Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[N:18][CH:17]=1.Cl>CN(C=O)C.O>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:8][C:9]3[N:10]=[C:11]([CH3:14])[S:12][CH:13]=3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[N:18][CH:17]=1
Reactant: COc1cc2c(Cl)cnnc2cc1O
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)cnnc2cc1OCc1csc(C)n1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 47.9 %

Procedure:
The starting material 4-chloro-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline was obtained by adding potassium carbonate (786 mg, 5.7 mmol) followed by 4-chloromethyl-2-methylthiazole (308 mg, 2 mmol) to a suspension of 4-chloro-7-hydroxy-6-methoxycinnoline (0.4 g, 1.9 mmol), (prepared as described for the starting material in Example 10), in DMF (10 ml). After stirring for 4.5 hours at 60° C. the reaction mixture was diluted with water and acidified to pH4 with 2M hydrochloric acid. After extraction with ethyl acetate, the organic layer was washed with water and then brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography using methylene chloride/ethyl acetate (2/8) as eluent to give 4-chloro-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline as a solid (293 mg, 48%).
Reaction SMILES: [OH:1][C:2]1[N:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C1C(=O)N([I:19])C(=O)C1>C(Cl)Cl>[OH:1][C:2]1[N:10]=[C:9]([OH:11])[C:8]([I:19])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: NC(=O)c1ccc(O)nc1O
Solvent: ClCCl
Product: NC(=O)c1cc(I)c(O)nc1O
Reaction time: 0.33 h

Procedure:
A mixture of compound 2,6-dihydroxynicotinamide (20 g, 0.13 mol) and NIS (29.2 g, 0.13 mol) in DCM (1000 mL) was stirred at r.t for 20 min. The mixture was concentrated in vacuo to afford crude compound 2,6-dihydroxy-5-iodonicotinamide. (50 g) which was used for the next step directly. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 11.04 (bs, 1H), 8.46 (s, 1H), 2.55 (s, 4H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C1C=C[C:9]2N(O)N=[N:12][C:10]=2[CH:11]=1>CN(C=O)C>[CH:3]([NH:12][CH:10]([CH3:9])[CH3:11])([CH3:4])[CH3:2].[NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: c1cc[nH]c1
Product: CC(C)NC(C)C

Procedure:
Chloropyrrolotriazine (1) (compound 3 of Scheme 9) can be reacted with an aniline (1a) (e.g., compound 1 of Scheme 11) in anhydrous DMF at rt to afford compound (2). Reaction of compound (2) with an aq. base such as NaOH with heating affords compound (3). Compound (3) can be reacted with an amine R2NH2 in the presence of a coupling reagent, such as HOBt, with or without a base such as diisopropylamine, in an organic solvent, such as DMF to afford compound (4). Compound (4) can be reacted with hydrogen in the presence of a catalyst, such as Pd/C, in an organic solvent, such as MeOH to afford compound (5). Reaction of compound (5) with an isocyanate in an organic solvent, such as DCE affords compound (6).
Reaction SMILES: [NH2:1][CH:2]([CH:6]([CH3:11])[C:7]([F:10])([F:9])[F:8])[C:3](O)=[O:4].[Al]>C1COCC1>[NH2:1][CH:2]([CH:6]([CH3:11])[C:7]([F:10])([F:9])[F:8])[CH2:3][OH:4]
Reactant: CC(C(N)C(=O)O)C(F)(F)F
Agent: [Al]
Solvent: C1CCOC1
Product: CC(C(N)CO)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a chilled (00° C.) solution of 2-amino-4,4,4-trifluoro-3-methylbutanoic acid (736 mg, 4.30 mmol) in THF (9 mL) was added aluminum (111) lithium hydride (2.26 mL, 9.03 mmol, 4M) dropwise. After addition complete, the reaction was allowed to stir at ambient temperature for 1 hour. Cool to 0° C. and quench w/sat. Na2SO4 soln, added EtOAc (50 mL), Na2SO4, filtered, conc. in vacuo afforded material that was a mixture of the title compound and the starting material acid in a 3:2 ratio which was used crude in the next step. 1H NMR (400 MHz, CDCl3) δ 3.71 (dd, J=10.7, 3.7 Hz, 1H), 3.57 (dd, J=10.4, 5.2 Hz, 1H), 3.45 (ddd, J=10.7, 8.0, 4.8 Hz, 2H), 3.28 (ddd, J=8.2, 5.3, 2.9 Hz, 1H), 3.06 (td, J=7.3, 3.6 Hz, 1H), 2.44-2.20 (m, 2H), 2.04-1.54 (m, 1H), 1.21-1.08 (m, 7H). 19F NMR (376 MHz, CDCl3) δ−68.33 (s), −70.12 (s).
Reaction SMILES: C[O:2][C:3](=[O:48])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[C:38]=3[Cl:47])[CH2:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-]>C1COCC1.O>[ClH:47].[Cl:47][C:38]1[C:39]([C:43]([F:44])([F:45])[F:46])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:21]([CH2:22][CH:23]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][CH2:19][CH2:18][O:17][C:13]1[N:12]=[C:11]([N:8]2[CH2:7][CH2:6][N:5]([CH2:4][C:3]([OH:48])=[O:2])[CH2:10][CH2:9]2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cl
Product: O=C(O)CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring solution of [4-(6{-3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-pyridin-2-yl)-piperazin-1-yl]-acetic acid methyl ester (46 mg, 0.07 mmol) in THF (2 ml) and H2O (0.5 ml) was added LiOH (6 mg, 0.13 mmol). The reaction mixture was stirred for 24 h at RT and then concentrated. The aqueous mixture was acidified to pH=3 with 1 N HCl (aq) and extracted with EtOAc (three times). The organic extracts were dried over Na2SO4, filtered, and concentrated. The free base was dissolved in dichloromethane and 1 N HCl (Et2O) was added. The solution was concentrated under vacuum to provide the title compound as a white solid, 26 mg (45%). MS (ESI) 667.2 (M+).
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][CH2:14][O:15][CH2:16][CH2:17]O>>[C:1]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOCCO
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)OCCOCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and ethyl cellosolve as starting materials to give the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.[CH2:15]([O:17][C:18]([C:20]#[C:21][C:22](OCC)=[O:23])=[O:19])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18]([C:20]1[N:6]2[N:5]=[C:4]([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:3][C:2]2=[N:1][C:22](=[O:23])[CH:21]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Nc1nnc(CCc2ccccc2)s1
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sc(CCc3ccccc3)nn12
Reaction time: 8 h

Procedure:
8.1 g of 2-amino-5-(β-phenylethyl)-1,3,4-thiadiazole are heated with 6.8 g of acetylene dicarboxylic acid diethyl ester in 100 ml of ethanol until a clear solution has formed. After standing overnight, the solution is concentrated by evaporation to dryness. The residue crystallises on triturating with ether. 2-(β-Phenylethyl)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 95° to 98° C. is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][C:36]1[CH:48]=[CH:47][CH:46]=[CH:45][C:37]=1[CH2:38][N:39]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27]([NH:44][CH:41]2[CH2:42][CH2:43][N:39]([CH2:38][C:37]3[CH:45]=[CH:46][CH:47]=[CH:48][C:36]=3[CH3:35])[CH2:40]2)=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1CN1CCC(N)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5C)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) to prepare a solution. Triphosgene (110 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 1-(2-Methylbenzyl)-3-pyrrolidinamine (96 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (101 mg, yield 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH:25]=3)[N:18]=2)=[CH:4][C:3]=1[N+:35]([O-])=O>[Pd].O1CCCC1>[CH3:34][N:32]([CH3:33])[CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[N:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]4=[N:9][C:8]=3[C:5]3[CH:4]=[C:3]([NH2:35])[C:2]([NH2:1])=[CH:7][CH:6]=3)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)CCc1cccc(Nc2nccc(-c3c(-c4ccc(N)c([N+](=O)[O-])c4)nc4ccccn34)n2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C)CCc1cccc(Nc2nccc(-c3c(-c4ccc(N)c(N)c4)nc4ccccn34)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 50 mL pressure bottle was charged with 4-(2-(4-amino-3-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)-N-(3-(2-(dimethylamino)ethyl)phenyl)pyrimidin-2-amine (60 mg, 0.121 mmol) from EXAMPLE 10A and tetrahydrofuran (20 mL). The solution was treated with 50% palladium on carbon (30.0 mg, 0.282 mmol) and stirred for 24 hours at 30 psi at ambient temperature. The mixture was filtered through a nylon membrane and solvents were concentrated to provide the title compound. MS (ESI+) m/e 465.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[N:5]=[CH:6][NH:7]2.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:4]1[C:3]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:2]=2[Cl:1])[N:7]=[CH:6][N:5]=1
Reactant: COc1cc2[nH]cnc(=O)c2c(Cl)c1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2ncnc(Cl)c2c(Cl)c1OC
Temperature: 85 °C
Yield: 65 %

Procedure:
A mixture of 5-chloro-6,7-bis(methyloxy)-4(1H)-quinazolinone (100 mg, 0.42 mmol, prepared according to J. Med. Chem. (1999) 42 3860) in POCl3 (2 mL) was heated at 80-90° C. for 8 hours before being concentrated. The residue was treated with saturated aqueous NaHCO3 and extracted with EtOAc. The organic extract was dried (Na2SO4) and concentrated to give 4,5-dichloro-6,7-bis(methyloxy)quinazoline (70 mg, 65%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.94 (s, 1 H), 7.56 (s, 1 H), 4.05 (s, 3 H), 3.87 (s, 3 H). MS (m/z) 258.9 (M+H+).
Reaction SMILES: [CH:1]([S:3]([O:6][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=[O:5])=[O:4])=[CH2:2].[CH2:40]([NH2:42])[CH3:41]>CO>[CH2:40]([NH:42][CH2:2][CH2:1][S:3]([O:6][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=[O:4])=[O:5])[CH3:41]
Reactant: C=CS(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Reactant: CCN
Solvent: CO
Product: CCNCCS(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
4-Ethenesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0734 g, 0.133 mmol) was dissolved in methanol (1.5 mL), and the solution was added with 70% aqueous ethylamine solution (1.5 mL), followed by stirring at room temperature for 5 hours. The solvent was evaporated under reduced pressure and the residue was purified by thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-[2-(ethylamino)ethanesulfonyloxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0338 g, 43%).
Reaction SMILES: [Cl-:1].C([O:5][C@@H:6]([CH2:36][N+:37]([CH3:40])([CH3:39])[CH3:38])[CH2:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27][O:28][C:29]4[CH:33]=[CH:32][O:31][N:30]=4)[O:24][C:23]3=[O:34])=[CH:18][C:17]=2[F:35])[CH2:12][CH2:11]1)=[O:9])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl-:1].[OH:5][C@@H:6]([CH2:36][N+:37]([CH3:38])([CH3:40])[CH3:39])[CH2:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27][O:28][C:29]4[CH:33]=[CH:32][O:31][N:30]=4)[O:24][C:23]3=[O:34])=[CH:18][C:17]=2[F:35])[CH2:14][CH2:15]1)=[O:9]
Reactant: CC(=O)O[C@H](CC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1)C[N+](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C[N+](C)(C)C[C@H](O)CC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Yield: 76.6 %

Procedure:
3-(4-(4-((3R)-3-Acetoxy-4-trimethylarnmoniobutanoyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one chloride (200 mg, 0.33 mmol) and potassium carbonate (67 mg, 0.49 mmol) were stirred at ambient temperature under nitrogen in MeOH (20 ml) for 5 hours. The mixture was evaporated to dryness, the solid triturated with water, filtered and washed with water (20 ml) to give the desired product (137 mg). MS (ESP): 506 (M+) for C24H33FN5O6;
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[Cl:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 1,2-dichloro-4-nitro-benzene (9.2 g, 48 mmol), 4-chloro-phenol (6.2 g, 48 mmol) and potassium carbonate (19.9 g, 144 mmol) in DMF (80 mL) was heated to 90° C. for 16 hours. After cooling to room temperature the mixture was poured into water (600 mL) and extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (13.5 g, 99%).
Reaction SMILES: CC[C:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[C:9](=O)[CH2:8]3)[CH2:5][CH:4]=1.[Na].[O:25]1CCCC1>>[CH3:21][C@:20]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH2:16][OH:25])[CH2:14][CH2:13][C:12](=[O:22])[CH:11]=4)[C@@H:3]1[CH2:4][CH:5]=[CH:6]2
Reactant: CCC1=CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1CCOC1
Agent: [Na]
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(CO)[C@H]1CC2
Reaction time: 0.5 h

Procedure:
Refer to FIG. 192. Anh. ammonia (ca. 75 ml) was distilled through a KOH tower into a 250 ml flamedried 3-neck flask fitted with an inlet adapter, a magnetic stirring bar, a dry ice/acetone condenser, 35 and a stoDPer. A solution of 6β,19-epoxy-17-iodoandrosta-4,16-diene 3-ethylene ketal (18, 880.4 mg, 1.938 mmol) in dry tetrahydrofuran (THF, 45 ml) was added, followed by metallic sodium (0.20 g, 8.7 mg-atom) cut in small pieces. After stirring under argon pressure for 30 min. the reaction was quenched with the addition of abs. ethanol (1.0 ml). Ammonia was allowed to boil off overnight, 50 ml of water were added, and the mixture was extracted with three 25 ml portions of methylene chloride. The combined organic extracts were washed with 50 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. After washing the residue with 10 ml of methylene chloride the combined filtrates were concentrated under reduced pressure. The intermediate ketal proved remarkably unreactive, but was finally hydrolyzed by refluxing 18 h in 5 ml of chloroform and 2.5 ml of 4 N hydrochloric acid. To the cooled hydrolysis mixture ethyl acetate (50 ml) was added and the layers were separated. The organic phase was washed with 25 ml of saturated sodium bicarbonate+25 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. The resulting brown foam was purified by flash chromatography (50% ethyl acetate/hexanes on silica gel) followed by preparative TLC (50% ethyl acetate/hexanes on silica gel GF, 1000μ thickness) to give a partially crystalline film (66.7 mg, 0.233 mmol, 12%). 1H-NMR: 5.92 ∂, 1H, s, 4-H; 5.87-5.64 ∂, 2H, mult., 16,17-H's; 4.10∂ and 3.94 ∂, 2H, AB, 19-H's; 0.79 ∂, 3H, s, 18-Me.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[C:11]([C:16]([F:19])([F:18])[F:17])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1(C2C(C(O)=O)=C(C(F)(F)F)ON=2)C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([C:16]([F:18])([F:17])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(-c2ccc(F)cc2)noc1C(F)(F)F
Agent: O=C(O)c1c(-c2ccccc2)noc1C(F)(F)F
Product: OCc1c(-c2ccc(F)cc2)noc1C(F)(F)F
Yield: 55 %

Procedure:
As described for example 128d, 3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazole-4-carboxylic acid (3.0 g, 11 mmol), instead of 3-phenyl-5-trifluoromethyl-isoxazole-4-carboxylic acid, was converted to the title compound (1.58 g, 56%) which was obtained as a yellow solid. MS: m/e=262.0 [M+H]+.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.Cl[C:23]([O:25][CH3:26])=[O:24]>N1C=CC=CC=1>[CH3:26][O:25][C:23]([O:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C@:20]1([CH3:21])[C:14](=[CH:15][C:16](=[O:17])[CH2:18][CH2:19]1)[CH2:13][CH2:12]3)=[O:24]
Reactant: COC(=O)Cl
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Product: COC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 76 %

Procedure:
Testosterone is treated with methyl chloroformate in pyridine to give 17β-methoxycarbonyloxyandrost-4-en-3-one in 76% yield after recrystallization from methanol. A solution of the 17β-methoxycarbonyloxyandrost-4-en-3-one in toluene is pyrolyzed at 460° C., and the crude product is recrystallized from acetone at room temperature to give androsta-4,16-dien-3-one in 90% yield. The androsta-4,16-dien-3-one is reduced at −55° with lithium tris(1,2-dimethylpropyl)hydridoborate in tetrahydrofuran to give a mixture of androsta-4,16-dien-3β-ol and androsta-4,16-dien-3α-ol; and chromatography on silica gel using dichloromethane/ethyl acetate gives pure androsta-4,16-dien-3β-ol and pure androsta-4,16-dien-3α-ol, each in 48% yield. These may be recrystallized (androsta-4,16-dien-3β-ol from cyclohexane at room temperature and androsta-4,16-dien-3α-ol from petroleum ether at −30° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[NH2:9][C:10]1[N:14]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]=1.[CH3:27][C:28](C)=[O:29]>>[Br-:8].[NH2:9][C:10]1[NH:11][C:12]2[C:26]([CH2:27][C:28]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:29])=[CH:25][CH:24]=[CH:23][C:13]=2[N+:14]=1[CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: Nc1nc2ccccc2n1CCN1CCOCC1
Reactant: CC(C)=O
Reactant: Clc1ccc(Br)cc1
Product: Nc1[nH]c2c(CC(=O)c3ccc(Cl)cc3)cccc2[n+]1CCN1CCOCC1
Product: [Br-]
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 2.33 g (10 mmol) of 4-chlorophenyl bromide in 25 ml of acetone is added to a hot solution of 2-amino-1-(2-morpholinoethyl)benzimidazole (2.46 g, 10 mmol) in 75 ml of acetone. The mixture is stirred, heated at the boil for 5 minutes and maintained at room temperature. Three hours later a precipitate of the title compound appears, which is filtered and washed with acetone and with ether.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C1C(=O)N([Br:22])C(=O)C1>ClCCl>[Br:22][C:11]1[CH:12]=[CH:13][C:14]2[N:2]([CH3:1])[C:3]3[C:8]([C:9]=2[CH:10]=1)=[CH:7][CH:6]=[CH:5][CH:4]=3
Reactant: Cn1c2ccccc2c2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cn1c2ccccc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 1b (2.5 g, 13.8 mmol) in dichloromethane (80 mL) was added NBS (2.4 g, 13.8 mmol) portion-wise in an ice-water bath. After complete addition, the solution mixture was warmed to room temperature and stirred overnight. The resulting solution was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1:10) as eluent to afford 2b (2.11 g) in 59% yield. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=2.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.54 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 7.50 (td, J=8.0 Hz, J=1.2 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.27-7.22 (m, 2H), 3.82 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[CH3:19][N:20]([CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[S:21]([CH3:24])(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:27]3[CH2:28][CH2:29][CH2:30][CH:26]3[CH2:25][N:20]([CH3:19])[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:4][C:5]=2[N:6]=1
Reactant: CN(CC1CCCN1)S(C)(=O)=O
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CC1CCCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(C)(=O)=O
Temperature: 80 °C
Yield: 87.9 %

Procedure:
To a mixture of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (0.50 g) and N-methyl-N-pyrrolidin-2-ylmethyl-methanesulfonamide (390 mg) in acetonitrile (10 mL) was added potassium carbonate (490 mg). The reaction mixture was heated at 80° C. for 16 h and then allowed to cool to room temperature. The reaction mixture was then partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The combined organics were washed with brine (30 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give N-[1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-pyrrolidin-2-ylmethyl]-N-methyl-methanesulfonamide as a pale yellow solid (580 mg).