Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:15]([O:28][CH3:29])=[CH:14][C:3]=1[CH2:4][NH:5][C:6]1[C:7]([NH2:13])=[CH:8][C:9]([I:12])=[CH:10][CH:11]=1.[CH:30](OCC)(OCC)OCC>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:15]([O:28][CH3:29])=[CH:14][C:3]=1[CH2:4][N:5]1[C:6]2[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=2[N:13]=[CH:30]1
Reactant: COc1ccc(COc2cc(F)c(CNc3ccc(I)cc3N)cc2OC)cn1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: COc1ccc(COc2cc(F)c(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a stirred solution of N1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodobenzene-1,2-diamine (0.36 g, 0.70 mmol) in ethanol (10 mL) was added triethyl orthoformate (0.31 g, 2.11 mmol) and p-toluenesulfonic acid (0.007 g, 0.035 mmol). The reaction mixture was heated to reflux. After 30 min, the brown solution was allowed to cool to room temperature and was concentrated. The residue was partitioned between water and dichloromethane. The phases were separated, and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (Combi-Flash, 12 g SiO2 column, 1-5% methanol/dichloromethane elute) afforded 0.25 g (68%) of 1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-1H-benzo[d]imidazole as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]>C1COCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCC(=O)Nc1cccc(C)c1C
Solvent: C1CCOC1
Product: COC(=O)CCCNc1cccc(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a partial suspension of methyl 4-(2,3-dimethylphenylamino)-4-oxobutanoate (0.20 g, 0.85 mmol) in THF (8.5 mL) at 0° C. was added 1 M borane tetrahydrofuran complex (2.55 mL, 2.55 mmol) over 2 min. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was cautiously quenched with 50% saturated ammonium chloride, and then excess 50% saturated ammonium chloride and DCM were added. The resulting mixture was stirred vigorously for 15 min. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (PHENOMENEX® Axia Luna column, 5μ, C18, 30×75 mm; 15 min gradient from 100% A: 0% B to 0% A:100% B and 3 min 100% B (A=90% H2O/10% MeCN+0.1% TFA); (B=90% MeCN/10% H2O+0.1% TFA); detection at 220 nm) to afford the title compound (85 mg, 45% yield). LCMS, [M+H]+=222.1.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)([O-])=[O:2]>CN1CCOCC1.[Pt]>[CH2:9]1[CH2:8][N:7]([CH2:6][C:5]2[C:4]([NH:1][OH:2])=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccccc1CN1CCCC1
Agent: [Pt]
Solvent: CN1CCOCC1
Product: ONc1ccccc1CN1CCCC1

Procedure:
The N-(2-nitrobenzyl)-pyrrolidine (20 mmol) was dissolved in N-methyl-morpholine (20 ml). Platinum on carbon (5 mol-%, 0.17 mmol, 350 mg, Degussa Type F105 RS/W) was added. The reaction vessel was evacuated and flushed with nitrogen three times, before a hydrogen atmosphere was applied. Thin layer chromatography control showed complete consumption of the starting material after 4 hours. The platinum catalyst was removed by filtration over celite. The crude product was obtained after evaporation of all volatiles under reduced pressure in a purity of >90%, as measured by 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:23][CH2:24][N:25]([CH2:33][CH2:34]Cl)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[CH3:31][C:28]([O:27][C:26]([N:25]1[CH2:33][CH2:34][C:5]2([C:6](=[O:11])[NH:7][C:8]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]2=3)[CH2:23][CH2:24]1)=[O:32])([CH3:29])[CH3:30]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1ccc(F)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 9.3 %

Procedure:
To a stirred solution of 5-fluoro-1,3-dihydro-2H-indol-2-one (1.80 g, 11.9 mmol) in tetrahydrofuran (30 mL) was added dropwise a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (35.7 mL, 35.7 mmol) at −78° C. for 15 min and the mixture was stirred for 1.5 h at the same temperature. To the mixture was added dropwise a solution of tert-butyl bis(2-chloroethyl)carbamate (2.88 g, 11.9 mmol) in tetrahydrofuran (10 mL) at −78° C., then this resulting mixture was slowly warmed up to room temperature and stirred for 19 h at the same temperature. The reaction mixture was quenched by the addition of ammonium chloride aqueous solution, and concentrated to give a brown residue. The crude material was partitioned between ethyl acetate and water, and then the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane/acetone (3/1) to afford 356 mg (15%) of the title compound as a slight brown syrup:
Reaction SMILES: [NH2:1][C:2]1([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:34])=[C:28]([CH2:30][C:31](Cl)=[O:32])[CH:29]=1>ClCCl>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:34])=[C:28]([CH2:30][C:31]([NH:1][C:2]2([C:12]([O:14][CH3:15])=[O:13])[CH2:3][CH2:4][C:5]3([O:9][CH2:8][CH2:7][O:6]3)[CH2:10][CH2:11]2)=[O:32])[CH:29]=1
Reactant: Cc1ccc(Br)cc1CC(=O)Cl
Reactant: COC(=O)C1(N)CCC2(CC1)OCCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, 5.47 g (25.41 mmol) of methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate [T. Satoh et al., Tetrahedron 63 (2007), 4806-4813], 3.86 g (38.12 mmol) of triethylamine and 155 mg (1.27 mmol) of N,N-dimethylaminopyridine were dissolved in 45 ml of dichloromethane. A solution of 6.29 g (25.41 mmol) of (5-bromo-2-methylphenyl)acetyl chloride (Example 3A) in 45 ml of dichloromethane was then added dropwise to the mixture. The resulting reaction mixture was stirred at room temperature overnight. For work-up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous saturated sodium bicarbonate solution. After drying over sodium sulphate, the mixture was concentrated by evaporation and the residue was purified by chromatography on silica gel (mobile phase: hexane/ethyl acetate gradient/1% triethylamine) Evaporation and drying gave 3.64 g (34% of theory) of the title compound which was used without further characterization in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[OH:12].C(O)C.O.[SH-].[Na+]>O1CCCC1>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[OH:12])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C(O)c2ccccn2)c(Cl)c1
Agent: [Na+]
Agent: [SH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(O)c2ccccn2)c(Cl)c1
Yield: 23.7 %

Procedure:
(2-chloro-4-nitrophenyl)(pyridin-2-yl)methanol (1 g) was dissolved in tetrahydrofuran (15 ml), ethanol (15 ml) and water (15 ml), and sodium hydrosulfide (3.3 g) was added to the mixture, and the mixture was refluxed for 30 minutes. After concentration, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give (4-amino-2-chlorophenyl)(pyridin-2-yl)methanol (0.21 g) as colorless crystals.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][C:8]=1[F:16].CN(C)[CH:19]=[O:20]>>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:19]=[O:20])=[CH:12][NH:13]2)=[CH:9][C:8]=1[F:16]
Reactant: Fc1cc2cc[nH]c2cc1Cl
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(Cl)c(F)cc12
Temperature: 35 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
POCl3 (2.43 mL, 26.53 mmol) was added dropwise to N,N-dimethylformamide (15.0 mL) at −20° C. and stirred below −5° C. for one hour. A solution of 6-chloro-5-fluoroindole (3.0 g, 17.69 mmol) in dimethylformamide (5.0 mL) was added dropwise to the above reaction mixture at −20° C. The salt-ice bath was removed and the reaction mixture was warmed to 35° C. After one hour, the reaction was poured onto ice and basified by solid sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was washed with water and then concentrated to give 6-chloro-5-fluoro-1H-indole-3-carbaldehyde (3.4 g, 97%) as a light brown solid. 1H NMR (500 MHz, CDCl3): δ 10.02 (s, 1 H), 8.10 (d, 1H, J=9.5 Hz), 7.87 (s, 1 H), 7.49 (d, 1H, J=5.5 Hz).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33][CH3:34].C1COCC1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22][CH2:23]2)[CH:15]=[CH:14][C:10]=1[C:11]([N:33]([CH3:34])[CH3:32])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Reactant: CNC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Yield: 56.5 %

Procedure:
A solution of 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoic acid (80 mg, 0.2 mmol), 2 M dimethylamine THF solution (0.38 ml, 0.78 mmol), tiethylamine (0.08 ml, 0.57 mmol) and diphenylphosphoryl azide (0.045 ml, 0.2 mmol) in 15 ml THF was stirred for 16 hours. The run was quenched with 1 ml water and all the solvents were evaporated under vacuum. 2-(benzylamino)-N,N-dimethyl-4-(4-benzoylpiperazin-1-yl)benzamide (50 mg, 60%) was obtained by flash column chromatograph (60% ethyl acetate in hexanes). 1H NMR (500 MHz, DMSO-d6) δ (ppm) 2.95 (d, 6H), 3.15-3.20 (s, br, 4H), 3.62 (s, br, 2H), 3.70 (s, br, 2H), 4.38 (d, 2H), 6.22 (d, J=2.2 Hz, 1H), 6.24 (dd, J=2.2, 8.3 Hz, 1H), 7.00 (dd, J=2.5, 8.4 Hz, 1H), 7.32-7.48 (m, 10H), 8.82 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 30.1, 30.8, 48.1, 48.9, 49.4, 99.5, 103.7, 111.1, 120.7, 126.6, 127.6, 127.7, 129.0, 129.1, 130.3, 130.5, 130.6, 136.0, 139.6, 149.5, 153.4, 170.8, 172.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12](OC)[CH:11]=1.[CH3:26][NH2:27].CS(C)=O.Cl>O>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH:27][CH3:26])[CH:11]=1
Reactant: CN
Reactant: COc1ccccc1OCCNC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(C(=O)NCCOc2ccccc2OC)ccc1[N+](=O)[O-]
Yield: 89 %

Procedure:
A mixture comprising N-[2-(2-methoxyphenoxy)ethyl]-3-methoxy-4-nitrobenzamide (4.0 g, 11.6 mmol), aqueous methylamine (40%, 10 mL) and DMSO (2 mL) in a sealed tube was heated at 110° C. for 4 hours, cooled and then poured into water (25 mL). The dilution was treated with 3M aqueous hydrochloric acid to give an orange solid. The solid was isolated by filtration to provide N-[2-(2-methoxyphenoxy)ethyl]-3-methylamino-4-nitrobenzamide (3.56 g, 89% yield); MS (PB-PCI) C17H19N3O5 m/e calc 345.35; found 346 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][C:4]([C:10]([O-:12])=O)=[N:3]1.[NH2:13][NH2:14]>CO>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][C:4]([C:10]([NH:13][NH2:14])=[O:12])=[N:3]1
Reactant: NN
Reactant: Cn1nc(C(=O)[O-])cc1[N+](=O)[O-]
Solvent: CO
Product: Cn1nc(C(=O)NN)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of 1-methyl-5-nitro-1H-pyrazole-3-carboxylate (3.81 g, 20.6 mmol, Princeton) in MeOH (20 mL) at was added hydrazine (2.0 mL, 35% in water, 41.2 mmol) The reaction mixture was heated to about 60° C. for about 2 h. The reaction was cooled to ambient temperature and concentrated under reduced to afford 1-methyl-5-nitro-1H-pyrazole-3-carbohydrazide (3.81 g, 20.6 mmol, 100%, which was used without further purification). LC-MS (Table 1, Method g) Rt=0.90 min, m/z 186 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH:23](C(OC)=O)[C:24]([O:26]C)=[O:25])([O-:3])=[O:2]>Cl>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:23][C:24]([OH:26])=[O:25])([O-:3])=[O:2]
Reactant: COC(=O)C(C(=O)OC)c1ccc(-c2cccc(NC(=O)C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: Cl
Product: O=C(O)Cc1ccc(-c2cccc(NC(=O)C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 73.4 %

Procedure:
Dimethyl 2-[2-nitro-4-(3-trifluoroacetamidophenyl)phenyl]malonate (4.4 g) was refluxed overnight in 50 mL 6 N hydrochloric acid. The reaction mixture was cooled to room temperature and the solids were collected by vacuum filtration, washed with water, and dried under vacuum to give 2.7 g (73% yield) of 2-[2-nitro-4-(3-trifluoroacetamidophenyl)phenyl]acetic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O:13][C:14](=O)[C:15]([C:28]#[N:29])=[CH:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=1)C>>[C:28]([C:15]1[C:14](=[O:13])[O:9][C:5]2[C:6]([C:16]=1[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=1)=[CH:7][CH:8]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:4]=2)#[N:29]
Reactant: CCOC(=O)C(C#N)=Cc1cc(Br)c(OC)c(OC)c1
Reactant: CN(C)c1cccc(O)c1
Product: COc1cc(-c2c(C#N)c(=O)oc3cc(N(C)C)ccc23)cc(Br)c1OC
Yield: 0.5 %

Procedure:
The title compound was prepared from 3-dimethylaminophenol and 3-(3-bromo-4,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester by a procedure similar to that described for Example 16 in 0.5% yield. 1H NMR (CDCl3): 7.21-7.18 (m, 2H), 6.98 (d, J=1.8 Hz, 1H), 6.62 (dd, J=2.4, 9 Hz, 1H), 6.53 (d, J=2.7 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.15 (s, 6H).
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([CH:20]2[CH2:22][CH2:21]2)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:8][CH:9]=1)[CH3:3].[C:23]([O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][C:32]=1[CH3:38])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:23]([O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH:2]([C:4]2[C:5]([CH:20]3[CH2:22][CH2:21]3)=[N:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:8][CH:9]=2)[CH3:3])=[CH:33][C:32]=1[CH3:38])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(Cl)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: Cc1cc(S)ccc1OCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(SC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)ccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of 180 mg (0.551 mmol) [rac]-5-(1-chloro-ethyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 28H]) and 140 mg (0.551 mmol) (4-mercapto-2-methyl-phenoxy)-acetic acid tert-butyl ester in 3 ml DMF was added 315 mg (0.66 mmol) cesium carbonate. The reaction mixture was stirred for 3 h at RT and then partitioned between ether, 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/Heptan 1:9 to give 150 mg of pure [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid tert-butyl ester.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:33])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])[CH:17]=2)[CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13]>O1CCCC1.CO>[F:3][C:4]1[CH:5]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:33])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])[CH:17]=2)[CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)O)c(F)c2)c1
Yield: 81 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 200 mg (5.0 mmol, 4.7 eq) of sodium hydroxide, 210 mg (0.51 mmol, 1 eq) of methyl (E)-3-[3-fluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate (prepared in Example 3b) in 6 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 165 mg of (E)-3-[3-fluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white powder. (m.p.=148-149° C.). Yield=81%
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:6]2[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:16][CH:17]=1
Reactant: CCCCc1nc(Cl)c(COC)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(N)cc1
Yield: 90.3 %

Procedure:
To a solution of 2-n-butyl-4-chloro-5-methoxymethyl-1-(4-nitrobenzyl)imidazole (11.22 g) in methanol (100 mL) under N2 was carefully added 1.0 g of 10% palladium on charcoal. Hydrogen gas was then bubbled through the solution for 4 hours. The solution was filtered through Celite® and the solvent removed in vacuo to yield 9.23 g of an amber oil. NMR (200 MHz, CDCl3) δ 7.99 (s, 1H); 6.78 (d of d, 4H, J=5,5 Hz); 5.05 (s, 2H); 4.24 (s, 2H); 3.27 (s, 3H); 2.59 (t, 2H, J=7 Hz); 1.62 (t of t, 2H, J=7,7 Hz); 1.32 (t of q, 2H, J=7,7 Hz); 0.84 (t, 3H,J=7 Hz). Mass Calcd. for C16H23ClN3O; 307.1451. Found: 307.1460.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1>>[C:7]([C:6]1[CH:9]=[C:2]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)[CH:3]=[CH:4][C:5]=1[F:10])#[N:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)c(C#N)c2)CC1

Procedure:
The title compound was prepared from 5-bromo-2-fluorobenzonitrile and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate using a method similar to that described for D10a.
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])[CH2:8][CH:7]([CH2:14][CH2:15][CH3:16])[CH2:6]2.[Br:17]Br.C1CCN2C(=NCCC2)CC1>CC#N>[Br:17][C:8]1[C:7]([CH2:14][CH2:15][CH3:16])=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[OH:13]
Reactant: BrBr
Reactant: CCCC1CC(=O)c2ccc(OC)cc2C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCc1cc2cc(OC)ccc2c(O)c1Br

Procedure:
Treatment of 6-(methyloxy)-3-propyl-3,4-dihydro-1(2H)-naphthalenone (93) (0.50 g, 2.29 mmol) with bromine followed by DBU in CH3CN gave 0.62 g of compound 94 as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 1.01 (t, J=7.4 Hz, 3H), 1.65-1.75 (m, 2H), 2.79 (t, J=7.7 Hz, 2H), 3.90 (s, 3H), 6.06 (s, 1H), 7.00 (d, J=2.4 Hz, 1H), 7.08 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.17 (s, 1H), 8.07 (d, J=9.1 Hz, 1H). LCMS (ESI): m/z 295 (M+H)+, m/z 293 (M−H)−.
Reaction SMILES: C1C[C@H:9]2[N:4](C[C@H:6]3[C@@H:13]4[CH2:14]C[CH2:16][CH2:17][N:12]4C[C@@H:8]2[CH2:7]3)CC1.C(OC([N:25]1CCCC1)=O)(C)(C)C.C([Li])(CC)C.C1CCCCC1.O1CCCC1.BrC1C=NC=CN=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.F[B-](F)(F)F.[H+].[ClH:72].O1CCOCC1>C(OC)(C)(C)C.ClCCl.[Cl-].[Zn+2].[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[ClH:72].[NH:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[C:13]1[CH:14]=[N:25][CH:16]=[CH:17][N:12]=1
Reactant: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Agent: [Pd+2]
Agent: Brc1cnccn1
Agent: CC(=O)[O-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: c1cnc([C@H]2CCCN2)cn1
Temperature: -78 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
According to WO 2008/053319, to a solution of (−)-sparteine (2.7 g, 11.7 mmol) and pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 11.7 mmol) in dry methyl tert-butyl ether was added at −78° C. 1.4 M sec-butyllithium in cyclohexane (8.3 ml, 11.7 mmol) over 30 min and the mixture was stirred at −78° C. for 3 h. 0.5 M zinc chloride solution in tetrahydrofuran (14 ml, 7 mmol) was added at −78° C. and the mixture was stirred for 30 min at −78° C. and 30 min at 25° C. This mixture was added via a syringe to a solution of 2-bromopyrazine (1.48 g, 9.34 mmol), palladium(II) acetate (105 mg, 0.467 mmol) and tetrafluoroboric acid tri-tert-butylphosphine adduct (169 mg, 0.584 mmol) at −78° C. The mixture was stirred and allowed to slowly warm to 25° C. overnight. The solid was filtered off, to the solution was added aqueous sodium hydrogencarbonate, and the mixture was extracted 3 times with dichloromethane, solvents were evaporated and the residue was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 750 mg of crude product which was dissolved in dichloromethane (5 ml) and treated with 4 N hydrogen chloride in dioxane (0.8 ml, 3.2 mmol) for 2 days, and after addition of water was lyophilized to give 200 mg (17%) of crude (R)-2-pyrrolidin-2-yl-pyrazine hydrochloride which was used without purification in the next step. LC/MS (method 7): Rt=0.14 min; m/z=150.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([CH3:18])([CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=1)[NH2:6].Br[CH:20]([CH2:25][CH2:26][CH2:27]Br)[CH2:21][C:22]([O-:24])=[O:23].C(N(CC)CC)C>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]2[CH2:27][CH2:26][CH2:25][CH:20]2[CH2:21][C:22]([OH:24])=[O:23])[CH:7]=[C:8]([C:10]([CH3:17])([CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=1
Reactant: CCCCCCC(C)(C)c1cc(N)cc(OC)c1
Reactant: O=C([O-])CC(Br)CCCBr
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCC(C)(C)c1cc(OC)cc(N2CCCC2CC(=O)O)c1
Reaction time: 1 h

Procedure:
A mixture of 24.9 g. (0.10 mole) 3-methoxy-5-(1,1-dimethylheptyl)aniline, 34.5 g. (0.12 mole) methyl dl-3,6-dibromocaproate, 15 g. triethylamine and 100 ml. ethyl ether is stirred under nitrogen at room temperature for 20 hours. The ether is evaporated and the residue heated at 90°-120° C. for three hours. Additional methyl dl-3,6-dibromocaproate (5 g.) and triethylamine (5 g.) is added and heating continued at 90° C. for 2 hours and finally at 120° C. for one hour. The reaction mixture is worked up as described in Example 16 to provide the methyl ester of the desired product which is hydrolyzed in methanolic sodium hydroxide by the method of Example 17 to provide the title acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[ClH:22].[CH3:21][C:17]1[CH:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:20]=[CH:19][N:18]=1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(NC2CCNCC2)ccn1

Procedure:
A solution of 4-(2-methyl-pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.31 g, 4.50 mmol) in dioxane (20 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 192.1 [M+H]+.