Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CO.[CH2:5]([C:7]1[C:8](=[S:47])[NH:9][C:10](=[O:46])[N:11]([CH:45]=1)[C@@H:12]1[O:44][C@H:33]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[C@@H:23]([O:24]C(=O)C2C=CC=CC=2)[C@H:13]1[O:14]C(=O)C1C=CC=CC=1)[CH3:6]>C(O)(=O)C>[CH2:5]([C:7]1[C:8](=[S:47])[NH:9][C:10](=[O:46])[N:11]([CH:45]=1)[C@@H:12]1[O:44][C@H:33]([CH2:34][OH:35])[C@@H:23]([OH:24])[C@H:13]1[OH:14])[CH3:6]
Reactant: CCc1cn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]c1=S
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=S
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Sodium hydride (0.1 g) (60% dispersion in mineral oil) was added to dry methanol (50 ml) under an atmosphere of nitrogen at 0° C. The product from step (i) (3.0 g) was added to the above solution and the whole was refluxed for 2 hours. After cooling to room temperature, glacial acetic acid (0.28 ml) was added and the volatiles were then removed under reduced pressure. The residue was dissolved in water (20 ml) and then extracted three times with diethyl ether (20 ml). The aqueous phase was evaporated to dryness under reduced pressure. The resulting solid was triturated with acetone and filtered to leave 5-ethyl-4-thiouridine as a yellow solid (1.39 g).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C@H:14]([NH:16][CH2:17][C@@H:18]2[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][N:20]([C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([O:40]C)=[O:39])=[CH:34][CH:33]=3)=[O:30])[CH2:19]2)[CH3:15])[CH:11]=[CH:12][CH:13]=1.[OH-].[Li+].Cl>CO.O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C@H:14]([NH:16][CH2:17][C@@H:18]2[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][N:20]([C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]([OH:40])=[O:39])=[CH:36][CH:37]=3)=[O:30])[CH2:19]2)[CH3:15])[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(OC(=O)N2C[C@H](CN[C@H](C)c3cccc(OC)c3)[C@@H](c3ccccc3)C2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc([C@@H](C)NC[C@H]2CN(C(=O)Oc3ccc(C(=O)O)cc3)C[C@@H]2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 2.0 ml THF, 1.0 ml water and 0.5 ml methanol mixed solution of 261 mg of 4-(methoxycarbonyl)phenyl(3S,4S)-3-({[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate was mixed with 45 mg of lithium hydroxide and stirred at room temperature for 20 hours. The reaction solution was acidified by adding 1 M hydrochloric acid and post-treated and purified in the standard method to obtain 136 ml of 4-({[(3S,4S)-3-({[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}oxy)benzoic acid as a colorless amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1.O>CN(C)C=O>[N+:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])([O-:22])=[O:21]
Reactant: Nc1cccc(S)c1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(SCc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 3-aminobenzenethiol (0.51 mL, 4.8 mmol) and sodium methoxide (0.31 g, 5.8 mmol) in N,N-dimethylformamide (5.3 mL) was stirred at 25° C. for 10 minutes (min). The reaction mixture was treated with a solution of 1-(bromomethyl)-3-nitro-benzene (1.0 g, 4.8 mmol) in N,N-dimethylformamide (4.5 mL) dropwise and stirred at 25° C. for 1 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude brown oil. This material was purified by flash column chromatography to give the desired product (1.2 g, 95%) as a tan oil. LCMS for C13H13N2O2S (M+H)+: m/z=261.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[C:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)=[O:15])[C:5](F)=[CH:4][N:3]=1.CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:16]([CH:17]3[CH2:19][CH2:18]3)[C:14](=[O:15])[CH:9]3[CH2:10][O:11][CH2:12][CH2:13][N:8]3[C:6]=2[N:7]=1
Reactant: O=C(NC1CC1)C1COCCN1c1nc(Cl)ncc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
A scintillation vial equipped with a magnetic stirrer was added 4-(2-chloro-5-fluoropyrimidin-4-yl)-N-cyclopropylmorpholine-3-carboxamide (325 mg, 1.081 mmol), DMF (5 ml), Cs2CO3 (528 mg, 1.621 mmol). The reaction was stirred at 60° C. for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate three times and the combined organic layers washed with sat. NaCl. The organic layers were dried with Na2SO4, filtered and dried in-vacuo to give a yellow solid. The crude material was washed with diethyl ether and filtered to afford 2-chloro-5-cyclopropyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (121 mg, 0.431 mmol, 39.9% yield) as a white solid. MS [M+H] found 281.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].N>O1CCCC1.O>[CH3:20][S:21]([O:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2)(=[O:23])=[O:22]
Reactant: O=C1CCc2cc(CO)ccc21
Reactant: CS(=O)(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc2c(c1)CCC2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of Example 332C (3.8 g, 23.6 mmol) and triethylamine (4.3 mL, 30.7 mmol) in tetrahydrofuran (50 mL) was added methanesulfonyl chloride (2.2 mL, 28.3 mmol) dropwise at about 0° C. After about 30 min stirring at about 0° C., the reaction mixture was diluted with water and was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to give the above intermediate. MS (DCI/NH3): m/z 258 (M+NH4)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.O1CCCNCC1.[C:16]([OH:21])(=[O:20])[C:17]([OH:19])=[O:18]>CO>[C:16]([OH:21])(=[O:20])[C:17]([OH:19])=[O:18].[OH:1][CH2:2][C@@H:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: OCC1CNCCO1
Agent: C1CNCCOC1
Agent: O=C(O)C(=O)O
Solvent: CO
Product: OC[C@H]1CNCCO1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a mixture of 2-hydroxymethylmorpholine and 1,4-oxazepane compound (20.0 g, 2-hydroxymethylmorpholine:1,4-oxazepane compound=75.8:24.2) synthesized in Example 5 were added methanol (100 ml) and oxalic acid (13.6 g, 0.151 mol) and the mixture was stirred for 30 min. Methanol was evaporated under reduced pressure. To the residue was added 2-propanol (50 ml) and the mixture was subjected twice to azeotropic distillation with dehydrating. To the residue after azeotropic distillation with dehydrating was added ethyl acetate (100 ml) at 40° C., and the mixture was cooled to 10° C. After crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (25 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine oxalate (12.6 g) (2-hydroxymethylmorpholine:oxalic acid=1:1, yield from (S)-epichlorohydrin 40.5%). The obtained (R)-2-hydroxymethylmorpholine oxalate was analyzed by HPLC to find an optical purity of 99% ee.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[F:10][C:4]1[CH:3]=[C:2](/[CH:13]=[CH:12]/[C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: C=CC(=O)OCC
Reactant: COc1cc(F)cc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Product: CCOC(=O)/C=C/c1cc(F)cc(OC)c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 86.5 %

Procedure:
To a solution of 1-bromo-3-fluoro-5-methoxybenzene (15 g, 73.16 mmol), tris(2-methylphenyl)phosphane (1.781 g, 5.85 mmol) and ethyl acrylate (11.90 mL, 109.74 mmol) in TEA (135 mL) was added palladium(II) acetate (0.329 g, 1.46 mmol) at room temperature under nitrogen atmosphere, and the mixture was stirred at 90° C. for 2 days. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give ethyl (E)-3-(3-fluoro-5-methoxyphenyl)acrylate (14.2 g, 63.3 mmol, 87%) as a colorless oil.
Reaction SMILES: [Na].[N:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:3]=[N-:4].[CH3:11][Si:12]([CH3:22])([CH3:21])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[NH4+].[Cl-]>CCO>[N:2]([C:5](=[CH:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([Si:12]([CH3:11])([CH3:22])[CH3:21])[CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:3]=[N-:4]
Reactant: C[Si](C)(C)c1cccc(C=O)c1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccc([Si](C)(C)C)c1)N=[N+]=[N-]
Temperature: -10 °C
Reaction time: 4 h
Yield: 26.9 %

Procedure:
To a solution of 2 g (87.5 mmol) of sodium in 30 mL of anhydrous EtOH, maintained under a nitrogen atmosphere and cooled to −10° C., is added, dropwise, a mixture of 31.4 mL (87.5 mmol) of ethyl azidoacetate (at 34% in CH2Cl2) and 3.9 g (21.87 mmol) of 3-trimethylsilylbenzaldehyde prepared according to the procedure described in the preceding step, diluted with 3 mL of EtOH. The reaction mixture is stirred at 0° C. for 4 hours. It is then hydrolysed by adding, with vigorous stirring, 100 mL of aqueous NH4Cl solution (30%). The aqueous phase is extracted with 3×50 mL of EtOAc. The combined organic phases are washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude reaction product is purified by chromatography on a column of silica gel, eluting with an isocratic mixture of heptane and CH2Cl2 (80/20). 1.7 g of the expected ethyl 2-azido-3-(3-trimethylsilylphenyl)propenoate are thus isolated in the form of a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[SH:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][S:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: CCOC(=O)CCS
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCSCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A mixture of 1-(bromomethyl)-4-nitrobenzene (Aldrich, 3.8 g; 17.6 mmol) in acetone (100 ml) was treated with potassium carbonate (2.22 g; 15.9 mmol) and ethyl 3-mercaptopropanoate (Aldrich, 2.14 g; 15.9 mmol). After stirring at RT for 18 hours the mixture filtered and the solid washed with acetone. The organic fractions were combined and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of Et2O to give the title compound as an off-white solid (3.6 g, 84%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.CCN(C(C)C)C(C)C.[C:24]1([NH:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:33][CH2:32][CH2:31][NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1
Reactant: NCCNc1ccccc1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1cc(NCCNc2ccccc2)nc(N2CCOCC2)n1
Temperature: 75 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (prepared as described in Method 22; 932 mg, 4.0 mmol) and DIEA (0.7 mL, 4.0 mmol) in ACN (40 mL), neat N1-phenyl-ethane-1,2-diamine (0.523 mL, 4.0 mmol) was slowly added. The reaction mixture was stirred at 70-80° C. under nitrogen. After 20 hours, the reaction mixture was cooled down, and the solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (120 mL) and 0.1 M NaHCO3 (50 mL). The organic layer was washed with additional 0.1 M NaHCO3 (2×50 mL), brine (50 mL), dried, filtered and concentrated to give N1-(6-chloro-2-morpholinopyrimidin-4-yl)-N2-phenylethane-1,2-diamine, as an off-white solid (1.29 g, 96%). LC/MS (m/z): 334.0 (MH+), Rt 1.94 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2.[CH3:18][C:19]1(OC)[CH2:23][CH2:22][C:21]([CH3:26])(OC)O1>>[CH3:18][C:19]1[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]3)[C:21]([CH3:26])=[CH:22][CH:23]=1
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1C(F)(F)F
Reactant: COC1(C)CCC(C)(OC)O1
Product: Cc1ccc(C)n1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1C(F)(F)F

Procedure:
12.2 mmol of 6-amino-7-trifluoromethyl-2,3(1H,4H)-quinoxalinedione were reacted with 12.2 mmol of 2,5-dimethyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Na+].Cl[C:8]1[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:4][C:8]1[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=1)[C:2]#[CH:3]
Reactant: O=Cc1cnc(Cl)s1
Reactant: C#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCOc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 130.5 %

Procedure:
0.37 g of propargyl alcohol was dissolved in 100 ml of tetrahydrofuran, and 0.9 g of 60% sodium hydride was added in portions. The mixture was stirred at room temperature for 1 hour. Thereafter, 3.0 g of 2-chloro-1,3-thiazole-5-carbaldehyde was added to the reaction mixture and the mixture was stirred at room temperature for 3 hours. After aqueous saturated ammonium chloride was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.44 g of 2-(2-propynyloxy)-1,3-thiazole-5-carbaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([Li])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[CH3:11][Si:12](Cl)([Cl:14])[Cl:13]>C1COCC1>[CH3:1][C:2]1[CH:3]([Si:12]([Cl:14])([Cl:13])[CH3:11])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: C[Si](Cl)(Cl)Cl
Reactant: [Li]C1C(C)=C(C)C(C)=C1C
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(Cl)Cl)C(C)=C1C
Temperature: -78 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
(2,3,4,5-Tetramethylcyclopentadienyl)lithium (1.33 g, 10.37 mmol) was dissolved in 80 mL THF and cooled to −78° C., and MeSiCl3 (1.70 g, 11.4 mmol) was added via a syringe. After addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. Volatiles were removed under vacuum at room temperature, and the residue was extracted twice with hexanes (2×20 mL). The hexane fractions were combined and the solvent was removed under vacuum to give a pale yellow oil (tetramethylcyclopentadienyl methyl silicon dichloride); 2.0 g, 82% yield. 1H-NMR (C6D6): δ (ppm): 2.95 (broad s, 1 H; Me4CpH), 1.92 (s, 6H;), 1.63 (s, 6H; Me4Cp), 0.19 (s, 3 H; MeSi).
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25]CC3C=CC=CC=3)[CH:21]=2)[C:16]=1[C:33](=[O:49])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:36][CH:35]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].CO>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:50])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:25])[CH:21]=2)[C:16]=1[C:33](=[O:49])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:36][CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccc1-c1ccc2cc(OCc3ccccc3)ccc2c1C(=O)c1ccc(OCCN2CCCCC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(F)ccc1-c1ccc2cc(O)ccc2c1C(=O)c1ccc(OCCN2CCCCC2)cc1
Yield: 94.8 %

Procedure:
To a round bottom flask add (2-{6-benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-5-fluoro-phenyl)-carbamic acid tert-butyl ester (0.075 g, 0.11 mmol), ammonium formate (0.056 g, 0.89 mmol), methanol (5 mL) and a slurry of 10% Pd/C (0.012 g, ˜15% by weight) and ethanol (2 mL). Heat the mixture, with stirring, at reflux for 30 minutes. Cool the reaction to ambient temperature and filter it through a pad of Celite, then rinse the Celite with hot methanol. Evaporate the filtrate in vacuo and purify the resulting residue by radial chromatography over silica (4-9% MeOH gradient in CH2Cl2) to provide the product 61 mg (94%): mass spectrum (ion spray) m/z=585 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[CH2:12][NH:13][C:14](=[O:30])[NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:17]=2)=[CH:3]1>C(O)(=O)C>[CH2:28]([O:27][C:25]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([N:15]2[C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[CH:12][NH:13][C:14]2=[O:30])=[CH:17]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)n1cc(NC(=O)NCC(=O)c2cn(C)c3ccccc23)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)n1cc(-n2c(-c3cn(C)c4ccccc34)c[nH]c2=O)c2ccccc21
Temperature: 110 °C
Yield: 74 %

Procedure:
The product of step b) (2.63 g, 6.29 mmol) was suspended in acetic acid (30.0 ml) and heated to 110° C. until all the starting material has been consumed after about 3 hours. The solvent was removed and the residue titurated with diethyl ether to give the sub-title compound (1.84 g, 74%) as an off-white solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:26])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC(C)=CC=3)C3(C4=CC5OCOC=5C=C4OC3)C2=O)C=CC=CC=1>>[OH:25][C:22]1[CH:23]=[CH:24][C:19]2[O:18][CH2:17][C:10]3([C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]3=[O:26])[C:20]=2[CH:21]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc(O)cc12
Agent: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2C(c1ccccc1)c1ccccc1
Product: O=C1Nc2ccccc2C12COc1ccc(O)cc12

Procedure:
Following the procedure as described in EXAMPLE 1.28, and making non-critical variations using 1′-(diphenylmethyl)-5-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, the title compound was obtained (48%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.85 (s, 1H), 7.21 (dt, 1H), 7.06 (d, 1H), 6.94 (dd, 1H), 6.89 (d, 1H), 6.72 (d, 1H), 6.54 (dd, 1H), 6.02 (d, 1H), 4.70 (d, 1H), 4.57 (d, 1H); MS (ES+) m/z 254.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: COc1cc2c(c(-c3cc(Cl)ccc3Cl)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(OC)cc(-c3cc(Cl)ccc3Cl)c2O1

Procedure:
The title compound was prepared (0.061 g, 56%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.139 g, 0.29 mmol) and methylamine (0.090 g, 2.9 mmol). mp 179-181° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:11]=1[N:21]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][C:17]([F:18])([F:19])[F:20])[CH:13]=[CH:12][C:11]=1[N:21]1[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]1
Reactant: COc1cc(OC(F)(F)F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC(F)(F)F)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Trifluoroacetic acid (90 mL) was added to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 4-[2-methoxy-4-(trifluoromethoxy)phenyl]-1-piperazinecarboxylate (Description 17, 3.4 g) in dichloromethane (135 mL) and the mixture was stirred at room temperature for 1 h. The mixture was allowed to warm to room temperature, saturated aqueous sodium bicarbonate solution (380 mL) was added and the mixture was extracted with dichloromethane. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a pale brown solid (1.84 g, 74%). 1H NMR (250 MHz, CDCl3) δ3.28-3.58 (8H, m), 3.87 (3H, s), 6.77 (1H, d, J 1.9 Hz), 6.84 (1H, d, J 8.9 Hz), and 6.91-6.95 (1H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:23]1([CH2:22][CH2:21][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:10][C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[N:8][C:7](=[O:17])[C:6]=3[CH:18]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2ccccn2)sc2ccc(OCCCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.6 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), 1-bromo-3-phenylpropane (0.86 g, 4.3 mmol) and potassium carbonate (0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at room temperature for 20 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.48 g, 92%).