Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]O.[CH3:3][S:4][C:5]1[NH:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[N:9]=1>CO>[CH3:3][S:4]([C:5]1[NH:6][CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[N:9]=1)=[O:1]
Reactant: OO
Reactant: CSc1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Solvent: CO
Product: CS(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Temperature: 60 °C

Procedure:
Hydrogen peroxide (36%, 100 ml) was added over a period of 2 hours, while stirring, to a hot (60° C.) solution of 2-methylthio-4-(4-nitro-phenyl)-1H-imidazole (19.6 g) in methanol (500 ml). After an additional 24 hours of heating at 60° C., the mixture was cooled to room temperature, filtered, and the filter cake was dried to give 16.1 g of the title compound.
Reaction SMILES: [NH2:1][S:2](Cl)(=[O:4])=[O:3].CC(N(C)C)=O.[N:12]1([CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:21]([C:31]#[N:32])=[CH:20][CH:19]=2)[CH:16]=[N:15][CH:14]=[N:13]1>CCOC(C)=O>[S:2](=[O:4])(=[O:3])([O:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[CH:23]=[C:18]([CH2:17][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)[CH:19]=[CH:20][C:21]=2[C:31]#[N:32])=[CH:25][CH:26]=1)[NH2:1]
Reactant: N#Cc1ccc(Cn2cncn2)cc1-c1ccc(O)cc1
Reactant: NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Cn2cncn2)cc1-c1ccc(OS(N)(=O)=O)cc1

Procedure:
As general method using H2NSO2Cl (4.63 mL, 1.39 mmol), DMA (1.5 mL) and 19 (0.077 g, 0.279 mmol). The reaction mixture was poured into EtOAc (30 mL). The organic layer separated was washed with distilled H2O (30 mL×4), brine (30 mL), dried (MgSO4) and evaporated in vacuo to give white residues. Column chromatography (CH2Cl2/acetone 80:20) eluted 15 as a white solid (0.074 g, 75%), mp 159-162° C.; 1H NMR δH (270 MHz, DMSO-d6) 5.60 (s, 2H), 7.41-7.46 (m, 314), 7.51 (s, 1H), 7.67 (d, J=8.2, 2H), 7.98 (d, J=7.9, 1H), 8.03 (s, 1H), 8.17 (br s, 214) and 8.73 (s, 1H);
Reaction SMILES: [CH2:1]1[C@H:9]2[C@H:4]([CH2:5][C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[CH2:8]2)[CH2:3][NH:2]1.Br[CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[C:19]1(=[O:28])[N:18]([CH2:17][CH2:16][CH2:15][N:2]2[CH2:3][C@H:4]3[C@H:9]([CH2:8][C:7]4[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=4[CH2:5]3)[CH2:1]2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc2c(c1)C[C@H]1CNC[C@H]1C2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCN1C[C@H]2Cc3ccccc3C[C@H]2C1
Temperature: 25 °C
Yield: 770.6 %

Procedure:
A mixture of cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole (32 mg, 0.018 mmol), N-(3-bromopropyl)phthalimide (49 mg, 0.18 mmol), potassium iodide (31 mg, 0.18 mmol), and potassium carbonate (51 mg, 0.37 mmol) in 3 mL of methylethyl ketone was heated at reflux for 8 hours. The mixture was cooled to room temperature, the solids were filtered, and the filtrate was concentrated in-vacuo. The residue was dry-loaded onto a 1×5 cm silica column, and eluted with ethyl acetate followed by 20% methanol/chloroform. Obtained 50 mg of white solids. Yield=78%. NMR (300 MHz, CDCl3) δ 7.84-7.79 (m, 2H), 7.71-7.66 (m, 2H), 7.14-7.06 (m, 4H), 3.74 (t, 2H, J=7 Hz), 2.95-2.90 (m, 2H), 2.74-2.68 (m, 2H), 2.55-2.35 (m, 6H), 1.91-1.80 (m, 4H).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)(=[O:13])=[O:12])[CH2:9][C@@H:2]12.C(=O)([O-])[O-].[Na+].[Na+].I[CH:31]([CH3:33])[CH3:32].O>CS(C)=O>[CH:31]([N:6]1[CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=3)(=[O:13])=[O:12])[CH2:9][C@H:2]2[CH2:1]1)([CH3:33])[CH3:32]
Reactant: CC(C)I
Reactant: O=S(=O)(N[C@H]1C[C@H]2CNCCN2C1)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N1CCN2C[C@@H](NS(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Example 42 (30 mg, 0.078 mmol) in dimethyl sulfoxide (1 mL) was added sodium carbonate (8.24 mg, 0.078 mmol) and 2-iodopropane (13.22 mg, 0.078 mmol). The mixture was stirred at room temperature for 3 days. The mixture was poured into 10 mL water, and the crude product was extracted with dichloromethane (3×8 mL). The combined organic fractions were concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.91 (dd, 6H, J=7 Hz), 1.10 (m, 1H), 1.85 (m, 3H), 2.12 (m, 1H), 2.22 (m, 1H), 2.69 (m, 3H), 3.69 (m, 4H), 7.85 (m, 1H), 8.06 (m, 3H); MS (ESI) m/z 392 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][NH2:7].[CH2:8]([O:10][C:11](=[O:25])[CH:12]=[C:13](OCC)[CH2:14][CH:15](OCC)OCC)[CH3:9]>C(O)(=O)C>[CH2:8]([O:10][C:11](=[O:25])[CH2:12][C:13]1[N:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[N:7]=[CH:15][CH:14]=1)[CH3:9]
Reactant: CCOC(=O)C=C(CC(OCC)OCC)OCC
Reactant: NNc1nccs1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccnn1-c1nccs1

Procedure:
A mixture of thiazol-2-ylhydrazine (2.2 g, 19.1 mmol) and 3,5,5-triethoxy-pent-2-enoic acid ethyl ester (70% purity, 7.1 g, 19.1 mmol) is refluxed in acetic acid overnight. Acetic acid is removed. To the residue is added NaHCO3 (aq.) (40 mL) and ethyl acetate (100 mL). The insoluble material is filtered. The organic layer is dried and solvent removed. The crude is subjected to column separation (hexane/ethyl acetate 3:1) to give (2-thiazol-2-yl-2H-pyrazol-3-yl)-acetic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=O)=[C:4](Cl)[N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1COCC1>[Cl:8][C:6]1[C:5]2[N:9]=[CH:10][S:22][C:4]=2[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: C1CCOC1
Product: Nc1nc(Cl)c2ncsc2n1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 124.6 %

Procedure:
To a solution of N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (12 g, 57 mmol) in THF (250 mL) was added Lawesson's reagent (17.5 g, 43 mmol). The reaction mixture was stirred at 65° C. for 30 minutes. The reaction mixture was then filtered, and the filtrate was concentrated. The crude yellow solid obtained was triturated using diethyl ether to afford the title compound (10 g, 93.4%) as a pale yellow solid. LCMS (ES+) 186.95 (M+H)+, RT 1.31 minutes (method 1).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([Cl:27])[C:19]=1Cl.O>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([Cl:27])[C:19]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: FC(F)(F)c1ccc2sc(S)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(Sc2nc3cc(C(F)(F)F)ccc3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
To a solution of 2-mercapto-5-trifluoromethyl-benzothiazole (239) (470 mg, 2.0 mmol) in DMF (20 mL) was added NaH (Aldrich, 60% suspension in hexanes, 80 mg, 2.0 mmol). After the resulting mixture was stirred at ambient temperature for 20 minutes, was added 1,2,3-trichloro-5-nitrobenzene (Acros, 452 mg, 2.0 mmol). The mixture was then heated at 60° C. for 4 hours. After cooled to room temperature, the mixture was poured to water and stirred for 1 hour. The solid product was collected by vacuum filtration to give 258 as a pale yellow solid (840 mg, 99%) which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13]Br)[CH3:10]>CN(C)C=O>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH3:10]
Reactant: CCOC(CBr)OCC
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COCCCCO)OCC
Temperature: 0 °C
Yield: 41.9 %

Procedure:
To a mixture of 56.3 g of 1,4-butanediol and 400 ml of N,N-dimethylformamide was slowly added 11.0 g of 60% sodium hydride (in oil) with stirring under ice cooling. After stirring at room temperature for 12 hours, 49.3 g of bromoacetaldehyde diethylacetal was added dropwise to the reaction mixture, which was stirred at 60° C. for 8 hours. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 21.6 g of 4-(2,2-diethoxyethoxy)butanol (yield, 41%), nD23.2 1.4314.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([NH2:26])[S:25][C:21]=2[CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([NH:26][C:14](=[O:16])[CH2:13][C:10]3[CH:9]=[CH:8][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[CH:12][CH:11]=3)[S:25][C:21]=2[CH:20]=1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: O=C(O)Cc1ccc(-c2ccncc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2nc(NC(=O)Cc3ccc(-c4ccncc4)cc3)sc2c1

Procedure:
To a mixture of 2-(4-(pyridin-4-yl)phenyl)acetic acid 3-1 (45 mg, 0.21 mmol), 6-methoxybenzo[d]thiazol-2-amine 3-2 (36 mg, 0.20 mmol), and DIEA (32 mg, 0.25 mmol) in DMF (0.5 mL) under stirring was added HATU (84 mg, 0.22 mmol). The solution was stirred for 2 hours before it was subject to reverse phase HPLC for purification to give compound 3 as white solid. MS m/z 376.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 12.60 (s, 1H), 8.70 (m, 2H), 7.87 (m, 2H), 7.78 (m, 2H), 7.72 (d, 1H, J=8.8 Hz), 7.63 (d, 1H, J=2.8 Hz), 7.58 (m, 2H), 7.11 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 3.96 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [NH3:1].[C:2]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[OH:32])[O:8][CH2:9][CH:10]([NH:12][CH2:13][CH:14]([OH:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](OC)=[O:24])=[C:19]([OH:27])[CH:18]=1)[CH3:11])(=[O:4])[NH2:3]>O1CCOCC1>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH:14]([OH:28])[CH2:13][NH:12][CH:10]([CH3:11])[CH2:9][O:8][C:7]2[CH:29]=[CH:30][C:31]([OH:32])=[C:5]([C:2](=[O:4])[NH2:3])[CH:6]=2)=[CH:18][C:19]=1[OH:27])(=[O:24])[NH2:1]
Reactant: COC(=O)c1ccc(OCC(O)CNC(C)COc2ccc(O)c(C(N)=O)c2)cc1O
Reactant: N
Solvent: C1COCCO1
Product: CC(COc1ccc(O)c(C(N)=O)c1)NCC(O)COc1ccc(C(N)=O)c(O)c1
Reaction time: 1.5 h

Procedure:
A mixture of 50 ml of dioxan and 500 ml of concentrated ammonia solution is added to 21.5 g of 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-(3-hydroxy-4-methoxycarbonylphenoxy)propan-2-ol. The reaction mixture is stirred for 1-2 hours, and as soon as it is homogeneous, left to stand for 3 days at 20°-30°. By concentration by evaporation, 20 g of crude, crystalline 1-(4-carbamoyl-3-hydroxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]propan-2-ol is obtained as a diastereoisomeric mixture having a melting point of 180°-190°. A hydrochloride is formed which melts at 238°-243° (from ethanol/methanol).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:37][C:34]4[CH:33]=[CH:32][C:31]([CH2:30][C:27]5[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=5)=[CH:36][CH:35]=4)=[O:3])([CH2:5][CH2:6]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(Cc2ccccc2)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(Cc4ccccc4)cc3)(CC1)CC2
Yield: 41.2 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminodiphenylmethane (62.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-phenylmethylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (31.1 mg).
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([OH:16])([CH3:15])[C:6]([NH:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:7])C.[OH-].[Li+]>O1CCCC1.O>[OH:16][C:5]([CH3:15])([C:6]([NH:8][CH2:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[O:7])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(C)(O)C(=O)NCCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(C(=O)O)C(=O)NCCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2.30 g (7.87 mmol) 2-hydroxy-2-methyl-N-(3,3,3-trifluoro-propyl)-malonamic acid ethyl ester in 40 ml of tetrahydrofurane were added 0.33 g (7.87 mmol) of lithium hydroxide in 20 ml of water and the mixture was stirred overnight at room temperature. After concentration in vacuo water (50 ml) was added and the mixture was acidified to pH 1. Extraction with ethylacetate gave 1.46 g (81%) of the title compound as a solid, MS m/e (%): 228.1 (M−H, 100).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:21]I>CN(C)C=O.O>[CH3:21][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: CI
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
17.5 g of cis-4,5-diphenyl-imidazolidine-2-thione are dissolved in 200 ml of dimethylformamide and first a solution of 3.2 g of sodium hydroxide in 20 ml of water and then 11.6 g of methyl iodide are added. The mixture is stirred for 6.5 hours at room temperature and evaporated to dryness, the residue is stirred with 350 ml of water and, after leaving to stand for some time, the mixture is filtered with suction, the solid material from the mixture is dissolved, whilst still moist, in 350 ml of ethanol and 50 ml of 2 N sodium hydroxide solution and 170 ml of water are added. The crystalline precipitate is filtered off with suction, filtered through silica gel using chloroform as the eluant and recrystallised from isopropanol/petroleum ether. cis-2-Methylthio-4,5-diphenyl-imidazoline with a melting point of 132°-134° is obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].I([O-])(=O)(=O)=[O:26].[Na+].O>CO>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:17])=[O:26])=[CH:14][CH:15]=2)[CH:9]=1)=[O:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CNC(=O)c1cc(-c2ccc(SC)cc2)c(-c2ccc(F)cc2)s1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=O)c1cc(-c2ccc(S(C)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 0 °C
Reaction time: 48 h
Yield: 63.4 %

Procedure:
A mixture of N-methyl-5-(4-fluorophenyl)-4-[4-(methylthio)phenyl]thiophene-2-carboxamide (1.66 g), sodium periodate (1.05 g) and water (1 ml) in methanol (100 ml) was stirred at 0° C. for 2 days. The insoluble was filtered and the filtrate was evaporated. The residue was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was recrystallized from ethanol to give colorless crystals of N-methyl-5-(4-fluorophenyl)-4-[4-(methylsulfinyl)phenyl]thiophene-2-carboxamide (1.1 g).
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[N:4][CH:3]=1.[H-].[Na+].Br[CH2:10][CH2:11][O:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.O>[Br:1][C:2]1[N:6]=[CH:5][N:4]([CH2:10][CH2:11][O:12][C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:3]=1
Reactant: BrCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1cnc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 5-bromo-1H-imidazole as prepared in part A (2.2 g, 15 mmol) in DMF (22 mL) at 0° C. was added NaH (658 mg, 60% dispersion, 2.42 mmol) in small portions. The resulting solution was allowed to warm to r.t. and then stirred for 1 hr. The solution was cooled to 0° C. and 1,1′,1″-[(2-bromoethoxy)methanetriyl]tribenzene (5.5 g, 15 mmol) in DMF (10 mL) was added drop-wise. The resulting solution was allowed to warm to r.t. where stirring continued until the reaction was judged complete by TLC (16 hr). The suspension was diluted with water and extracted with DCM (2×50 mL). The organics were dried (MgSO4), filtered, and concentrated to a solid that was recrystallized (EtOAc/Hex) to give 4.47 g of the title compound (69%).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.[CH3:27][Mg]Br.[Cl-].[NH4+].O>C1C=CC=CC=1>[OH:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15]([OH:17])([CH3:16])[CH3:27])[CH2:6]1
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 3α-acetoxy-5α-pregnan-20-one (120 mg, 360.5 g/m, 0.32 mmol) in 25 mL of dry benzene, was added 4.6 mL of 3M methylmagnesium bromide dropwise. After the addition of methylmagnesium bromide was completed, the reaction mixture was allowed to stir at room temperature for 18 h and then refluxed for 2 h. The excess methylmagnesium bromide was decomposed by dropwise addition of 30 mL of saturated ammonium chloride solution in an ice bath. The solution product was poured into water and extracted with chloroform twice. The extracts were dried over magnesium sulfate and evaporated to give 110 mg of crude product. The product was recrystallized in methanol to give 83 mg of 3α,20-dihydroxy-20-methyl-5α-pregnane.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[N:10]=[N:11][NH:12][N:7]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2nn[nH]n2)cc1
Temperature: 125 °C

Procedure:
A mixture of 4-aminobenzonitrile (10 g, 84.6 mmol), sodium azide (16.5 g, 254 mmol) and ammonium chloride (13.6 g, 254 mmol) in DMF was heated at 125° C. for 16 hours. The cooled mixture was filtered and the filtrate was concentrated in vacuo. The residue was added water (200 mL) and diethyl ether (200 mL) which resulted in crystallisation. The mixture was filtered and the solid was dried in vacuo at 40° C. for 16 hours to afford 5-(4-aminophenyl)-2H-tetrazole.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:17])[CH2:14][CH2:15]Cl)[CH:9]=[CH:10][CH:11]=1)[CH:4]=[CH2:5].C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:3]([C:6]1[CH:7]=[C:8]([N:12]2[CH2:15][CH2:14][C:13]2=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH:4]=[CH2:5]
Reactant: C=CCc1cccc(NC(=O)CCCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C=CCc1cccc(N2CCC2=O)c1
Reaction time: 8 h

Procedure:
Sodium hydride (0.1 mole; 57% dispersion in mineral oil) is charged into a glass reaction flask. The mineral oil is removed by washing the sodium hydride with benzene, and dimethyl sulfoxide (50 ml) is thereafter slowly added with stirring. The mixture is stirred until no more hydrogen gas evolves. A solution of N-(3-allylphenyl)-β-chloropropionamide (0.08 mole) in carbon tetrachloride (50 ml) is added dropwise to the reaction flask with stirring while maintaining the temperature of the reaction mixture below about 30°C. After the addition is completed the reaction mixture is allowed to stand at room temperature for a period of about 8 hours. After this time benzene is added and the reaction mixture is washed with water and aqueous sodium bicarbonate. The washed mixture is then dried over anhydrous magnesium sulfate, is filtered, and is stripped of solvents under reduced pressure to yield the desired product N-(3-allylphenyl)-2-azetidinone as the residue.
Reaction SMILES: [Cl:1][CH:2]([C:10]([CH3:31])=[CH:11][CH:12]([C:22]1[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C:23]=1[CH3:30])[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:3][CH2:4][C:5]([CH3:9])=[CH:6][CH:7]=O.[OH-].[K+]>O.C(Cl)Cl>[C:16]1([S:13]([CH:12]([C:22]2[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C:23]=2[CH3:30])[CH:11]=[C:10]([CH3:31])[CH:2]([Cl:1])[CH2:3][CH2:4][C:5]([CH3:9])=[CH:6][CH:7]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=[CH:3][CH:2]=[C:10]([CH3:31])[CH:11]=[CH:12][C:22]2[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C:23]=2[CH3:30])(=[O:15])=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=CC=O)CCC(Cl)C(C)=CC(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C=CC=C(C)C=CC1=C(C)CCCC1(C)C)=CC=CC=C(C)CCC(Cl)C(C)=CC(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A 100-ml round-bottom flask was charged with a solution of 2.14 g (6.4 mmoles) of vitamin A acetate, 1.68 g (6.4 mmoles) of triphenylphosphine and 0.64 g (6.4 mmoles) of concentrated sulfuric acid in 10 g of methanol, and the contents were stirred at 25° C. for 3 hours. Thereafter, methanol was removed by distillation in vacuo from the reaction mixture to obtain a tar-like vitamin A phosphonium salt. This was dissolved in 10 g of water and to the solution was added 10 ml of a solution of 3.0 g (6.4 mmoles) of 6-chloro-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,7-nonadien-1-al in methylene chloride. To this mixture was added gradually 10.84 g (12.8 mmoles) of a 7.7% aqueous solution of potassium hydroxide at 8° C., and the resulting mixture was stirred for 30 minutes. After completion of the reaction, an organic layer was separated from an aqueous layer and washed with water, followed by distilling off of the solvent, to give 6.72 g (purity: 40.9%, 3.85 mmoles, yield: 60.2%) of an oily substance. This substance was purified by silica gel chromatography (hexane/ethyl acetate=85/15) to give 2.05 g of 1-phenylsulfonyl-4-chloro-1,18-di(2,6,6-trimethyl-1-cyclohexen-1-yl)-3,7,12,16-tetramethyloctadeca-2,7,9,11,13,15,17-heptaene.