Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@:7]([N:13]=[C:14]=[S:15])([CH3:12])[C:8]([O:10]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:24]C(C)([O-])C.[K+].CI>O1CCCC1.O>[CH3:12][C@:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:10])[N:23]([NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]([S:15][CH3:24])=[N:13]1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)[C@@](C)(N=C=S)c1ccccc1
Reactant: NNc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CSC1=N[C@@](C)(c2ccccc2)C(=O)N1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 114.6 %

Procedure:
682 g (3.08 mol) of methyl (+)-(2S)-2-phenyl-2-(isothiocyanato)propionate, dissolved in 4 liters of anhydrous tetrahydrofuran, are introduced into a 20 liter reactor through which passes a stream of argon. Cooling is carried out to 15° C. 343 g (3.08 mol) of phenylhydrazine, dissolved in 2 liters of tetrahydrofuran, are run in over 30 minutes, the temperature being maintained between 15° C. and 18° C. The mixture is kept stirring for 40 minutes and then cooled to 0° C. A solution of 346 g (3.08 mol) of potassium tert-butoxide in 4 liters of tetrahydrofuran is nm in over 1 hour, the temperature being maintained at 0° C. The mixture is stirred for a further 2 hours at 0° C. and the formation of a pale-pink precipitate is observed. 218 ml (3.39 mol) of methyl iodide are run in over 15 minutes, the temperature being maintained between 0° C. and 3° C., and the temperature is then allowed to rise to room temperature while continuing to stir for 2 hours. The reaction mixture is poured onto 5 liters of water. After separating, the aqueous phase is extracted with 3 times 3 liters of ethyl acetate. The combined organic phases are washed with 5 liters of water, dried over magnesium sulfate and the concentrated under reduced pressure. 1099 g of a brown solid are obtained. The latter is recrystallized from 2 liters of toluene.
Reaction SMILES: [CH2:1]([Cl:4])[CH2:2][OH:3].CCOCC.[CH2:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]([CH3:13])[CH3:12]>C(N(CC)CC)C>[CH2:10]([S:14]([O:3][CH2:2][CH2:1][Cl:4])(=[O:16])=[O:15])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: OCCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)CS(=O)(=O)OCCCl
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A mixture was formed containing 6.7 ml. of ethylene chlorohydrin, 70 ml. of ether and 15.6 g. of isobutane sulfonyl chloride. Then, 14 ml. of triethylamine was added dropwise to the mixture with stirring in an ice bath over a period of 30 minutes at 12°-14°C. While stirring the mixture was allowed to warm to 23°C. (1 hour) and was then washed with water (100 ml.), dried over magnesium sulfate and evaporated to yield 19.7 g. of a colorless oil. nD30 1.4502.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[CH2:12]2)=[C:4]([Se:19][CH3:20])[N:3]=1>CCOC(C)=O.C1CCCCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[CH2:12]2)=[C:4]([Se:19][CH3:20])[N:3]=1
Reactant: C[Se]c1nc(N)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C[Se]c1nc(N)nc2c1ncn2[C@@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
The procedure was the same as that used for the synthesis of 7a except that 500 mg (0.0015 mol) of 2 was used and the yield from the EtOAc-cyclohexane mixture was 200 mg (39%) of product, mp 167°-170°. For analysis the sample was dried in vacuo over Drierite for 1 hr. at the temperature of refluxing toluene: mp unchanged; uv λmax (pH 1) 334 nm ( ε 14 400); uv λmax (MeOH) 313 nm ( ε 15 800); uv λmax (pH 11) 316 nm ( ε 15 500).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[C:14]([O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1)([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>ClCCl>[C:14]([O:18][C:19](=[O:28])[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][NH:27][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])=[CH:24][CH:25]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)c1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(CNS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
2-Nitro-benzenesulfonyl chloride (8.55 g, 38.6 mmol) and 4-aminomethyl-benzoic acid tert-butyl ester (8.0 g, 38.6 mmol) were mixed in 400 mL of dichloromethane. Triethylamine (10.8 mL, 77.2 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction was partitioned between 1M HCl and dichloromethane. The organic layer was dried (magnesium sulfate), filtered, and rotary evaporated to give 14.46 g (95%) of 4-[(2-nitro-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester as an off-white solid. 1H-NMR (CDCl3); δ 8.00 (dd, 1H), 7.84 (m, 3H), 7.67 (m, 2H), 7.27 (dd, 2H), 5.76 (bt, 1H), 4.36 (d, 2H), and 1.57 (s, 9H). MS: M+=392.1 Da Step (2): Synthesis of 4-[(2-Amino-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccccc3F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluoro-benzoyl chloride (42 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H32FN3O3+H: 502, observed: 502.
Reaction SMILES: [H-].[Na+].[C:3]1([C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.I[CH2:19][CH3:20]>CN(C=O)C>[CH2:19]([N:17]1[CH:16]=[CH:15][N:14]=[C:13]1[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[CH3:20]
Reactant: CCI
Reactant: c1ccc2c(-c3ncc[nH]3)cccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccnc1-c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (2.40 g, 60% mineral oil suspension, 60 mmol) in anhydrous DMF (30 ml) is added a solution of 2-naphthalen-1-yl-1H-imidazole (9.70 g, 50 mmol) in DMF (70 ml) at rt. The resulting mixture is stirred at 50° C. for 1 hr, and then cooled to 0° C., after which iodoethane (8.19 g, 52.5 mmol, 1.05 eq.) is added dropwise. The mixture is stirred at rt for 1 hr, and then heated to 50° C. and stirred for an additional 8 hr. The reaction mixture is cooled to rt, and poured into ice-water (500 ml). The mixture is extracted with EtOAc (100 ml×3). The combined organic layers are washed with water and brine, dried over anhydrous sodium sulfate, and solvent is evaporated at reduced pressure. The crude product is purified by flash chromatography on silica gel to give the title compound. LCMS 223 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:17]([O-])=O)[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[H][H]>[Ni].C(O)C>[NH2:17][C:9]1[C:10]([F:16])=[C:11]([F:15])[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(N)c2c1=O
Yield: 34.7 %

Procedure:
A suspension of 1.9 g (5.3 mmoles) of ethyl 1-cyclopropyl-5-nitro-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 0.5 g of Raney nickel and 100 ml of ethanol was shaken in a hydrogen atmosphere at pressures of 42.5-50 psi and temperatures of 24°-26.5° C. for ten hours. The mixture was filtered through Celite and some insoluble product was dissolved in tetrahydrofuran with filtration. The combined filtrates were evaporated in vacuo and the residue was chromatographed on silica gel to give 600 mg of the title compound, mp 223°-225° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:20]1>N1C=CC=CC=1.CN(C)C=O>[CH2:30]([N:29]([CH2:28][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:20]1)[CH2:32][CH3:33])[CH3:31]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CCN(CC)CC1CNc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCN(CC)CC1CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2ccccc21
Yield: 44.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 150 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 238 mg of (2,3-dihydro-1H-indol-3-ylmethyl)diethylamine and 140 mg of N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride in a mixture of 0.1 ml of pyridine and 3 ml of N,N-dimethylformamide. 108 mg of 2-(2-{3-[(diethylamino)methyl]-2,3-dihydro-1H-indol-1-yl}-2-oxoethyl)-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a cream solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].ClC[C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16].O1CCOC[CH2:23]1>>[C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][S:7][CH2:23][NH:17][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:13]=1)(=[O:3])[CH3:2]
Reactant: C1COCCO1
Reactant: NC(=O)c1ccccc1CCl
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Product: CC(=O)N[C@@H](CSCNC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-acetyl-L-cysteine (0.5 g, 3.06 mmol) was dissolved in 50 ml of dry dioxane. Chloromethyl benzamide (0.52 g, 3.06 mmol) was added and the colorless solution was stirred at 25° C. for 18 hours. The dioxane was evaporated under vacuum with minimal amount of heating to give a colorless oil: NMR (CDCl3 +DMSO) δ8.05-7.38 (m, 5, aryl), 4.58 (d, 2, --SCH2NH--), 2.01 (s, 3, --CH3).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=[O:11])[CH3:8])[CH3:3].C(O)(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]
Reactant: CC(C)=CCCC(C)=CC=O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)=CCCC(C)CC=O

Procedure:
Prior to the biotransformation, 0.5 ml of permeabilized cells were vortexed with 0.15 ml toluene in 2 ml screw capped glass vials and incubated for 10 min at room temperature. The other components were then added to give 1 ml of aqueous phase with the same composition as the aqueous/NADPH system, with only citral and isopropanol omitted. The reaction was started by addition of 0.05 ml of 0.4 M citral in toluene and the vials were turned vertically on a wheel at 30° C. After 3 h the complete sample was extracted with 0.4 ml freshly prepared solution of 0.15% [v/v] 1-octanol (internal GC standard) in chloroform. After centrifugation 0.4 ml of the lower organic phase (toluene/chloroform mixture) was removed for GC analysis. Strains that formed citronellal were compared in a toluene and a methyl tertiary-butylether (MTBE) two-phase system as detailed below.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:33][O:34][C:35](=[O:42])[CH2:36][NH:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH:22][S:38]([NH:37][CH2:36][C:35]([O:34][CH3:33])=[O:42])(=[O:40])=[O:39])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CNS(=O)(=O)Cl
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CNS(=O)(=O)NNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A solution of 1.08 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide in 10 ml of dichloromethane was cooled to 0° C. under a nitrogen atmosphere and treated with 0.8 ml of pyridine and a solution of 1.5 g of N-(chlorosulphonyl)-glycine methyl ester in 5 ml of dichloromethane. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was then diluted with ethyl acetate and washed with 2M aqueous hydrogen chloride and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulphate and evaporated and the residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (3:2) for the elution to give 0.831 g of methyl(E)-2-[[2-[2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleryl]hydrazino]sulphonamido]acetate in the form of a solid.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:5][CH2:4]1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][NH:32][CH3:33].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][N:32]([CH3:33])[C:12](=[O:14])[CH2:11][CH2:10][O:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH2:4][CH2:5]1
Reactant: CNCCN(C)C
Reactant: CN([C@H]1CC[C@H](OCCC(=O)O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(C)CCN(C)C(=O)CCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
120 mg (0.29 mmol) of trans-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid in 3 mL of CH2Cl2 were treated with 0.057 mL (0.44 mmol, 1.5 eq) of N,N,N′-trimethylethylenediamine and 0.48 mL (0.36 mmol, 1.5 eq) of NMM. The solution was cooled to 0° C. and 73.0 mg (0.38 mmol, 1.3 eq) of EDCI and 9 mg (0.06 mmol, 0.2 eq) of HOBT were added. The mixture was stirred at RT for 2 days, partitioned between CH2Cl2 and a saturated aqueous solution of NaHCO3. The organic phase was washed with brine, dried over Na2SO4 and evaporated. Column chromatography with CH2Cl2:MeOH 9:1 gave 118 mg (82%) of trans-N-(2-dimethylamino-ethyl)-N-methyl-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionamide as colorless oil, MS: 494 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2].[CH3:26]OS(OC)(=O)=O>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([N:17]([CH3:26])[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2]
Reactant: CCN1CCCC1CNC(=O)c1cc(NS(=O)(=O)CC)ccc1OC
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCCC1CNC(=O)c1cc(N(C)S(=O)(=O)CC)ccc1OC
Yield: 26.8 %

Procedure:
To a solution of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-ethanesulfonamidobenzamide (266 mg) in dry acetone (7 ml), potassium carbonate and dimethylsulfate (100 mg) are added, and the resultant mixture is refluxed for 30 minutes. After evaporating the acetone, the residue is mixed with water and shaken with methylene chloride. The organic layer is washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residue is dissolved in methylene chloride, and the resultant mixture is chromatographed on a column of alumina, which is eluted with methylene chloride. After evaporating the eluate to remove the methylene chloride, the residue is washed with isopropy ether and recrystallized from ethyl acetate/isopropyl ether in that order to give N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-(N-methylethanesulfonamido)benzamide (74 mg) as crystals melting at 85° to 87° C.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[CH:11]([CH2:13][C:14](O)=[O:15])=[CH2:12]>>[CH3:4][O:3][C:2]1[CH:5]=[C:6]2[C:7](=[CH:8][C:1]=1[O:9][CH3:10])[C:14](=[O:15])[CH2:13][CH:11]2[CH3:12]
Reactant: C=CCC(=O)O
Reactant: COc1ccccc1OC
Product: COc1cc2c(cc1OC)C(C)CC2=O
Temperature: 60 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
A mixture of 19.1 ml (150 mmol) of veratrol and 19.2 ml (225 mmol) of vinylacetic acid in 230 g of 83% polyphosphoric acid was stirred for 15 h at 60° C. and then poured into 500 ml of ice water. After 30 minutes (min) of stirring, the product was extracted three times, each time with 200 ml of ether. The combined organic phases were washed twice, each time with 100 ml of 2N NaOH, once with 100 ml of water and once with 50 ml of saturated sodium chloride solution, dried over sodium sulfate and freed from solvent on a rotary evaporator. After recrystallizing the residue (in AcOEt/pentane), 22.8 g (74%) of 5,6-dimethoxy-3-methylindan-1-one were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:24]([CH3:26])[CH3:25])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:8])=[O:4].C1COCC1>CCCCCCC>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:24]([CH3:26])[CH3:25])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=[O:15])=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(C)C
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(S)-Benzyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylate (40 g) and 5% Pd/Alumina were charged to a Parr reactor followed by THF (160 mL). The reactor was sealed and purged with nitrogen (6×20 psig) followed by a hydrogen purge (6×30 psig). The reactor was pressurized to 30 psig with hydrogen and agitated at room temperature for approximately 15 hours. The resulting slurry was filtered through a GF/F filter and concentrated to approximately 135 g solution. Heptane (120 mL) was added, and the solution was stirred until solids formed. After an addition 2-3 hours, additional heptane (240 mL) was added drop-wise, the slurry was stirred for approximately 1 hour, then filtered. The solids were dried to afford the title compound (S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H][H].N>C(O)C.[Ni]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1ccc(F)cc1F
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1ccc(F)cc1F

Procedure:
13.9 g (0.10 mol) of 2,4-difluorobenzonitrile are dissolved in 100 ml of ethanol and hydrogenated in a pressurized reactor at 75°-80° C. using hydrogen gas after 1.4 g of Raney nickel in ethanol has been added and after 17 g (1.0 mol) of ammonia gas have been injected. The take-up of hydrogen is complete after about 2 hours. The reaction mixture is cooled, decompressed and filtered and then freed from solvent in a vacuum rotary evaporator. The resultant oil is subjected to fractional distillation at 70°-75° C. in vacuo (19 mbar). 9.5 g (66% of theory) of a colourless liquid are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1.Cl[C:32]([F:38])([F:37])C(OC)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[F:37][CH:32]([F:38])[O:30][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]([CH3:28])([CH3:29])[CH2:9][C:10]([OH:27])([C:23]([F:25])([F:26])[F:24])[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH:14]=[CH:13]1
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cc(F)ccc1O
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cc(F)ccc1OC(F)F
Temperature: 60 °C

Procedure:
A mixture of 1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (0.05 g), methyl 2-chloro-2,2-difluoroacetate (0.014 mL) and cesium carbonate (0.195 g) in 1.5 mL of DMF was heated at 60° C. for 20 hours, cooled to room temperature, diluted with ethyl acetate, and washed with aqueous acetic acid, water, and brine. The residue was purified by reverse-phase HPLC using acetonitrile/water as the eluent. The product rich fractions were concentrated in vacuo and provided 1-[4-(2-difluoromethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one, m.p. 150° C.-155° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][N:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:36][N:37]1[CH:41]=[C:40]([S:42](Cl)(=[O:44])=[O:43])[N:39]=[C:38]1[CH3:46]>CN(C1C=CN=CC=1)C>[CH3:36][N:37]1[CH:41]=[C:40]([S:42]([N:24]2[CH2:25][CH2:26][CH:21]([C:12]3[C:11]4[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][CH:7]=5)[CH:10]=4)[NH:14][N:13]=3)[CH2:22][CH2:23]2)(=[O:44])=[O:43])[N:39]=[C:38]1[CH3:46]
Reactant: NC(=O)c1cc(-c2ccc(CO)cc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5ccc(CO)cc5)cc34)CC2)cn1C
Yield: 30.9 %

Procedure:
Following the general procedure of Example 11, 5-[4-(hydroxymethyl)phenyl]-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Example 73) (0.07 mmol), diisopropylethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (33 mg, 0.17 mmol) were reacted to give the title compound (11 mg, 31% for 3 steps).