Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4]([CH:5]=O)[C@@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].N1CCCCC1.[CH3:21][CH:22](C(O)=O)[C:23]([OH:25])=[O:24].C(OCC)C>N1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[C:22](/[C:23]([OH:25])=[O:24])\[CH3:21])[C@@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)[C@H]1[C@@H](C=O)C1(C)C
Reactant: CC(C(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: C/C(=C\[C@H]1[C@H](C(=O)OC(C)(C)C)C1(C)C)C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Under a nitrogen atmosphere, 0.165 g of tert-butyl (±)-cis-2,2-dimethyl-3-formylcyclopropanecarboxylate was dissolved in 5 mL of anhydrous pyridine. Seventeen-hundredths milliliters (0.17 mL) of piperidine and 0.197 g of methylmalonic acid was then added thereto, and the resulting mixture was stirred at a temperature of 60° C. for a time period of 1 hour. After the mixture was allowed to cool to room temperature, 100 mL of diethyl ether was added to said mixture and the resulting mixture was washed with 3N-hydrochloric acid and then saturated brine to obtain an organic layer therefrom. The organic layer was dried over anhydrous magnesium sulfate and thereafter the solvent was evaporated under reduced pressure in order to produce a residue. The residue was subjected to silica gel column chromatography, wherein the eluent was a mixture of n-hexane and ethyl acetate at a volume to volume ratio of 3:1 to give 0.199 g of tert-butyl (±)-trans-2,2-dimethyl-3-{2-carboxy-(E)-1-propenyl}cyclopropanecarboxylate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:8]([N+:17]([O-])=O)=[C:9]3[CH2:16][O:15][CH2:14][CH2:13][C:10]3=[N:11][CH:12]=2)=[N:2]1.ClC(Cl)(Cl)C(NC1C=[N+]([O-])C2CCCCC=2C=1)=O>CO.[C].[Pd]>[NH2:17][C:8]1[C:7]([NH:6][C:3]2[CH:4]=[CH:5][O:1][N:2]=2)=[CH:12][N:11]=[C:10]2[CH2:13][CH2:14][O:15][CH2:16][C:9]=12
Reactant: O=[N+]([O-])c1c(Nc2ccon2)cnc2c1COCC2
Agent: [Pd]
Agent: O=C(Nc1cc2c([n+]([O-])c1)CCCC2)C(Cl)(Cl)Cl
Solvent: CO
Product: Nc1c(Nc2ccon2)cnc2c1COCC2
Yield: 72.7 %

Procedure:
To a solution of 435 mg of Compound 7 obtained in (3) above in 95% aqueous methanol is added 10% palladium carbon (40 mg) as catalyst, and the resultant mixture is hydrogenated at ordinary temperature under atmospheric pressure. The reaction mixture is filtered, and the hardly soluble solid is washed out with dimethylformamide. The filtrate is concentrated in vacuo, and the residue is recrystallized from methanol-methylene chloride to give 280 mg of the titled compound (II2b) as light brown crystals. Yield: 72% mp.: 209° to 211° C. Elemental Analysis (%) C12H12N4O3Calculated: C, 55.38; H, 4.65; N, 21.53 Found: C, 55.08; H, 4.54; N, 21.24 NMR (d6 -DMSO) δ: 2.73 (2H, t); 3.90 (2H, t); 4.51 (2H, s); 5.93 (2H, s, NH); 7.06 (1H, d); 7.93 (1H, s); 9.15 (1H, d); 10.07 (1H, s, NH)
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].O.Cl.[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccccc1C(=O)c1ccccc1
Yield: 93 %

Procedure:
To a mechanically stirred solution of 1000 grams (7.12 moles) of benzoylchloride in 6000 grams of toluene was added 1000 grams (7.50 moles) of anhydrous aluminum chloride over a 20-30 minute period. The temperature of the reaction mixture rose to near the boiling point during the addition, and heating at reflux was maintained for three additional hours. After cooling, 1200 milliliters of water were added, slowly at first, followed by 1000 milliliters of concentrated hydrochloric acid. The organic layer was separated, washed twice with hot water and concentrated by simple distillation. Vacuum distillation of the residual oil provided 1300 grams (93% yield) of white, semi-solid methyl benzophenone; (b.p. 180°-200° C., 10-15 mm Hg; m.p. 50°-55° C.). The infrared spectrum revealed a carbonyl band at 1660 cm-1.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@H:3]([OH:5])[CH3:4].[C:7]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Si:11]([O:6][CH2:1][CH2:2][C@H:3]([OH:5])[CH3:4])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](O)CCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-Butane-1,3-diol (5.00 mL), tert-butylchlorodimethylsilane (8.82 g), N,N-dimethylpyridin-4-amine (0.34 g) and triethylamine (23.2 mL) were suspended in dichloromethane (60 mL) and stirred at room temperature overnight. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organics were dried over magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 5-10% ethyl acetate/hexane) to furnish to afford the title compound (8.33 g) having the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:24]CC1>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH:16]([OH:24])[C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCCc1cccc(C(=O)OC(C)(C)C)c1
Reactant: C1CCOC1
Product: COC(=O)C(O)CCc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a solution of methyl 4-(3-tert-butoxycarbonylphenyl)butanoate (200 mg, 0.71 mmol) in THF (2 ml) at −78° C. was added dropwise potasium bis(trimethyl)amide (0.5 M in toluene, 1.6 ml, 0.8 mmol). The mixture was stirred at this temperature for 0.5 hours and treated with dropwise addition of a solution of trans-2-phenylsulfonyl-3-phenyloxaziridine (223 mg, 0.8 mmol) in THF (2 ml). The mixture was stirred at −78° C. for 3 hours, quenched with aqueous ammonium chloride, warmed room temperature and diluted with ethyl acetate. The organic phase was washed with aqueous ammonium chloride, brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane:ethyl acetate=9:1) to give the title compound (90 mg, 43%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([O:27]C(C)C)[CH:24]=[C:23]([C:31](=[O:37])[NH:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:22]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.ClB(Cl)Cl.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:31](=[O:37])[NH:32][CH2:33][CH:34]([CH3:35])[CH3:36])[CH:24]=[C:25]([OH:27])[CH:26]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(OC(C)C)cc(C(=O)NCC(C)C)c3)cc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(O)cc(C(=O)NCC(C)C)c3)cc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 250 mL RBF was added 2-(4-fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-isopropoxyphenyl)-N-methylbenzofuran-3-carboxamide (1.3409 g, 2.67 mmol) in dichloromethane (20 mL). The flask was sealed with a septa, placed under N2 and stirred for 5 minutes. To this mixture was then added (cold) 1M trichloroborane (8.00 mL, 8.00 mmol) in dichloromethane. The solution was stirred at room temperature for 6 hours. The reaction mixture was cooled to 0° C. and methanol was added to quench the reaction. The flask was allowed to warm to room temperature and the volatiles were removed to give a quantitative yield of a tan solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.06 (d, J=6.78 Hz, 6H), 1.97-2.12 (m, 1H), 3.01-3.12 (m, 3H), 3.29 (t, J=6.53 Hz, 2H), 7.27-7.40 (m, 4H), 7.64 (s, 1H), 7.72 (s, 2H), 7.98 (s, 1H), 8.03 (dd, J=8.66, 5.40 Hz, 2H), 8.56 (br. s., 1H). LCMS Rt 2.157 min., m/z 461.03 (M+H), 97.6% purity.
Reaction SMILES: [F:1][C:2]1[C:18]([N:19]2[C:28](=[O:29])[C:23]3[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=3[C:20]2=[O:21])=[CH:17][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15]C)[N:7]=[N:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[C:18]([N:19]2[C:20](=[O:21])[C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[C:28]2=[O:29])=[CH:17][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[OH:15])[N:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccccc1-n1nnc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc2c(cc1F)nnn2-c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-[5-fluoro-1-(o-methoxyphenyl)-1H -benzotriazol-6-yl]-1-cyclohexene-1,2-dicarboximide (1.00 g, 0.003 mol) in methylene chloride is slowly added to a one molar boron tribromide in methylene chloride solution (5 mL, 0.005 mol) at -20° C. The reaction mixture is stirred at room temperature overnight, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a tan solid. Flash column chromatography of the solid using silica gel and 2.5% to 10% ethyl acetate in methylene chloride solutions gives the title product as a white solid, mp 274°-275° C.
Reaction SMILES: [F:1]/[C:2](=[C:13](/[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[O:22][C:21]([CH3:29])([CH3:28])[CH:20]=[C:19]2[CH3:30])\[CH2:14][CH3:15])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C.C1COCC1>[F:1]/[C:2](=[C:13](/[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[O:22][C:21]([CH3:29])([CH3:28])[CH:20]=[C:19]2[CH3:30])\[CH2:14][CH3:15])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OC)OC(C)(C)C=C2C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC/C(=C(F)/C=C/C(C)=C/C(=O)O)c1cc2c(cc1OC)OC(C)(C)C=C2C

Procedure:
Following General Procedure G, a solution of ethyl 6-fluoro-7-(7-methoxy-2,2,4-trimethyl-2H-chromen-6-yl)-3-methyl-nona-2E,4E,6E-trienoate (Compound 116,204 mg, 0.51 mmol) in ethanol and THF was hydrolyzed with 1M NaOH. Purification by flash chromatography (silica gel, 75:25 hexane/ethyl acetate) afforded the title compound as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([F:11])[C:7]([F:12])=[CH:6]2>C(O)(=O)C.[Zn]>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([N:3]2[CH:2]=[C:10]3[C:5]([CH:6]=[C:7]([F:12])[C:8]([F:11])=[CH:9]3)=[N:4]2)=[CH:18][CH:17]=1
Reactant: Fc1cc2nn(-c3ccc(Cl)cc3)c(Cl)c2cc1F
Agent: [Zn]
Solvent: CC(=O)O
Product: Fc1cc2cn(-c3ccc(Cl)cc3)nc2cc1F
Yield: 82.1 %

Procedure:
Zinc powder (14.7 g, 225 mmol) was added to a suspension of 3-chloro-2-(4-chloro-phenyl)-5,6-difluoro-2H-indazole (16.8 g, 56 mmol) in acetic acid (118 ml). The suspension was heated under reflux conditions for 2 h. The hot solution was filtered, the filtrate was poured onto ice water/brine 1/1 and extracted two times with TBME. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a brown solid which was crystallized from dichloromethane/n-heptane to give the title compound (12.1 g, 46 mmol; 81%) as brown crystals. MS: m/e=265.1 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[O:18][N:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[O-]CC.[Na+].O>C(O)C>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[C:14](=[O:18])[CH2:15][C:16]#[N:17])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-c1ccno1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A solution of 5-(2-nitro-4-trifluoromethylphenyl)-isoxazole (4.91 g.) in ethanol (35 ml) was added dropwise to a solution of sodium ethoxide in ethanol (prepared from 0.6 g sodium in 25 ml ethanol). The mixture was stirred at room temperature for 3 hours, poured into water (150 ml) and acidified to pH 1. It was extracted with ether (2×75 ml) and the combined extracts were washed with water, dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was triturated with petroleum spirit (bp 60°-80° C.) and filtered to give 3-(2-nitro-4-trifluoromethylphenyl)-3-oxopropionitrile (4.9 g) as an off-white solid mp 79.5°-80.5° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=1)=[O:32]>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=2)=[O:32])[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Product: O=C(COCCCc1c[nH]cn1)c1cccc([N+](=O)[O-])c1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of 2-bromo-1-(3-nitrophenyl)ethanone are treated as described in Example 74.
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)=[CH:7][CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C(OCC)C>[CH3:20][O:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([O:21][CH3:22])[CH:16]=1)/[CH:12]=[CH:11]/[C:8]1[CH:7]=[CH:6][C:5]([SH:4])=[CH:10][CH:9]=1
Reactant: COc1cc(/C=C/c2ccc(SC(=O)N(C)C)cc2)cc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1cc(/C=C/c2ccc(S)cc2)cc(OC)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of (E)-S-4-(3,5-dimethoxystyryl)phenyl dimethylcarbamothioate (50 mg, 0.14 mM) in ethyl ether (10 mL) was added LiAlH4 (6 mg, 0.14 mM) at 0° C. The reaction mixture was stirred at 65° C. for 3 h. The mixture was poured into water (10 mL) and a solution of 1M HCL (10 mL). The crude mixture was purified by column chromatography eluting with hexanes:ethyl acetate (4:1) and gave ARS27.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:22])=O)[CH:16]=3)[O:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[C:27]=1[OH:33])=[O:25]>>[C:24]([C:26]1[C:27]([OH:33])=[C:28]([NH:32][C:20]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[O:11][CH:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:19][CH2:18]3)=[O:22])[CH:29]=[CH:30][CH:31]=1)(=[O:25])[CH3:23]
Reactant: CC(=O)c1cccc(N)c1O
Reactant: O=C(O)c1ccc2c(c1)CCC(CCCc1ccccc1)O2
Product: CC(=O)c1cccc(NC(=O)c2ccc3c(c2)CCC(CCCc2ccccc2)O3)c1O
Yield: 45 %

Procedure:
Following the process described in example 1 (point K), starting from 2-(3-phenylpropyl)-6-chromanecarboxylic acid and 3-amino-2-hydroxyacetophenone, the title compound was prepared (45% yield).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>ClCCl.N>[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(N)cc1
Reactant: COC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: N
Solvent: ClCCl
Product: COc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 77 from 1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-methoxyaniline in dichloromethane and methanolic ammonia.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:19][CH3:20])[N:9]=2)=[C:6]([F:21])[CH:5]=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])(=[O:25])=[O:24].Cl[C:35]([O:37][CH3:38])=[O:36].C(OCC)C>C(Cl)Cl.O>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[S:23]([N:22]([C:3]1[CH:4]=[CH:5][C:6]([F:21])=[C:7]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[CH:11][N:10]([CH2:19][CH3:20])[N:9]=2)[C:2]=1[F:1])[C:35](=[O:36])[O:37][CH3:38])(=[O:24])=[O:25]
Reactant: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(N(C(=O)OC)S(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
N-{2,4-difluoro-3-[1-ethyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-2,5-difluorobenzenesulfonamide (80 mg, 0.168 mmol) was suspended in 3.5 mL of DCM and TEA (18.7 mg, 25.8 μL, 0.185 mmol) was added. Methyl chloroformate (17.5 mg, 13.0 L, 0.185 mmol) was added to the solution so obtained, and the reaction mixture was stirred at room temperature for 3 hours, diluted with DCM, and poured in water. The organic layer was washed three times with water, once with brine, dried over Na2SO4 and concentrated to dryness. The solid so obtained was taken up with ethyl ether and filtered (72 mg, 80% yield)
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Boc-Val-OH (8.69 g, 40.0 mmol) and Gly-OBzl.HCl (8.07 g, 40.0 mmol) were dissolved in methylene chloride (100 ml), and the solution was maintained at 0° C. Triethylamine (6.13 ml, 44.0 mmol), HOBt (1-hydroxybenzotriazole, 6.74 g, 44.0 mmol), and WSC.HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 8.44 g, 44.0 mmol) were added to the solution, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (50 ml), 5% citric acid aqueous solution (50 ml×twice), saturated brine (50 ml), 5% sodium hydrogencarbonate aqueous solution (50 ml×twice), and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, then the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to obtain white crystals of Boc-Val-Gly-OBzl (13.2 g, 36.2 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:11]([O:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:27]=2)[C:22]([CH2:36][O:37][CH3:38])=[N:21][C:20]=1[C:39](O)=[O:40])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:1]([O:5][C:6](=[O:10])[C@@H:7]([NH:8][C:39]([C:20]1[N:21]=[C:22]([CH2:36][O:37][CH3:38])[C:23]2[C:28]([C:19]=1[O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:27][CH:26]=[C:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24]=2)=[O:40])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: COCc1nc(C(=O)O)c(OCc2ccccc2)c2ccc(Oc3ccccc3)cc12
Product: COCc1nc(C(=O)N[C@@H](C)C(=O)OC(C)(C)C)c(OCc2ccccc2)c2ccc(Oc3ccccc3)cc12

Procedure:
Synthesized from (S)-alanin tert-butyl ester and 4-Benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid (Example A-68 c) in analogy to Example A-68 d); MS-(+)-ion: M+23=565.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[CH:5]=[C:6]([CH3:10])[C:7]([OH:9])=[O:8]>CO.O=[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8]
Reactant: CC(=Cc1ccc(F)c(F)c1)C(=O)O
Agent: O=[Pt]=O
Solvent: CO
Product: CC(Cc1ccc(F)c(F)c1)C(=O)O

Procedure:
3,4-difluoro-α-methylcinnamic acid (28 g; 0.141 mol), PtO2 (1 g) in MeOH (250 ml) is hydrogenated at 45 p.s.i. until the theoretical uptake is completed. The catalyst is filtered off, and the material is evaporated to one-third of its original volume. A 15% potassium hydroxide solution (10 ml) is added, and the mixture is refluxed for 30 minutes. It is poured into water and extracted with ether (2×100 ml). The aqueous layer is acidified with concentrated HCl and ice, to produce an oil which is extracted into ether. The ether solution is dried over MgSO4, and is evaporated to leave 3,4-difluoro-α-methylhydrocinnamic acid (m.p. 55-56° C.) as a clear oil which crystallizes.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(C)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:11]2[CH:10]=[CH:9][NH:8][CH2:13][CH2:12]2)=[CH:16][CH:17]=1
Reactant: CC1(c2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Clc1ccc(C2C=CNCC2)cc1
Yield: 125.4 %

Procedure:
To a cold (0° C.) solution of N-benzyl-4-(4-chlorophenyl)-4-methylpiperidine (3) (0.41 g, 1.4 mmol) in CH2Cl2 was 1.1 equivalent of 1-chloroethylchloroformate. The reaction was then heated to reflux for 2 hrs. Excess solvent was removed and the residue was brought up into methanol. The mixture was refluxed for 2 hrs and excess methanol was removed under reduced pressure. Precipitation of the hydrochloride salt 4 by the addition of CH2Cl2 followed by filtration resulted in the quantitative isolation of the desired crystalline product 4 (100%, 0.34 g). MS m/z: (M+210)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[CH3:12][O:13][C:14]1[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=1[CH:16]=[N+:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]([C:15]1[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=1[O:13][CH3:12])[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: COc1ccccc1C=[N+]1CCCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1c[nH]c2ccc(Cl)cc12)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-chloro-1H-indole and 1-(2-methoxy-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 24.