Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:6]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([C:30](O)=[O:31])[CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].B>C1COCC1>[CH2:33]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[N:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([CH2:30][OH:31])[CH2:10]1)=[O:8])[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)[C@H](C(=O)O)C1
Agent: B
Solvent: C1CCOC1
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)[C@H](CO)C1
Reaction time: 24 h
Yield: 97.8 %

Procedure:
1.24 g (2.44 mmole) of (S)-4-(dipentylcarbamoyl)-1-(diphenylcarbamoyl)piperazine-2-carboxylic acid dissolved in 6 ml of THF was cooled to 0° in an ice bath. To this 9 ml (9 mmole) of 1.0M borane solution in THF was slowly added during a 15 min. period. The resulting mixture was stirred for 24 hr at 25°. The excess hydride was destroyed carefully with 20 ml of a 1:1 mixture of THF and water. The aqueous phase was saturated with anhydrous potassium carbonate. The THF layer was separated and aqueous layer was extracted with ether. The combined organic phase was dried over magnesium sulfate. The solvents were removed on a rotary evaporator to yield 1.18 g (98%) of (S)-4-(dipentylcarbamoyl)-1-(diphenyl-carbamoyl)-2-(hydroxymethyl)piperazine as a white solid, mp 133°-134°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[N+:14]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:10]=[CH:11][C:3]=1[C:2]([F:13])([F:12])[F:1])([O-:16])=[O:15]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(CO)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 20 %

Procedure:
4-(Trifluoromethyl)benzoic acid (15 g, 78.9 mmol) in 90 mL of concentrated sulfuric acid was treated dropwise with a mixture of fuming nitric acid (2 mL) and sulfuric acid (24 mL). The reaction mixture was stirred at ambient temperature for 48 hours and quenched into ice-water. The resulting precipitate (12 g) was collected by filtration, washed with water and dried under reduced pressure. The resulting dry solid (12 g) was dissolved in THF (300 mL), cooled to 0° C., treated with 1M borane-tetrahydrofuran complex (80 mL) and stirred at ambient temperature overnight. Methanol (5 mL) was added dropwise followed by dropwise addition of concentrated HCl (5 mL), refluxed for 1 hour and evaporated to dryness and partitioned between water and diethyl ether. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 30% ethyl acetate hexanes to provide the title compound (3.6 g, 20% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:19]=[C:20]([NH2:22])[N:21]=3)[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Mg].II>CO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([C:15]([F:17])([F:16])[F:18])[CH2:12][N:11]3[N:19]=[C:20]([NH2:22])[N:21]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1nc2c(-c3ccc(F)c(F)c3)cc(C(F)(F)F)cn2n1
Agent: II
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc2n(n1)CC(C(F)(F)F)CC2c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 8-(3,4-difluorophenyl)-6-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (500 mg, 1.59 mmol) and magnesium (309 mg, 12.7 mmol) in methanol (80 mL) and THF (40 mL) was added iodine (2 mg, 7.88 μmol), stirred for 10 minutes at room temperature, then sonicated for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was dissolved in THF and dried over Na2SO4, then filtered off, washed thoroughly with THF and the solvents were evaporated. The crude material was purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as mixture of racemic diastereomers as white solid (324 mg, 64%).
Reaction SMILES: [CH2:1]([C:14]1[NH:18][CH:17]=[C:16]([C:19]([OH:21])=[O:20])[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(Cl)(=O)OCC.C(N(CC)CC)C.[Br:35][CH2:36][CH2:37]O.Cl>O1CCCC1>[CH2:1]([C:14]1[NH:18][CH:17]=[C:16]([C:19]([O:21][CH2:37][CH2:36][Br:35])=[O:20])[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCc1cc(C(=O)O)c[nH]1
Reactant: OCCBr
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCc1cc(C(=O)OCCBr)c[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.4 %

Procedure:
To a solution (20 ml) of 1.47 g (5.0 mmol) of 5-tridecylpyrrole-3-carboxylic acid in tetrahydrofuran were added 0.60 g (5.53 mmol) of ethyl chlorocarbonate and 0.60 g (5.94 mmol) of triethylamine, and the whole was stirred at room temperature for 10 minutes. After adding 1.88 g (15 mmol) of 2-bromoethanol, the mixture was heated under reflux for 1.5 hours. After further addition of 0.94 (7.5 mmol) of 2-bromoethanol, the mixture was heated under reflux for 9 hours. The resulting mixture was cooled, acidified with a diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. A removal of the solvent under reduced pressure afforded an oily product, which was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/10) to obtain 1.05 g (53% yield) of 2-bromoethyl 5-tridecylpyrrole-3-carboxylate, m.p. 67°-69.5° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[N:10]1[CH2:14][CH2:13][CH2:12]C1.C(N)(=[O:18])C=C>C(O)(=O)C.O>[NH:10]1[C:14](=[O:18])[CH2:13][CH2:12][C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:1][C:2]1=2
Reactant: C1=C(N2CCCC2)Cc2ccccc21
Reactant: C=CC(N)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC2=C(Cc3ccccc32)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(1H-inden-2-yl)-pyrrolidine (5.34 g) and acrylamide (6.15 g) is stirred in argon atmosphere at 100° C. for 30 min. The temperature is then rised to 130° C. and stirring continued for another 15 min. After cooling to room temperature, water (50 mL) and acetic acid (5 drops) are added and the mixture is stirred for 30 min. The mixture is filtered and the organic phase of the filtrate is separated and washed with brine. After drying (MgSO4) and evaporating the solvent, the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→0:1) to give a brown solid that is triturated with ethyl acetate and dried to afford the title compound. Yield: 1.12 g (21% of theory); Mass spectrum (ESI+): m/z=186 [m+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:25])[NH:11][N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=1.N>O>[Cl:34][C:29]1[CH:28]=[C:27]([N:11]2[C:10](=[O:25])[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:13]=[N:12]2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Cc2ccc(F)cc2)cc1
Agent: N
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 62 substituting 4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-bromo-2-chloro-1-fluorobenzene in place of 4-iodo-1-fluorobenzene (yield: 0.110 g, 74%). mp 153–156° C. 1H NMR (300 MHz, DMSO d6) δ 3.30 (s, 3H), 3.89 (bs, 2H), 7.02–7.07 (m, 4H), 7.59 (m, 1H), 7.65–7.72 (m, 4H), 8.07 (m, 2H), 8.12 (s, 1H). MS (DCI/NH3) m/z 487 (M+H)+, 504 (M+NH4)+. Anal. calc. for C24H17ClF2N2O3S.0.25 H2O: C, 58.65; H, 3.58; N, 5.64. Found: C, 58.41; H, 3.56; N, 5.36.
Reaction SMILES: [C:1](=[O:26])([O:23][CH2:24]Cl)[O:2][CH2:3][CH2:4][O:5][C:6](=[O:22])[C@H:7]([CH:19]([CH3:21])[CH3:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[I-:27].[Na+]>C(#N)C>[C:1](=[O:26])([O:23][CH2:24][I:27])[O:2][CH2:3][CH2:4][O:5][C:6](=[O:22])[C@H:7]([CH:19]([CH3:21])[CH3:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOC(=O)OCI
Temperature: 60 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a solution of 2-(N-CBz-L-valyloxy)-ethyl chloromethyl carbonate (3.88 g, 10 mmol) in acetonitrile (50 mL), was added sodium iodide (7.50 g, 50 mmol). The solution was stirred for 4 h at 60° C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH1Cl2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (Na2SO4) and concentrated under reduced pressure, to give 4.51 g 2-(N-CBz-L-valyloxy)-ethyl iodomethyl carbonate.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32](=O)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC=O
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
To a suspension of methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (500 mg, 1.20 mmol) in anhydrous DCE (8 mL) were added hexanal (0.25 mL, 2.07 mmol) and sodium triacetoxyborohydride (825 mg, 3.89 mmol). The reaction mixture was stirred at 70° C. for 3.5 hrs. Then the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×10 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure. Purification by flash chromatography on silicagel (cHex/EtOAc) gave 460 mg (77%) of the title compound as a pale yellow oil. HPLC, Rt: 6.3 min (purity: 99.9%). 1H NMR (CDCl3) δ: 7.47 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.18 (m, 5H), 6.95 (dd, J=10.1, 9.0 Hz, 1H), 6.74 (m, 1H), 4.52 (s, 2H), 3.91 (s, 3H), 3.38 (t, J=7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.60 (m, 4H), 1.42-1.25 (m, 8H), 0.92 (m, 6H).
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[C:8]([N+:17]([O-:19])=[O:18])=[C:9]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:10]([OH:12])=[O:11].[C:20]([O-])([O-])=O.[Na+].[Na+]>CO>[NH2:6][C:7]1[C:8]([N+:17]([O-:19])=[O:18])=[C:9]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:10]([O:12][CH3:20])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Cl)cc(C(=O)O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(N)c1[N+](=O)[O-]
Yield: 88.5 %

Procedure:
Concentrated H2SO4 (1.5 ml) was added to a mixture of 3-amino-5-chloro-2-nitrobenzoic acid (70; 3.5 g, 16.2 mmol) in MeOH (120 ml). The resulting reaction mixture was stirred under reflux for 3 days. It was then neutralized with saturated aqueous Na2CO3 and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography afforded methyl 3-amino-5-chloro-2-nitrobenzoate 71 (3.3 g, 88.5%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O1CCCC1.C([O-])(=O)C.[Na+].Cl.[NH2:30][OH:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=[N:30][OH:31])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccsc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: ON=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccsc21
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A 100 mL round bottomed flask charged with 4-(3,4-dichlorophenyl)-5,6-dihydro-1-benzothiophen-7(4H)-one (1.29 g, 4.34 mmol), tetrahydrofuran (11.0 mL) and ethanol (12.5 mL). The mixture was stirred and sodium acetate (1.117 g, 13.62 mmol) and hydroxylamine hydrochloride (0.9242 g, 13.30 mmol) were added. The mixture was stirred for 16 h at 50° C. under an atmosphere of Nitrogen. The reaction was then cooled to rt, giving a pale yellow solution with much white ppt. The reaction was quenched into ˜75 ml saline solution w/stirring and the resulting mixture was transferred to a separatory funnel and extracted with ethyl acetate (2×). the extracts were combined, washed with saline, dried over sodium sulfate, filtered, and evaporated to leave 1.27 g (94% yield) product as pale yellow powder. LCMS: (FA) ES+ 312, 314. 1H NMR indicated that the product was an ˜3:1 mixture of geometric oxime isomers.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]#[N:24])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:25][CH3:26])=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH2:24])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:25][CH3:26])=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c3c(OCC#N)cccc3n(Cc3ccccc3)c2c1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c3c(OCCN)cccc3n(Cc3ccccc3)c2c1
Temperature: 40 °C
Yield: 57.7 %

Procedure:
To a mixture of [(9-benzyl-7-methoxy-9H-carbazol-4-yl)oxy]acetonitrile (0.9 g, 2.6 mmol) in dry THF (50 mL) is added borane-methylsulfide complex (0.75 mL, 7.9 mmol). The mixture is heated at 40° C. overnight. Methanol is slowly added to mixture until addition of methanol did not evolve gas. The solvents are removed under reduced pressure. Methanol (50 mL) is added to the residue then removed under reduced pressure. Methanol (100 mL) and concentrated hydrochloric acid (3 mL) is added to the residue. The mixture is heated at 75° C. for 2.5 h. The mixture is neutralized with saturated potassium carbonate and partitioned between water and ethyl acetate. The layers are separated and the organic layer washed twice with brine. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography, silica gel (100 mL) using CH2Cl2: CH3OH (95:5) as eluent gave 0.52 g (58%) of the title compound; 1H NMR (DMSO-d6) δ2.48, 3.8, 4.12, 5.59, 6.69, 6.8, 7.14, 7.2, 8.03; Anal. Calcd for C22H22N2O2: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.00; H, 6.54; N, 7.92.
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:19])=[C:8]([CH3:18])[CH2:9][CH2:10][CH2:11][CH2:12]CS([O-])(=O)=O.[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.C(=O)([O-])O.[Na+]>O>[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([O:31][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([CH3:18])=[C:7]([F:6])[F:19])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: CC(CCCCCS(=O)(=O)[O-])=C(F)F
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCCCOC(=O)c1ccc2[nH]ccc2c1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To 7 ml of N,N-dimethylformamide were dissolved 0.68 g (3.0 mmol) of 6,6-difluoro-5-methyl-5-hexenylmethanesulfonate and 0.58 g (3.6 mmol) of 1H-indole-5-carboxylic acid, followed by the addition of 0.75 g (8.9 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:3) to obtain 0.81 g (yield: 93%) of 6,6-difluoro-5-methyl-5-hexenyl 1H-indole-5-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].N1C=CC=CC=1.[O:19]1[CH2:24][CH2:23][N:22]([S:25](Cl)(=[O:27])=[O:26])[CH2:21][CH2:20]1>C(#N)C>[O:19]1[CH2:24][CH2:23][N:22]([S:25]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[C:7]3[OH:12])(=[O:27])=[O:26])[CH2:21][CH2:20]1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: Nc1cccc2c(O)cccc12
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2c(O)cccc12)N1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of 4.8 g. of 5-amino-1-naphthol in 210 ml. of acetonitrile were added 2.5 ml. of pyridine and a mixture of 75 ml. of acetonitrile and 5.6 g. of morpholinosulfonyl chloride was added dropwise thereto under stirring and ice-cooling. Stirring was continued at room temperature for 2 hours and reaction was conducted at 40° C. for 1 hour. The mixture was concentrated and the residue was added to about 150 ml. of water containing 3 ml. of conc. hydrochloric acid. The precipitate thus separated was recovered by filtration, washed with water and then dried to give 6.7 g. of the desired product with m.p. 220°-223° C. (with dec.).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH3:22])=[C:12]([F:23])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)=O.O.[NH2:25][NH2:26]>CCO>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]2[C:5]([C:3]([NH:25][NH2:26])=[O:2])=[CH:6][C:7]3[NH:11][CH:10]=[N:9][C:8]=3[C:12]=2[F:23])=[C:16]([CH3:22])[CH:17]=1
Reactant: COC(=O)c1cc2nc[nH]c2c(F)c1Nc1ccc(Br)cc1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(Br)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Yield: 80.3 %

Procedure:
6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8a (0.051 g, 0.135 mmol) is suspended in EtOH (5 mL) and hydrazine hydrate (0.118 g, 2.023 mmol) is added. The reaction mixture is heated at reflux for 16 hours. The reaction mixture is concentrated under reduced pressure and purified by FCC eluted with 97:3 ethyl acetate:MeOH to give 0.041 g (81%) of clean desired product: LC/MS ESI (+) m/z 378, 380 (M+ Br pattern) detected.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:19]
Reactant: NCCN1CCSCC1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)NCCN2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 150 ml of methylene chloride under nitrogen atmosphere add 3.1 g (14.3 mmole) of 4-thiomorpholinethanamine and 4.42 g (43.6 mmole) of triethylamine. Stir the mixture at ambient temperature for 1 hour, then cool the mixture to -10° C. To the cooled mixture add slowly 3.67 g (15.1 mmole) of 4-[(methylsulfonyl)amino]benzoyl chloride, keeping the temperature below 5° C. When the addition is complete, allow the reaction mixture to stir at ambient temperature. Monitor the progress of the reaction by thin layer chromatography on silica gel (acetonitrile:ammonium hydroxide, 9:1). Upon completion of the reaction, remove the solvent in vacuo. To the resulting solid add 50 ml of water. To the mixture add 50% sodium hydroxide until pH of 14 is reached. Wash the aqueous layer with 3×50 ml of diethyl ether. Add concentrated hydrochloric acid until a white precipitate forms (pH=8.5). Filter the solid and recrystallize from methanol/ethanol to yield the title compound.
Reaction SMILES: [CH3:1][C:2](/[CH:4]=[N:5]/O)=O.[CH3:7][C:8]1([CH3:16])[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]1>OC(C)=O.O.[Zn]>[CH3:1][C:2]1[C:11]2[C:10](=[O:15])[CH2:9][C:8]([CH3:7])([CH3:16])[CH2:13][C:12]=2[NH:5][CH:4]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CC(=O)/C=N/O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Yield: 44.2 %

Procedure:
To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H2O (7:3, 200 mL) was added zinc powder (14.95 g, 2 eq) slowly with cooling by a water bath at room temperature. The mixture then was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then the mixture was extracted with dichloromethane (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated. The crude product was purified by flash chromatography eluting with 5% ethyl acetate in dichloromethane. The combined organic fractions were concentrated, triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give the pure title compound (9 g, 45% yield) as a solid. LCMS m/z: (M+H)=178.1.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1>>[CH3:10][C:11]1[N:16]=[C:15]([S:17][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[N:14]=[C:13]([OH:18])[CH:12]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1ccccn1
Agent: Br
Product: Cc1cc(O)nc(SCc2ccccn2)n1
Yield: 86 %

Procedure:
As per procedure from Example 1, 2-(bromomethyl)pyridine hydrobromide and 6-methyl-2-sulfanylpyrimidin-4-ol were combined to provide the title compound as a white solid (86% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.68 (s, 3H), 4.47 (s, 2H), 6.00 (s, 1H), 7.25 (dd, 1H), 7.47 (d, 1H), 7.72 (dd, 1H), 8.50 (d, 1H); M+234.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C)C=O>[CH:12]1([NH:18][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)cc1NC1CCCCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 19.1 %

Procedure:
A mixture of 15.09 g (78 mmol) 2,4-dichloronitrobenzen, 7.7 g (78 mmol) cyclohexylamine, 7.9 g (78 mmol) triethylamine and 100 ml dimethylformamide was stirred at 80° C. for 3 h. After cooling to 25° C. the mixture was evaporated, dissolved in 200 ml ether and filtered. The ether solution was washed with water and evaporated to the half volume. The precipitate was filtered off to give 3.8 g (19%) N-cyclohexyl-2-nitro-5-chloraniline. M.p. 124.5° C. 1H-NMR (CDCl3): 8.2 (2H, m), 6.8 (1H, d), 6.5 (1H, dd), 3.5 (1H, broad s), 2.4-0.8 (10H, m).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](N1C=CN=C1)=[S:8].Cl.[CH3:15][O:16][C:17](=[O:27])[CH:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19]>CN(C)C=O>[CH3:15][O:16][C:17](=[O:27])[CH:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:19][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[S:8]
Reactant: S=C(Nc1nccs1)n1ccnc1
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)NC(=S)Nc1nccs1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A solution of 1-[(2-thiazolyl)thiocarbamoyl]imidazole (4.21 g, 20.0 mmol) and DL-phenylalanine methyl ester hydrochloride (4.31 g, 20.0 mmol) in N,N-dimethylformamide (150 mL) was heated at 90° C. for 3 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystalllized from ether-hexanes to provide 3.26 g (51%) of the titled product: