Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])C(OC)=O)=[CH:5][C:4]=1[N+:15]([O-])=O.[C:18]([O:21][CH2:22]C)(=[O:20])C>[Pd].C(O)C>[NH2:15][C:4]1[CH:5]=[C:6]([CH2:9][CH2:14][C:18]([O:21][CH3:22])=[O:20])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)C(C)c1ccc(OC)c([N+](=O)[O-])c1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccc(OC)c(N)c1
Yield: 95 %

Procedure:
Methyl 4-methoxy-3-nitrophenylpropanoate (2.70 g, 11.3 mmol), 10% palladium on carbon (200 mg) and a mixed solvent (100 mL) of ethyl acetate with ethanol (1:1 v/v) were mixed and hydrogenation was carried at an initial pressure of 294.3 kPa. After completion of the hydrogenation, the catalyst was removed by filtration and the filtrate was concentrated to obtain 2.35 g (95%) of the title compound as a yellow oily product.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].Cl.[N:31]1([CH2:38][CH2:39][O:40][C:41]2[CH:49]=[CH:48][C:44]([C:45](O)=O)=[CH:43][CH:42]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:38][CH2:39][O:40][C:41]2[CH:49]=[CH:48][C:44]([CH2:45][CH2:2][CH2:1][NH:3][C:4]3[C:5]([CH:13]4[CH2:14][CH2:15][C:16]5[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=5[CH2:22]4)=[CH:6][C:7]4[O:11][CH2:10][O:9][C:8]=4[CH:12]=3)=[CH:43][CH:42]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: Cl
Product: Oc1ccc2c(c1)CCC(c1cc3c(cc1NCCCc1ccc(OCCN4CCCCCC4)cc1)OCO3)C2
Yield: 76.5 %

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride (80 mg) according to an analogous synthetic method to Example 337 described below, the title compound (42 mg) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7](I)[S:6][N:5]=2)[CH2:3][CH2:2]1.C([Li])CCC.[CH2:15]([Sn:19]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])Cl)[CH2:16][CH2:17][CH3:18].C(=O)(O)[O-].[Na+]>C1COCC1>[CH:1]1([C:4]2[CH:8]=[C:7]([Sn:19]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][CH2:16][CH2:17][CH3:18])[S:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Ic1cc(C2CC2)ns1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C2CC2)ns1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a cold (−78° C.) solution of 3-cyclopropyl-5-iodoisothiazole (100 mg, 0.398 mmol) in anhydrous THF (2.0 mL) was added n-butyllithium (0.299 mL, 0.478 mmol) dropwise. The reaction mixture was stirred for 60 minutes at −78° C. A solution of tributylchlorostannane (0.129 mL, 0.478 mmol) in anhydrous THF (2.0 mL) was added to the reaction mixture, which was stirred for 30 minutes −78° C. and subsequently allowed to warm to ambient temperature over a 1 hour period. Saturated aqueous sodium bicarbonate was added to the reaction mixture. The aqueous phase was extracted with EtOAc and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (19:1) to give the title compound as a colorless oil (142.8 mg, 87%). 1H NMR (500 MHz, CDCl3) δ ppm 0.85-0.93 (m, 9H), 0.95-1.05 (m, 4H), 1.09-1.17 (m, 6H), 1.28-1.38 (m, 6H), 1.47-1.61 (m, 6H), 2.20-2.29 (m, 1H), 6.93 (s, 1H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([S:14]([CH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[N:29]([CH3:35])/[C:30](=[N:33]/[CH3:34])/[S:31][CH:32]=3)[CH2:23][CH:22]1[C:36](O)=[O:37])=[O:20])(=[O:16])=[O:15])[CH:8]=[CH:7]2.[CH2:39]([NH2:42])[CH2:40][OH:41].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(N(CC)CC)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([S:14]([CH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[N:29]([CH3:35])/[C:30](=[N:33]/[CH3:34])/[S:31][CH:32]=3)[CH2:23][CH:22]1[C:36]([NH:42][CH2:39][CH2:40][OH:41])=[O:37])=[O:20])(=[O:16])=[O:15])[CH:8]=[CH:7]2
Reactant: C/N=c1\scc(CN2CCN(C(=O)CCS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C(C(=O)O)C2)n1C
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C/N=c1\scc(CN2CCN(C(=O)CCS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C(C(=O)NCCO)C2)n1C
Yield: 55.1 %

Procedure:
1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxylic acid dihydrochloride (0.4 g) obtained in Example 24 was dissolved in DMF (20 mL), and triethylamine (0.2 mL) was added thereto. With ice cooling, 2-ethanolamine (0.04 g), HOBt (0.12 g) and WSC (0.16 g) were added thereto, and the mixture was mixed at room temperature for 16 hours. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a basic silica gel column to give the title compound (0.21 g) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1.[Na]>CN(C)C=O>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:34]4[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:40])[F:41])=[CH:36][CH:35]=4)=[O:39])[CH:7]=[CH:6][CH:5]=3)=[N:9][N:10]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc(N)c3)n2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
1 g (2.7 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-pyrimidin-2-amine was dissolved in 290 ml of dry dimethylformamide and 386 μl of p-trifluoromethyl-phenylisocyanate were added. The reaction was then stirred at room temperature overnight. The mixture was poured into aqueous sodium hydrogenocarbonate and extracted with dichloromethane. The organic layer was then dried over sodium sulphate and evaporated. The crude was purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3; from 9/1 to 8/2), affording 800 mg (53%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]5[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=5[F:40])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])[CH2:17]3)[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:58](Cl)(=[O:60])[CH3:59]>ClCCl>[C:58]([NH:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]5[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=5[F:40])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:41]([O:43][CH2:44][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[O:42])[CH2:17]3)[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1)(=[O:60])[CH3:59]
Reactant: NCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21

Procedure:
The solution of 0.220 g of benzyl 3-[4-(2-aminoethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[3-(2,5-difluorophenoxy)propoxy]phenyl}piperidine-1-carboxylate in 7.5 ml of dichloromethane is cooled to 0° C. with stirring and admixed with 0.042 ml of triethylamine. 0.023 ml of acetyl chloride in 0.50 ml of dichloromethane are slowly added dropwise. Subsequently, the mixture is stirred at 0° C. over 1 hour. The reaction mixture is poured onto ice-water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with brine (20 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.75 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.46.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.[H-].[Na+].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>O1CCCC1.C(OCC)(=O)C>[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2nonc2N)nc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
To a stirred suspension of 0.5 g of 4-(1H-benzoimidazol-2-yl)-furazan-3-ylamine (CAS 332026-86-5) (2.49 mmol; 1.0 eq.) in 15 mL of dry tetrahydrofuran cooled to 0° C. are added portionwise 0.075 g of sodium hydride (2.98 mmol; 1.2 eq.). After stirring for 10 min at 0-5° C., the resulting clear solution is treated with 0.54 mL of 2-(trimethylsilyl)ethoxymethyl chloride (2.91 mmol; 1.17 eq.). The reaction solution is stirred for 0.5 h at 0-5° C. and then diluted with 30 mL of ethyl acetate. The solution is washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered and concentrated to dryness. The oily residue is triturated in diisopropylether (10 mL) and the solvent is removed under reduced pressure to give 0.78 g of the desired product as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[C:6]([Cl:12])=[N:7][CH:8]=[N:9][C:10]=1[Cl:11].[CH3:14]I>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:5]1[C:6]([Cl:12])=[N:7][CH:8]=[N:9][C:10]=1[Cl:11])[CH3:14]
Reactant: CI
Reactant: COC(=O)Cc1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Product: COC(=O)C(C)c1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a solution of KH (30%, 13.3 g, 125 mmol) in THF (200 mL) at 0° C. was added (4,6-Dichloro-pyrimidin-5-yl)-acetic acid methyl ester (20.0 g, 90.0 mmol) and MeI (290.0 g, 8.8 mL, 141.0 mmol) in THF (200 mL) slowly. After addition, the mixture was stirred at room temperature for 30 min, and then heated to reflux for 1 hour. After cooling to 0° C., the mixture was quenched with saturated aqueous NH4Cl. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3×200 mL). The organic phase was combined and dried. After removal of the solvent, the residue was subject to column chromatography, eluted by hexane/ethyl acetate (5:1) to give 2-(4,6-Dichloro-pyrimidin-5-yl)-propionic acid methyl ester (17.6 g, 83%). 1H NMR (CDCl3, 400 MHz) δ 8.69 (s, 1H), 4.39 (dd, J=14.4 Hz, J=7.2 Hz, 1H), 3.73 (s, 3H), 1.57 (d, J=7.21 Hz, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(N(CC)CC)C.Cl.[C:32]1([CH3:46])[CH:37]=[CH:36][C:35]([C:38]2([C:41](=N)OCC)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.C(O)(=O)C>C(O)C>[N:19]1([C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][N:11]([C:7]3[N:8]=[C:9]4[NH:10][C:41]([C:38]5([C:35]6[CH:34]=[CH:33][C:32]([CH3:46])=[CH:37][CH:36]=6)[CH2:39][CH2:40]5)=[N:3][C:4]4=[CH:5][CH:6]=3)[CH2:12]2)=[O:18])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(c2ccc(C)cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1ccc(C2(c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)CC2)cc1
Temperature: 130 °C

Procedure:
To a suspension of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (220 mg, 0.60 mmol) in ethanol (2 mL) was added triethylamine (250 μL, 1.8 mmol), a solution of ethyl 1-(p-tolyl)cyclopropanecarbimidate hydrochloride (140 mg, 0.58 mmol) in ethanol (1 mL), and acetic acid (0.5 mL, 8.70 mmol). The reaction mixture was heated in a microwave for 45 min at 130° C. The solvent was removed under reduced pressure. Ethyl acetate (10 mL) was added to the residue and the solution was washed with aqueous sodium hydroxide (1N, 5 mL). The aqueous layer was extracted with ethyl acetate (10 mL×3). The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 430.2; HPLC retention time 2.51 min (Method A).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:18])=O.FC(F)(F)C1C=C2C(=CC=1)NC(=O)C=N2>>[Cl:18][C:9]1[CH:8]=[N:7][C:6]2[C:11](=[CH:12][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnc2ccc(C(F)(F)F)cc2[nH]1
Agent: O=c1cnc2cc(C(F)(F)F)ccc2[nH]1
Product: FC(F)(F)c1ccc2ncc(Cl)nc2c1

Procedure:
This 7-trifluoromethylquinoxalin-2-one was allowed to react with phosphorus oxychloride (in the same manner as described above for 6-trifluoromethylquinoxalin-2-one) to yield the intermediate 2-chloro-7-trifluoromethylquinoxaline having a melting point of about 119°-120° C. This compound was allowed to react with ammonia, in the manner described above, to yield the 2-amino-7-trifluoromethylquinoxaline, having a melting point of about 192°-194° C., and identified by IR spectrum.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][CH2:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.C(N(CC)CC)C.O>CN(C=O)C>[Si:1]([O:9][CH2:10][CH2:11][CH2:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCCCc1nc2ccccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To this end, tert-butyldimethylsilyl chloride (TBDMSCI) (14.68 g, 97.37 mmol) was added a little at a time to a solution of 2-(3-hydroxypropyl)-benzimidazole (15.60 g, 88.52 mmol) in DMF (265 ml) and triethylamine (20.27 ml, 145.41 mmol). The mixture was stirred at RT overnight and then admixed with water (800 ml) and extracted with diethyl ether. The organic phase was dried over sodium sulphate and chromatographed over silica gel (mobile phase: cyclohexane/ethyl acetate=6:1), giving 25 g (97%) of colourless crystals. MS (DCI): 291 (M+H)+
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].[CH2:23](C([SnH3])=C(CCCC)CCCC)[CH2:24]CC>C1(C)C=CC=CC=1.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>[CH:12]1([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:21])=[C:3]([F:22])[C:2]=3[CH:23]=[CH2:24])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Yield: 79.9 %

Procedure:
3.72 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 4.4 g of tributylvinyl stannan and 0.46 g of tetrakis(triphenylphosphine)palladium(0) are refluxed in 40 ml of absolute toluene for 2 to 3 hours under a nitrogen atmosphere. The mixture is filtered under hot conditions, and the product which has precipitated at room temperature is filtered off with suction, washed with toluene and dried. 2.55 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylate are obtained (79% of theory).
Reaction SMILES: C(O)=O.CC(O[C:8]([CH3:10])=O)=O.[N+:11]([C:14]1[CH:23]=[C:22]2[C:17](C[CH2:19][NH:20][CH2:21]2)=[CH:16][CH:15]=1)([O-:13])=[O:12].Cl>C1COCC1.CO>[CH3:19][N:20]1[CH2:10][CH2:8][C:17]2[C:22](=[CH:23][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[CH2:21]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CO
Solvent: O=CO
Solvent: C1CCOC1
Product: CN1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 1311 %

Procedure:
Formic acid (9.4 mL, 250 mmol) was added dropwise to Ac2O (19 mL, 202 mmol) at 0° C. The solution was stirred at 50° C. for 45 min, then cooled to −18° C., diluted with THF (100 mL) and a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline [(a) Tercel, M.; et al., J. Med. Chem. 1996, 39, 1084-1094; (b) Zhu, Z., et al., J. Med. Chem. 2003, 46, 831-837] (251) (13.8 g, 5.0 mmol) in THF (100 mL) was added and stirred at −15 to −18° C. for 30 min. The solution was warmed to 20° C., the solvent evaporated and the residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL). The aqueous fraction was extracted with EtOAc (3×250 mL), dried and the solvent evaporated. The residue was dissolved in THF (200 mL), cooled to 10° C. and BH3-DMS solution (10 M, 19.4 mL, 194 mmol) was added. The solution was stirred at 20° C. for 1 h, diluted with MeOH (30 mL) and acidified with HCl solution (1 M, 45 mL). The solution was stirred at 40° C. for 15 min, the solvent evaporated and the residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL). The aqueous fraction was extracted with EtOAc (3×250 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give isoquinoline 252 (12.6 g, 85%) as an orange solid: 1H NMR δ 8.09 (dd, J=8.4, 2.3 Hz, 1H, H-6), 7.95 (d, J=2.3 Hz, 1H, H-8), 7.37 (d, J=8.4 Hz, 1H, H-5), 4.27 (d, J=16.1 Hz, 1H, H-1), 3.94 (d, J=16.1 Hz, 1H, H-1), 3.23-3.34 (m, 2H, CH2), 2.99-3.18 (m, 2H, CH2), 2.17 (s, 3H, NCH3); MS (APCI) m/z 193 (MH+, 100%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:21])[N:13]([CH2:17][CH:18]4CC4)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:22])[CH:4]=1.C(=O)C>>[F:24][C:2]([F:1])([F:23])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:21])[N:13]([CH2:17][CH3:18])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:22])[CH:4]=1
Reactant: CC1CCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2N1CC1CC1
Agent: CC=O
Product: CCN1c2cc3c(C(F)(F)F)cc(=O)[nH]c3cc2CCC1C

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 187 (Structure 33 of Scheme VI, where R1=methyl, n=1) and acetaldehyde. 1H NMR (400 MHz, CDCl3) 11.19 (br. s, 1H), 7.11 (s, 1H), 7.00 (s, 1H), 6.80 (s, 1H), 3.55 (m, 1H), 3.47-3.32 (m, 2H), 2.93-2.80 (m, 2H), 1.93-1.79 (m, 2H), 1.22 (t, 3H, J=7.0), 1.18 (d, 3H, J=6.4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:20][C@H:10]2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:5][CH:4]=1.ClC1C=CC=CC=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[SH:35]>CO>[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35][C@@H:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C@@H:10]([OH:20])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]
Reactant: Nc1ccccc1S
Reactant: COc1ccc([C@@H]2O[C@H]2C(=O)Nc2ccccc2)cc1
Solvent: Clc1ccccc1
Solvent: CO
Product: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxy-N-phenylpropionamide (539 mg) and chlorobenzene (5 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-aminothiophenol (275 mg) and ferric chloride hexahydrate (0.054 mg) in methanol (0.1 ml) is added immediately to the reaction mixture. The mixture is stirred at the same temperature for 5 minutes, and cooled to room temperature. The precipitated crystals are collected by filtration, washed with chlorobenzene, and dried at 50° C. to give (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)-N-phenylpropionamide (582 mg).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][N:21]=[CH:24][N:25]([CH3:27])[CH3:26])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Product: CN(C)C=NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 95 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine is added to dimethylformamide dimethyl acetal, and the reaction mixture is heated to 95° C. The reaction mixture is cooled and quenched by addition of water, and the resulting aqueous mixture is extracted with EtOAc. The organic layer is washed with water, brine, dried (MgSO4), and evaporated under reduced pressure to give N′-(6-Benzenesulfonyl-naphthalen-1-ylmethyl)-N,N-dimethyl-formamidine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>O1CCOCC1>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:11]2[N:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])[CH2:6][CH2:5]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: OCCN1CCNCC1
Solvent: C1COCCO1
Product: O=C(O)c1cccnc1N1CCN(CCO)CC1

Procedure:
Operation was carried out in a manner similar to the one previously described in Example 5, using 10.4 g of 1-(2-hydroxyethyl)piperazine and 6.3 g of 2-chloronicotinic acid in 100 ml dioxane under reflux for 18 hours. Grams 3.9 of 2-[4-(2-hydroxyethyl)piperazin-1-yl]nicotinic acid, melting at 148°-171° C. (with decomposition), were obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]2[OH:39])(=O)=O)=CC=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[Cl:36][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][C:24]=1[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][CH3:35])=[CH:32][CH:33]=1)[C@:17]1([C@H:16]([OH:37])[C@@H:15]([OH:38])[C@H:14]([OH:39])[C@@H:13]([CH2:12][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[O:18]1)[O:19][CH2:20]2
Reactant: C1COCCN1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CN3CCOCC3)[C@@H](O)[C@H](O)[C@H]2O)cc1

Procedure:
((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (20 mg, 0.034 mmol) was dissolved in 1 mL of morpholine. Then the solution was allowed to reflux overnight. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 15 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.37 (s, 1H), 7.18 (s, 1H), 7.11 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 5.17 (d, J=13.2 Hz, 1H), 5.11 (d, J=13.2 Hz, 1H), 4.65-4.60 (m, 2H), 4.18-4.00 (m, 4H), 3.82-3.50 (m, 7H), 3.31-3.25 (m, 1H), 3.08-2.99 (m, 2H), 2.61 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H); MS ESI (m/z) 490 (M+1)+, calc. 489.