Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:15][C:14]=2[F:29])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:42][O:43][CH2:44][CH2:45][OH:46]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:15][C:14]=2[F:29])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:42][O:43][CH2:44][CH2:45][OH:46])=[O:7]
Reactant: NOCCO
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(C#CCOC2CCCCO2)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCOC2CCCCO2)cc1F
Yield: 69 %

Procedure:
The title compound was prepared from reaction of 3,4-difluoro-2-{2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]anilino}benzoic acid with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E, then purified by column chromatography on silica gel (50% EtOAc/PE) as eluant), to give 3,4-difluoro-2-{2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]anilino}-N-(2-hydroxyethoxy)benzamide as a white solid (69%) which was used directly in the next step. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.87 (br s, 1 H), 7.46–7.39 (m, 1 H), 7.31 (dd, J=12.2, 1.8 Hz, 1 H), 7.28–7.20 (m, 1 H), 7.14 (dd, J=8.3, 1.6 Hz, 1 H), 6.79 (ddd, J=8.8, 8.8, 4.7 Hz, 1H), 4.80 (br s, 1H), 4.46 (d, J=16.1 Hz, 1H), 4.36 (d, J=16.0 Hz, 1 H), 3.84 (t, J=4.8 Hz, 2 H), 3.75 (ddd, J=11.5, 8.6, 3.3 Hz, 2 H), 3.55 (t, J=4.8 Hz, 2 H), 3.51–3.44 (m, 2 H), 1.76–1.60 (m, 2 H), 1.55–1.42 (m, 4 H). HRMS (EI+) calcd. for C23H23F3N2O5 464.1559 (M+), found 464.1558.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.S([O-])([O-])(=O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([N:1]2[C:9]3=[N:8][CH:7]=[CH:6][CH:5]=[C:4]3[CH:3]=[CH:2]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 7-azaindole (25 g), para-toluenesulfonyl chloride (44.5 g) and a catalytic amount of tetrabutylammoniun sulfate in dry toluene (300 mL) was added sodium hydroxide (160 g in 500 mL of water). The biphasic solution was stirred at ambient temperature for 3 hours then extracted twice with toluene (100 mL). The combined extracts were dried over magnesium sulfate then concentrated under vacuo. The resultant solid was triturated with diethyl ether then dried at 60° C. under vacuo to yield the title compound (39.74 g) as a pale yellow solid, m.p. 136-138° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]=1.[OH-].[NH4+:13]>C(O)(C)C>[NH2:13][C:2]1[CH:11]=[N:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]=1
Reactant: [NH4+]
Reactant: Clc1cnc2ncccc2n1
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1cnc2ncccc2n1
Temperature: 115 °C

Procedure:
A mixture of 2-chloro-pyrazino[2,3-b]pyridine (3.35g), isopropanol (20 mL) and concentrated ammonium hydroxide (50 mL) was heated at 115° C. for 17 h in a sealed tube. The tube was cooled and the product was collected and recrystallized from ethanol to afford 2-amino-pyrazino[2,3-b]pyridine as a yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[F:20][C:21]1[S:25][C:24]([NH2:26])=[N:23][CH:22]=1>>[F:20][C:21]1[S:25][C:24]([NH:26][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:23][CH:22]=1
Reactant: Nc1ncc(F)s1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2ncc(F)s2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 5-Fluoro-thiazol-2-ylamine instead of 3-Chloroaniline to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=333.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][NH:19][C:20](=[O:35])[C:21]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:26])[C:22]([F:25])([F:24])[F:23])=O)=[N:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.C(N(CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[CH2:28]([O:27][C:21]([C:20]1[O:35][C:16]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([C:12]([F:13])([F:14])[F:15])[N:4]=2)=[N:18][N:19]=1)([CH3:26])[C:22]([F:25])([F:24])[F:23])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(OCc1ccccc1)(C(=O)NNC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OCc1ccccc1)(c1nnc(-c2nc(C(F)(F)F)c(C(F)(F)F)nc2N)o1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 3-amino-W-(2-(benzyloxy)-3,3,3-trifluoro-2-methylpropanoyl)-5,6-bis(trifluoromethyl)pyrazine-2-carbohydrazide (step 1) (510 mg, 0.982 mmol) in DCM (20 ml) was treated with triethylamine (0.411 ml, 2.95 mmol) and stirred at RT. Tosyl chloride (562 mg, 2.95 mmol) was added and stirring continued for 30 minutes. The reaction mixture was partitioned between EtOAc (50 ml) and 1M HCl (50 ml), shaken and separated. The organic portion was washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo to give a yellow oil. The crude product was purified by mass directed LC-MS eluting with MeCN/Water/0.1% TFA. The clean fractions were poured into EtOAc (50 ml) and washed with saturated NaHCO3 (50 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound as a white crystalline solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:26])=[O:27])=[CH:33][CH:32]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccc(Cl)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
Lithium hydroxide monohydrate (0.013 g, 0.30 mmol) was added to a stirred solution of {4-[4-(4-chloro-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.037 g, 0.076 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(4-chloro-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.035 g, 98%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s., 1 H) 8.14 (d, J=7.82 Hz, 2 H) 8.09 (d, J=8.80 Hz, 2 H) 7.97-8.04 (m, 1 H) 7.90 (s, 1 H) 7.77 (d, J=7.82 Hz, 2 H) 7.53 (d, J=7.83 Hz, 2 H) 7.38 (td, J=8.30, 2.40 Hz, 1 H) 6.63 (d, J=10.76 Hz, 1H) 3.83 (s, 2 H) 2.02 (s, 3 H). MS calcd. for C25H18ClFO4S [(M−H)−] 467, obsd. 467.3.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][O:23][C:17]=2[CH:16]=1)=O.[OH-].[Na+]>C(O)C>[CH2:22]1[O:21][C:18]2[CH:19]=[CH:20][C:15]([CH:13]=[CH:12][C:7]([C:6]3[CH:1]=[CH:2][C:3]4[O:11][CH2:10][O:9][C:4]=4[CH:5]=3)=[O:8])=[CH:16][C:17]=2[O:23]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
A mixture of piperonal (460 mg) and 3,4-methylenedioxyacetophenone (500 mg) in ethanol (20 ml) was treated with 1M NaOH solution (4 ml), then the mixture was stirred overnight. The pale yellow crystalline solid was filtered off, washed with water then cold aqueous ethanol and dried to give pure bis(3,4-methylenedioxy)chalcone DC-0006B (476 mg, 53%).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[CH:18][CH:17]=1)[CH2:12]2)=O)(C)(C)C.Cl.O1CCOCC1>ClCCl>[CH3:31][S:28]([N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([CH:11]3[CH2:10][CH:9]4[NH:8][CH:13]([CH2:14][CH2:15]4)[CH2:12]3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)(=[O:29])=[O:30]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1ccc(N3CCN(S(C)(=O)=O)CC3)cc1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(C3CC4CCC(C3)N4)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
3-[4-(4-Methanesulfonylpiperazin-1-yl)phenyl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.758 g, 1.69 mmol) is solubilized in 158 ml of dichloromethane. 4N HCl in dioxane (4.2 ml, 16.8 mmol) is then added. After stirring for 16 h at ambient temperature, the reaction medium is concentrated, taken up with water, and washed with ethyl acetate. The pH of the aqueous phase is then adjusted to 10 with a 5N aqueous solution of sodium hydroxide. After extraction with dichloromethane, and washing with water and then with a saturated aqueous sodium chloride solution, the organic phase is dried over MgSO4 and then concentrated to dryness. 0.51 g of expected 3-[4-(4-methanesulfonylpiperazin-1-yl)phenyl]-8-aza-bicyclo[3.2.1]octane is obtained, which is subsequently used as it is.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:15]([OH:17])=O)[CH3:2].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][C@H:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][C@H:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:15]([C:4]3[N:3]([CH2:1][CH3:2])[C:11]4[C:6]([CH:5]=3)=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=[CH:9][CH:10]=4)=[O:17])=[CH:33][CH:32]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOc1cccc2c1cc(C(=O)O)n2CC
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(N)cc2)C1
Product: CCOc1cccc2c1cc(C(=O)Nc1ccc(O[C@H]3CCN(C(=O)OC(C)(C)C)C3)cc1)n2CC

Procedure:
This compound was prepared from N-ethyl-4-ethoxy-indole-2-carboxylic acid and (S)-3-(4-amino-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as described in the intermediate preparation section. LCMS for C28H35N3O5 calcd. (m/e) 493, observed 494 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][CH:3]=1.[C:11]1(=[O:24])[C:16]2=[CH:17][C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=3[N:15]2[CH2:14][CH2:13][NH:12]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:10][C:6]1[N:5]=[CH:4][CH:3]=[C:2]([N:12]2[CH2:13][CH2:14][N:15]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[CH:17]=[C:16]3[C:11]2=[O:24])[C:7]=1[CH:8]=[O:9]
Reactant: O=Cc1c(Br)ccnc1Cl
Reactant: O=C1NCCn2c1cc1c2CCCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1c(N2CCn3c(cc4c3CCCC4)C2=O)ccnc1Cl
Temperature: 65 °C
Yield: 133.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 104a (1.1 g, 5.0 mmol), 3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 101e (477 mg, 2.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (230 mg, 0.25 mmol), XantPhos (430 mg, 0.75 mmol), Cs2CO3 (1.6 g, 5.0 mmol), and 1,4-dioxane (50 mL). After three cycles of vacuum/argon flush, the mixture was heated at 65° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1) to afford 104b as a yellow solid (1.1 g, 80%). MS: [M+H]+ 330.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[C:5]([N+:21]([O-:23])=[O:22])[CH:4]=[N:3]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][N:2]1[C:6]([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[C:5]([N+:21]([O-:23])=[O:22])[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1N1CCCNCC1
Yield: 64 %

Procedure:
A solution of tert-butyl 4-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-diazepane-1-carboxylate (200 mg, 0.61 mmol) in DCM (4 mL) and TFA (4 mL) was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, basified with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified via silica gel column chromatography (0-10% methanol/DCM) to gave 1-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-diazepane (88 mg, 64%). This was dissolved in acetonitrile (3 mL). tert-Butyl 3-iodoazetidine-1-carboxylate (221 mg, 0.78 mmol) and DIPEA (5 eq) were added and the mixture was heated at 75° C. for 7 days, with additional iodide and DIPEA added on days 2 and 3. The reaction mixture was cooled to room temperature, water (20 ml) was added and the mixture was extracted with DCM (50 mL). The organic layer was washed with water (20 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-10% methanol/DCM) to gave tert-butyl 3-[4-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-diazepan-1-yl]azetidine-1-carboxylate (144 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.Br[C:45]1[N:50]=[CH:49][CH:48]=[CH:47][N:46]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32]([C:45]3[N:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1
Reactant: Brc1ncccn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(ncn4-c4cccc(NS(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ncccn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of N-(3-{1-(4-chloro-phenyl)-6-oxo-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,6-dihydro-purin-9-yl}-phenyl)-methane sulfonamide (prepared as described in example 26, 0.55 g, 0.88 mmol) in N,N-dimethylformamide (15 mL) is degassed with argon for 0.5 h. Then 2-bromo-pyrimidine (0.21 g, 1.32 mmol), cesium carbonate (0.57 g, 1.76 mmol), Pd(dppf)2Cl2 (0.032 g, 0.044 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 4 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford N-{3-[1-(4-chloro-phenyl)-6-oxo-2-(4-pyrimidin-2-yl-phenyl)-1,6-dihydro-purin-9-yl]-phenyl}-methane sulfonamide. 1H NMR (DMSO-d6, 400 MHz) δ 10.13 (br, 1H), 9.18 (s, 1H), 9.15 (s, 2H), 8.52 (s, 1H), 8.04 (m, 1H), 7.80 (m, 3H), 7.60 (m, 2H), 7.50 (m, 5H), 7.18 (dd, 1H), 3.02 (s, 3H); LC-MS calculated for C28H20ClN7O3S (M+H+) 570.1, found 569.9.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]2[OH:20].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:20])[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:7]2[O:12][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: Cc1cc2c(cc1C)C(O)N(c1cccc(F)c1)C2=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1c2cc(C)c(C)cc2C(=O)N1c1cccc(F)c1
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
To a solution of 5,6-dimethyl-2-(3-fluorophenyl)-3-hydroxyisoindolin-1-one (0.15 g, 0.55 mmol) in anhydrous tetrahydrofuran (5 ml) was added 60% sodium hydride (24 mg, 0.60 mmol), and stirred on ice for 10 minutes. Then, ethyl bromoacetate (67 ml, 0.60 mmol) was added thereto, and stirred at 25° C. overnight. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extracting with ethyl acetate. The extract was washed with saturated brine, dried, and concentrated under reduced pressure to give 0.19 g of 5,6-dimethyl-2-(3-fluorophenyl)-3-ethoxycarbonylmethyloxy-isoindolin-1-one [IUPAC name: ethyl 2-{[2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}-acetate].
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.S(=O)(=O)(O)O>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:11][CH:3]([C:2]([Cl:1])([Cl:12])[Cl:13])[C:4]2[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=2)=[CH:17][CH:16]=1
Reactant: OC(c1ccc(Cl)cc1)C(Cl)(Cl)Cl
Reactant: Oc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: Clc1ccc(OC(c2ccc(Cl)cc2)C(Cl)(Cl)Cl)cc1
Reaction time: 2 h

Procedure:
α-trichloromethyl-p-chlorobenzyl alcohol, 5.0g, was stirred with p-chlorophenol, 2.6g, and sulfuric acid, 35 ml, was added dropwise. After 2 hrs. of stirring, the mixture was poured onto ice and extracted with ether. After drying with sodium sulfate, the ether was removed under vacuum and the residue was recrystallized from ethanol to give α-trichloromethyl-p-chlorobenzyl p-chlorophenyl ether, mp 101°C. This method of synthesis is referred to in Table I as method A.
Reaction SMILES: [CH3:1][CH:2]([NH2:28])[CH:3]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[CH2:4][C:5]1[O:6][C:7]([C:10](=[O:18])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1.ClCC1OC(C(=O)NC2C=CC=CC=2)=CC=1.C1OC2C=CC(CC(=O)C)=CC=2O1.[N+](C1C=CC(CC(=O)C)=CC=1)([O-])=O.ClCC1O[C:76]([C:78]([O:80][CH2:81]C)=[O:79])=CC=1.C(=O)([O-])[O-].[K+].[K+].BrCC(OC)=O>CN(C)C=O.O>[CH3:81][O:80][C:78]([CH2:76][NH:28][CH:2]([CH3:1])[CH:3]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[CH2:4][C:5]1[O:6][C:7]([C:10](=[O:18])[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)=[O:79]
Reactant: CC(N)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: CC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)Cc1ccc2c(c1)OCO2
Agent: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNC(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
200 mg of N-[(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]amine prepared in the same manners as in Reference Example 4(1) to (3) by using 3,4-methylenedioxyphenylacetone and 2-(chloromethyl)-5-phenylcarbamoylfuran prepared in Reference Example 5 instead of 4-nitrophenylacetone and ethyl 5-(chloromethyl)-2-furancarboxylate used as the starting materials in Reference Example 4 was dissolved in 3 ml of dimethylformamide, and 88 mg of potassium carbonate was added. 88 mg of methyl bromoacetate was added under cooling with ice, and the resulting solution was stirred at room temperature for 15 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography [Kieselgel™60F254, Art™5717; hexane/ethyl acetate=1/1] to give 159 mg of the title compound as a colorless foamy substance.
Reaction SMILES: [CH:1]([Cl:4])(Cl)[Cl:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH2:14])=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].O>CC1CCCCC1>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:12][CH:11]=3)[CH2:14][C:1]2([Cl:4])[Cl:2])=[CH:20][CH:19]=1
Reactant: ClC(Cl)Cl
Reactant: C=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC1CCCCC1
Solvent: O
Product: COc1ccc(C2(c3ccc(OC)cc3)CC2(Cl)Cl)cc1
Temperature: 20 °C

Procedure:
Chloroform (0.2 moles) was added dropwise with stirring to a solution of 1,1-di-(p-methoxyphenyl)ethylene (0.1 mole) in methyl cyclohexane containing potassium tert-butoxide (0.4 moles) at 0°C. The mixture was allowed to warm to 20°C. overnight and then poured into water. The oil phase was separated and the solvent recovered. The residual solid was recrystallized from petroleum ether to give 1-(p-methoxyphenyl)-1-(p-methoxyphenyl)-2,2-dichlorocyclopropane, m.p. 141°C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[C:13]1[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCn1cc(Br)cn1
Reactant: Fc1c(Cl)ccc2cc[nH]c12
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCn1cc(-n2ccc3ccc(Cl)c(F)c32)cn1
Temperature: 140 °C
Yield: 36 %

Procedure:
To a stirred solution of 6-chloro-7-fluoro-1H-indole 8 (400 mg, 2.36 mmol) in toluene (10 mL) were added 4-bromo-1-ethyl-1H-pyrazole 4 (Step 3 above; 414 mg, 2.36 mmol), potassium phosphate (1.25 g, 5.91 mmol), N,N′-dimethylethylenediamine (84 mg, 0.95 mmol) and Cu(I)I (45 mg, 0.24 mmol) at RT under inert atmosphere. The resulted solution was purged with argon and sealed the tube. The reaction mixture was then heated to 140° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to RT, diluted with hexane (10 mL) and filtered through a short pad of celite. The filtrate was washed with water (2×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel chromatography; 8-10% EtOAc/Hexanes) to afford compound 9 (224 mg, 36%) as a light brown thick liquid. 1H NMR (500 MHz, CDCl3): δ 7.64 (s, 1H), 7.61 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.12-7.07 (m, 2H), 6.60-6.59 (m, 1H), 4.22 (q, J=7.5 Hz, 2H), 1.55 (t, J=7.5 Hz, 3H); LC-MS (ESI): 94.7%; m/z 264.1 (M+H+); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 3.87 min; 5 mM NH4OAc: ACN; 0.8 mL/min).