Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[N:17]=[C:16]([NH:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH:14][CH:13]=1.[OH2:24]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:11][C:12]1[N:17]=[C:16]([NH:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH:14][CH:13]=1)=[O:24]
Reactant: O
Reactant: CC(C)(C)CNc1cccc(CSc2nc3ccccc3[nH]2)n1
Product: CC(C)(C)CNc1cccc(CS(=O)c2nc3ccccc3[nH]2)n1

Procedure:
The title compound (100 mg) was prepared by the method of Example 85 using 1.52 g (4.65 mmole) of 6-[(1H-benzimidazol-2-ylthio)methyl]-N-(2,2-dimethylpropyl)-2-pyridinamine (see Example 106) instead of 6-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis. Analysis. Calc'd. for C18H22N4SO*¼ H2O: C, 62.31; H, 6.48; N, 16.15; S, 9.24. Found: C, 62.19; H, 6.47; N, 15.76; S, 9.09.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:35]([NH2:37])=[O:36])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=3)[C:6]=2[CH:34]=1.[CH2:38](N(CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[Cl:1][C:2]1[C:3]([C:35]([NH2:37])=[O:36])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][N:20]([CH3:38])[C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:22])=[CH:16][CH:17]=3)[C:6]=2[CH:34]=1
Reactant: CCN(CC)CC
Reactant: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCN(C)C(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 37.8 %

Procedure:
A mixture of 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide (Example 111, step 4, 500 mg, 1.45 mmol), triethylamine (293 mg, 2.90 mmol) and methanesulfonyl chloride (322 mg, 2.9 mmol) in dichloromethane (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water, and extracted with dichloromethane (50 ml). The organic layer was washed with brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 304 mg (50%) of the title compound as white solids.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[S:30][C:29]([C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.CCOC(C)=O>C(#N)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:35][C:34]2[CH:37]=[CH:38][C:31]([C:29]3[S:30][C:26]([Cl:25])=[CH:27][CH:28]=3)=[CH:32][CH:33]=2)[CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(CN2CCNCC2=O)cc2cnccc21
Reactant: O=Cc1ccc(-c2ccc(Cl)s2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1c(CN2CCN(Cc3ccc(-c4ccc(Cl)s4)cc3)CC2=O)cc2cnccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 2-(2-oxo-piperazin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.10 g, 0.30 mmol) in acetonitrile (5 mL) is added 4-(5-chloro-thiophen-2-yl)-benzaldehyde (0.067 g, 0.30 mmol) followed by triacetoxyborohydride (0.13 g, 0.60 mmol) and glacial acetic acid (1 drop). The resulting mixture is stirred at room temperature overnight then poured into EtOAc and washed with water (×2) and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness then purified by column chromatography using EtOAc as the eluent to yield the title compound (0.90 g, 0.17 mmol). ESI MS [M+H]+=537.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22].[NH:35]1[CH2:40][CH2:39][CH2:38][C@@H:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[F:34][C:2]([F:1])([F:33])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:35]2[CH2:40][CH2:39][CH2:38][C@@H:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36]2)=[O:29])=[CH:31][CH:32]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][N:17]=2)=[CH:8][C:7]=1[CH3:22]
Reactant: Cc1cc(-c2ncc(C(F)(F)F)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ncc(C(F)(F)F)cn4)cc3C)cc2)C1

Procedure:
A solution of 4-((4,4,4-trifluoro-1-(2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)butyl)amino)benzoic acid, ethyl (3R)-piperidine-3-carboxylate (2.29 mL), 1-hydroxybenzotriazole (2.01 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.85 g) and diisopropylethylamine (2.60 mL) in dimethylformamide (30 mL) was stirred at room temperature overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.96 g).
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]([CH3:30])[CH2:7][N:8]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:9][C@@H:10]([NH:12]C(OC(C)(C)C)=O)[CH3:11])(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.ClC(Cl)C>ClCCl>[CH3:1][S:2]([O:5][C@H:6]([CH3:30])[CH2:7][N:8]([CH2:9][C@@H:10]([NH2:12])[CH3:11])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])(=[O:4])=[O:3]
Reactant: C[C@H](CN(C[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)OS(C)(=O)=O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)CN(C[C@@H](C)OS(C)(=O)=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (1R)-2-([(benzyloxy)carbonyl]{(2S)-2-[(tert-butoxycarbonyl)amino]propyl}amino)-1-methylethyl methanesulfonate (2.29 g, 5.15 mmol) in anhydrous dichloromethane (38 mL) was added TFA (38 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 hour. Reaction was complete as determined by TLC. Most of TFA was azeotropped with dichloroethane. The residue was then diluted with dichloromethane and washed with 2N Na2CO3 (aq.), organic layer was dried over MgSO4. Solvent evaporation afforded (R)-1-(((S)-2-aminopropyl)(benzyloxycarbonyl)amino)propan-2-yl methanesulfonate in quantitative yield (1.8 g) as oil. It was carried to the next step immediately.
Reaction SMILES: Cl.[CH:2]1([C:8]2[CH:17]=[C:16]([C:18](=[O:27])[CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].C[O-].[Na+].[BH4-].[Na+].S([O-])([O-])(=O)=O>C(O)C>[CH:2]1([C:8]2[CH:17]=[C:16]([CH:18]([OH:27])[CH2:19][CH2:20][CH:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(CCC1CCNCC1)c1cc(C2CCCCC2)nc2ccccc12
Agent: C[O-]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: OC(CCC1CCNCC1)c1cc(C2CCCCC2)nc2ccccc12
Yield: 28 %

Procedure:
The operation was as in Example 5, starting from 5.1 g of 1-(2-cyclohexyl-4-quinolyl)-3-(4-piperidyl)-1-propanone monohydrochloride, 1.3 ml of a 10N aqueous solution of sodium hydroxide (instead of sodium methylate) and 0.53 g of sodium borohydride in 100 ml of ethanol. 1.3 g of 1-(2-cyclohexyl-4-quinolyl)-3-(4-piperidyl)-1-propanol (racemic) were finally obtained in the form of the sulfate melting at 260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[CH:8]=O.[C:10]1([C:16]2[O:17][C:18]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]2[C:19]=3[CH2:20][C:21](=[O:28])[NH:22]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1.Cl>CC(O)C.O>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:20]1\[C:21](=[O:28])[NH:22][C:23]2[CH:24]=[CH:25][C:26]3[N:27]=[C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[O:17][C:18]=3[C:19]\1=2
Reactant: O=C1Cc2c(ccc3nc(-c4ccccc4)oc23)N1
Reactant: COc1cc[nH]c1C=O
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3nc(-c4ccccc4)oc3c21

Procedure:
3-Methoxypyrrole-2-carboxaldehyde (13 mg, 0.105 mmol)(Bellamy, supra) and 2-phenyl-6,8-dihydro-oxazolo[5,4-e]-indol-7-one (17 mg, 0.068 mmol)(Starting Material 4) were suspended in a solution of 10% piperidine (Aldrich) in 2-propanol (1 mL). The mixture was heated at reflux for 2 h. The mixture was cooled, poured into water, and the aqueous mixture was made acidic with concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with water, brine, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the crude product was purified by reverse phase HPLC using acetonitrile—water as solvent. (Yield 10 mg, 41%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].S(Cl)(Cl)=O.Cl.CN.[CH:19]([N:22](CC)C(C)C)(C)C>ClCCl.C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([C:6]([NH:22][CH3:19])=[O:7])[CH:9]=[CH:10][CH:11]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc(CCl)c1
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNC(=O)c1cccc(CCl)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
5 g (29.31 mmol) of 3-chloromethylbenzoic acid were suspended in 20 ml of abs. toluene, 5.23 g (43.96 mmol) of thionyl chloride were added dropwise and the mixture was stirred at 90° C. overnight. After cooling to RT, excess thionyl chloride and toluene were evaporated and the residue was dried under high vacuum for 1 h. Under argon, the residue was dissolved in 40 ml of abs. dichloromethane and cooled to 0° C., and 2.18 g (32.24 mmol) of methylamine hydrochloride were added. At 0° C., 7.58 g (58.62 mmol) of N,N-diisopropylethylamine were slowly added dropwise, and the reaction mixture was stirred at 0° C. for 15 min. 100 ml of dichloromethane were added, and the reaction mixture was washed three times with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated using a rotary evaporator.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13].[C:15](=[S:17])=S.O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:14][C:12]1[C:3]2[C:2](=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=2[O:10][CH3:11])[O:1][C:15](=[S:17])[CH:13]=1
Reactant: S=C=S
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(OC)c2c(O)cc(=S)oc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
336.0 g of potassium t-butoxy was suspended in 2 liters of toluene. Under cooling on ice, 2 liters of 196.0 g of 2'-hyroxy-4',6'-dimethoxyacetophenone and 72.0 ml carbon disulfide in toluene were added dropwise to said suspension. The mixture was stirred for 20 hours at room temperature, and 7 liters of water was added for extraction of a toluene layer. This toluene solution was adjusted to pH 4-5 by addition of 800 ml of 10% sulfuric acid (aq.) and was then stirred for 5 hours at room temperature. The solution was allowed to stand overnight. The resulting yellow crystals were collected by filtration under reduced pressure, sufficiently washed with water and dried at 50° C. for 3 days under reduced pressure, thus giving rise to 160.0 g crude 4-hydroxy-5,7-dimethoxychromene-2-thion.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[Cs+].[Cs+].ClC[C:23]1[CH2:27][CH2:26][CH2:25][CH:24]=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:14][C:23]1[CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: ClCC1=CCCC1
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Clc1ccc(Nc2nccs2)cc1OC1=CCCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
Following the general procedure for O-allylation, Method B, a mixture 2-chloro-5-(thiazol-2-ylamino)phenol (88 mg, 0.39 mmol) and Cs2CO3 (127 mg, 0.39 mmol) in acetone was treated with 1-(chloromethyl)cyclopentene (60 mg, 0.39 mmol) at 0° C. The reaction mixture was heated to 60° C. and stirred for 3 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 8/2) in 25% yield (29 mg).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[CH3:14][O:15][CH2:16][C:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:22][C:17]2([CH2:16][O:15][CH3:14])[CH2:21][CH2:20][CH2:19][CH2:18]2)[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: COCC1(N)CCCC1
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1(COC)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.018 g, 0.09 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added 1-methoxymethyl-cyclopentylamine (17 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 290 (M+H)+; 1H NMR (CD3OD) δ 4.84 (m, 2H), 3.48 (m, 2H), 3.41 (s, 3H), 3.31 (m, 2H), 2.43 (d, 1H), 2.30-2.48 (m, 4H), 1.72-1.96 (m, 8H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[Cl:15])[CH3:2].[CH:18](OCC)(OCC)[O:19][CH2:20][CH3:21]>C(OC(=O)C)(=O)C>[Cl:15][C:8]1[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=1[C:6](=[O:16])[C:5](=[CH:18][O:19][CH2:20][CH3:21])[C:4]([O:3][CH2:1][CH3:2])=[O:17]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl

Procedure:
In accordance with the above reaction scheme, a solution of 2-chloro-4,5-difluorobenzoic acid (V) in acetonitrile containing a catalytic amount of dimethylformamide is reacted under an inert atmosphere with the dropwise addition of oxalyl chloride, giving 2-chloro-4,5-difluorobenzoic acid chloride (VI) which is dissolved in diethyl ether and slowly added to a cold solution of magnesium diethylmalonate, followed by the addition to ice water and acidification to pH 2.5, giving (2-chloro-4,5-difluorobenzoyl)propanedioic acid diethyl ester (VII). A solution of compound (VII) in p-dioxane and water is heated at reflux, then evaporated and distilled, giving 2-chloro-4,5-difluoro-β-oxobenzenepropanoic acid ethyl ester (VIII). A solution of compound (VIII) and triethyl orthoformate in acetic anhydride is heated at 150° C. for 2 hours, giving 2-chloro-α-(ethoxymethylene)-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (IX). Cyclopropylamine is added to a solution of compound (IX) in ethanol, giving 2-chloro-α-[(cyclopropylamino)methylene]-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (X). Compound (X) is reacted with sodium hydride in dry dimethylformamide under an inert atmosphere with heat, giving 1-cyclopropyl-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester (XI). Ester (XI) is then refluxed with acid, giving the desired 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (XII).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:17]1([C@H:23]2[O:25][C@@H:24]2[CH2:26][OH:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C@@H:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:24]([OH:25])[CH2:26][OH:27])[C:6]1=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: OC[C@H]1O[C@@H]1c1ccccc1
Reactant: CC(C)(C)n1c(=O)[nH]c2ccccc21
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(=O)n([C@@H](c2ccccc2)[C@H](O)CO)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1-tert-butyl-1,3-dihydro-benzimidazol-2-one (0.66 g, 3.5 mmol) and sodium hydride (60% dispersion in mineral oil, 0.15 g, 3.8 mmol) in anhydrous dimethylformamide (4 mL) was stirred for 10 minutes under nitrogen at room temperature. A solution of [(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4, 1.07 g, 7.1 mmol) and titanium isopropoxide (2.14 mL, 7.1 mmol) in dimethylformamide (4 mL) that was aged for 20 minutes was then added and the mixture was stirred at room temperature under nitrogen for 12 hours. After disappearance of the epoxide, the mixture was partitioned between a 1N aqueous solution of hydrochloric acid (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel column (60% ethyl acetate in hexane) to give 1-tert-butyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-benzimidazol-2-one as an oil. MS (ES) m/z 341.2.
Reaction SMILES: [C:1]1(=[N:7]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:9](=[O:13])(=[O:12])([OH:11])[OH:10]>>[S:9](=[O:11])(=[O:10])([OH:13])[OH:12].[S:9]([OH:13])([OH:12])(=[O:11])=[O:10].[C:1]1(=[O:10])[NH:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ON=C1CCCCC1
Agent: O=S(=O)(O)O
Product: O=C1CCCCCN1

Procedure:
The method according to claim 1, wherein the cyclohexanone oxime is subjected to the Beckmann rearrangement reaction in sulfuric acid or fuming sulfuric acid to obtain ε-caprolactam sulfate.
Reaction SMILES: [Br-].[N:2]1([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:28]1([CH3:49])[CH:33]=[CH:32][C:31]([C:34]([C:36]2[N:41]=[C:40](/C=C/C(OCC)=O)[CH:39]=[CH:38][CH:37]=2)=O)=[CH:30][CH:29]=1>C1COCC1>[CH3:49][C:28]1[CH:33]=[CH:32][C:31](/[C:34](/[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][N:41]=2)=[CH:8]\[CH2:7][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:30][CH:29]=1
Reactant: c1ccc([P+](CCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)/C=C/c1cccc(C(=O)c2ccc(C)cc2)n1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1ccc(/C(=C\CN2CCCC2)c2ccccn2)cc1

Procedure:
A solution of 25 mL of 1.6 M n-BuLi/hexanes was added to a stirred and cooled (0° C.) suspension of (2-pyrrolidinoethyl)triphenylphosphonium bromide (17.24 g, 39.18 mmol) in dry THF (250 mL) over a period of ˜4 min. The ylide-forming reaction mixture was stirred an additional 10 min at 0° C., followed by the addition of one aliquot of a solution of 5c (4.52 g, 15.3 mmol) in dry THF (75 mL). After stirring at 0° C. for only 2 min, the reaction mixture was quenched by the addition of water (100 mL). The reaction mixture was then extracted twice with EtOAc and the combined organics were dried with Na2SO4, filtered, and evaporated to dryness. Chromatography over silica gel using MeOH/EtOAc (starting at 5% MeOH) gave 1.42 g (25%) of E,E-7c as a yellow crystalline solid and 2.42 g (42%) of E,E-7c. The structure of the products were confirmed by 1H NMR and MS. (Triprolidine ester E,E-7e was similarly prepared.)
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][C:18]([C:25]([F:28])([F:27])[F:26])=[CH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])=[CH:12][CH:11]=1>O1CCCC1>[Br:1][C:19]1[C:20]([C:21]([F:22])([F:23])[F:24])=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[NH:17][C:18]=1[C:25]([F:28])([F:26])[F:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1cc(C(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Solvent: C1CCOC1
Product: FC(F)(F)c1[nH]c(-c2ccc(Cl)cc2)c(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
N-Bromosuccinimide (0.9 g, 5 mmol) is added to a solution of 2-(p-chlorophenyl)-3,5-bis(trifluoromethyl)pyrrole (0.78 g, 2.5 mmol) and tetrahydrofuran (50 mL). The reaction mixture is stirred at room temperature overnight then concentrated in vacuo to give a solid. The solid is chromatographed using silica gel and 20% ethyl acetate in hexanes as eluant to yield the title compound as a light green solid (0.376 g, mp 71°-75° C., 38%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:3].CC[O-].[Na+].Cl>C(O)C>[F:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:1][C:2]2=[O:3]
Reactant: CCOC(=O)C(=O)Nc1ccc(F)cc1C(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(F)cc2c(=O)[nH]1
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a suspension of ethyl ((2-(aminocarbonyl)-4-fluorophenyl)amino)(oxo)acetate (1.50 g, 5.90 mmol) in ethanol (30 mL) was added dropwise sodium ethylate (20% ethanol solution, 2.40 g, 7.08 mmol) under ice-cooling, and the mixture was stirred for 2 hr. The reaction mixture was adjusted to pH 3-4 with 1N hydrochloric acid, and the precipitated insoluble material was collected by filtration. The filtered cake was washed with water and ethanol to give the title compound as a white powder (1.05 g, 75%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([CH2:12]O)([CH2:10]O)[CH2:8]O)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.ClCCl>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:14])[C:7]([CH2:12][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])([CH2:10][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[CH2:8][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C(CO)(CO)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CC(CS(=O)(=O)c2ccc(C)cc2)(CS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)cc1
Reaction time: 15 h

Procedure:
A solution of t-butyl-tris(hydroxymethyl)acetate (9.9 g, 0.048 mol) in 50 mL of pyridine is cooled to 0° C. and then portions of p-toluenesulfonyl chloride (30.1 g, 0.158 mol) are added over 1 hr. The mixture is kept at 0° C. for 15 hrs. Then dichloromethane (200 mL) is added and the solution is washed four times with 100 mL of 10% hydrochloric acid, once with 100 mL of saturated sodium bicarbonate and once with 100 mL of saturated sodium chloride. The organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure to give t-butyl-tris(tosylmethyl)acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]([NH2:28])=[NH:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O[CH:32](OCC)[CH2:33][CH:34](OCC)OCC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]3[N:28]=[CH:34][CH:33]=[CH:32][N:27]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(CC(OCC)OCC)OCC
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCC(=N)N)CCC2c2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C(CCCc3ncccn3)CCC2c2ccc(F)cc2)cc1
Yield: 20 %

Procedure:
A stirred solution of (2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-butyramidine (0.33 g, 0.82 mmol) in 1,1,3,3-tetraethoxy-propane (7 ml) and DMF (1.5 ml) was heated for 1 h at 150° C. Evaporation and purification by column chromatography on silica gel (dichloromethane/MeOH 98:2) yielded the title compound (73 mg, 20%) as a light brown oil, MS: m/e=440.2 (M+H+).