Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.C(=O)([O-])[O-].[K+].[K+].[O:16]1[CH2:18][C:17]21[C:31]1[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:25]1([CH2:33][O:32]1)[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]2=1>CCOCC>[CH:23]1[C:24]2[CH:25]([CH:33]=[O:32])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]([CH:18]=[O:16])[C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc2c(c1)C1(CO1)c1ccccc1C21CO1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=CC1c2ccccc2C(C=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A mixture of 0.1 ml. of boron trifluoride etherate in 40 ml. of ether and 2.0 g. of potassium carbonate is stirred at 0° C. for 10 minutes. A solution of 500 mg. of dispiro[oxirane-2,9'(10'H)-anthracene-10',2"-oxirane] in 20 ml. of ether is added. The resulting mixture is stirred at 0° C. for an additional 2 minutes, and filtered. The ether filtrate is washed twice with a mixture of 10 ml. of saturated sodium bicarbonate solution and 10 ml. of ice-water, then dried over anhydrous sodium sulfate and filtered. The ether is removed and the residue is recrystallized from ether/hexane to give 384 mg. of the desired product as yellow crystals, m.p. 132°-135° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:6].[CH3:12][N:13]([CH3:18])[S:14](Cl)(=[O:16])=[O:15]>C1COCC1.O>[CH3:3][O:4][C:5]([C:7]1[CH:11]=[CH:10][N:9]([S:14](=[O:16])(=[O:15])[N:13]([CH3:18])[CH3:12])[N:8]=1)=[O:6]
Reactant: COC(=O)c1cc[nH]n1
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccn(S(=O)(=O)N(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
Sodium hydride (1.57 g, 41.03 mmol) was added to a solution of 1H-pyrazole-3-carboxylic acid methyl ester (3.45 g, 27.36 mmol) in THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes. Then dimethylsulfamoyl chloride (4.41 mL, 41.03 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with water and the product extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield 1-dimethylsulfamoyl-1H-pyrazole-3-carboxylic acid methyl ester (4.8 g, 75% yield) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1([CH3:21])[CH:14]=[CH:13][C:12]([S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19]([NH:18][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:21])=[CH:10][CH:11]=2)(=[O:17])=[O:16])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)cc1
Yield: 94.3 %

Procedure:
A solution of 6.25 g (49.00 mmoles) of 4-chloroaniline in 10 ml of methylene chloride was added to a solution of 9.85 g (49.95 mmoles) of p-toluenesulfonyl isocyanate in 75 ml of methylene chloride with stirring. The mixture became quite warm and a heavy white precipitate formed. An additional 100 ml of methylene chloride were added. The reaction mixture was stirred an additional 15 minutes, and the precipitate was recovered by filtration affording 15.0 g of the title product as a white solid. A small amount of the material was crystallized from diethyl ether to provide the title compound (87% yield) with a melting point of 174-176_C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[O:21][C:22](=[O:39])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C@@H:35]([CH3:38])[CH2:36][CH3:37])=[CH:25][CH:24]=1.[Cu][C:41]#[N:42].N>CN1CCCC1=O>[C:41]([C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[O:21][C:22](=[O:39])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C@@H:35]([CH3:38])[CH2:36][CH3:37])=[CH:25][CH:24]=1)#[N:42]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(OC(=O)c3ccc(OCCCCC[C@@H](C)CC)cc3)c(Br)c2)CC1
Reactant: N#C[Cu]
Agent: N
Solvent: CN1CCCC1=O
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(OC(=O)c3ccc(OCCCCC[C@@H](C)CC)cc3)c(C#N)c2)CC1
Temperature: 185 °C
Reaction time: 0.5 h
Yield: 5.5 %

Procedure:
A mixture of 2 g of (S)-4-(6-methyloctyloxy)benzoic acid 2-bromo-4-[2-(trans-4-pentylcyclohexyl)ethyl]phenyl ester, 0.5 g of anhydrous copper(I) cyanide and 50 ml of absolute 1-methyl-2-pyrrolidone was heated to 185° C. on a oil-bath for 2 hours. The cooled mixture was subsequently treated with 50 ml of 15% ammonia solution and stirred for 30 minutes. Thereafter, the reaction mixture was extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed twice with 250 ml of water each time, dried over magnesium sulphate and concentrated. Chromatography of the residue on silica gel with toluene/hexane (vol. 1:1) gave 0.1 g of (S)-4-(6-methyloctyloxy)benzoic acid 2-cyano-4-[2-(trans-4-pentylcyclohexyl)ethyl]phenyl ester; m.p. (C-Ch) 80° C., transition S*C -Ch 50° C. (monotropic), cl.p. (Ch-I) 120° C.
Reaction SMILES: C(O)(=O)C.C(#N)C.C([O-])(=O)C.[Na+].[C:13]([C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][CH:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C.[Mn+3].C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[C:13]([C:21]1[N:22]2[C:27](=[CH:26][CH:25]=1)[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:23]2)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(CCc1cc[nH]c1C(=O)c1ccccc1)C(=O)OCC
Agent: [Mn+3]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21

Procedure:
To a warm, preferably 60°-80° C., mixture of a high valence metal ion, preferably a manganese(III) salt, and more preferably manganese(III) acetate, in an alkanoic acid, preferably acetic acid, or a polar aprotic solvent such as acetonitrile, is added a weak base, preferably sodium acetate, and a compound of formula IV, preferably 2-benzoyl-[3,3-di(ethoxycarbonyl)propyl]pyrrole. The reaction is stirred, preferably at 50°-70° C. until the reaction is complete. The reaction mixture is diluted with a polar solvent, such as diethyl ether, and filtered. The resulting solution is washed with water and aqueous base, preferably 10% sodium hydroxide, dried, and concentrated under reduced pressure. The product, a compound of formula I, preferably diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate, may be isolated by conventional means.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:21]([BH3-])#[N:22].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>C(O)(=O)C.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH3:15][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([CH2:1][NH:22][CH3:21])[CH:4]=2)[CH:14]=1
Reactant: [BH3-]C#N
Reactant: Cc1ccc(C#N)c(Oc2cccc(C=O)c2)c1
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2cc(C)ccc2C#N)c1
Yield: 19.2 %

Procedure:
2-(3-Formyl-phenoxy)-4-methyl-benzonitrile (0.26 g, 1.1 mmol), methylamine (2M in methanol, 2.5 mL, 5.0 mmol) and sodium cyanoborohydride (80 mg, 1.3 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (30 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.1 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-methyl-2-(3-methylaminomethyl-phenoxy)-benzonitrile fumarate (78 mg, 20%) as a tan solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([N:14]2[C:18](=[O:19])[CH2:17][S:16][C:15]2=[O:20])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[C:35]3[C:30](=[CH:31][C:32]([CH:36]=O)=[CH:33][CH:34]=3)[CH:29]=[N:28]2)=[C:24]([C:40]([F:43])([F:42])[F:41])[CH:23]=1>>[Cl:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[C:35]3[C:30](=[CH:31][C:32](/[CH:36]=[C:17]4/[C:18](=[O:19])[N:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[C:15](=[O:20])[S:16]/4)=[CH:33][CH:34]=3)[CH:29]=[N:28]2)=[C:24]([C:40]([F:41])([F:43])[F:42])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(N2C(=O)CSC2=O)CC1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1N1CCNCC1

Procedure:
((5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperazin-1-yl-1,3-thiazolidine-2,4-dione was prepared from 4-(2,4-dioxo-thiazolidin-3-yl)piperazine-1-carboxylic acid tert-butyl ester and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure F.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]([CH3:21])[CH3:20])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[F:28][C@H:29]1[C@@H:34]([CH2:35][OH:36])[CH2:33][CH2:32][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:30]1>CN(C)C=O>[F:28][C@H:29]1[C@@H:34]([CH2:35][O:36][C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH:19]([CH3:20])[CH3:21])=[CH:14][N:13]=3)=[CH:4][CH:3]=2)[CH2:33][CH2:32][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:30]1
Reactant: Cc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)[C@H](F)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
4-fluoro-N-isobutyl-N-(5-isopropyl-3-methylpyridin-2-yl)benzenesulfonamide (35 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (DMF) (3 mL) and to this solution was added sodium hydride (2 mg, 0.10 mmol, 60% wt in mineral oil) followed by tert-butyl cis-3-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (22 mg, 0.10 mmol). The reaction was stirred overnight at room temperature, under nitrogen, then quenched with water and concentrated in vacuo. The crude product was extracted to the organic phase of an aqueous workup between ethyl acetate and water. The organic phase was then passed through a hydrophobic frit and concentrated in vacuo to give the title compound (53 mg). LCMS (2 min, formic) Rt 1.53 min, m/z (ES+) 578 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH:27]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C@H:31]2[CH3:36])[CH2:29][CH2:28]1>>[CH:27]1([N:30]2[CH2:35][CH2:34][N:33]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:21])[CH2:32][C@H:31]2[CH3:36])[CH2:29][CH2:28]1
Reactant: C[C@@H]1CNCCN1C1CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C4CC4)[C@H](C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-cyclopropyl-2-methylpiperazine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.26 (br. s., 1 H) 0.36-0.51 (m, 2 H) 0.61 (d, J=5.56 Hz, 1 H) 0.93-1.29 (m, 3 H) 1.65 (br. s., 1 H) 2.16-2.40 (m, 1 H) 2.43 (s, 3 H) 2.58 (br. s., 1 H) 2.75-3.03 (m, 2 H) 3.15 (br. s., 1 H) 3.43-3.59 (m, 1 H) 4.09 (br. s., 1 H) 7.66 (d, J=8.32 Hz, 1 H) 7.73 (s, 1 H) 7.78 (d, J=8.08 Hz, 1 H) 8.06 (dd, J=8.59, 2.02 Hz, 1 H) 8.15 (s, 1 H) 8.38 (br. s., 1 H) 8.53 (d, J=1.77 Hz, 1 H); ESI-MS m/z [M+H]+ 443.3.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[O:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[C:20](C1NC=CN=1)(C1NC=CN=1)=[S:21]>C(Cl)Cl>[N:13]([C:12]1[C:7]([O:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3][C:2]([F:1])([F:18])[F:19])=[N:8][CH:9]=[CH:10][CH:11]=1)=[C:20]=[S:21]
Reactant: Nc1cccnc1Oc1ccccc1OC(F)(F)F
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccccc1Oc1ncccc1N=C=S
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 133a (16.21 mg, 0.0600 mmol) in anhydrous DCM (1.0 ml) was added dropwise to a cold solution of thiocarbonyl diimidazole (21.39 mg, 0.1200 mmol) in anhydrous DCM (0.50 ml). The reaction was stirred at 0° C. for 1 h and then warmed to rt with stirring for 2 h. The mixture was concentrated down to afford crude 133b which was taken directly onto the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([O:28][CH3:29])[C:13]([N:20]3[CH2:25][CH:24]([CH3:26])[NH:23][CH:22]([CH3:27])[CH2:21]3)=[C:14]([F:19])[CH:15]=2)[N:10]([CH2:30][C:31]([F:34])([F:33])[F:32])[CH:9]=1)=[O:7].N1C=CC=CC=1.[Cl-].[C:47]([O:52][CH2:53][CH3:54])(=[O:51])[C:48]([O-])=[O:49]>ClCCl.C(OCC)(=O)C>[CH2:53]([O:52][C:47](=[O:51])[C:48]([N:23]1[CH:22]([CH3:27])[CH2:21][N:20]([C:13]2[C:12]([O:28][CH3:29])=[C:11]3[C:16]([C:17](=[O:18])[C:8]([C:6]([NH:5][CH2:4][C:3]4[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:2]=4[Cl:1])=[O:7])=[CH:9][N:10]3[CH2:30][C:31]([F:33])([F:34])[F:32])=[CH:15][C:14]=2[F:19])[CH2:25][CH:24]1[CH3:26])=[O:49])[CH3:54]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(CC(F)(F)F)c12
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)N1C(C)CN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4Cl)cn(CC(F)(F)F)c3c2OC)CC1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
200 mg of the compound from Example 37A are dissolved in 3 ml of dichloromethane and 0.26 ml of pyridine and 71 μl of ethyl oxalate chloride are then added. The mixture is stirred at RT for 3 h. For the work-up, the mixture is diluted with ethyl acetate, and extracted by shaking twice with water, once with a saturated sodium hydrogen carbonate solution and once with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, concentrated in vacuo, and dried under high vacuum. 220 mg of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17](SC)=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Cl[C:23]1C=C(C=CC=1)C(OO)=O.[O-:33][S:34]([O-:36])=O.[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH:15]=[CH:16][C:17]([S:34]([CH3:23])(=[O:36])=[O:33])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2ccccc2-c2ccc(F)cc2)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccccc2-c2ccc(F)cc2)cc1
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
To a stirred solution of 550 mg (1.9 mmol) of crude 1-(4-fluoro-phenyl)-2-[4-(methylthio)phenyl]benzene (Step 3) in 10 mL of methylene chloride at ambient temperature was slowly added 1.3 g (4.1 mmol) of 3-chloroperoxybenzoic acid (ca. 55%). Stirring was continued for 20 minutes prior to the addition of 1 g of Na2SO3. The reaction was allowed to stir for an additional 10 minutes and the solvent removed in vacuo. The residue was dissolved in ethyl acetate and the resulting solution washed twice with saturated NaHCO3 and dried over MgSO4. Recrystallization from ethyl acetate/hexane gave 437 mg (94%) of 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 178.0-179.0° C.; NMR (CDCl3) δ 3.05 (s, 3H), 6.93 (t, J=8 Hz, 2H), 7.03-7.09 (m, 2H), 7.32 (d, J=8 Hz, 2H), 7.38-7.50 (m, 4H), 7.80 (d, J=8 Hz, 2H). MS (FAB): m/e 333 (M+Li). Anal. Calc'd for C19 H15FO2S: C, 69.86; H, 4.60; F, 5.79. Found: c, 69.74; H, 4.72; F, 5.51.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[C:50]([O:51][CH3:52])=[CH:49][CH:48]=[CH:47][C:46]=1[O:53][CH3:54]>>[CH3:54][O:53][C:46]1[CH:47]=[CH:48][CH:49]=[C:50]([O:51][CH3:52])[C:45]=1[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1OCCCCBr
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4c(OC)cccc4OC)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.066 g of 2-(4-bromobutoxy)-1,3-dimethoxybenzene are used to prepare the title compound. Rf=0.22 (2:1 EtOAc-heptane); Rt=5.73.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].Cl[CH2:21][CH2:22][O:23][CH2:24][CH2:25]Cl.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][C:5]=1[O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14]
Reactant: COC(=O)c1cc(N)ccc1O[Si](C)(C)C(C)(C)C
Reactant: ClCCOCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(N2CCOCC2)ccc1O[Si](C)(C)C(C)(C)C
Yield: 17.8 %

Procedure:
A solution of 5-amino-2-(tert-butyl-dimethyl-silanyloxy)benzoic acid methyl ester (4.5 g, 16 mmol), 2-chloroethyl ether (1.9 mL, 16.2 mmol), and diisopropylethylamine (5.6 mL, 32.1 mmol) in DMF (50 mL) was stirred at 100° C. for 48 h. The reaction mixture was poured into 10% aqueous NaHCO3 (100 mL) and extracted with ether (200 mL). The organic layer was washed with water (5×100 mL) and brine (100 mL), dried over magnesium sulfate (MgSO4), and concentrated to a red syrup. The residue was purified by flash chromatography (silica gel, 4×15 cm, eluted with 9/1 hexanes/EtOAc) to yield 2-(tert-butyl-dimethyl-silanyloxy)-5-morpholin-4-yl-benzoic acid methyl ester (1.0 g, 18%).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:34][CH:33]4[CH:28]([CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH2:32]4)[CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:34][CH:33]4[CH:28]([CH2:29][NH:30][CH2:31][CH2:32]4)[CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CC4CCN(C(=O)OC(C)(C)C)CC4C3)co2)C2CC2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CC4CCNCC4C3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AN using tert-butyl 2-{[2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazol-4-yl]carbonyl}octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (245 mg, 0.42 mmol), TFA (1 mL) and DCM (3 mL). Following the completion of the reaction the solvent was removed in vacuo, the residue redissolved in DCM (2 mL), absorbed on to 2 g SCX cartridge and washed with DCM (5 mL) and MeOH (5 mL). The title compound was eluted with 7 N NH3 in MeOH (10 mL) and concentrated in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([O:18][CH2:19][CH:20]1[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)=[O:17])([O-:3])=[O:2].C(O)(C(F)(F)F)=O>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:17])[O:18][CH2:19][CH:20]1[CH2:21][NH:22][CH2:23]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(COC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])OCC1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-((((2-nitro-5-(thiophen-2-yl)phenyl)carbamoyl)oxy)methyl)azetidine-1-carboxylate (0.50 g, 1.15 mmol, 1 eq.) in dichloromethane (10 mL) was added TFA (3 mL) at 0° C. The reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure. A saturated solution of sodium bicarbonate was added. The obtained solid was filtered and dried under reduced pressure to afford azetidin-3-ylmethyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.35 g, 91%
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>C(O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8](=[N:12][OH:13])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccnc(N)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a suspension of 1-(2-aminopyrimidin-4-yl)ethanone (3a) (4 g) in ethanol (70 mL) and water (14 mL) was added hydroxylamine hydrochloride (4.05 g) followed by sodium acetate (7.18 g) and the mixture was stirred at room temperature for one hour. After this time the reaction mixture was concentrated in vacuo, water was added and stirred for 15 minutes. The precipitate was collected by filtration and washed with water and dried in vacuo at 40° C. overnight to afford the title product (4.29 g) as a light yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2)=[O:17].N1CCCCC1>C(O)C>[CH3:14][O:15][C:16]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13])=[O:17]
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: COC(=O)c1ccc2c(c1)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 74.9 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 88.6 mg 5-methoxycarbonyl-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 123 mg (69%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([CH3:15])[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].[CH:23](OCC)(OCC)OCC>>[N:10]1([CH2:9][CH:8]([CH3:15])[CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:19][CH:18]=[C:17]([N+:20]([O-:22])=[O:21])[CH:16]=3)[N:1]=[CH:23]2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: CCOC(OCC)OCC
Reactant: CC(CNC(=O)c1cc([N+](=O)[O-])ccc1N)Cn1ccnc1
Product: CC(Cn1ccnc1)Cn1cnc2ccc([N+](=O)[O-])cc2c1=O

Procedure:
A mixture of 3.03 g of 2-amino-N-[3-(1H-imidazol-1-yl)-2-methylpropyl]-5-nitrobenzamide and 10 ml of triethyl orthoformate is heated at reflux temperature for 20 hours and concentrated to obtain the above compound.