Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].N1CCCCC1.CC(O)=O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:14]2[S:10][C:11](=[O:16])[NH:12][C:13]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(O)cc2)S1
Yield: 85 %

Procedure:
A mixture of p-hydroxybenzaldehyde (vi; 0.5 mmol), 2,4-thiazolidinedione, (0.6 mmol), and catalytic amounts of piperidine and AcOH was refluxed in toluene (5 mL) for 24 h. The precipitated product was filtered, washed with toluene (3×10 mL), and dried in vacuo at 60° C. overnight, yielding 5-(4-hydroxybenzylidene)-thiazolidine-2,4-dione (vii) in a 85% yield.
Reaction SMILES: [CH:1]1[C:18]2[C:5](=[C:6]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[CH2:22][Br:23])[C:7]3[C:16]([CH:17]=2)=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1)[CH3:29].[PH4+].[AsH4+]>C(#N)C.C(OCC)C>[Br-:23].[C:37]([C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N+:28]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([C:6]3[C:7]4[C:16](=[CH:15][C:14]5[C:9]([CH:8]=4)=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH:17]=[C:18]4[C:5]=3[CH:4]=[CH:3][CH:2]=[CH:1]4)[CH:20]=2)([CH3:27])[CH3:29])=[CH:36][CH:35]=1)#[N:38]
Reactant: CN(C)Cc1ccc(C#N)cc1
Reactant: BrCc1cccc(-c2c3ccccc3cc3cc4ccccc4cc23)c1
Agent: [AsH4+]
Agent: [PH4+]
Solvent: CCOCC
Solvent: CC#N
Product: C[N+](C)(Cc1ccc(C#N)cc1)Cc1cccc(-c2c3ccccc3cc3cc4ccccc4cc23)c1
Product: [Br-]

Procedure:
A mixture of (B) and N,N-dimethyl-4-cyanobenzylamine in acetonitrile was refluxed for 2 hr. The reaction mixture was then poured into diethyl ether, and the crude product was collected by filtration. The crude product was recrystallized from ethanol. The same reaction can be used to prepare the corresponding phosphonium and arsonium salts.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([OH:23])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[C:9]([F:25])[CH:10]=[C:11]([F:24])[CH:12]=3)=[CH:4][CH:3]=1.[CH3:28][C@H](NC)[C@H](O)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH3:28])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[C:9]([F:25])[CH:10]=[C:11]([F:24])[CH:12]=3)=[CH:4][CH:3]=1
Reactant: O=C(O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(F)cc(F)cc21
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Product: COC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(F)cc(F)cc21

Procedure:
Following the method of Example 18, Step II to Step IV, but using 9-p-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid from Example 30, Step III and using 1(-)ephedrine in Step III, there is obtained the title compound.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Br.[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][CH2:3][CH:2]([F:5])[F:1])=[CH:9][CH:8]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: FC(F)CBr
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: FC(F)CNCc1ccc(Cl)nc1
Temperature: 100 °C
Yield: 83.1 %

Procedure:
19.9 g (0.135 mol) of 2,2-difluoro-1-bromoethane, 10 g (0.067 mol) of 1-(6-chloropyridin-3-yl)methanamine and 8.2 g of triethylamine are initially charged with 31 g of N-methylpyrrolidone. The mixture is heated to 100° C. for 2 hours and then cooled again to 80° C. The N-methylpyrrolidone is distilled off at 80° C. under reduced pressure and the reaction mixture is poured onto 50 ml of water. 2 ml of 45% sodium hydroxide solution are used to adjust the pH to 12, and the mixture is then extracted twice with 30 ml of toluene. The product is subsequently finely distilled under reduced pressure. This gives 11.5 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine (corresponds to 83.1% yield).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[OH:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(O)(=O)C.O>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:36])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Yield: 76.3 %

Procedure:
To a solution of 3-hydroxy-7beta-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester (1) in dimethylformamide (9.5 parts, dried over Molecular Sieves) at -50° C. under nitrogen is added sodium borohydride (4 equivalents) at -53° to -48° C. over 3 minutes. After 30 minutes at the same temperature, glacial acetic acid (1.4 parts) and then water (10 parts) are added to the mixture gradually, and extracted with ethyl acetate. The extract is washed with 5% aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated. The residue is crystallized from a mixture of dichloromethane (4 parts) and n-hexane (1.7 parts) to give 3-hydroxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (2). Yield: 76.3%. mp. 196°-198° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=[S:6])[NH:4][NH2:5].[Cl:8][C:9]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:10]=1[C:11](=O)[CH2:12]Cl>>[ClH:8].[Cl:8][C:9]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:10]=1[C:11]1[CH2:12][S:6][C:3]([N:2]([CH3:7])[CH3:1])=[N:4][N:5]=1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: CN(C)C(=S)NN
Product: CN(C)C1=NN=C(c2ccc(Cl)cc2Cl)CS1
Product: Cl

Procedure:
4.16 g (0.035 mole) of 4,4-dimethyl-thiosemicarbazide and 7.82 g (0.035 mole) of 2,4-dichlorophenacyl chloride are reacted under the conditions of Example 2. After concentration, ethyl acetate is added to the residue and further concentration is employed. A yellow, needle-like solid is produced. The solid is dried under high vacuum at 65° C. Subsequently, it is recrystallized from methanol/ethyl acetate and again dried under high vacuum to produce 5-(2,4-dichlorophenyl)-N,N-dimethyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 219°-222° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:29])=O.CN(C)C=O>CCCCCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5]([Cl:29])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl

Procedure:
To a stirred solution of 2-Methoxy-6-pentadecylbenzoic Acid (6.5 g, 16 mmol) in hexane (60 mL) were added thionyl chloride (2.5 g, 21 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to reflux for 1 h After the reaction was complete, the solvent was evaporated under reduced pressure to yield the desired 2-Methoxy -6-pentadecylbenzoyl Chloride, which was redissolved in dichloromethane (50 mL) and used for the condensation with anilides.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:22]3[N:23]=[C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:29][CH:28]=4)[N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=2)[CH:12]=1)C.O>C(OCC)C>[N:36]1([CH2:35][CH2:34][O:33][C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:24]3[N:25]=[C:21]4[CH:20]=[CH:19][CH:18]=[C:17]([C:13]5[CH:12]=[C:11]([CH2:10][OH:9])[CH:16]=[CH:15][CH:14]=5)[N:22]4[N:23]=3)=[CH:32][CH:31]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CCOC(=O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a slurry of lithium aluminium hydride (82.6 mg, 2.12 mmol) in diethylether (10 mL) was added 3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-benzoic acid ethyl ester (0.50 g, 1.06 mmol) portionwise. The mixture was stirred at room temperature for 6 hrs. Water was added to quench the hydride and the aqueous layer was removed. The organic layer was concentrated in vacuo, and the crude product loaded onto an SCX column, which was washed with methanol and the product eluted with 2M ammonia in methanol, then concentrated in vacuo. Yield: 0.35 g, 76%. A small amount was purified by preparatory HPLC. RT: 2.32, MI: 430, Method: 2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[I:9]N1C(=O)CCC1=O.O.CCOCC>CN(C=O)C>[NH2:1][C:2]1[C:7]([I:9])=[N:6][C:5]([Cl:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Nc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
5-Amino-2-chloropyridine (3.0 g) was dissolved in DMF (40 mL), N-iodosuccinimide (5.25 g) was added and the reaction mixture was stirred at room temperature for 3 hours. Water and MTB-ether were added to the reaction mixture, the layers were separated and the organic layer was washed 3× with water, washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=3:1, Rf=0.30) to afford 4.80 g of the title compound of the formula
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:19]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:17]
Reactant: CNc1ccc(F)cc1F
Reactant: Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(F)cc3F)cc1CO2
Reaction time: 24 h

Procedure:
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid was converted to the acid chloride as in Example 3, then treated with N-methyl-2,4-difluoroaniline (1.5 equiv), and triethylamine (5 equiv) in dichloromethane and N,N-dimethyl-4-aminopyridine (0.2 equiv) at 24° C. After about 24 hr, the reaction mixture was diluted with dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:2 hexanes/ethylacetate) provided 167bp. 1H NMR (500 MHz, CDCl3) δ 7.29 (m, 1H), 6.95-6.98 (m, 4H), 6.78 (d, J=8.2 Hz, 1H), 5.04 (s, 2H), 3.39 (s, 3H), 2.27 (s, 3H). LCMS (ESI) m/z: 372.1.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1.O>[Br:12][CH2:13][C:14]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:15]
Reactant: O=C(Br)CBr
Reactant: COC(=O)c1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1NC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of methyl anthranilate (5 g, 0.033 mol) in anhydrous DMF (25 mL) and anhydrous dioxane (25 mL) was cooled to 0° C. in a 250 mL 3-necked flask, fitted with a magnetic stirrer and a constant addition funnel. Bromoacetyl bromide (6.7 g, 2.9 mL, 100 mol %) was added dropwise, keeping the internal temperature between 0° C. and 2° C. After the addition was complete (20-25 min), the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water (100 mL) and the white crystalline compound which precipitated was filtered, washed sequentially with 5% HBr (100 mL) and water (200 mL), and then dried in a vacuum oven at 40°-45° C. overnight. The product was triturated with ether and then dried in vacuo for 5 h, yielding 7.9 g (88%) of the title compound as a white solid: mp 81°-82° C.; 1H NMR (DMSO-d6) δ11.07 (s, 1H, NH), 8.23 (dd, 1H, J=1.2, J=8.4), 7.94 (dd, 1H, J=1.6, J=8), 7.66-7.62 (m, 1H), 7.27-7.23 (m,1H), 4.23 (s, 2H), 3.87 (s, 3H); 13C NMR (DMSO-d6) δ171.64, 167.28, 138.81, 134.03, 130.67, 124.02, 122.90, 121.22, 52.51, 30.37; MS (EI, m/z) 271 (M+), 273 (M+2+). HRMS (EI) calcd for C10 H10NO3Br 270.9844, found 270.9838. Anal. Calcd for C10 H10NO3Br: C, 44.14; H, 3.70; N, 5.15. Found: C, 44.18; H, 3.67; N, 4.94.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[C:15](#[N:22])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C(OCC)C>ClCCl>[CH3:8][C:3]1[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:14])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10].[NH2:13][N+:19]1[CH:20]=[CH:21][C:16]([C:15]#[N:22])=[CH:17][CH:18]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: N#Cc1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: N#Cc1cc[n+](N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A solution of O-(mesitylsulfonyl)hydroxylamine (prepared as described in Synthesis, 1977, 1; 2.17 g, 10.1 mmol) in anhydrous dichloromethane (21 mL) was added dropwise to a stirred solution of isonicotinonitrile (1.05 g, 10.1 mmol) in anhydrous dichloromethane (10 mL) at 0° C. and the mixture was stirred at ambient temperature for 1 hour and 30 minutes. Diethyl ether was then added to the mixture and the precipitate that formed was collected by filtration, washed with diethyl ether and dried in vacuo to give the title compound (3.03 g, 94%) as a white solid.
Reaction SMILES: BrC[C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([C:14]1C=CC([N+]([O-])=O)=CC=1CBr)=[O:13].BrC(C1C=CC=CC=1)C=O>>[N+:9]([C:7]1[CH:6]=[CH:5][C:4]([C:12](=[O:13])[CH3:14])=[CH:3][CH:8]=1)([O-:11])=[O:10]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1CBr)c1ccc([N+](=O)[O-])cc1CBr
Agent: O=CC(Br)c1ccccc1
Product: CC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 98 %

Procedure:
One proceeds according to Example 14 but bromomethyl-p-nitro-phenyl-ketone is used as starting material in the place of α-bromo-α-phenyl-acetaldehyde. The reaction mixture is not worked up by the extraction method according to Example 14 but by precipitating the product with 50 ml of water, filtering off the same and washing it three times with 20 ml of water each. Thus 16.1 g of the desired compound are obtained, yield 98%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[C:10]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:10][O:8][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cnccn1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cnccn1
Reaction time: 72 h
Yield: 7.7 %

Procedure:
To pyrazine-2-carboxylic acid (15.0 g, 121 mmol) in DMF (150 mL) were added K2CO3 (50 g, 363 mmol) and MeI (9.0 mL, 145 mmol). After stirring for 3 days, the reaction mixture was filtered and then concentrated. The residue was dissolved in ethyl acetate, washed with water (3 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash column chromatography eluted with 10-30% ethyl acetate in hexanes gave the title product (1.28 g, 8%).
Reaction SMILES: [CH:1]1([NH:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]1O[CH:10]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([OH:21])(C)C>>[CH:1]1([N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:21])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ONC1CCCCC1
Reactant: c1ccc(C2CO2)cc1
Reactant: CC(C)O
Product: Oc1ccccc1CCN(O)C1CCCCC1
Yield: 33 %

Procedure:
A solution of 2.14 g of N-cyclohexylhydroxylamine and 2.23 of styrene oxide in 50 ml of isopropanol is heated at 45° C. for 3 hours and under reflux for 20 hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by liquid chromatography to afford the title compound in a 33% yield as a yellow oil.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)CCC.[F:20][C:21]1[CH:49]=[CH:48][C:24]([CH2:25][NH:26][C:27](=[O:47])[C:28]2[CH:33]=[CH:32][C:31]([S:34]([N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:39](I)=[CH:38]3)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1.CN(C=O)C>O.CCOC(C)=O>[F:20][C:21]1[CH:49]=[CH:48][C:24]([CH2:25][NH:26][C:27](=[O:47])[C:28]2[CH:29]=[CH:30][C:31]([S:34]([N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:39]([C:6]4[CH:11]=[N:10][CH:9]=[CH:8][N:7]=4)=[CH:38]3)(=[O:36])=[O:35])=[CH:32][CH:33]=2)=[CH:23][CH:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3cnccn3)c3ccccc32)cc1
Reaction time: 16 h

Procedure:
Degas DMF with N2 for 30 minutes. Add 2-tributylstannyl pyrazine (0.214 g, 0.58 mmol), N-(4-fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide 0.300 g, 0.56 mmol) and tetrakis(triphenylphosphine)Pd(0) (0.100 g, 0.086 mmol) to DMF (5.0 ml). Heat and stir at 100° under N2 for 16 h. Pour the reaction mixture into H2O-EtOAc. Separate the EtOAc layer and extract several times with H2O, wash with brine, dry (MgSO4) and filter through celite. Remove the solvent on the rotary evaporator to give an oil. Chromatograph on the chromatron using a 1 mm plate and elute with 1% CH3OH—CH2Cl2 to give the title compound. Mass spectrum (m/e) (M+H) 487.1240; found: 487.1220.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:23])([CH3:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:5][CH:4]=1)=[O:2].[Mn]([O-])(=O)(=O)=[O:31].[K+].O>CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]([OH:31])=[O:2])=[CH:8][CH:7]=2)=[C:10]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:11]=1)([CH3:23])[CH3:22])[CH3:21]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCOC(=O)CC(C)(C)c1ccc(-c2ccc(C=O)cc2)c(OCCCOC)c1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CC(C)(C)c1ccc(-c2ccc(C(=O)O)cc2)c(OCCCOC)c1
Reaction time: 18 h
Yield: 96 %

Procedure:
Ethyl 3-[4′-formyl-2-(3-methoxypropoxy)biphenyl-4-yl]-3-methylbutanoate (1.0 g, 2.5 mmol) was dissolved in acetone (40 mL) and a solution of potassium permanganate (1.4 g, 8.8 mmol) and water (20 mL) was added at room temperature. The mixture was stirred for 18 hrs and then filtered. Dichloromethane was added and the mixture was then acidified at 0° C. with HCl 1N. The aqueous layer was extracted three times with dichloromethane and the combined organic layers were washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 1.0 g, (96%) of the desired product as a brown solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14](OC)=[O:15])[CH2:3]1.[Li+].[BH4-].O.Cl>C1COCC1>[OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of compound 236 (6.4 g, 26.09 mmol) in THF (80 mL) at 0° C. was added a solution of LiBH4 (2.063 g, 94.76 mmol) in one shot. The suspension was stirred at 0° C. for 1 h then at room temperature overnight. The mixture was cooled to 0° C. and water (52 mL) then 6N HCl (20 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×70 mL). The combined organics were washed with 2N NaOH, 2N HCl and brine (20 mL each). The organic layers were dried over Na2SO4 filtered and concentrated to afford title compound 237 (5.4 g, 95%) as clear oil. LRMS (ESI): (calc.) 217.13. (found) 256.3 (M+K).
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH:10]([NH2:18])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])(=[O:21])[CH3:20].[Na+].C(OC(=O)C)(=O)C>C(OCC)(=O)C.O>[C:2]1([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH:10]([NH:18][C:19](=[O:21])[CH3:20])[CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1Cc2ccccc2C(c2ccccc2)C1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1Cc2ccccc2C(c2ccccc2)C1
Reaction time: 24 h
Yield: 80.1 %

Procedure:
To a solution of 180 mg (0.80 mmol) of 4-phenyl-2-aminotetraline HCl in 3.5 ml ethyl acetate and 2.0 ml water, was added 360 mg of sodium acetate. To this mixture 0.6 ml of acetic anhydride was then added and the mixture was stirred for 24 hrs. The addition of 2 ml of water resulted in the formation of two layers. After separation, the water layer was extracted twice with ethyl acetate. The combined organic layers were washed 3 times with a saturated solution of sodium bicarbonate and once with a saturated solution of sodium chloride. After drying over magnesium sulfate, the organic solution was evaporated under reduced pressure to yield 4-phenyl-2-acetamidotetralin as a white solid (170 mg, 79%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]2[C:14]=1[N:13]([CH3:15])[C:12](=[O:16])[CH:11]=[CH:10]2.[H][H].[Cl:31]N1C(=O)CCC1=O.Cl>ClCCl.O1CCCC1>[Cl:31][C:18]([CH2:17][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:16])[N:13]2[CH3:15])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: [H][H]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C(Cc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(Cl)(Cc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Yield: 85.8 %

Procedure:
Sodium hydride (60% in oil) (1.0 g) was added under ice cooling to a tetrahydrofuran (THF) solution (140 ml) of 13.59 g of diethyl 2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethyl)malonate, and stirring was carried out until the generation of hydrogen stopped. N-chlorosuccinimide (5.6 g) was added, followed by stirring for 1 hour. The reaction mixture was added to cold hydrochloric acid, and extraction with dichloromethane was performed. After drying over anhydrous sodium sulfate, the dry product was concentrated under reduced pressure, diisopropyl ether was added to the residue, and the precipitated solid was collected by filtration and dried to thereby obtain 12.77 g (yield: 86%) of diethyl 2-chloro-2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethyl)malonate as a light yellow powder.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)ccc1Sc1ccccc1
Solvent: ClCCl
Product: Cc1cc(CCl)ccc1Sc1ccccc1
Reaction time: 1 h

Procedure:
The 1-hydroxymethyl-3-methyl-4-phenylthiobenzene obtained above is dissolved in methylene chloride (100 ml), and thereto is added with stirring thionyl chloride (23.34 ml) under ice cooling. The mixture is stirred for one hour, and the reaction mixture is washed with ice water (100 ml×3), and thereto is added ethyl acetate (500 ml). The mixture is washed in order with 5% aqueous sodium hydrogen carbonate solution (50 ml×4) and saturated aqueous sodium chloride solution (100 ml×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-chloromethyl-3-methyl-4-phenylthiobenzene.