Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(C)C[C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][N:5]=1.C([O-])([O-])=O.[K+].[K+].[CH:18]([Cl:21])(Cl)Cl>>[CH2:4]([N:5]1[C:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:9]=2[N:10]=[C:6]1[CH2:18][Cl:21])[CH2:9][CH3:8]
Reactant: CC(N)Cc1ncccc1N
Reactant: ClC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCn1c(CCl)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-aminopropyl-3-aminopyridine (172) (5.3 g, 35 mmol) is dissolved in 100 mL CHCl3 at room temperature. Ethylchloromethylimidate hydrochloride (14 g, 89 mmol) is added followed by K2CO3 (25 g, 180 mmol). The suspension was stirred vigorously at room temperature for 3 hours. The reaction mixture is filtered through Celite and the, solvent removed in vacuo. The residue is passed through a short plug of silica gel eluting with ethyl acetate to afford 3.7 g of 1-propyl-2-chloromethyl-7-azabenzimidazole (183).
Reaction SMILES: S=[C:2]1[C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[NH:3]1.[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH2:28]>O1CCCC1.[Hg](Cl)Cl>[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH:28][C:2]1[C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[N:3]=1
Reactant: COC(CN)OC
Reactant: O=C(N[C@@H]1CCc2ccccc2NC1=S)OCc1ccccc1
Agent: Cl[Hg]Cl
Solvent: C1CCOC1
Product: COC(CNC1=Nc2ccccc2CC[C@H]1NC(=O)OCc1ccccc1)OC
Temperature: 25 °C
Yield: 92.2 %

Procedure:
Combine benzyl N-[(3R)-2-thioxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]carbamate (8.71 g, 26.68 mmol), mercury dichloride (HgCl2) (9.42 g, 34.69 mmol), and aminoacetaldehyde dimethyl acetal (11.65 mL, 106.73 mmol;) in tetrahydrofuran (250 mL) and heat to 55° C. for 20 minutes. Cool the mixture to ambient temperature and filter it through diatomaceous earth. Wash the cake with THF and ethyl acetate and concentrate the filtrate under reduced pressure. Dissolve the resulting oil in dichloromethane, wash with warm water (4×) and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure to give the title compound (9.78 g, 92%) as a solid: MS (m/z): 398 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]2[S:21][CH:20]=[CH:19][C:10]=2[N:11]=[C:12]([C:14]([O:16][CH2:17]C)=[O:15])[N:13]=1)=[O:7]>CO.O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]2[S:21][CH:20]=[CH:19][C:10]=2[N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:13]=1)=[O:7]
Reactant: CCOC(=O)c1nc(C(=O)c2cccs2)c2sccc2n1
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(C(=O)c2cccs2)c2sccc2n1
Yield: 77.4 %

Procedure:
A solution of ethyl 4-(2-thienylcarbonyl)thieno[3,2-d]pyrimidine-2-carboxylate (100 mg, 0.31 mmol) in MeOH (5 mL) was refluxed for 2 h, cooled, diluted with water and filtered to give the title compound (73 mg, 74%) as a cream solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: Brc1cccc2cc[nH]c12
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
7-Bromoindole(0.37 g, 1.9 mmol) was dissolved in dry DMF. K2CO3 (0.52 g, 3.8 mmol) and methyliodide (0.13 mL, 2.08 mmol) were added. The reaction was stirred at room temperature for 5 days, after which H2O (20 mL) was added, the water phase was extracted with Et2O (3×20 mL), and the combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by chromatography, eluent EtOAc:petroleum ether 1:20 to give 7-bromo-1-methylindole as a crystalline compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[O:5][C:6]1[C:7](Cl)=[N:8][CH:9]=[N:10][C:11]=1Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH2:29])(=[O:28])=[O:27]>C(OCC)(=O)C>[OH:2][CH2:3][CH2:4][O:5][C:11]1[N:10]=[CH:9][N:8]=[C:7]([NH:29][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])(=[O:28])=[O:27])[C:6]=1[O:5][C:4]1[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1S(N)(=O)=O
Reactant: COc1ccccc1Oc1c(Cl)ncnc1Cl
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccccc2OC)ncnc1OCCO

Procedure:
By reacting 5-(2-methoxyphenoxy)-4,6-dichloropyrimidine with o-methoxyphenylsulfonamide and thereafter with ethylene glycol Na, there was obtained N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-o-methoxybenzenesulfonamide, m.p. 164°-165° C. (from ethyl acetate).
Reaction SMILES: CC1(C)C([C:7]2[CH:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C@H:21]([CH2:26][O:27][CH3:28])CC(O)=O)[CH:18]=[CH:19][CH:20]=3)[CH:10]=[CH:9][C:8]=2C2C=C(OC)C=CC=2F)=CCC1.CC1(C)C(C2C=C(C[O:52]C3C=C([C@@H](COC)CC(O)=O)C=CC=3)C=CC=2C2C=C(OC)C=CC=2F)=CCC1>>[CH2:13]([O:14][C:15]1[CH:16]=[C:17]([C:21](=[O:52])[CH2:26][O:27][CH3:28])[CH:18]=[CH:19][CH:20]=1)[C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:12]=1
Reactant: COC[C@H](CC(=O)O)c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(C3=CCCC3(C)C)c2)c1
Reactant: COC[C@@H](CC(=O)O)c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(C3=CCCC3(C)C)c2)c1
Product: COCC(=O)c1cccc(OCc2ccccc2)c1

Procedure:
(3R)-3-(3-(((2-(5,5-Dimethyl-1-cyclopenten-1-yl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)phenyl)-4-(methyloxy)butanoic acid or (3S)-3-(3-(((2-(5,5-dimethyl-1-cyclopenten-1-yl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)phenyl)-4-(methyloxy)butanoic acid (74). Compound 74.2 was obtained from compound 74.1 by a method analogous to that used for the preparation of compound 5.7 as described in Example 5 using a Peterson olefination followed by hydrogenation and final chiral separation. Coupling with 14.5 and hydrolysis was carried out according to the methods described herein. 1H NMR (400 MHz, CDCl3) δ ppm 7.39 (dd, 1H), 7.33 (d, 1H), 7.28 (d, 1H), 7.24 (t, 1H), 6.96 (t, 1H), 6.88 (m, 2H), 6.84 (bd, 1H), 6.79 (m, 2H), 5.52 (bt, 1H), 5.08 (s, 2H), 3.75 (s, 3H), 3.56 (dd, 1H), 3.48 (t, 1H), 3.40 (m, 1H), 3.33 (s, 3H), 2.88 (dd, 1H), 2.65 (dd, 1H), 2.24 (dt, 2H), 1.65 (t, 2H), 0.85 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([N:21](CC)[CH:22]([CH3:24])C)=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]([NH:29][CH:30](C)C)[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([O:12][N:11]=2)[CH2:18][CH2:17][N:16]([C:19]([NH:21][C:22]2[CH:28]=[CH:27][N:29]=[CH:30][CH:24]=2)=[O:20])[CH2:15]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1)C(C)C
Reactant: CCNC(C)C
Product: O=C(Nc1ccncc1)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Yield: 16.4 %

Procedure:
The title compound was synthesized using the method described for the compound of Example 109, replacing 4-aminopyridine for ethylisopropylamine. After the usual work-up procedure evaporation, the crude was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient EtOAc-MeOH/NH3 from 98:2 to 85:15) to afford a pale yellow solid. Yield: 16.4%.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2([CH3:15])[CH3:14])=[C:7]([C:16]2([CH2:19][CH:20]=O)[CH2:18][CH2:17]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25]([CH:27]=[C:28]([CH3:34])[CH2:29]P(=O)([O-])[O-])=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:26])[CH:27]=[C:28]([CH3:34])[CH:29]=[CH:20][CH2:19][C:16]1([C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[C:12]3[C:8]=2[CH2:9][CH2:10][C:11]3([CH3:14])[CH3:15])[CH2:18][CH2:17]1)[CH3:23]
Reactant: CCOC(=O)C=C(C)CP(=O)([O-])[O-]
Reactant: CC(C)(C)c1cc2c(c(C3(CC=O)CC3)c1)CCC2(C)C
Product: CCOC(=O)C=C(C)C=CCC1(c2cc(C(C)(C)C)cc3c2CCC3(C)C)CC1
Yield: 62.5 %

Procedure:
The above unsaturated alcohol (16) (30 mg, 0.16 mmol) was converted to the cyclopropyl alcohol as described in Example 1 to give 33 mg of [1-(6-t-butyl-1,1-dimethyl-indan-4-yl)-cyclopropyl]-ethanol (17) as a pale yellow oil in 67% yield that was used directly for the next step. The above cyclopropyl alcohol (33 mg, 0.15 mmol) was oxidized as described in Example 1 to give 32 mg of 1-(6-t-butyl-1,1-dimethyl-indan-4-yl)-cyclopropaneacetaldehyde (18) as a clear oil in 100% yield. The above cyclopropyl aldehyde 18 (32 mg, 0.15 mmol) and 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (200 mg, 0.77 mmol) were condensed as described for Example 1 to give 37 mg of ethyl-6-[1-(6-t-butyl-1,1-dimethyl-indan-4-yl)-cyclopropyl]-3-methyl-2,4-hexadienoate (19) as a pale yellow oil in 69% yield.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])[CH3:3].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1>>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:17]2[CH:18]=[C:19]([NH2:23])[N:20]=[CH:21][N:22]=2)=[CH:7][C:6]=1[C:12]([F:14])([F:13])[F:15])[CH3:1]
Reactant: Nc1cc(Cl)ncn1
Reactant: CN(C)Cc1ccc(N)cc1C(F)(F)F
Product: CN(C)Cc1ccc(Nc2cc(N)ncn2)cc1C(F)(F)F
Temperature: 150 °C
Reaction time: 5 h

Procedure:
The title compound is prepared as described in Example 152A but using 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (218 mg, 1.46 mmol, 1 eq.), 6-chloro-pyrimidin-4-ylamine, and stirring the reaction mixture for 5 h at 150° C. The crude product is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 92:8) to afford the title compound as a white solid. ESI-MS: 312.1 [MH]+; tR=1.20 min (purity: 100%, gradient J); TLC: Rf=0.16 (DCM/MeOH+1% NH3aq, 92:8).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12]>CS(C)=O.O.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:15][CH:14]([O:17][CH2:18][CH3:19])[O:13][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CBr)OCC
Reactant: Sc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(CSc1cccc(Br)c1)OCC
Temperature: 25 °C
Reaction time: 120 h
Yield: 103.7 %

Procedure:
To a stirred solution of 3-bromothiophenol (5.0 g, 26 mmol) in DMSO (40 mL) was added a solution of KOH pellets (85% by wt, 2.15 g, 32 mmol) in water (4 mL) followed by bromoacetaldehyde diethyl acetal (4.5 mL, 29 mmol). The mixture was stirred at rt for 5 d, diluted with ether (300 mL) and washed with water (3×100 mL). The combined water washes were extracted with ether (100 mL). The combined ether extracts were washed with brine (100 mL), dried over MgSO4 and concentrated to afford (3-bromophenyl)(2,2-diethoxyethyl)sulfane (8.23 g, 100%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C@:20]2([CH3:31])[CH2:25][C@@H:24]([C:26]([F:29])([F:28])[F:27])[O:23][C:22]([NH2:30])=[N:21]2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1>>[NH2:30][C:22]1[O:23][C@H:24]([C:26]([F:28])([F:29])[F:27])[CH2:25][C@:20]([C:14]2[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=[C:12]([NH:11][C:8](=[O:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[CH:13]=2)([CH3:31])[N:21]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: Cn1cc(N)cc([C@]2(C)C[C@@H](C(F)(F)F)OC(N)=N2)c1=O
Product: Cn1cc(NC(=O)c2ccc(Cl)cn2)cc([C@]2(C)C[C@@H](C(F)(F)F)OC(N)=N2)c1=O

Procedure:
This step was performed using procedures analogous to those described in Method H Step 2 (Example 66) above, but using 5-chloro-picolinic acid and 5-amino-3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-1-methylpyridin-2(1H)-one. MS m/z=444.0 [M+H]+. Calculated for C18H17ClF3N5O3: 443.8
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])([O-:13])=[O:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:10])([F:9])[CH:3]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)C(=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(Nc1cccc([N+](=O)[O-])c1)C(F)(F)F
Reaction time: 0.33 h
Yield: 43.9 %

Procedure:
To a solution of methyl trifluoropyruvate (500 mg) and 3-nitroaniline (442 mg) in methylene chloride (32 mL), titanium tetrachloride (350 μL) was added at room temperature, and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture, sodium triacetoxyborohydride (1.35 g) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, water and methylene chloride were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 20% hexane in ethyl acetate) to obtain methyl 3,3,3-trifluoro-2-((3-nitrophenyl)amino)propanoate (C13, 391 mg).
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][N:20]=[C:14]2[CH2:13]1)=[O:11])=O)C.[ClH:31]>CO>[ClH:31].[ClH:31].[NH2:7][C@H:8]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][N:20]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)ccc1F
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)ccc1F

Procedure:
The title compound was prepared from 7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(2,5-difluorophenyl)butanoyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (349.8 mg, 0.72 mol, from Step A) in 1.5 mL of methanol saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Evaporation of solvent gave 299 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CD3OD): δ 3.10-3.17 (m, 2H), 2.89-2.99 (m, 2H), 3.94-4.22 (m, 4H), 4.33 (m, 1H), 4.91-5.48 (m, 2H), 7.07-7.23 (m, 3H), 8.05 (m, 1H). ESI-MS 389(M+1).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.[CH:20]1([CH2:23]Cl)[CH2:22][CH2:21]1>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[N:12]([CH2:23][CH:20]4[CH2:22][CH2:21]4)[CH:11]=[N:10][C:9]=3[N:8]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: ClCC1CC1
Reactant: O=c1c2[nH]cnc2n(CC2CC2)c(=O)n1CC1CC1
Product: O=c1c2c(ncn2CC2CC2)n(CC2CC2)c(=O)n1CC1CC1

Procedure:
1,3-Tri-cyclopropylmethyl-xanthine was prepared from 1,3-di-cyclopropylmethyl xanthine and cyclopropylchloromethane using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 78° C.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C1(O)C=CC=CC=1.[CH3:22][O:23][C:24](=[O:28])[CH:25](Br)[CH3:26]>>[CH:6]([C:5]1[CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]([O:1][CH:25]([CH3:26])[C:24]([O:23][CH3:22])=[O:28])=[C:3]([O:13][CH3:14])[CH:4]=1)=[O:7]
Reactant: COC(=O)C(C)Br
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1c(OC)cc(C=O)cc1[N+](=O)[O-]

Procedure:
Using 4-hydroxy-3-methoxy-5-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a dark oil: 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.95 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.80 (d, J=1.8 Hz, 1 H), 5.15 (q, J=6.8 Hz, 1H), 3.95 (s, 3H), 3.63 (s, 3H), 1.50 (d, J=6.8 Hz, 3H). ESI-MS: m/z 284.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH3:9].C(Cl)(=O)C(C)(C)C.[S:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[CH2:47][CH2:48][NH2:49]>C(Cl)Cl>[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH:49][CH2:48][CH2:47][C:43]4[S:42][CH:46]=[CH:45][CH:44]=4)=[O:32])=[CH:28][N:27]=3)=[O:25])[CH2:22][CH2:23]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:9])[CH3:10]
Reactant: NCCc1cccs1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCc3cccs3)cn2)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Triethylamine (0. 8 ml) was added to 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid (2g) in methylene chloride (30 ml) for dissolution and cooled. With the slow addition of pivaloyl chloride (0. 7 ml) at 0° C.˜5° C., the mixture was stirred at 5° C for 1 hour. With the successive addition of triethylamine (0.9 ml) and 2-thiophenethylamine (0.75 g), the mixture was stirred at 5° C.˜10° C. for 2 hours. The solution was washed with an aqueous sodium bicarbonate and water. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was treated with ether for crystallization. The solid, so obtained, was recrystallized with ethanol and hexane to give a desired compound of 1.92 g (yield: 74%).
Reaction SMILES: C(O[C:6]1[C:11]([F:12])=[CH:10][N:9]=[C:8]([CH:13]([CH:16]2[CH2:18][CH2:17]2)[C:14]#[N:15])[C:7]=1[O:19][CH3:20])(C)(C)C.FC(F)(F)C(O)=O.[Cl:28]CCl>>[Cl:28][C:6]1[C:11]([F:12])=[CH:10][N:9]=[C:8]([CH:13]([CH:16]2[CH2:18][CH2:17]2)[C:14]#[N:15])[C:7]=1[O:19][CH3:20]
Reactant: ClCCl
Reactant: COc1c(C(C#N)C2CC2)ncc(F)c1OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(C#N)C2CC2)ncc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of (4-tert-butoxy-5-fluoro-3-methoxypyridin-2-yl)cyclopropylacetonitrile (0.9 g, 3 mmol) [Example 8] and trifluoroacetic acid (2 mL) in dichloromethane was stirred at room temperature for 25 minutes. The solvent was removed in vacuo and the oily residue dissolved in 15 mL of dichloromethane and 2 mL of dimethylformamide. The resulting solution was cooled in an ice-bath and treated dropwise with phosphoryl chloride (2.4 mL). The solution was allowed to warm to ambient temperature and stirred overnight. The mixture was then poured onto ice and extracted with dichloromethane (2×20 mL). The combined extracts were washed with water, saturated sodium bicarbonate, water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/hexane (1:4) to provide the title compound (0.4 g, 60%). 1H NMR (400 MHz, CDCl3) δ 8.32 (s. 1H), 4.05 (s, 3H), 3.77 (d, 1H), 1.58-1.49 (m 1H), 0.80-0.71 (m, 1H), 0.68-0.55 (m, 2H), 0.52-0.43 (m, 1H). MSCI: m/z=241 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[O:16][CH3:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:28])[CH:11]=2)[CH:6]=1>C(O)(=O)C>[F:28][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:29])=[O:2])[CH:14]=[C:13]2[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[O:16][CH3:17]
Reactant: COC(=O)Cc1cc(C(OC)c2ccc(S(C)(=O)=O)cc2)c2cc(F)ccc2c1
Solvent: CC(=O)O
Product: COC(c1ccc(S(C)(=O)=O)cc1)c1cc(CC(=O)O)cc2ccc(F)cc12

Procedure:
Starting with {6-fluoro-4-[(4-methanesulfonyl-phenyl)-methoxy-methyl]-naphthalen-2-yl}-acetic acid methyl ester, and using the method analogous to the one described for example 2-1, final step, 6-fluoro-4-[(4-methanesulfonyl-phenyl)-methoxy-methyl]-naphthalen-2-yl}-acetic acid (36 mg, 99%) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm: 7.78-7.93 (m, 3 H), 7.75 (br. s, 1 H), 7.50-7.68 (m, 4 H), 7.16-7.31 (m, 1 H), 5.80 (s, 1 H), 3.84 (s, 2 H), 3.45 (s, 3 H), 3.02 (s, 3 H); HRMS (ESI+) cald. for C21H19FO5S [(M+Na)+] 425.0829, obsd. 425.0827.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12](/[C:17](/[C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:18]/[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:13][C:14]=1[O:15][CH3:16]>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12](/[C:17](/[C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[CH:18]/[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:13][C:14]=1[O:15][CH3:16]
Reactant: COc1nc(/C(=C/C2CCCC2)c2ccc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1Cl
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(/C(=C/C2CCCC2)c2ccc(S(=O)(=O)N3CCNCC3)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (0.2 mL) was added to a solution of tert-butyl 4-({4-[(E)-1-(5-chloro-6-methoxypyridin-2-yl)-2-cyclopentylethenyl]phenyl}sulfonyl)piperazine-1-carboxylate (178 mg) in chloroform (3 mL), and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure to give 1-({4-[(E)-1-(5-chloro-6-methoxypyridin-2-yl)-2-cyclopentylethenyl]phenyl}sulfonyl)piperazine as a crude product.
Reaction SMILES: C(OC([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:28]([O:30][CH3:31])=[O:29])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH2:26]([O:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[CH:16]=[CH:15][C:14]3[NH:8][CH2:9][CH2:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[CH:18]=2)=[CH:24][CH:23]=1)[CH3:27]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 92.9 %

Procedure:
In ethyl acetate (50 ml) was dissolved methyl 1-(t-butoxycarbonyl)-7-(4-ethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.1 g). To the solution was added 6N hydrochloric acid (10 ml) and the mixture was stirred at 80° C. for 40 minutes, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-(4-ethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.78 g) as yellow crystals.