Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N+:3]=1[O-:9].[N+:10]([O-])([OH:12])=[O:11].N>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([Br:8])[N+:3]=1[O-:9]
Reactant: [O-][n+]1c(Br)cccc1Br
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)[n+]([O-])c(Br)c1
Temperature: 62.5 °C
Reaction time: 0.21 h
Yield: 83 %

Procedure:
A solution of 2,6-dibromopyridine 1-oxide (34.0 g, 0.13 mol) in sulfuric acid (120 mL) was cooled to 0-5° C. followed by addition of nitric acid (60 mL). The reaction mixture was stirred at the same temperature for 10-15 min then heated to 60-65° C. for 20 h. The reaction was then cooled to rt, poured into ice-cold water and neutralized with aqueous ammonia solution. The resulting solution was stirred for 10 min at 0-5° C. then filtered and dried to obtain the desired product as a pale yellow solid (32 g, 83%).
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.Br[C:21]1[CH:22]=[CH:23][C:24]2[C:25]3[CH2:32][CH2:31][CH2:30][C:26]=3[NH:27][C:28]=2[CH:29]=1.[CH:33]([Si:36]([S:43][Si](C(C)C)(C(C)C)C(C)C)([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])([CH3:35])[CH3:34].[K]>O1CCCC1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[CH:40]([Si:36]([CH:33]([CH3:35])[CH3:34])([CH:37]([CH3:39])[CH3:38])[S:43][C:21]1[CH:22]=[CH:23][C:24]2[C:25]3[CH2:32][CH2:31][CH2:30][C:26]=3[NH:27][C:28]=2[CH:29]=1)([CH3:42])[CH3:41]
Reactant: CC(C)[Si](S[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Reactant: Brc1ccc2c3c([nH]c2c1)CCC3
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[Si](Sc1ccc2c3c([nH]c2c1)CCC3)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
Palladium dibenzylidene-acetone (0.155 g, 5 mol %) and tricyclohexylphosphine (0.19 g, 20 mol %), were weighed out into a flask pre-flushed with argon, and subsequently flushed with argon for 5 min before dissolution in toluene (20 mL). The deep red mixture was stirred at room temperature for 5 minutes under argon, then 6-bromo-1,2,3,4-tetrahydrocyclopent[b]indole (0.8 g, 3.4 mmol) was added in one portion. After a further 5 min a solution of potassium (triisopropylsilyl)sulfide (Tetrahedron Letts., 1994, 35(20), 3221-3224 and 3225-6)) in tetrahydrofuran (6 mL) was added via syringe over 4 min The mixture was stirred for 45 min at room temperature, heated at 80° C. (bath temp) for 70 min then cooled to room temperature over 16 h. The mixture was partitioned between toluene (40 mL) and water (60 mL). The separated aqueous layer was extracted with toluene (30 mL) and the combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography [SiO2; heptane-ethyl acetate (98:2) to (96:4)] to yield 1,2,3,4-tetrahydro-6-(triisopropylsilyl)thio cyclopent[b]indole as a pale yellow solid (0.85 g, 73%); NMR (400 MHz, CDCl3) δH 7.76 (1H, br s, NH), 7.43 (1H, d, J 1.5 Hz), 7.27-7.25 (1H, m), 7.18 (1H, dd, J 8.2, 1.5 Hz), 2.85 (2H, obs dt, J 6.9, 1.6 Hz), 2.79 (2H, obs t, J 7.0 Hz), 2.52 (2H, obs quint, J 7.0 Hz), 1.29-1.19 (3H, m), 1.08 (18H, d, J 7.0 Hz); HPLC: [Supelcosil ABZ+; 1.0 ml/min, methanol-10 mM aqueous ammonium acetate solution, (90:10)] 99% (11.1 min).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]#[N:9])[CH:4]=[CH:3]1.[CH2:10]([O:12][C:13](=[O:23])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]O)[CH:16]=1)[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:10]([O:12][C:13](=[O:23])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:7]2[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6]2)[CH:16]=1)[CH3:11]
Reactant: CCOC(=O)Nc1cccc(CO)c1
Reactant: N#Cc1ccc(=O)[nH]n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc(Cn2nc(C#N)ccc2=O)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under a nitrogen atmosphere, 1 g (8.3 mmol) of 6-oxo-1,6-dihydropyridazine-3-carbonitrile (prepared in accordance with WO 2002/079200) is suspended in 50 ml of THF, and 2.4 g (12.4 mmol) of ethyl(3-hydroxymethylphenyl)carbamate and 5 g (12.4 mmol) of triphenyphosphine are added. 1.95 ml (12.4 mmol) of diethyl azodicarboxylate is added dropwise to this suspension at 2-10° C. with ice-cooling. The suspension is stirred at room temperature for 15 h. The suspension is filtered, and the filter residue is washed with dichloromethane, the filtrate is evaporated to dryness, taken up in ethyl acetate, and the organic phase is extracted with 1N HCl and saturated sodium hydrogencarbonate solution. The organic phase is subsequently dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[CH:13][N:12]3[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1)=O.C(N(CC)CC)C.Cl.Cl.[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[NH:46][N:45]=[C:44]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[N:43]=2)=[N:40][CH:41]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)(Cl)Cl>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[NH:46][N:45]=[C:44]([CH:47]3[CH2:52][CH2:51][N:50]([CH2:1][C:3]4[CH:8]=[CH:7][C:6]([C:9]5[N:10]=[C:11]6[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[CH:13][N:12]6[C:19]=5[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:5][CH:4]=4)[CH2:49][CH2:48]3)[N:43]=2)=[N:40][CH:41]=1
Reactant: N#Cc1cccn2c(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12
Reactant: Clc1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1cccn2c(-c3ccccc3)c(-c3ccc(CN4CCC(c5n[nH]c(-c6ccc(Cl)cn6)n5)CC4)cc3)nc12
Reaction time: 0.08 h

Procedure:
To a solution of 0.230 g (0.712 mM) of 2-(4-formylphenyl)-3-phenylimidazo[1,2-a]pyridine-8-carbonitrile in 5 mL of THF is added triethylamine (2 eq). The reaction mixture is stirred for 5 minutes. To this solution is added 5-chloro-2-[3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl]pyridine dihydrochloride (Intermediate E) (1.5 eq) followed by acetic acid (2.5 eq). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH(OAc)3 (6 eq) over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained is taken up in chloroform and washed with water, dried and concentrated. The crude is purified on a flash column chromatography to obtain the desired compound.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[S:9][C:5]=2[CH:4]=1>Br.C(O)(=O)C>[OH:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(C)sc2c1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc2ccc(O)cc2s1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of 6-methoxy-2-methyl-benzothiazole (2.5 gm, 0.014 mol) in 30% HBr in acetic acid (15 mL) was stirred for 2 days at 70° C. After cooling, the solid was filtered, washed with ether, and dried in vacuo. The solid was taken up in water (20 mL) and neutralized with saturated NaHCO3 solution. The resulting solid was filtered, washed with water, and dried in vacuo at 40° C.; yield 1.2 gm.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.[CH3:10][Sn:11](Cl)([CH3:13])[CH3:12].[Cl-].[NH4+].O>O1CCCC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Sn:11]([CH3:13])([CH3:12])[CH3:10])=[CH:3][CH:2]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: C[Sn](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc([Sn](C)(C)C)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
p-Tolylmagnesium bromide solution (Aldrich) (1.0M solution in diethyl ether) (53 ml, 0.0530 mol) was added dropwise to trimethyltin chloride (6.92 g, 0.0347 mol) in tetrahydrofuran (50 ml) under nitrogen at -10° C. The suspension was allowed to warm slowly to room temperature over 3 hours; then saturated ammonium chloride solution (10 ml) was added, followed by sufficient water to dissolve the precipitate. The solution was extracted three times with diethyl ether-hexane (1:1). The combined organic phase was washed with brine, dried (magnesium sulfate) and the solvents removed in vacuo. Vacuum distillation of the residue afforded a colorless liquid (bp 39°-40° C., 0.1 mm Hg) which was further purified by flash chromatography (silica gel, hexane) to give p-tolyltrimethyltin (7.30 g, 82%) as a colorless liquid; 1H NMR (300 MHz, CDCl3) δ7.40 (d, J=7.7 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 2.34 (s, 3H), 0.30 (s, 9H).
Reaction SMILES: [C:1]([C:4]1([CH2:14][S:15][C:16](=[O:18])[CH3:17])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=O.CN1CCOCC1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:37]([O:44][C:45](=[O:50])[CH:46]([OH:49])[CH2:47][NH2:48])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:16]([S:15][CH2:14][C:4]1([C:1]([NH:48][CH2:47][CH:46]([C:45]([O:44][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:50])[OH:49])=[O:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:18])[CH3:17]
Reactant: CC(=O)SCC1(C(=O)O)CCc2ccccc2C1
Reactant: NCC(O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)SCC1(C(=O)NCC(O)C(=O)OCc2ccccc2)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 2-carboxy-2-[(acetylthio)methyl]-1,2,3,4-tetrahydronaphthalene (2.88 g, 10.0 mmol) in dry dimethylformamide (20 mL). To this solution add N-methyl morpholine (1.01 g, 10.0 mmol), isoserine benzyl ester tosylate salt (3.67 g, 10.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g, 10.0 mmol). Stir the reaction mixture for 18 hours under an atmosphere of argon at ambient temperature then partition between ethyl acetate and dilute HCl. Wash the organic solution with water, saturated sodium hydrogen carbonate then brine. Dry the solution (MgSO4) and concentrate in vacuo. Purify the residue by column chromatography (ethyl acetate:hexane) to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:22]([CH3:28])[CH2:23][N:24]([CH2:26][CH3:27])[CH3:25])[C:10]=2[CH:9]=1)=S.[ClH:30].C(O)(=O)/C=C/C(O)=[O:35]>C(O)C.C(OC(C)C)(C)C>[ClH:30].[CH3:1][CH:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:22]([CH3:28])[CH2:23][N:24]([CH2:26][CH3:27])[CH3:25])[C:10]=2[CH:9]=1)=[O:35]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(=S)NCCC(C)C)cc21
Agent: Cl
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(=O)NCCC(C)C)cc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
N-(3-Methylbutyl)-10-[(2RS)-1-(N-ethyl-N-methyl-amino)-2-propyl]-2-phenothiazinecarbothioamide (0.3 g) is dissolved in a solution of fumaric acid (81 mg) in absolute ethanol (5 cc) and the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange product of meringue-like consistency is dissolved in acetic acid (5 cc) and mercuric acetate (0.23 g) is added. The orange suspension obtained is stirred for 16 hours at a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 60° C. The residue is taken up with distilled water (10 cc) and filtered and the filtrate is alkalinized with caustic soda (d=1.33) to pH 13 and extracted with ethyl acetate (2×10 cc). The combined organic phases are washed with saturated aqueous sodium chloride solution (10 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (0.15 g) is dissolved in ethyl acetate (2 cc), and isopropyl ether (20 cc) is added. The solution obtained is cooled to a temperature in the region of 5° C. and a solution (5.1 cc) of 0.065N hydrochloric acid in isopropyl ether is added dropwise and with stirring. The precipitate formed is drained, washed with isopropyl ether (3×5 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-(3-Methylbutyl)-10-[(2RS)-1-(N-ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarboxamide hydrochloride (0.13 g) is thereby obtained in the form of an off-white solid, m.p. 110-120° C. (melts forming a paste).
Reaction SMILES: [C:1]([CH:6]([CH2:12][C:13]#[CH:14])[C:7](OCC)=[O:8])(OCC)=[O:2].C(=O)(O)O.[NH2:19][C:20]([NH2:22])=[NH:21]>C(O)C>[NH2:21][C:20]1[NH:22][C:1](=[O:2])[C:6]([CH2:12][C:13]#[CH:14])=[C:7]([OH:8])[N:19]=1
Reactant: N=C(N)N
Reactant: C#CCC(C(=O)OCC)C(=O)OCC
Agent: O=C(O)O
Solvent: CCO
Product: C#CCc1c(O)nc(N)[nH]c1=O

Procedure:
A mixture of 5.0 g ethyl 2-carboethoxy-4-pentynoate [J. Org. Chem. 40, 851 (1975)] and 2.5 g of guanidine carbonate was heated to reflux in 50 ml of absolute ethanol for 24 hours. The suspension was then cooled to 20° and the solid product was collected. This was subsequently dissolved in 30 ml of water and acidified to pH 3 with 1N hydrochloric acid whereupon a thick precipitate formed. The mixture was warmed briefly to produce a filterable suspension which was then cooled, filtered and rinsed with water, then acetone. The yield of 2-amino-6-hydroxy-5-(2-propynyl)-4(3H)-pyrimidinone was 1.3 g (32%) as a slightly pink powder, m.p. 292°-293° dec. An NMR spectrum (60 MHz) in trifluoroacetic acid solution exhibited absorptions at 2.2 (1H), and 3.6 (2H) indicating the title compound.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@H]([C@@H]([C@@H](CO)O)O)O.O=C[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
Recovery of carbohydrate and non-carbohydrate products from wheat straw was not greatly affected by scale of the reaction column (FIGS. 12(A), 12(B)). No differences were observed in the recovery of glucose or of the minor hemicellulose carbohydrates galactose, arabinose, and mannose for all column scales (FIG. 12(A)). The pilot-scale apparatus produced approximately 26 g more xylose per kilogram of dry straw than did the scale-up unit (FIG. 12(A)). However, the solid residues from both scales yielded equal amounts of residual xylan. The scale-up column came up to operating temperature much faster than the pilot-scale column, so the difference in xylose production was probably due to the creation of furfural from the higher temperature during the initial stages of hydrothermal treatment. The production of xylose from the bench-scale apparatus was 30 g/kg of dry straw less than the scale-up, and 56 g/kg of dry straw less than the pilot-scale apparatus, with an overall yield of 39% in the liquid fraction. The residual xylan in the solid residue was over three times greater than the other scale reaction columns, and 40% of the potential xylan remained. Hence, the difference was mostly due to incomplete hydrolysis due to insufficient residence time.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:23].[CH3:24][O:25][CH2:26][CH:27]1[CH2:32][NH:31][CH2:30][CH2:29][NH:28]1>N1C=CC=CC=1>[F:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:31]1[CH2:30][CH2:29][NH:28][CH:27]([CH2:26][O:25][CH3:24])[CH2:32]1)[N:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:8]=[C:7]([C:19]([OH:21])=[O:20])[C:6]2=[O:22]
Reactant: COCC1CNCCN1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: COCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)CCN1

Procedure:
A 906 mg portion of 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1.4 g of 2-(methoxymethyl)piperazine were added to 10 ml of pyridine and reacted as described in Example 81, giving 187 mg of the desired product, mp 216°-218° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[CH2:29][OH:30].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[CH2:29][OH:30]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Br)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4Br)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 16 (0.36 g, 0.76 mmol) and dry pyridine hydrochloride (3.6 g, 31.6 mmol) was heated at 180° C. for 1.5 h. The reaction mixture was cooled to room temperature, treated with water (50 mL) and basified using an aqueous saturated Na2CO3 solution. It was extracted using CHCl3 (3×100 mL). The organic extract was washed with water, dried (anhydrous Na2SO4) and concentrated. Traces of pyridine were removed using high vacuum. Purification was carried out using a silica gel column and a mixture of 5% methanol+1% liquor ammonia in CHCl3 as eluant to obtain title compound.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH2:8][S:9][CH3:10])[C:5]([OH:7])=[O:6].I[CH3:12]>CN(C=O)C>[CH3:12][O:3][CH:4]([CH2:8][S:9][CH3:10])[C:5]([OH:7])=[O:6]
Reactant: CI
Reactant: CSCC(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(CSC)C(=O)O
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
To a stirred solution of sodium hydride (0.176 g, 4.41 mmol) in DMF (5 mL) was added a solution of 2-hydroxy-3-(methylthio)propanoic acid (0.25 g, 1.836 mmol) in 1 mL DMF at 25° C. and stirred for 10 min Vigorous bubbling was observed upon addition of NaH. Then iodomethane (0.126 mL, 2.020 mmol) was added and the solution was stirred at 25° C. overnight. The reaction was quenched by addition of 2 N HCl, extracted with 3×10 mL of EtOAc, the combined organic layers were washed with water (2×20 mL), concentrated and purified by column chromatography, eluted with 0-100% EtOAc/hexane, gave 2-methoxy-3-(methylthio)propanoic acid (126 mg, 0.839 mmol, 45.7% yield) as colorless oil: 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 4.03 (dd, J=6.9, 4.4 Hz, 1H), 3.51 (s, 3H), 2.98-2.93 (m, 1H), 2.86 (dd, J=14.1, 6.9 Hz, 1H), 2.21 (s, 3H); EIMS m/z 150.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])[CH3:13]>>[CH:12]([C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:17][CH:16]=1)([CH3:14])[CH3:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-isopropylaniline to yield 2-[(4-isopropylphenyl)amino]phenylacetic acid.
Reaction SMILES: [F:1][C:2]1[C:22]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.O>C(O)(=O)C.Cl>[F:1][C:2]1[C:22]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Temperature: 110 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
A suspension of 10.5 g of ethyl 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate in 100 cm3 of acetic acid and 100 cm3 of 17.5% aqueous hydrochloric acid solution was heated, with stirring, at a temperature around 110° C. for approximately 4 hours. After cooling to approximately 20° C., 25 cm3 of water were added to the reaction mixture. The insoluble material was filtered off and washed 3 times with 200 cm3 of water and 2 times with 100 cm3 of ethanol. 9.3 g of 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at approximately 320° C., which solid was used without additional purification in the subsequent stages.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:23](=[O:28])[C:24]([O:26][CH3:27])=[O:25].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23](=[O:28])[C:24]([O:26][CH3:27])=[O:25])[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: COC(=O)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[C@@H]1CN(C(=O)C(=O)OC)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (200 mg, 0.593 mmol) was suspended in dichloromethane (5 mL). Methyl chloroglyoxylate (0.070 mL, 0.76 mmol), triethylamine (0.250 mL, 1.80 mmol) and DMAP (catalytic amount) were added under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=7/3→1/0) to obtain 208.1 mg of the title compound as a colorless oily substance (91%).
Reaction SMILES: [F:1][CH:2]=[C:3]([F:5])[F:4].[CH:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([OH:13])[CH:7]=1.[OH-].[K+]>CN(C=O)C>[F:4][C:3]([F:5])([O:13][C:8]1[CH:9]=[CH:10][C:11]([NH2:12])=[CH:6][CH:7]=1)[CH2:2][F:1]
Reactant: FC=C(F)F
Reactant: Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ccc(OC(F)(F)CF)cc1
Temperature: 0 °C
Yield: 25 %

Procedure:
Gaseous trifluoroethylene was bubbled into a mixture of 7.0 g (64.1 mmol) of p-aminophenol, 0.7 g (12.8 mmol) of powdered KOH, and 70 ml dry DMF at 90° C. for 11/4 hours. The mixture was poured into ice water and extracted 2 times with ether. The combined ether layers were washed with diluted aqueous NaOH, washed with water, dried over MgSO4 and filtered. HCl was bubbled into the ether solution. The resulting gray solid was collected by filtration to give 3.6 g (25 percent of theoretical) of the above-named aniline as the HCl salt along with a 20 percent impurity of 4-(1,2-difluoroethenyloxy)benzene-amine.