Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([OH:8])=[N:6][CH:7]=1.Cl[CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([O:8][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][CH:7]=1
Reactant: Oc1ncc(Br)cc1F
Reactant: ClCCn1cccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)cnc1OCCn1cccn1
Temperature: 90 °C

Procedure:
A vigorously stirred mixture of 5-bromo-3-fluoro-2-hydroxypyridine (440 mg, 2.3 mmol), 1-(2-chloroethyl)-1H-pyrazole (330 mg, 2.5 mmol) and K2CO3 (380 mg, 2.77 mmol) in DMF (5 mL) was heated to 90° C. for 16 h. After cooling to room temperature the solvent was removed in vacuo and the crude partitioned between water and EtOAc. The aqueous was extracted with EtOAc (×3) and the combined organics dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (gradient: 20%-100% EtOAc in pet. ether 40-60) yielded 5-bromo-3-fluoro-2-(2-pyrazol-1-yl-ethoxy)-pyridine as a clear oil.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:8]2[C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 79.8 %

Procedure:
In 50 ml of dimethylformamide, there were stirred 10.3 g of 2-phenyl-4-chloro-5-formylimidazole, 11.3 g of p-nitrobenzyl bromide and 5.2 g of anhydrous potassium carbonate at 110°-120° C. for 2 hours. The reaction mixture was poured in ice-water and the resulting precipitate was put on a column of 100 g silica gel, elution being carried out with chloroform. The first fraction was concentrated to dryness and recrystallized from ethanol. By the above procedure was obtained 13.6 g of 1-(p-nitrobenzyl)-2-phenyl-4-chloro-5-formylimidazole as colorless needles, m.p. 150°-152° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][C@H:20]([CH2:22]OS(C)(=O)=O)[O:19][C:18]2=[O:28])=[CH:13][C:12]=1[F:29].[N-:30]=[N+:31]=[N-:32].[Na+].O>CN(C=O)C>[N:30]([CH2:22][C@@H:20]1[O:19][C:18](=[O:28])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([N:3]3[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])=[C:12]([F:29])[CH:13]=2)[CH2:21]1)=[N+:31]=[N-:32]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3Cc4ccccc4C3=O)c(F)c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3Cc4ccccc4C3=O)c(F)c2)C(=O)O1
Temperature: 70 °C
Yield: 73.4 %

Procedure:
To the mesylate from Example 2 (0.95 g, 1.78 mmols) in DMF (25 mL) was added sodium azide (0.47 g, 7.23 mmols) and heated to 70° C. for 16 hrs. After cooling to rt water was added and the mixture extracted with ethyl acetate (6×25 mL), washed with brine (4×10 mL), dried over Na2SO4, concentrated to give 0.48 g of a tan solid. MS (M+1)=354 m/z.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[CH:4]=1.[CH3:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18]>>[CH3:13][O:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])[CH2:2][CH2:14][PH:15](=[O:19])[O:16][CH2:17][CH3:18]
Reactant: COc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: CCOP(C)OCC
Product: CCO[PH](=O)CCc1ccc([N+](=O)[O-])c(OC)c1
Temperature: 100 °C
Yield: 195.5 %

Procedure:
A mixture of 4-(chloromethyl)-2-methoxy-1-nitrobenzene (1.1 g, 5.46 mmol) and diethyl methylphosphonite (0.89 g, 1.2 mmol) were heated at 100° C. for 16 h in a sealed tube. The reaction mixture was concentrated in vacuo and the residue crude purified using an Isco Combiflash system eluting with 0→5% MeOH in DCM as eluent to afford 0.641 g of ethyl (3-methoxy-4-nitrobenzyl)methylphosphinate (yield: 43% yield). MS (ES+): m/z 273.99 [MH+] (ZQ3, polar 5 min).
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:21][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:13]2[CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)OCO4)nc12
Reactant: CS(=O)(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
To a solution of 8-((6-iodobenzo[d][1,3]dioxol-5-yl)thio)-9H-purin-6-amine (150 mg, 0.36 mmol) in 10 mL of dry DMF was added N-(3-bromopropyl)methanesulfonamide (300 mg, 1.4 mmol) and Cs2CO3 (190 mg, 0.58 mmol). The resulting mixture was stirred at a temperature of about 25° C. for 3 hrs, condensed under reduced pressure and purified by flash chromatography to provide compound WS34 as white solid (49 mg, 25% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([NH:24][C:25]1[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C(OCC)(=O)C>[C:16]([NH:24][C:25]1[CH:34]=[C:33]([O:35][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: BrCCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.13 g of potassium carbonate and 0.10 mL of (2-bromoethyl)benzene were added to 2 mL of N-dimethylformamide solution containing 0.13 g of methyl 2-(benzamido)-4-hydroxybenzoate, and stirred at room temperature for 3 hours. 0.10 mL of (2-bromoethyl)benzene was added to the reaction mixture and stirred at 50° C. for 4 hours and at 80° C. for 3 hours. After the reaction mixture was cooled to room temperature, 0.10 g of potassium carbonate and 0.10 mL of (2-bromoethyl)benzene were added and stirred at 80° C. for 2 hours and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/b hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=8:1] to obtain 0.13 g of methyl 2-(benzamido)-4-(phenethyloxy)benzoate as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH:7]=[O:8].[I:15]I.C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[OH:14][C:5]1[C:4]([I:15])=[C:3]([O:2][CH3:1])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: II
Reactant: COc1cc(O)c(C=O)cc1[N+](=O)[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1c([N+](=O)[O-])cc(C=O)c(O)c1I
Reaction time: 15 h
Yield: 73 %

Procedure:
To the stirred solution of 2.0 g (10.2 mmol) (1.52 mmol) of 4-methoxy-5-nitrosalicylaldehyde and 2.58 g (10.2 mmol) of iodine in 60 ml of carbon tetrachloride, 4.8 g (11.2) mmol) of [bistrifluoroacetoxyl) iodo]benzene was added slowly and then the reaction mixture was stirred for 15 hrs. at RT. To this reaction mixture, 60 ml of hexanes was added and then the formed solid was collected by filtration, washed with hexanes, dilute HCl, water, and dried to give 2.4 g of D. (Yield: 73%): 1H NMR (CDC13) δ12.48 (s, 1H), 9.81 (s, 1H), 8.35 (s, 1H), 4.07 (s, 3H); MS (70 eV) m/e (% relative intensity) M+2 =325 (1.78), M+1 =324 (11) M=323 (100), 293 (41), 276 (51), 262 (11), 120 (8.5), 119 (8.6), 108 (38), 107 (22), 92 (23), 80 (10) 79 (18), 77 (18), 64 (12), 63 (10), 62 (10), 61 (10), 51 (14), 49 (23); IR (nujol) 1660, 1608, 1557, 1512, 1467, 1376, 1312, 1080, 970, 725 cm-1
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:20])[N:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:32]([O:34][C:35]([CH3:37])=[CH2:36])=[O:33].Cl>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:32](=[O:33])[O:34][C:35]([CH3:37])=[CH2:36])[N:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3ncccc3c2)n1
Reactant: C=C(C)OC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)Nc1cc(C(C)(C)C)nn1-c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 348 %

Procedure:
A solution of 5-tert-butyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine from Example B3 (1.00 g, 3.8 mmol) in THF (20 mL) was cooled to −78° C. and treated with lithium bis(trimethylsilyl)amide (1.0 M in THF, 7.5 mL, 7.5 mmol). The resultant mixture was stirred at −78° C. for 30 min. Isopropenyl chloroformate (0.45 mL, 0.41 mmol) was added and stirring was continued at −78° C. for 30 min. The reaction mixture was quenched at −78° C. with aq HCl (2 N, 4 mL, 8 mmol), was warmed to RT and partitioned between water (200 mL) and EtOAc (200 mL). The organic layer was separated, washed with brine, dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography to provide prop-1-en-2-yl 3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-ylcarbamate (0.5 g, 38% yield). MS (ESI) m/z: 351.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11](N)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[I:22]I.N(OCCC(C)C)=O>[Cu]I.COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][C:11]([I:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1cnc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1
Reactant: II
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: COCCOC
Product: Fc1ccc(-c2ncc(I)nc2-c2ccc(F)cc2)cc1
Reaction time: 2 h

Procedure:
A solution of 5,6-bis(4-fluorophenyl)pyrazin-2-amine (1 g, 3.53 mmol, 1.00 equiv), ethylene glycol dimethyl ether (50 mL), I2 (450 mg, 1.78 mmol, 0.50 equiv), CuI (200 mg, 1.05 mmol, 0.30 equiv), and isoamyl nitrite (2.75 g, 10.87 mmol, 3.08 equiv) was stirred for 10 min at room temperature, then for an additional 2 h at 60° C. in an oil bath. The resulting mixture was concentrated in vacuo, and purified via silica gel column chromatography (ethyl acetate/petroleum ether (1:40)) resulting in 1 g (72%) of 2,3-bis(4-fluorophenyl)-5-iodopyrazine as brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:10][CH:9]=1)[NH2:6])[CH3:2].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[C:8]([CH2:7][C@@H:5]([C:4]([OH:3])=[O:25])[NH:6][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:9][N:10]=[C:11]1[CH2:21][CH2:22][CH2:23][CH3:24].[CH2:1]([O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:10][CH:9]=1)[NH:6][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:2]
Reactant: CCCCc1ncc(C[C@H](N)C(=O)OCC)n1Cc1ccccc1Cl
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCCc1ncc(C[C@H](NCc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Product: CCCCc1ncc(C[C@H](NCc2ccccc2)C(=O)OCC)n1Cc1ccccc1Cl

Procedure:
The title compound is prepared by reductive alkylation of 2-n-butyl-3-(2-chlorophenyl)methylhistidine ethyl ester with benzaldehyde in the presence of sodium cyanoborohydride to give 3-[(2-chlorophenyl)methyl]-2-n-butyl-N-benzylhistidine ethyl ester. Hydrolysis of the ester group is accomplished according to Example 2 (iii) to provide the title compound.
Reaction SMILES: [N:1]12[CH2:11][CH2:10][CH2:9][N:8]=[C:7]1[CH2:6]CC[CH2:3][CH2:2]2.[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21](F)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13].[C:30](#N)C>>[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21]([N:8]3[CH2:7][CH2:6][C:10]4([CH2:3][CH2:2][N:1]([CH3:30])[CH2:11]4)[CH2:9]3)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: CC#N
Reactant: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4(CCN(C)C4)C3)cc21

Procedure:
A suspension of 0.65 g (3.05 mmol) 2-methyl-2,7-diaspiro[4.4]nonane dihydrochloride in 40 ml acetonitrile was treated with 1.33 g (9.0 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.76 g (3.0 mmol) 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added. The mixture was refluxed overnight and the hot solution was filtered. After crystallizing at room temperature the product was filtered and washed with acetonitrile to afford 0.72 g of the title compound, mp 239°-241° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:10])[C:8]=1[CH3:9])N.C(ON=O)(C)(C)C.C(I)[I:19]>>[Br:1][C:2]1[CH:3]=[C:4]([I:19])[CH:6]=[C:7]([Br:10])[C:8]=1[CH3:9]
Reactant: ICI
Reactant: Cc1c(Br)cc(N)cc1Br
Agent: CC(C)(C)ON=O
Product: Cc1c(Br)cc(I)cc1Br

Procedure:
To a solution of 3,5-dibromo-4-methylaniline (4.17 g, 15.74 mmol) in CH2I2 (10 mL) was added tert-butylnitrite (3.0 mL, 23.61 mmol) slowly at 0° C. while stirring vigorously. The ice bath was removed and the reaction mixture was stirred at rt while the reaction was very exothermic, then placed in 80° C. oil bath and heated for 20 min. CH2I2 was distilled off under high vacuum, and the remaining residue was purified by flash chromatography eluting with 100% hexane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To a suspension of 4′-chloro-4-ethylbenzenesulfonanilide (4.70 g (15.9 mmol)) in 15 ml of acetic acid, 97% fuming nitric acid (0.69 ml (16.1 mmol)) was added dropwise with stirring at room temperature. The resulting mixture was stirred at 50° C. for 30 minutes and then allowed to cool to room temperature. Water (100.0 ml) was added to the reaction mixture and the resulting crystals were filtered and washed with waterto give 5.35 g (99%) of 4′-chloro-4-ethyl-2′-nitrobenzenesulfonanilide as pale yellow crystals.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:23]([OH:25])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.Br[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:23]([O:25][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CC(C)(C)CBr
Reactant: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(O)c2)ncn1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OCC(C)(C)C)c2)ncn1)C1CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(6-((6-(2-fluoro-5-methoxyphenyl)-5-hydroxypyridin-3-yl)methoxy)pyrimidin-4-yl)propanoate (60 mg) in DMF (1.3 mL) were added 1-bromo-2,2-dimethylpropane (80 μL) and cesium carbonate (83 mg), and the mixture was stirred at 80° C. for 20 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (20 mg) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][C:2]([NH:9][S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11])([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[Cl:15][C:16]1[C:21](I)=[CH:20][CH:19]=[CH:18][C:17]=1OC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:2]([NH:9][S:10](/[CH:13]=[CH:14]/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15])(=[O:12])=[O:11])([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: COc1cccc(I)c1Cl
Reactant: C=CS(=O)(=O)NC(C)(C)CC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1ccccc1Cl
Temperature: 140 °C
Yield: 31.8 %

Procedure:
Ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (10 g, 46 mmol) and 2-chloroiodoanisole (4.8 mL, 39.1 mmol) was dissolved in N,N-dimethylformamide (DMF) (75 mL). Palladium acetate (169 mg, 0.75 mmol) and triphenylphosphine (420 mg, 1.6 mmol) was added to the reaction mixture followed by triethylamine (14.7 mL, 106 mmol). The reaction was flushed with nitrogen and heated at 140° C. for 16 hours. The reaction was cooled to room temperature whereupon 1N HCl (275 mL) was added. The aqueous solution was extracted with ethyl acetate (3×225 mL) and the combined organic solution was dried over MgSO4, filtered and concentrated in vacuo to afford a solid. The solid was dissolved in dichloromethane and purified by dry flash chromatography (SiO2, heptane to 1:1 heptane: ethyl acetate). The fractions were combined to afford (E)-2-(2-chloro-phenyl)-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (4.1 g, 32% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([N+:30]([O-])=O)[CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Zn].C(O)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2C(=O)OCc2ccccc2)cc1N
Reaction time: 2 h
Yield: 56.5 %

Procedure:
5,6-Dichloro-2-(4-methoxy-3-nitro-phenyl)-benzoimidazole-1-carboxylic acid benzyl ester (1.14 g, 2.4 mmol) from Step B was combined with glacial acetic acid (50 mL). Zinc dust (7.81 g, 120 mmol) was then gradually added to the stirred reaction mixture. After 2 hours, the zinc was filtered from the reaction mixture and the filtrate concentrated to an oil via rotary evaporation (60° C.). The oil was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine, dried (magnesium sulfate), filtered and the solvent removed. The solid was triturated with 7:3 hexane:ethyl acetate to give the product (0.6 g), mp 150-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:9]
Reactant: O=C(O)c1cc(Cl)cnc1N1CCC(c2ccccc2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(c4ccccc4)C3)CC2)cc1
Yield: 51.3 %

Procedure:
The title compound (D143) (210 mg) was prepared according to the experimental procedure described in Description 142 starting from 5-chloro-2-(3-phenylpyrrolidin-1-yl)nicotinic acid (D99) (260 mg, 0.860 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (195 mg, 0.86 mmol).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([C:12](OCC)=[O:13])[CH:9]=[CH:8][N:7]=1)[CH3:4]>C(O)C.ClCCl>[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][N:7]=1)[CH3:4]
Reactant: CCOC(=O)c1ccnc(OCC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOc1cc(CO)ccn1
Reaction time: 3 h
Yield: 75.4 %

Procedure:
0.508 g of sodium borohydride is added portionwise to a solution of 0.524 g of ethyl 2-ethoxypyridine-4-carboxylate in 5.2 ml of ethanol, under an inert atmosphere of argon at a temperature in the region of 0° C. The reaction mixture is refluxed with stirring for 3 hours and then concentrated to dryness under reduced pressure. The residue thus obtained is taken up in 50 ml of dichloromethane and then washed with 50 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. 0.310 g of 2-ethoxy-4-(hydroxymethyl)pyridine is thus obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[C:5]([NH2:14])=[C:6]([N+:11]([O-])=O)[C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2]>[Pd].O1CCCC1>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH2:11])[C:5]=1[NH2:14])[CH3:16]
Reactant: CCN(CC)c1ccc(F)c([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(F)c(N)c1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under hydrogen gas atmosphere, a mixture of N1,N1-diethyl-4-fluoro-3-nitrobenzene-1,2-diamine (380 mg, 1.67 mmol), 10% palladium on carbon (50% wet, 80 mg) and tetrahydrofuran (8 mL) was stirred at room temperature for 20 hr. The reaction mixture was filtered and concentrated in vacuo to give N1,N1-diethyl-4-fluorobenzene-1,2,3-triamine as a brown oil, which was used for the next step without further purification. To a solution of above crude compound in tetrahydrofuran (16 mL) was added 2,4-dichlorophenyl isothiocyanate (320 mg, 1.57 mmol) at room temperature. The resultant mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture to give a solid, which was washed with diisopropyl ether to afford the title compound as a colorless solid (306 mg, 0.762 mmol, 49%).
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH3:9])=[C:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH3:10][Li].O>CCOCC>[CH3:1][C:2]([C:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1)([CH3:10])[CH2:8][CH3:9]
Reactant: CCC(C)=C1C=CC=C1
Reactant: [Li]C
Solvent: O
Solvent: CCOCC
Product: CCC(C)(C)C1=CC=CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of 8.00 g (66.6 mmol) of 6-methyl-6-ethylfulvene in 40 ml of ether, 66.0 ml (75.2 mmol) of an ether solution of methyllithium was dropwise added in an nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. Then, 30 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (165° C./270 mmHg) to obtain 8.40 g (61.66 mmol) of a light yellow liquid (yield: 93%) The analyzed values are given below.