Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[C:11]([NH:21][C@H:22]([C:34]([N:36]1[CH2:43][CH2:42][CH2:41][C@H:37]1[C:38](O)=[O:39])=[O:35])[CH:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24](=[O:26])[OH:25])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][C:38](=[O:39])[C@@H:37]2[CH2:41][CH2:42][CH2:43][N:36]2[C:34](=[O:35])[C@H:22]([CH:23]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:24](=[O:25])[OH:26])[NH:21][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=C(N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(N[C@H](C(=O)N1CCC[C@H]1C(=O)Oc1ccc([N+](=O)[O-])cc1)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 2 h

Procedure:
p-Nitrophenol (3.0 Kg) is added to the concentrated ethyl acetate solution of N-carbobenzoxy-β-benzyl-L-aspartyl-L-proline prepared as described in Example II above. The solution is cooled below 5° C. Dicyclohexylcarbodiimide (4.5 Kg) is dissolved in ethyl acetate (10-20 L) and added, maintaining the temperature below 5° C. The solution is stirred at reduced temperature for two hours and then for three hours at 20°-30° C. The dicyclohexylurea is removed by filtration and washed with ethyl acetate (20-30 L). The filtrate is concentrated in vacuo below 60° C. The concentrate is dissolved in hot isopropyl alcohol (50-70 L) and cooled below 25° C. The solids are collected on a filter, rinsed with isopropyl alcohol and dried below 40° C. Melting point=88°-91° C.; specific rotation=-70° to -73° (C=1, ethyl acetate).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[S:60]1[CH2:64][C@@H:63]([C:65](OCC#N)=[O:66])[N:62]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH2:61]1>C(#N)C>[S:60]1[CH2:64][C@@H:63]([C:65]([O:40][C@H:39]2[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36][C@@H:35]2[CH2:34][O:33][P:30]([O:29][C@H:28]2[CH2:27][C@H:26]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:25][C@@H:24]2[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:66])[N:62]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH2:61]1
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.6 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (148 mg, 0.233 mmol) and (R)-3-tert-butyl 4-(cyanomethyl) thiazolidine-3,4-dicarboxylate (Compound tk28) (254 mg, 0.933 mmol) in acetonitrile (0.7 mL) was added to buffer A (30 mL), and the mixture was stirred at room temperature for 1.5 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (4R)-4-((2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl) 3-tert-butyl thiazolidine-3,4-dicarboxylate (Compound tk29) (64.7 mg, 33%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[CH3:23][O:24][CH2:25][CH:26]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:26][CH2:25][O:24][CH3:23]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Reactant: COCC=O
Product: COCC=NOCCC1=C(C)/C(=C/c2ccncc2)c2ccc(F)cc21

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with methoxyacetaldehyde by the method of Example 1.
Reaction SMILES: [C-]#[N:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:14]S([O-])(=O)=O.O>CN(C)C=O>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][C:14]#[N:2]
Reactant: CCCCC(CCS(=O)(=O)[O-])c1ccc(Cl)cc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC#N)c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a suspension of 11.3 g (0.23 mole) of sodium cyanide in 100 ml of dry dimethyl formamide (DMF) is added dropwise a solution of 50 g (0.154 mole) of 2-(2,4-dichlorophenyl)-hexylmethane sulfonate in 50 ml of DMF. The reaction mixture is stirred at 70° overnight. It is then poured into 500 ml of water and extracted with ether. The combined ether extracts are washed with water, then saturated saline solution and finally dried over magnesium sulfate. Solvent is evaporated under reduced pressure to give 37 g of crude product which is further purified by vacuum distillation (107.5°-110°/0.05 mm) to give 33.9 g (86%) of expected product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[CH2:19]([N:26]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:31][C@H:28]1[CH2:29][CH2:30][N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27]1)=[O:18]
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and (3S)-1-benzylpyrrolidin-3-ylamine. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 50:50:1, changing to 20:80:1, by volume, hexane:ethyl acetate:0.88 aqueous ammonia solution, in 10% increments. The product was further purified by recrystallisation from ethyl acetate:hexane to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-1-benzylpyrrolidin-3-yl]-2-piperidinecarboxamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18].Cl>C1COCC1.O>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([C:17]([OH:19])=[O:18])=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(C(=O)O)cc1
Reaction time: 0.33 h
Yield: 86 %

Procedure:
1-Bromo-4-trimethylsilyl-benzene (0.426 ml, 2.18 mmol) was dissolved in THF (20 ml), and n-butyllithium (1.59 M solution in n-hexane, 1.51 ml, 1.40 mmol) was added dropwise at −78° C. After stirring for 20 minutes, crushed dry ice (excess) was added. The reaction solution was stirred at room temperature for one hour, and 1 M hydrochloric acid and water were then added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 4-trimethylsilanyl-benzoic acid (363 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:31][NH2:32]>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15][NH:32][CH2:31][C:30]1[CH:33]=[CH:34][C:35]([Cl:36])=[C:28]([Cl:27])[CH:29]=1)([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:5])[CH3:2]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(OCC)P(=O)(C[C@@H](O)CCl)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(OCC)P(=O)(C[C@@H](O)CNCc1ccc(Cl)c(Cl)c1)OCC

Procedure:
A solution of 7.2 g of 3-chloro-2(R)-hydroxy-propyl-(diethoxymethyl)phosphinic acid ethyl ester, 3.6 g of Hunig base and 6.5 g of 3,4-dichlorobenzylamine in 20 ml of anhydrous ethanol is heated at reflux for 4 days. The mixture is concentrated to dryness by evaporation and the residue is partitioned between dichloromethane and water. The organic phase is separated off, dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel, yielding 3-[N-(3,4-dichlorobenzyl)amino]-2(S)-hydroxy-propyl(diethoxymethyl)phosphinic acid ethyl ester in the form of a yellowish oil; 1H-NMR (CD3Cl3 /D2O): δ=7.43 (1H, m, phenyl), 7.39 (1H, m, phenyl), 7.15 (1H, m, phenyl), 4.70 (1H, s, CHP), 4.20 (3H, m, CHO+CH2OP), 3.83 (2H, m, CH2OC), 3.70 (4H, m, CH2 phenyl+CH2OC), 2.65 (2H, m, CH2N), 2.20-1.71 (2H, m, CH2P), 1.40-1.26 (6H, m, 3xCH3).
Reaction SMILES: O1CCC[CH2:2]1.Cl(O)(=O)(=O)=O.C[CH:12]([CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[C:20]([CH:22]=[CH2:23])[CH3:21])[CH:13]=[O:14]>O>[CH3:2][C:16](=[CH:17][CH2:18][CH:19]=[C:20]([CH:22]=[CH2:23])[CH3:21])[CH2:15][CH2:12][CH:13]=[O:14]
Reactant: C1CCOC1
Reactant: C=CC(C)=CCC=CCC(C)C=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: C=CC(C)=CCC=C(C)CCC=O

Procedure:
A solution of 13.4 g. (53 mM) of the C12 -aldehyde diethylacetal, prepared according to the method described in paragraph c), 250 ml. of tetrahydrofuran, 60 ml. of water and and 0.5 ml. of 72% perchloric acid was left for 20 hours at room temperature under nitrogen. Water was added and the mixture was extracted with pentane (3x). The organic layers were washed with 5% NaHCO3 and water, dried over sodium sulphate and evaporated. The remaining oil was distilled to yield 9.2 g. (99%) of 4 methyl-8-vinyl-4,7-nonadienal, b.p. 73°-75°/0.3 Torr. IR(CHCl3): 2720, 1720, 1640, 1605, 995, 905 cm-1. NMR(CCl4): 1.4 - 1.8 ppm (m, 6 H), 2.2 - 2.5 ppm (m, 4H), 2.78 ppm (t, J = 7 cps, 2 H), 4.6 - 5.5 ppm (m, 4 H), 6.20 ppm (about 75%) / 6.64 ppm (about 25%) (2 d of d, J = 10 and 17 cps, 1 H), 9.55 ppm (t, J = about 1.5 cps, 1 H).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][S:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=O)=[CH:18][CH:17]=1.C(OCC)(=O)C>O1CCCC1>[CH3:14][S:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=[CH:3][C:1]#[N:2])=[CH:18][CH:17]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CSc1ccc2c(c1)C(=O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(=CC#N)CCC2
Reaction time: 0.5 h

Procedure:
Under an inert atmosphere and at 0° C., diethyl cyanomethylphosphonate (7.6 ml, 46.8 mmol) is added dropwise to a suspension of sodium hydride (2.25 g, 46.8 mmol) in 50 ml of tetrahydrofuran. Stirring is carried out at 0° C. for 30 minutes; the compound obtained in Step C (6 g, 31.2 mmol), dissolved in 50 ml of tetrahydrofuran, is then added and the reaction mixture is stirred at ambient temperature for 3 hours. After hydrolysis and extraction with ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on silica gel (eluant: petroleum ether/dichloromethane 50/50) to yield the unsaturated nitrile of the title.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26]1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[N:12]([C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Reactant: O=C1CCCC(=O)O1
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=O)CCCC(=O)O)OCO3

Procedure:
By using the product of Example 26 as starting material and performing the acylation according to Example 14 with glutaric acid anhydride, finally recrystallizing the raw product from ethanol the pure aimed product was obtained, m.p.: 148°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][C:14]2[CH:19]=[C:18](F)[CH:17]=[CH:16][C:15]=2[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][C:14]2[CH:19]=[C:18]([N:30]3[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]3)[CH:17]=[CH:16][C:15]=2[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(OC)cc(C(C)Nc2cc(F)ccc2C(=O)C(F)(F)F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)cc(C(C)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)C(F)(F)F)c1
Yield: 26.5 %

Procedure:
1-(2-(1-(3,5-Dimethoxyphenyl)ethylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (600 mg, 1.62 mmol), t-butyl piperazine-1-carboxylate (300 mg, 1.62 mmol), N,N-diisopropylethylamine (418 mg, 3.24 mmol) were stirred at 80° C. in dry acetonitrile (25 mL) for 21 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 20% ethyl acetate in hexanes to afford the title compound (231 mg, 27% yield). 1H NMR (400 MHz, CDCl3): δ 9.30 (d, 1H), 7.59 (d, 1H), 6.48 (s, 2H), 6.33 (s, 1H), 6.13 (d, 1H), 5.68 (s, 1H), 4.44 (m, 1H), 3.43 (m, 4H), 3.25 (m, 2H), 3.20 (m, 2H), 1.59 (d, 3H), 1.46 (s, 9H); MS (ESI) m/z: Calculated for C27H34F3N3O5: 537.25; Observed: 560.3 (M++Na).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][S:11](=[O:15])(=[O:14])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C2CCS(=O)(=O)CC2)cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ncc(C2CCS(=O)(=O)CC2)cc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To an ice cold solution of 4-(6-aminopyridin-3-yl)tetrahydro-2H-thiopyran 1,1-dioxide (140 mg, 0.62 mmol) in DCM (15 mL) was added NBS (110 mg, 0.62 mmol) in two portions. The reaction mixture was stirred at 0° C. for 20 min. The reaction solution was diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated to give 4-(6-amino-5-bromopyridin-3-yl)tetrahydro-2H-thiopyran 1,1-dioxide (190 mg, 0.62 mmol). LCMS (m/z): 305/307 (MH+), 0.33 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH:17]=[CH:16][CH2:15][CH2:14]1.C(C1NC=CN=1)(C1NC=CN=1)=O.C(Cl)(=O)C(Cl)=O>>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]([N:13]3[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18]3)=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1=CCNCC1
Reactant: O=C(O)c1ccc2ncoc2c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: O=C(c1ccc2ncoc2c1)N1CC=CCC1

Procedure:
Coupling of 1,3-benzoxazol-6-carboxylic acid with 1,2,3,6-tetrahydropyridine is performed in the same manner as described for the preparation of Invention Compound V through activation with carbonyl diimidazole or by activation with other suitable reagents such as oxalyl chloride. The product can be isolated by the same methods as described for the isolation of Invention Compound V and purified by chromatography on silica gel. EIMS m/z=228 (parent), 146 (base), and 118. 1H NMR δ 2.2 (br, 2), 3.4-4.3 (br m, 4), 5.7-5.95 (br m, 2), 7.52 (dd, 1, J=8.39, 1.49 Hz), 7.64 (d, 1, J=8.41 Hz), 7.87 (d, 1, J=1.32 Hz), and 8.16 ppm (s, 1).
Reaction SMILES: [NH3:1].[Na].[Cl:3][C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][C:5]=1[O:11][CH3:12]>CCCCCC.O.O.O.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:1])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COc1cc(Cl)ccc1Cl
Reactant: N
Agent: [Fe+3]
Agent: O=[N+]([O-])[O-]
Agent: [Na]
Solvent: O
Solvent: CCCCCC
Product: COc1cc(N)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
900 mL of ammonia was condensed at −78° C. 1 g of thinly shaven strips of sodium was added followed by 1.0 g of iron (III) nitrate nonahydrate. Upon disappearance of the deep blue color 25 g of thinly shaven strips of sodium was added. After 30 mins of stirring at −78° C., 50 g of 2,5-dichloroanisole was added as a solution in hexane (70 mL) dropwise and the reaction warmed to −45° C. for 2 hrs. Upon completion the ammonia was allowed to evaporate. The crude pot was then diluted in chloroform and 100 g of NH4Cl was added slowly. The combines were taken up in a separatory funnel and washed with water (3×) followed by brine (1×). The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting solid can be used without further purification. Yield: 99%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[NH:7][N:6]=1.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O>CN(C=O)C>[C:21]([O:20][C:18](=[O:19])[CH2:17][N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:5]([C:4]([F:3])([F:14])[F:15])=[N:6]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1nc(C(F)(F)F)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% [w/w] dispersion in mineral oil, 632 mg, 15.8 mmol) was added portionwise to a stirred solution of 4,5,6,7-tetrahydro-3-(trifluoromethyl)-indazole (3.00 g, 15.8 mmol) in DMF (60 mL), and the mixture stirred at RT for 30 min. Tert-butyl bromoacetate (2.33 mL, 15.8 mmol) was added and the reaction mixture stirred at 80° C. for 2 h, and allowed to cool to RT. Water (50 mL) was added and the resulting solution extracted with EtOAc (3×200 mL), washed with water (200 mL), brine (200 mL), dried over sodium sulfate, and concentrated in vacuo to afford (3-Trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Br:9])[CH:3]=1
Reactant: Cc1cc(Br)ccn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)ccn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a stirred room temperature solution of 4-bromo-2-methylpyridine (1.72 g, 10 mmol) in carbon tetrachloride at was added N-bromosuccinimide (1.9 g, 10.5 mmol). The mixture was warmed at 90° C. After 30 minutes, the mixture was cooled, and benzoyl peroxide (100 mg) was added and refluxing was continued. After 7 hours, the mixture was cooled to room temperature, washed with aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 4-bromo-2-bromomethylpyridine as a brown oil [MS m/z 250/252/254 (MH+)] which was determined to be 75% pure and was used without further purification. The remaining material was determined to be 4-bromo-2-dibromomethylpyridine.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][C:12](=[O:37])[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)[CH:5]=1.[OH-].[Li+].C(#N)C.Cl>O>[C:25]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:22]([O:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][C:12]([CH2:11][NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:38])=[O:2])=[O:37])[CH2:20][CH2:19]1)=[O:36]
Reactant: COC(=O)c1cccc(NCC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)CNc1cccc(C(=O)O)c1
Yield: 87.6 %

Procedure:
A solution of 3-({3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]-propionyl}methylamino)benzoic acid methyl ester (6.80 g, 13.2 mmol) and lithium hydroxide (1.58 g, 65.9 mmol) in a 1:1 mixture of acetonitrile:water (25.0 mL) was stirred at room temperature overnight. The pH of the reaction mixture was adjusted to pH 5 with aqueous hydrochloric acid (1M) and this mixture was extracted with DCM (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10% MeOH in DCM) to give the title compound (5.80 g, 87% yield) as an off-white powder.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:16][CH:15]=1.[N:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:21][C:22]([C:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)([OH:33])[CH3:32])=[CH:23][N:24]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)c1ccncc1
Reactant: Clc1ccc(-c2nccs2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(Cl)cc2)s1
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
To a solution of diisopropylamine (0.2 mL, 1.538 mmol) in dry THF (5 mL), was added 1.6M n-BuLi in hexanes (0.96 mL, 1.538 mmol) slowly at −78° C. The reaction mixture was stirred for 30 min, 2-(4-chlorophenyl)thiazole (0.2 g, 1.025 mmol) in THF (10.0 mL) added, the mixture stirred for 30 min, a solution of 1-(pyridin-4-yl)ethanone (0.17 mL, 1.538 mmol) in THF (5.0 mL) added, and the mixture was stirred for 2 hours at −78° C. The reaction mixture was quenched with saturated NH4Cl (50 mL) solution and extracted with EtOAc (2×100 mL). The organic layer was washed with water (2×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (1% methanol in dichloromethane) to obtain 1-(2-(4-chlorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol as off-white solid (0.1 g, 31% yield) in 99.9% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, 2H), 7.87 (d, 2H), 7.82 (s, 1H), 7.51-7.47 (m, 4H), 6.66 (s, 1H), 1.92 (s, 3H); LC-MS m/z calculated for [M+H]+ 317.04. found 317.4.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17]
Reactant: CCCn1c(=O)c(C#N)c(O)c2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Product: CCCn1c(=O)c(C#N)c(Cl)c2ccccc21
Yield: 41 %

Procedure:
In 10 ml of phosphorus oxychloride was refluxed 1.0 g (4.1 mmol) of 1,2-dihydro-4-hydroxy-1-propyl-2-oxo-3-quinolinecarbonitrile for 1 hour. The reaction mixture was dried under reduced pressure, and the residue was partitioned between chloroform and water. The chloroform layer was dried under reduced pressure to obtain 0.44 g (41%) of the titled compound as a yellow crystal.