Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][C:21]1[CH:61]=[CH:60][C:24]([O:25][C@@H:26]2[CH2:31][CH2:30][C@H:29]([N:32]3[C:37](=[O:38])[C:36]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([C:46]5[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=5)=[CH:42][CH:41]=4)=[C:35]([CH2:54][CH2:55][CH3:56])[N:34]4[N:57]=[CH:58][N:59]=[C:33]34)[CH2:28][CH2:27]2)=[CH:23][CH:22]=1)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[OH:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][C@@H:26]2[CH2:27][CH2:28][C@H:29]([N:32]3[C:37](=[O:38])[C:36]([CH2:39][C:40]4[CH:41]=[CH:42][C:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[C:52]5[NH:53][C:4](=[O:7])[O:5][N:3]=5)=[CH:44][CH:45]=4)=[C:35]([CH2:54][CH2:55][CH3:56])[N:34]4[N:57]=[CH:58][N:59]=[C:33]34)[CH2:30][CH2:31]2)=[CH:60][CH:61]=1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](Oc3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@@H](Oc3ccc(O)cc3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.49 g), sodium hydrogen carbonate (0.79 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-({4-[cis-4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.31 g) was added, and the mixture was stirred at 90° C. for 23 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.028 g, 9.8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:17])[CH2:13][C:14]([CH3:16])=O)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[NH2:19][C:20]([NH2:22])=[S:21].S(Cl)(Cl)(=O)=O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[C:6]([NH:11][C:12]([C:13]3[S:21][C:20]([NH2:22])=[N:19][C:14]=3[CH3:16])=[O:17])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)CC(=O)Nc1cccc2c1CCC2(C)C
Reactant: NC(N)=S
Solvent: c1ccccc1
Solvent: O=S(=O)(Cl)Cl
Product: Cc1nc(N)sc1C(=O)Nc1cccc2c1CCC2(C)C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
1.00 g (4.08 mmol) of N-(1,1-dimethyl-4-indanyl)acetoacetamide and 0.62 g (8.16 mmol) of thiourea were dissolved in 10 ml of benzene and to this solution was added dropwise a solution of 0.55 g (4.08 mmol) of sulfuryl chloride in 5 ml of benzene at room temperature. After reacting for 2 hours at this temperature, the reaction mixture was refluxed for 1 hour, and left overnight. Then, the resulting solution was concentrated and dissolved in hot water and thereafter neutralyzed with 28% aqueous ammonia to give a precipitate. This precipitate was filtered, washed with water and dried to obtain 1.00 g of N-(1,1-dimethyl-4-indanyl)-2-amino-4-methylthiazole-5-carboxamide (yield 81%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:4](Br)=[N:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH3:14])[CH2:9][CH2:8][C:7]=2[N:15]=1.[Na].[CH3:18]O>>[ClH:1].[ClH:1].[NH2:2][C:3]1[C:4]([CH3:18])=[N:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH3:14])[CH2:9][CH2:8][C:7]=2[N:15]=1
Reactant: CCN1CCc2nc(N)c(Br)nc2CC1
Reactant: CO
Agent: Cl
Agent: [Na]
Product: CCN1CCc2nc(C)c(N)nc2CC1
Temperature: 150 °C
Reaction time: 10 h

Procedure:
1 gm (3.3 mmols) of 2-amino-3-bromo-7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine hydrochloride were admixed with a solution of 1 gm (43.5 mmols) of sodium in 50 ml of methanol, and the mixture was stirred for 10 hours at 150° C. in an autoclave. Thereafter, the reaction mixture was evaporated, the residue was taken up in 2N sodium hydroxide, and the solution was extracted with chloroform. The chloroform extract solution was evaporated, the residue was dissolved in acetone, and the solution was admixed with ethanolic hydrochloric acid, yielding the hydrochloride in the form of white crystals.
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH3:11])[CH:6]([O:9][CH3:10])[O:7][CH3:8])[CH:2]=[CH2:3].C1(C)C=CC=CC=1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[CH2:1]([N:4]([CH:5]([CH3:11])[CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:22](=[O:23])[O:24][CH2:25][CH3:26])[CH:2]=[CH2:3]
Reactant: C=CCNC(C)C(OC)OC
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCN(C(=O)OCC)C(C)C(OC)OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
125 g (0.785 mol) of allyl-(1,1-dimethoxyprop-2-yl)amine are initially introduced into 400 ml of toluene, a solution of 40 g of sodium hydroxide in 200 ml of water is added, the mixture is cooled in an ice-bath to 0° C. and 95 g (0.876 mol) of ethyl chloroformate are added dropwise. The mixture is then stirred for 3 hours at room temperature, and the aqueous phase is separated off and extracted twice using 100 ml of toluene each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([CH3:30])[CH:26]=4)[C:21]3=[O:31])[CH2:16][C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:44]([NH:46][NH2:47])=[O:45]>C(OCC)(=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([CH3:30])[CH:26]=4)[C:21]3=[O:31])[CH2:16][C:17]3[O:19][CH:44]=[N:46][N:47]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1.[C:44](=[N:46][NH:47][C:17](=[O:18])[CH2:16][CH:15]([C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)[N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH3:30])[CH:26]=2)[C:21]1=[O:31])=[O:45]
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccc(C)cc3C2=O)cc1OC1CCCC1
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(CC(=O)NN=C=O)N2C(=O)c3ccc(C)cc3C2=O)cc1OC1CCCC1
Product: COc1ccc(C(Cc2nnco2)N2C(=O)c3ccc(C)cc3C2=O)cc1OC1CCCC1
Yield: 174.5 %

Procedure:
2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]-5-methylisoindoline-1,3-dione was prepared by the procedure of Example 1. Reaction of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(5-methyl-1,3-dioxoisoindolin-2-yl)propanoic acid (2.33 g, 5.5 mmol), carbonyidiimidazole (1.07 g, 6.59 mmol) and formic hydrazide (436 mg, 7.26 mmol) in ethyl acetate (20 mL) gave crude N-carbonylamino-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(5-methyl-1,3-dioxoisoindolin-2-yl)propanamide (2.24 g, 4.8 mmol), which was then treated with phosphorus oxychloride (0.9 mL, 9.6 mmol) in acetonitrile (10 mL). The product was obtained as a white solid (728 mg, 32% overall yield): mp, 184.0-186.5° C.; 1H NMR (CDCl3) δ 1.55-2.00 (m, 8H, C5H8), 2.48 (s, 3H, CH3), 3.81 (s, 3H, CH3), 3.82 (dd, J=6.1, 15.7 Hz, 1H, CHH), 4.36 (dd, J=10.3, 15.7 Hz, 1H, CHH), 4.74-4.81 (m, 1H, OCH), 5.79 (dd, J=5.9, 10.3 Hz, 1H, NCH), 6.80 (d, J=8.4 Hz, 1H, Ar), 7.10 (dd, J=2.0, 8.3 Hz, 1H, Ar), 7.18 (d, J=2.0 Hz, 1H, Ar), 7.47 (d, J=7.5 Hz, 1H, Ar), 7.59 (s, 1H, Ar), 7.67 (d, J=7.6 Hz, 1H, Ar), 8.28 (s, 1H, CH); 13C NMR (CDCl3) δ 21.95, 24.09, 27.75, 32.77, 51.79, 56.00, 80.48, 111.73, 114.51, 120.16, 123.34, 123.95, 129.05, 130.22, 132.03, 134.65, 145.44, 147.75, 150.03, 153.00, 164.08, 167.98, 168.11; Anal Calcd for C25H25N3O5+0.13 Et2O: C, 67.05; H, 5.80; N, 9.19. Found: C, 66.95; H, 5.88; N, 8.97. (HNMR showed the sample contained 0.13 equiv. of ether).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:17]([N:20]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:21]2[S:25][N:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1B1OCC(C)(C)CO1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH3:43][O:44][C:45]1[CH:52]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:50]=[CH:49][C:46]=1[CH2:47]Br>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([S:17]([N:20]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:21]2[S:25][N:24]=[CH:23][N:22]=2)(=[O:18])=[O:19])[CH:6]=[CH:7][C:8]=1[CH2:47][C:46]1[CH:49]=[CH:50][C:51]([C:53]([F:54])([F:55])[F:56])=[CH:52][C:45]=1[O:44][CH3:43])#[N:2]
Reactant: COc1cc(C(F)(F)F)ccc1CBr
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(B3OCC(C)(C)CO3)c(C#N)c2)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Cc3ccc(C(F)(F)F)cc3OC)c(C#N)c2)c(OC)c1
Temperature: 65 °C

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 29, 45.5 mg, 0.086 mmol) in tetrahydrofuran (1 mL) was added a 2 M aqueous solution of potassium carbonate (116 μL, 3.03 mmol) and 2-methoxy-4-(trifluoromethyl)benzyl bromide (21 mg, 0.08 mmol). The solution was sparged with nitrogen before the addition of tetrakis(triphenylphosphine)palladium (0) (9.2 mg, 0.0008 mmol). The reaction mixture was heated at 65° C. for 6 hours. The reaction mixture was cooled to ambient temperature and partitioned between 1N aqueous citric acid solution (2 mL) and ethyl acetate (10 mL). The organic layer was washed with a saturated aqueous solution of sodium chloride (2 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give a yellow oil. The material was purified by silica gel column chromatography (ISCO™ companion, 12 g column, 0-50% ethyl acetate in heptane gradient elution). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a yellow oil, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7](Cl)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:25]([O:31][C@@H:32]1[C@H:36]([O:37][S:38]([CH3:41])(=[O:40])=[O:39])[C@@H:35]([CH2:42][O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])[O:34][C@H:33]1[N:50]1[CH:57]=[CH:56][C:54]([NH2:55])=[N:53][C:51]1=[O:52])(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:55][C:54]2[CH:56]=[CH:57][N:50]([C@@H:33]3[O:34][C@H:35]([CH2:42][O:43][C:44](=[O:49])[C:45]([CH3:46])([CH3:47])[CH3:48])[C@@H:36]([O:37][S:38]([CH3:41])(=[O:40])=[O:39])[C@H:32]3[O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:51](=[O:52])[N:53]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@H](OC(=O)C(C)(C)C)[C@@H]1OS(C)(=O)=O
Solvent: c1ccncc1
Product: COc1ccc(C(Nc2ccn([C@@H]3O[C@H](COC(=O)C(C)(C)C)[C@@H](OS(C)(=O)=O)[C@H]3OC(=O)C(C)(C)C)c(=O)n2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
4,4'-Dimethoxytrityl chloride (685 mg, 2.02 mmol) was added to a solution of Compound C5 (825 mg, 1.69 mmol) in anhydrous pyridine (4 ml) and the mixture was stirred at room temperature for 3 hours. After cooling, aqueous 50% pyridine was added to decompose an excess of the reagent, and the mixture was extracted with ether containing a small amount of chloroform. The organic layer was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The organic solvents were evaporated, the remaining pyridine was removed as the toluene azeotrope and the residue was subjected to silica gel chromatography [eluant; chloroform-ethyl acetate-triethylamine (80:20:1)] to give 1.280 g of the desired compound, C6 (yield 96%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14])=O)(C)(C)C.C(OC([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27]O)=O)(C)(C)C.N.[ClH:30]>>[ClH:30].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:25]1[CH:26]=[N:22][C:27]([Cl:30])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: Cl
Agent: N
Product: Clc1ccc(OC[C@H]2CCCN2)cn1

Procedure:
Following the procedures described in Example 45 steps a-c, substituting (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol for the (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol of step 45a thereof, the title compound was prepared. mp 157-159° C. MS (DCI/NH3) m/e: 213/215 (M+H)+ and 230/232 (M+NH4)+. 1H NMR (D2O, 300 MHz) d: 8.10 (d, J=3.0 Hz, 1H), 7.53-7.43 (m, 2H), 4.45 (dd, J=10.7, 7.7 Hz, 1H), 4.15-4.08 (m, 1H), 3.41 (t, J=7.2 Hz, 2H), 2.34-1.88 (m, 4H). Anal. Calc. for C10H14Cl2N2O.0.3 HCl: C, 46.18; H, 5.54; N, 10.77; Found C, 46.35; H, 5.51; N, 10.66.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[Cl:26][C:27]1[S:31][C:30]([S:32]([N:35]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]2)(=[O:34])=[O:33])=[CH:29][C:28]=1[N+:41]([O-])=O>>[Cl:26][C:27]1[S:31][C:30]([S:32]([N:35]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]2)(=[O:34])=[O:33])=[CH:29][C:28]=1[NH:41][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:14]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)N2CCC(O)C2)sc1Cl
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cc(S(=O)(=O)N2CCC(O)C2)sc1Cl)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and (RS)-1-(4-amino-5-chloro-thiophene-2-sulfonyl)-pyrrolidin-3-ol (example B.18) according to general procedure II. Yellow solid. MS (ISP) 622.2 [(M+H)+]; mp 274° C.
Reaction SMILES: C/C=[C:3](/[CH:28]([CH3:30])[CH3:29])\[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21]C[C@H](O)[CH2:24][C:19]4=[CH:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7].C(=O)=[O:32].CC(C)=O.O=[O+][O-].O=O.[C:43]([OH:46])(=O)[CH3:44]>[Zn].C(Cl)Cl>[O:32]=[C:3]([CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:12]2([CH3:27])[C@H:11]([C@H:16]3[C@H:15]([CH2:14][CH2:13]2)[C@:20]2([CH3:21])[C:19]([CH2:24][C@H:43]([CH2:44][CH2:26]2)[OH:46])=[CH:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:7])[CH:28]([CH3:29])[CH3:30]
Reactant: CC(=O)O
Reactant: C/C=C(\CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Reactant: O=C=O
Agent: O=O
Agent: O=[O+][O-]
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 70.3 %

Procedure:
Fucosterol (4.1 g) was dissolved in 100 ml. of methylene chloride, and while cooling the solution with dry ice-acetone to about -20° C., the fucosterol was oxidized for 30 minutes with ozone at a rate of generation of 0.86 g/hr and in a concentration of 17.2 g/m3 (O2). After the reaction, 8 g of zinc powder and 200 ml. of acetic acid were added, and the resulting ozonide was reductively decomposed at room temperature for 24 hours. The resulting zinc acetate was separated by filtration, and washed with an aqueous solution of sodium carbonate. The methylene chloride phase separated was thoroughly washed with water, and dried with anhydrous sodium sulfate. The methylene chloride was evaporated off at reduced pressure, and the resulting white crystals were column-chromatographed using silica gel as a carrier (eluted with a benzene-n-hexane mixed solvent) to afford 2.8 g of 24-ketocholesterol in a yield of 70.3%.
Reaction SMILES: BrBr.[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:8].C1OCCOCCOCCOCCOCCOC1.[F-:34].[K+]>C(OCC)(=O)C.O.O1CCOCC1>[Cl:3][CH2:4][CH2:5][CH:6]([F:34])[C:7]([C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: [F-]
Agent: BrBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(F)cc1)C(F)CCCl
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
A 1,4-dioxane (50 mL) solution of bromine (8.76 g, 54.8 mmol) was added to a 1,4-dioxane (50 mL) solution of 4-chloro-4′-fluorobutyrophenone (10.0 g, 49.8 mmol) at room temperature over 15 minutes, and the mixture was stirred at the same temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was subjected to extraction twice with hexane. The organic layer thus obtained was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, an aqueous solution of 1.5 M sodium sulfite, and brine, and then was dried over anhydrous sodium sulfate. A portion (13.0 g) of a crude product (14.3 g) obtained by distilling off the solvent under reduced pressure was dissolved in N,N-dimethylformamide (90 mL), and 18-crown-6 (18.4 g, 69.8 mmol) and potassium fluoride (4.05 g, 69.8 mmol) were added to the mixture at room temperature. The mixture was stirred at the same temperature for 2 and a half hours, and then 18-crown-6 (6.15 g, 23.3 mmol) and potassium fluoride (1.35 g, 23.3 mmol) were added to the mixture, and the mixture was further stirred at the same temperature for one hour. Water was added to the reaction mixture, and the mixture was subjected to extraction twice with hexane. The organic layer thus obtained was washed with water and brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5, v/v) to give the title compound (5.47 g, yield: 55%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(CN)CCCCC1.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:39]([CH2:38][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3([CH2:30][O:29][C:28]4[CH:31]=[C:32]5[C:36](=[CH:37][C:27]3=4)[CH2:35][CH2:34][O:33]5)[C:18]2=[O:17])=[CH:40][CH:41]=1
Reactant: Nc1ccccc1F
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1ccccc1F)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-fluoroaniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-fluorophenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (75%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.42 (ddd, J=8.1, 8.1, 1.2 Hz, 1H), 8.16-7.99 (m, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.25-7.01 (m, 6H), 6.77 (d, J=7.7 Hz, 1H), 6.49 (s, 1H), 6.43 (s, 1H), 5.03 (ABq, 2H), 4.86 (ABq, 2H), 4.55 (t, J=8.6 Hz, 2H), 3.10-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 164.8, 161.8, 161.3, 152.7 (d, J=243.1 Hz), 141.7, 140.1, 134.0, 132.6, 128.7, 127.7 (2C), 126.3 (d, J=9.8 Hz, 2C), 124.7, 124.6 (d, J=3.9 Hz), 124.0, 123.6, 121.8, 119.9 (2C), 118.7, 114.8 (d, J=19.2 Hz, 2C), 109.0, 93.2, 80.6, 72.3, 57.7, 43.7, 29.0; MS (ES+) m/z 507.1 (M+1).
Reaction SMILES: [NH2:1][C:2]([NH2:24])=[N:3][C:4](=[O:23])[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][C:13]2C=N[CH:16]=[CH:17][CH:18]=2)=[C:7]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=1.[N+:25]([C:28]1C=C(C(C)=CC=1OC1C=NC=CC=1)C(OC)=O)([O-])=O>>[ClH:11].[NH2:24][C:2]([NH2:1])=[N:3][C:4](=[O:23])[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:28][N:25]=2)=[C:7]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:6]=1
Reactant: CS(=O)(=O)c1cc(C(=O)N=C(N)N)c(Cl)cc1Oc1cccnc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2cccnc2)cc1C
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)c(Cl)cc1Oc1ccccn1
Product: Cl

Procedure:
N-diaminomethylene-3-methylsulfonyl-4-(3-pyridyloxy)-6-chlorobenzamide, m.p. 215-216°; with methyl 3-nitro-4-(3-pyridyloxy)-6-methylbenzoate,
Reaction SMILES: [C:1](NC(N)=N)#[N:2].[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[N:15]=[C:16]=[N:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([S:25]([NH:28][CH:29]2[CH2:33][CH2:32][O:31][NH:30]2)(=[O:27])=[O:26])[C:19]=1[O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].[N:42]#CN.C(N(CC)C(C)C)(C)C.[F-].[Cs+]>>[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[N:15]([C:1]#[N:2])[C:16]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([S:25]([NH:28][CH:29]2[CH2:33][CH2:32][O:31][NH:30]2)(=[O:27])=[O:26])[C:19]=1[O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:37])=[NH:42]
Reactant: N#CNC(=N)N
Reactant: N#CN
Reactant: CC(C)(C)[Si](C)(C)Oc1c(N=C=Nc2cccc(Cl)c2Cl)ccc(Cl)c1S(=O)(=O)NC1CCON1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1c(NC(=N)N(C#N)c2cccc(Cl)c2Cl)ccc(Cl)c1S(=O)(=O)NC1CCON1
Yield: 40 %

Procedure:
Following the general procedure for cyanoguanidine formation outlined in example 1, N-(2,3-dichlorophenyl)-N′-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″-tetrahydroisoxazylaminosulfonyl)phenyl]carbodiimide (547 mg, 0.95 mmol), cyanamide (159 mg, 3.8 mmol) and N,N-diisopropylethylamine (150 mg, 1.14 mmol) were reacted, followed by desilylation with Cesium fluoride (174 mg, 1.14 mmol) to form the desired product (190 mg, 40%). LC-MS m/z 504.
Reaction SMILES: CI.[CH3:3][C:4]1([CH3:26])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[NH:14][CH:15]=2)[O:5]1.[C:27](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:27][N:14]1[CH:15]=[C:11]([B:6]2[O:5][C:4]([CH3:26])([CH3:3])[C:8]([CH3:9])([CH3:10])[O:7]2)[CH:12]=[C:13]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2c[nH]c(C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl iodide (0.27 mL, 4.3 mmol) was added to a mixture of benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (0.7 g, 2 mmol) and cesium carbonate (1.4 g, 4.3 mmol) in DMF (5.0 mL) and then the reaction was stirred at r.t. for 1 h. LCMS showed the reaction was complete. The mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-10%) to afford the desired product. LCMS (M+H)+: m/z=342.2.