Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6].[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40](Cl)(=[O:42])=[O:41])=[CH:39][C:34]=2[O:33][CH2:32]1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40]([NH:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:11]=3[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6])(=[O:41])=[O:42])=[CH:39][C:34]=2[O:33][CH2:32]1
Reactant: COC(=O)c1cc(N)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3c(c2)OCO3)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.04 g of methyl 3-amino-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in pyridine (30 ml), treated dropwise while cooling with ice with a solution of 1.1 g of benzo[1,3]-dioxol-5-sulphonyl chloride in toluene (10 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained the desired methyl 3-(benzo[1,3]dioxol-5-sulphonylamino)-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a resin.
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([O:35]CC2C=CC=CC=2)[CH:22]=1)[CH:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1)[CH3:4].[ClH:43].[H][H]>[C].[Pd].CO>[ClH:43].[OH:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:35])[CH:22]=1)[CH:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1)[CH3:4]
Reactant: [H][H]
Reactant: CC(C(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C(O)c1ccc(O)c(O)c1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To 130 ml of a methanol solution containing 1.75 g of 1-[3-hydroxy-3-(3,4-dibenzyloxyphenyl)-2-propyl]-4-(2-keto-1-benzimidazolinyl)-piperidine is added 1 ml of a methanol solution containing 120 mg of hydrogen chloride, and, 0.2 g of palladium carbon is added thereto. The mixture is vigorously shaked in a hydrogen stream at room temperature. After stirring overnight, the catalyst is removed by filtration and the mother liquor is concentrated under reduced pressure. The resultant oily material is crystallized by adding a small amount of n-butanol. The crystals are collected by filtration, and dried to obtain 1.06 g of the crude crystals. Recrystallization thereof from n-butanol yields 0.8 g of 1-[3-hydroxy-3-(3,4-dihydroxyphenyl)-2-propyl]-4-(2-keto-1-benzimidazolinyl)-piperidine hydrochloride having m.p. 187°-189° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(F)c2)n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccc(F)c2)n1
Yield: 49.2 %

Procedure:
The title compound was prepared from 3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-amine (1.24 mg, 5.32 mmol) and phenyl chloroformate (2.0 mL, 16.0 mmol) using the procedure in Example 118A to give phenyl 3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-ylcarbamate (926 mg, 2.62 mmol, 49%). 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 7.79-7.23 (m, 8H), 6.38 (s, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 354 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH2:19].N1C=CC=CC=1.S(=[N:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Br:38])[C:32](Cl)=[O:33])=O>O1CCCC1>[NH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Br:38])[C:32]([NH:19][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:5][C:4]=1[CH3:18])=[O:33]
Reactant: O=S=Nc1cc(C(=O)Cl)ccc1Br
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(Br)c(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
To a solution of 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine (0.31 g, 1.1 mmol) (prepared according to EP 1,006,102) in anhydrous tetrahydrofuran (2 ml), at 20° C., was added sequentially pyridine (0.174 g, 2.2 mmol) and a solution of 3-sulfinylamino-benzoyl chloride (0.25 g, 0.86 mmol) (Example 1.2) in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred at ambient temperature for three hours. The reaction mixture was quenched by addition of water (5 ml). After separation of the phases, the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:3) to give 3-amino-4-bromo-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.235 g, 78% yield). 1H-NMR (DMSO-d6, 400 MHz): 7.53 (d, 1H), 7.44 (s, 2H), 7.38 (d, 1H), 7.10 (q, 1H), 5.6 (s, 2H), 2.24 (s, 6H) ppm.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)ccn2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc(-c2ccnc(N3CCNCC3)c2)cc1
Yield: 99.9 %

Procedure:
A solution of tert-butyl 4-(4-phenylpyridin-2-yl)piperazine-1-carboxylate (390 mg, 1.15 mmol) and 2N methanol solution of hydrogen chloride (30 ml) was stirred at room temperature for 4 hours, and the solvent was distilled away under reduce pressure. To the residue was added 1N aqueous solution of sodium hydroxide (10 ml), extracted with chloroform (10 ml), and the extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduce pressure to give the titled compound 275 mg (100%) as an oil product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[I:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([I:19])[CH:21]=1)=[O:14]
Reactant: NCc1cccc(I)c1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCc1cccc(I)c1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(3-iodobenzyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.23 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.43 mmol of 3-iodobenzylamine. LC/MS [6.37 min; 574 (M+1)]
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[O:4][CH2:5][Cl:6]
Reactant: O=C(Cl)OCCl
Reactant: COCCOCCOCCOCCOCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOCCOCCOCCOCCOC(=O)OCCl

Procedure:
In a manner similar to the method described in Example 3, chloromethyl chloroformate (Aldrich) was reacted with pentaethylene glycol monomethyl ether (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give chloromethyl 2,5,8,11,14-pentaoxahexadecan-16-yl carbonate. This material was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), chiral 3-oxo-2,4,7,10,13,16,19-heptaoxaicosyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C44H54Cl2F2N3O12: [(M+H)+]: 924, found: 924.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[CH3:14][NH2:15]>O>[CH3:14][NH:15][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CN
Agent: Cl
Solvent: O
Product: CNCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
2-Chloromethylquinoline hydrochloride (3.00 g, 14.01 mmol) was suspended in aqueous methylamine (40 mL, 40 wt % in H2O) at 10° C. under a N2 atmosphere. After 20 minutes, the reaction mixture was warmed to room temperature and stirred for 3 hours. The mixture was diluted with water and extracted with methylene chloride. The organic extracts were dried (MgSO4) and concentrated to afford 2.22 g (92%) of pure product as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:45]1[CH2:50][CH2:49][CH:48]([CH2:51][S:52](Cl)(=[O:54])=[O:53])[CH2:47][CH2:46]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:36][C:33]1[CH:34]=[CH:35][N:22]2[C:23]=1[C:24](=[O:32])[N:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]([C@@H:18]([NH:17][C:15]1[C:16]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:1][S:52]([CH2:51][CH:48]5[CH2:49][CH2:50][O:45][CH2:46][CH2:47]5)(=[O:54])=[O:53])[CH:7]=4)=[CH:9][N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[C:11]=3[N:12]=[CH:13][N:14]=1)[CH3:19])=[N:21]2
Reactant: O=S(=O)(Cl)CC1CCOCC1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc(N)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc(NS(=O)(=O)CC5CCOCC5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 54.9 %

Procedure:
(S)-2-(1-((5-(2-Aminopyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with (tetrahydro-2H-pyran-4-yl)methanesulfonyl chloride (26 mg, 0.13 mmol) and triethylamine (36 μl, 0.26 mmol) in pyridine (2 ml) according to the method described in Preparation 15b. The residue was purified using SP1® Purification System (hexane-ethyl acetate) to give 55 mg (53% yield) of the title compound. Purity 98%.
Reaction SMILES: [C:1](O)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(O)(=O)C>CCOCC>[CH2:1]([OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCCCCCO
Yield: 26.1 %

Procedure:
4 g of docosanoic acid are dissolved in 150 ml of anhydrous ether. LeAlH4 is progressively introduced. On completion of the reaction, 150 ml of an aqueous solution of 1 N acetic acid are introduced. The ethereal phase is then separated off, decanted and dried. Rectification in vacuo gives approximately 1 g of 1-docosanol.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:11](=[O:20])[C:12]([Cl:19])=[C:13]([Cl:18])[C:14](=[O:17])[C:15]=1[Cl:16].Cl.C(OCC)(=O)C>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:14]1([OH:17])[C:13]([Cl:18])=[C:12]([Cl:19])[C:11](=[O:20])[C:10]([Cl:9])=[C:15]1[Cl:16])[CH3:8]
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Yield: 94 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.82 g (3.33 mmol) of 2,3,5,6-tetrachloro-1,4-benzoquinone in 26 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.04 g of the desired product (yield 94%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH2:23])=[O:22])=[O:10])[CH:7]=1.[H-].[Na+].I[CH2:31][CH3:32].O>CN(C=O)C>[CH2:31]([O:1][CH2:2][C:3]1[C:4]([C:24]([F:26])([F:25])[F:27])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH2:23])=[O:22])=[O:10])[CH:7]=1)[CH3:32]
Reactant: CCI
Reactant: NC(=O)c1c(NC(=O)Cn2cc(CO)c(C(F)(F)F)n2)sc2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 65 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 2-(2-(4-(hydroxymethyl)-3-(trifluoromethyl)pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (20 mg, 0.05 mmol) in DMF (2 mL) was added NaH (7 mg, 0.29 mmol) under an atmosphere of N2. The reaction mixture was stirred at RT for 30 min before addition of iodoethane (20 mg, 0.13 mmol). The reaction mixture was heated at 65° C. for 3 h then left to stand at RT overnight. Water (2 mL) was added and the reaction mixture extracted with EtOAc (3×5 mL). The combined EtOAc layers were washed with water (3×10 mL), brine (10 mL), dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative reverse phase HPLC to give the desired product as a clear gum (6.7 mg, 0.016 mmol, 31%).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]([C:8]2[CH:9]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[NH:10][C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:7])[CH2:5][CH2:4]1.Br[CH2:35][C:36]1[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=1)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>CCCCC.O1CCCC1>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[N:10]([CH2:35][C:36]3[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=3)[C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=3)[C:13]([CH3:14])=[C:8]2[C:6]([CH:3]2[CH2:5][CH2:4]2)=[O:7])=[CH:33][CH:32]=1)#[N:31]
Reactant: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)N(Cc2cccc(C(=O)OC(C)(C)C)c2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (12.1 mg, 0.31 mmol; 60% suspension in mineral oil) is washed with pentane (3×3 ml), then treated with a solution of 4-{5-(cyclopropylcarbonyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 22) (100 mg, 0.235 mmol) in tetrahydrofuran (5 ml). After 5 minutes, the reaction is treated with a solution of tert.-butyl 3-(bromomethyl)benzoate (77 mg, 0.28 mmol) in tetrahydrofuran (5 ml) and then stirred at room temperature overnight (16 h). The reaction mixture is quenched with water (50 ml) and extracted with ethyl acetate (3×150 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[N:16])[CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:16][CH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:8]#[N:7])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C#N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl(trans-4-cyanocyclohexyl)methylcarbamate (500 mg) in dichloromethane (10 mL) was slowly added trifluoroacetic acid (2 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred for 1 hour and concentrated to provide the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:8][CH2:7][CH:6]([OH:9])[CH2:5][O:4]1.[H-].[Na+].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl>>[Cl:1][CH2:2][CH:3]1[O:8][CH2:7][CH:6]([O:9][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[F:12])[CH2:5][O:4]1
Reactant: Fc1ccccc1CCl
Reactant: OC1COC(CCl)OC1
Agent: [H-]
Agent: [Na+]
Product: Fc1ccccc1COC1COC(CCl)OC1

Procedure:
By the method of Example 43, 2-chloromethyl-5-hydroxy-1,3-dioxane was reacted with sodium hydride and o-fluorobenzyl chloride to yield 2-chloromethyl-5-(2-fluorobenzyloxy)-1,3-dioxane. This mixture of isomers was distilled using a short path distillation apparatus at 0.1 mm to obtain three fractions. Fraction 1, b.p. 95°-100°/0.1 mm was found by VPC analysis to be 3.8% cis-2-chloromethyl-5-(2-fluorobenzyloxy)-1,3-dioxane (the remainder in each case being the trans isomer). Fraction 2, b.p. 98°-102°/0.1 mm was 13.8% cis isomer. Fraction 3, b.p. 165°-170°/0.1 mm was 99% cis and solidified on standing; the solid was sublimed to a solid, m.p. 60°-62°, which was found by nmr analysis to 94% cis isomer and 6% trans isomer.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([CH3:7])[O:5][C:4]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([OH:25])[CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)=[CH:10][CH:9]=2)=[N:3]1.Cl[C:27]1[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH3:1][C@@H:2]1[C@H:6]([CH3:7])[O:5][C:4]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)[O:25][C:27]3[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=3)=[CH:10][CH:9]=2)=[N:3]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Reactant: CS(=O)(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (420 mg, 1.22 mmol) synthesized in Example (109c) was dissolved in acetonitrile (20 mL), and 2-chloro-5-(methylsulfonyl)pyrazine (345 mg, 1.46 mmol) synthesized in Example (97c) and cesium carbonate (1.02 g, 3.13 mmol) were added at room temperature, followed by stirring at room temperature overnight under nitrogen atmosphere. To this reaction solution, water (30 mL) was added, and extraction was carried out with methylene chloride (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-3%) to afford the desired compound (513 mg, yield 84%) as a white solid.
Reaction SMILES: CS(O[C@@H:6]([C@H:28]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][CH2:30][CH2:31][OH:32])[CH2:7][O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.CC(C)([O-])C.[K+].C(O)(=O)C>C(O)(C)(C)C>[CH2:34]([O:33][C@@H:28]1[CH2:29][CH2:30][CH2:31][O:32][C@H:6]1[CH2:7][O:8][C:9]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CS(=O)(=O)O[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](CCCO)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: c1ccc(CO[C@@H]2CCCO[C@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
A solution of 26.08 g of (2R, 3R)-3-benzyloxy-6-hydroxy-1-triphenylmethoxy-2-hexyl methanesulfonate (prepared as described in Preparation 21) dissolved in 290 ml of t-butanol was added dropwise to a solution of 7.01 g of potassium t-butoxide in 250 ml of t-butanol, whilst maintaining the temperaure at 25° C. The mixture was then stirred at 40° C. for 4 hours. At the end of this time, 0.56 ml of acetic acid were added to the mixture, and the solvent was removed by distillation under reduced pressure. The residue was diluted with water, and then extracted three times with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was then subjected to column chromatography through 430 g of silica gel. 21.04 g of the title compound were obtained from those fractions eluted with a 95:5 by volume mixture of hexane and ethyl acetate, as crystals melting at 86.0°-88.0° C. (after recrystallization from methanol).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][P:14](=[O:18])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: Fc1cccc(F)c1CBr
Product: CCOP(=O)(Cc1c(F)cccc1F)OCC
Temperature: 135 °C
Reaction time: 8 h

Procedure:
2,6-difluorobenzyl bromide (3.0 g, 14.5 mmol) was combined with triethylphosphite (6.2 mL, 36.2 mmol) and the mixture heated and stirred at 135° C. overnight. The mixture was put under hi-vacuum and heated to 80° C. for 10 hours. The final product was a slightly yellow-tinted oil (3.30 g, 86% yield). 1H NMR (400.14 MHz, DMSO) δ 7.36 (m), 7.10 (m, 2H), 3.96 (m, 4H), 3.20 (d, J=21.08 Hz, 2H), 1.16 (t, J=7.05 Hz, 6H). 13C {1H} NMR (100.62 MHz, CDCl3) δ 161.0 (ddd, J=249.0, 7.3, 6.2 Hz, 2C), 128.4 (dt, J=10.2, 3.82 Hz), 111.0 (ddd, J=18.9, 6.0, 3.5 Hz, 2C), 108.5 (dt, J=19.8, 10.5 Hz), 62.1 (d, J=6.5 Hz, 2C), 20.6 (dt, J=142.1, 2.3 Hz), 16.0 (d, J=6.2 Hz, 2C). 31P{1H} NMR (161.97 MHz, DMSO): δ 24.68. Analysis calculated (found) %: C, 50.01 (49.71), H, 5.72 (5.78). MS (FAB, m/z): 265 (M+, 100%). Exact mass calculated (found) for [M+H]−, m/z): 265.08051 (265.08278).