Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:33][CH:32]=3)[CH:10]=[CH:11][C:12]=2[NH:13][C:14]([C:16]2[N:17](COCC[Si](C)(C)C)[CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CCOC(C)=O.C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]([C:31]3[CH:32]=[CH:33][C:34]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])=[CH:35][CH:36]=3)[CH:10]=[CH:11][C:12]=2[NH:13][C:14]([C:16]2[NH:17][CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1C1=CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)cc1
Yield: 44 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (g) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (3-cyclohex-1-enyl-4′-methanesulfonylamino-biphenyl-4-yl)-amide (as prepared in the previous step, 29.5 mg, 0.0498 mmol). Silica gel chromatography (5-10% EtOAc/DCM) afforded the title compound (10.1 mg, 44%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.29 (d, 1H, J=8.6 Hz), 8.01 (s, 1H), 7.60 (d, 2H, J=8.6 Hz), 7.53 (dd, 1H, J=8.4, 2.0 Hz), 7.42 (d, 1H, J=2.0 Hz), 7.33 (d, 2H, J=8.6 Hz), 5.89 (m, 1H), 2.98 (s, 3H), 2.23-2.38 (m, 4H), 1.77-1.93 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C24H23N5O3S, 462.2 (M+H), found 461.9.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1
Reactant: Fc1ccccn1
Reactant: COC(=O)c1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccccn2)c2ncccc12
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (22.70 mg, 0.568 mmol, 60% suspension in mineral oil) was added to a solution of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate (100 mg, 0.568 mmol) in DMF (1419 μl) at RT. After 10 min, 2-fluoropyridine (48.8 μl, 0.568 mmol) was added to the mixture and the mixture was heated at 100° C. for 14 h. After being cooled to RT, the reaction mixture was directly purified by HPLC followed by neutralization (aq. NaHCO3) to afford the title compound as a colorless film.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([CH2:7][C@@H:8]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)[N:3]1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][CH:32]=[N:33]3)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.[ClH:36]>O1CCOCC1>[ClH:36].[NH:10]1[CH2:11][CH2:12][C@@H:8]([CH2:7][C:4]2[N:3]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:35]=[C:34]5[C:29]([CH:30]=[CH:31][CH:32]=[N:33]5)=[CH:28][CH:27]=4)=[CH:24][CH:25]=3)[C:2](=[O:1])[NH:6][N:5]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(-c2ccc3cccnc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Into an 8 mL vial was placed 1,1-dimethylethyl (3S)-3-({5-oxo-4-[4-(7-quinolinyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)-1-pyrrolidinecarboxylate (0.382 mmol). Added was 4N HCl in dioxane (2.0 mL). The vial was capped and the solution was agitated at room temperature for 1 h. The reaction was concentrated in vacuo to afford the title compound as the HCl salt (150 mg, 96%). No further purification was performed on this compound. MS(ES)+ m/e 372.2 [M+H]+.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([C:45](=[O:48])[NH:46][CH3:47])=[CH:41][CH:40]=3)[C:19](=[O:37])[N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[C:26]3[NH:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:30]=3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[NH2:17][CH:18]([C:19](=[O:37])[N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[C:26]1[NH:27][CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:30]=1)[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]([NH:46][CH3:47])=[O:48])=[CH:43][CH:44]=1
Reactant: CNC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2c2nc(-c3ccccc3)c[nH]2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CNC(=O)c1ccc(CC(N)C(=O)N2CCCCC2c2nc(-c3ccccc3)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 38.1 %

Procedure:
To a solution of 148 mg (0.21 mmol) of the product from step C in 2 mL of chloroform was added 2 ml of piperidine. The resulting mixture was allowed to stir at room temperature under argon for 3.5 hours. The reaction mixture was then concentrated and the residue purified on a Gilson prep LC system. The product was lophilized to obtain 47 mg (0.08 mmol, 48% yield) of the desired product as a white powder assumed to be a TFA salt. 1H NMR (300 MHz, CD3OD): δ 1.20–1.45 (2H, m), 1.50–1.80 (4H, m), 1.90–2.40 (2H, m), 2.90 (3H, d), 2.95–3.21 (2H, m), 3.78 (1H, m), 4.54 (1H, d), 5.12 (1H, s), 5.92 (1H, t), 7.28 (1H, d), 7.33–7.88 (10H, m). TLC (90:9:9, CHCl3:MeOH:NH4OH) Rf=0.33
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15](=[N:18][C:19]#[N:20])SC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH2:21]([NH2:23])[CH3:22]>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:23][CH2:21][CH3:22])=[N:18][C:19]#[N:20])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CSC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Reactant: CCN
Solvent: CCO
Product: CCNC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-guanidino-4-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]thiazole (1.1 g.) in ethanol (25 ml.) was treated with 70% w/v aqueous ethylamine (5 ml.) at room temperature. The mixture was stirred overnight at room temperature and the solution evaporated to dryness. The residue was crystallized from methanol to give 2-guanidino-4-[2-(2-cyano-3-ethylguanidino)ethylthiomethyl]thiazole (0.53 g.), m.p. 181°-182° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:17]([NH:18][C:19](=[O:29])[CH:20]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[C:21]([OH:23])=[O:22])[C:16](=[O:30])[N:10]2[C:11]=1[P:12]([O-:15])(=[O:14])[O-:13])(=O)C.[Na+:31].[Na+].[Na+].[OH-].[Na+].Cl>CCOC(C)=O>[OH:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:17]([NH:18][C:19](=[O:29])[CH:20]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[C:21]([OH:23])=[O:22])[C:16](=[O:30])[N:10]2[C:11]=1[P:12]([O-:15])(=[O:13])[O-:14].[Na+:31].[Na+:31].[Na+:31]
Reactant: CC(=O)OCC1=C(P(=O)([O-])[O-])N2C(=O)[C@@H](NC(=O)C(C(=O)O)c3ccsc3)[C@H]2SC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(O)C(C(=O)N[C@@H]1C(=O)N2C(P(=O)([O-])[O-])=C(CO)CS[C@H]12)c1ccsc1
Temperature: 30 °C

Procedure:
Trisodium 3-acetoxymethyl-7β-(2-[3-thienyl]- 2-carboxyacetamido)-3-cephem-4-phosphonate (1 g.) is dissolved in 100 ml. of a solution of citrus acetyl esterase (J.D.A. Jeffery, et. al., Biochem. J. (1961) 81, 591). The pH is adjusted to 6.6 and the mixture is maintained at 30° C. 1 N NaOH is added dropwise to maintain the pH at 6.6 as the reaction proceeds and the reaction is continued until no further pH change occurs. 10 g. Nacl is added and the mixture is layered with 50 ml. EtOAc, the pH is adjusted to 2.1 with HCl and the mixture is stirred vigorously. The EtOAc layer is separated and washed once with water and then layered with water and stirred and the pH of the aqueous phase is adjusted to 5.9 with 6 N NaOH. The aqueous layer is separated and freeze-dried to give trisodium 3-hydroxymethyl-7β-(2-[3-thienyl]-2-carboxyacetamido)-3-cephem-4-phosphonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1.[Si:9](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CN=C1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][O:8][Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:5][CH:6]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(Br)cs1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cc(Br)cs1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
To a 250-mL round bottom flask fitted with a magnetic stir bar under a N2 atmosphere was added (4-bromothiophen-2-yl)methanol (2.0 g, 10 mmol, 1 equiv) and 30 mL of anhydrous DCM. The reaction mixture was then cooled to 0° C. and the tert-butyl-diphenylsilyl chloride (3.4 g, 3.2 mL, 12.4 mmol, 1.2 equiv) was added followed by imidazole (1.06 g, 15.5 mmol, 1.5 equiv). The reaction was stirred for 16 h and was allowed to equilibrate to rt. The reaction mixture was subsequently taken up in 75 mL DCM and washed with water (100 mL). The organic layer was then dried (Na2SO4), filtered, and evaporated in vacuo. The resulting residue was chromatographed over silica gel (0-10% EtOAc in heptane over 18 min.-retention time (tR) of product: 4-12 min) to give the desired ((4-bromothiophen-2-yl)methoxy)-tert-butyl diphenyl silane (4.3929 g, 98%). 1H-NMR (400 MHz, CD3CN) δ ppm 7.66-7.71 (m, 4H), 7.39-7.51 (m, 6H), 7.29 (d, J=1.46 Hz, 1H), 6.77-6.81 (m, 1H), 4.89 (d, J=0.93 Hz, 2H), 1.06 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[N:15]1([CH2:21][CH2:22][CH2:23][OH:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:21][CH2:22][CH2:23][O:24][C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCC(c2ccc(Cl)nc2)=NN1
Reactant: OCCCN1CCCCC1
Product: O=c1ccc(-c2ccc(OCCCN3CCCCC3)nc2)n[nH]1

Procedure:
This compound was prepared using the intermediate from step 1 example 139 and 3-piperidin-1-yl-propanol using methods described for example 146; Mp 155-158° C. MS m/z 315 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:20])[C:8]=1[N:9]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[NH:10][C:11]([O:13][CH3:14])=[O:12].[C:21]1(C)C=CC=CC=1>C(OCC)C>[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:20])[C:8]=1[N:9]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[N:10]([CH3:21])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COCC(=O)N(NC(=O)OC)c1c(C)csc1C
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COCC(=O)N(c1c(C)csc1C)N(C)C(=O)OC

Procedure:
0.73 g (0.03 mol) NaH and 7.95 (0.03 mol) methyl 2-(2,4-dimethylthien-3-yl)-2-(methoxyacetyl)-hydrazinecarboxylate in 100 ml dry toluene are heated under reflux for 3 hours. The reaction mixture is then, together with 9.52 g (0.067 mol) CH3J, transferred into a sealed cylinder and heated 20 hours at 110°. The mixture is, after cooling, diluted with diethylether, washed with water, dried and evaporated to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[F:11].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:13])=[CH:6][C:5]=1[F:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1F
Temperature: 60 °C
Yield: 82 %

Procedure:
To a solution of 2-fluoro-4-methyl-benzoic acid methyl ester (1.12 g, 6.66 mmol) in carbon tetrachloride (12 mL) add N-bromosuccinimide (1.18 g, 6.66 mmol) and benzoyl peroxide (10 mg). Heat the resulting mixture to 60° C. for 15 hours then concentrate under vacuum to half and filter. Concentrate the filtrate under vacuum and purify the resulting crude product by flash chromatography on silica gel (eluting with 5/1 heptane/ethyl acetate) to give the title compound (1.35 g) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[C:10]1(C)C(O)=CC=C[CH:11]=1>>[CH2:10]([C:5]1[C:4]2[O:9][CH:2]=[CH:1][C:3]=2[CH:8]=[CH:7][CH:6]=1)[CH3:11]
Reactant: CCc1ccccc1O
Reactant: Cc1ccccc1O
Product: CCc1cccc2ccoc12

Procedure:
7-Ethyl-benzofuran is prepared by the method described in J.Chem.Soc. 1920, 1534, but using o-ethylphenol inste of o-cresol. The MS. of the product thus obtained shows the following ion peaks with the relative intensities given within brackets: 131 (100%), 146 (38%) and 77 (10%).
Reaction SMILES: C(C1C=CC=CC=1)(=[O:3])C.C[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:16]=[CH:15][C:14]=1[O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:12].Cl[O-]>>[F:28][C:27]([F:30])([F:29])[CH2:26][O:25][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:18][C:13]=1[C:11]([OH:12])=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: [O-]Cl
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
replacing the methyl moiety of the acetophenone function of said 2,5-bis(2,2,2-trifluoroethoxy)acetophenone using hypochlorite to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid; and
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]([NH:21][NH2:22])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:22][NH:21][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccccc1
Temperature: 100 °C
Yield: 66 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added benzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 129 mg of the title compound (66%) as a yellow solid in 99.8% purity by HPLC (Rt: 4.72, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([OH:15])=O.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([Cl:19])=[O:15]
Reactant: O=C(O)/C=C1\CCc2c(F)cc(F)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C1\CCc2c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of (E)-2-(4,6difluoro-1-indanylidene)acetic Acid (5.49 g, 0.026 mol) in a mixture of dichloromethane: dimethylformamide (50 mL: 5 drops) was treated with oxalyl chloride (6.6 g 0.052 mol, Aldrich) and allowed to stir at ambient temperature for 18 h. The resulting solution was concentrated in vacuo and the residue used without further purification.
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH:18]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][Cl:28])([CH3:16])[C:14](=[O:29])[CH:13](Br)[CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=O)C.[OH2:31].[OH-].[Na+].Cl>N1C=CC=CC=1>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:18]1[CH2:17][C@@:15]2([CH3:16])[C@@H:11]([CH2:12][CH:13]([OH:31])[C:14]2=[O:29])[C@H:10]2[C@H:19]1[C:20]1[CH:21]=[CH:22][C:5]([OH:4])=[CH:6][C:7]=1[CH2:8][CH2:9]2
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2C(CCCCCCl)C[C@]2(C)C(=O)C(Br)C[C@@H]12
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: C[C@]12CC(CCCCCCl)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC(O)C2=O

Procedure:
A solution of 15.3 g of crude 3-acetoxy-16-bromo-11-(5-chloropentyl)-estra-1,3,5(10)-trien-17-one in 237 ml of pyridine is mixed with 79 ml of water and then with 50 ml of sodium hydroxide solution (1N) and stirred for 24 hours at room temperature. Then, 25 ml of hydrochloric acid (2N) is added, it is evaporated to the dry state in a vacuum, diluted with 11 of ethyl acetate, washed with hydrochloric acid (2N), washed neutral with water, washed with common salt solution, dried on sodium sulfate and evaporated to the dry state in a vacuum. 4.2 g of crude 11-(5-chloropentyl)-3,16-dihydroxy-estra-1,3,5(10)-trien-17-one is obtained, and after chromatography on silica gel with hexane/ethyl acetate, 2.5 g of pure 11-(5-chloropentyl)-3,16-dihydroxy-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:16]=[C:17]([Br:23])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>CN(C=O)C>[CH3:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([Br:23])=[CH:16][C:15]=1[O:14][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7]
Reactant: O=C1CCCC1Cl
Reactant: COc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1OC1CCCC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
17.7 g (0.15 mol) of 2-chlorocyclopentanone and 41.4 g (0.3 mol) of potassium carbonate are added to a solution of 20 g (0.1 mol) of 3-hydroxy-4-methoxy-bromobenzene in 300 ml of absolute DMF and the mixture is stirred at RT for 12 h. After filtering off the solids, the filtrate is concentrated, the residue is taken up in 500 ml of ethyl ether and the solution is extracted by shaking with 3×200 ml of distilled water. Column chromatography affords 21.1 g of the title compound as a brown oil [TLC (petroleum ether/ethyl acetate 6:4) Rf =0.47].
Reaction SMILES: B(F)(F)F.CCOCC.Br[CH2:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1)=O.[CH3:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][C:29](=[O:31])[NH2:30]>C1COCC1>[CH3:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[O:31][CH:11]=[C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:30]=1
Reactant: COc1cccnc1C(=O)CBr
Reactant: COC(=O)CCCCC(N)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CCCCc1nc(-c2ncccc2OC)co1
Temperature: 80 °C
Yield: 33.4 %

Procedure:
Add boron trifluoride etherate (0.30 mL, 1.00 mmol) to a sealed tube containing 2-bromo-1-(3-methoxy-pyridin-2-yl)-ethanone (231 mg, 1.00 mmol), 5-carbamoyl-pentanoic acid methyl ester (222 mg, 1.39 mmol), and THF (anhydrous, 3 mL). Flush with N2, seal, heat at 80° C. overnight. Partition between saturated aqueous NaHCO3 solution and 20% i-PrOH/CHCl3, separate layers. Extract from aqueous layer with 20% i-PrOH/CHCl3 (×3), dry combined organic layers with MgSO4 and concentrate. Adsorb on SiO2 and purify by flash chromatography on silica gel eluting with 1-3% methanol/CHCl3 to afford the title compound (97 mg, 33%). MS (IS) 291 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]1=2.[Br:14]N1C(=O)CCC1=O.O.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:14][CH:11]1[CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]=2[C:2]1=[O:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2c(c1)CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc2c(c1)CCC(Br)C2=O
Temperature: 60 °C
Yield: 86.2 %

Procedure:
5-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (1.0 g, 5.8 mmol), 1-bromopyrrolidine-2,5-dione (1.04 g, 5.8 mmol) and 4-methylbenzenesulfonic acid hydrate (0.111 g, 0.58 mmol) were ground in a porcelain mortar. The resulting powder was placed in a vial, and heated at 60° C. for 12 mins. The mixture became a muddy liquid at 60° C. After cooling to room temperature, the mixture was dissolved in CH2Cl2 (80 mL). The solution was washed with saturated NaHCO3, water, brine, and dried (MgSO4). Solvent was evaporated off to give racemic 6-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (1.25 g, 5.0 mmol, 86% yield) as a yellow solid: LCMS=249.98 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=[S:6])[NH:4][NH2:5].Cl[C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].S(=O)(=O)(O)O>>[CH3:1][N:2]([CH3:7])[C:3]1[S:6][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:5][N:4]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CN(C)C(=S)NN
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nnc(N(C)C)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A solution of 4,4-dimethyl-3-thiosemicarbazide (2.0 g, 16.8 mmol) and ethyl chloro-oxo-acetate (2.3 g, 16.8 mmol) were mixed under an inert atmosphere and cooled to 0° C. in an ice bath. Sulfuric acid (2 mL) was added slowly. After the effervescence ceased, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for 3 hours. To the white heterogeneous mixture, ethyl acetate (100 mL) was added and the organic layer was washed twice with 2% sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residual solid was dissolved in ethyl acetate and the desired compound was precipitated with ether to yield the ethyl 5-(dimethylamino)-1,3,4-thiadiazole-2-carboxylate (IIIc) (1.9 g, 9.4 mmol). The ester, (IIIc) was dissolved in anhydrous methyl acetate (4 mL) and solution purged with an inert atmosphere. To this yellow solution sodium hydride (60% dispersion in mineral oil, 0.53 g, 13.25 mmol) was added providing a light yellow precipitate. The reaction mixture was then heated to 65° C. and it turned to a light green precipitate. Additional methyl acetate (4 mL) was added and in ten minutes the reaction mixture became a tan solid. The reaction was removed from the heat and an additional methyl acetate (20 mL) was added. The mixture was neutralized with acetic acid. The solid was filtered off and the filtrate was evaporated. The solid from the filtrate was washed with ether to yield the desired β-ketoester, ethyl 3-[5-(dimethylamino)(1,3,4-thiadiazol-2-yl)]-3-oxopropanoate, (Vd) (5.2 mmol) as a yellow solid. A mixture of the β-ketoester (Vd) (1.2 g, 1.31 mmol), ethanol (2 mL) and hydrazine hydrate (0.063 g, 1.96 mmol) was heated to 65° C. for two hours. The precipitate was filtered to obtain the pyrazolone (VIi) (0.075 g, 0.36 mmol) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH2:17].C([O-])(=O)C.[Na+]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(N)cc1OC
Reactant: Clc1ncnc2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(Nc2ncnc3ccccc23)cc1OC

Procedure:
The title compound was prepared from 4-chloro-quinazoline (82.3 mg, 0.5 mmol), 3,4-dimethoxy-aniline (76.6 mg, 0.5 mmol) and sodium acetate (49.2 mg, 0.6 mmol) similar to example 20 to give 138 mg (92.5%) of off white solids. 1H NMR (CDCl3): 8.74 (s, 1H), 7.91 (t, J=8.7 Hz, 2H), 7.57 (t, J=8.1 Hz, 1H), 7.57 (t, J=8.1 Hz, 1H), 7.45 (s, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.16-7.13 (m, 1H), 6.92 (d, J=8.4 Hz, 1H), 3.93-3.91 (m, 6H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[OH:12][C:6]1[CH:11]=[CH:10][C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:8][CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
To chlorosulfonic acid (248 mL, 3.37 mol) cooled to −3° C. was added dropwise a solution of phenol (70 g, 0.744 mot) in 250 mL of anhydrous methylene chloride over a period of 1 hour under argon gas. The mixture was warmed to rt over 1 h and was stirred at rt for 1.5 h. The mixture was poured over ice, stirred for 30 min, and was extracted with methylene chloride (4×2 L). The resulting organic layer was dried over MgSO4 and concentrated in vacuo to yield 4-hydroxybenzenesulfonyl chloride as a sticky brown solid (41.49 g, 29%): 1H NMR (400 MHz, d6-DMSO) δ 7.29–7.38 (d, 2 H), 6.58–6.69 (d, 2 H).