Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH3:25]>O1CCOCC1.ClCCl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH3:25])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccsc1N
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1sccc1C
Yield: 36.4 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (3.6 g, 0.0137 mol) and 2-amino-3-methylthiophene (3.4 g, 0.03 mol) in 1,4 dioxan (30 ml) under a nitrogen atmosphere were stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure to give an oil. The oil was taken up in dichloromethane and extracted with 2N hydrochloric acid (3×100ml). The dichloromethane extracts were then washed with sodium carbonate solution (100 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a solid. The solid was purified by flash chromatography using a gradient elution of dichloromethane/methanol (0-5%, 500 ml). The fractions containing the product were combined and evaporated under reduced pressure to give a solid, (1.94 g), m.p. 130°-132°. Recrystallization from ethyl acetate gave the title compound, (1.7 g), m.p. 132°-133°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:5]=O.[N:17]1([CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:5][NH:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:26][CH:27]=1
Reactant: Cc1cc(C=O)ccc1OC1CCCCO1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: Cc1cc(CNc2ccc(OCCN3CCCC3)cc2)ccc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.8 %

Procedure:
To a solution of 3-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (0.700 g, 3.18 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.624 g, 3.02 mmol) in 20 mL methylene chloride was added magnesium sulfate (1.82 g, 15.12 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated. The residue was redissolved in 20 mL methylene chloride and was treated with magnesium sulfate (1.82 g, 15.12 mmol). The reaction was again stirred overnight at room temperature. The reaction was filtered and concentrated. The residue was again redissolved in 20 mL methylene chloride and was treated with magnesium sulfate (1.82 g, 15.12 mmol). The reaction was once again stirred overnight at room temperature. The reaction was filtered and concentrated. The resulting oil was dissolved in 12 mL ethanol and 6 mL methanol and was treated with sodium borohyride (0.560 g, 14.80 mmol) which was added in two portions over a period of 1 hr. The reaction was stirred at room temperature for 4 days at which time the solvent was removed in vacuo. To the residue was added water, and the mixture was extracted three times with methylene chloride. The combined organic layers were washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered, and concentrated to afford 1.46 g of the title compound. MS 411.4 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].CO.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cnn(-c3ccc(F)cc3)c2cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)c1cc2c(cnn2-c2ccc(F)cc2)cc1CC(C)(C)C(=O)O
Yield: 99.2 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-yl)-2,2-dimethylpropanoate (87 mg, 0.236 mmol) was heated to 100 C overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2×EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, and concentrated in vacuo to give 83 mg (99% yield) of acid 3-(1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-yl)-2,2-dimethylpropanoic acid. MS found: (M+H)+=355.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11][CH3:12])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.O.[CH3:20]O>>[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11][CH3:12])[C:5]([O:7][CH3:20])=[O:6]
Reactant: CO
Reactant: CSc1ccc(C(=O)O)c(C)c1N
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(SC)c(N)c1C
Temperature: 60 °C

Procedure:
2 g of 3-amino-2-methyl-4-methylsulfanylbenzoic acid (0.01 mol) were dissolved in 20 ml of methanol and admixed with 2.0 g of conc. sulfuric acid, and the mixture was heated at 60° C. for 2 h. After cooling, the reaction mixture was poured into water, neutralized and extracted with ethyl acetate. After washing and drying, the solvent was removed.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C@@H:10]([O:15][CH2:16][C:17]2[C:18]([NH2:32])=[N:19][C:20](=[O:31])[N:21]([CH:30]=2)[C@@H:22]2[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[CH2:23]2)[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:33]([O-:35])=[O:34])[CH:3]=1.[CH2:36]([N-:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[C:37]#[CH:38].CCN(CC)CC>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:9][O:8][C:7]1[C:2]([C:38]#[C:37][CH2:36][NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])=[CH:3][C:4]([N+:33]([O-:35])=[O:34])=[C:5]([C@@H:10]([O:15][CH2:16][C:17]2[C:18]([NH2:32])=[N:19][C:20](=[O:31])[N:21]([CH:30]=2)[C@@H:22]2[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[CH2:23]2)[C:11]([CH3:13])([CH3:14])[CH3:12])[CH:6]=1
Reactant: C#CC[N-]C(=O)C(F)(F)F
Reactant: COc1cc([C@@H](OCc2cn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)nc2N)C(C)(C)C)c([N+](=O)[O-])cc1I
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc([C@@H](OCc2cn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)nc2N)C(C)(C)C)c([N+](=O)[O-])cc1C#CCNC(=O)C(F)(F)F
Yield: 91.6 %

Procedure:
A solution of compound 66 (245 mg, 0.4 mmol), N-propargyltrifluoroacetylamide (603 mg, 4.0 mmol), tetrakis(triphenylphosphine)-palladium(0) (92 mg, 0.8 mmol), CuI (30 mg, 0.16 mmol), and Et3N (240 μL, 1.7 mmol) in anhydrous DMF (5.0 mL) was stirred at 50° C. for 12 hours. The mixture was concentrated in vacuo and purified by silica gel column chromatography to yield 5-{(S)-1-[5-methoxy-4-(3-trifluoroacetamido-1-propynyl)-2-nitrophenyl]-2,2-dimethyl-propyloxy}methyl-2′-deoxycytidine 67 (230 mg, 91%). 1H NMR (400 MHz, MeOD-d4): δ 7.98 (s, 1H, Ph-H), 7.92 (s, 1H, H-6), 7.19 (s, 1H, Ph-H), 6.15 (t, 1H, J=6.4 Hz, H-1′), 5.21 (s, 1H, Ph-CH), 4.41 (d, 1H, J=13.2 Hz, 5-CH2a), 4.33 (m, 3H, H-3′ and CH2), 4.27 (d, 1H, J=13.2 Hz, 5-CH2b), 3.96 (s, 3 H, OCH3), 3.88 (m, 1H, H-4′), 3.72 (m, 2H, H-5′), 2.30 (m, 1H, H-2′a), 2.12 (m, 1H, H-2′b), 0.84 (s, 9H, C(CH3)3).
Reaction SMILES: [F:1][C:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=O)([F:4])[F:3].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO.O>[F:1][C:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=[N:17][OH:18])([F:4])[F:3]
Reactant: O=C(c1ccc2c(c1)OCO2)C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C(c1ccc2c(c1)OCO2)C(F)(F)F
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Trifluoromethyl(3,4-methylenedioxyphenyl) methanone (1.46 g, 0.0067 mole), hydroxylamine hydrochloride (1.06 g), 0.015 mole) and sodium acetate (0.86 g, 0.010 mole) were dissolved in a mixture of methanol (4 ml) and water (4 ml) and heated to reflux for 4.5 hours. After cooling to room temperature, water (10 ml) was added and the mixture extracted with ether (3×15 ml). The combined extracts were washed with water (20 ml) and brine (20 ml) and dried over anhydrous sodium sulfate. After filtration and removal of the solvent in vacuo the residue was recrystallized from a mixture of dichloromethane and petroleum spirit (40°-60° C.) to give trifluoromethyl(3,4-methylenedioxyphenyl)methanone-oxime (1.2 g), (76.9%) m.p. 96.0° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:16]=[CH:15][C:9](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:8][C:7]=1[O:17][CH3:18])[CH2:2][CH2:3][CH3:4].Cl[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[C:9]1[CH:15]=[CH:16][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:7]([O:17][CH3:18])[CH:8]=1
Reactant: OCCCCCCCl
Reactant: CCCCOc1ccc(/C=C/C(=O)O)cc1OC
Product: CCCCOc1ccc(/C=C/C(=O)OCCCCCCO)cc1OC
Yield: 79.3 %

Procedure:
Following the procedure of Example 1 and using 1.38 g (5.50 mmol) (E)-4butoxy-3-methoxycinnamic acid, 0.84 g (5.50 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) and 0.68 g (5.0 mmol) 6-chlorohexanol gave 1.39 g (79%) (E)-4-butoxy-3-methoxycinnamic acid 6-hydroxyhexyl ester as colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[CH2:22]([S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:30]4[CH:29]=[CH:28][C:27]([S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])=[CH:32][CH:31]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: CCS(=O)(=O)c1ccc(-c2ccc3oc(-c4ccc(OC)c([N+](=O)[O-])c4)nc3c2)cc1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.15 mmol) and 4-(ethylsulfonyl)phenylboronic acid (214 mg, 1.75 mmol) the subtitle compound was obtained (88 mg, 12%). MS 439 m/z (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][OH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][O:18][CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CO)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.08 h
Yield: 37.1 %

Procedure:
A solution of 645 mg of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide in 2 ml of N,N-dimethylformamide was added under ice cooling to a suspension of 84.3 mg of sodium hydride in 1 ml of N,N-dimethylformamide, and the mixture was stirred for 5 minutes. Then, a solution of 299.3 mg of methyl iodide in 1 ml of N,N-dimethylformamide was added dropwise under ice cooling, and the mixture was stirred for 10 minutes. After the stirring, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated and purified by TLC (developing solvent: chloroform/methanol=19/l) to afford 250 mg of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]methoxyacetamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12]([S:14]C)=S)[CH2:11][CH2:10][CH2:9][S:8]1.[CH3:16][NH:17][CH3:18]>>[CH3:16][N:17]([CH3:18])[C:12]([C:7]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:11][CH2:10][CH2:9][S:8]1)=[S:14]
Reactant: CSC(=S)C1(c2ccccn2)CCCS1
Reactant: CNC
Product: CN(C)C(=S)C1(c2ccccn2)CCCS1
Temperature: 20 °C

Procedure:
A solution of methyl 2-(pyrid-2-yl)tetrahydrothiophene-2-carbodithioate (20 g) in dimethylamine (100 cc) is heated gradually for 3 hours 40 minutes, in an autoclave, up to a temperature of about 125° C. After cooling to a temperature of about 20° C., the autoclave is emptied and rinsed with methylene chloride (200 cc), the latter being added to the reaction mixture. The solution is concentrated to dryness (20 mm Hg; 2.7 kPa) at 40° C. The resulting residue (20.7 g) is dissolved in boiling ethanol (50 cc) and the solution, to which decolourising charcoal (0.5 g) is added, is filtered hot and then kept, after cooling, for 1 hour at a temperature of about 0° C. The crystals which have appeared are filtered off, washed twice with ethanol (20 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The resulting product (14.1 g) is dissolved in boiling ethanol (45 cc) and the solution, to which decolourising charcoal (0.5 g) is added, is filtered hot and then kept, after cooling, for 1 hour at a temperature of 0° C. The crystals which have appeared are filtered off, washed twice with ethanol (20 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 45° C. N,N-Dimethyl-2-(pyrid-2-yl)-tetrahydrothiophene-2-carbothioamide (11.8 g), melting at 100° C., is thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.Cl.[NH2:11][OH:12].C([O-])([O-])=O.[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[N:11][OH:12])[NH2:9])[CH:5]=[N:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1cncc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1cncc(Br)c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of 3-bromo-5-cyanopyridine (1.0 eq), hydroxylamine hydrochloride (1.5 eq.), K2CO3 (2.1 eq) in ethanol (0.1 M) was stirred at 80° C. for 3 days. The mixture was concentrated, diluted with EtOAc and aqueous NaHCO3. The title compound was isolated by filtration as beige solid.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].Cl[C:5]1[C:6]([C:11]#[N:12])=[N:7][CH:8]=[CH:9][CH:10]=1.CN(C=O)C.[H-].[Na+]>O>[CH2:1]([S:3][C:5]1[C:6]([C:11]#[N:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCS
Reactant: N#Cc1ncccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccnc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.9 mL of ethanethiol was added to a mixture of 1.39 g of 3-chloropyridine-2-carbonitrile and 10 mL of DMF, 0.52 g of 60% sodium hydride (oil-based) was added to the reaction mixture under ice cooling, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 1.52 g of 3-ethylsulfanylpyridine-2-carbonitrile.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)C.[BH4-].[Li+]>O1CCCC1.O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][C:7]=1[S:12]([NH2:13])(=[O:15])=[O:14]
Reactant: CCOC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(CO)ccc1Cl
Temperature: 4 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
To a solution of 4-chloro-3-sulfamoyl-benzoic acid ethyl ester (46.95 g, 166 mmol) in 500 mL of dry tetrahydrofuran is added dropwise, with stirring, 199 mL of a 2 M solution of lithium borohydride in tetrahydrofuran. The mixture is stirred and refluxed for 5 hr, then left at room temperature for 18 h, and is then carefully diluted with 400 mL of water. The mixture is cooled to 4° C. for 24 hours and filtered to yield 32.7 g (82%) of the title compound as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:15])OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: NCc1cccnc1
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: O=C(NCc1cccnc1)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 5 h
Yield: 95.2 %

Procedure:
4.22 g (0.02 mole) of ethyl N-(4-nitrophenyl)carbamate, 1.80 g (0.0167 mole) of 3-aminomethyl-pyridine and 3.18 g (0.0173 mole) of tributylamine are dissolved in 25 ml of dry toluene, and the mixture is boiled for 5 hours. The separated product is filtered off, washed twice with 10 ml of acetone, each, and dried. 4.33 g (85.1%) of N-(4-nitrophenyl)-N'-(3-pyridylmethyl)-urea are obtained; m.p.: 222°-224° C. (the authentic sample melts at 223°-225° C.).
Reaction SMILES: [Br:1]Br.[OH:3][CH:4]1[C:9]([CH3:11])([CH3:10])[O:8][C:7]2[CH:12]=[CH:13][S:14][C:6]=2[CH:5]1[N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20]>ClCCl>[Br:1][C:13]1[S:14][C:6]2[CH:5]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[CH:4]([OH:3])[C:9]([CH3:10])([CH3:11])[O:8][C:7]=2[CH:12]=1
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Reactant: BrBr
Solvent: ClCCl
Product: CC1(C)Oc2cc(Br)sc2C(N2CCCC2=O)C1O

Procedure:
A solution of bromine (0.20 mL, 3.92 mmol) in dichloromethane (5 mL) was slowly added to a solution of 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (1.0 g, 3.74 mmol) at -5° C. The resultant mixture was stirred at rt for 2 h. The resulting precipitate was collected by filtration and purified by medium pressure chromatography using 5% methanol in dichloromethane as the eluant to give the product as a colorless solid, 0.28 g (22%): mp 162°-165° C.; IR(KBr): 3287, 1666 and 1570 cm-1 ; MS: m/z 346 (MH+); 1H NMR (CDCl3): δ1.30 (s, 3H), 1.47 (s, 3H), 2.06 (m, 2H), 7.50 (m, 2H), 3.23 (bs, 1H, exchanges with D2O), 3.34 (m, 2H), 3.76 (d, J=9.1 Hz, 1H) 5.16 (d, J=9.1 Hz, 1H) and 6.56 (s, 1H). Anal. Calcd. for C13H16BrNO3S: C, 45.10; H, 4.66; N, 4.05.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6]([S:8]([O:11][CH3:12])(=[O:10])=[O:9])=[CH2:7]>[I-].[Zn+2].[I-]>[CH:5]12[O:1][CH:2]([CH:6]([S:8]([O:11][CH3:12])(=[O:10])=[O:9])[CH2:7]1)[CH:3]=[CH:4]2
Reactant: C=CS(=O)(=O)OC
Reactant: c1ccoc1
Agent: [I-]
Agent: [Zn+2]
Product: COS(=O)(=O)C1CC2C=CC1O2
Yield: 34 %

Procedure:
To a four-necked flask having a capacity of 300 mL and equipped with a stirrer, a dropping funnel, and a thermometer, 150 g (2.20 mol) of furan and 15.0 g of zinc iodide were added, and 41.5 g (0.34 mol) of methyl vinylsulfonate was added to the flask from the dropping funnel at 25 to 27° C. The resultant mixture was continuously stirred at the same temperature for 2 days, and then the resultant reaction mixture was transferred to a 1 L separatory funnel. The reaction mixture was washed twice with 300 mL of water, and then unreacted furan was removed through evaporation under reduced pressure, to thereby obtain 22.0 g of methyl 7-oxabicyclo[2.2.1]hept-2-ene-5-sulfonate.
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:11]([C:13]1[CH:31]=[CH:30][C:16]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:29])=[C:24]([CH:28]=2)[C:25](Cl)=[O:26])=[O:18])=[CH:15][CH:14]=1)#[N:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:25](=[O:26])[C:24]2[CH:28]=[C:20]([NH:19][C:17](=[O:18])[C:16]3[CH:30]=[CH:31][C:13]([C:11]#[N:12])=[CH:14][CH:15]=3)[CH:21]=[CH:22][C:23]=2[CH3:29])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(N)cc1
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1ccc(NC(=O)c2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)cc1
Yield: 16.4 %

Procedure:
4-n-Propylaniline (0.11 g) was added to a stirred suspension of 5-(4-cyanobenzamido)-2-methylbenzoyl chloride (0.224 g), triethylamine (0.21 ml) and methylene chloride (5 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.049 g); NMR Spectrum: (DMSOd6) 0.87 (t, 3H), 1.56 (m, 2H), 2.33 (s, 3H), 2.48 (m, 2H), 7.13 (d, 2H), 7.28 (d, 1H), 7.63 (m, 2H), 7.83 (m, 3H), 8.01 (d, 1H), 8.1 (m, 2H); Mass Spectrum: M+H+ 398.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[CH:3]([NH:11][C@@H:12]([CH2:17][S:18]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:13]([O:15][CH3:16])=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[SH:18][CH2:17][C@H:12]([NH:11][CH:3]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)[C:2]([F:1])([F:38])[F:39])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccc(F)cc1)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CS)NC(c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a stirred solution of (2R)-methyl 2-((2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)-3-(tritylthio)propanoate (24.8 g; 44.8 mmol) in anhydrous dichloromethane (200 mL), previously cooled to in an ice-water bath under nitrogen, was added trifluoroacetic acid (14 mL; 20.7 g; 182 mmol; 405 mole %), followed by triethylsilane (14.4 mL; 10.5 g; 90.1 mmol; 200 mole %). The reaction mixture was stirred at ambient temperature for 2 h then concentrated in vacuo. The residue was redistilled from dichloromethane and the residue absorbed onto silica gel (30 g). The absorbed sample was applied to a column of SiO2 (660 g) and eluted with 2% ethyl acetate in hexane, gradually increased to 10% EtOAc in hexane to give 11.74 g (84.5%) of (2R)-methyl 3-mercapto-2-((2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)propanoate which was used directly in the next step. LC-MS, negative ion mode: m/z=310 [M−H]− (100%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[Br:12][C:13]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>C1COCC1>[Br:12][C:13]1[CH:21]=[CH:20][C:19]([S:22]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4]2)(=[O:24])=[O:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(S(=O)(=O)n2ccc3ccccc32)ccc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a cooled (20° C.) suspension of sodium hydride (6.59 grams, 164.74 mmol) in 20 mL of THF, was added solution of indole (6.24 grams, 53.33 mmol in 25 mL tetrahydrofuran), slowly over a period of 10 minutes, maintaining mass temperature at 25° C. under nitrogen atmosphere. The mass was diluted with tetrahydrofuran (20 mL). The reaction mixture was further stirred for 1 hour at the same temperature. Then added a solution of 2-bromo-5-chlorosulfonyl benzoic acid (20.01 grams, 66.81 mmol) in tetrahydrofuran (30 mL) slowly over a period of 10 minutes., The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was quenched onto 600 mL cold Water. The reaction mass was acidified with conc. hydrochloric acid to pH 2 and extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with brine solution (2×50 mL), water (2×100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 17.81 grams technical product. The material was used as such in the next step, with out further purification.