Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C2C(=CC=C(C=O)C=2)NC=1.[Cl-].C(OC([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C(OCC)=O)C.CN(C)C(=N)N(C)C.[CH2:50]([O:52][C:53](=[O:69])/[C:54](/[O:66][CH2:67][CH3:68])=[CH:55]/[C:56]1[CH:57]=[C:58]2[C:62](=[CH:63][CH:64]=1)[NH:61][CH:60]=[C:59]2[CH3:65])[CH3:51]>ClCCl>[CH2:50]([O:52][C:53](=[O:69])[CH:54]([O:66][CH2:67][CH3:68])[CH2:55][C:56]1[CH:57]=[C:58]2[C:62](=[CH:63][CH:64]=1)[NH:61][CH:60]=[C:59]2[CH3:65])[CH3:51]
Reactant: CCOC(=O)/C(=C/c1ccc2[nH]cc(C)c2c1)OCC
Agent: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: Cc1c[nH]c2ccc(C=O)cc12
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc2[nH]cc(C)c2c1)OCC

Procedure:
In analogy to the procedures described in preparation 1a) and 1b), 3-methyl-1H-indole-5-carbaldehyde [Helv. Chim. Acta (1968), 51(7), 1616-28] was reacted with (1,2-diethoxy-2-oxoethyl)triphenyl phosphonium chloride in dichloromethane in the presence of tetramethyl guanidine to give.(Z)-2-ethoxy-3-(3-methyl-1H-indol-5-yl)-acrylic acid ethyl ester, which was subsequently hydrogenated to yield the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[S:26])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=2)[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][OH:11].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14](=[S:26])[NH:13][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH2:9][CH2:10][O:11][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:6]([Cl:12])[CH:5]=2)=[CH:17][CH:18]=1)(=[O:25])[CH3:24]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCO)c(Cl)c2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCOC(=O)c3ccccc3)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To an ice cooled solution of N-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is added benzoyl chloride (0.08 g) and the mixture is stirred at 0° C. for 1.5 hours. The mixture is then diluted with ethyl acetate, washed successively two times with 2% aqueous hydrochloric acid, once with saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (5% methanol in dichloromethane is used as the eluant) and product containing fractions are combined, evaporated under reduced pressure, and the residue is recrystallized from acetone-hexanes to provide the desired product as a white powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][NH2:20])=[O:7].C(N(CC)CC)C.[CH2:29]([O:36][C:37](OC1CC(=O)NC1=O)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][NH:20][C:37](=[O:38])[O:36][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1sccc1-c1ccccc1CN
Reactant: O=C1CC(OC(=O)OCc2ccccc2)C(=O)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCNC(=O)c1sccc1-c1ccccc1CNC(=O)OCc1ccccc1

Procedure:
27 mg (0.09 mmol) of 3-(2-aminomethylphenyl)thiophene-2-carboxylic acid (3-methylbutyl)amide were dissolved in 3 ml of dry dichloromethane, and the solution was treated with 10 mg (0.1 mmol) of triethylamine and 24 mg (0.1 mmol) of benzyloxycarbonyloxysuccinimide. After a reaction time of 18 h, the mixture was diluted with 20 ml of dichloromethane, washed with saturated NaHCO3 solution and the organic phase was dried and concentrated. After purification by RP-HPLC, 27 mg (70%) of a colorless substance were obtained. MS (ES+): m/z=437 (M+1). 1H-NMR (CDCl3): δ=7.54-7.24 (10H, m), 6.90 (1H, d, J=4.8 Hz), 5.52 (1H, br s), 5.05 (3H, br s), 4.17 (2H, d, J=6.2 Hz), 3.16 (2H, m), 1.14 (1H, m), 1.07 (2H, q, J=7.0 Hz), 0.73 (6H, d, J=6.2 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][O:11]/[N:12]=[C:13](/[C:21]1[O:26][CH2:25][CH2:24][O:23][N:22]=1)\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C1(C)C=CC=CC=1>[CH3:10][O:11]/[N:12]=[C:13](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1)\[C:21]1[O:26][CH2:25][CH2:24][O:23][N:22]=1
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: CO/N=C(/C1=NOCCO1)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CO/N=C(\C1=NOCCO1)c1ccccc1Oc1ncnc(Cl)c1F
Temperature: 82.5 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a solution of 4,6-dichloro-5-fluoropyrimidine (DCFP) (100 g, 0.564 mol) in toluene (500 mL) was added (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) (77.8 g, 0.466 mol), K2CO3 (76 g, 0.55 mol), followed by the addition of DMF (50 mL) at ambient temperature. The reaction mixture was stirred at 80-85° C. for 1-2 h. The progress of the reaction was monitored by the HPLC analysis. Upon completion of the reaction, the reaction mixture was washed with water (500 mL) and 10% brine solution (250 mL) to obtain the product in toluene layer meeting the desired specifications. Yield—88-98%.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N:16]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[NH:36])[NH2:35])=[CH:30][CH:29]=1)=[O:5])C.[OH-].[Na+]>>[OH:5][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N:16]([S:22]([CH3:25])(=[O:23])=[O:24])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34](=[NH:35])[NH2:36])=[CH:32][CH:33]=1)=[O:3]
Reactant: CCOC(=O)Cn1c(COc2ccc(C(=N)N)cc2)nc2ccc(N(CCN(C)C)S(C)(=O)=O)cc21
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCN(c1ccc2nc(COc3ccc(C(=N)N)cc3)n(CC(=O)O)c2c1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 3 from 1-ethoxycarbonylmethyl-2-[(4-amidinophenyl)-oxymethyl]-6-[N-(2-dimethylaminoethyl)-methanesulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:29]([C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:39]([C:36]3[CH:37]=[CH:38][C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:34][CH:35]=3)(=[O:41])=[O:40])=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3c(c2)c(-c2ccccc2)c(C(=O)O)n3Cc2ccccc2)cc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate and 4-tert-butylbenzene sulfonyl chloride followed the procedure of Example 1 Step 3 as a pale yellow solid: 1H NMR (DMSO-d6) δ 1.25 (s, 9H, 5.76 (s, 2H, 7.05-7.15 (m, 4H, 7.20-7.30 (m, 5H, 7.30-7.45 (m, 3H, 7.50-7.60 (m, 5H; MS (ESI) m/z 537 [M-H]−; HRMS calcd for C32H31N2O4S: 539.2002; found (ESI+): 539.1999.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]([CH3:26])=[N:14][N:15]2C1CCCCO1)C(=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][NH:2][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]([CH3:26])=[N:14][NH:15]2
Reactant: Cc1nn(C2CCCCO2)c2cccc(CN(C)C(=O)OC(C)(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cccc2[nH]nc(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A mixture of tert-butyl methyl((3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methyl)carbamate (85 mg, 0.23 mmol) in DCM (8 mL) and TFA (1 mL) was stirred at RT overnight. The reaction mixture was concentrated in vacuo. The residue was purified SiO2 chromatography eluting with petroleum ether:EtOAc to afford N-methyl-1-(3-methyl-1H-indazol-4-yl)methanamine (109) as white solid (30 mg, 72.4%). MS (ESI): m/z=176 [M+1]+.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[C:19]1([C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:27]2[N:31]=[CH:30][NH:29][N:28]=2)[OH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:26][C:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:27]1[N:31]=[CH:30][N:29]([CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[N:28]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1nc[nH]n1
Reactant: O=C(OCc1ccccc1)N1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(Cn2cnc(C(O)(c3ccccc3)c3ccccc3)n2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
Benzyl 4-(bromomethyl)piperidine-1-carboxylate (5 g, 16 mmol) was dissolved in dimethylformamide (40 ml) and diphenyl-(1H-[1,2,4]triazol-3-yl)-methanol (Tetrahedron: Asymmetry, 8(9), 1491-1500; 1997; 3.35 g, 13.65 mmol) added, followed by potassium carbonate (3.69 g, 26.7 mmol). After stirring at 70° C. for 18 hours the solvent was removed in vacuo, and the residue partitioned between ethyl acetate (150 ml) and water (150 mL). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo to furnish the title compound as a white solid in 81% yield, 5.2 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[N:29]1([C:35](Cl)=[O:36])[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:35]([N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])=[O:36])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: O=C(Cl)N1CCNC1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCCNC(=O)N2CCNC2=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a solution of 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (1.0 g) in a mixture of chloroform (dried over alumina) (20 ml) and triethylamine (2 ml) was added imidazolidin-2-on-1-yl carbonyl chloride (0.36 g) in one portion and the mixture stirred at room temperature for 18 hours. After evaporation to dryness, the resultant oil was partitioned between 5% aqueous sodium carbonate and methylene chloride. The combined organic liquors were dried (MgSO4), filtered and evaporated to give 0.7 g of a yellow oil which crystallised from diisopropyl ether on standing to give pure title compound, (0.4 g), m.p. 145° C. Found: C, 54.94; H, 5.62; N, 10.62. C24H29ClN4O7 requires C, 55.33; H, 5.61; N, 10.76%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH3:11].C(Cl)Cl.[N-:16]=[N+:17]=[N-:18].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]([CH3:11])=[N:18][N:17]=[N:16]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1ccc(I)cc1Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(I)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A suspension of N-(2-chloro-4-iodo-phenyl)-acetamide (2.39 g, 8.09 mmol) in acetonitrile (40 mL) at 25° C. was treated with methylene chloride (5 mL) to obtain a clear solution. The resulting solution was then treated with sodium azide (1.05 g, 16.18 mmol), and the reaction mixture was cooled to 0° C. The reaction mixture was then treated with trifluoromethanesulfonic anhydride (3.42 g, 12.13 mmol), and the resulting reaction mixture was allowed to warm to 25° C. where it was stirred overnight. The reaction mixture was then concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and water (50 mL), and the two layers were separated. The aqueous layer was further extracted with ethyl acetate (1×30 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.53 g, 59%) as a white solid: mp 128-130.5° C.; EI-HRMS m/e calcd for C8H6ClIN4 (M+) 319.9327, found 319.9325.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:7]=[C:6]([NH:16][S:17]([CH2:20][CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:19])=[O:18])[C:5]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].[CH3:36][OH:37]>>[CH3:36][O:37][C:4]1[N:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:7]=[C:6]([NH:16][S:17]([CH2:20][CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:19])=[O:18])[C:5]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: CO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)CCCC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1Oc1c(NS(=O)(=O)CCCC(C)(C)C)nc(-c2ncccn2)nc1OC
Temperature: 105 °C
Reaction time: 4 h

Procedure:
Sodium hydride (60% oil dispersion 354 mg) was cautiously added to a suspension of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-4,4-dimethyl-1-pentanesulfonamide (580 mg) in dry methanol (5 ml) in a 10 mm Wheaton reacti-vial™ and the resulting mixture stirred at 105° C. for 4 hours. The reaction was then partitioned between ethyl acetate (20 ml) and 2N aqueous hydrochloric acid (10 ml) and the organic phase separated. The aqueous was extracted with ethyl acetate (20 ml ) and the organic phases combined, washed (water 2×20 ml), dried (Na2SO4) and evaporated under reduced pressure. Column chromatography on silica eluting with a solvent gradient of dichloromethane:methanol 100:0 changing to 98.5:1.5 gave N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-4,4-dimethyl-1-pentanesulfonamide as an off-white coloured solid (189 mg).
Reaction SMILES: OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CC=C1CCCC2.[C:22]1([Si:28]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:29][CH2:30][C@@:31]23[C@@H:48]4[C@H:39]([C@H:40]5[C@@:44]([CH2:46][CH2:47]4)([CH3:45])[C:43](=[O:49])[CH2:42][CH2:41]5)[CH2:38][CH2:37][C:36]2=[CH:35][C:34](=O)[CH2:33][CH2:32]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:57]1([Si:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:29][CH2:30][C@@:31]23[C@@H:48]4[C@H:39]([C@H:40]5[C@@:44]([CH2:46][CH2:47]4)([CH3:45])[C:43](=[O:49])[CH2:42][CH2:41]5)[CH2:38][CH:37]=[C:36]2[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H]1CCC2=O
Agent: C[C@]12CC[C@H]3[C@@H](CC=C4CCCC[C@@]43CO)[C@@H]1CCC2=O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4CCCC[C@@]43CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H]1CCC2=O

Procedure:
Substituting 19-hydroxy-5-androsten-17-one for the 19-hydroxy-4-androstene-3,17-dione above results in the formation of 19-triphenylsiloxy-5-androsten-17-one.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]([Cl:30])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[CH:27]3)=[N:22]2)=[CH:17][CH:16]=1)(C)(C)C.Cl>O1CCOCC1>[ClH:30].[Cl:30][C:29]1[N:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][N:8]3[CH2:7][C:6]([OH:31])=[O:5])=[CH:16][CH:17]=2)[N:22]=[C:23]2[C:28]=1[CH:27]=[CH:26][CH:25]=[CH:24]2
Reactant: CC(C)(C)OC(=O)CN1CCC[C@@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CN1CCC[C@@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 145.7 %

Procedure:
A mixture of the product of step 1 (0.4 g, 0.91 mmol) and HCl (4 M in dioxane, 2.3 mL, 9.1 mmol) in dioxane (5 mL)was stirred at room temperature for 16 h. After the solvent was removed, the residue was triturated with ether to provide the title compound (280 mg, 62%) as a hydrochloride salt. 1H NMR (400 MHz, DMSO) δ 7.71-7.66 (m, 4H), 7.40 (m, 1H), 7.22 (m, 3H), 4.4.50-4.27 (m, 4H), 4.04 (br, 1H), 3.70 (br, 2H), 2.28 (m, 1H), 2.04 (m, 2H), 1.98 (m, 1H), LC/MS (APCI) m/z: 94%.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:22](=O)[CH3:23])[C:15]([O:17][CH:18]1[CH2:21][CH2:20][CH2:19]1)=[O:16].[NH2:25][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:27][C:28]#[N:29].CC(C)([O-])C.[K+]>CC(O)C>[C:28]([C:27]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]([C:15]([O:17][CH:18]2[CH2:19][CH2:20][CH2:21]2)=[O:16])=[C:22]([CH3:23])[NH:25][C:26]=1[C:30]([F:33])([F:32])[F:31])#[N:29]
Reactant: N#CC=C(N)C(F)(F)F
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OC1CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC1=C(C(=O)OC2CCC2)C(c2cccc3c(=O)cc(C)oc23)C(C#N)=C(C(F)(F)F)N1

Procedure:
A solution of 345 mg (1.06 mmol) of cyclobutyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate in 30 ml of 2-propanol is mixed with 143.85 mg (1.06 mmol) of 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation in analogy to K. Krespan, J. Org. Chem. 34, 42-45 (1969)] and 17.8 mg (0.16 mmol) of potassium tert-butoxide and stirred under reflux for 12 h. After cooling, the mixture is concentrated. The residue is purified on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). After concentration of the product fractions, the residue is crystallized from diethyl ether. 50.9 mg (10.8% of theory) of the title compound are obtained as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[CH:10]=[CH:11]/[C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]>ClCCl.C(O)C.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(/C=C/C(=O)OCc2ccccc2)ccc1F
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1cc(CCC(=O)O)ccc1F
Reaction time: 2 h
Yield: 101.8 %

Procedure:
Benzyl (E)-3-(3-cyano-4-fluorophenyl)-acrylate (Int. A6) (1.72 g, 6.1 mmol) was dissolved in 1:1 dichloromethane/ethanol (50 ml) and 10% palladium on charcoal (0.5 g) added. The mixture was hydrogenated for 2 h at ambient pressure, filtered and concentrated to provide the title compound as a white solid (1.2 g, 100%). 1H-NMR (CDCl3) δ 2.69 (2H, t), 2.97 (2H, t), 7.11 (1H, m), 7.43 (3H, m).
Reaction SMILES: [CH3:1][C:2]([C:6]1([OH:21])[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)([CH3:5])[CH:3]=[O:4].CC(C)=[O:24].Cl.O.[Mn]([O-])(=O)(=O)=O.[K+]>>[CH2:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:6]([C:2]([CH3:1])([CH3:5])[C:3]([OH:24])=[O:4])([OH:21])[CH2:7]1)=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C=O)C1(O)CCN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(C(=O)O)C1(O)CCN(C(=O)OCc2ccccc2)C1
Temperature: 15 °C
Reaction time: 6 h

Procedure:
Benzyl 3-(1,1-dimethyl-2-oxoethyl)-3-hydroxypyrrolidine-1-carboxylate (12.70 g, 0.04359 mol) was dissolved in acetone (179.5 mL, 2.444 mol) and cooled to 15° C. and 1.0 M of hydrogen chloride in water (65.39 mL, 0.06539 mol) was added dropwise. After addition of the HCl was complete, a solution of potassium permanganate (11.0 g, 0.0697 mol) in acetone (493.6 mL, 6.722 mol) was added dropwise. The reaction mixture was stirred at room temperature for 6 h, filtered and the filter cake was washed with acetone. The filtrate was evaporated, in vacuo, diluted with methylene chloride, dried, filtered and the solvent was evaporated, in vacuo, to provide a crude product which was used directly in next step. LCMS (M+H) 308.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)=O)C.[OH-].[Na+]>CCOCC>[OH:3][CH2:4][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(C=Cc2ccccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: OCc1ccc(C=Cc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium dihydro bis (2-methoxyethoxy) aluminate (7.25 g. 0.025 m) was added dropwise to a solution of 2-(4-ethoxycarbonylstyryl) pyridine (6.35 g 0.25 m) in 100 ml dry ether. The mixture was stirred for 3 hours at room temperature followed by gently refluxing for a further 3 hours. On cooling, 20% sodium hydroxide solution was added to the reaction mixture. The ether layer was separated and dried over anhydrous magnesium sulphate. The solvent was removed by rotary evaporation and the solid which was removed was recrystallised from ethanol. The product was identified and shown to be pure by G.L.C. I.R. N.M.R. and analysis.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[CH2:12]>N1C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:11]=[CH2:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1ccc(N)nc1
Solvent: c1ccncc1
Product: C=Cc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 5-isopropylpyridin-2-amine (400 mg, 2.94 mmol) in pyridine (5 mL), stirred at room temperature, was added 4-vinylbenzene-1-sulfonyl chloride (760 mg, 3.75 mmol). The reaction mixture was stirred for 30 minutes then stood overnight. The solvent was evaporated in vacuo and the crude sample purified by normal phase chromatography on silica (Si) (0-50% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the title product, 670 mg, as an off-white solid. LCMS (2 min, formic) Rt 0.98 min, m/z (ES+) 303 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8](I)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.[CH3:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([OH:29])[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([N:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][C:25]3=[O:29])=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: Cc1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-n2ccc(C)cc2=O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 80 °C
Reaction time: 10 h
Yield: 82.9 %

Procedure:
To a mixture of 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (500 mg, 1.03 mmol), 4-methylpyridin-2-ol (168 mg, 1.54 mmol) and K2CO3 (283 mg, 2.05 mmol) in DMF (5 mL) was stirred at 80° C. for 10 hours and concentrated in vacuo to remove DMF. The reaction mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=1:1) to give the product of 5-bromo-N-methyl-2-(4-methyl-2-oxopyridin-1 (2H)-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (400 mg, yield: 83%). 1H-NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 7.85 (s, 1H), 7.67 (s, 1H), 7.22 (d, J=7.2 Hz, 1H), 6.52 (s, 1H), 6.28 (d, J=1.6 Hz, 1H), 3.32 (s, 3H), 3.06 (s, 3H), 2.89 (d, J=4.8 Hz, 3H), 2.31 (s, 3H). MS (M+H)+: 468/470.