Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13](S(C2C=CC=CC=2)(=O)=O)[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:34][S:35]SC.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.O>[CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[S:35][CH3:34])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: CSSC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CSc1[nH]c2ccccc2c1C(=O)NCc1ccccc1
Temperature: -20 °C
Yield: 85.9 %

Procedure:
A solution of the above N-benzyl-1-(phenylsulfonyl)indole-3-carboxamide [XXIV: R8 =CH2Ph] (4.2 g, 11 mmol) in dry THF (200 mL) was treated at -78° C. with a solution of 2.5M n-BuLi in hexanes (9.1 mL, 23 mmol), and the stirred mixture was allowed to warm to -20° C. for 15 minutes, before being recooled to -78° C., when it was treated with methyldisulfide (2.5 mL, 28 mmol). The mixture was allowed to warm to 20° C., then quenched with water (25 mL). Volatiles were removed under reduced pressure, and the residue was extracted with EtOAc. Workup of the organic layer gave a crude product. This was dissolved in MeOH (300 mL), mixed with a solution of K2CO3 (6.9 g, 50 mmol) in water (125 mL), and heated under gentle reflux under N2 for 2 hours to ensure complete hydrolysis of the phenylsulfonyl group (J. Org. Chem. 1985;50:5451-5457). MeOH was removed under reduced pressure, and the residue was diluted with water and extracted with CH2Cl2. Chromatography of the resulting oil on Al2O3 (eluting with CH2Cl2) gave N-benzyl-2-(methylthio)indole-3-carboxamide [XXV: R8 =CH2Ph] (2.8 g, 88% yield) as an oil.
Reaction SMILES: [C:1](Cl)(=O)OCC.[C:7]([OH:17])(=O)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ClCCl.[CH3:21][O:22][C:23]([CH2:25][C@H:26]([NH2:30])[C:27](O)=[O:28])=[O:24].Cl>C(N(CC)CC)C>[C:7]([NH:30][CH:26]([C:27](=[O:28])[CH3:1])[CH2:25][C:23]([O:22][CH3:21])=[O:24])(=[O:17])[CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C[C@H](N)C(=O)O
Reactant: CCOC(=O)Cl
Reactant: O=C(O)C=Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(NC(=O)C=Cc1ccccc1)C(C)=O

Procedure:
Ethyl chlorocarbonate (2.0 ml) was added dropwise to a mixture of cinnamic acid (2.96 g), dichloromethane (60 ml) and triethylamine (2.8 ml) under cooling with ice-sodium chloride and stirring, and the whole mixture was stirred for 10 minutes. L-Aspartic acid β-methyl ester hydrochloride (3.67 g) was added and triethylamine (5.6 ml) was further added dropwise. The resulting mixture was stirred at room temperature for 40 minutes, washed with 2N hydrochloric acid and water and dried over anhydrous magnesium sulfate. The solvent was then distilled off. To the thus-obtained N-cynnamoyl-L-aspartic acid β-methyl ester were added acetic anhydride (15 ml), triethylamine (15 ml) and 4-dimethylaminopyridine (0.2 g) and the mixture was stirred for 30 minutes, poured into water, stirred for 10 minutes for decomposition and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was treated with isopropyl ether to give methyl 3-cinnamoylamino- 4-oxovalerate as crystals; yield 2.65 g (48.1%). Recrystallization from ethyl ether gave colorless needles melting at 82°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.[CH3:14][C:15]1C=CC(S(OCCC=C)(=O)=O)=[CH:17][CH:16]=1>>[CH2:17]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc2c(c1)CCNC2=O
Product: C=CCCN1CCc2cc(OC)ccc2C1=O

Procedure:
The title compound 49 is prepared according to the procedure reported in step B of Example 8 with amide 42 (0.32 g, 1.8 mmol) and but-3-enyl 4-methylbenzenesulfonate (1.63 g, 4 equiv) as reactants. Yellow oil. (Yield 0.29 g, 69%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]C)[N:3]=1.B(Br)(Br)Br>ClCCl>[CH3:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[N:3]=1
Reactant: COc1ccccc1C=C1N=C(C)N(C)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1=NC(=Cc2ccccc2O)C(=O)N1C
Temperature: -40 °C
Yield: 91.6 %

Procedure:
3,5-Dihydro-2,3-dimethyl-5-(2′-methoxybenzylidene)imidazol-4-one (2 g) was dissolved in dichloromethane (30 ml) and boron tribromide (2 ml) was added dropwise while stirring the mixture at −40° C. Thereafter, the reaction mixture was stirred under ice-cooling for 1 hr, and the reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3,5-dihydro-2,3-dimethyl-5-(2′-hydroxybenzylidene)imidazol-4-one (1.72 g) as red crystals. The crystals and (S)-glycidyl nosylate (2 g) were dissolved in dimethylformamide (20 ml) and potassium carbonate (2.2 g) was added. The mixture was heated at 50° C. for 3 hr, and the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily product (2.27 g). This oily product and 4-(naphthalen-2-yl)piperidine were dissolved in methanol (20 ml) and the mixture was refluxed under heating for 2 hr. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.25 g) as an oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:10]([C:20]#[N:21])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.CCN(CC)CC.[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:29][N:30]([CH3:35])[S:31](=[O:33])(=[O:32])[O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[CH:8]=[CH:9][C:10]=2[C:20]#[N:21])=[CH:14][CH:15]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N#Cc1ccc(Cn2cncn2)cc1-c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)Oc1ccc(-c2cc(Cn3cncn3)ccc2C#N)cc1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
To a white suspension of 19 (0.075 g, 0.271 mmol) and NEt3 (0.292 mL, 2.71 mmol) in anhydrous CH2Cl2 (2 mL) at 0° C. under an inert atmosphere was added to a colourless solution of N,N-dimethylsulfamoyl chloride (0.408 mL, 3.80 mmol) in anhydrous CHACl2 (3 mL). The resulting white suspension was left to stir under an inert atmosphere at room temperature for 70 h forming a clear orange/brown solution. The reaction mixture was diluted in CH2Cl2 (30 mL) and washed with distilled H2O (30 mL×3) and brine (30 mL). The organic fraction was separated, dried (MgSO4), filtered and solvent removed in vacuo to leave yellow residues. Column chromatography (CH2Cl2/acetone 75:25) eluted 21 as a viscous yellow oil (0.093 g, 90%); 1H NMR δH (270 MHz, CDCl3) 3.00 (s, 6H), 5.44 (s, 2H), 7.28-7.33 (m, 2H), 7.39 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H), 7.76 (d, J=7.9 Hz, 1H), 8.00 (s, 1H) and 8.18 (s, 1H); LCMS (APCI−) m/z (rel intensity) 382 (100, [M−H]+; HRMS (ES+) m/z calcd. for C18H18N5O3S [M+H]+: 384.1125, found 384.1143.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2](=[O:3])([O:14][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCCCCCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCOC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Chloroethyl chloroformate (10.0 g, 69.9 mmol) and 1-hexanol (6.5 g, 63.6 mmol) were dissolved in chloroform (80 ml) at 0° C. Pyridine (5.5 g, 69.5 mmol) was added dropwise during 17 minutes maintaining the temperature below 10° C. After stirring at room temperature for 20 hours the organic phase was washed three times with 1 normal hydrochloric acid, once with a saturated sodium hydrogen carbonate solution and finally twice with water. The organic solution was dried with magnesium sulfate and the solvent was removed at reduced pressure. The residue (11.6 g) was distilled in vacuo (Bp. 61°-72° C., 3×10-3 mbar). Yield: 9.0 g. 1H-NMR (CDCl3): delta=0.89 (CH2CH3); 1.28-1.40 (CH2CH2CH×2CH3); 1.69 (OCH2CH2); 1.83 (CH3CH); 4.20 (OCH2); 6.43 ppm (CH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=O)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCOC.CC1C=CC(S([CH2:33][N+:34]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>CCO>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([C:33]#[N:34])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(C#N)C2
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300 mg, 1.33 mmol) was added DME (9 mL) and EtOH (0.2 mL). The mixture was cooled to 0 C when TOSMIC (530 mg, 2.65 mmol) and potassium tert-butoxide (609 mg, 5.2 mmol) were added. The mixture was stirred to room temperature and then heated at 50 C for 18 h. After this time the reaction was evaporated and loaded onto a silica column and eluted with heptane-10% to 30% ethyl actetate to give the title compound (216 mg, 69%). Method B HPLC-MS: MH+ requires m/z=237. Found: m/z=237, Rt=1.35 min (86%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]1[CH2:12][C:11]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:10][O:9][C:8]1=[O:28].O.CCO[CH2:42][CH3:43].[CH3:44][N:45]([CH:47]=O)[CH3:46]>>[Cl-:26].[Cl:27][C:22]1[CH:21]=[C:20]([C:11]2([CH2:13][CH2:14][N+:45]34[CH2:47][CH2:29][C:5]([C:43]5[CH:42]=[CH:30][CH:31]=[CH:3][CH:2]=5)([CH2:6][CH2:46]3)[CH2:4][CH2:44]4)[CH2:10][O:9][C:8](=[O:28])[N:7]([CH2:6][C:5]3[CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:4]=3)[CH2:12]2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CCOCC
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Solvent: O
Product: O=C1OCC(CC[N+]23CCC(c4ccccc4)(CC2)CC3)(c2ccc(Cl)c(Cl)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: [Cl-]
Temperature: 60 °C

Procedure:
A mixture of 0.53 g of 4-phenyl-1-azabicyclo[2.2.2octane and 1.4 g of the compound obtained in step C of EXAMPLE 4 in 5 ml of DMF is heated at 60° C. for 5 hours. After cooling to RT, the reaction mixture is poured into water and extracted with DCM, the organic phase is washed twice with 2 N HCl solution and three times with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM and then a DCM/MeOH mixture (92/8; v/v) as the eluent. The product obtained is taken up with ether and the precipitate formed is wrung to give 0.21 g of the expected product. M.p.=138° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[O:7]1[CH2:9][CH:8]1[C:10]([O:12][CH3:13])=[O:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[OH:7][CH:8]([CH2:9][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C1CO1
Reactant: Ic1cn[nH]c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C(O)Cn1cc(I)cn1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 4-iodo-1H-pyrazole (10 g, 51 mmol), methyl oxirane-2-carboxylate (6.8 g, 67 mmol) and tripotassium phosphate (12 g, 57 mmol) in dioxane (80 mL) was stirred at 90° C. for 4 hours. After cooling to room temperature, the mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc) to afford methyl 2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)propanoate. MS ESI calc'd. for C7H10IN2O3 [M+H]+ 297. found 297. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=3.2 Hz, 2H), 4.51-4.46 (m, 3H), 4.27-4.25 (m, 1H), 1.31-1.28 (m, 3H).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][C:13]([C:20]([OH:22])=[O:21])=[C:12]2[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1.O1[CH2:37][CH2:36][CH2:35]C1>CN(C)C=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][C:13]([C:20]([O:22][C:36]([CH3:35])([CH3:37])[CH3:1])=[O:21])=[C:12]2[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C1CCOC1
Reactant: COc1ccc(-c2c(C(=O)O)[nH]c3cc(OC)c(OC)cc23)cc1OC
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C(=O)OC(C)(C)C)[nH]c3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Yield: 70 %

Procedure:
N,N-Dimethylformamide (3 drops) and oxalyl chloride (0.59 ml) were added to a solution of 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylic acid (2.0 g) in tetrahydrofuran (50 ml). The mixture was stirred for an hour at room temperature and concentrated under reduced pressure. The residue was dissolved in benzene (20 ml). This benzene solution was added to a solution of tert-butanol (0.79 ml) and N,N-dimethylaniline (0.85 ml) in benzene (30 ml), followed by stirring overnight at room temperature. The mixture was successively washed with water, sodium hydrogen carbonate saturated aqueous solution and water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from acetone to give tert-butyl 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (1.61 g, 70%) as colorless prisms.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][C:5]=1[Cl:15].[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>ClCCl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][C:5]=1[Cl:15]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(I)c(NC(C)=O)cc1Cl
Solvent: ClCCl
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(NC(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 209.5 %

Procedure:
To a stirred solution of 2-Chloro-4-acetamido-5-iodobenzoic acid methyl ester (2.5 g, 2.8 mmol) in dichloromethane (15.0 mL) were cuprous iodide (0.135 g, 0.71 mmol) and dichloro(bistriphenylphosphine)palladium(II) (0.25 g, 0.31 mmol). The mixture was cooled in an ice bath and added ethynyltrimethylsilane (0.825 g, 8.4 mmol). The resulting mixture was stirred under nitrogen at room temperature for 16 h. The mixture was diluted with dichloromethane (15.0 mL), washed with 5% citric acid, followed by water and dried (MgSO4). After the removal of the solvent, mixture was purified by silica gel flash chromatography using 20% ethyl acetate in heptane to afford the title compound as a light brown powder (1.9 g, 86%), m/z=252 (MH+—SiMe3).
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]([CH3:13])([CH3:12])[CH3:11].[N+:17]([O-:20])([OH:19])=[O:18]>OS(O)(=O)=O>[C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:17]([O-:19])=[O:18])[C:6]([F:9])=[CH:5][C:4]=1[C:10]([CH3:11])([CH3:12])[CH3:13].[C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[C:8]([N+:17]([O-:20])=[O:18])=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]([CH3:11])([CH3:12])[CH3:13]
Reactant: COC(=O)Oc1ccc(F)cc1C(C)(C)C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)Oc1c([N+](=O)[O-])cc(F)cc1C(C)(C)C
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 12 %
Yield: 55 %

Procedure:
To a solution of 2-tert-butyl-4-fluorophenyl methyl carbonate (1.81 g, 8 mmol) in H2SO4 (98%, 1 mL) was added slowly a cooled mixture of H2SO4 (1 mL) and HNO3 (1 mL) at 0° C. The mixture was stirred for 2 h while warming to room temperature, poured into ice and extracted with diethyl ether. The ether extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (0-10% EtOAc-Hexane) to give 2-tert-butyl-4-fluoro-5-nitrophenyl methyl carbonate (C-7-a) (1.2 g, 55%) and 2-tert-butyl-4-fluoro-6-nitrophenyl methyl carbonate (C-6-a) (270 mg, 12%). 2-tert-Butyl-4-fluoro-5-nitrophenyl methyl carbonate (C-7-a): 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J=7.1 Hz, 1H), 7.55 (d, J=13.4 Hz, 1H), 3.90 (s, 3H), 1.32 (s, 9H). 2-tert-butyl-4-fluoro-6-nitrophenyl methyl carbonate (C-6-a): 1H NMR (400 MHz, DMSO-d6) δ 8.04 (dd, J=7.6, 3.1 Hz, 1H), 7.69 (dd, J=10.1, 3.1 Hz, 1H), 3.91 (s, 3H), 1.35 (s, 9H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([C:21]#[N:22])(C)C.C(N(CC)CC)C.C(O)C>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:21]#[N:22])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)[Si](C)(C)OCc1cc[n+]([O-])cc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(C#N)c1

Procedure:
A solution of 37.9 g of 4-(tert-butyl-dimethylsilyloxymethyl)-pyridine-N-oxide, 84 ml of trimethylsilyl cyanide and 44 ml triethylamine is stirred under nitrogen at reflux for 21/2 hours Dark solution is cooled in an ice bath, then 40 ml of ethanol added followed by 500 ml of ethyl acetate. The solution is washed twice with water, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using ethyl acetate/hexane (1:10) to yield 4-(tert-butyl-dimethylsilyloxymethyl)-2-cyanopyridine.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1Br.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[C:21]([F:27])[CH:20]=1.[OH-].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1[O:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][C:21]=1[F:27]
Reactant: O=c1c(Br)c(Br)cnn1-c1ccc(Cl)c(Cl)c1
Reactant: OCc1ccc(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(Br)c(OCc2ccc(Cl)cc2F)cnn1-c1ccc(Cl)c(Cl)c1
Reaction time: 24 h
Yield: 54.2 %

Procedure:
To a mixture of 2.0 g (5.0 m mol) of 4,5-dibromo-2-(3,4-dichlorophenyl)-3(2H)-pyridazinone and 0.84 g (5.2 m mol) of 4-chloro-2-fluorobenzyl alcohol was added 80 ml of N,N-dimethylformamide. The resulting mixture was cooled with ice, incorporated with 0.4 g of potassium hydroxide and then stirred for one day. Then, the procedures in Synthesis Example 2 were repeated to give a crude product. The crude product was recrystallized from benzene to give 1.3 g of the intended compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH:24]=[O:25])=[CH:4][CH:3]=1.[CH3:28][Mg]Br>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH:24]([OH:25])[CH3:28])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CCC(C=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(C)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a solution of 2-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]butanal (333 mg, 0.790 mmol) in tetrahydrofuran (8 mL) was added dropwise methylmagnesium bromide (3 M solution in diethyl ether, 0.395 mL, 1.19 mmol) at −78° C., and the mixture was stirred at −78° C. for 1 h. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous solid (192 mg, 0.437 mmol, 55%).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([CH3:15])([CH3:14])[C:6](=O)[CH:7]=[C:8](SC)[S:9][CH3:10].CS>C(O)C>[C:5]([C:6]1[CH:7]=[C:8]([S:9][CH3:10])[NH:3][N:2]=1)([CH3:15])([CH3:14])[CH3:4]
Reactant: NN
Reactant: CSC(=CC(=O)C(C)(C)C)SC
Agent: CS
Solvent: CCO
Solvent: O
Product: CSc1cc(C(C)(C)C)n[nH]1
Yield: 48 %

Procedure:
Hydrazine hydrate (4 g, 3.9 ml) was added dropwise to a cooled solution of the product of Example 1 (15 g) in ethanol (75 ml). The reaction mixture was refluxed until evolution of methyl mercaptan ceased (2 hours), and allowed to cool. Most of the ethanol was evaporated off, and the residue was pitched into water, and ether extracted. The ethereal solution was dried over magnesium sulphate, and evaporated to give a pale yellow solid, which was recrystallised from 1:1 benzene/60°-80° petrol to give 3-t-butyl-5-(methylthio)pyrazole, 6.0 g, (48% yield), melting point 142°-4°.
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[N:9][N:10]=1)=[O:5])C.[CH2:29]([NH2:34])[CH2:30][CH:31]([CH3:33])[CH3:32].[C-]#N.[Na+]>>[CH3:32][CH:31]([CH3:33])[CH2:30][CH2:29][NH:34][C:4]([C:6]1[S:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:25])([F:27])[F:26])[CH2:13][CH2:12]2)=[N:9][N:10]=1)=[O:5]
Reactant: CC(C)CCN
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Agent: [C-]#N
Agent: [Na+]
Product: CC(C)CCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-[4-(2-Trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester (0.100 g, 0.24 mmol) was added to the mixture of isoamylamine (2 mL) and sodium cyanide (0.023 g, 0.48 mmol). The reaction mixture was stirred for 16 hours at room temperature and then evaporated to dryness. The residue was redissolved in 50 mL of ethyl acetate and the solution was washed sequentially with water (2×15 mL), brine (2×15 mL), then dried over anhydrous Na2SO4, and concentrated. The title compound was obtained as a white powder in quantitative yield (0.110 g). 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J=7.8 Hz, 1H), 7.62 (dd, J=7.5, 7.5 Hz, 1H), 7.55 (dd, J=7.5, 7.5 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.01 (t, J=7.8 Hz, 1H), 4.03-4.08 (m, 1H), 3.85-3.91 (m, 1H), 3.62-3.74 (m, 2H), 3.51-3.55 (m, 2H), 3.40-3.46 (m, 2H), 3.32-3.35 (m, 2H), 1.61-1.69 (m, 2H), 1.45-1.51 (m, 1H), 0.92 (d, J=6.6 Hz, 6H). MS (ES+) m/z 456.4 (M+1).