Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[C:30]([C:31]#[C:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:29][N:13]([C@@H:14]2[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:41])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+].[CH3:58][S:59]([CH3:61])=O>>[C:1]([NH:9][C:10]1[C:30]([C:31]#[C:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:37])([F:38])[F:39])=[CH:29][N:13]([C@@H:14]2[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[C@@H:16]([O:17][CH2:58][S:59][CH3:61])[CH2:15]2)[C:12](=[O:41])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)C[C@@H]1O
Reactant: CS(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CSCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
The starting material (13) (2.85 g, 4.79 mmol) was dissolved in dry DMSO (40 ml) under N2 atmosphere. Acetic acid (2.7 ml, 47.9 mmol) and acetic anhydride (14.4 ml, 143.7 mmol) were added sequentially and slowly to the starting material, which was then stirred for 18 h at room temperature. Saturated NaHCO3 (150 ml) solution was carefully added to the reaction mixture. The aqueous layer was extracted with EtOAc (3×150 ml). The organic layers were combined, dried (MgSO4), filtered and evaporated to yield an orange liquid that was subsequently azeotroped with toluene (4×150 ml) until material solidified. Crude residue purified on silica gel (petroleum ether:EtOAc 3:1 to 2:1) to yield a yellow crystalline solid (14) (1.58 g, 50%). 1H NMR (d6 DMSO): δ 0.00 (s, 6H, CH3), 0.78 (s, 9H, tBu), 1.99 (s, 3H, CH3), 2.09 (m, 1H, H-2′), 2.28 (m, 1H, H-2′), 3.66 (d, 1H, J=11.5, 2.9 Hz, H-5′), 3.74 (dd, 1H, J=11.3, 2.9 Hz, H-5′), 3.99 (m, 1H, H-4′), 4.09 (m, 1H, CH2NH), 4.29 (m, 1H, H-3′), 4.61 (s, 2H, CH2S), 6.00 (m, 1H, H-1′), 7.37 (m, 2H, Ph), 7.50 (m, 2H, Ph), 7.80 (d, 1H, J=7.55 Hz, HAr), 7.97 (s, 1H, H-6), 9.79 (br t, 1H, NHCH2), 12.64 (br s, 1H, NH). Mass (−ve electrospray) calcd for C29H37F3N4O6SSi 654.79. Found 653.2.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-:39][Si](C)(C)C)(C)C.[Na+].C1(P(C2C=CC=CC=2)(ON)=O)C=CC=CC=1>CN(C=O)C.C1COCC1>[NH2:39][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[O:11])[CH:7]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:6]2[N:5]([C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)[C:4]1=[O:34]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccncc3)c3ccccc32)C(C)C)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)N(c3ccncc3)C3C=CC=CC32)C(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 80 mg (0.175 mmol) 2-(2,4-Dioxo-5-pyridin-4-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl )-acetamide in 3 mL DMF was added 0.210 mL (0.209 mmol, 1.2 equiv) 1N Sodium bis(trimethylsilyl)amide in THF at 0° C. After stirring 0.5 h, 62 mg (0.262 mmol; 1.5 equiv) O-(diphenyl-phosphinyl)hydroxylamine (Harger, J. C. S. Perkin I, 3284-3288 (1981)) was added and the reaction mixture stirred 16 h at ambient temperature. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude product was purified by flash chromatography on 5 g silica gel eluted successively with EtOAc (100 mL), DCM/CH3OH (19:1, 100 mL). Appropriate fractions were combined and concentrated in vacuo to give the title compound as a clear glass: low resolution MS (FAB) m/z 474.2 (MH+); TLC Rf=0.31 (DCM/CH3OH, 19:1)).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]=1.[CH2:12]([Li])[CH2:13][CH2:14][CH3:15].Br[CH2:18][CH2:19]Br>C1COCC1.CCCCCC>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:15][CH2:14][CH:13]2[C:12]3[C:4](=[CH:5][CH:6]=[CH:18][CH:19]=3)[C:3]([O:2][CH3:1])=[CH:11]2)[CH:4]=1
Reactant: BrCCBr
Reactant: COC1=CCc2ccccc21
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC1=CC(CCC2C=C(OC)c3ccccc32)c2ccccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
10.9 g (75 mmol) of 3-methoxyindene (prepared as described in J. Am. Chem. Soc. 106 (1984) 6702) were dissolved in 100 ml of THF, and 47 ml (75.2 mmol) of a 1.6M butyllithium solution in hexane were added. The mixture was stirred at 50° C. for 2 hours, 3.25 ml (30.1 mmol) of 1,2-dibromoethane in 30 ml of THF were added dropwise at -78° C., and the mixture was warmed to room temperature. The solvent was stripped off, and the product was extracted with toluene. Yield 6.2 g (64%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH2:17][CH3:18])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH2:17][CH3:18])[C:9]2[C:14]([C:15]=1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cccnc2n(CC)c1=O
Reactant: CN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCN(C)CC2)c2cccnc2n(CC)c1=O

Procedure:
A stirred mixture of 4.2 g. (0.015 mole) of 1-ethyl-1,2-dihydro-4-chloro-2-oxo-1,8-naphthridine-3-carboxylic acid ethyl ester (prepared in the manner described in Example 30), 1.5 g. (0.015 mole) of N-methylpiperazine and 1.6 g. (0.015 mole) of sodium carbonate in 20 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with 50 ml. of 20% aqueous sodium carbonate and this mixture was extracted with 50 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was diluted with 50 ml. of ethanol. This solution was slowly acidified with an ethereal hydrochloric acid solution. The precipitate which formed was collected and was recrystallized from ethanol to give 2.5 g. of product as the hydrochloride, m.p. 230°-233° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([C:12]([NH2:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[S-2:17].[Na+].[Na+].Br[C:21]1[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1>CN(C)C=O>[CH3:16][O:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([S:17][C:21]3[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)=[CH:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[C:12]([NH2:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Br)s1
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Sc3ccc([N+](=O)[O-])s3)c2cc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
4-Chloro-7-methoxyquinoline-6-carboxamide (1.18 g, 5.00 mmol) and sodium sulfide (1.20 g, 5.50 mmol) were heated and stirred in dimethylformamide (10 ml) at 60° C. for 3 hours. After cooling the reaction solution to room temperature, 2-bromo-5-nitrothiophene (1.25 g, 6.00 mmol) was added and the mixture was further heated and stirred at 60° C. for 1 hour. The reaction solution was returned to room temperature and then poured into ice water (50 ml), and the precipitated crystals were filtered out, washed with water and methanol and then blow-dried to obtain the title compound (700 mg, 1.94 mmol, 39%) as yellowish-brown crystals.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:39])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[O:28])=[C:22]([O:37][CH3:38])[CH:21]=3)=[CH:13][CH:12]=2)[CH2:9][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(#N)C.C(O)C>[CH2:40]([N:8]1[CH2:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:39])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[O:28])=[C:22]([O:37][CH3:38])[CH:21]=3)=[CH:13][CH:12]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Product: COc1cc(CC(=O)Nc2ccc(C3CN(Cc4ccccc4)CC3C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
A stirred solution of 1-benzyl-4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (2.95 g, Reference Example 16) in a mixture of acetonitrile (150 mL) and ethanol (125 mL), at 50° C., was treated slowly with aqueous sodium hydroxide solution (0.46 mL, 30%). After stirring for 8 hours at room temperature and then gentle stirring for a week, the mixture was filtered. The solid was washed with dichloromethane (30 mL), then dried under reduced pressure (2.7 kPa) and then treated with water (200 mL). The mixture was acidified by addition of hydrochloric acid (3.5 mL, 1 M), then allowed to stand at room temperature for 15 hours, then treated with ethyl acetate (400 mL) and then filtered to give the title compound (1.16 g) as a white powder, m.p. 255° C. 1H-NMR [400 MHz, (CD3)2SO]: δ 2.27 (s, 3H); 2.45 to 2.60 (m, 1H); 2.80 to 3.00 (m, 4H); 3.49 (m, 1H); 3.57 (s, 2H); 3.58 and 3.68 (2 d, J=14 Hz, 2H); 3.90 (s, 3H); 6.85 (bd, J=8 Hz, 1H); 6.95 (bt, J=7 Hz, 1H); 7.02 (bs, 1H); 7.05 to 7.20 (m, 2H); 7.20 to 7.30 (m, 3H); 7.30 to 7.40 (m, 4H); 7.52 (bd, J=8 Hz, 2H); 7.82 (bd, J=8 Hz, 1H); 8.04 (d, J=8 Hz, 1H); 8.48 (bs, 1H); 8.59 (bs, 1H); 10.07 (bs, 1H). MS(LSIMS): 593[M+HI]+.
Reaction SMILES: [C:1]1([S:17]([O-:20])(=O)=[O:18])[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na+].O=P(Cl)(Cl)[Cl:24].S1(CCCC1)(=O)=O>C(#N)C>[Cl:24][S:17]([C:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1)(=[O:20])=[O:18]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2S(=O)(=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)c2c1cccc2S(=O)(=O)Cl
Temperature: 110 °C

Procedure:
Sodium anthraquinone-1-sulfonate (50.0 g) was combined with POCl3 (31 mL) and a 1:2 (v/v) mixture of sulfolane (100 mL) and acetonitrile (200 mL). The mixture was stirred and heated to 110° C. under a nitrogen atmosphere for 44 hours. The mixture was allowed to cool to room temperature and was then further cooled in a refrigerator. The mixture was filtered and the filtrate was poured onto ice in a beaker and this mixture was stirred for 1 hour. The brown precipitate was filtered, washed with deionized water, dried in air and then further dried overnight in a vacuum oven at 45° C. and less than lmmHg pressure to give 12.08 g of the product as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[CH3:11][C:12]([N+:19]#[C-:20])([CH3:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15].[CH3:21][O:22][C:23]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O>Cl(O)(=O)(=O)=O>[Br:9][C:5]1[CH:6]=[C:7]([Br:8])[C:2]2[N:3]([C:20]([NH:19][C:12]([CH3:18])([CH3:11])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:25]([C:24]3[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:23]=3[O:22][CH3:21])[N:1]=2)[C:4]=1[CH3:10]
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: Cc1nc(N)c(Br)cc1Br
Reactant: COc1cccc(C=O)c1OC
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1cccc(-c2nc3c(Br)cc(Br)c(C)n3c2NC(C)(C)CC(C)(C)C)c1OC

Procedure:
Compound (6) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-3,5-dibromo-6-methylpyridine solution (0.1 M, DCM), 0.575 ml of 1,1,3,3-tetramethylbutyl isocyanide solution (0.2 M, DCM), 0.500 ml of 2,3-dimethoxybenzaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1)[CH2:2][CH3:3].[C:12]1([CH3:24])[CH:17]=[CH:16][C:15]([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH2:1]([CH:4]1[CH2:5][C:6](=[O:11])[CH:7]([C:22](=[O:23])[NH:21][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:24])=[CH:13][CH:14]=2)(=[O:19])=[O:20])[C:8](=[O:10])[CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCC1CC(=O)CC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: CCCC1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(C)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-propyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-PROPYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 132.5°-133.5° C. (corr.).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@H:10]([CH:14]2[CH2:17][NH:16][CH2:15]2)[CH:11]([CH3:13])[CH3:12])[CH:6]=[C:7]([F:9])[CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:25]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>C(#N)C>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C@H:25]([N:16]2[CH2:15][CH:14]([C@@H:10]([C:5]3[CH:6]=[C:7]([F:9])[CH:8]=[C:3]([F:2])[CH:4]=3)[CH:11]([CH3:13])[CH3:12])[CH2:17]2)[C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:39][CH:38]=1
Reactant: CC(C)[C@H](c1cc(F)cc(F)c1)C1CNC1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 106 mg (0.5 mmole) of 3-[(1S)-1-(3,5-difluorophenyl)-2-methylpropyl]azetidine hydrochloride from Step 3 and 0.650 g (2 mmole) of Cs2CO3 in 5 mL dry acetonitrile was stirred at rt in a flask fitted with a small Dean-Stark trap. After 15 minutes, 0.306 g (1 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile was added and the mixture was heated at 60° C. After 18 h, the solution was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over Na2SO4. The solution was filtered and the filtrate was concentrated to an oil. The residue was purified by chromatography on a ChralPak AD column using 4% isopropanol-heptane to afford two enantiomers. Fractions containing the slower product diastereomer were pooled and concentrated to afford the title compound; Mass Spectrum: m/e=451 (M+1, 35Cl) and 453 (M+1, 37Cl).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:40])[C:16]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=3)[CH:19]=[C:18]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:43].[K+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:16]2[CH:21]=[C:20]([CH:19]=[C:18]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:17]=2)[O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:43])=[O:30])=[CH:25][CH:24]=2)=[O:40])[CH2:10][CH2:9]1)=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C=O)cc3)c2)CC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C(=O)O)cc3)c2)CC1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
0.5 g (0.9 mmol) of {4-[3-(4-cyano-phenoxy)-5-(4-formyl-phenoxy)-benzoyl-amino]-cyclohexyl}-carbamic acid tert-butyl ester was dissolved in 15 ml of THF and 0.43 g (2.7 mmol) of potassium permanganate, dissolved in 8 ml of water, was added to THF solution at 10° C. during 10 min. The reaction mixture stirred over night at RT. Reaction progress was monitored by TLC. Reaction mixture was filtered through celite and washed with THF and thus obtained mother liquor was concentrated under vacuo. Product was crystallized with ethyl acetate to afford 0.25 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.36 (9H, s), 1.78 (4H, m), 3.18 (1H, m), 3.66 (1H, m), 6.75 (1H, d), 6.94 (3H, m), 7.18 (2H, d), 7.36 (2H, s), 7.86 (4H, d), 8.38 (1H, d).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3]C1C=C2C(C=CN2)=CC=1.C(O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27]([NH2:29])=[O:28])[CH:22]=[C:21]2[N:30]=[C:31]=[O:32])C=C>>[F:1][CH:2]([F:13])[O:3][C:26]1[CH:25]=[C:24]2[C:20]([C:21]([N:30]=[C:31]=[O:32])=[CH:22][N:23]2[C:27]([NH2:29])=[O:28])=[CH:19][CH:18]=1
Reactant: FC(F)Oc1ccc2cc[nH]c2c1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Product: NC(=O)n1cc(N=C=O)c2ccc(OC(F)F)cc21

Procedure:
was prepared from 6-difluoromethoxy-1H-indole [200207-21-2] using the protocol described for steps B-E in Scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH2:16])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29]>C(#N)C.CO.C(OCC)C>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29].[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH:16][CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:12]
Reactant: ClCCSc1ccccc1
Reactant: CCN(CC)CCN
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: CCOCC
Product: CCN(CC)CCNCCSc1ccccc1
Yield: 43.2 %

Procedure:
A mixture of 60.24 g (0.350 mole) of [(2-chloroethyl)thio]benzene, 84 g (0.72 mole) of N,N-diethylethylenediamine, and 80.0 g (0.75 mole) of sodium carbonate in 1.5 liters of acetonitrile was refluxed for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over sodium sulfate, and the solvent was removed in vacuo to give an oil. This was dissolved in 800 ml of methanol. A solution of approximately 2 equivalents of maleic acid in methanol was added followed by the addition of anhydrous diethyl ether until the solution became slightly cloudy. A white solid precipitated at -5° C. to give 73.15 g (43.2%) of title compound, a white crystalline solid, mp 131°-133° C.
Reaction SMILES: [N+:1]([C:4]1[CH:39]=[CH:38][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[I-:40].[Na+]>CC(CC)=O>[N+:1]([C:4]1[CH:39]=[CH:38][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26][I:40])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OC(=O)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Temperature: 25 °C

Procedure:
(2S,4R)-1-(p-Nitrobenzyloxycarbonyl)-2-p-toluenesulfonyloxymethyl-4-benzoyloxypyrrolidine (35.82 g) was dissolved in 90 ml of methylethylketone, and 19.29 g of sodium iodide was added thereto, followed by stirring under reflux for 1 hour. The reaction mixture was cooled down to room temperature and filtered. The filtrate was distilled to remove the solvent. The residue was diluted with ethyl acetate, washed successively with water, a sodium hypochlorite solution and water and dried over anhydrous sodium sulfate. The solvent was removed by distillation to give (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-iodomethyl-4-benzoyloxypyrrolidine.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([N:13]([CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)[CH3:14])=[O:19]
Reactant: CNCCC#Cc1cccc(CF)n1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Product: CN(CCC#Cc1cccc(CF)n1)C(=O)c1c(Cl)cccc1Cl
Yield: 5.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from 4(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (180 mg, 0.93 mmol) and 2,6-dichlorobenzoyl chloride (255 mg, 1.22 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 18.5 mg of 2,6-dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide as a yellow oil (Yield: 5%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:5](=[O:17])[NH:4][C:3]=1[C:18]1[N:22]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[N:21]=[CH:20][CH:19]=1.[CH2:31]([N:33]([CH2:36]C)[CH2:34]C)[CH3:32].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:40].CNCC>C(Cl)Cl.CCOC(C)=O.C1CCCCC1>[C:27]([C:26]1[CH:25]=[CH:24][C:23]([N:22]2[C:18]([C:3]3[N:4]([C:34]([N:33]([CH2:31][CH3:32])[CH3:36])=[O:40])[C:5](=[O:17])[N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=4)[C:2]=3[CH3:1])=[CH:19][CH:20]=[N:21]2)=[CH:30][CH:29]=1)#[N:28]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CCNC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CCN(C)C(=O)n1c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(5-{5-Methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (107 mg, 0.262 mmol) was stirred in DCM (3 mL) and triethylamine (0.109 mL, 0.786 mmol) with N,N-dimethylaminopyridine (2 mg). To this mixture was added 4-nitrophenyl chloroformate (106 mg, 0.524 mmol) and the resulting mixture stirred at RT for 1 h. N-methylethylamine (93 mg, 1.57 mmol) in DCM (1 mL) was then added and stirring was continued for a further 2 h. The mixture was diluted with more DCM, washed with water, the organic phase separated, dried over Na2SO4 and evaporated. The product was purified by chromatography on a 12 g silica gel column, eluting with a gradient of 20% to 60% EtOAc in cyclohexane. The gum thus obtained was dissolved in a small quantity (<1 mL) of EtOAc and diluted with cyclohexane resulting in a formation of a white solid which was filtered off and dried. (65 mg, 50%).
Reaction SMILES: [C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)[C:6]([O:20][C@@H:21]2[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]2[OH:23])=[N:5]1)(=[O:3])[CH3:2].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC1C=C(C)C=C(C)N=1>[C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)[C:6]([O:20][C@@H:21]2[O:29][C@H:28]([CH2:30][O:31][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]2[OH:23])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(C(C)=O)c2C)cc1
Reactant: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(C(C)=O)c(C)c2Cc2ccc(SCC)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-acetyl-4-[(4-ethylthiophenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-methylpyrazole (0.03 g) in 2,4,6-trimethylpyridine (0.5 mL) was added ethyl chloro-formate (0.012 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% aqueous citric acid solution (5 mL), and the resulting mixture was stirred at room temperature overnight. The resulting precipitatse were collected by filtration and washed with 10% aqueous citric acid solution and water to give 1-acetyl-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-ethylthiophenyl)methyl]-5-methylpyrazole (0.020 g).