Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][C:30]=1[C:37]([F:40])([F:39])[F:38].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:20][C@@:12]([C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=2)([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:31][C:30]=1[C:37]([F:38])([F:39])[F:40]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1ccc([C@@](Cc2ccccc2)(NCc2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
(R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (21.5 mg, 0.057 mmol) in dichloroethane (0.5 mL) in a two drum vial was added 4-fluoro-3-(trifluoromethyl)benzaldehyde (21.9 mg, 0.114 mmol) followed by a drop of acetic acid. The reaction mixture was shaken for 20 minutes at room temperature before NaBH(OAc)3 (36.3 mg, 0.171 mmol) was added. The reaction was stirred at room temperature overnight. The solvents were removed and the residue was purified by preparative HPLC (phenominex C18 column, 21×100 mm, 5μ) using MeOH/H2O (with 0.1% TFA) to give (R)—N-(4-fluoro-3-(trifluoromethyl)benzyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine as a colorless oil (17.5 mg, 46% yield). LCMS: 4.32 min (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 3.78-3.91 (m, 4H), 6.60 (d, J=7.47 Hz, 2H), 7.14-7.27 (m, 7H), 7.35-7.48 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13]([OH:15])=O.Cl.[CH3:17][N:18](C)[CH2:19]CCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.CNC.C(N(CC)CC)C>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13]([N:18]([CH3:19])[CH3:17])=[O:15]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCc1c[nH]c2ccc(Br)cc12
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CCc1c[nH]c2ccc(Br)cc12

Procedure:
To a 250 mL argon purged round bottom flask fitted with a magnetic stirbar containing a yellow solution of 5-bromo-indol-3-propionic acid (52) (3.00 g, 11.19 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.36 g, 12.31 mmol), 1-hydroxybenzotriazole (1.51 g 11.17 mmol) and dimethylamine hydrochloride (912 mg, 11.19 mmol) in DMF (20 mL) was added triethylamine (4.7 mL, 25.83 mmol) resulting in the formation of a precipitate. The reaction was monitored by TLC (1:1 ethyl acetate, hexane). After 2 hours the argon purge needle was removed and additional dimethylamine hydrochloride added (0.3 eq). After a total of 20 hours, TLC revealed complete consumption of starting material. The reaction was diluted with water (40 mL) and ethyl acetate (40 mL). The reaction was transferred to a separatory funnel and the product was extracted into the organic layer. The organic layer was extracted again with water (20 mL) to remove the DMF, followed by 2 N NaOH (20 mL) and brine (15 mL). The yellow organic layer was dried over magnesium sulfate, filtered and concentrated to afford a white-pink solid. The product was purified by silica gel column chromatography (9:1 Ethyl acetate/hexanes) Yield: 1.407 g pure, compound 53, 1H NMR (DMSO) δ 11.00 (br s, NH), 7.68-7.67 (d, 1H, J=1.5), 7.31-7.28 (d, 1H, J=8.4 Hz), 7.72-7.14 (td, 2H, J=1.8, 8.4 Hz), 2.93-2.81 (m, 8 H), 2.64-2.59 (t, J=7.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[S-:18][C:19]#[N:20].[NH4+].BrBr>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:9]=2[S:18][C:19]#[N:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(Cl)cc2)[nH]1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(SC#N)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.9 %

Procedure:
A solution of ethyl 5-(p-chlorophenyl)pyrrole-2-carboxylate (0.95 g, 3.8 mmol) in acetic acid (20 mL) is treated with ammonium thiocyanate (1.75 g, 22.8 mmol), stirred at room temperature for five minutes, cooled to 15° C., treated with a solution of bromine (0.91 g, 5.7 mmol) in acetic acid (10 mL) and stirred at room temperature for several hours. The reaction mixture is filtered to remove solids and the filtrate is poured into water and stirred. The aqueous mixture is filtered to obtain an off-white solid. Flash chromatography of the solid using a 1:10 ethyl acetate/hexanes solution gives the title product as a white solid (0.99 g, mp 138°-141° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:13])[CH2:11][CH3:12])=[CH:5][CH:4]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CCC(=O)Cc1ccc(SC)cc1
Reactant: O=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCC(=O)C(=Cc1ccccc1)c1ccc(SC)cc1
Yield: 61.2 %

Procedure:
A mixture of 1-(4-methylthiophenyl)-2-butanone from Step 2 (9.74 g, 50 mmol), benzaldehyde (5.85 g, 55 mmol) and piperidine (0.5 mL) in toluene (200 mL) was heated at reflux with a Dean-Stark trap for 16 hours. The mixture was cooled and solvent was removed in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was washed successively with saturated ammonium chloride solution, water and brine, dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The crude pentenone was recrystallized from ethyl acetate and hexane to give 8.64 g of 2-(4-methylthiophenyl)-1-phenyl-1-pentene-3-one (60%) as light yellow crystals: mp 98°-99° C. Anal. Calc'd. for C18H18OS: C, 76.56; H, 6.42; N, 11.35. Found: C, 76.58; H, 6.17; N, 11.35.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\NCC1C=CC(O)=C(OC)C=1.Cl.[OH:27][C:28]1C=C(C=CC=1)CN.C(N(CC)CC)C>>[CH3:28][O:27]/[CH:14]=[C:5]1/[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]2[C:4]/1=[CH:3][CH:2]=[CH:11][CH:10]=2
Reactant: COc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)ccc1O
Reactant: NCc1cccc(O)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CO/C=C1/C(=O)NC(=O)c2ccccc21

Procedure:
Using the procedure described for the preparation of (4Z)-6-bromo-4-{[(4-hydroxy-3-methoxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione, 0.25 g (78% yield) of off-white solid is obtained from 0.2 g (0.98 mmol) of (4E)-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione and 0.2 g (1.08 mmol) of 4-methoxy]-3-hydroxyl-benzylamine hydrochloride, and 0.3 mL (2.94 mmol) of triethylamine: mp 192-193° C.; 1H NMR (DMSO-d6) δ 10.97 (s, 1H), 10.60 (m, 1H), 9.04 (s, 1H), 8.62 (d, J=9 Hz, 1H), 7.98 (d, J=6 Hz, 1H), 7.83 (d, J=6 Hz, 1H), 7.55 (t, J=6 Hz, 1H), 7.17 (t, J=6 Hz, 1H), 6.91 (d, J=6 Hz, 1H), 6.78 (m, 2H), 4.56 (d, J=4.5 Hz, 2H), 3.75 (s, 3H); MS (ESI) m/z 325.1 (M+H)+1.
Reaction SMILES: [CH:1]([C:3]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([O:20][CH3:21])[CH:4]=1)=[O:2].[BH4-].[Na+].O.[K+].[Br-]>C1COCC1.CCCCCC.CCOC(C)=O>[OH:2][CH2:1][C:3]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([O:20][CH3:21])[CH:4]=1
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(C=O)cc1OC
Agent: [BH4-]
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(CO)cc1OC
Reaction time: 0.08 h

Procedure:
To a clear yellow solution of methyl 4-(4′-formyl-2′-methoxy-5′-nitrophenoxy) butanoate (5) (1 g, 3.36 mmol) in THF (10 cm3) was added, portion wise, sodium borohydride (128 mg, 3.36 mmol). The solution quickly changed appearance, becoming deep orange after about 5 mins. The mixture was stirred for a further 55 mins before water was added (25 cm3), the subsequent yellow mixture was extracted with ether (3×30 cm3) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo providing a pale yellow solid. The solid, 6 was used without further purification (875 mg, 87.5%). A small amount of material (200 mg, 0.67 mmol) was purified via column chromatography (SiO2, hexane:EtOAc 2:1 v/v) so that complete characterisation data could be obtained. m.p. 100° C. [lit. (D. L. McMinn and M. M. Greenberg, Tetrahedron, 1996, 52, 3827.) m.p. 98-100° C.]. Found C, 52.2; H, 5.7; N, 4.7; C13H17NO7 requires C, 52.2; H, 5.7; N, 4.7%; Rf 0.24 (SiO2, hexane:EtOAc 2:1 v/v); νmax (KBr disc)/cm−1 3400-3100 (br), 3000-2800 (m), 1730 (s), 1280, 1220; δH (200 MHz, CDCl3) 2.20 (2H, q, J=7.3 Hz, CH2), 2.56 (2H, t, J 7.3 Hz, CH2), 2.61 (1H, br, OH), 3.70 (3H, s, OCH3), 3.98 (3H, s, OCH3), 4.13 (2H, t, J=7.3 Hz, CH2), 4.95 (2H, s, CH2), 7.15 (1H, s, H-3′), 7.71 (1H, s, H-6′) ppm; δC (100 MHz, CDCl3) 24.3 (CH2), 30.4 (CH2), 51.7 (OCH3), 56.4 (OCH3), 62.8 (CH2), 68.3 (CH2), 109.5 (CH), 111.2 (CH), 132.4, 139.6, 147.2, 154.3, 173.4 (COOCH3) ppm; m/z (FAB) 299 [(M+), 15%], 282 [(M-OH), 40%].
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])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:26](=[O:41])[N:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:28]([CH2:31][C@H:32]([OH:34])[CH3:33])[C:29]=2[CH3:30])=[O:24])=[CH:18][C:17]=1[F:42].[C:43]([NH:50][CH2:51][C:52](O)=[O:53])([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:26](=[O:41])[N:27]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:28]([CH2:31][C@H:32]([O:34][C:52](=[O:53])[CH2:51][NH:50][C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH3:33])[C:29]=2[CH3:30])=[O:24])=[CH:18][C:17]=1[F:42]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)O)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CNC(=O)OC(C)(C)C)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of (R)—N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.0 g, 3.5 mmol), N-Boc-glycine (1.23 g, 7.0 mmol) and DMAP (0.86 g, 7.0 mmol) in CH2Cl2 (45 mL) at 0° C. was added EDC solid (2.02 g, 10.5 mmol) in portions. The reaction mixture was stirred at 0° C. for 2 h, then warmed up to rt and continued to stir overnight. The reaction mixture was diluted with CH2Cl2 (50 mL), and washed with 0.5 N HCl aqueous (20 mL), saturated NaHCO3 (20 mL), and followed by brine (20 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (n-hexane/ethyl acetate at the ratio of 1:1 to 1:8) to give the title compound as a white powder (2.43 g, 95.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(OCC)(=O)C>[F:12][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(C)(=O)=O)ccc1F
Yield: 98.5 %

Procedure:
Methyl 5-amino-2-fluorobenzoate (50 g) and. 23.4 g of pyridine were dissolved in 300 ml of ethyl acetate, then 37 g of methanesulfonyl chloride was added thereto with ice-cooling and stirring and the mixture was made to react at room temperature for 3 hours. The reaction mixture was washed with water, dried, evaporated and the crystals separated out therefrom were filtered to give 72 g of methyl 2-fluoro-5-methanesulfonylaminobenzoate, m.p. 135°-137 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([OH:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)[O:13][CH:11]([CH3:12])[CH2:10]2
Reactant: COc1ccc(CC(C)O)cc1Cl
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: COc1cc2c(cc1Cl)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of 21.16 g (105.4 mmol) of 1-(3-chloro-4-methoxyphenyl)-2-hydroxypropane in 106 ml of dry benzene is mixed with 15.93 g (105.4 mmol) of 4-nitrobenzaldehyde and 14.36 g (105.4 mmol) of freshly melted zinc chloride, and dry hydrogen chloride gas is introduced for 3 hours. Then, the mixture is heated to boiling for 30 minutes. Working-up is carried out according to the process that is described in Example 3, Step A. The 6-chloro-3-methyl-7-methoxy-1-(4-nitrophenyl)-isochroman that is obtained is first isolated as an oily crude product, which crystallizes during treatment, however, with 370 ml of hot ethanol: 15.79 g (50%, melting point 118-120° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[N:25]=[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:27][C:28]=3[C:29]([F:32])([F:31])[F:30])=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:45]>CO>[ClH:45].[N:11]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[N:25]=[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:27][C:28]=3[C:29]([F:32])([F:30])[F:31])=[O:23])=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1ccc(N2CCCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
A mixture of 4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.64 g, 3.1 mmol) in methanol (50 mL) and hydrogen chloride in dioxane (4M, 10 mL, 40 mmol) was stirred at room temperature for 24 hr. The solvents were removed under vacuum to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-[1,4]diazepan-1-yl-phenyl)-amide hydrochloride salt (1.57 g, 99% yield) as a white solid. ES-MS for the neutral form C22H21F3N4O2 calcd. (m/e) 430, observed 431 (M+H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH:15][CH:16]=[O:17])[CH:12]=[CH:11][C:10]=1[S:18][CH2:19][CH3:20])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH2:19]([S:18][C:10]1[CH:11]=[CH:12][C:13]([NH:15][CH:16]=[O:17])=[CH:14][C:9]=1[S:6]([NH2:5])(=[O:7])=[O:8])[CH3:20]
Reactant: CCSc1ccc(NC=O)cc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCSc1ccc(NC=O)cc1S(N)(=O)=O

Procedure:
3.13 g of N-tert-butyl-2-ethylmercapto-5-formylaminobenzenesulfonamide are stirred in 20 ml of trifluoroacetic acid at room temperature. When the reaction has ended, volatile components are distilled off under a high vacuum. 3.20 g of a solid which has an adequate purity for further reactions are thus obtained; melting point: 127° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25].C(=O)([O-])[O-].[K+].[K+].I[CH:33]([CH3:35])[CH3:34]>CN(C)C=O>[CH2:22]([O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][C:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH:33]([CH3:35])[CH3:34])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:24]=[O:25])=[CH:6][N:7]=1)[CH3:23]
Reactant: CC(C)I
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(O)c(OC)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Cc2ncc(C=O)c3cc(OC(C)C)c(OC)cc23)c1
Temperature: 85 °C

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (60 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (235 mg, 1.70 mmol) and 2-iodopropane (0.085 mL, 0.85 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 1-(3-ethoxy-benzyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde as a colorless oil. The crude product was used without further purification. To a stirred solution of 1-(3-ethoxy-benzyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde in acetic acid (2 mL) was added selenium dioxide (189 mg, 1.70 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde as a major product (31 mg, 46% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([CH2:10][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: Clc1ccc(C2(COC3CCCCO3)CO2)cc1
Solvent: CN(C)C=O
Product: OC(COC1CCCCO1)(Cn1cncn1)c1ccc(Cl)cc1
Yield: 71.9 %

Procedure:
37 g (0.138 mol) of 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yl-oxymethyl)-oxirane are added to a mixture of 22.4 g (0.32 mol) of 1,2,4-triazole, 5 g (0.04 mol) of potassium tert.-butylate and 300 ml of dimethylformamide at room temperature, while stirring. After the addition has ended, the reaction mixture is stirred at 80° C. for 12 hours and is then concentrated by stripping off the solvent under reduced pressure. Water is added to the residue which remains, the resulting mixture is extracted three times with methylene chloride and the combined organic phases are dried over magnesium sulphate and concentrated by stripping off the solvent under reduced pressure. The product thus obtained is purified chromatographically on silica gel with methylene chloride/ethyl acetate =4:1 as the mobile phase. 33.5 g (72% of theory) of 2-(4-chlorophenyl)-1-[(tetrahydro-2H-pyran-2-yl)-oxy]-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in this manner in the form of pale yellow crystals of melting point 70° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([NH:18][CH2:19][C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:12]([CH3:27])=[C:11]([CH3:28])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].C(OCC)(=O)C>[NH2:15][C:14]1[C:9]([N:8]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:10][C:11]([CH3:28])=[C:12]([CH3:27])[C:13]=1[NH:18][CH2:19][C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1nc(N(Cc2ccccc2)Cc2ccccc2)c([N+](=O)[O-])c(NCC2(O)CCCCC2)c1C
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Cc1nc(N(Cc2ccccc2)Cc2ccccc2)c(N)c(NCC2(O)CCCCC2)c1C
Reaction time: 3 h

Procedure:
A mixture of 1-({[2-(dibenzylamino)-5,6-dimethyl-3-nitropyridin-4-yl]amino}methyl)cyclohexanol (4.00 g, 8.43 mmol) and 5% platinum on carbon (0.40 g) in ethyl acetate (84 mL) was hydrogenated at 50 psi (3.4×105 Pa) for 3 h on a Parr apparatus. The reaction mixture was filtered through CELITE filter agent, which was rinsed with ethyl acetate afterwards. The filtrate was concentrated to give 1-({[3-amino-2-(dibenzylamino)-5,6-dimethylpyridin-4-yl]amino}methyl)cyclohexanol and was used directly in the next step.
Reaction SMILES: Br.Br.[CH2:3]([O:5][C:6]([C:8]1([CH2:20][NH2:21])[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4].Cl[S:23]([C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][N:32]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])[CH2:33]2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH2:3]([O:5][C:6]([C:8]1([CH2:20][NH:21][S:23]([C:26]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][N:32]([C:36](=[O:41])[C:37]([F:40])([F:38])[F:39])[CH2:33]3)=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4]
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Reactant: CCOC(=O)C1(CN)CCN(c2ccncc2)CC1
Agent: Br
Solvent: c1ccncc1
Product: CCOC(=O)C1(CNS(=O)(=O)c2ccc3c(c2)CN(C(=O)C(F)(F)F)CC3)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
To 4-aminomethyl-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrobromide (423 mg) were added pyridine (2 ml) and 7-chlorosulfonyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (273 mg), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated and water was added. The mixture was extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=4:1) and dried under reduced pressure to give the title compound (222 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8](=[O:11])(=[O:10])[NH2:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:14].[CH:22]1(CCCN)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[NH2:9][S:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([N:12]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:3][CH2:2][CH3:1])[N:18]=[CH:17][N:16]=2)=[O:14])=[C:2]([CH3:1])[CH:7]=1)(=[O:11])=[O:10]
Reactant: NCCCC1CCCCC1
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1
Product: CCCN(c1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2C)ncn1)C1CCCCC1
Yield: 82 %

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (2-methyl-4-sulfamoyl-phenyl)amide (Intermediate 17) and cyclohexylpropylamine (Chembridge), the title compound was obtained as a beige solid in 82% yield.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([OH:15])[C:7](=[O:16])[C:6](=[O:17])[NH:5]2.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>CN(C=O)C>[OH:15][N:8]1[C:9]2[C:4](=[CH:3][C:2]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:6](=[O:17])[C:7]1=[O:16]
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2n(O)c1=O
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(-n3ccnc3)c([N+](=O)[O-])cc2n(O)c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
A mixture of 370 mg of 6-fluoro-1-hydroxy-7-nitroquinoxaline-2,3-(1H,4H)-dione, 320 mg of imidazole and 37 ml of DMF was stirred at 100° C. for 4 hours. The reaction mixture was concentrated and, then, diluted with water. The aqueous layer was neutralized with hydrochloric acid and the resulting crystals were recovered by filtration and washed with water to provide 214 mg of 1-hydroxy-6-(1-imidazolyl)-7-nitroquinoxaline-2,3-(1H,4H)-dione 1/2 hydrate.