Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[H-].[Na+].Cl[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:8][O:7][C:6]1[C:4]([O:5][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1]
Reactant: COc1cccc(C=O)c1O
Reactant: ClCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cccc(C=O)c1OCCCN1CCOCC1

Procedure:
o-Vanillin (30.4 g), dissolved in 160 ml of dimethylformamide, is treated with 9.6 g of 50% sodium hydride, then with 130 ml of 2 N N-(3-chloropropyl)morpholine in toluene following the procedure described in Example 1A, yielding 42.9 g of the title compound, boiling point 178°-183° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[F:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(F)c(F)c2F)n1

Procedure:
The tide compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,3,4-trifluorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (2.3 mg) with purity >90%. MS (pos) m/z 381.4.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16](=O)[CH:17]=[CH:18]N(C)C)=[C:11]3[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]([NH:34][C:35]([NH2:37])=[NH:36])[CH2:31][CH2:32][CH3:33]>>[CH2:30]([NH:34][C:35]1[N:37]=[C:16]([C:15]2[C:14]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[N:13][N:12]3[C:11]=2[CH:10]=[CH:9][N:8]=[C:7]3[NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:17]=[CH:18][N:36]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCNC(=N)N
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)nccc12
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(NC4CCCC4)nccc23)n1
Yield: 72 %

Procedure:
In a similar manner as described in Example 1 above, 3-[2-(butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine (80 mg, 72%) was prepared from 1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-one and N-butylguanidine. 1H NMR (CDCl3): δ 8.04 (d, 1H), 7.74 (d, 1H), 7.60 (dd, 2H), 7.48 (d, 1H), 7.13 (t, 2H), 6.36 (d, 1H), 6.25 (d, 1H), 5.05 (t, 1H), 4.51 (m, 1H), 3.42 (qt, 2H), 2.16 (m, 2H), 1.78 (m, 2H), 1.56–1.70 (m, 6H), 1.43 (m, 2H), 0.95 (t, 3H). MS m/z 446 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:25]=[C:24]([I:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].Cl>C(OCC)(=O)C.CN(C)C(=O)C>[CH2:7]([O:15][C:16]1[CH:25]=[C:24]([I:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(I)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(I)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (1.9 g) and benzyl bromide (1.2 mL) were sequentially added to an N,N-dimethylacetamide (20 mL) solution of methyl 2-hydroxy-4-iodobenzoate (2.5 g), followed by stirring at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, and then 1 mol/L hydrochloric acid and ethyl acetate were added thereto. The organic layer was separated, washed with 1 mol/L hydrochloric acid and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-80% hexane/ethyl acetate] to obtain 3.3 g of methyl 2-(benzyloxy)-4-iodobenzoate as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][CH:9]=3.[C:19](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.Cl>C1(C)C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH3:19])[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][CH:9]=3
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(c1)Sc1cc(OC)ccc1N2
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: Cl
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)Sc1cc(OC)ccc1N2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A suspension of 21.75 g (83.9 mmol) of 3,7-dimethoxyphenothiazine, 43.36 g (0.34 mmol) of dried, powdered potassium carbonate, 25.22 g (0.20 mol) of dimethyl sulphate and 1.35 g (4.19 mmol) of tris-[2-(2-methoxyethoxy)ethyl]amine in 300 ml of toluene was stirred at 110° for 1 hour, then cooled and poured into 1 l of ice-water. The mixture was acidified slightly with 2N hydrochloric acid solution and extracted with ethyl acetate. The combined organic phases were extracted with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was crystallized from ethanol/acetone, whereupon, after drying, 18.4 g (80.2%) of 3,7-dimethoxy-10-methylphenothiazine were obtained as a white solid of m.p. 166°-167°.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][C@H:3]1[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.Cl[C:18]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>O1CCCC1>[CH3:9][O:8][C:6]([C@@H:3]1[CH2:4][CH2:5][N:2]1[C:18]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1)=[O:7]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)[C@@H]1CCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CC[C@H]2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
(S)-methyl azetidine-2-carboxylate hydrochloride (1 g, 6.60 mmol) was diluted with Tetrahydrofuran (Volume: 20 ml) and treated with TRIETHYLAMINE (0.919 ml, 6.60 mmol). The reaction mixture was stirred vigorously and sonicated periodically, until a fine suspension resulted. This was stirred for 1 h and filtered through a small plug of celite. The plug was washed well with THF (20 mL) and the combined filtrate and washes were treated with methyl 6-chloro-5-nitronicotinate (0.714 g, 3.30 mmol). The reaction mixture was concentrated in vacuo and heated briefly (5 min) to 80° C. LCMS showed complete conversion. The reaction mixture was diluted with DCM (10 mL) and purified using flash column chromatography on silica gel (80 g SiO2, 20-30% ethyl acetate in hexanes) to afford the title compound (S)-methyl 6-(2-(methoxycarbonyl)azetidin-1-yl)-5-nitronicotinate (0.90 g, 3.05 mmol, 92% yield) as a yellow oil. [M+H] calc'd for C12H13N3O6, 295; found, 295.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][CH2:15][CH2:14][C@@H:13]3[C@H:8]([O:9][CH2:10][CH2:11][NH:12]3)[C:6]=2[CH:7]=1.[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]\[C:20]([OH:22])=[O:21].[CH3:25]N1CCO[C@@H]2C3C=CC=CC=3OCC[C@@H]12>>[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]\[C:20]([OH:22])=[O:21].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][CH2:15][CH2:14][C@@H:13]3[C@H:8]([O:9][CH2:10][CH2:11][N:12]3[CH3:25])[C:6]=2[CH:7]=1
Reactant: CN1CCO[C@@H]2c3ccccc3OCC[C@H]21
Reactant: Clc1ccc2c(c1)[C@H]1OCCN[C@@H]1CCO2
Agent: O=C(O)/C=C\C(=O)O
Product: CN1CCO[C@@H]2c3cc(Cl)ccc3OCC[C@H]21

Procedure:
Following essentially the same procedure but substituting trans-10-chloro-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine for the trans-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine above, results in the formation of trans-10-chloro-3,4,4a,5,6,11b-hexahydro-4-methyl-2H-[1]benzoxepino[5,4-b]-1,4-oxazine maleate having a mp. 142°-143° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]O)=[CH:17][CH:16]=1.S(Cl)([Cl:25])=O>C1(C)C=CC=CC=1>[Cl:25][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (5.00 g) in toluene (40 ml), thionyl chloride (1.85 ml) was added and the mixture was stirred for 30 minutes at room temperature. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to obtain 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (5.23 g, yield 99%) as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals. m.p. 108-109° C.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH2:34]([O:36][C:37](=[O:47])[CH2:38][CH2:39][C:40](=[O:46])[C:41]1[S:42][CH:43]=[CH:44][N:45]=1)[CH3:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:34]([O:36][C:37](=[O:47])[CH2:38][CH:39]([Br:1])[C:40](=[O:46])[C:41]1[S:42][CH:43]=[CH:44][N:45]=1)[CH3:35]
Reactant: [Br-]
Reactant: CCOC(=O)CCC(=O)c1nccs1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC(Br)C(=O)c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenyltrimethylammonium tribromide (3.4 g, 8.91 mmol) in DCM (20 mL) is added dropwise to a solution of 4-oxo-4-thiazol-2-yl-butyric acid ethyl ester (1.9 g, 8.91 mmol) in DCM (30 mL. The mixture is stirred overnight at room temperature. 5% NaHCO3 (40 mL) is added to the mixture. The organic layer is separated and the aqueous layer is extracted with DCM (2×40 mL). The combined organic layers are dried and solvent removed. The residue is purified by column (hexanes/ethyl acetate 3:1) to give 3-bromo-4-oxo-4-thiazol-2-yl-butyric acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]#[CH:16])[CH:6]=1)=[O:4].C#CCCCCCC.[I:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[F:18][C:2]([F:1])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]#[C:16][C:31]2[CH:32]=[CH:33][C:28]([I:27])=[CH:29][CH:30]=2)[CH:6]=1)=[O:4]
Reactant: C#CCn1cc(C(=O)C(F)(F)F)c2ccccc21
Reactant: Ic1ccc(I)cc1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: O=C(c1cn(CC#Cc2ccc(I)cc2)c2ccccc12)C(F)(F)F
Yield: 51 %

Procedure:
When the product of Step B was substituted for 1-octyne and 1,4 diiodobenzene was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 51% yield, as light yellow solid. 1H-NMR (CDCl3) 5.16 (s, 2H); 7.14 (d, 2H, J=8.30 Hz); 7.38-7.44 (m, 2H); 7.51-7.55 (m, 1H); 7.66 (tr, 2H, J=8.36 Hz); 8.12 (b, 1H); 8.40-8.43 (m, 1H).
Reaction SMILES: Cl.[C:2]([NH2:7])(=[NH:6])[CH:3]([CH3:5])[CH3:4].[CH3:8][O:9][C:10](OC)=[N:11][C:12]#[N:13].[OH-].[Na+]>>[NH2:13][C:12]1[N:7]=[C:2]([CH:3]([CH3:5])[CH3:4])[N:6]=[C:10]([O:9][CH3:8])[N:11]=1
Reactant: COC(=NC#N)OC
Reactant: CC(C)C(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1nc(N)nc(C(C)C)n1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
Cool the isobutyramidine hydrochloride solution in an ice bath. Charge 8 gm. (0.07 mole) dimethyl (N-cyanoimido)carbonate to the solution, followed by 5.8 gm. (0.073 mole) 50% NaOH, added dropwise. Stir while letting the mixture warm to room temperature for one hour. Remove the methanol by vacuum stripping, and slurry the resulting solids in75 ml. water. Cool and filter. Upon drying, 7.2 gm. (61.2%) 2-amino-4-isopropyl-6-methoxy-s-triazine is obtained, mp 116°-117° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24](OCC)=[O:25]>CCOCC>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17]([CH:24]=[O:25])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC=O
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Solvent: CCOCC
Product: COC(=O)[C@@H]1CN(C=O)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Yield: 84 %

Procedure:
A solution of trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(methoxycarbonyl)pyrrolidine (620 mg, 1.94 mmol) in 5 mL of ethyl formate was heated at reflux for 3 hr. The reaction was diluted with ether and concentrated. The residue was dissolved in ether and washed with 1M H3PO4. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (2:1, ethyl acetate:hexanes) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-1-formyl-4-(methoxycarbonyl)pyrrolidine as a colorless oil (567 mg, 84%). 1H-NMR (300 MHz): δ 3.11-3.21 (1, m), 3.65 (s, 3), 3.82 (s, 3), 6.73-6.82 (m, 3), 8.26 (s, 1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:27]([OH:29])=[O:28])C1C=CC=CC=1.CC1C=C(C)C(C)=C(C)C=1C.CCOCC>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:27]([OH:29])=[O:28]
Reactant: O=C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(OCc3ccccc3)cccc12
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(O)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a solution of 1.0 g of 7-benzyloxy-1-phenylsulfonyl-1H-indole-3-carboxylic acid in 5 mL of trifluoroacetic acid, 1.0 g of 1,2,3,4,5-pentamethylbenzene was added, and the resulting mixture was stirred at room temperature overnight. 20 mL of ether was added to the solution, insoluble matter was removed, the solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to obtain 0.25 g of 7-hydroxy-1-phenylsulfonyl-1H-indole-3-carboxylic acid as a gray solid. FAB−:316
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:10])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH3:11][S:12][C:13]1[N:17]([CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:16]2[CH:28]=[CH:29][CH:30]=[CH:31][C:15]=2[N:14]=1.N1CC(=O)NC1=O.C(O)(C(F)(F)F)=O>>[CH3:10][C:3]1([CH2:2][NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([CH2:18][N:17]3[C:16]4[CH:28]=[CH:29][CH:30]=[CH:31][C:15]=4[N:14]=[C:13]3[S:12][CH3:11])=[CH:20][CH:21]=2)[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7]1
Reactant: CC1(CN)NC(=O)NC1=O
Reactant: CSc1nc2ccccc2n1Cc1ccc(C(=O)O)cc1
Agent: O=C1CNC(=O)N1
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc2ccccc2n1Cc1ccc(C(=O)NCC2(C)NC(=O)NC2=O)cc1
Yield: 38.1 %

Procedure:
5-(aminomethyl)-5-methylhydantoin (109a) (55 mg, 0.31 mmol) was coupled with 4-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}benzoic acid (108 mg, 0.37 mmol) using general coupling method B to give 50 mg (39%) of the product hydantoin as a TFA salt. MS found: (M+H)+=425.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)=[CH:14][CH:15]=1
Reactant: CN(CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (300 mg, 0.759 mmol, 1 eq) was dissolved in dry DCM (3 ml) under argon atmosphere and TFA (290.6 μl, 5 eq) was added. Reaction mixture was stirred for overnight. In the reaction mixture was added more DCM (15 ml) and was extracted with saturated NaHCO3 (3×15 ml) and brine. Organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give a product methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-amine (211.5 mg, yield=82.1%, purity=87%). [M+H]+=296.31 1H NMR (300 MHz; CDCl3) δ/ppm 2.44 (s, 3H), 2.74-2.89 (m, 4H), 6.90-6.98 (m, 2H), 7.09-7.22 (m, 4H), 7.27-7.33 (m, 1H), 7.35-7.45 (m, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[C:26]1([C:32]2[N:37]=[C:36]3[NH:38][CH:39]=[C:40]([CH:41]=O)[C:35]3=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:41]/[C:40]3[C:35]4[C:36](=[N:37][C:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:33][CH:34]=4)[NH:38][CH:39]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2nc(-c3ccccc3)ccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4nc(-c5ccccc5)ccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.026 g, 0.075 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 6-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.013 g, 0.059 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (95:5)) to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.019 g, 46%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[CH2:5][CH:6]([C:9]#[N:10])[C:7]#[N:8].[H-].[Na+].Br[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[CH2:5][C:6]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])([C:7]#[N:8])[C:9]#[N:10]
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(F)c(F)c1
Yield: 21.3 %

Procedure:
Using 1.00 g of (3,4-difluorobenzyl)malononitrile, 10 ml of N,N-dimethylformamide, 0.20 g of sodium hydride (60% in oil), and 1.38 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.32 g of 2-(3,4-difluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (19)).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5](=S)[C:4]=2[CH:3]=1.[CH3:17][C:18]([OH:27])([CH3:26])[CH2:19][C@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1>>[CH3:26][C:18]([OH:27])([CH3:17])[CH2:19][C@H:20]1[CH2:25][N:24]([C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[S:11][C:10]=3[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=2)[CH2:23][CH2:22][NH:21]1
Reactant: CC(C)(O)C[C@H]1CNCCN1
Reactant: Cc1cc2c(s1)Nc1ccccc1NC2=S
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CC(C)(C)O)C1

Procedure:
In a manner similar to that described in Example 359, combine 2-methyl-4,9-dihydro-3-thia-4,9-diazabenzo[f]azulene-10-thione (0.574 g, 2.33 mmol) and (S)-2-methyl-1-piperazin-2-yl-propan-2-ol (0.369 g, 2.33 mmol) to obtain the title compound: mass spectrum (APCI): m/z=371.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[C:23]([NH:33][CH3:34])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([CH3:32])=[CH:27][CH:26]=2>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[C:23]([NH:33][CH3:34])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([CH3:32])=[CH:27][CH:26]=2
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: CNc1nc2ccc(C)cc2cc1CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CNc1nc2ccc(C)cc2cc1Cc1c(O)nc(C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (40 mg, 182 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 2 N aq. KOH solution (0.17 mL, 0.34 mmol) at RT followed by 3-(chloromethyl)-N,6-dimethylquinolin-2-amine hydrochloride MDE 32062 (39 mg, 152 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before to be extracted with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6 to 90:10) gave 12 mg of 6,7-dimethoxy-1-methyl-4-((6-methyl-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-((6-methyl-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 33 as a brown solid (14 mg, 19% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][S-:14].[Na+]>C(#N)C.CN(C=O)C>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([S:14][CH3:13])[N:7]=1
Reactant: C[S-]
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1nc(SC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of 6-chloro-2-methoxy-3-nitropyridine (300 mg, 1.591 mmol) in acetonitrile/DMF (2:1, 3 mL) was added sodium thiomethoxide (133 mg, 1.91 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was partitioned between water (30 mL) and EtOAc (30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give the title compound (290 mg, 91%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[C:10]1([C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[NH:1]1[CH:5]=[C:4]([S:6]([N:19]2[CH:20]=[C:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:17]=[CH:18]2)(=[O:8])=[O:7])[N:3]=[CH:2]1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Solvent: C1CCOC1
Product: O=S(=O)(c1c[nH]cn1)n1cnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
A round bottom flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 8.35 g of imidazole- 4-sulfonylchloride and 300 ml or THF. The solution was treated with 14.5 g of 4-phenylimidazole in one portion and the resulting solution stirred 18 hours at room temperature. The precipitate was filtered and the filtrate concentrated at reduced pressure. The solids were triturated with water, filtered, rinsed and dried at high vacuum over NaOH; then dissolved in hot ethyl acetate, treated with charcoal, filtered and concentrated to 600 ml. Hexane was added and induced crystallization. The product was filtered, rinsed and dried giving 12.02 g of white crystals in two crops of 1-(4-imidazolylsulfonyl)-4-phenylimidazole, mp 204.5-206; λmaxnujol 3.13 (NH), 7.27 (SO2N) and 8.61 μ (SO2N). NMR (DMSO, d6) 750-840 Hz, m, 1H; 495 Hz, t, J = 1Hz, 2H; 466-484 Hz, m, 4 H; 435-438 Hz, m, 3H.