Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:20]=[C:19](Cl)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:6]=1)(=[O:3])[CH3:2].[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]2>C(O)(C)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[C:19]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]4)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(-c2nc(Cl)c3ccccc3n2)c1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Solvent: CC(C)O
Product: CC(=O)Oc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 95 °C
Reaction time: 0.25 h

Procedure:
3-(4-Chloroquinazolin-2-yl)phenyl acetate (9.77 g, 29.97 mmole) was dissolved in isopropanol (290 mL) and tert-butyl 5-amino-1H-indazole-1-carboxylate (6.99 g, 29.97 mmole) was added. The solution was heated to 95° C. and stirred for 0.25 h. A gelatinous formation developed which was manually broken up and dissolution gradually occurred followed by formation of a yellow precipitate. The reaction was stirred for an additional 0.25 h, cooled to ambient temperature and filtered. The filtered solid was washed with ether and then dried under high vacuum overnight to give tert-butyl 5-(2-(3-acetoxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (14.58 g, mmol, 98%)
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[O:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[C:25](O)=[O:26]>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:25]([C@H:21]4[CH2:22][CH2:23][CH2:24][O:20]4)=[O:26])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: O=C(O)[C@H]1CCCO1
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)[C@H]3CCCO3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and (R)-tetrahydrofuran-2-carboxylic acid, the title compound was prepared as white powder. MS: m/e=379(M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[SH:20])/[C:17]([OH:19])=[O:18])=[CH:11][C:10]=1[O:21][CH3:22])C1C=CC=CC=1.II.O.S(=O)(O)[O-].[Na+]>O1CCCC1>[OH:8][C:9]1[C:10]([O:21][CH3:22])=[CH:11][C:12]2[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[S:20][C:13]=2[CH:14]=1
Reactant: COc1cc(/C=C(\S)C(=O)O)ccc1OCc1ccccc1
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)O)sc2cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Z)-3-(4-Benzyloxy-3-methoxy-phenyl)-2-mercapto-acrylic acid (21 g) and iodine (21 g) in tetrahydrofuran (300 ml) was stirred in 60° C. for 15 hours. Then it was poured into water (1 l) and 120 g sodium bisulfite was added. The product was extracted into ethylacetate and then it extracted into sodium bicarbonate. The water phase was acified by concentrated hydrochloric acid and stirred in room temperature for one hour. The solid was filtered, washed with water and dried under vacuum.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[C:16](=O)([O:19]C)[O:17][CH3:18]>O1CCCC1>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]([C:14]#[N:15])[C:16]([O:17][CH3:18])=[O:19])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)OC
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C#N)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
0.66 g (16.5 mmols) of sodium hydride and 2.6 g (15.0 mmols) of 4-tert-butylphenylacetonitrile were suspended in 50 ml of tetrahydrofuran. To the suspension was added dropwise 1.95 g (16.5 mmols) of dimethyl carbonate dissolved in 10 ml of tetrahydrofuran while stirring at room temperature. The mixture was refluxed with heating for 2 hours, and the solvent was distilled off under reduced pressure. Water was added to the residue, and the residue was acidified by diluted hydrochloric acid and twice extracted with 30 ml of ethyl acetate. The ethyl acetate extraction solutions were mixed, washed with a saturated brine solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue thus-obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), giving 1.8 g of the desired product (yield 52%)
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[N:14]([CH3:23])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])=O.[CH3:24][NH:25][C:26]([NH2:28])=[S:27].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:23][N:14]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:5]([C:3]1[N:28]=[C:26]([NH:25][CH3:24])[S:27][CH:2]=1)=[CH:13]2)[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16]
Reactant: CN(c1cccc2cc(C(=O)CCl)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CNC(N)=S
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CNc1nc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)cs1
Yield: 76.6 %

Procedure:
A mixed solution of N-[2-(2-chloroacetyl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (100 mg), N-methylthiourea (30 mg) and N,N-dimethylacetamide (6 ml) was stirred at 60° C. for 5 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:3-1:1), and the obtained oil was crystallized from ethyl acetate-hexane to give the title compound (84 mg, yield 77%) as pale-yellow prism crystals. melting point 162-163° C. MS:405 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[C:12]([OH:14])=O.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:34])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[C:12]([CH:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[O:14])=[CH:21][CH:22]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: COc1cccc2c1CCC2C(=O)O
Product: COc1cccc2c1CCC2C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1
Yield: 53.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 4-methoxyindan-1-carboxylic acid (0.20 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.27 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-4-methoxyindan-1-carboxamide (0.24 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].C1C(=O)N([Br:25])C(=O)C1>C1COCC1.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:17])[CH:4]([NH:5][C:6](=[O:8])[CH3:7])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([Br:25])[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(C)=O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(O)c(Br)c1)NC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To N-acetyl-L-tyrosine methyl ester (6 g, 25.3 mmol) in THF (60 mL) at rt was added NBS (5.4 g, 30.3 mmol) followed by five drops of sulfuric acid. The mixture was stirred for 16 h at rt The solvent was removed under reduced pressure and then water was added. The aqueous layer was extracted twice with EtOAc, and the combined extracts were dried over magnesium sulfate and concentrated to a solid. The solid was recrystallized from ethyl acetate/hexane (6 g, 75%). MS (M+H]+ 316.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[ClH:17].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[CH2:9][NH:8][CH2:16]2
Reactant: COc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: COc1cc2c(cc1Cl)CNC2

Procedure:
Prepared in analogy to Example A3 (e) from 5-chloro-6-methoxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and HCl. Off-white solid. MS (m/e): 186.1 ({37Cl}M+H+, 30%), 184.1 ({35Cl}M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH2:16][CH3:17])/[CH:12]=[CH:13]/[C:14]#[N:15].CN1CCOCC1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[N:5]2)([CH2:16][CH3:17])/[CH:12]=[CH:13]/[C:14]#[N:15])=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ncc2c(N)cccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (E)-4-(4-amino-1H-indazol-1-yl)-4-(4-chlorophenyl)hex-2-enenitrile (130 mg) and NMM (117 mg) in DCM (5 mL) was added MsCl (53 mg), Then the mixture was stirred at room temperature for 2 h. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (eluent: PE/EA=5/1) to afford the title compound as a pale yellow solid. LC/MS m/z=415.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[N:25]=[C:24]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=2)[O:23][N:22]=1>>[CH:1]1([C:4]2[N:5]([CH2:20][C:21]3[N:25]=[C:24]([C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=4)[O:23][N:22]=3)[C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:2][CH2:3]1
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3cc(F)cc(F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=8.5 Hz, 1H), 7.57 (m, 3H), 7.05 (t, J=8.5 Hz, 1H), 6.48 (s, 1H), 5.64 (s, 2H), 2.13 (m, 1H), 1.15 (m, 2H), 0.92 (m, 2H); MS (ES) m/z 445 (M+1).
Reaction SMILES: C([NH:5][C:6]([C:8]1[S:12][C:11]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])=[CH:10][C:9]=1[CH:23]=O)=[O:7])(C)(C)C.[NH2:25]N>C(O)(=O)C>[CH3:22][C:21]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[C:11]1[S:12][C:8]2[C:6](=[O:7])[NH:5][N:25]=[CH:23][C:9]=2[CH:10]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1cc(C=O)c(C(=O)NC(C)(C)C)s1
Reactant: NN
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)O)cc1-c1cc2cn[nH]c(=O)c2s1
Temperature: 110 °C

Procedure:
A solution of 3-(5-(tert-butylcarbamoyl)-4-formylthiophen-2-yl)-4-methylbenzoic acid (2.30 g, 6.7 mmol) in acetic acid (20 ml) was treated with hydrazine (0.73 ml, 20 mmol) and heated to 110° C. for 8 hrs. After cooling to RT the volatiles were removed in vacuo. The residue was recrystallized from MeOH. Yield: 1.01 g. MS (ESI, pos. ion) m/z: 287 (M+1).
Reaction SMILES: C1C([C@H]2OC3C=C(O)C=C(O)C=3C[C@H]2OC(C2C=C(O)C(O)=C(O)C=2)=O)=CC(O)=C(O)C=1.[CH:33]1[C:34]([C@H:42]2[O:51][C:50]3[CH:49]=[C:48]([OH:52])[CH:47]=[C:46]([OH:53])[C:45]=3[CH2:44][C@H:43]2[O:54]C(C2C=C(O)C(O)=C(O)C=2)=O)=[CH:35][C:36]([OH:41])=[C:37]([OH:40])[C:38]=1[OH:39]>>[CH:33]1[C:34]([C@H:42]2[O:51][C:50]3[CH:49]=[C:48]([OH:52])[CH:47]=[C:46]([OH:53])[C:45]=3[CH2:44][C@H:43]2[OH:54])=[CH:35][C:36]([OH:41])=[C:37]([OH:40])[C:38]=1[OH:39]
Reactant: O=C(O[C@@H]1Cc2c(O)cc(O)cc2O[C@@H]1c1cc(O)c(O)c(O)c1)c1cc(O)c(O)c(O)c1
Agent: O=C(O[C@@H]1Cc2c(O)cc(O)cc2O[C@@H]1c1ccc(O)c(O)c1)c1cc(O)c(O)c(O)c1
Product: Oc1cc(O)c2c(c1)O[C@H](c1cc(O)c(O)c(O)c1)[C@H](O)C2

Procedure:
(-) Epicatechin gallate (R1 =H, ##STR3## (hereinafter abbreviated to "ECg"); and (-) Epigallocatechin gallate (R1 =OH, ##STR4## (hereinafter abbreviated to "EGCg").
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[S:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CN(C=O)C.[Br:23]N1C(=O)CCC1=O.CCOC(C)=O>CCCCCC>[Br:1][C:2]1[C:6]([Br:23])=[C:5]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[S:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(N2CCOCC2)cc1Br
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(N2CCOCC2)c(Br)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
To a degassed solution of ethyl 3-bromo-5-morpholin-4-ylthiophene-2-carboxylate (0.688 g, 2.15 mmol) in DMF (14 mL, 180 mmol) was added N-bromosuccinimide (0.7648 g, 4.297 mmol) dropwise as a solution in degassed DMF (4.1 mL, 52 mmol). The mixture was wrapped in foil to protect from ambient light, and the reaction was stirred under argon at room temperature for 2 hours. The reaction mixture was quenched via addition of 10% sodium thiosulfate solution (10 mL) and then diluted with EtOAc (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (eluent: 0-25% EtOAc:hexane) afforded ethyl 3,4-dibromo-5-(morpholin-4-yl)thiophene-2-carboxylate (593 mg, yield 69%). LCMS: (FA) ES+ 398, 400, 402; 1H NMR (400 MHz, DMSO) δ 4.26 (q, J=7.1 Hz, 2H), 3.75 (dd, J=5.5, 3.8 Hz, 4H), 3.24-3.10 (m, 4H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[N:6]2[C:10]([CH2:18][CH:19]3[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]3)=[C:11](C(OCC)=O)[N:12]=[C:5]2[CH:4]=1)#[N:2].[CH3:27][Mg]Br.[Cl-].[NH4+].[CH2:32]1[CH2:36][O:35]CC1>>[F:26][C:22]1([F:25])[CH2:21][CH2:20][CH:19]([CH2:18][C:10]2[N:6]3[C:7]([CH3:9])=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]3=[N:12][C:11]=2[C:36]([OH:35])([CH3:32])[CH3:27])[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1nc2cc(C#N)cc(C)n2c1CC1CCC(F)(F)CC1
Reactant: C1CCOC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(C#N)cc2nc(C(C)(C)O)c(CC3CCC(F)(F)CC3)n12
Temperature: -50 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Ethyl 7-cyano-3-(4,4-difluorocyclohexylmethyl)-5-methylimidazo[1,2-a]pyridine-2-carboxylate (0.0410 g, 0.113 mmol) obtained in step 3 was dissolved in THF (1.0 mL), and the solution was stirred at −50° C. for 2 hours and then at 0° C. for 30 minutes after adding a THF solution of methylmagnesium bromide (1.1 mol/L) (0.446 mL, 0.500 mmol) at −50° C. Under ice-cooled condition, a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was filtered through a Presep (registered trademark; diatomaceous earth, granular type M, 4.5 g/25 mL). The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=80/20→65/35) to give 3-(4,4-difluorocyclohexylmethyl)-2-(2-hydroxypropan-2-yl)-5-methylimidazo[1,2-a]pyridine-7-carbonitrile (20.4 mg, yield 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH3:22])=[CH:12][C:11]=2[CH:23]([CH3:25])[CH3:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])(=[O:28])C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH:22]=[O:28])=[CH:12][C:11]=2[CH:23]([CH3:25])[CH3:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Agent: [Pb+4]
Solvent: CC(=O)O
Product: CC(C)c1cc(C=O)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 18 h
Yield: 13.9 %

Procedure:
To a solution of 160 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methyl-1-[(4-pyridyl)methyl]-1H-pyrrole in 3 ml of acetic acid was added 200 mg of lead tetraacetate over 30 min. After stirring for 2 h at room temperature a further 100 mg of lead tetraacetate was added and the mixture stirred for 18 h. After this time a further 100 mg of lead tetraacetate was added and the mixture stirred for 18 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petrol/ethyl acetate (1:4 then 1:2) then ethyl acetate for the elution to give 23 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-1-[(4-pyridyl)methyl]-1H-pyrrole-2-carbaldehyde, mass spectrum (ESI) m/z 405 [M+H]+, as a brown oil and 51 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-1-[(4-pyridyl)methyl]-1H-pyrrole-2-acylmethanol as an impure yellow foaming oil, Mass spectrum (ESI) m/z 447 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]#[C:13][Si](C)(C)C)[C:9]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:8]=2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>C[O-].[Na+].CO>[C:12]([C:10]1[C:9]2[N:18]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:20][C:8]=2[C:7]([OH:27])=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[N:11]=1)#[CH:13]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2nc(-c3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-4-trimethylsilanylethynyl-thiazolo[4,5-c]pyridine-6 carboxylic acid ethyl ester (113 mg, 0.28 mmole) and glycine (750 mg, 9.99 mmole) in 0.5 M sodium methoxide/methanol (20 ml) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (30 ml) and extracted with dichloromethane (2×40 ml). The remaining aqueous layer was acidified to pH=2 with 1N HCl. The suspension was extracted with ethyl acetate (2×40 ml), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (96 mg). MS: (+) m/z 354.20 (M+1), (−) m/z 352.16 (M−1).
Reaction SMILES: [OH:1][C:2]1[C:19]2[C@@H:18]3[C@@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([OH:21])[CH:3]=1.[N:22]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([S:28]([O:1][C:2]2[C:19]3[C@@H:18]4[C@@H:9]([C@H:10]5[C@@:14]([CH2:16][CH2:17]4)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]5)[CH2:8][CH2:7][C:6]=3[CH:5]=[C:4]([O:21][S:28]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)(=[O:30])=[O:29])[CH:3]=2)(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C[C@]12CC[C@@H]3c4c(O)cc(O)cc4CC[C@@H]3[C@@H]1CCC2=O
Reactant: O=S(=O)(Cl)N1CCCCC1
Product: C[C@]12CC[C@@H]3c4c(cc(OS(=O)(=O)N5CCCCC5)cc4OS(=O)(=O)N4CCCCC4)CC[C@@H]3[C@@H]1CCC2=O

Procedure:
The above compound is prepared from 1,3-dihydroxy-8α-estra-1,3,5(10)-trien-17-one by reaction with piperidinosulfonyl chloride analogously to Example 24.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[BH4-].[Na+]>CCO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(CO)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde (5.0 g, 27 mmol) in EtOH (100 mL) at rt was added portion wise NaBH4 (1.02 g, 1 eq). The mixture was stirred at RT for 2 h, concentrated in vacuo and partitioned between ether and water. The organic layer was washed with brine, dried over MgSO4 and concentrated. The title alcohol was recovered as a brownish solid (4.96 g, 98%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][C:23](=[O:39])[NH:24][C:25]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([O:36][CH2:37][CH3:38])=[CH:28][C:26]=4[N:27]=3)[CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:37]([O:36][C:29]1[C:30]([C:32]([F:35])([F:34])[F:33])=[CH:31][C:25]2[NH:24][C:23](=[O:39])[CH2:22][C:21]([C:17]3[CH:16]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=4)[CH:20]=[CH:19][CH:18]=3)=[N:27][C:26]=2[CH:28]=1)[CH3:38]
Reactant: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c1)=N2
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(S(N)(=O)=O)cc3)c1)=N2

Procedure:
The title compound was prepared from 3′-(8-ethoxy-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-biphenyl-4-sulfonic acid tert-butylamide (Example 7) (205 mg, 0.4 mmol) and TFA (5 mL) according to the general procedure I step 2. Obtained as an off-white solid (94 mg, 51%). MS (ISP) 503.8 [(M+H)+]; mp 245-250° C. (dec).
Reaction SMILES: FC(F)(F)C(O)=O.O[C:9]1([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[C:13]2[C:14]([CH3:34])=[C:15]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=2[O:11][C:10]1([CH3:36])[CH3:35].C([SiH](CC)CC)C>>[CH3:35][C:10]1([CH3:36])[CH:9]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[C:13]2[C:14]([CH3:34])=[C:15]([N:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH2:24][CH2:25]3)[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=2[O:11]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
To trifluoroacetic acid was added 1-(3-hydroxy-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine (350 mg, 0.72 mmol) obtained in Example 33 (3.5 mL) under ice cooling. The mixture was warmed to room temperature, and then triethylsilane (0.3 mL, 1.9 mmol) was added at room temperature. The mixture was stirred for 15 minutes and concentrated under reduced pressure. The residue was made to basic with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain 270 mg (yield 80%) of the title compound. mp. 189–191° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[N:18]([CH2:31][CH2:30][C:29]([O:33][CH3:34])=[O:32])[C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:27][CH:28]=1
Reactant: C=CC(=O)OC
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Product: COC(=O)CCn1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Yield: 59.8 %

Procedure:
The title compound was prepared by starting with 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione. This material (9.0 g, 22.4 mmol) was reacted with methyl acrylate as described in Example 1 to produce 6.54 g (59.8%) of methyl 3-[3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2,4-dioxothieno[3,4-d]pyrimidin-1-yl]propanoate as an orange oil after chromatography. A portion of this material was crystallized from CH2Cl2 /hexane to afford a peach-colored solid, mp 122°-123° C.