Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: BrC1CCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)C(c1cccc(Cl)c1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
A solution of diisopropylamine (1.80 mL, 12.9 mmol) in dry tetrahydrofuran (6 mL) under nitrogen was cooled to −78° C. and treated dropwise with a solution of n-butyllithium (2.4 M in hexanes, 5.4 mL, 12.9 mmol). The resulting solution was warmed to 0° C. and stirred for 15 min. The solution was re-cooled to −78° C. and treated, via cannula, with a solution of 3-chlorophenylacetic acid (1.0 g, 5.9 mmol) in tetrahydrofuran (6 mL). The reaction was then allowed to warm to 25° C. where it was stirred for 45 minutes and was then re-cooled to −78° C. Cyclopentyl bromide (0.76 mL, 7.1 mmol) was then added via syringe, and the resulting mixture was stirred at −78° C. for 1 hour. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride, and the tetrahydrofuran was removed in vacuo. The resulting residue was dissolved in a 2N aqueous solution of sodium hydroxide (30 mL) and washed with ethyl acetate (1×15 mL). The aqueous layer was then acidified to pH=1 with the addition of a 2 N aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (3×15 mL), and the combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and the product was purified via Biotage Horizon (FLASH 25 M, silica, gradient from 0% EtOAc/hexane to 40% EtOAc/hexane) to yield 1.08 g (79%) (3-chlorophenyl)(cyclopentyl)acetic acid as a clear oil. HRMS: calcd for C13H15ClO2−H, 237.06823; found (ESI, [M−H]−), 237.0682
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[S:17][CH3:18])[C:10]([O:12]C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[S:17][CH3:18])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(SC)c(OC2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CSc1ccc(C(=O)O)cc1OC1CCCC1

Procedure:
A suspension of methyl 3-cyclopentyloxy-4-(methylthio)benzoate (0.8 g; that is prepared as described in Reference Example 54) in methanol (10 mL) and water (5 mL) is treated with potassium carbonate (0.48 g) and the mixture is heated at reflux for 7 hours. The mixture is concentrated, and the resulting residue is partitioned between diethyl ether (20 mL) and water (20 mL). The aqueous layer is separated, acidified to pH 1 by treatment with dilute hydrochloric acid (2N), and extracted with dichloromethane (2×25 mL). The combined organic extracts are dried and concentrated, to give 3-cyclopentyloxy-4-(methylthio)benzoic acid (0.7 g) in the form of a white solid m.p. 150-152° C.
Reaction SMILES: C1(C([O:14][C:15](=[O:41])[C@@H:16]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)C2C=CC=CC=2)C=CC=CC=1.[H][H]>C(O)(C)(C)C.C(O)C.[Pd]>[CH3:39][C:37]([CH3:40])([O:36][C:34]([NH:33][C@@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=1)[C:15]([OH:41])=[O:14])=[O:35])[CH3:38]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(c2ccccc2)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)(C)O
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 92.9 %

Procedure:
(S)-2-[[(1,1-Dimethylethoxy)carbonyl]amino]-3-[4-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]phenyl]propanoic acid diphenylmethyl ester (1.6 g, 2.8 mmol) and 10% Pd/C (300 mg) in t-butanol (20 mL) was blanketed with hydrogen (1 atm). To prevent the solvent from freezing, a warm water bath (40° C.) was used to heat the reaction mixture. Upon the consumption of 2 equivalents of hydrogen, the mixture was filtered through celite. The celite pad was washed with ethanol (50 mL) and the filtrates combined and concentrated. The residue was purified by recrystallization from hexanes to give (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-[4-[3-(1,1-dimethylethoxy)3-oxopropyl]phenyl]propanoic acid (1.0 g, 2.6 mmol) in 94% yield, mp. 88.5°-90° C., [α]D -21.2° (0.90% in ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:31]3[CH2:32][CH2:33][N:28]([C:26]([C:23]4[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=4)=[O:27])[CH2:29][CH2:30]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(c1ccncc1)N1CCNCC1
Product: O=C(c1ccncc1)N1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 21 %

Procedure:
The title compound of Example 2 (0.51 g, 1.7 mmol) was reacted with the title product of Example 27 (0.33 g, 1.7 mmol) by the method of Example 4. Following chromatographic purification, 0.16 g of the title product was obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[CH:5]([CH2:22][C:23]#[CH:24])[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].C(N[C:31]1[CH:36]=CC=[CH:33][CH:32]=1)C>>[CH2:26]([N:3]([C:1]1[CH:33]=[CH:32][CH:31]=[CH:36][CH:2]=1)[C:4](=[O:25])[CH:5]([CH2:22][C:23]#[CH:24])[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:10])=[O:11])=[O:7])[CH3:27]
Reactant: C#CCC(C(=O)NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N(CC)CC
Reactant: CCNc1ccccc1
Product: C#CCC(C(=O)NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N(CC)c1ccccc1

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (4.00 g) obtained in Example 152 (4) and N-ethylaniline (1.53 mL). This was purified by silica gel column chromatography to give the title compound (98 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)=[CH:10][N:11]=2)[N:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30]Cl)[CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[O:8][C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)=[CH:10][N:11]=3)=[N:5]2)[CH:27]=[CH:26][N:25]=1
Reactant: Cc1nc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)o2)n[nH]1
Reactant: ClCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)o2)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.6 %

Procedure:
A mixture of 2-(5-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)oxazole (260 mg, 0.83 mmol), 2-chloro-4-(chloromethyl)pyridine (270 mg, 1.66 mmol) and Cs2CO3 (820 mg, 2.5 mmol) in dry DMF (5 mL) was stirred at RT for 72 h. The mixture was then diluted with H2O (50 mL) and extracted with DCM/MeOH (20/1 v/v, 4×50 mL). The combined organic layers were washed with H2O (3×40 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (DCM:MeOH=20:1 to 15:1) to afford the title compound as a white solid (100 mg, 27%). MS (ES+) C19H13ClF3N5O2 requires: 435. found: 436 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[S:9]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:33]NS(C1C=CC=CC=1)(=O)=O>C1COCC1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:9]([CH:12]([F:33])[C:13](=[O:15])[CH3:14])(=[O:10])=[O:11])=[CH:21][CH:20]=1
Reactant: CC(=O)CS(=O)(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=S(=O)(NF)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(F)S(=O)(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a stirring solution of the methyl ketone (Example 1, 0.6 g, 1.7 mmol) in dry THF (11 mL) at 0° C., under dry nitrogen was added LiHMDS (1.0 M/THF, 2.2 mL, 1.2 mmol) and the mixture stirred for 30 minutes without warming. After this time, the resulting enolate was lowered to −78° C., whereupon a solution of N-fluorobenzenesulfonamide (0.85 g, 2.7 mmol) in dry THF (5.0 mL) was added via canula. The reaction was then stirred for 30 minutes and then at room temperature for 1 hour, and was then diluted with water and extracted with ethyl acetate. The organic layers were combined, dried on Na2SO4, and filtered to give a mixture that was purified on SiO2 with 15%–20% EtOAcHexane to give (0.075 g, the fluorinated species as a colorless oil. Anal. Calcd for C16H13Cl2F1O3S1: 0.15H2O: Calcd C, 50.85; H, 3.55; Cl, 18.76; F, 5.03; O, 13.33; S, 8.48. Found: C, 50.45; H, 3.51; S, 8.15. 1H NMR (CDCl3, 400 MHz): δ 2.1 (s, 3H), 5.2 (d, 1H, J=49.0 Hz), 5.65 (s, 1H), 7.28–7.5 (m, 4H), 7.5–7.7 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[C:12]([CH2:14][CH2:15][C:16]3[N:17](S(N(C)C)(=O)=O)[CH:18]=[C:19]([CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][CH3:24])[N:20]=3)[N:11]([CH3:33])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]>C1COCC1.Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[C:12]([CH2:14][CH2:15][C:16]3[NH:20][C:19]([CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][CH3:24])=[CH:18][N:17]=3)[N:11]([CH3:33])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCc2nc(-c3ccc(F)c(F)c3)nn2C)n1
Agent: Cl
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cnc(CCc2nc(-c3ccc(F)c(F)c3)nn2C)[nH]1

Procedure:
A solution of 2-{2-[3-(3,4-difluorophenyl)-1-methyl-1H-1,2,4-triazol-5-yl]ethyl}-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (90 mg, 0.19 mmol) in THF (4 mL) and 2 M HCl (4 mL) was heated at 80° C. overnight. The volatiles were removed and the residue was washed with ethyl acetate, basified with 1 N aqueous sodium hydroxide and extracted with ethyl acetate. The combined phases were dried over sodium sulfate and concentrated to afford the title compound. LC-MS: m/e (374M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=4[Cl:25])[CH2:13][C@H:12]3[CH3:26])=[N:10][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1>>[Cl:25][C:18]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([NH:1][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][C:33]([C:32]([F:31])([F:42])[F:43])=[CH:34][CH:35]=5)=[CH:3][C:4]([C:27]([F:30])([F:29])[F:28])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:26])[CH2:13]2)=[N:22][CH:21]=[C:20]([CH2:23][OH:24])[CH:19]=1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(N)c2[nH]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NC(=O)c3ccc(C(F)(F)F)cc3)c2[nH]1

Procedure:
{6-[(3R)-4-(7-Amino-5-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-methanol from step (b) above (221 mg, 0.5 mmol) and 4-trifluoromethyl-benzoic acid (105 mg, 0.55 mmol, Aldrich) reacted under the conditions of Example 65 to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 613 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.Cl.[NH2:13]O.C([O-])=O.[Na+]>C(O)=O>[Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:13]
Reactant: NO
Reactant: O=Cc1c(F)cc(O)cc1Cl
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1c(F)cc(O)cc1Cl
Temperature: 105 °C
Reaction time: 3.5 h
Yield: 55.9 %

Procedure:
A solution of 2-chloro-6-fluoro-4-hydroxybenzaldehyde (WO 2008141249, 90 mg, 0.344 mmol) in formic acid (1 mL) was treated with hydroxylamine hydrochloride (23.9 mg, 0.344 mmol) and sodium formate (23.4 mg, 0.344 mmol) and stirred under nitrogen for 3.5 hours at 105° C. The mixture was concentrated in vacuo and the residue treated with saturated aqueous sodium bicarbonate solution (10 mL). The aqueous solution was extracted with ethyl acetate (2×10 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 30-50% EtOAc in heptanes to afford the title compound as a beige solid (33 mg, 56%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH:7]2[N:14]=[C:13]3[N:9]([CH2:10][CH2:11][S:12]3)[CH2:8]2)=[CH:5][CH:6]=1.O>CC(=O)C>[CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[N:14]=[C:13]3[N:9]([CH2:10][CH2:11][S:12]3)[CH2:8]2)=[CH:3][CH:2]=1
Reactant: c1ccc(C2CN3CCSC3=N2)cc1
Solvent: O
Solvent: CC(C)=O
Product: c1ccc([C@H]2CN3CCSC3=N2)cc1
Temperature: 15 °C
Yield: 116.9 %

Procedure:
To a refluxing solution of 20.43 g of tetramisole (0.1 mol) in 190 ml of 2-propanone and 10 ml. of water was added 15.9 g of L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (0.05 mol). The mixture was refluxed for another 5 minutes and cooled to 15° C. After 12 hours the precipitate was filtered off, washed with 2-propanone and dried under vacuo at 70° C., yielding 23.88 g of levamisole.L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (salt) (yield=91.6%) αD20 =-63.5° (c5, 1N HCl); mp. 127.6°-129.3° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])=[C:4]([F:14])[CH:3]=1.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:16][OH:17])[C:9]([F:12])([F:11])[F:10])=[C:4]([F:14])[CH:3]=1
Reactant: O=C(c1ccc(Br)cc1F)C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C(c1ccc(Br)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution consisting of 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone (3.12 g, 11.5 mmol) and MeOH (50 mL) were added hydroxylamine hydrochloride (4.00 g, 57.5 mmol) and sodium acetate (5.90 g, 71.9 mmol). The resulting mixture was heated at 64° C. for 19 h, at which time additional hydroxylamine hydrochloride (2.40 g, 34.5 mmol) and sodium acetate (3.54 g, 43.1 mmol) were added. Heating was continued for 24 h and the mixture was cool to rt and the mixture was filtered to remove solids. The filtrate was diluted with EtOAc (150 mL), washed with water (150 mL), dried (Na2SO4) and concentrated. The title compound was obtained as a 70:30 ratio of the E and Z oxime isomers (3.28 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].Cl.[NH2:13][OH:14]>CO.O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N:13][OH:14])([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccccc1C=NO
Temperature: 30 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
52.9 g (0.35 mol) of o-nitrobenzaldehyde was dissolved in 150 ml of methanol and an aqueous solution of 27.8 g (0.38 mol) of hydroxylamine hydrochloride in 35 ml of water was added dropwise over 30 minutes while maintaining the temperature at 30° C. The mixture was stirred at the same temperature for 2 hours and diluted with 300 ml of water. White crystals deposited were filtered, washed with water and dried. Thus, 53 g of o-nitrobenzaldoxime was obtained. Yield 91%; M.P. 95°-98° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:40]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1NCc1c(-c2ccc(OC(=O)c3ccccc3)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Reaction time: 0.5 h
Yield: 65 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-1, 25.0 mg, 0.0581 mmol) was dissolved in methylene dichloride (0.5 mL), and then triethylamine (16.2 μL, 0.116 mmol) and benzoyl chloride (8.7 μL, 0.075 mmol) were added thereto successively under ice cooling. The reaction mixture was stirred under ice cooling for 30 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (13.0 mg) as a colorless amorphous product. (Yield 65%)
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)(Cl)Cl.O[C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([O:29]C)=[O:28].[ClH:31]>C(Cl)(Cl)(Cl)Cl>[Cl:31][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1sccc1O
Reactant: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1sccc1Cl

Procedure:
14.5 liters of absolute carbon tetrachloride (refluxed for 1 hour with 500 g of P2O5 and then distilled) is placed in a 25 liter apparatus equipped with stirrer, dropping funnel, drainage cock and reflux condenser with gas outlet; while stirring, 2,200 g (10.05 moles) of PCl5 is added. Upon refluxing the mixture the PCl5 goes into solution (a small amount of PCl5 settles in the drainage cock). 660 g (4.18 moles) of methyl 3-hydroxythiophene-2-carboxylate (prepared as described in German Pat. No. 1,020,641) dissolved in 2 liters of absolute carbon tetrachloride is allowed to flow at a just continuous rate over a period of 4 hours into the boiling solution (vigorous evolution of HCl).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:10])[N:12]=1
Reactant: O=C(O)c1ccccc1N1CCOCC1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccccc2N2CCOCC2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Morpholin-4-yl-benzoic acid.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][CH2:9][C:10]([CH2:15][O:16][C:17](=[O:19])[CH3:18])([CH3:14])[C:11](O)=[O:12])(=[O:7])[CH3:6]>>[C:5]([O:8][CH2:9][C:10]([CH2:15][O:16][C:17](=[O:19])[CH3:18])([CH3:14])[C:11]([Cl:3])=[O:12])(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OCC(C)(COC(C)=O)C(=O)O
Product: CC(=O)OCC(C)(COC(C)=O)C(=O)Cl
Temperature: 100 °C

Procedure:
182 ml (2.5 moles) of thionyl chloride are poured over 218 g (1 mole) of 2,2-bis-acetonxymethyl propionic acid (step 1), followed by refluxing for 8 hours at a batch temperature of approximately 100° C. Excess thionyl chloride is distilled off in a water jet vacuum, leaving a pale yellow, oily product. Yield 236 g (100% of the theoretical).
Reaction SMILES: [Br:1]C(Br)(Br)C1C=C(C)C(O)=C(C)C=1.[Br:14][C:15]1[C:20]([CH3:21])=[C:19]([OH:22])[C:18]([CH3:23])=[C:17]([Br:24])[C:16]=1[CH3:25]>>[Br:1][CH2:25][C:16]1[C:15]([Br:14])=[C:20]([CH3:21])[C:19]([OH:22])=[C:18]([CH3:23])[C:17]=1[Br:24]
Reactant: Cc1c(O)c(C)c(Br)c(C)c1Br
Reactant: Cc1cc(C(Br)(Br)Br)cc(C)c1O
Product: Cc1c(O)c(C)c(Br)c(CBr)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The temperature is increased to 70° C. -75° C., and a solution is obtained. The solution is held at 70° C. -75° C. for 3 hours. The unreacted bromine is removed by distillation with the aid of 1 liter of carbon tetrachloride. When 1 liter of solvent remains with the product, the solution is cooled to 25° C. The light brown solid which is obtained is filtered and is dried under vacuum for 5 hours. A yield of 250 g (67 percent) is obtained, which analysis by gas chromatography shows to be 97 percent tribromomesitol and 3 percent dibromomesitol. The product has a melting point of 144° C. -146° C. and has the following proton nuclear magnetic resonance spectrum (CDCl3), δ: 2.30 (s, 6H), 4.90 (s, 2H), which is consistent with the structure of the product.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reaction time: 8 h
Yield: 103.4 %

Procedure:
A solution of 25.03 g (109.2 mmole) N-Boc isonipecotic acid was dissolved in 200 mL THF and treated with 200 mL 1 M borane-tetrahydrofuran complex in THF, and the mixture was stirred overnight. The mixture was concentrated under vacuum, diluted with 750 mL ethyl acetate, and washed with 150 ML 1 N HCl (6×) and then saturated brine. The organic layer was dried over sodium sulfate and concentrated to give 24.3 g of crude product as a white solid. This was used as is in the next step.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:33])([F:32])[C:24]([NH:26][CH2:27][CH:28]1[CH2:31][NH:30][CH2:29]1)=[O:25].N1C=CC=CC=1>C(N(CC)CC)C>[F:33][C:23]([F:22])([F:32])[C:24]([NH:26][CH2:27][CH:28]1[CH2:29][N:30]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:31]1)=[O:25]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: O=C(NCC1CNC1)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC(CNC(=O)C(F)(F)F)C3)c(F)cc2c1=O
Yield: 89.8 %

Procedure:
A solution of 0.8 g (2.8 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.92 g (4.2 mmoles) of 3-trifluoroacetamidomethylazetidine hydrochloride, 8 ml of pyridine and 1.7 g of triethylamine is heated under reflux for 3 hours. It is then evaporated under vacuum, diluted with water and filtered. 1.12 g (88.9%) of 7-(3-trifluoroacetamidomethyl-1-azetidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 145°-150° C.