Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:11]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[NH:13][C:12]1=[O:20])[CH2:8][CH2:9][CH3:10].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][N:23]=1.[I-].[Na+]>C1COCC1.CN(C=O)C>[CH2:7]([N:11]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([CH2:28][C:25]2[CH:24]=[N:23][C:22]([Br:21])=[CH:27][CH:26]=2)[C:12]1=[O:20])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1cn(CCCC)c(=O)[nH]1
Reactant: BrCc1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCc1cn(CCCC)c(=O)n1Cc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
Under nitrogen, 138 mL-(138 mmol) of 1.0 M potassium t-butoxide in THF was added to a stirred solution of 24.5 g (125 mmol) of 1,4-dibutylimidazol-2-one from step 2A in 370 mL of DMF at -30° C. at such a rate to maintain the solution temperature below -20° C. After 10 min, 50 g [138 mmol (69% purity)]of 2-bromo-5-bromomethylpyridine from step 4 and 2.7 g (18.1 mmol) of sodium iodide were added. The reaction was stirred at 0° C. for 2 h and then allowed to slowly warm to ambient temperature overnight. The reaction was partitioned between ethyl acetate and water; the organic layer was washed twice with brine and the combined aqueous phases were back-extracted with ethyl acetate. The ethyl acetate extractions were combined, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using hexane/ethyl acetate (25:75) gave 33 g (73%) of 1,4-dibutyl-1,3-dihydro-3-[(6-bromo-3-pyridinyl) methyl]-2H-imdazol-2-one as a reddish-brown waxy solid: NMR (CDCl3) δ0.89 (t, J=7 Hz, 3H), 0.95 (t, J=7 Hz, 3H), 1.25-1.51 (m, 6H), 1.57-1.71 (m, 2H), 2.22 (t, J=8 Hz, 2H), 3.60 (t, J=7 Hz, 2H), 4.80 (s, 2H), 5.90 (s, 1H), 7.43 (d, J=9 Hz, 1H), 7.49 (dd, J=9 and 2 Hz, 1H), 8.24 (d, J=2Hz, 1H).
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.C(=O)(O)[O-].[K+].[CH2:19](Br)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CS(C)=O>[CH2:19]([O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
10.0 g of caffeic acid and 6.1 g potassium bicarbonate were mixed in 50 mL of dimethylsulfoxide. 7.6 mL of phenethyl bromide were added and the reaction mixture was heated to 70° C. under agitation. The mixture was stirred for 3 hrs, and then cooled to <25° C. The reaction mixture was slowly added to 500 mL of water under agitation to precipitate the product, which was recovered by filtration. The crude product was washed with dilute potassium bicarbonate and toluene and was then recrystallized via cooling from 200 mL boiling toluene to obtain caffeic acid phenethyl ester The yield was 9.0 g and the assay was 100%.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)([CH2:10][OH:11])[CH2:8][OH:9])=[CH:4][CH:3]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[H-].[Na+]>CN(C=O)C>[CH2:28]([O:9][CH2:8][C:7]([CH2:10][O:11][CH2:6][C:5]1[CH:26]=[CH:27][CH:2]=[CH:3][CH:4]=1)([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:27][CH:26]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])=[CH:17][CH:18]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(OCC)c1ccc(CC(CO)(CO)Cc2ccc(Br)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccc(CC(COCc2ccccc2)(COCc2ccccc2)Cc2ccc(Br)cc2)cc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
A mixture of 2-(4-Bromobenzyl)-2-[4-(diethoxymethyl)benzyl]-1,3-propanediol(3 g, crude), benzyl bromide (3 mL), and NaH (1.2 g, 60% in mineral oil) in 30 mL of DMF was stirred for 14 h at 70° C. The mixture was then quenched with 5 mL of MeOH followed by 50 mL of saturated NH4Cl and extracted with 200 mL of 2:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 15:1 hexane EtOAc containing 1% of Et3N to give 2.5 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1)#[N:16].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([S:23][C:20]2[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)=[O:12])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: N#Cc1ccc(S)cc1
Reactant: CCCCCc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CCCCCc1ccc(C(=O)Sc2ccc(C#N)cc2)cc1

Procedure:
Quantities: compound 17 (0.51 g, 3.8 mmol), compound 10 (0.87 g, 4.5 mmol), 4-(dimethylamino)pyridine (0.19 g, 1.6 mmol). N,N'-dicyclohexylcarbodiimide (0.94 g, 4.6 mmol).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>>[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:10]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:16][CH:17]=2)[C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1ccc(CN(Cc2ccc(C(C)(C)C)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 4-tert-butylbenzylbromide (500 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.250 g (58.7%); MS m/z: 426.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.24 (s, 18H); 4.62 (s, 4H); 6.69 (br s, 1H); 6.74 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 7.17-7.22 (m, 4H); 7.31-7.33 (m, 5H); 7.94 (s, 1H); 11.89 (br s, 1H); HPLC (METHOD [A]): rt 20.49 min (86.5%)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1(=[CH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=2)[CH2:9][CH2:8]1.O>O1CCCC1>[C:7]1(=[CH:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:19][CH:20]=2)[CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc(C=C2CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(C=C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.3 %

Procedure:
To a suspension of lithium aluminum hydride (0.16 g) in tetrahydrofuran (30 mL) was added methyl 4-(cyclopropylidenemethyl)benzoate (0.80 g), and the mixture was stirred at room temperature for 5 hours. Water (0.4 mL) was added to the reaction mixture, and the mixture was stirred for 3 days. Insoluble materials were removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give 4-(cyclopropylidenemethyl)benzyl alcohol (0.69 g).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cn1c(Cl)ncc(Br)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cn1c(Nc2ccc(F)cc2)ncc(Br)c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.100 g, 0.448 mmol; prepared according to the procedure of Example 46, Step B), 4-fluorobenzenamine (0.056 ml, 0.582 mmol) and NaHCO3 (0.150 g, 1.79 mmol) in n-BuOH (3 mL) was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The EtOAc layer washed with H2O and saturated aqueous NaCl. The aqueous phase was re-extracted with EtOAc. The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.132 g, 99%) as a pale yellow solid that was used without further purification.
Reaction SMILES: [ClH:1].[OH:2][CH:3]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:7]=2[CH2:6][NH:5][CH2:4]1.CCOCC>C(O)C>[ClH:1].[OH:2][CH:3]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:7]=2[CH2:6][NH:5][CH2:4]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC(O)C2
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Nc1ccc2c(c1)CNCC(O)C2
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A suspension of 4-hydroxy-8-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride (1.80 g, 7.36 mmol) (G. L. Grunewald and V. H. Dahanukar, J. Heterocycl. Chem., 1994, 31, 1609) and 5% Pd--C (0.2 g) in ethanol (100 ml) was hydrogenated at 50 psi for 2 h. The catalyst was filtered off and the solvent was concentrated to give a solid. This solid was dissolved in hot ethanol (50 ml) and ether (200 ml) was added slowly. The solid was collected, washed with ether (100 ml) and air-dried to give the title compound as a yellow solid (1.44 g, 91%), m.p. 232.5-4° C.
Reaction SMILES: C([O-])(=O)C.[K+].Cl[C:7]1[C:8]([O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][N:12]=1.CC1(C)C(C)(C)OB([C:32]2[CH2:33][CH2:34][CH2:35][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:37]=2)O1>CC#N>[CH3:21][O:20][C:18]([C:17]1[CH:22]=[CH:23][C:14]([O:13][C:8]2[C:7]([C:34]3[CH2:33][CH2:32][CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:35]=3)=[N:12][CH:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1)=[O:19]
Reactant: COC(=O)c1ccc(Oc2nccnc2Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C=C(B2OC(C)(C)C(C)(C)O2)CCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2nccnc2C2=CN(C(=O)OC(C)(C)C)CCC2)cc1
Temperature: 80 °C

Procedure:
To a mixture of (amphos)2PdCl2 (0.145 g, 0.205 mmol), potassium acetate (1.045 g, 10.65 mmol), methyl 4-(3-chloropyrazin-2-yloxy)benzoate (1.084 g, 4.10 mmol), and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (1.900 g, 6.14 mmol) under N2 was added MeCN (7.0 mL) and Ar degassed water (0.70 mL). The reaction mixture was degassed with Ar (10 min) then heated to 80° C. for 20 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (10 mL), dried (MgSO4), and concentrated. Purification by ISCO (120 g SiO2, 10-100% EtOAc/hexanes) gave tert-butyl 5-(3-(4-(methoxycarbonyl)phenoxy)pyrazin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:38]2[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=2)[CH2:41]Cl)[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=2)[CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[C:38]([C:30]3[CH:31]=[C:32]([O:36][CH3:37])[C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[CH:29]=3)[CH:39]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Product: COc1cc(-c2cccc(CN(c3ccc(OC(F)(F)F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethoxy)phenyl]amino]piperidine (721 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].NCCC(O)=O>C(O)(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[C:17]2[NH:11][C:12](=[O:13])[NH:14][C:15]2=[O:16])=[CH:3][CH:4]=1
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(C=O)cc1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 136 g of p-anisaldehyde, 110 g. of hydantoin and 20 g. of β-alanine in 400 ml. of acetic acid is heated under reflux for seven hours. After a short period at reflux a clear solution is obtained; however, a solid appears after a few hours. The mixture is stirred at room temperature overnight, diluted with 400 ml. of water, filtered and the solid washed first with methanol and next with water. The solid is then slurried in 1.5 liters of boiling ethanol and filtered while still hot. The solid is dried in a vacuum oven to give the above named compound as a bright yellow solid, mp. 250°-253° C.
Reaction SMILES: O=[C:2]([CH3:25])[C:3](=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[C:4]([NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5].[CH3:26]/[C:27](/[NH2:31])=[CH:28]\[C:29]#[N:30]>C1(C)C=CC=CC=1>[C:29]([C:28]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:3]([C:4]([NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])=[C:2]([CH3:25])[NH:31][C:27]=1[CH3:26])#[N:30]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)NCC(=O)OC(C)(C)C
Reactant: C/C(N)=C\C#N
Solvent: Cc1ccccc1
Product: CC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)C(C(=O)NCC(=O)OC(C)(C)C)=C(C)N1
Yield: 98.7 %

Procedure:
A toluene solution containing 348 mg (1 mmol) of t-butyl 2-[N-[3-oxo-2-(3-nitrobenzylidene)butanoyl]amino]-acetate and 123 mg (1.5 mmol) of 3-aminocrotonitrile was refluxed for 4 hours. The reaction mixture was chromatographed on a silica gel column for purification, whereby 407 mg (98.7%) of t-butyl 2-[N-(5-cyano-1,4-dihydro-2,6-dimethyi-4-(3-nitro-phenyl)pyridine-3-carbonyl)amino]-acetate was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)[OH:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40].O>C(Cl)(Cl)Cl>[C:39]([O:24][CH:23]([C:17]1[C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=[C:19]([CH3:22])[N:18]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1)(=[O:41])[CH3:40]
Reactant: COc1cc2nccc(Oc3ccc(C)nc3C(O)c3cccc(C)n3)c2cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(C)nc3C(OC(C)=O)c3cccc(C)n3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-methanol (43 mg) was dissolved in chloroform (6 ml) to prepare a solution. Triethylamine (0.9 ml) and acetic anhydride (0.45 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (28 mg, yield 61%).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[OH:33][CH2:34][CH:35]1[O:40][CH2:39][CH2:38][NH:37][CH2:36]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.CCOC(C)=O.C(Cl)Cl>[OH:33][CH2:34][CH:35]1[CH2:36][N:37]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:38][CH2:39][O:40]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: OCC1CNCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOC(CO)C2)c(-c2ccn[nH]2)c1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
A mixture of 6-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.1, 150 mg, 0.321 mmol), 2-hydroxymethylmorpholine (75 mg, 0.643 mmol) and DIPEA (0.224 mL, 1.285 mmol) in iPrOH (0.6 mL) in a sealed vial was stirred at 140° C. for 4 h. The RM was dissolved in EtOAc, washed with water (3×20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in DCM (2.5 mL), treated with TFA (0.912 mL, 11.84 mmol) and stirred at RT for 2 h. The RM was diluted with EtOAc, washed with aq. sat. NaHCO3 solution (2×40 mL) and with water (2×40 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/MeOH 9:1) followed by preparative HPLC (Condition 10). Fractions containing product were combined and the solvent was evaporated off under reduced pressure to give an aqueous residue which was treated with Na2CO3 (100 mg) and extracted with EtOAc. The combined extracts were washed with water (2×20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC (Column 4-EP, from 20% to 25% in 6 min) to give the title compound as a white solid. HPLC (Condition 7) tR=5.738 min, UPLC-MS (Condition 3) tR=0.90 min, m/z=464.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.54-2.67 (m, 1H) 2.73-2.86 (m, 1H) 3.22-3.30 (m, 1H) 3.35-3.45 (m, 2H) 3.47-3.68 (m, 3H) 3.70-3.84 (m, 1H) 4.52-4.77 (m, 1H) 6.60/6.69 (s, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.79-7.96 (m, 3H) 8.20/8.35 (br. s, 1H) 8.74 (br. s, 1H) 10.36/10.41 (s, 1H) 13.03/13.19 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[C:22]5=[N:23][S:24](=[O:28])(=[O:27])[CH2:25][CH2:26][N:21]5[CH:20]=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1>C1COCC1.CO.[Pt](=O)=O>[O:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[C:22]5=[N:23][S:24](=[O:27])(=[O:28])[CH2:25][CH2:26][N:21]5[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc5c(c4)OCC5)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc(Oc4ccc5c(c4)OCC5)cc3)C2=N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
Platinum(IV) oxide (20 mg) was added to a solution of 9-[4-(2,3-dihydro-1-benzofuran-6-yloxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (100 mg) in THF (dry) (50 mL) and MeOH (50 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Platinum(IV) oxide (20 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (68.8 mg) as colorless crystals.
Reaction SMILES: [F:1][CH:2]([F:16])[CH:3]([OH:15])[CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[O:8][N:7]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C.C1COCC1>O>[F:16][CH:2]([F:1])[CH:3]([O:15][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[O:8][N:7]=1
Reactant: COC(=O)c1cc(OCC(O)C(F)F)no1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCC(OS(C)(=O)=O)C(F)F)no1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-(3,3-difluoro-2-hydroxypropoxy)isoxazole-5-carboxylate (370 mg), methanesulfonyl chloride (0.362 mL), triethylamine (0.652 mL) and THF (10 mL) was stirred at 0° C. for 1 hr, and then at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless oil (432 mg).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:21][CH:22]=2)=[CH:11][C:10]=1[CH2:29][O:30][C:31](=[O:38])[NH:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:33]1([NH:32][C:31]([O:30][CH2:29][C:10]2[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:21][CH:22]=3)[CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]([OH:39])=[O:5])=[O:38])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1COC(=O)NC1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1COC(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A 15 mL round bottom flask was charged with 3-{2-cyclopentylcarbamoyloxymethyl-4-[2-(2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid tert-butyl ester (0.097 g, 0.18 mmol), CH2Cl2 (1.2 mL), and then trifluoroacetic acid (1.2 mL). The solution was stirred at ambient temperature under a nitrogen atmosphere for 4 h and was concentrated. The residue was purified using radial chromatography (MeOH:CH2Cl2 2:98 to 10:90) to give a white solid (0.085 g, 93%). 1H NMR (400 MHz, CDCl3) δ 1.37 (br s, 2H), 1.63 (br s, 4H), 1.93-2.05 (m, 2H), 2.39 (s, 3H), 2.64 (br s, 2H), 2.91-3.18 (m, 4H), 3.99 (br s, 1H), 4.21 (s, 2H), 4.87 (br s, 1H), 5.10 (br s, 2H), 6.80 (s, 1H), 6.89 (s, 1H), 7.00-7.25 (br s, 1H), 7.36-7.52 (m, 3H), 7.95 (s, 2H). MS (ES) m/e 493 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1/[CH:6]=[C:7]1\[CH2:8][N:9]2[CH2:14][CH2:13][CH:12]\1[CH2:11][CH2:10]2.[C:15]([OH:20])(=[O:19])[C:16]([OH:18])=[O:17]>CO.C(O)C.C(OCC)C.[Pt]>[C:15]([OH:20])(=[O:19])[C:16]([OH:18])=[O:17].[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH:7]1[CH:12]2[CH2:11][CH2:10][N:9]([CH2:14][CH2:13]2)[CH2:8]1
Reactant: C(=C1\CN2CCC1CC2)\c1nccs1
Agent: [Pt]
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CO
Solvent: CCOCC
Product: c1csc(CC2CN3CCC2CC3)n1
Yield: 14 %

Procedure:
(±) Z 3((1,3-Thiazol-2-yl)methylene)-1-azabicyclo [2.2.2]octane (D34) (0.15g, 0.00073 moles) was hydrogenated in methanol (20ml) over a 5% platinum on sulphided carbon catalyst (0.6g) at 200 psi and 100° C. for 48h. The mixture was filtered through Kieselguhr and the filter pad washed with methanol (2×50ml). The combined filtrates were concentrated in vacuo and the residue subjected to column chromatography on TLC alumina eluting with 0.5% methanol/chloroform. This gave a white solid which was treated with anhydrous oxalic acid in ethanol/diethylether to give the title compound (E17) (0.03g, 14%) m.p. 126-130° C.