Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:50]=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:63]=[O:64]>CN(C)C=O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:63][OH:64])[CH:50]=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
To a solution of (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 1h (0.82 g, 1.16 mmol, obtained from the synthetic method described in step 7 of example 1) in N,N-dimethylformamide (20 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.02 mL, 0.12 mmol) and formaldehyde (1.7 mL, 23.2 mmol, 37% in water) in turn. The mixture was stirred at room temperature for 5 hours and quenched with 10 mL of saturated aqueous sodium bicarbonate. The resulting mixture was filtered. The filtrate was extracted with ethyl acetate (20 mL×1 and 10 mL×3). The combined organic layers were washed with water (10 mL×3) and then saturated aqueous sodium chloride (10 mL×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=5/1 to give the title compound 8a as yellow oil (0.56 g, 65.1%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ(ppm): 9.99 (s, 1H), 7.55-7.49 (m, 2H), 7.43 (d, 1H), 7.34-7.24 (m, 13H), 7.07 (dd, 2H), 6.95 (d, 2H), 6.72 (d, 2H), 5.38 (dd, 1H), 4.84 (m, 3H), 4.72 (d, 1H), 4.56-4.43 (m, 2H), 4.16 (d, 1H), 4.01 (d, 1H), 3.92 (q, 2H), 3.81 (m, 3H), 3.57 (dd, 1H), 3.25 (d, 1H), 2.70 (s, 3H), 1.27 (t, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][C:30]([S:33](Cl)=[O:34])([CH3:32])[CH3:31].C(OCC)(=[O:38])C>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[S:33]([C:30]([CH3:32])([CH3:31])[CH3:29])(=[O:34])=[O:38])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[S:33]([C:30]([CH3:32])([CH3:31])[CH3:29])=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)S(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCNC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)S(=O)N(CCCCCCO[Si](C)(C)C(C)(C)C)C1CCCCC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCN(C1CCCCC1)S(=O)(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of N-(6-((tert-butyldimethylsilyl)oxy)hexyl)cyclohexanamine (246 mg, 0.78 mmol) and triethyl amine (0.22 mL, 1.57 mmol) in methylene chloride (10 mL) at 0° C. was added 2-methylpropane-2-sulfinic chloride (0.13 mL, 1.01 mmol). The mixture was stirred for 2 hours before it was diluted with ethyl acetate and washed with saturated bicarbonate solution and brine. The organic phase was separated and concentrated. Purification on silica gel with ethyl acetate: hexanes from 0:1 to 3:7 provided desired compound, N-(6-((tert-butyldimethylsilyl)oxy)hexyl)-N-cyclohexyl-2-methylpropane-2-sulfinamide, as a clear oil (282.5 mg, 87%). 1H NMR (300 MHz, CDCl3): δ 3.55 (t, J=6.4 Hz, 2H), 3.14 (ddd, J=5.3, 11.7, 14.3 Hz, 1H), 2.94-2.76 (m, 1H), 2.64-2.46 (m, 1H), 2.04-1.92 (m, 2H), 1.84-1.64 (m, 3H), 1.64-1.38 (m, 7H), 1.38-0.94 (m, 6H), 1.14 (s, 9H), 0.85 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:6][CH:5]=[CH:4][NH:3]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][CH:45]1[CH2:52][CH:51]2[N:53]([CH3:54])[CH:47]([CH2:48][CH2:49][CH2:50]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:54][N:53]1[CH:47]2[CH2:48][CH2:49][CH2:50][CH:51]1[CH2:52][CH:45]([NH:44][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:7]4[C:2](=[O:1])[NH:3][CH:4]=[CH:5][CH:6]=4)=[N:12][C:11]=13)=[O:19])[CH2:46]2
Reactant: O=C(O)c1cccc2oc(-c3ccc[nH]c3=O)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccc[nH]c4=O)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.4 %

Procedure:
A mixture of 2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxylic acid (102 mg, 0.40 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.80 mmol), 1-hydroxybenzotriazole (108 mg, 0.80 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (135 mg, 0.49 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.22 mL, 1.60 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (3×100 mL). The combined organic layers were washed with water (2×50 mL), brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by preparative HPLC to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxamide (21 mg, 13%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.94 (br s, 1H), 8.53 (dd, J=7.3, 1.7 Hz, 1H), 8.22 (d, J=7.7 Hz, 1H), 7.76-7.69 (m, 2H), 7.48 (t, J=7.9 Hz, 1H), 6.58 (t, J=6.7 Hz, 1H), 4.64-4.55 (m, 1H), 3.15-3.10 (m, 2H), 2.68-2.62 (m, 2H), 2.54 (s, 3H), 2.15-1.95 (m, 3H), 1.60-1.47 (m, 4H), 1.15-1.10 (m, 2H); MS (ESI+) m/z 393(M+H); HPLC>99% (AUC), tR=12.23 min.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].C=O.[BH3-][C:29]#N.[Na+]>CC(O)=O>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[N:22]([CH3:29])[C@H:21]([CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C(C)C)CO3
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(C)[C@H](C(C)C)CO3
Yield: 87.3 %

Procedure:
Compound 121 was prepared according to General Method 5 (EXAMPLE 2) from (3R)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.010 g, 0.028 mmol) with paraformaldehyde (0.008 g, 0.280 mmol) and NaCNBH3 (0.009 g, 0.140 mmol) in AcOH (1 mL) to afford 0.009 g (90%) of (3R)-3,4-dihydro-8-isopropoxy-3-isopropyl-4-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow oil. This material (0.009 g, 0.025 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with conc. HCl (0.5 mL) and AcOH (1 mL) to afford 0.006 g (86%) of Compound 121 as a yellow solid. Rf 0.6 (9:1 CH2Cl2;MeOH); 1H NMR (400 MHz, CDCl3) δ 12.49 (broad s, 1H), 7.13 (s, 1H), 7.06 (d, 1H, J=8.9), 7.02 (d, 1H, J=8.9), 4.43 (dd, ABX, 1H, J=10.9, 1.8), 3.86 (dd, ABX, 1H, J=10.9, 2.9), 3.03 (s, 3H), 2.93–2.88 (m, 1H), 2.02–1.91 (m, 1H), 0.99 (d, 3H, J=6.9), 0.95 (d, 3H, J=6.9).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)([C:6]1[S:7][CH:8]=[CH:9][N:10]=1)[CH3:5].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:8]1[S:7][C:6]([C:4]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)([OH:3])[CH3:5])=[N:10][CH:9]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2nccs2)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
Bromine (0.071 mL, 1.383 mmol) was added dropwise to a stirred mixture of the product of Step 1 (180 mg, 0.576 mmol) and sodium acetate (236 mg, 2.88 mmol) in acetic acid (2.31 mL), and the mixture was stirred at room temperature for 2 h. Acetic acid was removed by evaporation under vacuum and the residue was treated with saturated NaHCO3 solution, and extracted with ethyl acetate (×3). The combined organic fractions were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to give tert-butyl 4-[1-(5-bromo-1,3-thiazol-2-yl)-1-hydroxyethyl]piperidine-1-carboxylate (87 mg, 0.222 mmol, 38.6%). APCI: [M+H]+ m/z 379.1.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)=O)(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1cccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1cccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[3-(1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(3-methoxy-phenyl) acetamide, prepared as in Intermediate 74, (250 mg, 0.363 mmol) and 4N HCl in dioxane (2 mL) is stirred at RT for 2 h. Diethyl ether (40 mL) is added and the resultant mixture stirred vigorously for 20 min. The solids were allowed to settle and the solvent is decanted. This procedure is repeated three times and the final solid dried by concentration in vacuo to afford the title compound (197 mg) as a white powdery solid: 1H NMR (300 MHz, CDCl3) δ8.05 (d, 1H, J=8.6), 7.76 (d, 1H, J=8.5), 7.67 (t, 1H, J=8.8), 7.5-7.2 (m, 12H), 7.16 (t, 1H, J=6.3), 6.98 (t, 2H, J=7.3), 5.05 (m, 1H, J=6.9), 4.36 (s, br, 2H), 3.94 (t, 1H, J=7.0), 3.82 (s, br, 2H), 3.74 (s, 3H), 1.16 (m, 6H); Low resolution MS (FAB) m/e 588 (M+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30](Br)[CH:29]=[C:28](Br)[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[N:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C(OCC)(=O)C.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>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:38]3[CH:39]=[N:34][CH:35]=[N:36][CH:37]=3)[CH:29]=[C:28]([C:38]3[CH:39]=[N:34][CH:35]=[N:36][CH:37]=3)[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: O=C(O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(Br)c2)c1CCC(=O)O
Reactant: OB(O)c1cncnc1
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: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3cncnc3)cc(-c3cncnc3)c2)c1CCC(=O)O
Temperature: 160 °C
Yield: 55.9 %

Procedure:
To a solution of 4-{2-(2-carboxy-ethyl)-3-[6-(3,5-dibromo-phenoxy)-hexyl]-phenoxy}-butyric acid (150 mg, 0.26 mmol) in ethanol (2 mL) in a 20 mL microwave tube were added tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 0.03 mmol), pyrimidin-5-ylboronic acid (189 mg, 3.0 mmol), and potassium carbonate (212 mg, 1.53 mmol) at room temperature. The microwave tube was sealed and heated to 160° C. in a microwave oven for 30 minutes. Then, the reaction mixture was cooled to room temperature and diluted with water (20 mL) and ethyl acetate (20 mL). The two layers were separated and the ethyl acetate layer was discarded. Then, the aqueous layer was acidified with 1.0 N hydrochloric acid and the organic compound was extracted into ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 4-{2-(2-carboxy-ethyl)-3-[6-(3,5-di-pyrimidin-5-yl-phenoxy)-hexyl]-phenoxy}-butyric acid (85 mg, 57%) as a light yellow solid: ES(+)-HRMS m/e calculated for C33H36N4O6 (M+Na)+ 607.2527, found 607.2527.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:17]=[C:18]=[O:19])[CH2:14][CH2:15][CH3:16]>C1(C)C(C)=CC=CC=1.N12CCC(CC1)CN2>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:18]([NH:17][CH2:13][CH2:14][CH2:15][CH3:16])=[O:19])(=[O:11])=[O:10]
Reactant: NS(=O)(=O)c1ccccc1CCl
Reactant: CCCCN=C=O
Agent: C1CN2CCC1CN2
Solvent: Cc1ccccc1C
Product: CCCCNC(=O)NS(=O)(=O)c1ccccc1CCl
Yield: 74.8 %

Procedure:
A mixture of 2-(chloromethyl)benzenesulfonamide (13.2 g, 64 mmol) and butyl isocyanate (7.0 g, 71 mmol) in xylene (80 ml) was contacted with diazabicyclo[2.2.2]octane (0.25 g) and heated to reflux for 5.0 hrs. Volatiles were removed under vacuum and the residue was treated with 0.5N NaOH (200 ml) and extracted with ethyl acetate (75 ml). The aqueous layer was separated, chilled, acidified (pH 4) with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to give 14.6 g of white solid. A sample was recrystallized from toluene to give m.p. 104°-106°.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.IC>C1COCC1>[C:13]1([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24]([CH3:1])([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1CCN(CCc2ccccc2)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To 2.64 mL (18.9 mmol) of diisopropylamine in 30 mL of dry THF at -78° was added 6.9 mL (17.3 mmol) of 2.5 M n-butyllithium in hexanes. The mixture was allowed to warm to room temperature and then was cooled once again to -78°. To the stirred solution was added 4.11 g (15.7 mmol) of 1-(2-phenylethyl)-4-carboethoxypiperidine in 25 mL of dry THF. The mixture was allowed to warm to -40° and 0.98 mL (15.7 mmol) of iodomethane was added to the reaction mixture. The mixture was stirred at -40° for 15 minutes and then allowed to stir at room temperature for 3 hours. The mixture was evaporated to dryness and the residue was dissolved in water. The aqueous solution was extracted with methylene chloride and the extracts were dried and evaporated to give 3.70 g of 1-(2-phenylethyl)-4-methyl-4-carboethoxypiperidine as a yellow oil. NMR (CDCl3) δ7.15-7.21 (m, 5H); 4.11-4.20 (q, 4H); 2.71-2.94 (m, 4H): 2.52-2.61 (m, 2H): 2.11-2.24 (m, 4H); 1.47-1.59 (m, 2H); 1.21-1.30 (t, 3H); 1.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([OH:28])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:36][C:37]#[N:38]>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([CH:3]=1)[O:28][CH2:36][C:37]#[N:38]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.10 g, 0.24 mmol), and cesium carbonate (0.12 g, 0.38 mmol) in dioxane (1 mL) was added bromoacetonitrile (0.034 g, 0.28 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction was diluted with ethyl acetate and washed with water. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give the title compound (0.11 g).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C@H:45]2[O:47][CH2:46]2)=[CH:39][C:38]=1[N:48]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[S:49]([CH3:52])(=[O:51])=[O:50])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[F:28][C:2]([F:27])([F:1])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:46][C@H:45]([OH:47])[CH2:44][O:43][C:40]3[CH:41]=[CH:42][C:37]([O:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:38]([N:48]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[S:49]([CH3:52])(=[O:50])=[O:51])[CH:39]=3)[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: CC(C)(C)OC(=O)N(c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1)S(C)(=O)=O
Reactant: O=S(=O)(Oc1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1)C(F)(F)F
Solvent: CCO
Product: CC(C)(C)OC(=O)N(c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)CC2)ccc1OCc1ccccc1)S(C)(=O)=O

Procedure:
A mixture of 5.52 g of trans-4-[4-(benzylamino)cyclohexyl]phenyl trifluoromethanesulfonate (13.3 mmol) and of 5 g of 4-benzyloxy-3-(N-(tert-butoxycarbonyl)-N-(methylsulfonyl)amino)-1-((2S)-2,3-epoxypropoxy)benzene (11.2 mmol) in ethanol (72 ml) is brought to reflux for 5 h. The solvent is evaporated under reduced pressure and trans-4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(tert-butoxycarbonyl)(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenyl trifluoromethanesulfonate is obtained in the form of an oil (6.94 g, 72%) after purification on silica gel (eluent: dichloromethane/methanol 98/2). [M+H+]=863.4
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([CH:7]([CH2:35][CH3:36])[CH:8]1[O:34][CH:9]1[C:10]1[N:14]=[CH:13][N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:11]=1)[CH3:6].[ClH:37]>>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:5]([CH:7]([CH2:35][CH3:36])[CH:8]([OH:34])[CH:9]([Cl:37])[C:10]1[N:14]=[CH:13][NH:12][N:11]=1)[CH3:6]
Reactant: Cl
Reactant: CCC(CC)C1OC1c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=[PH](O)O
Product: CCC(CC)C(O)C(Cl)c1nc[nH]n1

Procedure:
Diethyl (2RS,3RS)-2,3-epoxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.39 g, prepared as described in Example 52) was treated with hydrochloric acid, as described in Example 53 for the (RS,SR) isomer, to give diethyl (2RS, 3RS)-3-chloro-2-hydroxy-3(1,2,4-triazol-3-yl)propane phosphonate (0.21 g) as a colourless oil, probably as its hydrochloride. NMR(D2O): δ1.15(6H,t), 2.15(2H,m), 4.00(4H,m), 4.45(1H,m), 5.17(1H,d), 8.75(1H,s). (No internal standard, solvent signal at δ4.67).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9]Cl)[C:5](CCl)=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH:20]([OH:22])=O.[OH-:23].[Na+]>O>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:23])[C:5]([CH2:20][OH:22])=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nc(Cc2ccccc2)c(CCl)c(CCl)c1O
Reactant: O=CO
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(Cc2ccccc2)c(CO)c(CO)c1O
Reaction time: 0.17 h

Procedure:
A solution of 20 g of crude 2-methyl-4,5-di-(chloromethyl)-6-benzyl-pyridin-3-ol in 40 g of 75% strength formic acid is heated under reflux. After 10 minutes, a solution of 10.7 g of sodium hydroxide in 15 ml of water is added and heating is continued for 1 hour. The mixture is concentrated to dryness under reduced pressure. The residue is digested in 100 ml of acetone, the insoluble constituent is filtered off, the filtrate is concentrated and the residue thus obtained is boiled for 1/2 hour in 50 ml of water. After again concentrating the mixture, the residue is recrystallized from acetone. 5.7 g of 2-methyl-4,5-di-(hydroxymethyl)-6-benzyl-pyridin-3-ol, of melting point 158°-159° C., are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([O:14][Si](C)(C)C)([CH3:13])[C:11]#[N:12].[ClH:19]>C1COCC1.C(OCC)C>[ClH:19].[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([OH:14])([CH3:13])[CH2:11][NH2:12]
Reactant: COc1ccc(C(C)(C#N)O[Si](C)(C)C)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(C)(O)CN)c(F)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
2-(2-Fluoro-4-methoxy-phenyl)-2-trimethylsilanyloxy-propionitrile (2.8 g, 10.47 mmol) was dissolved in dry THF (30 mL) and stirred at room temperature under nitrogen. A 2.0 M solution of borane-dimethylsulfide complex (15.7 mL, 31.41 mmol) was added dropwise and the reaction was heated at reflux for 3 hours then cooled to room temperature. Concentrated HCl was carefully added dropwise until the evolution of gas ceased. The reaction mixture was diluted with diethyl ether and a white precipitate formed. The solids were collected and washed with additional ether to give 2.5 g (100%) of 2-(2-fluoro-4-methoxy-phenyl)-2-hydroxy-propylamine hydrochloride. Electrospray mass spectrum (M−1)=199.99 (free amine)