Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([Cl:10])[CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][S:19]([CH3:18])(=[O:21])=[O:20])=[C:4]([Cl:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Br)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-chlorobenzyl alcohol (3.56 g) and anhydrous triethylamine (3 ml) in anhydrous dichloromethane (36 ml) was added dropwise methanesulfonyl chloride (1.4 ml) under a nitrogen flow under ice-cooling. The mixture was stirred for 1 hr and the reaction mixture was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was concentrated to give 4-bromo-2-chloro-1-(methanesulfonyloxymethyl)benzene as a pale-brown solid (4.77 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][OH:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23]3)O1.C(OCC)(=O)C.Cl>O.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:11][CH2:10][C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23]3)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2ccc3cc(O)ccc3c2)OC1(C)C
Reactant: OCC#Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCC#Cc1ccc(-c2ccc3cc(O)ccc3c2)cc1

Procedure:
13.0 g (0.047 mol) of sodium metaborate octahydrate are initially introduced in 100 ml of water, and a solution of 7.00 g (33.1 mmol) of 3-(4-bromophenyl)prop-2-yn-1-ol (CAS No. 37614-58-7) and 9.00 g (33.3 mmol) of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (CAS No. 269410-21-1) in 200 ml of THF is added. After addition of 1.00 g (1.40 mmol) of bis(triphenylphosphine)palladium(II) chloride, the batch is heated under reflux for 5 h, 100 ml of ethyl acetate are subsequently added, and the mixture is acidified using 2 M hydrochloric acid. The org. phase is separated off, dried over sodium sulfate and evaporated. The residue is filtered through silica gel with toluene/ethyl acetate (3:2), and the crude product is recrystallised from toluene/ethyl acetate, giving 6-[4-(3-hydroxyprop-1-ynyl)phenyl]naphthalen-2-ol as a colourless solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([F:19])[CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:20][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1cc(F)cc(F)c1
Product: N#Cc1cc(C=O)ccc1Oc1cc(F)cc(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 3,5-difluorophenol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH3:9].[CH3:10][S:11](Cl)(=[O:13])=[O:12].[Cl-].[Cl-].[Cl-].[Al+3].[C:19](Cl)(=[O:22])[CH2:20][CH3:21].Cl>N1C=CC=CC=1.ClCCl.C1(C)C=CC=CC=1>[CH2:8]([C:3]1[CH:4]=[C:5]([C:19](=[O:22])[CH2:20][CH3:21])[CH:6]=[CH:7][C:2]=1[NH:1][S:11]([CH3:10])(=[O:13])=[O:12])[CH3:9]
Reactant: CCc1ccccc1N
Reactant: CCC(=O)Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(NS(C)(=O)=O)c(CC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 2-amino-1-ethylbenzene (5 ml, 5.0 g, 41 mmol) in pyridine (3.5 ml) and dichloromethane (10 ml), methanesulfonyl chloride (3.2 ml. 4.7 g, 41 mmol) was added dropwise over 10 min at 0° C. The reaction mixture was stirred at rt for 1 hour. After cooling to 0° C. aluminum trichloride (13.8 g, 103 mmol) was added to the reaction mixture carefully. Then propionyl chloride (3.6 ml, 3.8 g, 41 mmol) was added dropwise over 15 min. The reaction mixture was diluted with toluene (25 ml) and poured into 2 M hydrogen chloride aqueous solution (50 ml) under stirring at 0° C. The precipitate solids were filtered, washed with water and dried in vacuo to get a desired product (4.5 g, 43% yield) as yellow solids.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[CH3:17][C:18](=[O:21])[C:19]#[CH:20].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][CH:20]=[C:19]([C:18](=[O:21])[CH3:17])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C#CC(C)=O
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1=CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (9.76 g, 0.041 mol) in CH2Cl2 (40 mL) at 0° C., was added dropwise over a 5 minutes period but-3-yn-2-one (2.0 g, 0.029 mol) followed by trifluoroacetic acid (0.22 mL, 0.003 mol) (very exothermic reaction). The ice bath was removed after 30 minutes, and the solution was stirred at 25° C. for an additional 2 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/Heptane 1:1) afforded 2.90 g (49%) of the title compound as a yellow oil. ES-MS m/e: 202.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[CH3:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[C:33]1([CH2:39][CH2:40][SH:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:21][C:2]1([CH3:1])[CH:11]=[C:10]([CH2:12][S:41][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[S:23][CH3:22])[CH:8]=2)[NH:3]1
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: SCCc1ccccc1
Reactant: CSc1ccccc1B(O)O
Product: CSc1ccccc1-c1ccc2c(c1)C(CSCCc1ccccc1)=CC(C)(C)N2

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 2-(methylthio)phenylboronic acid. Bromination and coupling reaction with 2-phenylethanethiol gave 59 mg of the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[Br:13]>CC(O)=O>[Br:13][C:7]1[C:6]([CH3:5])=[C:11]([N+:1]([O-:4])=[O:2])[CH:10]=[CH:9][C:8]=1[CH3:12]
Reactant: Cc1cccc(C)c1Br
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(C)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Fuming nitric acid (32.5 ml) was slowly added to a solution of 2,6-dimethyl-bromobenzene (10 g, 54 mmol) in AcOH (75 ml) cooled in an ice bath. The resulting mixture was allowed to warm to room temperature, stirred for 1 h, and heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and poured into ice water with stirring. The resultant precipitate was collected by suction filtration to afford the title compound (10 g) which was used without further purification.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][CH:29]=[CH:28]2.[OH-].[Na+]>CN(C=O)C.CO>[N:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccc2ncccc2c1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-2-indolinone and 3 equivalents of 6-amino-quinoline in DMF followed by treatment with 1N sodium hydroxide solution in MeOH.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[ClH:19].[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:28]3[CH2:29][CH2:30][CH:25]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:26][CH2:27]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: C1CCN(C2CCNCC2)C1
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCC(N4CCCC4)CC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 58 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 4-(pyrrolidin-1-yl)piperidine as described in Steps 5 and 6, Example 24 to give the title compound as a yellow solid (58% yield). LC/MS: RT 2.12 min; m/e 436; 1H NMR (δ, ppm): 11.89 (1H, br), 10.87 (1H, br), 7.64 (1H, d), 7.36 (1H, s), 7.29 (1H, d), 3.75 (2H, d), 3.46 (2H, m), 3.08-3.28 (2H, s), 2.87-3.08 (2H, s), 2.35-2.60 (2H, q), 2.35 (3H, s), 2.08-2.24 (2H, m), 1.69-2.03 (6H, m), 1.10 (3H, t).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22]([OH:24])=O)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:52][O:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH2:59])=[CH:56][CH:55]=1>ClCCl.CN(C=O)C>[CH3:52][O:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH:59][C:22]([C@@H:20]2[CH2:21][C@H:19]2[C:16]2[CH:17]=[CH:18][C:13]([NH:12][CH2:11][C:10]3[CH:25]=[CH:26][CH:27]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)=[CH:14][CH:15]=2)=[O:24])=[CH:56][CH:55]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CNC(=O)[C@@H]2C[C@H]2c2ccc(NCc3cccc(Oc4ccccc4)c3)cc2)cc1
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
To a mixture of racemic-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid (I-2a) (0.14 g, 0.40 mmol) in dichloromethane (3 mL) and DMF (1 mL) was added HATU (0.23 g, 0.60 mmol). The mixture was stirred for 15 min followed by addition of 4-methoxybenzylamine (0.96 g, 0.80 mmol). The solution stirred for 6 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a white ppt which was filtered and dried under high vacuum to give the title compound as a white powder (0.12 g, 62%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 6H), 7.19-7.07 (m, 5H), 6.99 (t, J=7.9 Hz, 2H), 6.91 (t, J=8.3 Hz, 2H), 6.54 (d, J=8.4 Hz, 2H), 5.78 (s, 1H), 4.42-4.40 (m, 2H); 4.28 (s, 2H), 4.00 (s, 1H), 2.46-2.42 (m, 1H), 2.34 (s, 3H), 1.60-1.55 (m, 1H), 1.48-1.44 (m, 1H), 1.21-1.14 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:32][C:33](=[N:67][C:68](=[O:75])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH:41]([C:54]2[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[C:56]([O:62][CH2:63][CH2:64]O)[C:55]=2[F:66])[C:42]2[NH:46][C:45](=[O:47])[N:44]([C:48]3[N:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[N:43]=2)=[CH:36][CH:35]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.ClCCl>[NH2:32][C:33](=[N:67][C:68](=[O:75])[C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH:41]([C:42]2[NH:46][C:45](=[O:47])[N:44]([C:48]3[N:49]=[CH:50][CH:51]=[CH:52][N:53]=3)[N:43]=2)[C:54]2[C:55]([F:66])=[C:56]([CH:57]=[C:58]([O:60][CH3:61])[CH:59]=2)[O:62][CH2:63][CH2:64][O:15][C:14](=[O:16])[C:11]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)=[CH:36][CH:35]=1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: O=C(O)c1ccncc1
Agent: CN(C)C(F)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(OCCOC(=O)c2ccncc2)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under nitrogen atmosphere, triethylamine (0.348 mL) was added under ice-cooling to a mixture of 4-pyridinecarboxylic acid [CAS No. 55-22-1] (61.6 mg), TFFH (132 mg), and dichloromethane (5 mL), and the resulting mixture was stirred for 1 hour. To the mixture, a mixture of N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (Example 1a, 150 mg), DMAP (5 mg), and DMF (2.5 mL) was added dropwise. After stirring the resulting mixture at room temperature for 3 days, the solvent in the mixture was concentrated under reduced pressure. The residue obtained was purified by reverse phase silica gel column chromatography (mixed solvent of acetonitrile-water, containing 0.1% of acetic acid) to obtain the captioned compound (188 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2(O)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)cn2)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C#N)cn2)CC1
Reaction time: 18 h
Yield: 63.7 %

Procedure:
To a stirred mixture of tert-butyl 4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound 26.2, 500 mg, 1.65 mmol, 1.00 equiv) in pyridine (20 mL) was added dropwise phosphoryl trichloride (2.5 g, 16.34 mmol, 9.90 equiv) at 10-15° C. The resulting solution was stirred for 18 h at 15˜20° C. The reaction was then carefully quenched by the addition of 20 mL of water and extracted with 3×100 mL of ethyl acetate. The combined organic phases were washed with 2×50 mL of aqueous HCl (1 M) followed by 1×100 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100 to 1:7) as eluent to yield 0.3 g (64%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].[Cl:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:13]([C:22](F)=[O:23])=[CH:12][N:11]=1.Cl>CN(C=O)C.O>[NH2:2][C:1]1[N:16]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])[C:14]2[N:15]=[C:10]([Cl:9])[N:11]=[CH:12][C:13]=2[C:22](=[O:23])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CC(C)(O)CNc1nc(Cl)ncc1C(=O)F
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1c(N)c(C(N)=O)c(=O)c2cnc(Cl)nc21
Temperature: 3.5 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a solution, cooled to 2-5°C. on an ice bath, of 4.4 g (52.36 mmol) of cyanoacetamide in 70 mL of anhydrous DMF are added portionwise 4.19 g (104.72 mmol) of 60% sodium hydride. The mixture is stirred for 15 minutes at 2-5°C., and this suspension is then added rapidly to a solution of 12.35 g (49.87 mmol) of the acid fluoride prepared in step 17.2 in 70 mL of anhydrous DMF, precooled to 2-5°C. The mixture is stirred overnight at room temperature and is then cooled to 2-5°C. on an ice bath, and 2.09 g (52.36 mmol) of 60% sodium hydride are added portionwise. The reaction mixture is stirred for 3 hours at room temperature and then poured into a mixture of ice, 100 mL of water and 150 mL of aqueous 1N HCl. The yellow precipitate formed is isolated by filtration, rinsed with water and then dried in an oven. After triturating in methanol and drying in an oven, 8.84 g of the expected product are finally obtained in the form of a yellow solid. Yield=57%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH:34]1([CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:36][CH2:35]1>>[CH:34]1([CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:1](=[NH:2])[C:3]3[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]4[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]5[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=5)(=[O:20])=[O:19])=[CH:14][CH:13]=4)[CH:6]=[CH:7][CH:8]=3)[CH2:40][CH2:39]2)[CH2:36][CH2:35]1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: C1CN(CC2CC2)CCN1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCN(CC2CC2)CC1
Yield: 57 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalent of 1-(cyclopropylmethyl)piperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)OC2=O.[C:13]1([CH:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:36]1CCOC[CH2:37]1>>[C:30]1([CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][N:29]([C:1]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH2:6])[CH:37]=[O:36])[CH2:24][CH2:25]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: C1COCCO1
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: Nc1ccccc1N(C=O)CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
Isatoic anhydride (1.02 g) and 1-diphenylmethyl-4-(3-aminopropyl)piperazine (2.12 g) were dissolved in 1,4-dioxane (20 ml) and the mixture was stirred at room temperature for 4 hours. 1,4-dioxane was removed and the residue was purified by silica gel column chromatography (ethyl acetate), followed by recrystallization of the resultant from ethyl acetate-hexane to obtain 2.47 g of N-(3-(4-(diphenylmethyl)piperazinyl)propyl)(2-aminophenyl)formamide. Yield: 92%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Br[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:16]1)[N:6]=[C:5]2[I:11]
Reactant: CC(C)(C)OC(=O)N1CCCC(CCBr)C1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: CC(C)(C)OC(=O)N1CCCC(CCn2nc(I)c3cc(F)ccc32)C1
Yield: 56 %

Procedure:
The title compound was prepared in 56% yield from 5-fluoro-3-iodo-indazole and tert-butyl 3-(2-bromoethyl)piperidine-1-carboxylate according to the general procedure for Preparation 10A. 1H NMR (400 MHz, CDCl3): δ 1.16-1.32 (2H, m), 1.37-1.62 (11H, m), 1.78-1.87 (3H, m), 2.70-2.76 (1H, m), 2.90-2.93 (1H, m), 3.75-3.88 (2H, m), 4.42 (2H, t, J=2.0, 7.2 Hz), 7.11 (1H, d, J=8.4 Hz), 7.21 (1H, td, J=2.0, 8.8 Hz), 7.38 (1H, dd, J=4.0, 9.2 Hz).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:27])[C:4]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)[CH2:6][CH2:5]1.CO.C(Cl)(Cl)[Cl:31]>CCl>[ClH:31].[ClH:1].[ClH:31].[CH3:27][N:3]([CH3:2])[C:4]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][NH:12][CH3:13])[CH2:6][CH2:5]1
Reactant: ClC(Cl)Cl
Reactant: CN(CCN1CCC(c2ccccc2)(N(C)C)CC1)C(=O)OC(C)(C)C
Agent: CCl
Agent: Cl
Solvent: CO
Product: CNCCN1CCC(c2ccccc2)(N(C)C)CC1

Procedure:
HCl gas was passed through a solution of 9 g (1 eq) tert-butyl 2-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethyl(methyl)carbamate in 600 ml CH3Cl for 30 min. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). Once the conversion was complete, the passage of HCl gas was continued for a further 30 min and the completeness of the conversion again monitored by thin-layer chromatography (20% MeOH/CHCl3). Once the conversion was complete, the solvent was removed under reduced pressure and 7.2 g (96%) of the desired product obtained in the form of a white solid.
Reaction SMILES: C(O[C@H:10]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:37])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H](C)CC[C@H](C)C(C)C)[CH2:11]1)(=O)C1C=CC=CC=1.[O:38]=[O+][O-].N1C=C[CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH3:42][CH:43]([CH:44]=[O:38])[C@@H:19]1[C@:29]2([CH3:37])[C@H:16]([C@H:15]3[C@H:32]([CH2:31][CH2:30]2)[C@:33]2([CH3:36])[C@H:12]([CH2:11][CH2:10][CH2:35][CH2:34]2)[CH2:13][CH2:14]3)[CH2:17][CH2:18]1
Reactant: CC(C)[C@@H](C)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=[O+][O-]
Reactant: c1ccncc1
Solvent: ClCCl
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
A solution of pyridazino 3',4',5',6':7,8,14,15!-3β-benzoyloxy-5α-ergostane (34, 3.2 g, 6.08 mmol) in CH2Cl2 (105 mL) and pyridine (1 mL) was cooled to -78° C. in a dry ice-acetone bath and ozone gas (approximately 0.95 mmol O3/ min) was bubbled through the solution for 25 min. Then the excess O3 was removed by bubbling through argon gas. The reaction mixture was treated with methyl sulfide (3 mL) and stirred at ambient temperature for 20 min. The solvent was evaporated under reduced pressure, leaving 3.90 g of tan fluff. Purification by flash column chromatography on 77 g of Merck grade 60 silica gel using MeOH/CHCl3 (2:98) yielded 1.65 g (59%) of aldehyde (36), mp 248°-252° C. EIMS (m/z): 458 (M+). 1H NMR: δ9.72 (d, 1H, J=2.6 Hz), 8.06 (d, 2H, J=8.3 Hz), 7.57 (dd, 1H, J=7.4, 7.4 Hz), 7.45 (dd, 2H, J=7.4, 7.9 Hz), 5.05 (m, 1H), 3.23 (dd, 1H, J=4.4, 18.7 Hz), 3.22 (dd, 1H, J=7.1, 16.4 Hz), 3.09 (dd, 1H, J=11.0, 16.4 Hz), 2.76 (ddd, 1H, J=2.6, 7.0, 10.8 Hz), 2.67 (dd, 1H, J=13.0, 17.3 Hz), 1.25 (d, 3H, J=7.0 Hz ) , 1.13 (s, 3H) , 0.88 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:14][CH2:13][CH2:12]3)=[CH:5][CH:4]=1.Cl.[NH2:30][OH:31].C(N(CC)CC)C>O1CCCC1.CO>[OH:31][NH:30][C:23](=[NH:24])[C:22]1[CH:21]=[CH:20][C:19]([N:15]2[C:16]3[C:11](=[CH:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:1])[F:27])=[CH:4][CH:5]=4)=[CH:18][CH:17]=3)[CH2:12][CH2:13][CH2:14]2)=[CH:26][CH:25]=1
Reactant: NO
Reactant: N#Cc1ccc(N2CCCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N=C(NO)c1ccc(N2CCCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 107 %

Procedure:
305 mg 4-[6-(4-Trifluoromethyl-phenyl)-3,4-dihydro-2H-quinolin-1-yl]-benzonitrile were dissolved in a mixture of 10 ml tetrahydrofuran and 10 ml methanol. 1.19 g hydroxylamine hydrochloride were added followed by the addition of 2.42 ml triethylamine. The reaction mixture was stirred at 90° C. for four hours. The solvents were removed in vacuo and the resulting residue poured into 50 ml water and extracted five times with portions of 50 ml ethylacetate. The combined organic extracts were washed with 100 ml brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 355 mg crude N-Hydroxy-4-[6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinolin-1-yl]-benzamidine. This material was used without further purification.