Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH:13]([CH3:16])[CH2:14]Cl)[CH:10]=[CH:11][C:5]=2[CH:4]=1.[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][C:13]([CH3:16])([N:23]([CH3:22])[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)[CH3:14])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC(C)CCl)C=C2
Product: COc1ccc(CCN(C)C(C)(C)CN2C=Cc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
This compound was prepared analogous to Example 1(b) by reacting 1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-2-methyl-3-chloro-propane with N-methyl-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:12])[C:8]([F:11])([F:10])[F:9].F[C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([C:40]([F:43])([F:42])[F:41])[CH:15]=1.[Cl-].[Na+]>O1CCCC1.CN1CCCC1=O.[Cl-].[Na+].O.O.C(OC)(C)(C)C>[F:9][C:8]([F:11])([F:10])[CH2:7][O:12][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:16]([C:40]([F:43])([F:42])[F:41])[CH:15]=1
Reactant: Fc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)c(C(F)(F)F)c1
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: COC(C)(C)C
Product: FC(F)(F)COc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)c(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
Potassium tert-butoxide (98% m/m, 39.17 g, 342.1 mmol) was suspended in tetrahydrofuran (190 mL) and a solution of trifluoroethanol (35.65 g, 356.4 mmol) in tetrahydrofuran (28 mL) was added at room temperature (exothermic). The mixture was stirred for 15 min, and a solution of 4-fluoro-2-trifluoromethyl-1-tritylsulfanyl-benzene (125 g, 285 mmol) in 1-methyl-2-pyrrolidon (240 mL) and tetrahydrofuran (290 mL) was added. The resulting brown solution was stirred for 30 min at room temperature, followed by 2 h at 45° C. internal temperature. After that, water (720 mL), brine (125 mL), and tert-butyl-methylether (720 mL) were added and phases were separated. The organic layer was washed with a solution of sodium chloride (59.3 g, 1015 mmol) in water (380 mL) and concentrated in vacuo at 40° C. to a volume of ca. 400 mL. The solution was diluted with ethanol (300 mL), and additional ethanol (480 mL) was continuously added to the distillation, while the overall volume was kept constant at ca. 700 mL (solvent exchange). The resulting suspension was stirred for 14 h at room temperature and 1 h at 0° C. before water (140 mL) was added and the suspension was stirred for further 1.5 h at 0° C. After filtration, the precipitate was washed with cold ethanol/water 5:1 (v/v, 288 mL) and dried in vacuo to yield the title compound as fine yellow crystals (140.9 g, 95%). MS (EI): m/z=243 [CPh3]+. 1H NMR (CDCl3, 600 MHz): δ 4.26 (q, J=8.0 Hz, 2H), 6.61 (dd, J=2.9 Hz, 8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 7.07 (d, J=2.9 Hz, 1H), 7.18-7.25 (m, 9H), 7.33-7.37 (m, 6H).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:2]1.CNC.CN(C)[P:18](N(C)C)N(C)C>>[N:1]12[P:18]3[N:9]([CH2:8][CH2:7][CH2:6][N:5]3[CH2:4][CH2:3][CH2:2]1)[CH2:10][CH2:11][CH2:12]2
Reactant: C1CNCCCNCCCNC1
Reactant: CN(C)P(N(C)C)N(C)C
Agent: CNC
Product: C1CN2CCCN3CCCN(C1)P23
Yield: 75.8 %

Procedure:
A mixture of 4.20 g of 1,5,9-triazacyclododecane and 4.00 g of hexamethylphosphorous triamide is heated at 100° C. for about 6 hours, by which time evolution of dimethylamine is complete. Distillation under reduced pressure gives 3.70 g (76%) of 1,5,9-triaza- 13-phosphatricyclo[7.3.1.05,13 ]tridecane as a clear, colorless liquid which boils at 104°-135° C. at 0.60 mm. The product solidifies at room temperature. Its infrared absorption spectrum (neat) shows absorptions at 3.5, 6.85, 7.01, 7.52, 7.73, 8.00, 8.27, 8.66, 8.90, 9.02, 9.36, 9.56, 10.27, 10.89, 11.42, 11.73, 11.97 and 14.7 μ. The mass spectrum shows an M+ ion at 199; measured mass, 199.1264; calc'd, 199.1238.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](C)=[N:7]2.[C:13]([O:22][CH2:23][CH3:24])(=[O:21])/[CH:14]=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[CH:14][C:13]([O:22][CH2:23][CH3:24])=[O:21])[CH3:20]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: Cc1ccc2c(Br)cccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C(=O)OCC)c1cccc2ncccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-bromo-2-methylquinoline (2.87 g) in DMF (60 mL) at room temperature, diethyl maleate (5.15 mL), palladium acetate (0.16 g), tri(o-tolyl)phosphine (0.42 g) and potassium carbonate (3.80 g) were subsequently added then the reaction mixture was warmed to 100° C. and stirring continued overnight. After cooling, the reaction mixture was quenched with water and extracted twice with diethyl ether. The combined organic layers were collected, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting with cyclohexane-ethyl acetate from 100 to 60%) to give 3.51 g of the title compound as a slightly yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.C(O)C>[Pd].C(O)(=O)C>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CNCCO1
Yield: 98.8 %

Procedure:
A mixture of 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide (5.0 g), ethanol (100 ml), and acetic acid (20 ml) is hydrogenated over 10% palladium on carbon (0.5 g) at 25° C. After the calculated amount of hydrogen is absorbed, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give the title compound (3.8 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)[OH:27])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=3[CH:25]=2)=[C:5]([CH3:35])[O:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(N(CC)C(C)C)(C)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:26](=[O:27])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[N:12]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C:11]=3[CH:25]=2)=[C:5]([CH3:35])[O:4][N:3]=1
Reactant: CCOc1nc2c(C(O)c3ccc(F)cn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1nc2c(C(=O)c3ccc(F)cn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-((5-fluoropyridin-2-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-1-carboxylate (57 mg, 0.12 mmol) in dichloromethane (6 mL) was added Dess-Martin periodinane (154.1 mg, 0.34 mmol). After 15 minutes, the reaction was quenched with saturated Na2S2O3(aq) (10 mL) and extracted with dichloromethane (3×10 mL). The combined organics were washed with water (30 mL) and brine (30 mL), and dried over Na2SO4. To the crude solution was added N,N-diisopropylethylamine (0.05 mL, 0.26 mmol), 4-(dimethylamino)pyridine (6.8 mg, 0.05 mmol), and di-tert-butyl dicarbonate (120.9 mg). After 90 minutes, the reaction mixture was washed with water (2×30 mL), dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography (0-50% ethyl acetate/hexane) afforded tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-benzo[d]imidazole-1-carboxylate as an amber residue.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:25])[C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:26]([N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1)[CH3:27].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:26]([N:28]1[CH:32]=[C:31]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:25])[C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:30]=[N:29]1)[CH3:27]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)OC)nc3)ccn2)cn1
Temperature: 90 °C
Yield: 28.6 %

Procedure:
A mixture of Example C5 (0.12 g, 0.33 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (80 mg, 0.36 mmol) and K2CO3 (0.14 g, 0.99 mmol) in dioxane (4 mL) and H2O (1 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.040 g, 0.034 mmol), sparged again with Ar and heated at 90° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain N-((5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-methoxy-2-methylpropanamide (40 mg, 28%). 1H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 10.20 (br s, 1H), 8.38 (d, J=5.7 Hz, 1H), 8.31 (s, 1H), 8.27 (d, J=2.9 Hz, 1H), 8.02 (br s, 1H), 7.98 (s, 1H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.71 (dd, J=5.7, 2.4 Hz, 1H), 4.14 (q, J=7.3 Hz, 2H), 3.21 (s, 3H), 1.37 (t, J=7.3 Hz, 3H), 1.36 (s, 6H); MS (ESI) m/z: 425.2 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4].[I-:35].[Na+]>C(#N)C>[I:35][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4]
Reactant: [I-]
Reactant: O=C(CBr)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Na+]
Solvent: CC#N
Product: O=C(CI)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-3′,4′,5′-tribenzyloxyacetophenone (5.17 g, 10.0 mmol) (11) and sodium iodide (2.25 g, 15 mmol) were dissolved in dry acetonitrile (50 mL) and stirred at room temperature overnight. The solution was filtered and acetonitrile removed under vacuum. Water (30 mL) was added and the solution was extracted with diethyl ether (4×25 mL). The organic phase was dried (MgSO4) and the solvents removed in vacuo. Recrystallisation from methylcyclohexane afforded the titled compound as yellow crystals, m.p. 110-112° C. Yield 3.6 g (64%). 1H NMR (300 MHz, CDCl3): δ=4.21 (2H, s), 5.15 (6H, s), 7.22-7.48 (17H, m); 13C NMR (75 MHz): δ=1.0, 71.3, 75.1, 109.0, 127.4, 127.9, 128.0, 128.1, 128.3, 128.4, 128.5, 136.3, 137.1, 143.4, 152.6, 191.5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:31]2[CH2:32][CH2:33][N:34]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[O:14])[CH2:35][CH2:36]2)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: O=S(=O)(c1ccc(-c2ccccn2)cc1)N1CCNCC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc(-c3ccccn3)cc2)CC1
Yield: 54 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-[4-(2-pyridyl)phenylsulphonyl]piperazine to give 1-[4-(2-pyridyl)phenyl-sulphonyl]-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 54% yield, m.p. 224-226° C.;
Reaction SMILES: O.[OH-].[Li+].[Si:4]([O:11][C@@H:12]([CH3:30])[C@H:13]([C:19]1[O:23][N:22]=[C:21]([C:24]([O:26]CC)=[O:25])[C:20]=1[CH3:29])[O:14][CH2:15][C:16]([CH3:18])=[CH2:17])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].[Si](O[C@@H](C)[C@H](C1ON=C(C(OCC(C)=C)=O)C=1C)OCC(C)=C)(C(C)(C)C)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>[Si:4]([O:11][C@@H:12]([CH3:30])[C@H:13]([C:19]1[O:23][N:22]=[C:21]([C:24]([OH:26])=[O:25])[C:20]=1[CH3:29])[O:14][CH2:15][C:16]([CH3:18])=[CH2:17])([C:7]([CH3:10])([CH3:8])[CH3:9])([CH3:5])[CH3:6]
Reactant: C=C(C)CO[C@@H](c1onc(C(=O)OCC)c1C)[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: C=C(C)COC(=O)c1noc([C@H](OCC(=C)C)[C@H](C)O[Si](C)(C)C(C)(C)C)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)CO[C@@H](c1onc(C(=O)O)c1C)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 70 °C

Procedure:
Lithium Hydroxide monohydrate (3.20 g, 76 mmol) was added portionwise to a mixture of ethyl 5-((1R,2S)-2-((tert-butyldimethyl silyl)oxy)-1-((2-methylallyl)oxy)propyl)-4-methylisoxazole-3-carboxylate and 2-methylallyl 5-((1R,2S)-2-((tert-butyldimethylsilyl)oxy)-1-((2-methylallyl)oxy)propyl)-4-methylisoxazole-3-carboxylate [4.5 g as an approximate 9:1 mixture containing residual Tetrabutyl ammonium iodide (25% w/w)] in THF/water (300 mL, 1.5/1.0) and the resulting mixture was heated gently at 70° C. After cooling to room temperature the layers were separated and the remaining aqueous was acidified with 1 M aqueous hydrochloric acid and extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude title compound;
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:10][C:6]=2[CH:5]=1.C([C@](C([O-])=O)(O)[C@](CC)(O)C([O-])=O)C.C(N(CC)CC)C.C(O)(=O)[C@H](C1C=CC=CC=1)O>CC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:23][C:17]1[CH:16]=[N:15][C:14]([CH2:13][S+:11]([O-:12])[C:9]2[NH:8][C:7]3[CH:24]=[CH:25][C:4]([O:3][CH3:2])=[CH:5][C:6]=3[N:10]=2)=[C:19]([CH3:20])[C:18]=1[O:21][CH3:22]
Reactant: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[C@@](O)(C(=O)[O-])[C@@](O)(CC)C(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The procedure was carried out as described in Raju et al, Organic Process Research & Development 2006, 10, 33-35, which is hereby incorporated by reference in its entirety. To a suspension of omeprazole sodium salt (5.53 g, 15.1 mmol, 1 equiv) in acetone (60 mL), were added a solution of diethyl-D-tartrate (3.1 g, 15.1 mol, 1 equiv) in acetone (3 mL), titanium (IV) isopropoxide (2.14 g, 7.55 mmol, 0.5 equiv) and triethylamine (4.75 g, 45.3 mmol, 3 equiv) at 35-40° C. To the resulting homogeneous solution was added L-(+)-mandelic acid (2.64 g, 17.4 mmol, 1.15 equiv). The mixture was cooled to ambient temperature and stirred for about 1-2 hours. The precipitate was filtered, washed with acetone (30 mL), and dried under reduced pressure to afford esomeprazole mandalate salt.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=[C:7]([Cl:15])[CH:6]=1>C1COCC1>[Cl:15][C:7]1[CH:6]=[C:5]([O:2][CH3:1])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1
Reactant: C[O-]
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(Cl)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
Sodium methoxide powder (0.136 g, 2.52 mmol) was added slowly to a stirred solution of methyl 4,6-dichloronicotinate (0.40 g, 1.94 mmol) in THF (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours, then concentrated in vacuo onto silica gel. Gradient chromatography, eluting with 5% EtOAc:c-Hex over 5 column volume and 5-50% over 15 column volume, gave methyl 6-chloro-4-methoxynicotinate (218 mg, 1.08 mmol, 56% yield) as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25]([O:32][C:33](=[O:37])[C@@H:34]([CH3:36])[NH2:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:25]([O:32][C:33](=[O:37])[C@@H:34]([CH3:36])[NH:35][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@@H](N)C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 23.0 g. (0.121 m) of N-t-butoxycarbonyl-L-alanine, 42.6 g. (0.121 m) of D-alanine benzyl ester p-toluenesulfonic acid salt and 17 ml. (0.121 m) of triethylamine in 400 ml. of cold (0° C.) methylene chloride was added dropwise 25.0 g. (0.121 m) of dicyclohexylcarbodiimide in 100 ml. of methylene chloride. After stirring overnight at room temperature the solids were filtered and the filtrate concentrated to an oil. The residue was dissolved in 400 ml. of ethyl acetate which was washed with a 1% hydrochloric acid solution, a 10% potassium carbonate solution, water and a brine solution. The organic phase was separated, dried over magnesium sulfate and concentrated to an oil. The residue was triturated with diethyl ether and the resulting solids filtered under nitrogen, 16.0 g. An additional 12.7 g. of the desired product crystallized from the filtrate.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH2:9][CH3:10])[C:6]([OH:8])=[O:7].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:7][C:6](=[O:8])[CH:5]([O:4][C:3]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:2]=2[CH3:1])[CH2:9][CH3:10])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: CCC(Oc1ccc(C)cc1C)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(Oc1ccc(C)cc1C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 1468.3 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.46 g of (2RS)-2-(2,4-dimethylphenoxy)butyric acid and 0.81 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give1.16 g of the title compound as a colorless foam.
Reaction SMILES: C(OC1C=C(OC(C)C)C(F)=C(C(C2N(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=C(C3C=CC=CC=3C(F)(F)F)N=2)NC2C=CC(C3N=C(C)ON=3)=CC=2)C=1)C.Br[C:64]1[N:65]=[C:66]([CH:88]([C:102]2[CH:107]=[C:106]([O:108][CH2:109][CH3:110])[CH:105]=[C:104]([O:111][CH:112]([CH3:114])[CH3:113])[C:103]=2[F:115])[NH:89][C:90]2[CH:95]=[CH:94][C:93]([C:96]3[N:100]=[C:99]([CH3:101])[O:98][N:97]=3)=[CH:92][CH:91]=2)[N:67]([C:69]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:68]=1.[NH:116]1[CH:120]=[C:119](B(O)O)[CH:118]=[N:117]1>>[NH:116]1[CH:120]=[C:119]([C:64]2[N:65]=[C:66]([CH:88]([C:102]3[CH:107]=[C:106]([O:108][CH2:109][CH3:110])[CH:105]=[C:104]([O:111][CH:112]([CH3:114])[CH3:113])[C:103]=3[F:115])[NH:89][C:90]3[CH:91]=[CH:92][C:93]([C:96]4[N:100]=[C:99]([CH3:101])[O:98][N:97]=4)=[CH:94][CH:95]=3)[N:67]([C:69]([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:82]3[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=3)[CH:68]=2)[CH:118]=[N:117]1
Reactant: OB(O)c1cn[nH]c1
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(F)(F)F)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3cn[nH]c3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 20 %

Procedure:
According to the procedure for the preparation of Intermediate 77.1, Intermediate 66.3 was coupled with 1H-pyrazol-4-ylboronic acid. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes, gradient) to afford 30 mg (20%) of Intermediate 237.1.
Reaction SMILES: [CH3:1][C:2]([NH:14][C:15](=[O:18])[CH2:16][CH3:17])([CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1>[Pd].CO>[NH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C:2]([NH:14][C:15](=[O:18])[CH2:16][CH3:17])([CH3:13])[CH3:1])=[CH:9][CH:8]=1
Reactant: CCC(=O)NC(C)(C)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCC(=O)NC(C)(C)Cc1ccc(N)cc1
Yield: 90.8 %

Procedure:
A mixture of N-[1,1-dimethyl-2-(4-nitro-phenyl)-ethyl]-propionamide (1 g, 4 mmol) and 10% palladium on charcoal (100 mg) in methanol (50 ml) was hydrogenated at atmospheric pressure. After filtration the solvent was evaporated and the residue dissolved in ethyl acetate. The solution was dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a yellow oil (800 mg, 91%).
Reaction SMILES: C(O)C.[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=O)=[CH:7][CH:6]=1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>O>[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](/[CH:15]=[N:18]/[OH:19])=[CH:7][CH:6]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)c2ccccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O/N=C/c1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round-bottom flask, was placed ethanol (100 mL), water (40 mL), 4-bromonaphthalene-1-carbaldehyde (4.3 g, 18.29 mmol, 1.00 equiv), hydroxylamine hydrochloride (1.52 g, 21.87 mmol, 1.20 equiv), sodium acetate (2.25 g, 27.43 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The solids were collected by filtration and washed with enough water. The solid was dried in an oven under reduced pressure. This resulted in 4.5 g (98%) of (E)-N-[(4-bromonaphthalen-1-yl)methylidene]hydroxylamine as a white solid.