Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6][CH2:5]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][CH:21]=1.C(O)(=O)C(O)=O>CN(C=O)C.C1COCC1.O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([OH:27])([CH3:28])[CH2:29][N:8]2[C:9]3[CH:10]=[CH:11][C:12]([CH3:18])=[CH:13][C:14]=3[C:15]3[CH2:16][CH2:17][N:4]([CH3:3])[CH2:5][CH2:6][C:7]2=3)=[CH:24][CH:25]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC1(c2ccc(F)cc2)CO1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(F)cc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (67 mg, 0.28 mmol) in 5 mL of DMF, 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.934 mmol) was added and stirred at RT for 5 min. 2-(4-Fluorophenyl)-2-methyloxirane (212 mg, 1.39 mmol) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by column chromatography using 10% methanol-DCM. The freebase (30 mg, 0.082 mmol) was dissolved in THF (1.0 mL) and oxalic acid (10 mg, 0.082 mmol) in THF (1.0 mL) was added slowly, the mixture was stirred at RT for 20 min. and the formed solid was filtered, washed with ether and dried to afford the product as oxalate salt (15 mg, brown solid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([O-])([OH:10])=[O:9]>O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([O-:10])=[O:9]
Reactant: Clc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Cl

Procedure:
According to the equation of the process according to the invention, chlorobenzene is reacted with nitric acid to give nitrochlorobenzene and water. Thus, chlorobenzene and nitric acid are introduced into the process, and nitrochlorobenzene and water are discharged, the sulfuric acid/water mixture described being the reaction medium. Since, in the case of industrial implementation, it is advantageous to use dilute nitric acids, the dilution water of the nitric acid must be discharged in addition to the water of the reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]3)[CH2:7][C:6]2=1.[O:25]=[C:26]1[NH:31][C:30]2[CH:32]=[C:33]([CH:36]=O)[CH:34]=[CH:35][C:29]=2[S:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([NH:24][CH2:36][C:33]4[CH:34]=[CH:35][C:29]5[S:28][CH2:27][C:26](=[O:25])[NH:31][C:30]=5[CH:32]=4)[CH2:20][CH2:19]3)[CH2:7][C:6]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(CN1CCC(N)CC1)CO3
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Product: COc1ccc2ncc3c(c2c1)CC(CN1CCC(NCc2ccc4c(c2)NC(=O)CS4)CC1)CO3

Procedure:
The titled compound is prepared as an off-white lyophilized powder following Scheme 1 and in analogy to Example 18 using 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-piperidin-4-ylamine and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde as starting material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[C:12]([NH:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1)(=[O:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[C:20]1[C:19]2[C:23](=[CH:24][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:17][CH:18]=2)[NH:22][C:21]1=[O:25]
Reactant: COc1ccc(C=O)cc1Br
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Product: COc1ccc(C=C2C(=O)Nc3cc(NC(C)=O)ccc32)cc1Br

Procedure:
3-Bromo-4-methoxybenzaldehyde was condensed with 6-acetamido-2-oxindole to give N-[3-(3-bromo-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH2:12][N:11]([O:14][CH3:15])[CH2:10][CH2:9][NH:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH2:31][C:32](Cl)=[O:33]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH2:12][N:11]([O:14][CH3:15])[CH2:10][CH2:9][N:8]1[C:32](=[O:33])[CH2:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[CH3:23])=[O:6])[CH3:3]
Reactant: CCOC(=O)N1CCN(OC)CCN1
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(OC)CCN1C(=O)Cc1cc(C)ccc1C
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of 5-methoxy-[1,2,5]triazepane-1-carboxylic acid ethyl ester hydrochloride salt (1.33 g, 4.84 mmol), triethylamine (1.68 ml, 1.22 g, 12.07 mmol) and a catalytic amount of 4-dimethylaminopyridine in tetrahydrofuran (20 ml) at 0-5° C. was added a solution of (2,5-dimethyl-phenyl)-acetyl chloride (0.93 g, 5.09 mmol) in tetrahydrofuran (5 ml) dropwise. The suspension was stirred at 0-5° C. for one hour, and at room temperature for 4 hours. The solvent was evaporated, the residue diluted with ethyl acetate (50 ml) and water (20 ml), the layers separated and the aqueous phase extracted with ethyl acetate (2×25 ml). The combined organic layers were washed with water (2×20 ml) and brine (20 ml), dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 2:1). Yield: 1.1 g of 2-[2-(2,5-dimethyl-phenyl)-acetyl]-5-methoxy-[1,2,5]triazepane-1-carboxylic acid ethyl ester (compound P3.3) as a viscous oil. 1H-NMR (400 MHz, CD3OD): δ 1.14-1.39 (br m, 3H), 2.18 (s, 3H), 2.26 (s, 3H), 2.83-3.09 (br m, 4H), 3.13-3.32 (br m, 2H), 3.48 (s, 3H), 3.62 (br s, 2H), 3.78-4.32 (br m, overlapping signals, total 4H), 6.91 (s, 1H), 6.95 (d, J=7.8 Hz, 1H), 7.03 (d, J=7.8 Hz, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([Cl:19])[C:8](=[O:13])[C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Cl)Oc1ccc(Cl)cc1

Procedure:
22.7 g (0.1 mole) of 1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one in 100 ml of carbon tetrachloride were warmed to 60° C. 16.2 g (0.12 mole) of sulphuryl chloride were added dropwise to this solution, without further warming, at a rate such that continuous evolution of gas took place. When the addition had ended, the mixture was stirred under reflux and was then concentrated by distilling off the solvent in vacuo. 1-(4-Chlorophenoxy)-1-chloro-3,3-dimethyl-butan-2-one was obtained in quantitative yield and was subsequently reacted directly, without further purification. ##STR26##
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=2)[N:11]=1.[OH-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=2)[N:11]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccccc2o1
Temperature: 50 °C
Reaction time: 0.13 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(benzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (160 mg, 0.43 mmol, 1.00 equiv) in methanol (20 mL), sodium hydroxide (85 mg, 2.12 mmol, 4.99 equiv), water (2 mL). The resulting solution was stirred for 2 hs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with hydrogen chloride (2.5 M). The resulting solids were collected by filtration. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-1): Column, XbridgePrep Shield RP 18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (58% CH3CN up to 78% in 8 min, up to 100% in 2 min); Detector, UV 220 254 nm. This resulted in 70 mg (45%) of 2-(benzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](/[CH:29]=[CH:30]/[CH:31]=[O:32])[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=1)[CH2:29][CH:30]1[C:31](=[O:32])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])=[N:9][C:8]=2[CH:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C/C=C/c1cccc(Cl)c1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1cccc(Cl)c1
Yield: 46 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(3-chlorophenyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 13 as a white solid (62 mg, 46%). Analytical data for 13: 1H NMR (500 MHz, CDCl3) δ 9.41 (s, 1H), 7.88 (ddd, J=9.1, 6.0, 3.2 Hz, 1H), 7.40-7.29 (m, 3H), 7.31-7.22 (m, 2H), 7.10-7.02 (m, 2H), 7.02-6.93 (m, 4H), 4.09 (d, J=6.8 Hz, 1H), 3.58 (ddd, J=9.8, 6.9, 4.9 Hz, 1H), 3.31 (dd, J=14.9, 4.9 Hz, 1H), 2.42 (dd, J=14.9, 9.8 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.6, 159.1 (d, JCF=243.4 Hz), 155.4 (d, JCF=241.8 Hz), 148.9, 140.0, 136.8, 136.5, 134.4, 129.9, 129.3, 129.1, 128.5, 127.9, 127.3, 127.0, 118.3 (dd, JCF=12.6, 8.9 Hz), 117.1 (dd, JCF=25.6, 8.9 Hz), 116.6 (dd, JCF=24.8, 9.3 Hz), 114.5 (dd, JCF=26.8, 3.6 Hz), 110.7 (d, JCF=3.8 Hz), 47.0, 38.6, 32.6; IR (film) cm−1 1773, 1636, 1597, 1528, 1481, 1464, 1171, 1117, 1079, 813, 741; LRMS (ESI): Mass calcd for [M+H]+ C25H18ClF2N2O2: 451.1. found 451.3; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 5% IPA/3% MeOH/hexanes 0.5 mL/min, 280 nm), Rt1 (minor)=49.1, Rt2 (major)=70.2 min; er=>99:1.
Reaction SMILES: [C:1]([C:4]([C:18](=O)[CH3:19])=[CH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]#[N:17])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=1>C(O)(C)C>[C:1]([C:4]1[CH:5]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]#[N:17])=[CH:8][CH:7]=2)[C:23]2[C:24](=[O:28])[NH:25][CH:26]=[CH:27][C:22]=2[NH:21][C:18]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: Nc1cc[nH]c(=O)c1
Reactant: CC(=O)C(=Cc1ccc(C#N)c2ccccc12)C(C)=O
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)c2ccccc12

Procedure:
325 mg (1.23 mmol) of 4-(2-acetyl-3-oxobut-1-en-1-yl)-1-naphthonitrile are taken up in 20 ml of isopropanol and, after addition of 151 mg (1.23 mmol) of 4-aminopyridin-2(1H)-one, heated at the reflux temperature for 72 h. The mixture is then concentrated and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). The product fractions are combined, the solvent is removed, and the residue is stirred with diethyl ether. The precipitated product is filtered off and dried under high vacuum. 91 mg (21.2% of theory) of the title compound are obtained.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH3:28])[C:5]1([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[CH2:10][CH2:9][CH:8]([C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6]1.O>CO>[CH3:28][N:4]([CH3:3])[C:5]1([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[CH2:10][CH2:9][CH:8]([CH:11]([OH:19])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:6]1
Reactant: COc1cccc(C2(N(C)C)CCC(C(=O)Cc3ccccc3)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(C2(N(C)C)CCC(C(O)Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (24 mg, 0.6 mmol) was added to a solution of the product from stage 2 (112 mg, 0.3 mmol) in anhydrous methanol (5 ml) at 0° C. and the mixture was stirred at room temperature for 3 h. Further sodium borohydride (12 mg, 0.3 mmol) was then added and the mixture was stirred at room for a further 2 h. Water (20 ml) was added to the mixture. The solvent was removed i. vac. and the aqueous suspension was extracted with ethyl acetate (3×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (76 mg) was purified by flash chromatography (10 g, 20×1.1 cm) with methylene chloride/methanol [(95.5)+1% ammonia solution (30% in H2O)].
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[CH2:10][N:11](C)[CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrCCCCC1(C2C=CC(NC(=O)C(F)(F)F)=CC=2)[S:52][CH2:51][CH2:50][S:49]1>>[Si:1]([O:8][C@H:9]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])=[CH:19][CH:18]=2)[S:52][CH2:51][CH2:50][S:49]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CN(CCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: O=C(Nc1ccc(C2(CCCCBr)SCCS2)cc1)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCC1(c2ccc(NC(=O)C(F)(F)F)cc2)SCCS1)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 102, using Intermediate 45 in place of Intermediate 98. ES/MS calcd. for C32H43F3N3O4S2Si+ 682.2. Found m/z=682.4 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH:10]2[CH:8]([CH:9]2[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:6](=[O:28])[CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:44](OCC)(=[O:50])[C:45](OCC)=[O:46].Cl>CN(C=O)C>[CH2:13]([O:12][CH2:11][CH:9]1[CH:10]2[CH:8]1[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:6](=[O:28])[C:5]1[N:4]2[C:1](=[O:3])[CH:2]=[C:44]([OH:50])[C:45]=1[OH:46])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C2C(COCc3ccccc3)C21
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1c2c(O)c(O)cc(=O)n2C2C(COCc3ccccc3)C2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 5-acetyl-2-(4-fluorobenzyl)-7-[(benzyloxy)-methyl]-2,5-diazabicyclo[4.1.0]heptane-3-one (700 mg, 1.83 mmol) in DMF (10 mL) under nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (1.0 M, 2.0 mL, 2.0 mmol) was added. After 30 min, diethyl oxalate (401 mg, 2.74 mmol) in DMF (2 mL) was added. After stirring for 1 h at room temperature, the resultant mixture was treated with additional lithium bis(trimethylsilyl)amide (1.0 M, 7.1 mL, 7.1 mmol), and stirred at room temperature overnight. The reaction mixture was treated with 1 N HCl, concentrated under vacuum. The residue was partitioned between brine and chloroform. The aqueous layer was extracted with chloroform twice. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [OH-].[Na+].C(O)C.[CH2:6]([O:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([O:27]CC)=[O:26])[C:19]=3[N:18]=[C:17]2[CH3:30])=[C:13]([Cl:33])[CH:12]=1)[CH2:7][CH2:8][CH3:9].Cl>O>[CH2:6]([O:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][N:16]2[C:20]3[CH:19]=[C:24]([C:25]([OH:27])=[O:26])[CH:23]=[CH:22][C:21]=3[N:18]=[C:17]2[CH3:30])=[C:13]([Cl:33])[CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOc1ccc(Cn2c(C)nc3c(C(=O)OCC)cccc32)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc(Cn2c(C)nc3ccc(C(=O)O)cc32)c(Cl)c1
Reaction time: 4 h
Yield: 72.8 %

Procedure:
Sodium hydroxide (0.17 g), ethanol (8 ml), and water (4 ml) were added to 1-(4-butyloxy2-chlorobenzyl)(ethoxycarbonyl)-2-methylbenzimidazole (0.62 g) and the whole was s d for 4 hours at 80° C. The pH was adjusted to about 5 with 35% hydrochloric acid. Deposited crystals were filtered and dried to obtain crystals (0.42 g) of 1-(4-butyloxy-2-chlorobenzyl)-6-carboxy-2-methyl-benzimidazole. [Physicochemical properties of the compound]
Reaction SMILES: [CH:1]([C:4]1[S:5][C:6]([C:9]2([OH:19])[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:7][N:8]=1)([CH3:3])[CH3:2].Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[OH:19][C:9]1([C:6]2[S:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:8][CH:7]=2)[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: CC(C)c1ncc(C2(O)CCC3(CC2)OCCO3)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1ncc(C2(O)CCC(=O)CC2)s1
Yield: 107.8 %

Procedure:
A solution of 8-(2-isopropyl-1,3-thiazol-5-yl)-1,4-dioxaspiro[4.5]decan-8-ol (0.714 g, 2.52 mmol) in 15 mL of THF/N HCl (1:1) was stirred overnight at room temperature. The mixture was treated with Na2CO3 to PH 8 and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated to give 0.65 g of 4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanone in 98% yield. MS (EI) calcd: (M+H)+=240.1; found: 240.0.
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:47])([F:46])[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH2:45])[CH:41]=[CH:40][N:39]=2)=[CH:34][CH:33]=1>C1COCC1>[CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([NH:45][CH2:44][C:42]1[CH:41]=[CH:40][N:39]=[C:38]([C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:47])([F:30])[F:46])=[CH:33][CH:34]=2)[CH:43]=1)=[O:7])[CH3:2]
Reactant: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1cccc(F)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
Acid 4F (330 mg, 1.2 mmol) was dissolved in 15 ml of THF and at rt DEPC (1.3 equiv, 0.23 mL) and [2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 mol equiv., 335 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 mL) and washed with water (1×20 mL) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (EtOAc 1/petroleum ether 1) afforded 100 mg of a white solid. Yield=20% 1HNMR (DMSO, 200 MHz) δ 1.09 (3H, t, J=7.2 Hz), 3.44 (2H, q, J=6.8 Hz), 4.50 (2H, d, J=6 Hz), 5.21 (1H, s), 6.14 (1H, s), 7.34 (1H, dd, J=4.8), 7.65 (m, 4H), 7.81 (d, 2H, J=7.9), 8.01 (s, 1H), 8.31 (d, 2H, J=7.8), 8.65 (d, 1H, J=5.8), 8.92 (t, 1H). [M+1] 507.62 (C24H21F4N3O3S requires 507.50).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(Cl)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-chloro-phenylboronic acid to give [1-(4-Chloro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 351(MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1)#[N:2].[Br-].[Br-].[Br-].[Al+3].[Cl:19][C:20]([Cl:24])([Cl:23])[C:21]#[N:22]>>[Cl:19][C:20]([Cl:24])([Cl:23])[C:21]1[N:22]=[C:21]([C:20]([Cl:24])([Cl:23])[Cl:19])[N:22]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[N:2]=1
Reactant: N#Cc1ccc(SCCC(=O)O)cc1
Reactant: N#CC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Br-]
Product: O=C(O)CCSc1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1

Procedure:
A solution containing 22 g of 3-(4-cyanophenylthio) propionic acid (106 mmol) and 2 g of aluminum tribromide (AlBr3) in 150 g of trichloroacetonitrile was dried at room temperature and bubbled with HCl. The solution was heated with a heat-gun in order to dissolve the starting materials remaining undissolved. The process of reaction was checked by TLC. The reaction product was formed gradually with the lapse of time. Then, the reaction was quenched after 24 hours and the reaction mixture was extracted with 1000 mL of diethyl ether. The resultant product was washed with deionized water and dried over anhydrous magnesium sulfate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[C:4]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][C:16]([Cl:22])=[N:15]3)=[O:11])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26].N1C=CC=CC=1>C(Cl)Cl>[Cl:22][C:16]1[CH:17]=[N:18][C:19]2[C:14]([N:15]=1)=[CH:13][C:12]([C:10]([C:4]1[C:3]([F:23])=[C:2]([NH:1][S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[CH:7]=[C:6]([F:8])[C:5]=1[F:9])=[O:11])=[CH:21][CH:20]=2
Reactant: Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Yield: 15.1 %

Procedure:
To a solution of (3-amino-2,5,6-trifluorophenyl)(3-chloroquinoxalin-6-yl)methanone (40 mg, 0.119 mmol, 1.0 eq.) in DCM (5 mL) was added propane-1-sulfonyl chloride (84.6 mg, 0.593 mmol, 5.0 eq.) and pyridine (94 mg, 1.19 mmol, 10.0 eq.). The mixture was heated under reflux overnight, then concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) and Prep-TLC to afford N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)propane-1-sulfonamide (8 mg, 15.2%). LRMS (M−H−) m/z calculated 442.0, found 442.0. 1H NMR (CDCl3, 400 MHz) δ 8.91 (s, 1 H), 8.27-8.41 (m, 3 H), 7.71-7.77 (m, 1 H), 6.63 (s, 1 H), 3.13-3.17 (t, 2 H), 1.86-1.94 (q, 2 H), 1.07-1.11 (t, 3 H).