Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH:21]([O:24][C:25]1[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:23])[CH3:22]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:30][C:27]2[CH:26]=[C:25]([O:24][CH:21]([CH3:23])[CH3:22])[NH:29][N:28]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (0.41 g, 2.1 mmol) and DIEA (0.31 ml, 1.8 mmol) in THF (10 ml) was added 5-isopropoxy-1H-pyrazol-3-amine (0.20 g, 1.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (DCM:EtOAc=2.5:1) to give the title compound as a yellow solid (0.19 g, 45%). MS: Calcd.: 298; Found: [M+H]+ 299.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CO.[N+]([O-])(O)=[O:15].NC(N)=O>CC(C)=O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:15])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: O=[N+]([O-])O
Agent: NC(N)=O
Solvent: CC(C)=O
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Yield: 125 %

Procedure:
A solution of 5.0 g. of acetonine in 21 g. of methanol was added with 19 g. of acetone and 4.0 g. of urea nitrate. The mixture was maintained at room temperature for 24 hours to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 125%.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>O1CCCC1.O>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1cnc2[nH]ccc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cnc2[nH]ccc2c1)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a reaction vial, 1H-Pyrrolo[2,3-b]pyridin-5-ylamine (35, 0.1 g, 0.8 mmol) is dissolved in 7 mL of tetrahydrofuran and triethylamine (0.10 mL, 0.75 mmol) and nicotinoyl chloride (36, 0.16 g, 1.1 mmol) are added. The reaction is stirred at room temperature for 16 hours, then diluted with water and extracted 3× with ethyl acetate. The organic layers are combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)(c2ccc(F)cc2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1(c2ccc(F)cc2)CCC(O)CC1)OCc1ccccc1
Yield: 91.5 %

Procedure:
1.5 g of [1-(4-Fluoro-phenyl)-4-oxo-cyclohexyl]-carbamic acid benzyl ester (77) were dissolved in 30 mL of dry THF and 182 mg of sodium borohydride were added. When conversion was complete, the mixture was poured into 15 mL of water. pH was adjusted to 2 by addition of 2N HCl and the aqueous layer was extracted with ethyl acetate. The combined organic layer was extracted with brine, dried over magnesium sulfate and evaporated to dryness to give 1.38 g of the desired product as a mixture of cis and trans isomers, the cis isomer (referring to the position of alcohol and Z-amine) being the major one. Rt=2.20 min (Method E). Detected mass: 344.2 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[F:19][C:17]([F:18])([F:20])[C:14]1[CH:15]=[CH:16][C:11]([O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:21])=[O:2])=[N:12][CH:13]=1
Reactant: COC(=O)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid methyl ester (285 g, 0.95 mmol) and NaOH (200 mg, 4 mmol) in methanol:THF:water (1:1:1, 3 mL) was stirred at room temperature for 8 h. Solvents were evaporated. Crude mass was taken in water (20 mL), acidified to pH 4.0 and extracted with ethyl acetate to obtain 3-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid was prepared (215 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][F:25])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CN(C)CCN(C)C1C=CC(NC2C(=O)N(C)C=C(B3OC(C)(C)C(C)(C)O3)C=2)=NC=1.[C:57]([O:60][CH2:61][C:62]1[C:67]([N:68]2[CH2:79][CH2:78][N:77]3[C:70](=[CH:71][C:72]4[CH2:73][C:74]([CH3:81])([CH3:80])[CH2:75][C:76]=43)[C:69]2=[O:82])=[CH:66][C:65]([F:83])=[CH:64][C:63]=1Br)(=[O:59])[CH3:58]>>[F:83][C:65]1[CH:64]=[C:63]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][F:25])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:62]([CH2:61][O:60][C:57](=[O:59])[CH3:58])=[C:67]([N:68]2[CH2:79][CH2:78][N:77]3[C:70](=[CH:71][C:72]4[CH2:73][C:74]([CH3:80])([CH3:81])[CH2:75][C:76]=43)[C:69]2=[O:82])[CH:66]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(CCF)CC3)cn2)c1=O
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: CN(C)CCN(C)c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(CCF)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Yield: 33 %

Procedure:
Following Example 186f, 273a (which was prepared in situ from 217d using conditions analogous to those used to prepare 270d) (200 mg, 0.49 mmol) and 189a (176 mg, 0.39 mmol) were reacted to give 273b (115 mg, 33% yield).
Reaction SMILES: O[C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C([O-])([O-])=O.[K+].[K+]>>[CH2:18]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: CC1(O)c2ccccc2C(=O)N1c1ccncc1
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Product: C=C1c2ccccc2C(=O)N1c1ccncc1
Temperature: 200 °C
Yield: 66 %

Procedure:
A mixture of 2,3-dihydro-3-hydroxy-3-methyl-2-(4-pyridyl)-1H-isoindol-1-one (10.20 g) and phosphorus pentoxide (6.03 g) was heated under vacuum at 200° C. for 20 minutes. Ice water was then added and the mixture was basified with K2CO3 solution. The resulting solid was filtered, dried and passed through a column of florisil (ethyl acetate) to give 6.23 g of a solid. A 2.0 g portion was recrystallized from methanol to give 1.37 gof platelets, mp: 173°-174° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].B(F)(F)F.C(OCC)C.C([SiH](CC)CC)C>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)OCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 85 °C
Yield: 65 %

Procedure:
A mixture of 4-(5-bromo-2-chlorobenzoyl)phenethyl acetate (intermediate BF) (1 g, 2.62 mmol), borontrifluoride diethylether (0.65 mL, 10.4 mmol) and triethylsilane (0.84 mL, 10.4 mmol) was heated at 85° C. for 2 h in a sealed tube. The reaction vessel was cooled to room temperature and ice-water (50 mL) was added. The product was extracted with ethyl acetate (2×25 mL), washed with brine (25 mL), dried (Na2SO4), filtered and evaporated. Purification on silica gel using an ISCO column with 5% ethyl acetate in hexane gave intermediate BG (620 mg, yield 65%). 1H NMR (300 MHz, CDCl3): δ 7.27-7.10 (m, 7H), 4.27 (t, J=6.9, 7.2 Hz, 2H), 4.03 (s, 2H), 2.92 (t, J=6.9, 7.2 Hz, 2H), 2.05 (s, 3H.
Reaction SMILES: [O:1]1[C:10]2[CH2:9][CH2:8][CH:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Br:18]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:18][C:2]1[O:1][C:10]2[CH2:9][CH2:8][CH:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)C1CCc2occc2CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1CCc2oc(Br)cc2CN1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4,5,7,8-tetrahydrofuro[3,2-c]azepine-6-carboxylate (0.21 mmol) in chloroform (0.5 mL) and acetic acid (0.5 mL) is treated with N-bromosuccinimide (0.21 mmol) at RT. After 1 hour, the reaction is poured over saturated aqueous NaHCO3, and extracted with ethyl acetate (2×5 mL). The organic layers are washed with brine, dried, and purified by silica chromatography (20% ethyl acetate/hexanes) to give tert-butyl 2-bromo-4,5,7,8-tetrahydrofuro[3,2-c]azepine-6-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6])[CH3:2].C(N(CC)CC)C.[CH2:23]([O:30][C:31](=[O:38])[CH:32]([C:35](Cl)=[O:36])OC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:39](OCC)(=[O:41])C>>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([N:6]([O:41][CH3:39])[C:35](=[O:36])[CH2:32][C:31]([O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:38])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: COC(C(=O)Cl)C(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(O)cc1)N(OC)C(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a mixture of Tyrosine ethyl ester (40 g) and Triethylamine (40 ml) in Ethyl acetate (600 ml) at 0° C. temperature was added Chloro carbonyl methoxy-acetic acid benzyl ester (46.5 g) drop wise. The reaction mixture was further stirred at room temperature for 10 hours. The solids were filtered off and the organic phase was washed with 5% sodium bicarbonate solution (600 ml) and water (600 ml). It was dried over sodium sulphate and organic solvent was distilled. The crude was purified by column chromatography on silica gel using Hexane:Ethyl acetate (8:2) to get pure 2-(2-Benzyloxy carbonyl methoxy-acetyl amino)-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (30 g) as a light yellow syrup. The product was characterized by 1H NMR (CDCl3) δ 1.20 (t, 3H, CH3), 2.90 to 3.10 (m, 2H, CH2), 4.10 to 4.30 (m, 6H, 3X CH2), 4.85 (q, 1H, CH), 5.20 (s, 2H, CH2), 5.80 (bs, 1H, NH), 6.70 (d, 2H, Ar), 7.00 (d, 2H, Ar), 7.40 (m, 5H, Ar).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:22]1([C:28]2[N:29]([CH2:33][CH2:34][CH2:35][NH2:36])[CH:30]=[CH:31][N:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[C:22]1([C:28]2[N:29]([CH2:33][CH2:34][CH2:35][NH:36][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[O:9])[CH:30]=[CH:31][N:32]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccccn1
Reactant: NCCCn1ccnc1-c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCCCn1ccnc1-c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.8 %

Procedure:
A mixture of 1.85 g of picolinic acid and 2.43 g of 1,1'-carbonyldiimidazole in 60 ml of tetrahydrofuran was stirred at room temperature for 2 hours. Then 3.0 g of 2-phenyl-1H-imidazole-1-propanamine was added and the procedure as described in Example 33 was continued to obtain 5.7 g of a viscous oil. The oil was treated by preparative high pressure liquid chromatography using a PrepPAK®-500 Silica column (Waters Associates, Millipore) and ethyl acetate as eluent. Fractions were collected and fractions 5 and 6 were concentrated, treated with ether, and dried and gave 3.8 g of the compound of the Example as an oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[S:29](=[O:37])(=[O:36])[N:28]=1>C(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[S:29](=[O:36])(=[O:37])[N:28]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: NCCCCOn1cc(CN2CCCCC2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S1(=O)N=C(NCCCCOn2cc(CN3CCCCC3)cn2)c2ccccc21
Reaction time: 3 h
Yield: 29.4 %

Procedure:
3.5 g of 4-(4-piperidinomethylpyrazol-1-yloxy)butylamine and 1.4 g of triethylamine are dissolved in 50 ml of methylene chloride. A solution of 2.8 g of 3-chlorobenzoisothiazole 1,1-dioxide in 15 ml of methylene chloride is then added dropwise. After standing for 3 hours at room temperature, the reaction mixture is washed with water, the organic phase is evaporated down and the residue is chromatographed over neutral Al2O3 (activity level III), using methylene chloride as the mobile phase. 1.7 g of the title compound are obtained, the product being crystallized from ether.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:32][CH:31]=1>>[C:40]([O:39][C:37]([CH2:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:31][CH:32]=1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)Cc1ccc(N)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CC(=O)OC(C)(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and tert.butyl 4-aminophenylacetate Rf value: 0.5 (aluminium oxide, ethyl acetate) C30H30N2O5
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][C:14]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(SCCN)cc1
Reactant: C1COCCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(SCCNC(=O)N2CCOCC2)cc1
Reaction time: 2 h

Procedure:
To a solution of compound 1 (400 mg) in CH2Cl2 (10 mL) was added triphosgene (1.0 eq.) and triethylamine (2.5 eq.) at 0° C. The reaction mixture was stirred for 2 h. at r. t and morpholine (3.0 eq.) was added. The reaction was stirred until it appeared by TLC to be completed (˜4 h), and was washed with 1N HCl and sat NaHCO3 (3×10 mL). The solvents were removed by evaporation under reduced pressure to give product 16 (520 mg). The crude product appeared to be pure by TLC and NMR and used for the next step reaction without further purification.
Reaction SMILES: [ClH:1].N[CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[C:14]4[CH:28]=[CH:27][S:26][C:15]=4[C:16](=[O:25])[NH:17][C:18]=3[C:19]([CH3:24])=[CH:20][C:21]=2[O:22][CH3:23])=[CH:8][C:7]=1[F:29])[CH3:5].[CH2:30]=O.[BH3-][C:33]#[N:34].[Na+]>CO.C1COCC1>[ClH:1].[CH3:30][N:34]([CH3:33])[CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[C:14]4[CH:28]=[CH:27][S:26][C:15]=4[C:16](=[O:25])[NH:17][C:18]=3[C:19]([CH3:24])=[CH:20][C:21]=2[O:22][CH3:23])=[CH:8][C:7]=1[F:29])[CH3:5]
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CN)c(F)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CN(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.6 %

Procedure:
To a solution of (S)-9-(4-(1-aminopropan-2-yl)-3-fluorophenyl)-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one hydrochloride (110 mg, 0.27 mmol)) in a 1:1 mixture of MeOH/THF (3 mL) was added paraformaldehyde (7.5 mg, 0.24 mmol) followed by NaCNBH3 (70 mg 1.2 mmol) and stirred at rt for 16 h. The reaction mixture was quenched by the addition of 2 N NaHCO3 (1 mL), eluted through an SCX ion-exchange column and converted to HCl salt using General Procedure D-2 (Scheme II) to obtain the desired product (67 mg, 60%) as a white solid: ESI MS m/z 425 [C24H25FN2O2S+H]+;
Reaction SMILES: CC[O-].[Na+].[NH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH3:15])=[CH:10][CH:9]=[CH:8][N:7]=1.[N:16](OCCC(C)C)=O.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[OH:34]>C(O)C>[CH2:13]([O:12][C:11]1[C:6]([N:5]=[N:16][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][C:25]=2[OH:34])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:14][CH3:15]
Reactant: CCCOc1cccnc1N
Reactant: Oc1ccc2ccccc2c1
Reactant: CC(C)CCON=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCOc1cccnc1N=Nc1c(O)ccc2ccccc12
Temperature: 25 °C

Procedure:
Next, a flask was loaded with sodium ethylate (1.6 g), ethanol (14 ml), and 2-amino-3-propoxypyridine (3.8 g), and they were mixed. To the mixture, isopentyl nitrite (2.7 g) was dropwise added in 20 minutes with stirring. This was stirred at the reflux temperature for 4 hours, and then cooled to room temperature. Thereafter, to this, 2-naphthol (2.0 g) dissolved in ethanol (5 ml) was dropwise added in one hour. After stirring at room temperature for two hours, this mixture was heated to the reflux temperature, followed by stirring for additional 2 hours. The reaction mixture was filtrated and the filtrate was condensed to precipitate crystals. The crystals were filtrated for collection and recrystallized with dioxane-water to give intended crystals (0.59 g).
Reaction SMILES: [CH2:1]([S:13]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N1C=CN=C1)(N1[CH:28]=[CH:27]N=C1)=O.[Cl-].[Mg+2].[Cl-].C(O)(=O)[CH2:38][C:39]([OH:41])=[O:40].C([K])C.C(N(CC)CC)C>>[CH2:27]([O:41][C:39](=[O:40])[CH2:38][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][S:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:14])=[O:15])[CH3:28]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCCCCCCCS(=O)(=O)CCCC(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC[K]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCS(=O)(=O)CCCC(=O)CC(=O)OCC

Procedure:
The title compound was prepared from 4-(dodecylsulfonyl)butanoic acid (H. Gilman, et al, J. Am Chem. Soc. 74, 4452 (1952)) (2.50 g, 0.07 mol), 1,1'carbonyldiimidazole (1.50 g, 0.09 mol), magnesium chloride (1.41 g, 0.014 mol), ethyl potassium malonate (2.12 g, 0.012 mol), and triethylamine (1.73 g, 0.017 mol) using the procedure described in Example 3, Step A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][C@H:14]([CH3:18])[C:15](Cl)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:29][OH:30]>C1(C)C=CC=CC=1>[CH3:29][O:30][C:15](=[O:16])[C@H:14]([O:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[C:4]([F:21])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:20][CH:19]=1)[CH3:18]
Reactant: CO
Reactant: C[C@@H](Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 10.6 g (0.030 mol) of (R)(+)-2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid chloride in 100 ml toluene is added slowly, while stirring into a solution of 4.9 ml (0.035 mol) of triethylamine and 2 ml (0.035mol) of methanol in 40 ml of toluene, that is cooled in an ice/bath. When everything is added, the ice-bath is removed and the reaction mixture is stirred for 3 hours at room temperature. The reaction mixture is then poured into ice-water and the organic material is extracted twice with ethyl acetate. The ethyl acetate layer is washed with a saturated salt solution, dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatography over a silicagel column with a hexane/ethyl acetate solution. After evaporation of the solvent, a clear oil, the above ester remains n35D 1.5859, [α]20D =+38.8±0.5 (2 % acetone).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:20]\[OH:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:24]([O:31][CH2:32][C:33](Cl)=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[CH2:24]([O:31][CH2:32][C:33]([O:21]/[N:20]=[C:11]1/[C:10](=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[C:19]2[C:14]([CH2:13][CH2:12]/1)=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C=C2/C(=N/OC(=O)COCc3ccccc3)CCc3ccccc32)cc1
Reaction time: 0.25 h
Yield: 57.1 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one oxime (50 mg, 0.15 mmol) and benzyloxyacetylchloride (0.029 ml, 0.18 mmol) were added into dichloromethane (5.0 ml). Then, at 0˜5° C. triethylamine (0.026 ml, 0.18 mmol) was added, stirred for 15 minutes so as to complete the reaction. Afterward, an organic layer was separated by blending water, washed again with water and saturated brine and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and made to crystal by using diisopropylether. As a result, 40.7 mg of the present compound (productive yield 56%) was obtained as a white solid crystal.