Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]([CH3:4])=O.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:28][OH:29]>O.CO>[OH:29][N:28]=[C:2]([CH3:4])[CH2:1][C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: NO
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cccc(C2=C(CC(C)=NO)C(=O)NCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The mixture of 7.0 g of 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 3.88 g of potassium carbonate, 3.55 g of hydroxylamine hydrochloride, 5 ml of water and 60 ml of methanol is refluxed for 5 hours and then stirred at room temperature overnight. 80 ml of water are added, the precipitate collected and washed with ethanol and diethyl ether, to yield the 3-(2-hydroxyiminopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, melting at 155°-158°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]4([CH3:24])[CH2:21][O:20]C(C)(C)[O:18]4)=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([OH:18])([CH3:24])[CH2:21][OH:20])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)OCC(C)(c2ccn3c(-c4ccc(F)c(-c5cccnc5)c4)cnc3n2)O1
Agent: Cl
Product: CC(O)(CO)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2n1
Yield: 50 %

Procedure:
3-[4-Fluoro-3-(pyridin-3-yl)phenyl]-7-(2,2,4-trimethyl-[1,3]dioxolan-4-yl)imidazo[1,2-α]pyrimidine (1.00 g, 2.47 mmol) was stirred in 2N hydrochloric acid (20 ml) at 70° C. for 10 min. The reaction mixture was allowed to cool and was then loaded onto a strong cation-exchange cartridge. Non-basic impurities were removed by elution with methanol. Elution with 10% ammonia in methanol gave 2-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propane-1,2-diol as an oil (450 mg) which solidified on standing. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, d6-DMSO) 1.50 (3H, s), 3.67 (2H, m), 7.74 (1H, dd, J 11 and 8), 7.89 (3H, m), 8.13 (1H, dd, J 7 and 2), 8.51 (1H, d, J 8), 8.58 (1H, s), 8.85 (1H, dd, J 5 and 1), 9.12 (1H, s), 9.40 (1H, d, J 7).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:9][NH2:10]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][NH2:10])=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1ccc(Br)cn1
Temperature: 22 °C

Procedure:
A mixture of 22.1 g 5-bromo-2-fluoropyridine and 10 mL of 55% aqueous hydrazine in 165 mL of pyridine was heated at reflux for 7 hours. The mixture was cooled to 22° C. concentrated to near dryness. The resulting light yellow solids were suspended in aqueous sodium hydroxide and toluene, stirred, and the solids were collected by vacuum filtration to give 22 g of 5-bromo-pyridin-2-yl-hydrazine as a faint yellow solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([C:5]3[S:6][C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:3][CH:4]=3)[CH:12]=2)[CH2:14][CH2:15]1
Reactant: CN1CCN(c2ccnc(-c3ccc(Br)s3)c2)CC1
Reactant: OB(O)c1ccccc1
Product: CN1CCN(c2ccnc(-c3ccc(-c4ccccc4)s3)c2)CC1

Procedure:
The title compound was prepared by treating 1-[2-(5-bromo-thiophen-2-yl)-pyridin-4-yl]-4-methyl-piperazine with phenylboronic acid under conditions as described in Example 26.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:12][C@H:11]2[C@H:7]([CH2:8][C:9](=[O:13])[O:10]2)[C@H:6]1[CH2:14][CH:15]1[O:19][CH2:18][CH2:17][O:16]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CO>[CH2:17]1[CH2:18][O:19][CH:15]([CH2:14][C@H:6]2[C@H:5]([OH:4])[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:13])[O:10]3)[O:16]1
Reactant: CC(=O)O[C@@H]1C[C@@H]2OC(=O)C[C@@H]2[C@H]1CC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1C[C@@H]2[C@@H](CC3OCCO3)[C@H](O)C[C@@H]2O1

Procedure:
The acetal (55) (4.180 g) was treated with potassium carbonate (1.18 g) in methanol (100 ml) at room temperature for 2 hours with stirring. The reaction mixture was neutralized with addition of acetic acid, followed by the usual work up to give a crude product. The crude product was chromatographed on a column of silica gel to give the alcohol (56).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[CH2:13](I)[CH3:14]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][O:6][CH2:13][CH3:14])[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: CCI
Reactant: OCc1cc(Br)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
A solution of 3,5-dibromobenzyl alcohol (2.0 h, 8 mmol) in tetrahydrofuran (80 mL) was cooled to 5° C. and treated with sodium hydride (dispersion in oil 55%; 316 mg, 8 mmol). The mixture was left to warm to room temperature and stirred for 15 min. Ethyliodide (2.35 g, 15 mmol) was added and the mixture stirred for 5 h. For the working-up, the reaction mixture was evaporated, then extracted with a mixture of ethyl acetate and saturated sodium hydrogencarbonate solution. After the aqueous layer was re-extracted twice with ethyl acetate, the organic layers were combined, dried over sodium sulfate, and evaporated under reduced pressure. There were obtained 1.15 g of the title compound (yield: 52%) as a yellow oil in sufficient purity to be engaged in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.[NH2:26][CH:27]([C:29]1[CH:30]=[C:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=[CH:33][CH:34]=1)[CH3:28]>>[CH3:16][O:15][C:13]([C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[NH:26][CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:42])[CH:30]=1)[CH3:28])=[O:14]
Reactant: CC(N)c1cccc(NC(=O)OC(C)(C)C)c1
Reactant: COC(=O)c1cc(Cl)cc2c(Cl)ncnc12
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Cl)cc2c(NC(C)c3cccc(NC(=O)OC(C)(C)C)c3)ncnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4,6-dichloroquinazoline-8-carboxylate (574 mg; 2.23 mmol; 1.00 eq.) in acetonenitrile (5 ml) containing N-ethyl-N-isopropylpropan-2-amine (0.80 ml; 4.47 mmol; 2.00 eq.) was added tert-butyl [3-(1-aminoethyl)phenyl]carbamate (543 mg; 2.30 mmol; 1.03 eq.), the reaction mixture was stirred at RT overnight. Concentrated to get 4-[1-(3-tert-butoxycarbonylamino-phenyl)-ethylamino]-6-chloro-quinazoline-8-carboxylic acid methyl ester. To this crude was added methanolic ammonia (3.19 ml; 7.00 M; 22.33 mmol; 10.00 eq.) and stirred at RT for 48 h. The solvent was removed and the residue, {3-[1-(8-Carbamoyl-6-chloro-quinazolin-4-ylamino)-ethyl]-phenyl}-carbamic acid tert-butyl ester was treated with 4.0M hydrogen chloride in dioxane (5.58 ml; 4.00 M; 22.33 mmol; 10.00 eq.) and methaonl (6.45 ml). Stirred overnight, concentrated and purified by HPLC to collect the title product (130 mg) in 14% over all yield. MS (M+1) 342.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:4]=2[N:3]=1.[NH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[C:19]([OH:26])[CH:20]=[CH:21][CH:22]=2)[N:17]=1>>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([O:26][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:18]=3[N:17]=[C:16]([NH2:15])[CH:25]=[CH:24]4)=[N:3][C:4]=2[CH:10]=1
Reactant: FC(F)(F)c1ccc2[nH]c(Cl)nc2c1
Reactant: Nc1ccc2cccc(O)c2n1
Product: Nc1ccc2cccc(Oc3nc4cc(C(F)(F)F)ccc4[nH]3)c2n1

Procedure:
The reaction of 2-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazole (66 mg, 0.3 mol, prepared according to the procedure described in WO 2004/035549 A1) with 2-amino-8-hydroxyquinoline (48 mg, 0.3 mmol, Fluka) under the condition of Example 1 afforded the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 345 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C@@H:14]2[O:19][C@H:18]([CH3:20])[CH2:17][N:16]([C:21]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]4[C:22]=3[CH:23]=[CH:24][CH:25]=[N:26]4)[CH2:15]2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C@H:14]2[CH2:15][N:16]([C:21]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]4[C:22]=3[CH:23]=[CH:24][CH:25]=[N:26]4)[CH2:17][C@@H:18]([CH3:20])[O:19]2)[CH2:9]1
Reactant: C[C@@H]1CN(c2ccc(C#N)c3ncccc23)C[C@H](CN2CC[C@@H](NC(=O)OC(C)(C)C)C2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(C#N)c3ncccc23)C[C@H](CN2CC[C@@H](N)C2)O1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a stirred solution of tert-butyl((R)-1-(((2S,6R)-4-(8-cyanoquinolin-5-yl)-6-methylmorpholin-2-yl)methyl)-pyrrolidin-3-yl)carbamate (1.35 g, 3.0 mmol) in DCM (10 mL) was added TFA (8.1 mL). The reaction was stirred at rt after which time it was concentrated and azeotroped to dryness three times with toluene (10 mL each) and then dried under vacuo to provide crude 5-((2S,6R)-2-(((R)-3-aminopyrrolidin-1-yl)methyl)-6-methylmorpholino)quinoline-8-carbonitrile (1.39 g, 3.0 mmol, 100% yield) as the TFA salt.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[S:29][C:17]2[N:18]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:19](=[O:24])[N:20]([CH3:23])[C:21](=[O:22])[C:16]=2[C:15]=1[S:30][CH:31]([CH3:33])[CH3:32].O>CN(C)C=O>[N:1]1([CH2:13][C:14]2[S:29][C:17]3[N:18]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:19](=[O:24])[N:20]([CH3:23])[C:21](=[O:22])[C:16]=3[C:15]=2[S:30][CH:31]([CH3:33])[CH3:32])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(CCl)sc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(Cn3cnc4ccccc43)sc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
Benzimidazole (0.083 g) and sodium hydride (60% dispersion, 0.031 g) were added to 6-(chloromethyl)-3-methyl-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.21 g) in dry dimethylformamide (10 ml) and the reaction was stirred for 2 hours at room temperature. Water was added to the reaction mixture which was then extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with brine and dried, filtered and evaporated. The residue was triturated with diethyl ether to give the title compound (0.163 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[CH:25]([C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][C:37]=1[OH:38])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26]>>[C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][O:38][C:37]3[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][C:27]=3[CH:25]=[O:26])=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(O)c(C=O)c1
Reactant: BrCCCc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C=O)c1

Procedure:
Preparation takes place in analogy to Example XIII from 1,1′-biphenyl-4-ylmethyl 4-(3-bromopropyl)phenyl ether and ethyl 3-formyl-4-hydroxybenzoate.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C@H:5]1[CH2:6][C:7](=[N:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]1[C:1](=[O:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(=O)N1c2ccccc2C(=O)C[C@@H]1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1c2ccccc2C(=Nc2ccccc2)C[C@@H]1C

Procedure:
A solution of (2S)-1-acetyl-2-methyl-2,3-dihydro-4(1H)-quinolinone (20 mg, 0.098 mmol; preparation see Tetrahedron: Asymmetry (1998), 9(7), 1137–1142), aniline (36 μl, 0.394 mmol) and a catalytic amount of p-toluene sulfonic acid monohydrate was refluxed overnight in toluene (4 ml) containing molcular sieve 3 Å (0.9 g). The resulting mixture was filtered, concentrated and purified on silica (ethyl acetate:heptane 1:2) to obtain the sub-titled product (22.8 mg, 0.082 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]CC)=[O:14]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CCOC(=O)c1cccc(O)c1
Product: O=C(O)c1cccc(Oc2ccc(Br)nc2)c1

Procedure:
Prepared from 2-bromo-5-fluoropyridine and ethyl 3-hydroxybenzoate. 1H NMR (400 MHz, DMSO-d6) δ 13.12 (br. s., 1 H), 8.28 (d, 1 H), 7.78 (d, 1 H), 7.69 (d, 1 H), 7.56 (t, 1 H), 7.48-7.54 (m, 2 H), 7.39 (dd, 1 H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[N+:17]([O-])([O-:19])=[O:18].[Na+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([Cl:15])(=[O:13])=[O:14])=[CH:10][C:11]=1[N+:17]([O-:19])=[O:18])[CH3:2]
Reactant: CCOC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Nc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 82.1 %

Procedure:
To a stirred suspension of (4-chlorosulfonyl-phenyl)-carbamic acid ethyl ester (5 g, Reference Example 64) in concentrated sulfuric acid (25 ml) at 0° C., was added dropwise a suspension of sodium nitrate (1.61 g) in concentrated sulfuric acid and the reaction stirred for 3 hours. The reaction mixture was then poured onto ice, the resultant precipitate collected by filtration and dried in vacuo to give (4-chlorosulfonyl-2-nitro-phenyl)-carbamic acid ethyl ester (4.80 g) as a yellow solid. LC-MS (METHOD B): RT=3.32 minutes, 307.08 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](/[CH:7]=[CH:8]/[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:16]C1SC(C2CC2C(OCCCC)=O)=CC=1>>[CH3:1][C:2]1[S:6][C:5]([CH:7]2[CH2:16][CH:8]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)C1CC1c1ccc(C)s1
Reactant: Cc1ccc(/C=C/C(=O)OC(C)(C)C)s1
Product: Cc1ccc(C2CC2C(=O)OC(C)(C)C)s1

Procedure:
tert-Butyl (2E)-3-(5-methylthien-2-yl)prop-2-enoate was cyclopropanated according to the procedure described for EXAMPLE 136, STEP 2, providing, after chromatography, ten-butyl 2-(5-methylthien-2-yl)cyclopropanecarboxylate.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][O:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:3][C:4]#[N:5].[ClH:18].[H][H]>CO.[Pd]>[ClH:18].[OH:1][C@@H:2]([CH2:6][O:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH2:3][CH2:4][NH2:5]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CC#N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)CCN)cc1
Reaction time: 20 h

Procedure:
To a solution of (R)-3-hydroxy-4-(p-toluenesulfonyloxy)butyronitrile (17.4 g) in methanol (120 ml), 10 wt. % Pd on carbon (3.0 g) and conc. hydrochloric acid (30 ml) were added. The mixture was stirred in a hydrogen atmosphere of 4. 0 kg/cm2 at room temperature for 20 hours. After filtrating off the catalyst, the mixture was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (Wako Gel C200, an eluent: methanol/acetone (volume ratio of 3/7) to obtain pure (R)-3-hydroxy-4-(p-toluenesulfonyloxy)butylamine hydrochloride (18.4 g). Yield, 91 %.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C:4](=[O:23])[CH2:3]1)[C@:16]1([CH3:17])[C:11](=[C:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.CCCCCC.[C:30](OCC)(=[O:32])[CH3:31]>>[C:30]([O:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C:4](=[O:23])[CH2:3]1)[C@:16]1([CH3:17])[C:11](=[C:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)(=[O:32])[CH3:31]
Reactant: CCOC(C)=O
Reactant: CC1=C2CC[C@H]3[C@@H]4[C@@H](O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Solvent: CCCCCC
Product: CC(=O)O[C@H]1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CCC4=C(C)C(=O)CC[C@@]43C)[C@H]12

Procedure:
4.2 g of 15α-hydroxy-4-methylandrost-4-ene-3,17-dione is acetylated analogously to Example 1(a). Chromatography of the crude product on silica gel with a hexane-ethyl acetate gradient yields 3.9 g of 15α-acetoxy-4-methylandrost-4-ene-3,17-dione.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].Cl[CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13].C[O-].[Na+].[Na]>CO>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(Cl)C(=O)OC
Reactant: COc1ccccc1O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Temperature: 45 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
25 g of guaiacol and 37 g of dimethyl chloromalonate were added dropwise in succession to a sodium methylate solution from 150 ml of methanol and 4.6 g of sodium. The suspension was stirred at 45° C. for 1 hour with the exclusion of moisture, thereafter the methanol was distilled off. The residue was taken up in 200 ml of toluene and washed with water, 1% sodium hydroxide solution and water until the organic phase was colorless. After drying and evaporating the solvent, the residue was distilled. There were obtained 39.5 g of dimethyl (o-methoxyphenoxy)malonate. B.p. 128° C./7 Pa.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1>O1CCCC1.O>[CH2:9]([S:10][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCc1ccccc1
Reactant: Cc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccnc1SCc1ccccc1
Reaction time: 0.25 h
Yield: 222.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 1.44 g) in tetrahydrofuran (45 mL) was added dropwise phenylmethanethiol (465 mg) at room temperature and the mixture was stirred for 15 min. 2-Bromo-3-methylpyridine (2.0 g) was added to the reaction mixture, and the mixture was stirred at 60° C. for 1.5 hr. The reaction mixture was diluted with water, and concentrated under reduced pressure. The residual aqueous layer was extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-hexane-ethyl acetate=97:3) to give the title compound as a gray oil (yield 1.79 g, 72%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].Cl>CS(C)=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1Oc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of hydroquinone (1.21 g, 0.011 mol) and potassium hydroxide (0.894 g, 0.0159 mol) in anhydrous dimethylsulfoxide (7 mL) was heated at 120° for 30 minutes under a nitrogen atmosphere. A solution of 2,5-dichloronitrobenzene (1.90 g, 0.0099 mol) in dimethylsulfoxide (3 mL) was added dropwise over a 30 minute period at 120° then let the reaction stir for 1 hour at the same temperature. The reaction was then cooled in an ice bath and poured into 30 mL of ice water. The mixture was acidified with concentrated hydrochloric acid to pH 1 and extracted with ethyl ether (2×50 mL). The combined ethereal extracts were washed with water (3×150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. Purification of the residue by silica gel chromatography using methylene chloride as eluent provided the product as a tan solid (1.34 g, 51%).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].C([O-])([O-])=O.[Na+].[Na+].F[C:19]1[CH:20]=[N+:21]([O-:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26].O>CN(C=O)C>[N+:25]([C:24]1[CH:23]=[CH:22][N+:21]([O-:28])=[CH:20][C:19]=1[O:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:1]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Reactant: Oc1ccc2c(c1)CCCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5,6,7,8-tetrahydro-2-naphthol in 50 ml of DMF was added Na2CO3 (10 g) portionwise and this mixture was stirred for 15 minutes at room temperature. A solution of 3-fluoro-4-nitropyridine-N-oxide in 50 ml DMF was added dropwise and the reaction was allowed to proceed for four hours at room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat NaCl, anhy MgSO4).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[CH:6]=1)=[O:4].[C:16]([O:20][C:21]([N:23]1[CH2:27][C:26]([F:29])([F:28])[CH2:25][CH:24]1[C:30]([OH:32])=[O:31])=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN(CC)CC>CC#N>[C:16]([O:20][C:21]([N:23]1[CH2:27][C:26]([F:28])([F:29])[CH2:25][CH:24]1[C:30]([O:32][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[CH:6]=1)=[O:4])=[O:31])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1C(=O)OCC(=O)c1ccc2cc(Br)ccc2c1
Yield: 83 %

Procedure:
2-Bromo-1-(6-bromo-naphthalen-2-yl)-ethanone (1 g, 3.07 mmol) and 4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (849 mg, 3.38 mmol) were suspended in MeCN (15 mL) and treated with Et3N (0.45 mL, 3.22 mmol). After stirring o/n, the reaction mixture was concentrated. The resulting residue was dissolved in EtOAc and washed with water, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (0% to 20% EtOAc/Hex) to provide the title compound (1.27 g, 83%).