Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH2:26]([O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)Cc1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a mixture of diisopropylamine (1.1 mL, 7.7 mmol) and tetrahydrofuran (20 mL) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 4.5 mL, 7.1 mmol) at −78° C., which was stirred for 30 minutes at that temperature. Tributyltin hydride (1.7 mL, 6.5 mmol) was added dropwise to the reaction mixture at the same temperature and then stirred for 30 minutes at 0° C. The reaction mixture was cooled to −78° C., and a mixture of 4-benzyloxybenzyl chloride (1.5 g, 6.5 mmol) and tetrahydrofuran (10 mL) was added dropwise at that temperature. The reaction mixture was gradually warmed to room temperature. The reaction mixture was partitioned into water and n-heptane. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:30) to obtain the title compound (2.6 g, 83%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15](O)=[O:16].CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:12]([CH3:11])[CH:13]=1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ccc([N+](=O)[O-])c(C)c1)[C@@H](C)O
Yield: 900.1 %

Procedure:
The same operation as in Example (102a) was performed using threonine methyl ester hydrochloride (6.73 g, 39.6 mmol), 3-methyl-4-nitrobenzoic acid (7.18 g, 3.96 mmol), WSC hydrochloride (8.05 g, 42 mmol), DMAP (0.18 g, 1.5 mmol), N,N-diisopropylethylamine (5.42 g, 42 mmol) and dichloromethane (100 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/3, 2/3, 3/2, 3/1) to obtain 10.56 g of the title compound as a light yellow amorphous solid (90%).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][CH2:6][CH:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([CH3:32])[N:13]=[C:14]([CH2:17][N:18]4[CH2:23][C@@H:22]5[CH2:24][C@H:19]4[CH2:20][N:21]5C(OC(C)(C)C)=O)[C:15]=3[N:16]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C@H:19]12[CH2:24][C@H:22]([NH:21][CH2:20]1)[CH2:23][N:18]2[CH2:17][C:14]1[C:15]2[N:16]=[C:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:33])([CH3:1])[CH2:3][CH2:4]3)[S:9][C:10]=2[N:11]=[C:12]([CH3:32])[N:13]=1
Reactant: Cc1nc(CN2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)c2nc(C3CCC(C)(C)CC3)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(CN2C[C@@H]3C[C@H]2CN3)c2nc(C3CCC(C)(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To tert-butyl (1S,4S)-5-{[2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (476 mg) and DCM (10 mL) was added trifluoroacetic acid (2.0 mL), followed by stirring at room temperature for 2 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column to obtain 7-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylmethyl]-2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidine (332 mg).
Reaction SMILES: C(O[C:9](=O)[N:10](C)[CH:11]([C:13](=[O:36])[NH:14][CH:15]([C:19]([N:21]1[CH2:25][CH2:24][CH:23]2[NH:26][CH2:27][CH:28]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:22]12)=[O:20])[CH:16]([CH3:18])[CH3:17])[CH3:12])C1C=CC=CC=1.CCN(C(C)C)C(C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:48][S:49]([N:26]1[CH:23]2[CH:22]([N:21]([C:19]([CH:15]([NH:14][C:13](=[O:36])[CH:11]([NH:10][CH3:9])[CH3:12])[CH:16]([CH3:18])[CH3:17])=[O:20])[CH2:25][CH2:24]2)[CH:28]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:27]1)(=[O:51])=[O:50]
Reactant: CC(C)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(=O)N1CCC2NCC(Oc3ccccc3)C21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(Oc1ccccc1)CN2S(C)(=O)=O)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution containing 18 (150 mg, 0.28 mmol) in DCM (3 mL) was cooled to 0° C. DIPEA (74 mg, 0.57 mmol) and DMAP (4 mg, 0.03 mmol) were added followed by the addition of MsCl (36 mg, 0.32 mmol). After 1 h, the reaction mixture was warmed to ambient temperature, diluted with DCM, washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude sulfonamide which was used without further purification. Mass spectrum, m/z [601] (M+H)+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:29][C:30]#[N:31].CI>O1CCCC1>[F:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[CH:29]([CH3:1])[C:30]#[N:31]
Reactant: CC(C)NC(C)C
Reactant: N#CCc1cccc(F)c1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C#N)c1cccc(F)c1F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 51.5 %

Procedure:
A solution of 1.586 g (16 mmol) diisopropylamine in 25 ml tetrahydrofuran was cooled with sodium chloride/ice to −10° C. A solution of 9 ml (14 mmol) 1.6 M butyl lithium in hexanes was added drop-wise. After stirring for 10 min the resulting LDA solution was cooled to −78° C. and a solution of 2.00 g (13 mmol) 2,3-difluorophenyl-acetonitrile in 5 ml tetrahydrofuran slowly added. The reaction mixture was stirred at −78° C. for 40 min, then 2.22 g (16 mmol) methyl iodide were added and the cooling bath was removed after 5 min. The mixture was stirred for 2.5 h at room temperature, and then aqueous ammonium chloride solution was added. The mixture was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified using column chromatography (SiO2, heptanes/ethyl acetate 9:1) to yield 1.12 g of rac-2-(2,3-difluoro-phenyl)-propionitrile as a light yellow liquid; MS (EI): 167.1 (M+.), 152.1 (((M-CH3)+.), 100%).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15](=[N:18][C:19]#[N:20])SC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:21][N:22]([CH2:24][C:25]1[O:29][C:28]([CH2:30][S:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1)[CH3:23]>C(#N)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:34][CH2:33][CH2:32][S:31][CH2:30][C:28]2[O:29][C:25]([CH2:24][N:22]([CH3:23])[CH3:21])=[CH:26][CH:27]=2)=[N:18][C:19]#[N:20])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CSC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC#N
Product: CN(C)Cc1ccc(CSCCNC(=NC#N)NCCSCc2csc(NC(=N)N)n2)o1
Yield: 19.9 %

Procedure:
A solution of 2-guanidino-4-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]thiazole (0.5 g) and 2-[5-dimethylaminomethylfuran-2-ylmethylthio]ethylamine (0.33 g) in acetonitrile (10 ml) was heated under reflux for 48 hours. A further portion of 2-[5-dimethylaminomethylfuran-2-ylmethylthio]ethylamine (0.5 g) was added and the mixture was heated under reflux for 16 hours. The mixture was evaporated to dryness and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was dried with anhydrous magnesium sulphate and evaporated. The residual gum was triturated four times with warm diethyl ether (10 ml). The residue was further purified by applying to Merck 60 F254 preparative plates and eluting with acetonitrile/ammonia (s.g. 0.880) 7:1 v/v. The product was redissolved in acetonitrile (5 ml), and the solution filtered and evaporated to give 2-guanidino-4-[2-(2-cyano-3-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]guanidino)-ethylthiomethyl]thiazole as pale brown gum (0.15 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8](=O)[NH:9][C:5]=2[CH:4]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[NH:7][C:6]2[CH:11]=[CH:12][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][C:5]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2[nH]1
Product: FC(F)(F)c1ccc2[nH]c(Cl)nc2c1

Procedure:
Reflux 5-trifluoromethyl-1,3-dihydro-benzimidazol-2-one (17 g; Meanwell et al. (1995) J. Org. Chem. 60(6):1565-1582) for 14 hours in POCl3 (200 mL). Evaporate the solvent in vacuo, then carefully neutralize with saturated NaHCO3, and extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, and purify by flash chromatography (1:1 hexanes/EtOAc) to obtain 2-chloro-5-trifluoromethyl-1H-benzimidazole. B. 1′-(5-Trifluoromethyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one hydrochloride
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][OH:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>CO.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][O:13][C:30](=[O:31])[NH:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]([F:21])([F:33])[F:32])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: ONC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1C(F)(F)F)ONC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
2 g of 7-chloro-2-hydroxyamino-5-phenyl-3H-1,4-benzodiazepine are reacted with 1 g of 2-trifluoromethylphenyl isocyanate, analogously to Experiment 1a. Yield: 1.8 g of colorless crystals of melting point 190° C. (from methanol/dimethylformamide).
Reaction SMILES: Br[C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:13][C:14]1[C:15]([Sn](CCCC)(CCCC)CCCC)=[N:16][CH:17]=[CH:18][CH:19]=1>C1(C)C=CC=CC=1.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>[CH3:13][C:14]1[C:15]([C:2]2[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1nc(C)ccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(C)ccc1-c1ncccc1C
Temperature: 150 °C
Yield: 18.9 %

Procedure:
To the title compound of step B (509 mg, 2.2 mmol) and the title compound of step C (1.1 g, 2.9 mmol) in PhCH3 (6.6 mL) was added Pd(PPh3)4 (225 mg, 0.2 mmol). The reaction was degassed with N2 and heated at 150° C. for 1.5 h using microwave reactor. The reaction was cooled to rt, diluted with H2O and extracted with EtOAc. The organic layer was dried (MgSO4). Purification via silica gel chromatography (0-100% EtOAc in heptane) gave the title compound (101 mg, 18%). MS (ESI) mass calcd. for C14H14N2O2, 242.3; m/z found 243 [M+H]+.
Reaction SMILES: C(N[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1)CC1C=CC=CC=1.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[CH2:41][CH2:42][NH2:43]>>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[CH2:41][CH2:42][NH:43][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1
Reactant: NCCc1c(Cl)cccc1Cl
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccccc2)n1
Product: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2c(Cl)cccc2Cl)n1

Procedure:
Followed the same procedure described for the synthesis of 1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro -pyrido[1,2-a]pyrimidin-6-one, the sulfoxide (0.1 g, 0.27 mmol) was displaced with 2-(2,6-dichlorophenyl)ethylamine (0.16 g, 0.82 mmol) to give the title compound as a yellow solid. MS m/e 492 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[C:5]([Cl:30])=[CH:4][N:3]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O.C(O)(=O)C>ClCCl>[Cl:30][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)=[CH:7][C:2]([NH:1][CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4cc(N)ncc4Cl)ccnc3[nH]2)CC1
Reactant: O=Cc1cccc(F)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4cc(NCc5cccc(F)c5)ncc4Cl)ccnc3[nH]2)CC1
Reaction time: 8 h

Procedure:
To a solution of Example 307A (74 mg, 0.17 mmol) and 3-fluorobenzaldehyde (107 mg, 0.86 mmol) in dichloromethane was added acetic acid (0.05 mL, 0.86 mmol) and MP-CNBH3 (2.49 mmol/g) (278 mg, 0.69 mmol). The mixture was stirred overnight and the insoluble material was filtered off. The filtrated was concentrated. The residue was purified by flash chromatograph eluting with a gradient of 10%-50% ethyl acetate in hexanes to provide the title compound. LCMS: 537 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C:12]1[N:17]=[N:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=O)C>O.CO>[CH3:19][O:18][C:15]1[N:16]=[N:17][C:12]([CH2:11][OH:10])=[CH:13][C:14]=1[O:20][CH3:21]
Reactant: COc1cc(COC(C)=O)nnc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(CO)nnc1OC
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A solution of potassium carbonate (0.2 g) in water 2 mL) is added to a solution of 6-acetoxymethyl-3,4-dimethoxypyridazine (0.27 g) in methanol (6 mL) and the mixture stirred at 60-70° C. for 2 hours. After evaporating to dryness the residue is partitioned between ethyl acetate (10 mL) and brine (10 mL). The ethyl acetate phase is evaporated to dryness and the residue purified by flash chromatography (ethyl acetate as eluent on silica) to give 3,4-dimethoxy-6-hydroxymethylpyridazine as a white solid, m.p. 151-3° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@:7]([Cl:28])([C@H:8]([Cl:27])[CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[F:29]C(F)(F)C([O-])=O.[Na+].[F-].[Na+].FF>FC(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@:7]([Cl:28])([C@H:8]([Cl:27])[CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@@:11]3([F:29])[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)=O)CC[C@H]4[C@@H]3C[C@@H](Cl)[C@@]2(Cl)C1
Reactant: O=C([O-])C(F)(F)F
Agent: FF
Agent: [F-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: FC(Cl)(Cl)Cl
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)=O)CC[C@@]4(F)[C@@H]3C[C@@H](Cl)[C@@]2(Cl)C1

Procedure:
3β-Acetoxy-5α,6β-dichloropregnan-20-one (1.4 g) was dissolved in fluorotrichloromethane (250 ml) and chloroform (200 ml) containing sodium trifluoroacetate (ca. 2 g) and sodium fluoride (ca. 2 g). The resulting solution was cooled to -78° and vigourously stirred, whereupon fluorine from four 750 cc bottles (10% v/v fluorine in nitrogen) was bubbled through the solution over a period of 8 hours. The reaction solution was then poured into aqueous sodium thiosulphate and the organic layer was separated, washed with water, dried over potassium carbonate and evaporated to dryness to yield crude 3β-acetoxy-5α,6β-dichloro-14α-fluoropregnan-20-one.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][O:36][CH2:35]1>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][O:36][CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCC1CCOC1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCOC3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 138.8 %

Procedure:
A mixture of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) was heated at 60° C. with stirring for 1 h. 3-(2-Bromoethyl)tetrahydrofuran (123 mg) was added and the reaction was continued for 2 h. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give an oil (265 mg). The crude material was purified by normal phase chromatography (ISCO) using 0-15% MeOH/EtOAc as eluent to give the title compound (102 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Br:15])[CH:9]=1)=[O:7].[OH-].[K+].Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CS(C)=O>[Br:15][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][C:11]=1[O:14][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=C(c1ccc(O)c(Br)c1)c1cccs1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)c2cccs2)cc1Br
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 2-thienyl-(3-bromo-4-hydroxy-phenyl)ketone (14.5 g; M.p.=185° C.) in dimethylsulfoxide (50 ml) is added potassium hydroxide (2.8 g) and the mixture is heated to 50° C. for 30 minutes, after which ethyl α-bromoisobutyrate (9.75 g) is added thereto at room temperature. After a period of time of 3 hours, the solution is poured into water (100 ml) and the aqueous phase is extracted with ethyl ether. The organic phase is washed with an aqueous sodium hydroxide solution, and then with water, and the solvent is evaporated off after drying over sodium sulfate. The final product is recrystallized from petroleum ether (7 g; M.p.=80° C.).
Reaction SMILES: CC([N:5]([C@H:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[CH3:28])=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[O:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:29])[NH2:5])=[CH:14][CH:15]=1
Reactant: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 114.4 %

Procedure:
1,1-dimethylethyl{(1R)-1-methyl-2-[(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)amino]-2-oxoethyl}carbamate (Intermediate 15, 150 mg) was dissolved in 3 mL of dry dichloromethane. To this solution at 0° C. under argon was added dropwise 30 equivalents of TFA (0.866 mL, 11.24 mmol). The reaction was stirred at 0° C. for 4 hours. The reaction mixture was evaporated. The residue obtained was purified with an SCX cartridge (the cartridge was washed with 3 CV of methanol, then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N)). Evaporation of the volatiles, afforded the title compound (129 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][CH2:12][CH:13]=[CH2:14])[CH:5]=1.O[C:17]1C=C(C=C(O)C=1)C(OC)=O.C(=O)([O-])[O-].[K+].[K+].BrCC(C)=C>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([O:11][CH2:12][C:13]([CH3:17])=[CH2:14])[CH:7]=[C:8]([OH:10])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: C=CCOc1cc(O)cc(C(=O)OC)c1
Agent: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(C)COc1cc(O)cc(C(=O)OC)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl 3,5-dihydroxybenzoate (15.0 g, 89.2 mmol), potassium carbonate (24.7 g, 178.4 mmol) and 3-bromo-2-methyl-propene (9.0 mL, 89.2 mmol). Purification by column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow solid (7.80 g, 39% yield). 1H NMR (400 MHz, CDCl3) δ 7.13-7.22 (m, 2 H) 6.66 (t, J=2.27 Hz, 1 H) 5.81 (s, 1 H) 5.06-5.16 (m, 1 H) 4.93-5.04 (m, 1 H) 4.44 (s, 2 H) 3.91 (s, 3 H) 1.68-1.94 (m, 3 H); LCMS for C12H14O4 m/z 223.10 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][N:8]=1)(=O)=O.[CH3:21][Sn:22](Cl)([CH3:24])[CH3:23]>>[C:13]1([C:10]2[CH:11]=[CH:12][C:7]([Sn:22]([CH3:24])([CH3:23])[CH3:21])=[N:8][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Sn](C)(C)Cl
Reactant: O=S(=O)(Oc1ccc(-c2ccccc2)cn1)C(F)(F)F
Product: C[Sn](C)(C)c1ccc(-c2ccccc2)cn1

Procedure:
5-phenylpyridin-2-yl trifluoromethanesulfonate (1.5 mmol) was used in Procedure J with trimethyltin chloride to yield 5-phenyl-2-(trimethylstannyl)pyridine. The crude material (˜1.25 mmol) was used in Procedure K with N-(4-chloro-3-iodophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (1 mmol). Purified by silica gel chromatography (1% acetone/methylene chloride) to yield N-(4-chloro-3-(5-phenylpyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a tan solid: TLC Rf=0.15 (1% acetone/methylene chloride); MS (Q1) 467 (M)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH:24]=1)[C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: BrCC1CCCCC1
Product: CC(C)c1ccc(N(Cc2cnn(CC3CCCCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) and (bromomethyl)cyclohexane (0.142 mL) as starting materials, 5-benzyloxy-N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.26 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 105, N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.18 g) was obtained.