Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:29][CH2:30]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 79 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 79%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 3.27 (s, 4H), 3.88 (s, 3H), 4.14 (s, 4H), 6.59 (s, 3H), 7.01-7.10 (s, 1H), 7.24-7.36 (m, 2H), 7.47-7.71 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: Cc1ccccc1I
Product: Cc1ccccc1-n1ccc2ccc(Cl)cc21

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-2-methylbenzene: ESMS m/e: 241.9 (M+H)+.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[N:22][C:21]([NH2:24])=[C:20]4[O:25][C:26](Cl)=[CH:27][C:19]=34)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)(C)(C)C.CC1(C)C(C)(C)OB([C:39]2[C:47]3[S:46][N:45]=[N:44][C:43]=3[CH:42]=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[K+].[K+].Cl>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.CO.O.O1CCOCC1>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([C:16]2[CH:15]=[N:14][N:13]([C@H:10]3[CH2:9][CH2:8][C@H:7]([OH:6])[CH2:12][CH2:11]3)[CH:17]=2)=[C:19]2[CH:27]=[C:26]([C:39]3[C:47]4[S:46][N:45]=[N:44][C:43]=4[CH:42]=[CH:41][CH:40]=3)[O:25][C:20]=12
Reactant: CC1(C)OB(c2cccc3nnsc23)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
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: O
Solvent: CO
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3cccc4nnsc34)oc12
Temperature: 30 °C

Procedure:
A mixture of 4-{1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-1H-pyrazol-4-yl}-2-chloro-furo[2,3-c]pyridin-7-ylamine (179 mg, 0.400 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3-benzothiadiazole (105.0 mg, 0.4006 mmol), Pd(PPh3)4 (46.3 mg, 0.0400 mmol), potassium carbonate (166 mg, 1.20 mmol) and 4:1 1,4-dioxane:water (6 mL) was heated in a microwave reactor at 110° C. for 1 h. Aqueous 12 N hydrochloric acid (0.5 mL, 6 mmol) and methanol (2 mL) were added, and the solution was heated to 30° C. for 30 min. The organic solvent was removed in vacuo, and the material was extracted with DCM and saturated aqueous sodium bicarbonate (2×). The organic layer was purified by column chromatography (1 to 3% 7 N ammonia/methanol:DCM), followed by trituration from methanol (5 mL) and filtration to afford 80 mg (50%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.31-1.46 (m, 2 H), 1.82-2.02 (m, 4 H), 2.04-2.15 (m, 2 H), 3.48-3.61 (m, 1 H), 4.14-4.25 (m, 1 H), 4.71 (d, J=4.5 Hz, 1 H), 6.42 (s, 2 H), 7.94-8.03 (m, 3 H), 8.06 (s, 1 H), 8.26 (s, 1 H), 8.65 (dd, J=7.5, 0.6 Hz, 1 H), 8.81-8.89 (m, 1 H); MS (ESI): 433.14 [M+H]+; HPLC tR=1.18 min (TOF: polar—3 min).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH:9]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[N:14]=2)[CH2:10]1.Cl[C:24]1[C:29]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:28][CH:27]=[CH:26][N:25]=1>CC(N(C)C)=O>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[NH:17][C:13]([CH:11]3[CH2:12][N:9]([C:24]4[C:29]([CH:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[N:28][CH:27]=[CH:26][N:25]=4)[CH2:10]3)=[N:14][C:15]=2[CH:21]=1
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Reactant: Clc1nccnc1C1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Clc1ccc2[nH]c(C3CN(c4nccnc4C4CCOCC4)C3)nc2c1
Temperature: 80 °C

Procedure:
A mixture of cesium carbonate (0.82 g, 2.52 mmol), 2-(azetidin-3-yl)-5-chloro-1H-benzo[d]imidazole dihydrochloride (as described in Preparation 5) (0.18 gg, 0.63 mmol), and 2-chloro-3-(tetrahydro-2H-pyran-4-yl)pyrazine (0.13 g, 0.63 mmol) in DMA (1 mL) was heated to 80° C. for 20 h, then cooled to RT. The resulting suspension was partitioned between ethyl acetate and water, the layers were separated, and the organic layer was washed with water (2×), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 5-chloro-2-(1-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole as a white solid. [M+1] 370. IC50 (uM) 1.157.
Reaction SMILES: [BH4-].[Na+].[CH3:3][NH:4][C:5]1[CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(O)(=O)C>[CH3:3][NH:4][CH:5]1[CH2:11][CH:10]([OH:12])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[O:7][CH2:6]1
Reactant: CNC1=CC(=O)c2ccccc2OC1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CNC1COc2ccccc2C(O)C1
Temperature: 0 °C

Procedure:
Sodium borohydride is added in small portions to a solution of 18.8 g (0.1 mole) 3-methylamino-1-benzoxepin-5-(2H)-one in a mixture of 125 ml dioxane and 125 ml acetic acid cooled in an ice bath. The reaction solution is maintained in a cooled state during the addition of the sodium borohydride (0.4 mole) up to the end of the reaction. The reaction solution is then poured into ice water, made alkaline with sodium carbonate and extracted with dichloromethane. The organic solution is washed with saturated salt solution and dried over sodium sulfate. After removal of the solvent, 16.4 g (85% of the theoretical yield) of racemic-2,3,4,5-tetrahydro-3-methylamino-1-benzoxepin-5-ol is recovered in the form of an oil.
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][C:11]1[O:12][C:13]([C:15]2[C:20]([CH:21]=1)=[C:19]([CH3:22])[CH:18]=[CH:17][CH:16]=2)=O.C(=O)([O-])[O-].[NH4+:27].[NH4+].[OH-].[Na+]>C(O)(=O)C>[OH:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][C:11]1[NH:27][C:13](=[O:12])[C:15]2[C:20]([CH:21]=1)=[C:19]([CH3:22])[CH:18]=[CH:17][CH:16]=2
Reactant: Cc1cccc2c(=O)oc(CCN3CCC[C@@H]3CO)cc12
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc2c(=O)[nH]c(CCN3CCC[C@@H]3CO)cc12
Temperature: 25 °C
Yield: 75.7 %

Procedure:
(R)-3-[2-(2-hydroxymethylpyrrolidin-1-yl)ethyl]-5-methylisocoumarin hydrochloride (62 g) and acetic acid (186 mL) were added and ammonium carbonate (74.4 g) was gradually added to the mixture with stirring. After bubbling, the reaction mixture was heated and stirred at 130° C. for 2 hr with heating. After the completion of the reaction, the reaction mixture was cooled to room temperature and aqueous sodium hydroxide (140 g) solution (200 mL) was added. The mixture was stirred at 80° C., and after the completion of the reaction, the reaction mixture was concentrated. The methanol fraction was evaporated and the mixture was extracted twice with chloroform. The organic layer was extracted twice with 3N hydrochloric acid (300 mL and 100 mL), and potassium carbonate was added to the aqueous layer to basify the layer. The aqueous layer was extracted twice with chloroform, and the extract was dried over magnesium sulfate. The solvent was concentrated and ethyl acetate was added to the obtained residue. The mixture was further concentrated and the residue was dissolved in a small amount of ethyl acetate with heating. Diethyl ether was added to the solution and the precipitated crystals were collected by filtration to give (R)-3-[2-(2-hydroxymethylpyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (41.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH2:14][S:15][CH3:16].[CH3:17][O:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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:8]([C:6]1[C:5]([O:12][CH3:13])=[CH:4][C:3]([CH2:14][S:15][CH3:16])=[C:2]([C:24]2[C:19]([O:18][CH3:17])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1ncccc1B(O)O
Reactant: COc1cc(CSC)c(Br)cc1C(C)(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: CO
Solvent: ClCCl
Product: COc1cc(CSC)c(-c2cccnc2OC)cc1C(C)(C)C
Yield: 54.9 %

Procedure:
step 2—A sealed tube containing 80 (50 mg), 2-methoxy-3-pyridine boronic acid (38 mg), Na2CO3 (43 g) and Pd(PPh3)4 (19 mg) in a mixture of MeOH (4 mL) and DCM (1 mL) was irradiated in a microwave synthesizer at 120° C. for 30 min. The organic volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 50% EtOAc/hexane to afford 30 mg of 3-(5-tert-butyl-4-methoxy-2-methylsulfanylmethyl-phenyl)-2-methoxy-pyridine (82).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH2:7])(=[O:4])=[O:3].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][C:16]=2[C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:12]=[CH:11][N:10]=1.C(OCC)C>C(Cl)Cl.Cl>[CH3:22][CH:20]([C:18]1[S:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=2)=[C:16]([C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[N:17]=1)[CH3:21]
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2)c(-c2ccnc(Cl)n2)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1
Temperature: 56 °C
Yield: 21.1 %

Procedure:
[2-(Methylsulfonyl)ethyl]amine (267 mg, 2.169 mmol) and N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide (100 mg, 0.217 mmol) were combined and heated to 56° C. overnight. The reaction mixture was cooled to rt and diluted with DCM and 10% aqueous HCl. The layers were separated and the water layer was extracted twice more with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to yield an oil. The oil was chromatographed on silica gel eluting with 100% DCM to 4:6 [DCM:(9:1 EtOAc:MeOH)]. The clean fractions were combined and concentrated to yield an oil. Diethyl ether was added to the oil and concentrated to obtain the title compound as a light brown solid (25.1 mg, 20% yield). 1H NMR (400 MHz, DMSO-d6 heated to 60° C.) δ ppm 10.53-10.65 (m, 1H) 8.06-8.16 (m, 1H) 7.88 (s, 1H) 7.30-7.42 (m, 1H) 7.16-7.30 (m, 4H) 7.05 (d, J=3.6 Hz, 1H) 6.53-6.65 (m, 1H) 6.14-6.27 (m, 1H) 3.59-3.74 (m, 2H) 3.24-3.43 (m, 3H) 2.97 (br. s., 3H) 1.36 (dd, J=6.6, 2.7 Hz, 6H). MS (ESI): 548.0[M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH3:30])=[CH:11][CH:10]=1)#[N:2].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:30][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:33][N:32]=[N:31][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cccc2nc(C)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2nc(C)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Reaction time: 96 h

Procedure:
A mixture of ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole-7-carboxylate (2.5 g), sodium azide (3.9 g) and ammonium chloride (3.2 g) in DMF (30 ml) was stirred for 4 days at 110°-120° C. The reaction mixture was worked up according to the procedure described in Working Example 23 to give crystals. Recrystallization from ethanol afforded colorless prisms (1.36 g, 49%), m.p. 205°-206° C.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.Br[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[Cl-].[NH4+]>>[CH:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Br[Mg]c1ccccc1
Reactant: BrC1CCCCC1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Product: c1ccc(C2CCCCC2)cc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A mixture of phenyl magnesium bromide (1.25 mL of 0.96-M THF solution, 1.2 mmol) and TMEDA (181.1 μL, 1.2 mmol) was added to a mixture of bromocyclohexane (163.1 mg, 1.0 mmol) and FeCl3 (0.5 mL of 0.1-M THF solution, 5 mol %) at 0° C. over 20 minutes using an injection pump. After the addition of the mixture of Grignard reagent and TMEDA was completed, the reaction mixture was stirred at the temperature for 10 minutes. After treating with saturated aqueous ammonium chloride solution in a conventional manner, the reaction mixture was filtered through a pad of Florisil® and concentrated in vacuum. Using the internal standard (tetrachloroethane, 79 mg, 0.47 mmol), the crude product was analyzed by 1H NMR to give cyclohexylbenzene in a yield of 99%. GC analysis gave cyclohexylbenzene in a yield of 99%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12]2[C:21]3[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=3[C:15]3[CH:23]=[C:24](B4OC(C)(C)C(C)(C)O4)[CH:25]=[CH:26][C:14]=3[N:13]=2)=[C:6]([Cl:36])[CH:5]=1)(=[O:3])[CH3:2].Br[C:38]1[N:39]=[C:40]([C:43]([OH:46])([CH3:45])[CH3:44])[S:41][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.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:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12]2[C:21]3[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=3[C:15]3[CH:23]=[C:24]([C:38]4[N:39]=[C:40]([C:43]([OH:46])([CH3:45])[CH3:44])[S:41][CH:42]=4)[CH:25]=[CH:26][C:14]=3[N:13]=2)=[C:6]([Cl:36])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(O)c1nc(Br)cs1
Reactant: CC(=O)c1cc(Cl)c(Nc2nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3c3c(=O)[nH]ccc23)c(Cl)c1
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: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Cl)c(Nc2nc3ccc(-c4csc(C(C)(C)O)n4)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 5-[(4-acetyl-2,6-dichlorophenyl)amino]-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c]-2,6-naphthyridin-1(2H)-one (135 mg, 0.26 mmol) in THF (4 mL) was added 2-(4-bromo-1,3-thiazol-2-yl)propan-2-ol (114 mg, 0.52 mmol), Pd(Ph3P)4 (60 mg, 0.05 mmol) and sodium carbonate (0.129 mL, 0.26 mmol, 2M in water). The reaction was heated to 80° C. for 16 h. The reaction was diluted with ethyl acetate and extracted with water. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9]O)[CH2:4]1)[CH3:2].[BrH:11]>>[Br:11][CH2:9][CH:5]1[CH2:6][CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4]1
Reactant: Br
Reactant: CCN1CCCC(CO)C1
Product: CCN1CCCC(CBr)C1

Procedure:
A mixture of 5.0 g. (0.0349 mol.) of N-ethyl-3-hydroxymethylpiperidine and 52 ml. of 48% hydrogen bromide was refluxed for six hours then cooled and evaporated to dryness. The residue was made basic by addition of 5% aqueous sodium carbonate and extracted with methylene chloride. The methylene chloride solution was dried (MgSO4) and evaporated to dryness to give 3-bromomethyl-N-ethylpiperidine.
Reaction SMILES: Cl.[CH:2]([NH:5][C:6]1([C:10]([NH2:12])=[O:11])[CH2:9][NH:8][CH2:7]1)([CH3:4])[CH3:3].Cl[C:14]1[N:19]2[N:20]=[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[C:22]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:18]2[N:17]=[C:16]([CH3:37])[N:15]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:21]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[C:18]2[N:17]=[C:16]([CH3:37])[N:15]=[C:14]([N:8]3[CH2:9][C:6]([NH:5][CH:2]([CH3:4])[CH3:3])([C:10]([NH2:12])=[O:11])[CH2:7]3)[N:19]2[N:20]=1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reactant: CC(C)NC1(C(N)=O)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(N2CC(NC(C)C)(C(N)=O)C2)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reaction time: 1.5 h

Procedure:
To a mixture of 3-isopropylaminoazetidine-3-carboxylic acid amide hydrochloride salt (I-3A-1c; 72 mg, 0.361 mmol) and 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 102 mg, 0.261 mmol) in methylene chloride (1.3 ml) was added diisopropylethylamine (0.16 ml, 0.91 mmol), dropwise. After stirring for 90 minutes, the reaction was extracted from saturated aqueous NaHCO3 with methylene chloride. The combined extracts were dried (MgSO4), concentrated, in vacuo, and then purified on a Biotage™ Flash 12M column using 0-5% methanol in methylene chloride as eluant. The resultant solid was triturated from methanol and then dried, in vacuo, to afford 3A-1 (104 mg, 78%) as a colorless solid: +ESI MS (M+1) 510.1; 1H NMR (400 MHz, CD2Cl2) δ 7.47-7.34 (m, 6H), 7.21 (d, J=8.7 Hz, 2H), 6.96 (br s, 1H), 5.42 (br s, 1H), 5.22 (br m, 1H), 4.73 (br m, 2H), 4.18 (br m, 1H), 3.11 (septuplet, J=6.2 Hz, 1H), 2.48 (s, 3H), 1.06 (d, J=6.2 Hz, 6H).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:15][OH:16])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[S:6][C:5]=12>C1(C)C=CC=CC=1.O=[Mn]=O>[N:1]1[CH:2]=[C:3]([CH:15]=[O:16])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[S:6][C:5]=12
Reactant: OCc1cnc2sc3c(n12)CCCCCC3
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: O=Cc1cnc2sc3c(n12)CCCCCC3
Yield: 88.9 %

Procedure:
A solution of 5,6,7,8,9,10-Hexahydrocyclooct[d]imidazo[2,1-b]thiazole-3-methanol (Formula H-5) (1.6 g) in hot toluene (250 mL) was treated with MnO2 (3.8 g) and azeotropically distilled for 1 hour. The cooled mixture was filtered and the combined filtrate and ethyl acetate washes were evaporated to yield pure 5,6,7,8,9,10-Hexahydro-cyclooct[d]imidazo[2,1-b]thiazole-3-carboxaldehyde (Formula H-6) (1.41 g), m.p. 106-107°, after crystallization from hexane.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)C=C.[CH3:26][C:27]1C=CC=C[C:32]=1C>>[CH2:32]([C:6]1[C:5]([OH:4])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]2[C:7]=1[C:8]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)=[N:9][CH:10]=[N:11]2)[CH:27]=[CH2:26]
Reactant: C=CCOc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC
Reactant: Cc1ccccc1C
Product: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12

Procedure:
A solution of (6-allyloxy-7-methoxy-quinazolin-4-yl)-(3-chloro-4-fluoro-phenyl)-amine (0.92 g, 2.55 mmol) (from Example 18, Step C, supra) in o-xylene (150 mL) was heated at 150° C. for 7 hours. At the end of this period, TLC analysis indicated almost complete consumption of the starting material and the formation of desired product as the major spot. The solution was concentrated and filtered. The solid was collected and dried in vacuo to give the desired 5-allyl-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol as an off white solid. (Yield 0.65 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH2:12]=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:12][NH:8][CH2:7][CH2:6]2
Reactant: COc1cccc(CCN)c1
Reactant: C=O
Solvent: O
Product: COc1ccc2c(c1)CCNC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
A mixture of m-methoxyphenethylamine (25 g, 0.165 mol), 37% formaldehyde (12.7 mL) and water (12.7 mL) was stirred for 20 minutes. The reaction mixture was heated at 95°-100° C. for 1.5 hours, cooled, diluted with ice-water, and extracted with toluene (3x). The combined organic extracts were washed with saturated sodium chloride solution (2 ×30 mL), dried over magnesium sulfate, filtered and evaporated. The residual oil was heated with 6N hydrochloric acid (36 mL) for 3 hours, cooled, basified with 50% aqueous sodium hydroxide solution and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate and evaporated; the residue was converted to its hydrochloride salt with HCl (g) in isopropanol. The cream-colored crystalline hydrochloride salt was filtered and dried affording the title compound in 52% yield. m.p. 232°-234° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[N:8]=[C:7]([C:12]3[C:13](C4C=CC(OCC)=CC=4)=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=3)[NH:6][C:5]=2[C:4]([CH2:31][CH2:32][CH3:33])=[N:3]1.[OH-].[Na+].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[C:43]([OH:55])(=[O:54])[CH2:44][C:45]([CH2:50][C:51]([OH:53])=[O:52])([C:47]([OH:49])=[O:48])[OH:46]>CC(C)=O>[CH3:33][CH2:32][CH2:31][C:4]1[C:5]2[N:6]=[C:7]([C:12]3[CH:13]=[C:14]([S:18]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)(=[O:19])=[O:20])[CH:15]=[CH:16][C:17]=3[O:46][CH2:45][CH3:44])[NH:8][C:9](=[O:11])[C:10]=2[N:2]([CH3:1])[N:3]=1.[CH2:50]([C:45]([OH:46])([C:47]([OH:49])=[O:48])[CH2:44][C:43]([OH:55])=[O:54])[C:51]([OH:53])=[O:52]
Reactant: CN1CCNCC1
Reactant: CCCc1nn(C)c2c(=O)nc(-c3cccc(S(=O)(=O)Cl)c3-c3ccc(OCC)cc3)[nH]c12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Temperature: 25 °C
Yield: 72 %

Procedure:
In a 3-necked flask, 3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo(4,3-d)pyrimidin-5-yl)-(4-ethoxyphenyl)benzene sulfonyl chloride (10 g, 0.024 mol) was mixed with acetone (100 ml) and NaOH (0.974 g, 47%) at room temperature. N-methyl piperazine (2.68 g, 0.027 mol) was added dropwise to the mixture. Thereafter, the reaction was stirred for 45 mm, additional acetone (100 ml) was added, and then the mixture was heated to reflux. Citric acid (5 g, 0.024 mol) was added, and a white precipitate appeared immediately. The reaction was maintained at reflux for one hour and then allowed to cool to room temperature over 3 hours. The precipitate was collected by filtration, and dried at 50° C. under 10 mm Hg to give pure sildenafil citrate in 72% yield.