Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C[OH:40].O>O1CCOCC1>[OH:1][C:2]1[CH:38]=[CH:37][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26]([CH2:27][CH2:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:32])([F:33])[F:34])=[O:40])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CO
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCSCCCC(F)(F)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[8-(4,4,5,5,5-pentafluoropentylthio)octyl]-2,3-dihydro-4H-benzopyran (53 mg, 0.095 mmol) was dissolved in 1,4-dioxane (1.2 ml), methanol (1.2 ml) and water (0.3 ml). NaIO4 (24 mg, 0.11 mmol) was added dropwise thereto, and the reaction mixture was stirred for 8 hours at room temperature and then filtered. The filtrate was concentrated and the residue was subjected to column chromatography (n-hexane:ethyl acetate=2:1) to obtain 38 mg (yield: 70%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8]>C1COCC1>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])=[O:9]
Reactant: CNCCO
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)N(C)CCO
Reaction time: 18 h
Yield: 82.9 %

Procedure:
N-Methylethanolamine (2.96 g, 39.4 mmol) was added to a solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (5.5 g, 19.7 mmol, prepared according to Example 1 of Part A, supra) in THF (150 ml) and the mixture stirred at 20°-25° for 18 hours. After removing THF under reduced pressure, the residue was partitioned between EtOAc and H2O. The organic extract was washed with saturated NaCl solution and dried (Na2SO4). Flash chromatography of the residue over silica gel and elution with 1% MeOH-99% CHCl3 afforded pure sulfonamide. Recrystallization from EtOAc-hexane gave analytically pure product (5.2 g, 82.9%), m.p. 98°-101°.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:8]=[C:7]([CH:9]([CH3:23])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([F:22])[CH:11]=2)[O:6][N:5]=1.[CH3:24][SH:25].[Na]>C(O)C>[F:22][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]([C:7]1[O:6][N:5]=[C:4]([CH2:3][CH2:2][S:25][CH3:24])[N:8]=1)[CH3:23]
Reactant: CS
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCCl)no1
Agent: [Na]
Solvent: CCO
Product: CSCCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1

Procedure:
To a solution of 5.0 g of 3-(2-chloroethyl)-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole in 100 ml of ethanol was added 12.5 ml of 15% aqueous sodium methyl mercaptan. After stirring with reflux for 1 hour, the reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed over silica gel using methylene chloride to give 4.78 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-(2-methylthioethyl)-1,2,4-oxadiazole as a light yellow oil, nD21 1.5860.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]([N:12]=1)=[N:8][CH:9]=[CH:10][N:11]=2)=C.O=O.[O:15]=[O+][O-]>CO>[N:11]1[CH:10]=[CH:9][N:8]=[C:7]2[N:12]=[C:3]([CH:1]=[O:15])[CH:4]=[CH:5][C:6]=12
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc2nccnc2n1
Agent: O=O
Solvent: CO
Product: O=Cc1ccc2nccnc2n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
6-vinylpyrido[2,3-b]pyrazine (Intermediate 4.3) (1 g, 6.37 mmol, 1 eq.) was dissolved in methanol (20 mL) and cooled down to −70° C. A gentle flux of a mixture of oxygen/ozone was then bubbled through for 20 minutes. The reaction was monitored by TLC using cyclohexane/ethyl acetate (8/2). When the reaction was finished, dimethylsulfide (0.1 mL) was added and reaction was left at rt for 30 minutes. Methanol was evaporated under vacuum and 600 mg of pyrido[2,3-b]pyrazine-6-carbaldehyde was recovered. Crude material was analyzed without further purification (Intermediate 4.4). Amount: 0.60 g; Yield: 60%; Formula: C8H5N3O; HPLC Purity: 90%; HPLC H2O TFA 0.1%-ACN TFA 0.05%): Rt (min); Area %=0.90 min; 90%; 1H NMR (DMSO-d6) δ 10.1 (1, 1H), 9.05 (s, 1H), 8.95 (s, 1H), 8.70 (d, 1H, J=8 Hz), 8.20 (d, 1H, J=8 Hz); LC-MS: M/Z ESI: Rt (min) 0.76 min, 158.13 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:17])[C:5]1[C:13]2[C:12](=[O:14])[CH2:11][C:10]([CH3:16])([CH3:15])[CH2:9][C:8]=2[NH:7][N:6]=1.[Br:18][C:19]1[CH:26]=[C:25](F)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]>CS(C)=O.[NH4+].[Cl-].O>[Br:18][C:19]1[CH:26]=[C:25]([N:7]2[C:8]3[CH2:9][C:10]([CH3:15])([CH3:16])[CH2:11][C:12](=[O:14])[C:13]=3[C:5]([CH:4]([F:3])[F:17])=[N:6]2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: CC1(C)CC(=O)c2c(C(F)F)n[nH]c2C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CC(=O)c2c(C(F)F)nn(-c3ccc(C#N)c(Br)c3)c2C1
Reaction time: 0.33 h
Yield: 49.1 %

Procedure:
NaH (350 mg) was added to a solution of 3-difluoromethyl-6,6-dimethyl-1,5,6,7-tetrahydro-indazol-4-one (3.12 g) in DMSO (75 mL) at room temperature. After 20 minutes of stirring, 2-bromo-4-fluorobenzonitrile (4.67 g) was added and stirred at 45° C. overnight. The reaction was diluted with saturated aqueous NH4Cl (100 mL), H2O (100 mL). The mixture was extracted with ethyl acetate (4×150 mL), dried over Na2SO4, filtered, concentrated, purified by column chromatography eluting with a 1:2 mixture of ethyl acetate/hexanes. The concentrate of desired fractions was made into a slurry in ether, stirred for 2 h, filtered, washed by hexane to give pure solid 2-bromo-4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-benzonitrile (2.82 g, 49.2%). LCMS m/z: (M+H)=395.65, (MW: 394).
Reaction SMILES: C(O[C:4]1[C:5](=[O:14])[C:6](=[O:13])[C:7]=1[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])C.C(OC1C(=O)C(=O)C=1N[C@H](C)C(C)(C)C)C.[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38].[K+].[Br-]>>[C:9]([NH:8][C:7]1[C:6](=[O:13])[C:5](=[O:14])[C:4]=1[NH:38][CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[C:34]([O:33][C:32]([F:31])([F:42])[F:43])[CH:35]=1)([CH3:10])([CH3:11])[CH3:12]
Reactant: CCOc1c(NC(C)(C)C)c(=O)c1=O
Reactant: NCc1cccc(OC(F)(F)F)c1
Agent: CCOc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)Nc1c(NCc2cccc(OC(F)(F)F)c2)c(=O)c1=O
Yield: 66 %

Procedure:
The title compound was prepared according to the procedure for example 1-step 2 except that 3-ethoxy-4-(tert-butylamino)-cyclobut-3-ene-1,2-dione was used in place of using (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione and 3-trifluoromethoxy-benzylamine was used in place of 4-fluorobenzylamine. Yield: 66%; mp: 210-212° C.; 1H NMR (300 MHz, DMSO-d6): δ 1.36 (m, 9H), 4.76-4.81 (m 2H), 7.32-7.43 (m, 3H), 7.50-7.60 (m, 2H), 7.76-7.84 (brm, 1H); IR (KBr, cm-1): 3295m, 3239m, 3063w, 2973m, 1794m, 1655s, 1569s, 1542s, 1471s, 1446s, 1259-1168brs; MS (ES) m/z (relative intensity): 365 (M+ +Na, 50), 343 (M+ +H, 100); Anal. Calcd. for C16H17F3N2O3 : C, 56.14; H, 5.01; N, 8.18. Found: C, 55.91; H, 4.70; N, 7.99.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]1([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][C:35]=2[C:43](O)=[S:44])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.[CH3:47][NH:48][O:49][CH3:50].C(N(CC)CC)C>CN(C)C=O>[CH3:50][O:49][N:48]([CH3:47])[C:43]([C:35]1[NH:36][C:37]2[C:42]([C:34]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:44]
Reactant: OC(=S)c1[nH]c2ccccc2c1-c1ccccc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=S)c1[nH]c2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.64 g, 3.7 mmol) was added to a solution of 3-phenylthioindole-2-carboxylic acid (1.0 g, 3.7 mmol), N,O-dimethylhydroxylamine hydrochloride (0.54 g, 5.5 mmol) and triethylamine (1.5 mL, 11 mmol) in degassed dimethylformamide. The reaction was stirred at room temperature overnight. The precipitated product was filtered and the filter cake washed well with water. The solid was triturated with 30% ethyl acetate in hexane, filtered and dried at 60° C. in vacuo for 72 hours.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9].C(OCC)(=O)C.[P:33]([O:40]CC)([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>>[CH3:26][N:11]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)[S:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:2][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])(=[O:10])=[O:9]
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CCl
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12)OCC
Yield: 25 %

Procedure:
A solution of 2-(chloromethyl)-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (240 mg) in triethyl phosphite (5 mL) was stirred at 100° C. for 1 hr. The reaction mixture was subjected to silica gel column chromatography (ethyl acetate) to give the title compound (67 mg, yield 25%) as a pale-yellow amorphous. M+1=526.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[F:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43]Br>C(#N)C>[CH2:24]([N:23]([CH2:26][CH3:27])[C:21](=[O:22])[C:20]1[CH:28]=[CH:29][CH:30]=[C:18]([C@@H:9]([N:3]2[CH2:4][C@@H:5]([CH3:8])[N:6]([CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[C:40]([F:39])[CH:41]=3)[CH2:7][C@@H:2]2[CH3:1])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:19]=1)[CH3:25]
Reactant: CCN(CC)C(=O)c1cccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)NC[C@@H]2C)c1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCN(CC)C(=O)c1cccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)N(Cc3cccc(F)c3)C[C@@H]2C)c1
Reaction time: 3 h
Yield: 59.2 %

Procedure:
A solution of 3-((αR)-α-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide (0.49 g, 1.20 mmol) in acetonitrile (10 mL) was added to sodium iodide (100 mg), sodium carbonate (0.70 g, 6.64 mmol) and stirred under nitrogen at room temperature during the addition of 3-fluorobenzyl bromide (0.16 mL, 1.32 mmol). The reaction was complete in 3 hours. The solvent was removed by evaporation and the residue was partitioned between methylene chloride and water. The aqueous layer was extracted with methylene chloride twice more, and the combined organic extracts were dried (Na2SO4/MgSO4) and concentrated under reduced pressure. The residual brown oil was purified by chromatography on silica gel (EtOAc/CH2Cl2) to give 0.37 g (0.71 mmol) of the desired product as a light brown amorphous solid. The salt was made by dissolving the amine in ethanol and titrating to pH 3.92 with 0.2 M HCl in ethanol. The salt was redissolved in water and lyophilized to obtain a light brown powdery solid. 1H NMR (300 MHz, CDCl3): δ 1.04–1.22 (m, 12H); 1.93–2.08 (m, 2H); 2.51–2.76 (m, 5H); 3.10–3.60 (m, 4H); 3.78 (s, 3H); 3.84–3.89 (d, J=13.3 Hz, 1H); 5.11 (s, 1H); 6.76–7.46 (m, 12H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24](O)[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:20][C:19]=1[CH3:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:24]([C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[C:19]([CH3:32])[CH:20]=2)[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:12][CH:13]=1
Reactant: Cc1cc(C(O)CCCC(C)C)ccc1Br
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(OC(CCCC(C)C)c2ccc(Br)c(C)c2)cc1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (805 mg, 3.61 mmol) and 1-(4-Bromo-3-methyl-phenyl)-5-methyl-hexan-1-ol (824 mg, 2.89 mmol) in toluene (15.0 mL) was degassed and filled with nitrogen for 3 times. Tributylphosphine (1.1 mL, 4.33 mmol) was added to the reaction mixture under nitrogen at 0° C., followed by addition of 1,1′-(azodicarbonyl)-dipiperidine (1.1 g, 4.33 mmol). The reaction mixture was allowed to warm to room temperature and stirred over night, the mixture was loaded on silica gel column. Chromatography gave the title compound (890 mg, 1.82 mmol).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[N:30]3[CH:31]=[CH:32][CH:33]=[C:29]3[C:28](=[O:34])[NH:27][CH:26]=2)=[CH:20][C:10]=1[C:11]([N:13]1[CH2:19][CH2:18][CH2:17][NH2+:16][CH2:15][CH2:14]1)=[O:12].C=O.[CH3:37]C([O-])=O.[Na+]>CO.O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[N:30]3[CH:31]=[CH:32][CH:33]=[C:29]3[C:28](=[O:34])[NH:27][CH:26]=2)=[CH:20][C:10]=1[C:11]([N:13]1[CH2:19][CH2:18][CH2:17][NH+:16]([CH3:37])[CH2:15][CH2:14]1)=[O:12]
Reactant: CC(=O)[O-]
Reactant: O=C(c1cc(Cc2c[nH]c(=O)c3cccn23)ccc1F)N1CCC[NH2+]CC1
Agent: C=O
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: C[NH+]1CCCN(C(=O)c2cc(Cc3c[nH]c(=O)c4cccn34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1 in MeOH (0.1 M) was added TEA (2 eq), formaldehyde (5 eq), NaBH3(CN) (1.6 eq) and NaOAc (2.8 eq). The mixture was stirred overnight at RT and then the solvent was removed under reduced pressure and the product was isolated by purification at prep RP-HPLC using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). The desired fractions were lyophilized to afford the title compound. 1H NMR (600 MHz, DMSO-d6+TFA) (one major rotamer described) δ: 10.56-10.49 (1H, m), 9.78 (1H, br. S), 7.54-7.47 (1H, m), 7.44-7.37 (1H, m), 7.33-7.21 (2H, m), 6.88-6.93 (1H, m), 6.57-6.46 (2H, m), 4.08 (2H, s), 3.78-3.28 (6H, m, partially overlapped with D2O signal), 3.26-3.17 (2H, m), 2.85 (3H, s), 1.91-1.99 (2H, m). MS (ES) C21H23FN4O2 requires: 382, found: 383 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:29])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]([O:14][CH:15]3[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:12][C:11]=2[CH3:28])[CH2:5][CH2:4]1.C(O)(C(F)(F)F)=O.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH:17]1[CH2:18][CH:15]([O:14][C:13]2[CH:26]=[CH:27][C:10]([CH2:9][N:6]3[CH2:7][CH2:8][C:3]([CH2:2][OH:1])([CH3:29])[CH2:4][CH2:5]3)=[C:11]([CH3:28])[CH:12]=2)[CH2:16]1
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN1CCC(C)(CO)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(OC2CNC2)ccc1CN1CCC(C)(CO)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of 69B (3.10 g, 7.66 mmol) in DCM (100 mL) was added TFA (30 mL) and the reaction mixture was stirred at RT for 2 h. The mixture was transferred to a reparatory funnel and water was added. The aqueous phase was carefully basified with Na2CO3. The organic layer was separated and the basic aqueous layer was extracted ten times with. The combined organic layers were filtered through a phase separator and the solvent was removed by evaporation. The residue was dissolved in a mixture of THF (30 mL) and an aqueous solution of NaOH (1M, 40 mL). The mixture was stirred at RT for 4 h and then the solution was concentrated using a rotavapor. The aqueous residue was extracted several times with DCM. The aqueous layer was diluted with a saturated solution of NaHCO3 and the mixture was further extracted with DCM. The combined organic layers were filtered through a phase separator and the solvent was removed by evaporation. There was obtained 1.65 g (71%) of 69C as an oil. 1H NMR (500 MHz, CDCl3): δ 0.95 (s, 3H), 1.32 (m, 2H), 1.54 (m, 2H), 2.32 (m, 2H), 2.54 (m, 2H), 3.38 (s, 2H), 3.42 (s, 2H), 3.83 (m, 2H), 3.95 (m, 2H), 4.97 (m, 1H), 6.50 (dd, 1H), 6.57 (s, 1H), 7.16 (d, 1H), MS (APCI+) m/z 305 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[CH:14]([CH2:15][C:16](=[O:24])[CH:17]=[CH:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH2:25]1COC[CH2:26]1.C([Al](CC)CC)C.C[Si](Cl)(C)C>C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[CH:14]([CH2:15][C:16](=[O:24])[CH2:17][C@@H:18]1[CH2:25][CH3:26])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1CCOC1
Agent: CC[Al](CC)CC
Agent: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Product: CC[C@H]1CC(=O)CC2CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]3[C@]21C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.31 g (10 mmol) of 17β-acetoxy-androst-1-en-3-one and 143 mg (1 mmol) of CuBr are introduced into 15 ml of dry THF. 5.79 ml (11 mmol) of a 1.9 molar solution of triethylaluminum in toluene as well as 2.16 g (20 mmol) of trimethylsilyl chloride are added at 0° C. It is stirred for 1 hour at room temperature, then hydrolyzed with 10 ml of 2N hydrochloric acid and the product is extracted with methyl tert-butyl ether. After evaporation of the solvent and recrystallization from acetone, 3.2 g of 17β-acetoxy-1α-ethylandrostan-3-one (90% of theory) of melting point 159° C. is obtained.
Reaction SMILES: [BH4-].[Li+].[C:3]([NH:6][C:7]1([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:13][O:12][C:10](=[O:11])[CH2:9][CH2:8]1)(=[O:5])[CH3:4].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:3]([NH:6][C:7]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH2:8][CH2:9][CH2:10][OH:11])[CH2:14][CH2:13][OH:12])(=[O:5])[CH3:4]
Reactant: CC(=O)NC1(CCc2ccccc2)CCOC(=O)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NC(CCO)(CCCO)CCc1ccccc1

Procedure:
To a solution of lithium borohydride (220 mg) in tetrahydrofuran (100 ml), under a nitrogen atmosphere, a solution of 4-acetamido-4-(2-phenyl-ethyl)-6-hexanolide (1.4 g) in tetrahydrofuran (30 ml) was dropwise added over 10 minutes and the mixture was further refluxed under heating for 1.5 hours. After cooling, the reaction mixture was neutralized with a saturated aqueous ammonium chloride solution and the solvent was distilled away under reduced pressure. The residue obtained was dissolved in ethyl acetate and the mixture was washed with water and a saturated brine. The mixture was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 3-acetamido-3-(2-phenylethyl)hexane-1,6-diol as a crude product. The product was dissolved in pyridine (20 ml) without purifying, and acetic anhydride (10 ml) was added to the mixture at room temperature. The whole mixture was allowed to stand overnight. The solvent was distilled away under reduced pressure and the residue obtained was purified by silica gel chromatography (eluent; chloroform-ethyl acetate=2:1) to give the subject compound (0.50 g) as a colorless oily substance.
Reaction SMILES: COC1C=CC(C[N:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)=[CH:11][N:10]=[CH:9]2)=CC=1>FC(F)(F)C(O)=O>[O:14]=[C:13]1[NH:8][CH:9]=[N:10][CH:11]=[C:12]1[C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(-c2cncn(Cc3ccc(OC)cc3)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-c2cnc[nH]c2=O)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 63.8 %

Procedure:
Methyl 4-[1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl]benzoate (205 mg) was dissolved in trifluoroacetic acid (5 mL), followed by stirring at 70° C. for 15 hours. The reaction mixture was evaporated under reduced pressure, followed by two times azeotropy with toluene. Water was added to the resulting residue, followed by three times extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methanol/chloroform=2% to 5%) to obtain methyl 4-(6-oxo-1,6-dihydropyrimidin-5-yl)benzoate (86 mg) as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][C:9](=[O:11])[CH3:10].[CH3:12][O:13][CH2:14][CH2:15][C:16]#[CH:17].C(OCC)C>O1CCCC1>[CH3:12][O:13][CH2:14][CH2:15][C:16]#[C:17][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][C:9](=[O:11])[CH3:10]
Reactant: C#CCCOC
Reactant: CC(=O)Oc1cnccc1I
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCC#Cc1ccncc1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.95 mmol Palladium dichloride bis-triphenylphoshine and 0.97 mmol cupric chloride are dissolved in 64 ml tetrahydrofuran under an argon atmosphere. A solution of 30 mmol acetic acid 4-iodo-pyridin-3-yl ester [289473-46-7] and 38 mmol 4-methoxy-but-1-yne [36678-08-7] in 50 ml tetrahydrofuran is added in one portion and the reaction mixture is stirred at room temperature for 1 hour. 300 ml of diethyl ether are added and the precipitate is filtered off. The filtrate is washed successively with saturated, aqueous ammonium chloride solution (3×), water (2×) and brine. The organic layer is dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and identified based on its Rf value.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N+:8]=2[O-:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(-c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2ccccc2)[n+]1[O-]
Temperature: 25 °C

Procedure:
While stirring at room temperature, 4.8 g *28.5 mmol) of 2-phenyl-6-methyl-pyridine were dissolved in 50 ml of chloroform after which a solution of 7.8 g of 75% mCPBA (33.9 mmol) in 75 ml of chloroform were added dropwise. The reaction mixture showed only a slight rise in temperature. After stirring for 1.5 hr, the reaction mixture was shaken twice with 5% aqueous NaHCO3 solution and twice with an aqueous solution of Na2S2O3 to remove the excess of mCPBA, after which the reaction mixture proved to be negative on wet Kl/starch paper, The organic layer was dried on MgSO4. Removal of the drying agent by filtration and solvent by evaporation in vacuo yielded an oil which crystallized upon scratching to give 5.5 g (105%) of crude of 2-phenyl-6-methyl-pyridine-N-oxide, which was employed in the next step without further purification.