Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(OC)C=CC=CC=1.COC1C=CC(C[O:16][C:17](=[O:64])[CH:18]([NH:33][C:34]([NH:36][CH:37]([C:52]([O:54]CC2C=CC(OC)=CC=2)=[O:53])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:51])[C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[O:35])[CH2:19][CH2:20][C:21]([O:23]CC2C=CC(OC)=CC=2)=[O:22])=CC=1>C(O)(C(F)(F)F)=O>[C:52]([CH:37]([NH:36][C:34](=[O:35])[NH:33][CH:18]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:17]([OH:64])=[O:16])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:51])[C:44]1[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=1)([OH:54])=[O:53]
Reactant: COc1ccc(COC(=O)CCC(NC(=O)NC(CCCCNC(=O)c2ccc(F)cc2)C(=O)OCc2ccc(OC)cc2)C(=O)OCc2ccc(OC)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)CCC(NC(=O)NC(CCCCNC(=O)c1ccc(F)cc1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.3 %

Procedure:
A solution of 3% anisole in TFA (15 mL) was added to 5 (0.081 g, 0.1 mmol) at 0° C. The mixture was stirred at room temperature for 20 min then concentrated on a rotary evaporator. The crude material was purified by HPLC (Econosil C18 10 μm, 250×10 mm, H2O/CH3CN/TFA (75/25/0.1), 4 mL/min, with purified 6 eluting at about 9 min) to afford 0.035 g (79%) of 6. 1H-NMR (400 MHz, D2O) δ 7.66-7.69 (m, 2H), 7.11-7.16 (m, 2H), 4.12-4.19 (m, 2H), 3.28-3.31 (m, 2H), 2.39-2.43 (m, 2H), 2.07-2.09 (m, 1H), 1.79-1.90 (m, 2H), 1.55-1.69 (m, 3H), 1.39-1.40 (m, 2H). ESI-Mass calcd for C19H24FN3O8Na [M+Na]+ 464.1. found 464.4. FAB-HRMS calcd for C19H25FN3O8 [M+H]+ 442.1626. found 442.1646.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:2]([NH:1][C:13]([NH:12][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[S:14])[CH2:3][OH:4]
Reactant: NC(CO)c1ccccc1Cl
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccccc1Cl

Procedure:
The title compound was prepared with 2-amino-2-(2-chlorophenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.48 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.77-7.55 (m, 2H), 7.41-7.23 (m, 3H), 7.21 (d, J=8.5 Hz, 2H), 6.81 (dd, J=8.7, 2.6 Hz, 2H), 6.65 (d, J=6.8 Hz, 6H), 5.40 (s, 1H), 3.39 (qd, J=11.6, 4.9 Hz, 2H); ESIMS m/z 518 ([M+H]+).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.I[CH3:16]>C1COCC1>[CH3:16][O:3][CH:4]1[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in oil) (83 mg, 3.46 mmol) was added to tert-butyl 3-hydroxyazetidine-1-carboxylate (J Med chem., 44(1), 2001, 94) (0.3 g, 1.73 mmol) in THF (10 mL), at 0° C., under argon. The reaction was stirred for 30 mins then iodomethane (0.13 mL, 4.15 mmol) added. After stirring at 0° C. for 30 mins and at RT for 3 hours the volatiles were removed in vacuo. Ethyl acetate (40 mL) was added and the mixture washed with brine (40 mL), dried (MgSO4), filtered, and reduced in vacuo to give the desired compound. (0.32 g). 1H NMR δ (CDCl3): 1.42 (s, 9H), 3.27 (s, 3H), 3.81 (m, 2H), 4.06 (m, 2H), 4.11 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:30]=[C:29](F)[CH:28]=[CH:27][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:29]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([F:19])[CH:30]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 110 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenol (1.05 g, 5.34 mmol) in DMSO (10 mL) was added potassium carbonate (2.20 g 13.4 mmol, 2.5 eq.) and the suspension was left to stir for 5 minutes after which, ethyl 2,4-difluorobenzoate (1.0 g, 5.34 mmol) was added and the reaction mixture left to stir at 110° C. under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and quenched with 1N NaOH (10 mL) then extracted into ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered and evaporated. The resulting residue was purified by column chromatography (SiO2, 1:1 ethyl acetate: heptane) to give the desired product (mixture of regioisomers) as a colourless oil (1.8 g, 93% yield). This was taken directly on to the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([CH:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.C(Cl)Cl>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[OH:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Yield: 91.8 %

Procedure:
A solution of 31.2 g (0.079 mole) of α,α-bis-(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol in 400 ml of absolute ethanol was hydrogenated at 50 psi and 70° C. over 5% palladium-on-carbon over the weekend. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a gum as residue. Methylene chloride was added to the residue and the gum crystallized. The mixture was diluted with petroleum ether and the solid was collected by filtration, washed with petroleum ether and dried to yield 22 g (99%) of white solid which was recrystallized from isopropyl ether and 2-propanol, m.p. 159.5°-160.5° C.
Reaction SMILES: NC1N=C2C(NC=N2)=C([Cl:11])N=1.C(=O)([O-])[O-].[K+].[K+].O.NC1N=C2C(N=CN2[CH:29]2[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30]2([Cl:43])[Cl:42])=C(Cl)N=1>CS(C)=O>[Cl:11][C:30]([Cl:42])([Cl:43])[CH:29]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)C1(C(=O)OCC)C(n2cnc3c(Cl)nc(N)nc32)C1(Cl)Cl
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(=CC(Cl)(Cl)Cl)C(=O)OCC
Temperature: 25 °C
Yield: 82.8 %

Procedure:
In a one-liter four-necked flask, 50.0 g (294.9 mmol) of 2-amino-6-chloropurine (manufactured by Sumika Fine Chemicals Co., Ltd.) and 88.2 g (648.0 mmol) of potassium carbonate were added to 650 ml of dimethylsulfoxide, and 26.1 g (1449.9 mmol) of water was then added to the resulting mixture. The resulting mixture was stirred at room temperature. Next, 127.4 g (440.0 mmol) of diethyl 2,2,2-trichloroethylidenemalonate, which was prepared by the process described in U.S. Pat. No. 3,495,012, was added to the resulting mixture, and the mixture was stirred for two hours and a half at room temperature. Thereafter, the reaction mixture was filtered, and the filtrate was poured into water. The precipitated crystals were collected by filtration, washed with 100 ml of water, and then dried under reduced pressure, to give 101.5 g (240.1 mmol) of white crystals of 2-amino-6-chloro-9-(3,3-dicarboethoxy-2,2-dichlorocyclopropyl)purine. The yield was 82.8%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13](=[CH2:17])[CH2:14][CH2:15]O.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC=CC=1.O>[CH3:17][C:13](=[CH2:12])[CH2:14][CH2:15][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: C=C(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: O
Product: C=C(C)CCOc1cccc(NC(C)=O)c1
Temperature: 25 °C
Yield: 52 %

Procedure:
A suspension of the mixture of N-(3-hydroxy-phenyl)-acetamide and acetic acid 3-fonnylamino-phenyl ester (18.12 g, 0.12 mol), 3-methyl-but-3-en-1-ol (8.6 g, 0.1 mol), DEAD (87 g, 0.2 mol) and Ph3P (31.44 g, 0.12 mol) in benzene (250 mL) was heated at reflux overnight and then cooled to room temperature. The reaction mixture was poured into water and the organic layer was separated. The aqueous phase was extracted with EtOAc (300×3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give N-[3-(3-methyl-but-3-enyloxy)-phenyl]-acetamide (11 g, 52%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][C:36]([CH:39]3[CH2:41][CH2:40]3)=[CH:37][CH:38]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][C:36]([CH:39]3[CH2:40][CH2:41]3)=[CH:37][CH:38]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (193 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (342 mg, 88%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][C:18]2[S:19][C:20]([C:28]([CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])=[C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:21]1[N:22]=[C:18]([NH:17][C:15](=[O:16])[CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[S:19][C:20]=1[C:28]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CN1CCNCC1)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
Compound 560 (428 mg, 0.849 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added thereto at 0° C., followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was reslurried with diethyl ether to afford the entitled Compound 561 (263 mg, 7.7%).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH:7]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH:23]1[O:28][CH2:27][CH2:26][CH2:25][O:24]1.C(N(CC)CC)C.Cl.[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH:42][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([CH:7]([O:6][C:5]2[CH:21]=[CH:22][C:2]([Br:1])=[C:3]([CH:23]3[O:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH:4]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=1
Reactant: CC(C)CC(Oc1ccc(Br)c(C2OCCCO2)c1)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(Br)c(C3OCCCO3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[1-(4-bromo-3-[1,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzoic acid (940 mg, 2.09 mmol) in methylene chloride (21 mL) is added triethyl amine (0.88 mL, 6.28 mmol), DMAP (5.0 mg), 3-Amino-propionic acid methyl ester hydrochloride (438 mg, 3.14 mmol) and EDCI (1207 mg, 6.28 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving the titled compound (670 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([CH2:12][C:13](OCC)=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[BH4-].CC[O:22]CC>>[C:1]([N:8]1[CH2:11][CH:10]([CH:12]([OH:22])[CH3:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOCC
Reactant: CCOC(=O)CC1CN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Li+]
Product: CC(O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 55 °C

Procedure:
A stirred solution of 33-4 (0.96 g, 3.9 mmol) in ether (20 mL) at ambient temperature was treated with LiBH4 (0.34 g, 15.8 mmol) then heated to 55° C. After 45 min the cooled reaction was quenched with 5% KHSO4 (10 mL) and then diluted with EtOAc. The organic phase was washed with 5% KHSO4 and brine, dried (MgSO4), and concentrated to give 33-5 (0.79 g) as a colorless oil. Rf 0.46 (silica, EtOAc).
Reaction SMILES: [CH:1]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:24][C:25]([N:27]([CH2:32][CH2:33][NH:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N+:44]([O-:46])=[O:45])(=[O:37])=[O:36])[CH2:28][C:29]([OH:31])=O)=[O:26])[C:20](=[O:47])[N:19]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O>C1COCC1>[CH:1]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:24][C:25]([N:27]2[CH2:32][CH2:33][N:34]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[N+:44]([O-:46])=[O:45])(=[O:36])=[O:37])[C:29](=[O:31])[CH2:28]2)=[O:26])[C:20](=[O:47])[N:19]=1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2)c(=O)n1)OC(c1ccccc1)c1ccccc1
Temperature: -20 °C
Yield: 77.3 %

Procedure:
To a solution of N-{[4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetyl}-N-[2-(2-nitro-benzenesulfonylamino)-ethyl]-glycine (1.20 g, 1.8 mmol) in THF (24 mL) was added N-methylmorpholine (0.6 mL, 5.42 mmol) and then the mixture was cooled to −20° C. After stirring for 5 min at the same temperature, isobutyl chloroformate (0.30 mL, 2.31 mmol) was added to the reaction mixture. The resulting mixture was slowly warmed to 0° C. for 1 h. Then the reaction mixture was evaporated in vacuo and dissolved in a mixture of ethyl acetate and acetonitrile. The solution was washed with saturated NaCl solution and dried over sodium sulfate and filtered. The filtrate was evaporated in vacuo and triturated with methanol to precipitate solid. The solid was filtered off, washed with methanol, and dried in vacuo to give the titled compound 0.9 g (77%). 1H-NMR (500 MHz; DMSO-d6) δ 8.35 (t, 1H), 8.12˜7.95 (m, 3H), 7.90 (d, 0.6H), 7.84 (d, 0.4H), 7.48˜7.28 (m, 10H), 6.95 (d, 0.6H), 6.94 (d, 0.4H), 6.79 (s, 1H), 4.82 (s, 1.2H), 4.73 (s, 0.8H), 4.45 (s, 0.8H), 4.27 (s, 1.2H), 4.10˜3.95 (m, 2.4H), 3.95˜3.80 (m, 1.6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[CH3:26].[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=5)[C:3]([CH3:26])=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Reactant: COc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A solution of N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (38 mg, 0.1 mmol) in DME (1 mL) was added to a reaction tube containing 6-methoxypyridin-3-ylboronic acid (46 mg, 0.15 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol). Saturated Na2CO3 solution was added (100 μL) and the reaction was stirred at 80° C. overnight. The reaction was filtered, concentrated and purified by column chromatography (0-50% ethyl acetate in hexanes) to obtain 40 mg (44%) of a clear oil. ESI-MS m/z calc. 453.4. found 454.3 (M+1)+. Retention times: 2.06 minutes. H NMR (400 MHz, DMSO) 8.76 (s, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.82 (s, 1H), 7.74 (dd, J=2.4, 8.5 Hz, 1H), 7.55 (d, J=1.3 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.33 (dd, J=1.5, 8.3 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 3.88 (s, 3H), 2.31 (s, 3H), 2.13 (s, 3H), 1.51-1.49 (m, 2H), 1.18-1.15 (m, 2H).
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2(O)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:13]([CH3:24])[CH2:12]2)=[CH:7][CH:6]=1.NS(F)(F)[F:28].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[F:28][C:11]1([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:13]([CH3:24])[CH2:12]1
Reactant: CC1CC(O)(c2ccc(F)cc2)CCN1C(=O)OC(C)(C)C
Reactant: NS(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1CC(F)(c2ccc(F)cc2)CCN1C(=O)OC(C)(C)C
Yield: 90.1 %

Procedure:
To a dichloromethane solution (2.0 mL) of tert-butyl 4-(4-fluorophenyl)-4-hydroxy-2-methylpiperidine-1-carboxylate (60.0 mg, 0.194 mmol) synthesized in Reference Synthesis Example 279, bis(2-methoxyethyl))amino-sulfur trifluoride (46.9 mg, 0.291 mmol) was added at −78° C. and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, saturated sodium carbonate aqueous solution was added to the reaction solution and extraction from the resultant mixture with chloroform was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product (54.4 mg) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)cn1N
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CO
Product: COC(=O)c1cc(Cl)cn1N=Cc1ccc(Cl)cc1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester and 4-chloro benzaldehyde in refluxing methanol for 12 h. 1H NMR (CDCl3, δ in ppm): 8.35 (s, 1H), 7.78 (d, 2H, J=7.6 Hz), 7.42 (d, 2H, J=7.6 Hz), 7.19 (d, 1H, J=2.2 Hz), 6.89 (d, 1H, J=2.2 Hz), 3.83 (s, 3H).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1(O)[C:12]([CH3:14])([CH3:13])[CH2:11][C:10]([CH3:16])([CH3:15])[CH2:9][CH:8]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=1)([CH3:4])[CH3:3].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C(#N)C.O>[CH3:3][Si:2]([C:5]#[C:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][C:10]([CH3:16])([CH3:15])[CH2:9][C:8]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=1)([CH3:1])[CH3:4]
Reactant: Cc1cc(C2CC(C)(C)CC(C)(C)C2(O)C#C[Si](C)(C)C)ccc1F
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: O
Solvent: CC#N
Product: Cc1cc(C2=C(C#C[Si](C)(C)C)C(C)(C)CC(C)(C)C2)ccc1F
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of the hydroxy acetylene from Example 1, Step C above (20 g, 55.5 mmol) in acetonitrile (250 ml) is added 20 g (83 mmol) of Burgess reagent. The reaction mixture is heated at reflux for 14 hours, cooled to room temperature and diluted with H2O (1 L). The aqueous solution is extracted with ether and the combined ether layers are washed with H2O. The ether fraction is dried over MgSO4 and the solvent is removed under reduced pressure. Purification by silica gel chromatography (100% hexane) provides 12.7 g (67%) of 1-((trimethylsilyl)ethynyl)-2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohexene as an oil: 1H NMR δ=0.0 (s,9), 0.95 (s,6), 1.15 (s,6), 1.4 ((s,2), 2.1 (s,2), 2.2 (s,3), 6.85 (t,1), 7.25 (m,2).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][CH2:13][CH:14]=[O:15])[CH3:2]
Reactant: O=CCCl
Reactant: CCc1cccc(CC)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1cccc(CC)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Diethylaniline (100 grams), the dimethyl acetal of 2-chloroacetaldehyde (37.5 grams) and sodium carbonate (31.8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture was heated at a temperature of about 150°C for a period of about 30 hours. After this time the reaction mixture was cooled to room temperature and was filtered. The filtrate was then distilled under vacuum to yield the desired product the dimethyl acetal of 2-(2,6-diethylanilino)acetaldehyde as the residue having a boiling point of 120°C at 1 mm of Hg pressure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[C:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:11]=[N:12]2)=[C:7]([I:24])[N:6]=1)=[O:4].C1CCN2C(=NCCC2)CC1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.S([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:13]2[C:8]([CH:9]=[C:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:11]=[N:12]2)=[C:7]([I:24])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1O
Reactant: BrCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.3 %

Procedure:
To a dimethylformamide suspension (80 ml) of the above Compound 7 (8.76 g, 20 mmol) were added DBU (4.48 ml, 30 mmol) and benzylbromide (3.56 ml, 30 mmol), and the solution was stirred for 5 hours at room temperature. The reaction solution was added with 0.5M citric acid aqueous solution and 10% sodium hydrogen sulfite aqueous solution, and extracted twice with ethyl acetate. The organic phase was washed with water, saturated sodium hydrogen carbonate and saturated brine. After drying over anhydrous magnesium sulfate, the residue obtained by distilling off the solvent was subjected to silica gel chromatography. The precipitated crystals were collected by filtering, and washed with diisopropyl ether, to give 8-benzyloxy-3-(4-fluorobenzyl)-5-iodo[1,6]naphthyridine-7-carboxylic acid methyl ester 8 (7.64 g) in 72% yield.