Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][NH:13][C@H:14]([CH3:17])[CH2:15][OH:16])=[CH:10][CH:9]=1.C(N(CC)CC)C.[H-].[Na+].Cl>O1CCCC1.O>[CH3:6][O:7][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][N:13]2[C@H:14]([CH3:17])[CH2:15][O:16][CH2:2][C:3]2=[O:4])=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(CN[C@H](C)CO)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)COC[C@H]2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
Chloroacetyl chloride (15 g, 133 mmol) was added to a solution of (2R)-2-(4-methoxybenzylamino)-propan-1-ol (26 g, 133 mmol) and triethylamine (15 g, 148 mmol) in tetrahydrofuran (200 ml) and the solution was stirred for one hour. The solution was cooled at 0° C. and sodium hydride (60% dispersion in mineral oil, 5.8 g, 145 mol) was added. When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and pH was adjusted to 5-6 with 3N aqueous hydrochloric acid. The solution was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford (5R)-4-(4-methoxybenzyl)-5-methylmorpholin-3-one (19.6 g, 83.3 mmol, 63%) as colorless oil.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]([NH2:24])=[O:23])=[CH:13]1.C[O:26][C:27](=O)[C:28]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[N:37]([CH2:39][CH3:40])[CH:36]=[CH:35]2)=O.Cl>CN(C=O)C.CCOC(C)=O>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[C:22](=[O:23])[NH:24][C:27](=[O:26])[C:28]=2[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]3[C:38]=2[N:37]([CH2:39][CH3:40])[CH:36]=[CH:35]3)=[CH:13]1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: CCn1ccc2cccc(C(=O)C(=O)OC)c21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1ccc2cccc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c21
Temperature: 50 °C
Reaction time: 12 h
Yield: 38.6 %

Procedure:
A 1.0 M solution of KOtBu in THF (6 mL, 6 mmol) was added to a solution of 2-(1H-indol-3-yl)-acetamide (478 mg, 2.75 mmol) and (1-ethyl-1H-indol-7-yl)-oxo-acetic acid methyl ester (635 mg, 2.75 mmol) in DMF (20 mL). The deep red-orange solution was stirred 12 h at 50° C., allowed to cool, and 1N HCl added. The orange mixture was poured into EtOAc, and the EtOAc layer was separated and washed with 1N HCl, water, saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated onto SiO2. Flash chromatography (1:1 EtOAc:hexanes) followed by precipitation from hot methanol afforded the title compound (377 mg, 37%) as a orange-red solid. Heating under vacuum at 70° C. afforded material which was used without further purification. 1H NMR (400 MHz, DMSO-d6) 11.83 (br s, 1H), 11.13 (s, 1H), 7.94 (d, J=3 Hz, 1H), 7.61 (dd, J=8, 1.5 Hz, 1H), 7.3 (m, 2H), 6.93–7.0 (m, 3H), 6.48 (m, 3H), 6.48 (m, 2H), 6.3 (d, J=7 Hz, 1H), 4.0 (m, 2H), 1.06 (t, J=5 Hz, 3H). MS (electrospray, m/z) 354 (M−−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[Cl:16][C:17]1[CH:30]=[CH:29][C:20]2[S:21][C:22]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([CH3:24])[C:19]=2[CH:18]=1>N1C=CC=CC=1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:25]([C:22]3[S:21][C:20]4[CH:29]=[CH:30][C:17]([Cl:16])=[CH:18][C:19]=4[C:23]=3[CH3:24])(=[O:27])=[O:26])[CH:3]=2)[NH:7][CH:6]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: c1ccncc1
Product: Cc1c(S(=O)(=O)Nc2ccc3[nH]cc(CCN(C)C)c3c2)sc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.8 %

Procedure:
To a solution of 3.05 g (15 mMol) of 5-amino-3-(2-dimethylaminoethyl)-1H-indol in 100 ml of pyridine is added dropwise at ambient temperature a solution of 4.21 g (15 mMol) of 5-chloro-3-methyl-benzo[b]thiophene-2-sulphonyl chloride in 20 ml of pyridine. The reaction mixture is stirred at ambient temperature for 20 hours. It is then evaporated to dryness, slightly alkalinised with diluted ammonia and dissolved in ethyl acetate. The organic phase is washed with water and a saturated solution of sodium bicarbonate, it is separated and dried with anhydrous sodium sulphate. The organic solution is evaporated to dryness and the resulting solid is repeatedly washed with ethyl ether, to yield 5.5 g (82%) of N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methyl-benzo[b]thiophene-2-sulphonamide as a solid with m.p.=226–227° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[CH2:56]([CH:59]1[S:63][CH:62]([CH2:64]O)[CH2:61][CH2:60]1)[CH2:57][CH3:58]>C1COCC1>[CH2:56]([CH:59]1[S:63][CH:62]([CH2:64][O:55][C:52]2[CH:51]=[CH:50][C:49]([C:46]3[N:47]=[CH:48][C:43]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:44][N:45]=3)=[CH:54][CH:53]=2)[CH2:61][CH2:60]1)[CH2:57][CH3:58]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCC1CCC(CO)S1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1cnc(-c2ccc(OCC3CCC(CCC)S3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A fully reacted mixture of equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in THF is admixed with equimolar amounts of 4-(5-undecyl-pyrimidin-2-yl)phenol and 5-propyl-tetrahydrothiophen-2-yl-methanol (prepared by LiAIH4 reduction of methyl 5-propyl-tetrahydrothiophene-2-carboxylate). The mixture is stirred for 24 h at room temperature and then evaporated to dryness under reduced pressure. Purification by chromatography (silica gel, dichloromethane) and recrystallization affords the target compound. The compounds (I-13) and (I-14) can be obtained in a similar manner.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH:9]=[CH:10][C:11]([OH:13])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[N:2]1([CH2:8][CH:9]=[CH:10][C:11]([Cl:17])=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C=CCN1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C=CCN1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The HCl salt of 4-Piperidin-1-yl-but-2-enoic acid (250 mg, 1.48 mmol) was dissolved in dichloromethane (15 mL). Dimethylformamide (3 drops) was added. Oxalyl chloride (155 μL, 1.77 mmol) was added slowly and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was used as is.
Reaction SMILES: OO.[C:3]1([S:9][CH2:10][CH2:11][CH2:12][CH2:13][Cl:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-:15].[Na+].C(O)=[O:18]>>[C:3]1([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][Cl:14])(=[O:18])=[O:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: O=CO
Reactant: ClCCCCSc1ccccc1
Agent: OO
Agent: [Na+]
Product: O=S(=O)(CCCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
30% Aqueous hydrogen peroxide solution (27.6 ml) was dropwise added under ice-cooling to a solution of 4-phenylthiobutyl chloride (22.2 g) obtained in the same manner as in Preparation Example 99 in formic acid (150 ml), which was followed by stirring at room temperature for 1 hr. The reaction mixture was poured into ice water, neutralized with sodium hydroxide solution and extracted with chloroform. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform) and further recrystallized from hexane to give 21 g of 4-phenylsulfonylbutyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:36])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[N:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[N:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=4)[CH:22]=3)[CH2:18][C:17](=[O:36])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C(C)C)nc3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccc(C(C)C)nc3)c1)=N2

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example M161) (133 mg, 0.26 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (61 mg, 58%).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([OH:20])=O)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[N:6][C:5]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)(=[O:3])[NH2:2].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.Cl>O.CN(C)C=O>[Cl:27][C:23]1[CH:22]=[C:21]([C:5]2[N:6]=[C:7]([N:9]3[C:13]4[CH:14]=[C:15]([C:18]([N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[O:20])[CH:16]=[CH:17][C:12]=4[N:11]=[CH:10]3)[S:8][C:4]=2[C:1]([NH2:2])=[O:3])[CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1sc(-n2cnc3ccc(C(=O)O)cc32)nc1-c1cccc(Cl)c1
Agent: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.05 g (0.15 mmole) of 3-[5-Carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]-3H-benzoimidazole-5-carboxylic acid (I.10a), 0.050 mL of N-methyl-piperazine, 0.070 g (0.18 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) and 4 mL of dimethylformamide was stirred at room temperature for 16 hours. The mixture was poured into 50 mL of water and made acidic by addition of 1 M hydrochloric acid. The aqueous layer was extracted three times with 20 mL of ethyl acetate and then made basic by addition of potassium carbonate solution. The mixture was extracted three times with 20 ml, of ethyl acetate. The combined organic extracts were washed with 20 mL of water, 20 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (7:93) to give 0.021 g of 4-(3-chloro-phenyl)-2-[6-(4-methyl-piperazine-1-carbonyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.11) as a yellow solid. MH+/Z=481
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][CH:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(O)C>CCCCCC>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCCC1O
Solvent: CCCCCC
Solvent: CCO
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCC[C@@H]1O

Procedure:
Racemic (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(3-hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-phenyl]-methanone of Example 5 was subjected to chiral HPLC (Chiralpak AD, 21.1×250 mm, 50% ethanol in hexane). The second peak which eluted displayed a negative optical rotation and was arbitrarily assigned the (S)-configuration. The title compound was isolated as a white solid, [α]D=−36.69 (c=1.0, chloroform).
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=1>N1C=CC=CC=1>[N:1]1[NH:2][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[C:7]=1[C:6]1[C:15]([C:14]3=[O:18])=[CH:16][CH:17]=[CH:4][CH:5]=1
Reactant: NN
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2n[nH]c3cccc1c23
Temperature: 100 °C

Procedure:
Anhydrous hydrazine is added to a solution of 2-chloroanthraquinone (Aldrich) in 10 mL, pyridine, and the mixture heated at 100° C. for 16 hours. The mixture is cooled and the solvent is evaporated in vacuo. The residue is taken in hot 6N HCl, and the solid is collected by filtration. Flash chromatography of the crude material on silica gel affords anthra[1,9cd]pyrazol-6(2H)-one (“Compound 1”) as yellow solids.
Reaction SMILES: [Si]([O:8][C@H:9]([C:47]1[CH:48]=[CH:49][C:50]([OH:58])=[C:51]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:52]=1)[CH2:10][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C@@H:31]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:32][CH2:33][N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH:25]=2)=[CH:16][CH:15]=1)(C(C)(C)C)(C)C.CCN(CC)CC.F.F.F>O1CCCC1.CO>[CH:38]([N:34]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:32][C@@H:31]([C:26]1[CH:25]=[C:24]([CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:47]3[CH:48]=[CH:49][C:50]([OH:58])=[C:51]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:52]=3)[OH:8])=[CH:15][CH:16]=2)[CH:29]=[CH:28][C:27]=1[OH:30])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([CH3:39])[CH3:40]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCOc2ccc(CCNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Reaction time: 24 h

Procedure:
N-{5-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-({2-[4-(3-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}propoxy)phenyl]ethyl}amino)ethyl]-2-hydroxyphenyl}methanesulfonamide (Preparation 10, 98 mg, 0.11 mmol) was dissolved in tetrahydrofuran (4 ml) and methanol (2 ml) and triethylaminetrihydrofluoride (95 ul, 0.58 mmol) was added in one portion at room temperature. The reaction was stirred for 24 hours and the solvent removed under reduced pressure, the residue was dissolved in methanol (10 ml) and 880 ammonia (1 ml) and the solvent removed under reduced pressure to yield an off white solid. The solid was dissolved in methanol (1 ml) and precipitated with an excess of diisopropylether, the solid was collected by filtration to furnish the title compound as a white solid, 16 mg.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].N1C=CC=CC=1.[O:11]=[C:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=2)[NH:13]1>>[CH:2]([O:4][S:21]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:11])[CH2:20]2)(=[O:22])=[O:23])([CH3:3])[CH3:1]
Reactant: CC(C)O
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: c1ccncc1
Product: CC(C)OS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-propanol (1.8 mL, 23.8 mmol) and pyridine (7.0 mL, 86.4 mmol) at 0° C. was added 2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride (5.0 g, 21.6 mmol) in one portion. The resulting suspension was stirred at 0° C. for 45 mins and then warmed RT for 1 h. The reaction mixture was partitioned between DCM and 1M HCl. The organic layer was washed successively with 50 mL of 1M HCl, water, and brine. The organic layers were dried over MgSO4 and concentrated to produce an orange solid. Yield: 4.06 g (74%). 1H-NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 7.74 (dd, J=8.2, 1.9 Hz, 1H), 7.70 (s, 1H), 7.01 (d, J=8.2 Hz, 1H), 4.68-4.58 (m, 1H), 3.75-3.69 (m, 2H), 1.19 (d, J=6.2 Hz, 6H). LC/MS (10-99%): M/Z: M+(obs) 256.1; tR=2.10 min.
Reaction SMILES: Cl.[CH2:2]([C:6]1[C:14]([CH3:15])=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)[CH:3]([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:47]([O:50][C:51]1[C:60]([CH3:61])=[CH:59][C:54]([C:55]([NH:57][NH2:58])=[O:56])=[CH:53][C:52]=1[CH3:62])[CH:48]=[CH2:49]>C(Cl)Cl.CC(=O)OCC>[CH2:47]([O:50][C:51]1[C:60]([CH3:61])=[CH:59][C:54]([C:55]([NH:57][NH:58][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([CH3:15])[C:6]([CH2:2][CH:3]([CH3:4])[CH3:5])=[N:7][CH:8]=2)=[O:56])=[CH:53][C:52]=1[CH3:62])[CH:48]=[CH2:49]
Reactant: Cc1cc(C(=O)O)cnc1CC(C)C
Reactant: C=CCOc1c(C)cc(C(=O)NN)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCOc1c(C)cc(C(=O)NNC(=O)c2cnc(CC(C)C)c(C)c2)cc1C
Yield: 97.7 %

Procedure:
To a solution of 6-isobutyl-5-methyl-nicotinic acid hydrochloride (50 mg, 0.22 mmol), DIPEA (0.12 mL, 0.7 mmol) and TBTU (97 mg, 0.30 mmol) in DCM (5 mL) is added at 0° C. 4-allyloxy-3,5-dimethyl-benzoic acid hydrazide (50.6 mg, 0.23 mmol) and the mixture is stirred at 0° C. for 4 h. The mixture is diluted with EA (15 mL) and washed with 1M aq. NaH2PO4 (5 mL), 1M aq. NaOH (5 mL) and water (5 mL). The org. phase is dried (MgSO4), filtered and evaporated to provide 6-isobutyl-5-methyl-nicotinic acid N′-(4-allyloxy-3,5-dimethyl-benzoyl)-hydrazide (85 mg); LC-MS: tR=0.81 min, [M+1]+=396.20.
Reaction SMILES: C[C@@]12[C@](O)(C)CC[C@H]1[C@@H]1CC[C@H]3CC(=O)OC[C@]3(C)[C@H]1CC2.[CH3:23][C@@:24]12[C@H:34]3[CH2:35][CH2:36][C@:37]4([CH3:44])[C@:41]([OH:43])([CH3:42])[CH2:40][CH2:39][C@H:38]4[C@@H:33]3[CH2:32][CH2:31][C@H:30]1[CH2:29][C:27](=[O:28])[CH2:26][CH2:25]2>>[OH:43][C@@:41]1([CH3:42])[CH2:40][CH2:39][C@H:38]2[C@H:33]3[C@H:34]([CH2:35][CH2:36][C@:37]12[CH3:44])[C@:24]1([CH3:23])[C@H:30]([CH2:29][C:27](=[O:28])[CH:26]=[CH:25]1)[CH2:31][CH2:32]3
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O
Agent: C[C@]12COC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O
Product: C[C@]12C=CC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O

Procedure:
The present invention relates to a process for the synthesis of oxandrolone from mestanolone. The process comprises the steps of: (a) oxidizing mestanolone to form 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one; (b) hydroxylating the 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one to form 1α, 2α, 17β-trihydroxy-17α-methylandrostan-3-one; (c) cleaving the 1α, 2α, 17β-trihydroxy-17α-methylandrostan-3-one to form 17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid; and (d) reducing the 17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid to form oxandrolone.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][S:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH3:20][S:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:24][CH:23]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CSc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-methylsulfanylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methylsulfanylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17]([CH2:19][S:20][CH3:21])=[O:18]>C1COCC1.CO.ClCCl>[CH3:16][S:17]([C:19]([S:20][CH3:21])=[CH:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: O=Cc1cnccc1Oc1ccccc1
Reactant: CSCS(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CSC(=Cc1cnccc1Oc1ccccc1)S(C)=O
Yield: 12.1 %

Procedure:
To a stirred solution of 4-phenoxy-3-pyridinecarboxaldehyde (0.687 g, 3.45 mmol) and methyl methylsulphinylmethyl sulphide (0.429 g, 3.45 mmol) in THF was added dropwise Triton B (0.53 ml, 40% solution in methanol). The mixture was heated at reflux for 2 hours, allowed to cool and then diluted with dichloromethane (150 ml). The solution was washed with saturated brine (2×) and the solvent was evaporated. Flash chromatography (eluent ether-ethyl acetate) of the resulting residue gave 3-(2'-methylsulphinyl-2'-methylthiovinyl)-4-phenoxypyridine as a pale yellow gum (0.128 g); 1H NMR delta (CDCl3) 2.32 (3H, s), 2.77 (3H, s), 6.60 (1H, d), 6.9-7.5 (5H, m), 7.93 (1H, s), 8.32 (1H, d), 9.10 (1H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([O:15][CH2:16]C)=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][O-:19].[Na+].[Cl-].[NH4+]>CS(C)=O>[CH3:18][O:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Nc1ccc2c(Cl)nccc2c1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)Nc1ccc2c(OC)nccc2c1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
1-Chloro-6-ethoxycarbonylaminoisoquinoline (2.27 g, Production Example 41b) was dissolved in dimethyl sulfoxide (45 ml), to which was then added a 28% sodium methoxide solution (8.7 ml), followed by heating under stirring at 110° C. for 1.5 hours. After cooling as it was to room temperature, an aqueous saturated ammonium chloride was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (1.75 g, 84%) as a brown oil.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15].[CH2:20]([Li])[CH3:21]>C1COCC1.C1CCCCC1.C1C=CC=CC=1>[CH2:20]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:21]
Reactant: COc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Reactant: [Li]CC
Solvent: c1ccccc1
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.0 g (38 mmol) [1-(2,6-dimethoxy-phenyl)-meth-(E)-ylidene]-(1-isopropyl-2-methyl-propyl)-amine in 30 ml dry THF cooled to −20° C. were added 91.2 ml of a 0.5M solution of ethyl lithium in cyclohexane/benzene drop-wise to keep temperature below 0° C. Then the mixture was stirred at −20° C. for further 30 min and the reaction quenched by addition of water. The aqueous phase was extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. Purification of the crude product by flash chromatography on silica gel with a heptane/ethyl acetate gradient provided 4.30 g (E)-[1-(2-ethyl-6-methoxy-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine as colourless liquid: MS (EI): 261.4 (M+.), 218.3 ((M-((CH3)2CH)+.), 100%).