Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([OH:11])[C:8]([OH:12])=[C:7]([OH:13])[CH:6]=1)[CH3:2].[C:15](=O)([O-])[O-].[K+].[K+].BrCBr>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]2[O:12][CH2:15][O:13][C:7]=2[CH:6]=1)=[O:14])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(O)c(O)c(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: BrCBr
Product: CCOC(=O)c1cc(O)c2c(c1)OCO2
Temperature: 60 °C

Procedure:
5 g (25.2 mmol) of 3,4,5-Trihydroxy-benzoic acid ethyl ester was dissolved in 50 ml of DMF and treated at 0° C. with 13.95 g (101 mmol) of potassium carbonate and 4.39 g (25.2 mmol) of dibromomethane. The reaction solution was heated at 60° C. for 3 h. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (3/1).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([OH:25])[CH:23]=3)[CH:18]=[N:17]2)=[CH:12][CH:11]=1.C1COCC1.O>CCOC(C)=O>[Br:8][C:23]1[C:22]([OH:25])=[CH:21][CH:20]=[C:19]2[C:24]=1[N:16]([C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1)[N:17]=[CH:18]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccc2cnn(-c3ccc(F)cc3)c2c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc2cnn(-c3ccc(F)cc3)c2c1Br
Reaction time: 1 h
Yield: 62.9 %

Procedure:
NBS (16.2 g, 91 mmol) was added in one portion to a solution of 1-(4-fluorophenyl)-1H-indazol-6-ol (96, R1=4-Fluorophenyl) (20.3 g, 89 mmol) and THF (500 mL) under a nitrogen atmosphere at about 0° C. After about 1 h, water (500 mL) and EtOAc (400 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting solid was slurried in DCM (50 mL) then collected by filtration rinsing with DCM (4×25 mL). The solid was dried to afford 7-bromo-1-(4-fluorophenyl)-1H-indazol-6-ol (97, R1=4-Fluorophenyl) (17.2 g, 63% yield) as a faint orange solid. LC/MS, method 3, Rt=2.02 min, MS m/z 307 and 309 (M+H)+. 1H NMR (400 MHz, DMSO) δ 10.52 (d, J=0.9 Hz, 1H), 8.20 (d, J=0.9 Hz, 1H), 7.67 (dd, J=8.6, 0.9 Hz, 1H), 7.54-7.47 (m, 2H), 7.38-7.29 (m, 2H), 6.95 (dd, J=8.6, 0.9 Hz, 1H).
Reaction SMILES: C([CH:3]([C:38]([OH:40])=[O:39])[N:4]([C:19]([C:21]1[C:22]([CH3:37])=[N:23][N:24]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=2[Cl:36])[CH:25]=1)=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:7]([C:17]#[N:18])[CH:6]=1)C.[OH-].[Na+]>C(O)C>[Cl:36][C:27]1[CH:28]=[CH:29][C:30]([C:32]([F:34])([F:35])[F:33])=[CH:31][C:26]=1[N:24]1[CH:25]=[C:21]([C:19]([N:4]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[C:7]([C:17]#[N:18])[CH:6]=2)[CH2:3][C:38]([OH:40])=[O:39])=[O:20])[C:22]([CH3:37])=[N:23]1
Reactant: CCC(C(=O)O)N(C(=O)c1cn(-c2cc(C(F)(F)F)ccc2Cl)nc1C)c1ccc(OCC(C)(C)C)c(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(-c2cc(C(F)(F)F)ccc2Cl)cc1C(=O)N(CC(=O)O)c1ccc(OCC(C)(C)C)c(C#N)c1
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
Ethyl N-[1-(2-Chloro-5-trifluoromethylphenyl)-3-methylpyrazol-4-ylcarbonyl]-N-(3-cyano-4-neopentyloxyphenyl)glycine (1.8 g) was added to ethanol (15 ml). 10% aqueous sodium hydroxide solution (15 ml) was added and the mixture was stirred at a refluxing temperature for 30 min. The solvent was evaporated under reduced pressure, and dilute hydrochloric acid was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of chloroform-n-hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of diisopropyl ether-n-hexane to give the title compound (1.2 g), melting point: 189–190° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([NH:8][C:9](=O)[CH3:10])[C:6]#[N:7])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:8]=[C:9]([CH3:10])[S:22][C:6]=1[NH2:7])=[O:12])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C#N)NC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(C)sc1N
Yield: 115.5 %

Procedure:
To a solution of acetylamino-cyano-acetic acid ethyl ester (27.2 g, 0.160 mol) in anhydrous toluene (300 mL) was added Lawesson's reagent (32.0 g, 0.079 mol) and the resulting mixture heated at reflux for 18 h. The resulting yellow suspension was partitioned between an aqueous solution of HCl (1 M) and tert-butyl methyl ether. The layers were separated and the organic layer extracted with an aqueous solution of HCl (1 M). The combined aqueous layers was basified to pH 10 with an aqueous solution of NaOH (2 M), then extracted with EtOAc. The organic layer was isolated, dried (Na2SO4) and concentrated in vacuo to give the title compound as a pale yellow solid (17.0 g, 57%).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C[O-].[Na+]>CO>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[O:18][C:2]32[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]3=[O:11])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1c2ccccc2CC1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2ccccc2CC12OC2c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-bromo indanone and 5 g. of p-chloro-benzaldehyde in 20 ml of methanol under nitrogen is added at 5° to 10°C a solution of sodium methoxide in methanol (prepared by dissolving 1.15 g. of sodium in 50 ml of methanol). After 2 hours, 3'-(p-chlorophenyl)-spiro[indan-2,2'-oxirane]-1-one precipitates and is filtered off and recrystallized from methanol.
Reaction SMILES: N1C2C(=CC=CC=2)C(CCC(C2C=CC=CC=2)=O)=C1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][CH2:30]/[C:31](/[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][CH2:30]/[C:31](/[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:32]\[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:21]1
Reactant: CCOC(=O)/C=C(/CCc1c[nH]c2ccccc12)c1ccccc1
Agent: O=C(CCc1c[nH]c2ccccc12)c1ccccc1
Product: CCOC(=O)/C=C(\CCc1c[nH]c2ccccc12)c1ccccc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(1H-indol-3-yl)-1-phenylpropan-1-one, (Z)-ethyl 5-(1H-indol-3-yl)-3-phenylpent-2-enoate and (E)-ethyl 5-(1H-indol-3-yl)-3-phenylpent-2-enoate were obtained as light tan oils.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][OH:14])[CH2:8][CH2:7]1.C(N(CC)CC)C.O>CS(C)=O>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]=[O:14])[CH2:8][CH2:7]1
Reactant: OCC1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=CC1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.3 %

Procedure:
To a solution of {1-[2,4-bis(trifluoromethyl)benzyl]azepan-4-yl}methanol (901.4 mg) and triethylamine (1.06 mL) in DMSO (1.01 mL) was added sulfur trioxide pyridine complex (1.21 g). The reaction mixture was stirred at room temperature for 1.5 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (289.8 mg).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH2:18]([N:6]1[CH2:7][CH:8]([NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1CC(NC(=O)OC(C)(C)C)CN1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC(C(=O)O)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-Benzyl-4-tert-butoxycarbonylamino-pyrrolidine-2-carboxylic methyl ester and LiOH are dissolved in THF/H2O, and the resulting mixture is stirred for about 5 hours at room temperature. After removal of the solvent, the PH is adjusted to 6-7. The solid is collected and dried to afford 1-benzyl-4-tert-butoxycarbonylamino-pyrrolidine-2-carboxylic acid (40).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Mg]Br.[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:13][CH:12]=1
Reactant: Brc1ccc(I)cc1
Reactant: Cc1ccccc1[Mg]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(Br)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A stirred solution of 21.0 mL of (2-methylphenyl)magnesium bromide (42.0 mmol, 2.0M in diethyl ether) was evaporated in situ at room temperature. The syrupy residue was redissolved in 50 mL of THF and cooled to -20° C. under argon. To this solution was added a solution of 6.84 g (50.0 mmol) of thricefused zinc chloride. The resulting thick white slurry was warmed to room temperature and stirred for 1 hour. After cooling to -78° C., a solution of 11.32 g (40.0 mmol) of 1-bromo-4-iodobenzene and 500 mg (0.4 mmol) of tetrakis(triphenylphosphine)palladium in 50 mL of THF was added over the course of thirty minutes. After an additional 20 minutes, the cooling bath was removed, the reaction stirred at room temperature for 2 hours and then quenched with 100 mL of 1M hydrochloric acid. The mixture was extracted twice with hexanes, the extracts combined, washed once with saturated sodium bicarbonate solution and once with 10% sodium thiosulfate. The organic extract was dried (MgSO4) and evaporated. The crude product (11.3 g) was purified by distillation (bp 93°-95° C. at 0.5 Torr) to give 8.06 g (82%) of title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:16][CH:13]1[CH2:14][CH2:15][N:11]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)[CH2:12]1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N2CCC(O)C2)nc1
Temperature: 125 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
To a solution of 6-chloronicotinamide (0.16 g, 1 mmol) and pyrrolidin-3-ol (0.87 g, 1 mmol) in DMF (5 ml) was added K2CO3 (0.41 g, 3 mmol). The resulting solution was stirred under nitrogen at 125° C. for 24 h, and then allowed to cool to ambient temperature. The reaction mixture was then filtered and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated to afford the title compound (0.145 g, 70%) as a yellow solid. [LCMS RtA=1.23 min, [M+H]+=208.1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([C:20]([O:22]C)=[O:21])=[N:9]2)=[CH:4][CH:3]=1.Cl.O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([C:20]([OH:22])=[O:21])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1nn(-c2ccc(Cl)cc2)c2cccc(Cl)c2c1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1nn(-c2ccc(Cl)cc2)c2cccc(Cl)c2c1=O

Procedure:
To 10 g (28.6 mmole) of the above methyl ester (from step 2) in 150 ml of p-dioxane there is added 10 ml (4 eq.) of concentrated HCl with stirring under a nitrogen atmosphere. The mixture is heated up and refluxed for 5 hours. After cooling, the mixture is poured into water with stirring. Free acid is collected by filtration and dried over vacuum at 50° C. (9.5 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=3)[O:10][C:9](=[O:21])[CH:8]=2)[N:6]=1.[OH-].[Li+]>C1COCC1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=3)[O:10][C:9](=[O:21])[CH:8]=2)[N:6]=1
Reactant: COC(=O)c1ccc2c(-c3csc(C)n3)cc(=O)oc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(=O)oc3cc(C(=O)O)ccc23)cs1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(2-methyl-1,3-thiazol-4-yl)-2-oxo-2H-chromene-7-carboxylate (1.0 g, 3.32 mmol) in THF (33 ml) was added lithium hydroxide 1 M (16.6 ml, 16.6 mmol). The reaction was heated at 65° C. for 90 min, cooled to rt and evaporated. A solution of HCl 2N was then added to the residue and the mixture stirred for 1 h. The powder was filtered to give the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.37 (m, 1H), 8.28 (s, 1H), 7.87 (m, 2H), 6.85 (s, 1H), 2.80 (s, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15]([O:19][C:20](=[O:30])[CH:21]([CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH:22]([CH3:24])[CH3:23])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl>[C:15]([O:19][C:20](=[O:30])[CH:21]([CH2:25][S:26]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([Br:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)(=[O:27])=[O:28])[CH:22]([CH3:24])[CH3:23])([CH3:17])([CH3:18])[CH3:16]
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
A stirred suspension of 4-bromophenylpiperazine hydrochloride (2.84 g) and 2-chlorosulfonylmethyl-3-methyl-butyric acid tert-butyl ester (2.77 g) [preparation described in WO-A-98/05635] in dichloromethane (50 ml), cooled in an ice-bath, was treated with triethylamine (2 99 ml). The reaction was then stirred at room temperature for 2 h. The reaction mixture was then evaporated in vacuo, and the residue was dissolved in ethyl acetate (75 ml) and washed with 1% aqueous citric acid (2×50 ml), water (50 ml), saturated sodium bicarbonate (50 ml), saturated brine (50 ml), dried (MgSO4) and concentrated in vacuo to provide the title compound as a pale yellow gum (3.81 g, 79%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:16](=[O:18])[CH3:17])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].[CH:19]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH2:1]([O:3][C:4]1[C:5]([C:16](=[O:18])[CH2:17][CH3:19])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:14])([CH3:15])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1C(C)=O)C=CCC2(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOc1cc2c(cc1C(=O)CC)C=CCC2(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-25, 0.17 g, 0.68 mmol) in THF (33 mL) at −78° C. was added lithium diisopropylamide (1.5 M in cyclohexane, 0.55 mL 0.82 mmol). The cold bath was removed and the mixture was stirred for 2 h. The mixture was cooled to −78° C. again and methyl iodide (0.13 mL, 2.04 mmol) was added. The mixture was stirred at room temperature for 12 h then quenched with a saturated solution of NH4Cl and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 2% ethyl acetate in hexane) to give the title compound as a yellow oil.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1.C[O:22][B:23](OC)[O:24]C>C1COCC1>[CH3:20][S:19][C:16]1[CH:17]=[CH:18][C:13]([B:23]([OH:24])[OH:22])=[CH:14][CH:15]=1
Reactant: COB(OC)OC
Reactant: CSc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(B(O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
n-BuLi in hexane (2.5M, 625 mmol, 250 ml) is added slowly to a mechanically stirred solution of 4-bromothioanisole (100 g, 492 mmol) in THF (1 ) below −55° C. (internal temp.). After aging at −72° C. for 1 h trimethylborate (73 ml, 1.3 eq.) is added at such a rate to keep the internal temperature below −55° C. After 0.25 h at −78° C. the solution was allowed to warm to 0° C. for 10 min. 2N HCL (500 ml) is added and the solvent is evaporated. Water (500 ml) is added and the product is extracted with EtOAc (1.5 ). The organic layer is dried over Na2SO4, concentrated and the solid is stirred in hexane (500 ml) for 2 h. Filtartion gave 61.9 g (75%) of the desired product. 1H NMR (acetone-d6, 400 MHz) δ7.80 (d, 2H), 7.22 (d, 2H), 7.15 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>CN(C=O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][N:15]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:27]([O:26][CH3:25])[CH:28]=3)[CH2:16][CH2:17]2)=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2]
Reactant: O=Cc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCN(c3ccc([N+](=O)[O-])c(C=O)c3)CC2)cc1OC
Yield: 53 %

Procedure:
2-Nitro-5-piperazinylbenzaldehyde (5 g) was suspended in 50 ml of DMF and 6 ml of triethylamine was added to the suspension. A solution of 4.4 g of 3,4-dimethoxybenzoyl chloride in 20 ml of DMF was added dropwise thereto with ice cooling externally while stirring and the mixture was stirred at room temperature for 2 hours and poured into saturated saline and extracted with methylene chloride. After washing with water, the methylene chloride layer was dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation and to the residue was added methyl alcohol and the mixture was heated and cooled and crystals which formed were recrystallized form DMF to give 4.5 g of 2-nitro-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]benzaldehyde, m.p. 196°-198° C., yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH3:10])=[CH:4][CH:3]=1.[Br:24]NC(=O)CCC(N)=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH2:10][Br:24])=[CH:4][CH:3]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nnnc1C(CBr)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A slurry of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-propene (61.46 g, 0.197 mole) [prepared in Step C], N-bromosuccinamide (35.06 g, 0.197 mole) and catalytic amount of azobis isobutyronitrile or benzoyl peroxide in carbon tetrachloride (1.2 liters) was heated to reflux in an inert atmosphere for a period of 2 hours. The reaction mixture was cooled to ambient temperature and the solid from the reaction was filtered. The filtrate was concentrated under reduced pressure and the solid obtained was recrystallized from toluene-hexane to give 72 g (93%) of the title compound as white crystals; m.p.=159°-160° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([O:12][CH3:13])[C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1.[C-:14]#[N:15].[Na+].O>CS(C)=O>[CH3:13][O:12][C:5]1[C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=[C:3]([CH2:2][C:14]#[N:15])[CH:4]=1
Reactant: [C-]#N
Reactant: COc1cc(CCl)cc2c1OCO2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CC#N)cc2c1OCO2
Reaction time: 3 h
Yield: 60.2 %

Procedure:
To a solution of 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxole (10.2 g, 40 mmol) in DMSO (100 mL) was added NaCN (2.43 g, 50 mmol) at room temperature. The mixture was stirred for 3 h and poured into water (500 mL). The aqueous phase was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give the crude product, which was washed with ether to afford 2-(7-methoxybenzo[d][1,3]dioxol-5-yl)acetonitrile (4.6 g, 45%). 1H NMR (400 MHz, CDCl3) δ 6.49 (s, 2H), 5.98 (s, 2H), 3.91 (s, 3H), 3.65 (s, 2H). 13C NMR (400 MHz, CDCl3) δ 148.9, 143.4, 134.6, 123.4, 117.3, 107.2, 101.8, 101.3, 56.3, 23.1.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:16][C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1]
Reactant: Cc1cc(Cl)n(C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nn(C)c(Cl)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
A solution of 5-chloro-1,3-dimethyl-1H-pyrazole (0.500 g, 3.83 mmol) in carbon tetrachloride (2.0 mL) was charged with NBS (0.750 g, 4.21 mmol) and stirred at rt for 16 h. The reaction mixture was charged with silica gel and purified by chromatography on silica gel [ISCO Combiflash, 12 g cartridge, eluting with 100% heptane 10% EtOAc in heptane]. This resulted in 419 mg, 52% yield of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ=2.23 (s, 3H), 3.81 (s, 3H). MS (ES+): m/z 208.96, 210.93 (76/24) [MH+]. HPLC: tR=2.62 min (polar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=1)=[O:6]
Reactant: O=C(O)c1cc(-c2ccccn2)c(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC1CCCO1
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 95 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To a solution of 2,4-dichloro-5-(pyridin-2-yl)benzoic acid (Preparation 30, 3.76 g, 14.02 mmol) and ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (3.89 g, 16.83 mmol) in 2-methyltetrahydrofuran (150 mL) was added DIPEA (7.33 mL, 42 mmol) and the reaction was heated to 95° C. T3P (50% solution in EtOAc, 16.53 mL, 28 mmol) was added and the reaction was stirred at 95° C. for 18 hours. The reaction was cooled and partitioned between saturated aqueous sodium carbonate solution (200 mL) and EtOAc (200 mL). The organic layer was collected, washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with TBME to afford the title compound (5.72 g, 85%).