-7-hydroxy-3,4,10,11-tetrahydro-2-H-pyrazino[2,1-a]-2,6-naphthyridine-1,6,8(9H)-trione (53 mg, 0.14 mmol; Example 5), and sodium hydride (12.3 mg; 60% dispersion in oil) in DMF (2 mL) was stirred at 0° C. for 20 minutes. To the resultant solution, methyl iodide (96 mg, 0.68 mmol) was added and the reaction mixture was heated at 40° C. for four hours. The reaction mixture was quenched with methanol and concentrated under vacuum. The residue was purified by reverse phase high pressure liquid chromatography. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[N:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nnn[nH]1
Temperature: 93 °C

Procedure:
To a solution of (S)-2-Cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.55 mmol) in N,N-dimethyl-formamide (20 mL) is added sodium azide (174 mg, 2.68 mmol) and ammonium chloride (150 mg, 2.81 mmol). The solution is stirred at 93° C. over night. The solution is poured into 5% citric acid solution with ice, and the mixture is extracted with EtOAc. The organic extract is washed with brine, dried and concentrated under vacuum. The crude oil is used directly in the next step without further purification. M+H+=240.