Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([OH:14])=O)[C:9](=[O:15])[S:8][C:5]2=[N:6][CH:7]=1.O[N:17]1[C:21](=O)[CH2:20][CH2:19][C:18]1=O.C[N:25](C)C=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:17]3[CH2:21][CH2:20][NH:25][CH2:19][CH2:18]3)=[O:14])[C:9](=[O:15])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)Cn1c(=O)sc2ncc(Cl)cc21
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)N1O
Product: O=C(Cn1c(=O)sc2ncc(Cl)cc21)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of a mixture of 6-chloro-1-carboxymethyl-2-oxo-1,2-dihydrothiazolo[5,4-b]pyridine (3.47 g) and N-hydroxysuccinimide (1.96 g) in N,N-dimethylformamide (20 ml) was gradually added N,N-dicyclohexylcarbodiimide (3.51 g). The mixture was stirred for 1 hour at ambient temperature and dicyclohexylurea that precipitated from the reaction mixture was removed by filtration. To a solution of piperazine (6.11 g) in N,N-dimethylformamide (80 ml) was added dropwise the filtrate for a period of 1.5 hours below 20° c. The final mixture was stirred for 4 hours at ambient temperature, and then filtered. The filtrate was concentrated under reduced pressure below 50° C. and the residue was dissolved in 2N hydrochloric acid. The aqueous solution was washed with chloroform and then adjusted to pH 9 with an aqueous solution of sodium hydrogen carbonate. The turbid solution was extracted with chloroform, and the extract was dried over magnesium sulfate and concentrated under reduced pressure to give a white powder of 6-choro-2-oxo-1-[(1-piperazinyl)carbonylmethyl]-1,2-dihydrothiazolo[5,4 -b]pyridine (3.24 g).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].O[C:6]1C=CC=[CH:8][C:7]=1[CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][O:24][CH3:25])=[CH:19][CH:20]=2)[S:15][CH2:14][C:13]1([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=1)[CH3:26].Br[CH2:38][CH2:39][CH2:40][CH2:41][Cl:42].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:42][CH2:41][CH2:40][CH2:39][CH2:38][O:3][C:2]1[CH:4]=[CH:8][C:7]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][O:24][CH3:25])=[CH:19][CH:20]=3)[S:15][CH2:14][C:13]2([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:31][CH:32]=2)[CH3:26])=[CH:6][CH:1]=1
Reactant: CC(C)=O
Reactant: ClCCCCBr
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(OCCCCCl)cc2)cc1
Yield: 87 %

Procedure:
To acetone solution (2 ml) of (3RS,4RS)-4-(hydroxyphenyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methylthiochroman (70 mg, 0.15 mmol) were added 1-bromo-4-chlorobutane (36 μl, 0.31 mmol) and potassium carbonate (64 mg, 0.46 mmol), and the resulting mixture was heated under refluxing for 20 hours. After adding water, the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The crude product thus obtained was purified using silica gel plate (ethyl acetate:hexane=1:2) to obtain 73 mg (yield: 87%) of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:44])([CH3:43])[CH2:3][CH2:4][O:5][C:6](=[O:42])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([OH:41])([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:78]([O:83][CH2:84][CH3:85])(=[O:82])[C@H:79]([CH3:81])O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:44][Si:2]([CH3:43])([CH3:1])[CH2:3][CH2:4][O:5][C:6](=[O:42])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([O:41][CH:79]([C:78]([O:83][CH2:84][CH3:85])=[O:82])[CH3:81])([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24]
Reactant: CCOC(=O)[C@H](C)O
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(O)OC)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)OP(=O)(CC=CCC(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)C(=O)OCC[Si](C)(C)C)OC
Yield: 74.1 %

Procedure:
A solution of 2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (67 mg, 0.10 mmol) and PyBOP (234 mg, 0.450 mmol) in DMF (1.5 mL) was stirred with ethyl (S)-(−)-lactate (53 mg, 0.45 mmol) and DIEA (174 μL, 1.00 mmol) at ambient temperature for 1 hour, when complete consumption of the starting materials was observed. The reaction was worked up by addition of saturated aqueous sodium chloride and ethyl acetate. The organic layer was separated and washed with 5% aqueous solution of lithium chloride. The organic layer was dried in vacuo and the residue was purified by silica gel chromatography using MeOH—CH2Cl2 (0-20%) to provide 57 mg (74%) of the desired product as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 9H), 0.05 (s, 9H), 0.88-0.94 (m, 2H), 1.20-1.30 (m, 2H), 1.29 (t, 3H, J=7 Hz), 1.45 (d, 3H, J=7 Hz), 1.78 (s, 3H), 2.01-2.31 (m, 4H), 2.17 (s, 3H), 2.50-2.58 (m, 1H), 2.65 (d, 1H, J=22 Hz), 2.67 (d, 1H, J=22 Hz), 3.39 (d, 2H, J=7 Hz), 3.69 and 3.77 (d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07 (appt t, 2H, J=7 Hz), 4.20 (dq, 2H, J=3, 7 Hz), 4.29 (appt t, 2H, J=9 Hz), 4.85-4.99 (m, 1H), 5.12 (s, 2H), 5.19 (br t, 1H, J=6 Hz), 5.33-5.61 (m, 2H) ppm; 31P (121.4 MHz, CDCl3) δ 28.9, 29.9 ppm; MS (m/z) 791.4 [M+Na]+.
Reaction SMILES: C(O[C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1)(C)C.C[S:26]([C:29]1N=CC([C@@H](N)C)=C[CH:30]=1)(=[O:28])=[O:27].CS(C1N=CC(C(=O)C)=CC=1)(=O)=O.BrC1C=CC(S(C)(=O)=O)=NC=1>>[CH2:29]([S:26]([C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1)(=[O:28])=[O:27])[CH3:30]
Reactant: C[C@H](N)c1ccc(S(C)(=O)=O)nc1
Reactant: CC(C)Oc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Agent: CC(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CS(=O)(=O)c1ccc(Br)cn1
Product: CCS(=O)(=O)c1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1

Procedure:
Prepared analogously to Compound 1 using IM46 and (S)-1-(6-Methanesulfonyl-pyridin-3-yl)-ethylamine (prepared from 1-(6-Methanesulfonyl-pyridine-3-yl)-ethanone analogously to IM24, which was prepared from commercially available 5-Bromo-2-methanesulfonyl-pyridine CAS 98626-95-0). Yield from IM46=1.54 g (68%). 1H-NMR (500 MHz, DMSO) δ 8.80 (d, 1H), 8.72 (s, 1H), 8.02 (m, 2H), 7.27 (m, 2H), 7.20 (s, 1H), 7.12 (d, 2H), 5.08 (m, 1H), 3.27 (s, 3H), 2.20 (m, 1H), 1.95 (m, 1H), 1.42 (d, 3H), 1.37 (m, 1H), 1.22 (m, 1H). LC-MS (m/z) 345.1 (MH+), tR=1.21 min (method A).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[NH2:23][C@H:24]([C:32]([NH:34][CH2:35][C:36]([NH:38][C@H:39]([C:41]([OH:43])=O)[CH3:40])=[O:37])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH2:44][C@H:45]([CH2:50][OH:51])[CH2:46][CH:47]([CH3:49])[CH3:48].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:23][C@H:24]([C:32]([NH:34][CH2:35][C:36]([NH:38][C@H:39]([C:41]([NH:44][C@H:45]([CH:50]=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH3:40])=[O:37])=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: C[C@H](NC(=O)CNC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C[C@@H](C=O)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
29.9 g (70.7 mol) of Dess-Martin periodinane was suspended in 500 ml CH2Cl2 and stirred for 10 min. Moc-Phe-Gly-Ala-Leucinol (10.6 g, 23.5 mol) was dissolved in 100 ml CH2Cl2 and added at a moderate rate to the periodinane slurry. The mixture was stirred for 1h and poured into 150 ml NaHCO3 containing 123 g Na2S2 O3. The mixture was allowed to stir for 15 min and extracted with EtOAc. The organic phase was dried and filtered followed by removal of solvent. Chromatography (3.5% MeOH/CH2Cl2) on silica gave 5.1 g of pure white solid that is a mixture of the methoxy hemiacetal and aldehyde. 13C NMR (CDCl3,CD3OD) 17.62, 17.94, 21.53, 21.71, 22.99, 23.30, 23.39, 24.54, 37.05, 37.70, 37.92, 38.24, 42.87, 49.83, 51.79, 52.14, 52.40, 56.75, 57.19, 98.40, 99.18, 127.00, 128.60, 129.06, 136.44, 157.27, 169.19, 169.67, 172.73, 173.40, 200.43.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([CH3:23])[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>C1COCC1>[CH3:23][C:4]1[CH:3]=[C:2]([NH:1][C:34](=[O:35])[O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:22]=[CH:21][C:5]=1[O:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2C)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)Oc3ccccc3)cc2C)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 4-(2-(4-amino-2-methylphenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (200 mg, 0.65 mmol) in THF (4 mL) was added diisopropylethylamine (0.097 mL, 0.72 mmol) and phenyl chloroformate (102 mg, 0.65 mmol). The mixture was stirred for 3.5 hours at RT and used without purification.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[C:19]([O:23][C:24](=[O:45])[NH:25][CH2:26][C@H:27]([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][C:30]=1[F:44])[CH3:28])([CH3:22])([CH3:21])[CH3:20]>>[F:44][C:30]1[CH:31]=[C:32]([C:2]2[C:3]3[C:4]4[CH:18]=[CH:17][S:16][C:5]=4[C:6](=[O:15])[NH:7][C:8]=3[C:9]([CH3:14])=[CH:10][C:11]=2[O:12][CH3:13])[CH:33]=[CH:34][C:29]=1[C@H:27]([CH3:28])[CH2:26][NH:25][C:24](=[O:45])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 36 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (380 mg, 1.2 mmol) was reacted with (S)-tert-butyl2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (400 mg, 1.1 mmol) to afford the desired product (190 mg, 36%) as a yellow solid: ESI MS m/z 497 [C27H29FN2O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:13][N:12]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[F:31]>C(#N)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:9][CH2:10][CH2:11][N:12]([CH2:14][C@H:15]([O:20][C:29](=[O:30])[NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([F:31])[CH:24]=3)[C:16]([F:18])([F:19])[F:17])[CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H](CN1CCO[C@H](c2cccc(Cl)c2)C1)C(F)(F)F
Reactant: O=C=Nc1ccc(Cl)c(F)c1
Solvent: CC#N
Product: Cl
Product: O=C(Nc1ccc(Cl)c(F)c1)O[C@@H](CN1CCO[C@H](c2cccc(Cl)c2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.7 %

Procedure:
(S)-3-((R)-2-(3-chlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (59.5 mg, 192 μmol), TEA (26.8 μL, 192 μmol) and 1-chloro-2-fluoro-4-isocyanatobenzene (32.9 mg, 192 μmol) were combined in 2 mL of acetonitrile and stirred at room temperature overnight. The solution was purified by reverse phase column chromatography (50-100% acetonitrile in water). The desired fractions were pooled, treated with 5 drops of conc. HCl and the solution lyophilized to afford (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(3-chlorophenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride (56 mg, 56%) as a white solid. (M+H)+=481 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.81 (t, J=11.14 Hz, 1H) 3.00 (t, J=10.39 Hz, 1H) 3.16 (d, J=13.22 Hz, 1H) 3.44 (d, J=11.71 Hz, 1H) 3.56-3.79 (m, 2H) 4.20 (dd, J=13.22, 3.02 Hz, 1H) 4.36-4.59 (m, 1H) 5.55 (d, J=9.82 Hz, 1H) 5.70 (d, J=3.02 Hz, 1H) 7.17 (d, J=8.69 Hz, 1H) 7.29-7.44 (m, 5H) 7.50 (dd, J=10.77, 2.08 Hz, 1H) 8.82 (br. s., 1H).
Reaction SMILES: O1CCOC1.C(OP([CH2:14][CH:15]=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=[O:20])(OCC)=O)C.CC([O-])(C)C.[K+].[CH3:28][C:29]1[CH2:34][CH2:33][CH2:32][C:31]([CH3:36])([CH3:35])[C:30]=1/[CH:37]=[CH:38]/[C:39]([CH3:41])=O>C1COCC1>[CH3:28][C:29]1[CH2:34][CH2:33][CH2:32][C:31]([CH3:35])([CH3:36])[C:30]=1/[CH:37]=[CH:38]/[C:39](/[CH3:41])=[CH:14]/[CH:15]=[CH:16]/[C:17](/[CH3:21])=[CH:18]/[CH:19]=[O:20]
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Reactant: CCOP(=O)(CC=CC(C)=CC=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCO1
Solvent: C1CCOC1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Reaction time: 1.5 h

Procedure:
Phosphonate (I) (0.5 g, 1.72 mmol) in solution in THF (10 ml) was introduced under argon into a 25-ml two-necked flask. Potassium tert-butylate (0.275 g, 2.22 mmol) was added in small portions at -70° C. Stirring was continued at -70° C. for 90 minutes. β-ionone (0.34 g, 1.8 mmol) in solution in THF (1 ml) was then added. The solution was kept at -70° C. for 15 minutes and then at -20° C. for 1 hour.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=1.C(O)C>CS(C)=O>[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:29][CH:30]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Cc1cccc2c(C3=CCNCC3)c[nH]c12
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cccc2c(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.389 g, 2.05 mmol) and 7-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.400 g 1.87 mmol) using ethanol as reaction solvent. Yield 0.292 g (39%) as an orange foam. mp 155°-158° C. FDMS m/e=401 (M+ of free base). α[D]589 =+5.9 (c=1.05, dimethylsulfoxide).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9]C(C(O)=O)=[C:4]([CH2:11][OH:12])[CH:3]=1.[H-].[Na+].IC.[C:17](=O)([O-])[O-].[K+].[K+].[C:23]([O:26][CH2:27]C)(=[O:25])[CH3:24]>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:24]([C:23]([O:26][CH3:27])=[O:25])=[C:4]([CH2:11][O:12][CH3:17])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccc(F)cc1CO
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COCc1cc(F)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution of 4-fluoro-2-(hydroxymethyl)benzoic acid (Preparation 36, 0.185 g, 0.001087 mol) in tetrahydrofuran (5.0 mL) was added sodium hydride (0.110 g, 0.0028 mmol, 60% in mineral oil) portion wise. The reaction was stirred for 15 minutes at room temperature under nitrogen. Then 0.17 mL iodomethane (0.17 mL, 0.00272 mol) was added and the reaction mixture stirred at room temperature under nitrogen for 16 hours. The reaction was quenched with an aqueous solution of hydrochloric acid (2.0M, 10.0 mL) and product was extracted with ethyl acetate (15.0 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dimethyl sulfoxide (3.0 mL), then potassium carbonate (0.170 g, 0.00123 mol) and iodomethane (0.17 mL, 0.00272 mol) were added. The reaction mixture was stirred at 60° C. under nitrogen for 2 hours. The reaction was diluted with ethyl acetate (15.0 mL) and washed three times with water (15.0 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Title compound was isolated after purification using silica gel column chromatography eluting with 0-10% EtOAc in heptane as a colourless oil (0.135 g, 0.000681, 67% yield).
Reaction SMILES: N[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[S:13](=[O:15])=[O:14].[ClH:16]>>[Cl:8][C:3]1[C:2]([S:13]([Cl:16])(=[O:15])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: Cl
Reactant: O=S=O
Agent: O=N[O-]
Agent: [Na+]
Product: O=S(=O)(Cl)c1cccnc1Cl
Yield: 42 %

Procedure:
Under ice-cooling, thionyl chloride (24 mL) was added dropwise over 1 hr to water (140 mL) and the mixture was stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Separately, under ice-cooling, 3-amino-2-chloropyridine (10 g) was added to concentrated hydrochloric acid (80 mL) and the mixture was stirred. An aqueous solution (25 mL) of sodium nitrite (5.75 g) was added dropwise while keeping the inside temperature at not higher than 5° C., and the mixture was further stirred for 15 min. The reaction mixture was gradually added at 5° C. to the above-mentioned sulfur dioxide-containing solution added with cuprous chloride (140 mg). Under ice-cooling, the mixture was further stirred for 30 min, and the precipitate was collected by filtration and washed with water and ethanol to give the title compound (yield 6.99 g, 42%).
Reaction SMILES: CS(C)=O.[CH2:5]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)[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][CH3:19].[OH-].[Na+].[CH3:29]I>O>[CH2:5]([C:20]1[CH:21]=[C:22]([O:26][CH3:29])[CH:23]=[CH:24][CH:25]=1)[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][CH3:19]
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Into a two-liter round bottomed flask was placed dimethyl sulfoxide (500 mL), 3-pentadecyl phenol (100.0 g, 0.33 mol) and sodium hydroxide (73.55 g, 1.31 mol). To this mixture methyl iodide (93.5 g, 0.66 mol) was added drop wise with stirring at room temperature. After the addition, the reaction mixture was stirred for further 6 h. Then the reaction mixture was poured into deionized water (1.5 liters). The organic material was extracted by addition of diethyl ether. The diethyl ether layer was separated, washed with water, dried over anhydrous sodium sulfate, and finally evaporated to afford the crude product as a viscous liquid. This material was purified by silica gel column chromatography using petroleum ether as the eluent to obtain 3-pentadecyl anisole Yield 104.6 g (97%), MP 27-28° C.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][O:53][C:54]2[N:59]=[CH:58][C:57]([NH2:60])=[CH:56][CH:55]=2)[CH2:47][CH2:46]1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:60][C:57]4[CH:58]=[N:59][C:54]([O:53][CH2:52][CH2:51][N:48]5[CH2:49][CH2:50][O:45][CH2:46][CH2:47]5)=[CH:55][CH:56]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: Nc1ccc(OCCN2CCOCC2)nc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(OCCN5CCOCC5)nc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 6-(2-morpholinoethoxy)pyridin-3-amine as the aniline component. (37%, MS=600.3 (M+H))
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([O:13][C@@H:14]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH3:15])[C@@H:9]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C@@H:8]1[CH2:37]OS(C)(=O)=O)(=O)=O.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(O)C>[CH2:43]([N:50]1[CH2:37][C@@H:8]2[C@H:7]([CH2:12][CH2:11][C@H:10]([O:13][C@@H:14]([C:16]3[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([C:26]([F:28])([F:27])[F:29])[CH:17]=3)[CH3:15])[C@H:9]2[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:6]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NCc1ccccc1
Reactant: C[C@@H](O[C@H]1CC[C@H](COS(C)(=O)=O)[C@@H](COS(C)(=O)=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCO
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C

Procedure:
In a pressure tube was placed a solution of crude [(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]di(methylene) dimethanesulfonate (step H) in ˜20 mL ethanol and 1.2 mL (˜3 equiv.) benzylamine. The pressure tube was sealed and heated at 150° C. in an oil bath for 3 hr. The tube was cooled to RT and opened. The resulting mixture was transferred to a round bottom flask and the solvent removed under vacuum. The residue was diluted with 100 mL EtOAc, washed with 20 mL 5N aq. NaOH, dried over MgSO4 drying agent, filtered and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with EtOAc to give 1.6 g of the title compound. 1H-NMR (CDCl3): δ: 7.35-7.20 (5H, m), 7.50 (2H, s), 6.97 (2H, m), 6.85 (2H, t, J=8.2 Hz), 4.42 (1H, t, J=6.0 Hz), 3.75 (2H, d, J=13.4 Hz), 3.50 (2H, d, J=13.4 Hz), 3.30 (1H, m), 2.96 (1H, m), 2.52 (3H, m), 2.19 (2H, m), 1.98 (1H, m), 1.97 (1H, m), 1.86 (2H, m),.1.57 (1H, m), 1.33 (3H, t, J=6.0 Hz), 1.30 (1H, m). MS: (MH)+566.0.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[O:12]1[CH:18]2[CH:13]1[C:14]([CH3:31])([CH3:30])[O:15][C:16]1[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:19][C:17]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[O:3]=[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]1[C@@H:18]1[C:17]2[CH:19]=[C:20]([S:23]([C:26]([F:27])([F:29])[F:28])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=2[O:15][C:14]([CH3:30])([CH3:31])[C@H:13]1[OH:12]
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2C2OC21
Reactant: C[Si](C)(C)Oc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](n2ccccc2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.4 %

Procedure:
1.63 g of 2-trimethylsilyloxypyridine was added to a solution of 1.00 g of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl-2H-1-benzopyran (prepared as described in Preparation 8) in 1.2 ml of anhydrous tetrahydrofuran, and a solution of 2.54 g of tetrabutylammonium fluoride in anhydrous tetrahydrofuran was added to the resulting mixture through a syringe, whilst ice-cooling and under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 72 hours, after which it was poured into water and extracted with ethyl acetate. The extract was then washed with water, with a 5% w/v aqueous solution of hydrochloric acid, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and cyclohexane as the eluent, to afford 503 mg of the title compound as about a 1:1 mixture of rotational isomers, melting at 219°-220° C.