Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:4]=1[C:32](OCC)=[O:33].[CH:37]1([NH2:40])[CH2:39][CH2:38]1.C(#N)C.O>C(#N)C.C(O)(C(F)(F)F)=O.C1COCC1>[CH:37]1([N:40]2[C:32](=[O:33])[C:4]3[CH:5]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=4[S:28]([CH3:31])(=[O:29])=[O:30])[NH:6][C:7](=[O:19])[N:8]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=4)[C:3]=3[CH2:2]2)[CH2:39][CH2:38]1
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O
Reactant: NC1CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)N(C1CC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(rac)-Ethyl 6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (200 mg, 0.34 mmol; Example 13A) was dissolved in acetonitrile (5 ml), cyclopropylamine (58.4 mg, 1.02 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was then purified directly by preparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm, 100 Å; mobile phase A: water with 0.01% formic acid, mobile phase B acetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B→12 min 90% B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254 nm). The product-containing fractions were combined and once more subjected to HPLC separation [column: Sunfire C-18, 5 μm, 19 mm×150 mm; sample preparation: the sample was dissolved in 2 ml of acetonitrile+2 ml of 1% strength aqueous TFA solution+1 ml of THF; injection volume: 1000 μl; mobile phase: acetonitrile/water/1% aq. TFA 35:52:13 (0-10 min); flow rate: 25 ml/min; temperature: 40° C.; detection: 210 nm]. This gave 38 mg (22% of theory) of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=3)[S:8][C:7]=2[CH:33]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[S:8][C:7]=2[CH:33]=1
Reactant: CCOCCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CCOCCOc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Yield: 726.8 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl][4-(ethoxyethoxy)phenyl]methanone (0.35 g, 0.76 mmol) was converted to 2.4 g of the title compound by the procedure of Example 3 using 0.28 mL (3.79 mmol) of ethanethiol and 0.61 g (4.6 mmol) of aluminum chloride.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:21]2[CH:3]=[CH:2][CH:24]=[C:23]([F:25])[CH:22]=2)[CH:24]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1cccc(F)c1
Yield: 135.2 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 3-fluorobenezeneboronic acid (26 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a white solid (35 mg, 68%). LC-MS m/e 425.28 (M+H+)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:20])[C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14](OC)=[O:15])=[C:11]([CH3:18])[C:10]=2[CH:19]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C[N+]1([O-])CCOCC1>O1CCCC1.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:20])[C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH:14]=[O:15])=[C:11]([CH3:18])[C:10]=2[CH:19]=1
Reactant: COCCN(C)c1ccc2oc(C(=O)OC)c(C)c2c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: C1CCOC1
Solvent: CC#N
Product: COCCN(C)c1ccc2oc(C=O)c(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.7 %

Procedure:
A solution (10 mL) of methyl 5-[(2-methoxyethyl)(methyl)amino]-3-methyl-1-benzofuran-2-carboxylate (2.7 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (40 mL) of lithium aluminum hydride (0.38 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (1.0 mL), 1N aqueous sodium hydroxide solution (5.0 mL) and water (1.0 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (0.41 g) of {5-[(2-methoxyethyl)(methyl)amino]-3-methyl-1-benzofuran-2-yl}methanol as a pale-yellow oil. The obtained oil was dissolved in acetonitrile (20 mL), tetrapropylammonium perruthenate (0.07 g) and N-methylmorpholine N-oxide (0.46 g) were added to the solution at room temperature, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.09 g, 3%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([N:19]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[NH:25][CH3:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:27]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@H:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[N:25]([CH3:26])[C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN[C@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1

Procedure:
A solution of 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 198 mg, 1.087 mmol), (1S,2S)-1-N,1-N-dibenzyl-2-N-methylcyclopentane-1,2-diamine (291 mg, 0.988 mmol) and DIPEA (518 μl, 2.97 mmol) in DMSO (3.3 ml) was subjected to microwave irradiation at 140° C. for 4 hours. The reaction was diluted with ethyl acetate (20 ml), washed with a saturated solution of sodium bicarbonate (3×20 ml), brine (20 ml), filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (silica, 0-15% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][C:3]=1[N+:11]([O-])=O>CO>[NH2:11][C:3]1[CH:4]=[C:5]([S:7]([NH2:10])(=[O:8])=[O:9])[S:6][C:2]=1[Cl:1]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Solvent: CO
Product: Nc1cc(S(N)(=O)=O)sc1Cl

Procedure:
Hydrogenation of a stirred solution of 5-chloro-4-nitro-thiophene-2-sulfonamide [CAS-No. 61714-46-3; commercially available] (1.13 g, 4.66 mmol) in methanol (140 ml) on Raney-Nickel (1.13 g) for 3 h at room temperature yielded after removal of the catalyst by filtration, evaporation and column chromatography on silica gel (ethyl acetate/hexane) the title compound as a light brown solid. MS (ISP) 211.0 [(M−H)−], mp 138° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ncccc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccnc2C)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (288 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine as a colorless oil (yield 220 mg, 97%). A solution of the obtained 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine in ethyl acetate (3 mL) was added dropwise to a solution of fumaric acid (67 mg) in ethanol (3 mL) and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a white solid (yield 253 mg, 88%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: COC(=O)CCCC#CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCC#CCN1C(=O)c2ccccc2C1=O
Yield: 44.1 %

Procedure:
A mixture or potassium phthalimide (2.31 g) and methyl 7-bromohept-5-ynoate (3.0 g) in dimethylformamide (35 ml) was heated at 110° C. for 4.5 hours. The cooled solution was poured into water (75 ml) and the pH of the solution was adjusted to 6. The resulting solution was extracted with ether (4×200 ml) and the combined ether extracts were dried over magnesium sulphate, the solvent was removed and the residue was chromatographed on silica gel eluted with chloroform to give the title compound (1.56 g) m.p. 62°-63° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10](O)[N:9]=[CH:8]2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:10]1[N:9]=[CH:8][C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2cnc(O)nc12
Product: COc1cccc2cnc(Cl)nc12
Temperature: 142.5 °C
Reaction time: 0.02 h
Yield: 89 %

Procedure:
Neat POCl3 (400 mL) was added to 8-methoxyquinazolin-2-ol (5.0 g, 28.4 mmole) with stirring and cooling over an ice bath under argon. After ca. 1 minute, the reaction was removed from the ice bath and stirred at RT for ca. 20 minutes until a fine yellow suspension was formed. The reaction, fitted with a reflux condenser, was heated in an oil bath at 140-145° C. After about 1 hour, the reaction turned clear and colorless. LCMS showed that the reaction was complete. The POCl3 was evaporated under reduced pressure, and dried in vacuo. After 12 hours, the residue was partitioned between EtOAc (300 mL) and sat. NaHCO3 (200 mL). The mixture was stirred cautiously watching gas evolution until the pH reached ˜8. The layers were separated and the organic layer was washed with NaHCO3 (2×100 mL), water with 5% brine (2×100 mL), brine (100 mL), dried (Na2SO4), filtered and evaporated to a yellow solid. The crude product was purified by flash chromatography eluting with 50% EtOAc/Hexane and finishing with 100% EtOAc to produce a white solid after evaporating the correct fractions. The pure 2-chloro-8-methoxyquinazoline was isolated in 89% yield (4.9 g, 25.3 mmole).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8](Cl)[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:29][OH:30])[CH:20]=[N:21][C:22]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[C:10]2[NH:9][C:8]([N:26]3[CH2:27][CH2:28][N:23]([C:22]4[N:21]=[CH:20][C:19]([CH2:29][OH:30])=[CH:18][C:17]=4[Cl:16])[CH2:24][CH2:25]3)=[N:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: OCc1cnc(N2CCNCC2)c(Cl)c1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Product: OCc1cnc(N2CCN(c3nc4cc(C(F)(F)F)cc(Br)c4[nH]3)CC2)c(Cl)c1

Procedure:
4-Bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (180 mg, 0.6 mmol, Example 6b) reacted with (5-chloro-6-piperazin-1-yl-pyridin-3-yl)methanol (228 mg, 1 mmol, Example 60a) under. the conditions of Example 3c to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 490 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH:36]1(Br)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: BrC1CCCCC1
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: COc1ccc(CC2c3c(OC4CCCCC4)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with cyclohexyl bromide
Reaction SMILES: [H-].[Na+].Cl.[CH2:4]([O:8][NH2:9])[CH:5]=[CH:6][CH3:7].[C:10]([CH:13]1[C:18](=[O:19])[CH2:17][CH:16]([CH2:20][CH2:21][S:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:15][C:14]1=[O:33])(=O)[CH3:11].Cl>CN(C)C=O.O>[CH2:4]([O:8][NH:9][C:10](=[C:13]1[C:18](=[O:19])[CH2:17][CH:16]([CH2:20][CH2:21][S:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=2)[CH2:15][C:14]1=[O:33])[CH3:11])[CH:5]=[CH:6][CH3:7]
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Reactant: CC=CCON
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC=CCONC(C)=C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To the suspension of 0.3 g of sodium hydride (60% oil dispersion) in 10 ml of dimethylformamide, 0.09 g of 2-butenyloxyamine hydrochloride was added under cooling with ice-water bath and then stirred. After 30 minutes, 0.21 g of 2-acetyl-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione was added to the resulting solution which was then stirred for 7 hours under cooling with ice-water bath. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with ether. After removing ether, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.22 g of 2-[1-(2-butenyloxyamino)ethylidene]5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:3]=1[CH:4](O)[C:5]([OH:7])=[O:6].Cl>C(O)(=O)C>[CH3:1][C:2]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:3]=1[CH2:4][C:5]([OH:7])=[O:6]
Reactant: Cc1cc(C)c(C(O)C(=O)O)cc1C
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(C)c(CC(=O)O)cc1C
Temperature: 100 °C
Yield: 100.5 %

Procedure:
A mixture of 69.9 g of 2,4,5-trimethylmandelic acid, 38.3 g of 36% hydrochloric acid, 11.2 g of red phosphorus and 6 g of KI in 270 ml of glacial acetic acid is heated to 100° C. for 16 hours. Subsequently, the mixture is diluted at room temperature with 150 ml of glacial acetic acid. The excess of phosphorus is filtered off with suction and washed three times with 50 ml of glacial acetic acid. The filtrate is admixed with 150 ml of water and the acetic acid is substantially removed by rotary evaporation at bath temperature 50° C. 60 mbar. The remaining suspension is adjusted to pH 1 using 5 ml of 20% sulfuric acid and the solid is filtered off with suction. The solid is washed three times with 180 ml of water each time, and this water becomes the first filtrate. This causes solid to precipitate out once again, which is filtered off with suction through the already existing filtercake. The filtercake is washed once more with 100 ml of water and dried to constant weight. This results in 64.46 g of white solid which, by GC, contains 95.8% of target product=61.7 g=96.2% of theory.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:15])=[CH:6][CH:5]=1)#[N:3].[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:23]=[CH:22]2.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O>[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:17][CH:16]=3)[C:10](=[O:15])[CH2:11]1)(=[O:31])=[O:30])[CH:23]=[CH:22]2
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: N#Cc1ccc(CN2CCNCC2=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A mixture of 1-(4-cyanobenzyl)-2-piperazinone hydrochloride (201 mg), 6-chloronaphthalene-2-sulfonyl chloride (205 mg), sodium carbonate (254 mg), ethyl acetate (10 ml) and water (5 ml) was stirred at room temperature for 2 hours. The organic layer was separated, washed with saturated brine, dried (MgSO4) and concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give pale pink crystals of the title compound (239 mg).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16](OCC)=[O:17])[C:11]2=[O:15])[CH:7]([CH3:21])[CH2:6][CH2:5][C:4]=3[CH:3]=1.[NH2:22][NH2:23]>CO>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([NH:22][NH2:23])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:21])[CH2:6][CH2:5][C:4]=3[CH:3]=1
Reactant: CCOC(=O)c1cn2c3c(cc(F)cc3c1=O)CCC2C
Reactant: NN
Solvent: CO
Product: CC1CCc2cc(F)cc3c(=O)c(C(=O)NN)cn1c23
Temperature: 25 °C

Procedure:
Ethyl 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo-[ij]quinolizine-2-carboxylate (10 g., 0.0347 mole) is dissolved in methanol (200 ml.) containing 25 ml. of 97 percent hydrazine. The mixture is warmed to accelerate solution. The solution is stirred at room temperature, and solid begins to separate immediately. The solid is separated by filtration, washed with methanol and recrystallized from aqueous ethanol to provide 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrazide, m.p. 236°-238° C.
Reaction SMILES: B([C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:5]=1[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(O)O.FC(F)(F)S(O[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=1[F:33])(=O)=O>>[Cl:16][C:14]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=2[F:33])[CH:15]=1
Reactant: CS(=O)(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Reactant: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O
Product: C[C@H](Oc1ccc(Cl)cc1-c1ccc(S(C)(=O)=O)cc1F)C(=O)O

Procedure:
The title compound was prepared by the method of example 155 using the product from example 151 step (iv) and the product from example 149 step (i).
Reaction SMILES: [CH2:1]([CH:3]([CH2:25][CH3:26])[CH:4]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].Cl.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH2:25]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([NH:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:35])=[O:22])=[CH:23][CH:24]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:26]
Reactant: CCOC(=O)CCN
Reactant: CCC(CC)C(Nc1ccc(C(=O)O)cc1)c1sc2ccccc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ccccc3c2C)C(CC)CC)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a mixture of 4-{[2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl]amino}benzoic acid (250 mg) synthesized above, β-alanine ethyl ester hydrochloride (157 mg), 1-hydroxybenzotriazole monohydrate (156 mg), triethylamine (284 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (196 mg), and the mixture was stirred at room temperature for 2.5 days. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (330 mg, quantitative) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([N:17]3[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]3)=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:24](=[O:27])([O-])[O-:25].[K+].[K+]>CN(C=O)C.CO.O>[C:3]([O:25][C:24](=[O:27])[NH:23][CH:20]1[CH2:19][CH2:18][N:17]([C:11]2[CH:12]=[C:13]([O:14][CH2:15][CH3:16])[C:3]3[C:2]([NH2:1])=[C:6]([C:7](=[O:8])[NH2:9])[S:5][C:4]=3[CH:10]=2)[CH2:22][CH2:21]1)([CH3:13])([CH3:4])[CH3:2]
Reactant: CCOc1cc(N2CCC(N)CC2)cc2sc(C(N)=O)c(N)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc2sc(C(N)=O)c(N)c12
Temperature: 80 °C
Yield: 50 %

Procedure:
To a solution of 0.311 g (0.856 mmol) of the above amide in DMF (5 mL) was added 0.91 mL (1.0 mmol) of a 10% solution of 2-thioacetamide in MeOH along with 0.70 g (5.1 mmol) of potassium carbonate. The mixture was heated to 80° C. for 24 h then cooled to room temperature and diluted with H2O. The mixture was washed with CH2Cl2 and the combined organic phase was washed with H2O, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.093 g (25%) of [1-(3-amino-2-carbamoyl-4-ethoxy-benzo[b]thiophen-6-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a white powder.