Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH:11]([N:13]1[CH:16]([S:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][C:14]1=[O:37])O)([OH:10])=[O:9].S(Cl)([Cl:40])=O>C(Cl)Cl>[C:8]([CH:11]([N:13]1[CH:16]([S:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][C:14]1=[O:37])[Cl:40])([OH:10])=[O:9]
Reactant: O=C(O)C(O)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C(Cl)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A cooled (ice bath) solution of the triethylamine salt of 1-(1'-carboxy-1'-hydroxymethyl)-4-tritylthio-2-azetidinone (1.04 g, 2.0 mmol) in methylene chloride (5 ml) was treated dropwise, under N2, with thionyl chloride (0.16 ml, 2.2 mmol) in methylene chloride (2 ml). The solution was stirred at room temperature for 20 min and concentrated. The residue was diluted with benzene and filtered over a Celite/charcoal bed. The filtrate was evaporated in vacuo to give 870 mg (quantitative) of the title compound as an amorphous solid. It was used in the next step without further purification. ir νmax : 1775 cm-1 ; 1Hmr (CDCl3) δ: 9.22 (1H, bs), 7.27 (15H, m), 5.3 and 5.2 (1H, 2d, J=2 Hz), 4.6 (1H, m) and 2.8 ppm (2H, m).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([C@H:14]2[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][N:15]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:10]=[CH:11][C:12]=1[F:13].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>O1CCCC1>[F:6][C:7]1[CH:8]=[C:9]([C@H:14]2[CH2:19][C@@H:18]([O:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:16][N:15]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C[C@@H]1c1ccc(F)c(F)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C[C@@H]1c1ccc(F)c(F)c1
Yield: 102.2 %

Procedure:
Methanesulfonyl chloride (1.0 g, 3.2 mmol) was added to a mixture of (±)-1,1-dimethylethyl (2R,4S)-2-(3,4-difluorophenyl)-4-hydroxypiperidine-1-carboxylate (1.00 g, 3.0 mmol) (obtained by conducting reagent preparation 28 in the presence of di-tert-butyl dicarbonate) and triethylamine (0.70 g, 7.0 mmol), in tetrahydrofuran (25 mL) at 0° C., and the resulting mixture was at room temperature for two hours. The reaction mixture was then quenched with a cold mixture of water and ethyl acetate. The organic portion was separated, washed with 5% sodium hydroxide, 0.5M hydrochloric acid, water then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (5% to 75% ethyl acetate in hexanes gradient) to give (±)-1,1-dimethylethyl (2R,4S)-2-(3,4-difluorophenyl)-4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (1.2 g, 88% yield). MS (EI) for C17H23F2NO5S: 392 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[C:13]#[N:14])=[CH:5][CH:4]=1.N.CO>C(O)C.[Co]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[CH2:13][NH2:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)/C(=C/C#N)CC2
Agent: [Co]
Agent: N
Solvent: CCO
Solvent: CO
Product: COc1ccc2c(c1)/C(=C/CN)CC2
Temperature: 40 °C
Reaction time: 32 h
Yield: 85.6 %

Procedure:
To a solution of (E)-(6-methoxyindan-1-ylidene)acetonitrile (1.60 g, 8.64 mmol.) in ethanol (80 ml) were added a 2M ammonia/methanol solution (40 ml) and Raney cobalt (1.6 g). The reaction mixture was stirred, under hydrogen atmosphere (4 kgf/cm2) for 32 hours at 40° C. and for further 8 hours at 70° C. The Raney cobalt was filtered off, and then the solvent was distilled off. The residue was purified by means of a silica gel column chromatography (chloroform:methanol=9:1 to chloroform:methanol:triethylamine=90:8:2) to afford the titled compound (1.40 g, yield 86%, oily).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.Cl.[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH:9][C:7]3[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:10]3[CH2:19][CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=4)[CH2:11]3)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: O=C(O)Cc1ccc(OCCN2CCCCCC2)cc1
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(OCCN3CCCCCC3)cc1)C2
Yield: 17.7 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (425 mg) and [4-(2-azepan-1-ylethoxy)phenyl]acetic acid hydrochloride (700 mg) was used according to an analogous synthetic method to Example 337 to provide the title compound (140 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:9]([CH3:18])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:1]([N:8]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:9]([CH3:18])[C:10]([C:11]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:28][CH2:27]1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1(C(=O)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Yield: 43 %

Procedure:
A solution of ethyl(4S)-4-(dibenzylamino)-3-oxopentanoate (500 mg) synthesized according to the method described in Journal of Organic Chemistry, vol. 62, pp. 2292-2297 (1997), 1,2-dibromoethane (0.19 mL) and potassium carbonate (405 mg) in acetone (15 mL), was stirred under reflux overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→2/1) to give the title compound as a colorless oil (yield: 231.4 mg, 43.0%).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1([C:14]([OH:16])=[O:15])[CH:11]2[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:13][CH:5]1[CH2:6]3)[CH2:10]2.[C:17]1([N:27]2[C:31]([C:32]3[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:33]=3[O:40][CH3:41])=[CH:30][C:29]([C:42](Cl)=[O:43])=[N:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.Cl>O.O1CCCC1>[C:17]1([N:27]2[C:31]([C:32]3[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:33]=3[O:40][CH3:41])=[CH:30][C:29]([C:42]([NH:3][C:4]3([C:14]([OH:16])=[O:15])[CH:11]4[CH2:10][CH:9]5[CH2:8][CH:7]([CH2:6][CH:5]3[CH2:13]5)[CH2:12]4)=[O:43])=[N:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: NC1(C(=O)O)C2CC3CC(C2)CC1C3
Reactant: COc1cccc(OC)c1-c1cc(C(=O)Cl)nn1-c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1cccc2ccccc12
Reaction time: 0.17 h

Procedure:
0.107 g of sodium hydroxide in 1.36 ml of water and 0.51 ml of tetrahydrofuran are cooled to 0° C. 0.52 g of 2-amino-2-adamantanecarboxylic acid is added in a single portion, and 0.53 g of 1-(1-naphthyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolecarbonyl chloride, dissolved in 3 ml of tetrahydrofuran, is then added dropwise. The mixture is left for 10 minutes, and the same amount of the above acid chloride, in 3 ml of tetrahydrofuran, is added again; simultaneously, 1.32 ml of 2N sodium hydroxide are added. The reaction mixture is left for 4 days at room temperature; successively, ice-cold water is added and concentrated hydrochloric acid is added to pH 1, and the precipitate is filtered off. The crystals are washed with diisopropyl ether.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([O:15][C:16](=[O:18])[CH3:17])=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:19](O)=[O:20])=[CH:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O.C1C=CC=CC=1>CN(C)C=O>[C:1]([O:4][C:5]1[C:14]([O:15][C:16](=[O:18])[CH3:17])=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:19]([Cl:25])=[O:20])=[CH:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc2c(=O)c(C(=O)O)coc2c1OC(C)=O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2c(=O)c(C(=O)Cl)coc2c1OC(C)=O

Procedure:
A mixture of 7,8-diacetoxychromone-3-carboxylic acid (9.5 g, 31 mmol), thionyl chloride (2.6 ml), dimethylformamide (0.1 ml) and benzene (300 ml) was refluxed for 1.5 hours. After the addition of thionyl chloride (2.6 ml) was dimethylformamide (0.1 ml), the mixture was refluxed for a further one hour and evaporated to dryness. The residue was triturated with n-hexane to give the desired compound (9.3 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:18])[N:3]=1.C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:26][C:7]1[N:8]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:5]([N:6]=1)=[C:4]([NH2:18])[N:3]=[C:2]([Cl:1])[N:10]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(Cl)nc2c1ncn2CC1CCOCC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1nc(Cl)nc2c1nc(Br)n2CC1CCOCC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
To a solution of 2-chloro-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (1.30 g) in dry chloroform (32 mL) at room temperature was added NBS (2.16 g). The reaction was stirred at 60° C. for 6 h. the mixture was cooled, taken up in DCM (50 mL) and washed with water (50 mL). The organics were passed through a hydrophobic frit and concentrated in vacuo to give the title compound as a brown solid (1.36 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][C:3]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.C(Br)(Br)(Br)[Br:18].N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:18])=[CH:4][C:3]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: OCc1ccc(Br)c(OC2CCCCO2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: BrCc1ccc(Br)c(OC2CCCCO2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
The title compound was prepared adapting the method reported by Wada et al.[Wada, 1979] with the following modifications. To a solution of 4-bromo-3-(tetrahydropyran-2-yloxy)benzyl alcohol (3.0 g, 10.45 mmol), carbon tetrabromide (6.93 g, 20.90 mmol) and anhydrous pyridine (0.85 mL, 10.45 mmol) in anhydrous Et2O (50 mL) at 0° C. was added dropwise a solution of triphenylphosphine (5.48 g, 20.90 mmol) in anhydrous Et2O (10 mL). The mixture was stirred at 0° C. for 1 h and then at room temperature overnight. The solvent was removed in vacuo and the residue suspended in n-hexane and filtered. The filtered solid was washed with n-hexane and the combined filtrates concentrated in vacuo to ca. 10 mL. The residue was purified by flash column chromatography [SiO2, EtOAc/n-hexane (5:95)] to give 4-bromo-3-(tetrahydropyran-2-yloxy)benzyl bromide as a pale yellow oil (2.82 g, 77%) which slowly darkened on exposure to light and air; ¤H (270 MHz, CDCl3) 1.58-2.12 (m, 6H), 3.58-3.65 (m, 1H), 3.83-3.92 (m, 1H), 4.41 (d, J=12.6, 2H), 5.53 (m, 1H), 6.89 (dd, J=7.9, 2.0, 1H), 7.16 (d, J=2.2, 1H), 7.48 (d, J=8.2, 1H); LC-MS (APCI−): tR=4.71 min, m/z 266.95 (48, C12H1481Br2O4—C5H8O—H), 264.93 (100, C12H14Br2O4—C5H8O—H), 262.92 (50, C12H1479Br2O4—C5H8O—H); HPLC: tR=3.91 min (94%)
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:29][C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:33]([C:30]4([CH3:29])[CH2:32][CH2:31]4)=[O:34])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: CC1(C(=O)O)CC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)C2(C)CC2)C3)cc1

Procedure:
Compound fd was prepared according to the procedure described in Example 213 by reacting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 1-methylcyclopropanecarboxylic acid. LC-MS: m/z=+465 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C:3](O)=[O:4].O>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[C:3](=[O:4])[O:13][C:8]([C:9]([F:12])([F:11])[F:10])=[N:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C(=O)O)=C(NC(=O)C(F)(F)F)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1c(-c2ccccc2)nc(C(F)(F)F)oc1=O
Yield: 92.6 %

Procedure:
39.3 g of the product of Step B were refluxed in 80 ml of acetic anhydride and maintained at this temperature for 30 minutes and then allowed to cool. The acetic anhydride was expelled under reduced pressure and iced water was added to the residue. The precipitate obtained was separated, washed abundantly with water and then dissolved in ether. The organic solution was dried and concentrated to dryness under reduced pressure to obtain 34 g of the expected product melting at 70° C.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13]C)[N:8]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[NH:42][C:41](=[O:43])[O:40][N:39]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4].CC(=O)CC.Cl>O>[CH2:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][OH:13])[N:8]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[NH:42][C:41](=[O:43])[O:40][N:39]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CCOC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: Cl
Solvent: CCC(C)=O
Solvent: O
Product: CCCCc1nc(CCO)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
A mixture of 6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-(2-methoxyethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (1.0 g), 2-butanone (10 mL), water (6 mL) and concentrated hydrochloric acid (2 mL) was stirred at 100° C. for 1 hr. The reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.57 g, 59%) as a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:9]([C:21]([O:23][CH3:24])=[O:22])=[C:8]([CH3:25])[N:7]([CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:6]=1[CH3:37])=[O:4].[OH-].[K+]>CS(C)=O.O>[CH3:24][O:23][C:21]([C:9]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:37])[N:7]([CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:8]=1[CH3:25])=[O:22]
Reactant: COC(=O)C1=C(C)N(CCCOCc2ccccc2)C(C)=C(C(=O)OC)C1c1ccc(OC)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1=C(C)N(CCCOCc2ccccc2)C(C)=C(C(=O)O)C1c1ccc(OC)c(OC)c1
Temperature: 100 °C
Yield: 42 %

Procedure:
After 2.15 g (4.2 mmols) of 1,4-dihydro-4-(3,4-dimethoxy-phenyl)-2,6-dimethyl-1-(3-benzyloxypropyl)-3,5-pyridine-dicarboxylic acid 3,5-dimethyl ester prepared by the process described in Japanese Patent Application Laid Open No. 1-316357 was dissolved in 8 ml of dimethylsulfoxide, 320 mg (4.9 mmols) of potassium hydroxide dissolved in 0.5 ml of water was added to the solution. The mixture was heated at 100° C. for 5 hours. After the solvent was distilled off under reduced pressure, 10 ml of water was added to the residue followed by extraction twice with ethyl acetate. After the aqueous phase was rendered acidic with diluted hydrochloric acid, extraction was performed 3 times with chloroform. After washing with water, the extract was concentrated and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-n-hexane=1:1) to give 875 mg of 1,4-dihydro-4-(3,4-dimethoxyphenyl)-2,6-dimethyl-1-(3-benzyloxypropyl)-3,5-pyridinedicarboxylic acid 3-methyl ester as an oil. Yield, 42%. The obtained monocarboxylic acid was esterified by the method described in Example 1 to give 1,4-dihydro-4-(3,4-dimethoxyphenyl)-2,6-dimethyl-1-(3-benzyloxypropyl)-3,5-pyridine-dicarboxylic acid 3-methyl-5-[3 -(4-methylpiperazino)propyl] ester.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.[CH:32]1([C:35]2[S:39][C:38]([NH:40][C:41](=O)[O:42]C3C=CC=CC=3)=[N:37][N:36]=2)[CH2:34][CH2:33]1.CCN(CC)CC>C(Cl)Cl>[CH:32]1([C:35]2[S:39][C:38]([NH:40][C:41](=[O:42])[NH:1][C@@H:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]4[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]5[CH:19]=[CH:20][C:21]([C:24]([N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)=[O:25])=[CH:22][CH:23]=5)[N:9]=4)[CH2:3]3)=[N:37][N:36]=2)[CH2:34][CH2:33]1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=C(Nc1nnc(C2CC2)s1)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)Nc3nnc(C4CC4)s3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A suspension of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (40 mg, 0.094 mmol), phenyl 5-cyclopropyl-1,3,4-thiadiazol-2-ylcarbamate (29.5 mg, 0.113 mmol), and Et3N (0.016 mL, 0.113 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The reaction mixture was diluted with CH2Cl2, washed with water, and concentrated. The residue was purified by prep-HPLC. The product containing fractions were collected, neutralized with saturated NaHCO3, extracted with CH2Cl2, separated, and concentrated to give 28 mg of (R)-6-(3-(3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido)piperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a light pink solid. LCMS: (M+H)+=592.18. 1H NMR (400 MHz, CDCl3-MIX) δ ppm 11.09 (1H, s), 7.59 (2H, d, J=8.79 Hz), 7.55 (1H, d, J=9.23 Hz), 7.24-7.28 (2H, m), 6.04 (1H, d, J=8.79 Hz), 3.93 (1H, dd, J=13.18, 3.08 Hz), 3.73-3.86 (2H, m), 3.53 (7H, d, J=6.15 Hz), 3.31-3.41 (1H, m), 3.22-3.31 (2H, m), 2.11-2.21 (1H, m), 1.90-2.00 (1H, m), 1.67-1.79 (1H, m), 1.51-1.65 (2H, m), 1.03-1.12 (2H, m), 0.89-0.96 (2H, 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][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[O:17]=[C:7]1[C:6]2[CH:18]=[C:2]([O:1][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH:3]=[CH:4][C:5]=2[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8]1
Reactant: CC(C)(C)OC(=O)CCCCCBr
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCOc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.5 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.50 g, 1.9 mmol), tert-butyl 6-bromohexanoate (1.25 g, 4.9 mmol) and potassium carbonate (0.54 g, 3.9 mmol) and DMF (10 ml) was stirred at room temperature for 24 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. The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.75 g, 90%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]([C:22]1[N:23]([CH3:45])[C:24](=[O:44])[C:25]2[C:30]([C:31]=1[C:32]1[C:33]([CH3:43])=[C:34]3[C:39](=[C:40]([F:42])[CH:41]=1)[O:38][CH2:37][CH2:36][CH2:35]3)=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:50]([CH3:53])([CH3:52])[CH3:51])(=O)C.C([O-])(O)=O.[Na+]>Cl(O)(=O)(=O)=O>[C:50]([O:21][C@@H:20]([C:22]1[N:23]([CH3:45])[C:24](=[O:44])[C:25]2[C:30]([C:31]=1[C:32]1[C:33]([CH3:43])=[C:34]3[C:39](=[C:40]([F:42])[CH:41]=1)[O:38][CH2:37][CH2:36][CH2:35]3)=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:53])([CH3:52])[CH3:51]
Reactant: Cc1c(-c2c([C@H](O)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n(C)c(=O)c3ccccc23)cc(F)c2c1CCCO2
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1c(-c2c([C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)OC(C)(C)C)n(C)c(=O)c3ccccc23)cc(F)c2c1CCCO2
Reaction time: 18 h
Yield: 48.6 %

Procedure:
A solution of (S)-3-(2-((tert-butyldiphenylsilyl)oxy)-1-hydroxyethyl)-4-(8-fluoro-5-methylchroman-6-yl)-2-methylisoquinolin-1(2H)-one (92 mg, 0.148 mmol) in tert-butyl acetate (1994 μl, 14.80 mmol) was treated with 2 drops of 70% perchloric acid. After 18 h, the reaction mixture was poured into sat. aq. NaHCO3 and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by ISCO (0-30% EtOAc-hexanes) to afford (S)-3-(1-(tert-butoxy)-2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-(8-fluoro-5-methylchroman-6-yl)-2-methylisoquinolin-1(2H)-one (49 mg, 0.072 mmol, 48.9% yield) as a white foam: 1H NMR (400 MHz, CHLOROFORM-d) δ=8.45 (dd, J=1.5, 7.7 Hz, 1 H), 7.70-7.63 (m, 2 H), 7.63-7.56 (m, 2 H), 7.41 (none, 8 H), 6.89 (d, J=11.3 Hz, 1 H), 6.85-6.78 (m, 1 H), 4.83 (dd, J=2.0, 7.4 Hz, 1 H), 4.30 (t, J=5.2 Hz, 2 H), 3.88 (dd, J=7.5, 10.6 Hz, 1 H), 3.82 (s, 3 H), 3.58 (dd, J=2.0, 10.7 Hz, 1 H), 2.73-2.52 (m, 2 H), 2.20-2.07 (m, 2 H), 1.64 (s, 3 H), 1.16 (s, 9 H), 0.98 (s, 9 H); LC/MS (m/z) ES+=678 (M+1).