Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])[CH3:30]>N1C=CC=CC=1>[CH2:29]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][C:17]([C:16]([S:13]([CH2:12][CH:11]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])(=[O:14])=[O:15])([CH3:21])[CH3:20])=[O:18])[CH3:30]
Reactant: CCOCCOCCO
Reactant: CC(C)(C(=O)Cl)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: CCOCCOCCOC(=O)C(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
In an analogous manner to that of Example 2, paragraph (c), by reacting (RS)-2-[[2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride and diethylene glycol monoethyl ether in pyridine there was obtained benzyl rac-α-[[[1-[[2-(2-ethoxyethoxy)ethoxy]carbonyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamate as a colourless oil, MS: 385 (M-COObenzyl)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:3]([OH:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[C:35]([NH:1][CH:2]([CH:3]([OH:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of 20 mg of the resultant compound of Example 11 and 0.05 ml of triethylamine in 1 ml of dichloromethane was cooled to 0° C. and treated with 0.01 ml of acetic anhydride. After 30 min, the solution was partitioned between water and dichloromethane, and the organic phase was dried over Na2SO4 and concentrated to give 23 mg (100%) of the desired compound (Rf 0.5, 10% methanol in chloroform). Mass spectrum: (M+H)+ =413.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:9])([F:8])[S:4](Cl)(=[O:6])=[O:5].C(=O)([O-])O.[Na+].[OH:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].O>C(#N)C>[F:8][C:3]([F:9])([S:4]([O:15][N:16]1[C:20](=[O:21])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]1=[O:26])(=[O:6])=[O:5])[CH2:2][OH:1]
Reactant: O=S(=O)(Cl)C(F)(F)CO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)C(F)(F)CO
Temperature: 0 °C
Yield: 54.7 %

Procedure:
In 100 mL of acetonitrile, 25.5 g of a liquid of 2-hydroxy-1,1-difluoroethanesulfonyl chloride (purity: 98%, equivalent to 0.138 mol) was dissolved by stirring. The resulting solution was cooled to 0° C., admixed with 14.0 g (0.166 mol) of sodium hydrogencarbonate and 24.8 g (0.152 mol) of N-hydroxyphthalimide, and then, reacted at 0° C. for 24 hours. To the thus-obtained reaction solution, 125 mL of water was added. The reaction solution was subsequently extracted twice with 100 mL of ethyl acetate. The resulting organic layer was washed twice with 100 mL of water and subjected to concentration. The concentration residue was admixed with 75 mL of ethyl acetate, followed by heating the solution at 60° C. to dissolve the solid substance. Then, 150 mL of heptane was dropped into the solution. The solution was gradually cooled to 0° C. to precipitate a crystalline out of the solution. The crystalline precipitate was filtered out and dried. With this, 23.2 g of the target compound was obtained as a white solid (yield: 53%, purity: 97%, pure content: 22.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:34][C:35]([NH2:42])([CH3:41])[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH:42][C:35]([CH3:41])([CH3:34])[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9]2=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)CC(C)(C)N
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC(C)(C)CC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.620 g of the compound obtained in EXAMPLE 13, 1 ml of 1,1,3,3-tetramethylbutylamine, 0.7 g of BOP, 1 ml of DIPEA and 20 ml of DCM is stirred for 2 hours at RT. The reaction mixture is then washed with water, with a 1N solution of HCl and with a 1N solution of NaOH and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM as the eluent to give 0.28 g of the expected product in the form of white crystals. M.p.=180° C.
Reaction SMILES: [CH2:1]=O.[CH:3]1[C:15]2[CH:14]([CH2:16][O:17][C:18]([NH:20][C@@H:21]([CH2:25][S:26][S:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([OH:24])=[O:23])=[O:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1>C1(C)C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[C:28]([S:27][S:26][CH2:25][C@H:21]1[C:22](=[O:24])[O:23][CH2:1][N:20]1[C:18]([O:17][CH2:16][CH:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:19])([CH3:31])([CH3:30])[CH3:29]
Reactant: C=O
Reactant: CC(C)(C)SSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CC(C)(C)SSC[C@H]1C(=O)OCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
Paraformaldehyde (843 mg, 9.26 mmol) and 10-camphorsulfonic acid (75 mg, 0.324 mmol) were added to a solution of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound 2α-B) (2.00 g, 4.63 mmol) in toluene (10 ml), and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was returned to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→70/30) to afford (R)-(9H-fluoren-9-yl)methyl 4-((tert-butyldisulfanyl)methyl)-5-oxooxazolidine-3-carboxylate (Compound 2b-B) (1.936 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH2:8][CH2:9][C:10]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:12])[CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CCC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propionic acid (0.20 g, 0.40 mmol) was added 4-dimethylaminopyridine (0.075 g, 0.60 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.12 g, 0.60 mmol), methanesulfonamide (0.045 g, 0.48 mmol) and triethylamine (0.12 mL, 0.84 mmol). The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 10% aqueous acetic acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give the title compound (0.10 g, LRMS: 540.2).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][C:13]([OH:15])=O)[C:2]1=2.C(OC(=O)C)(=[O:18])C>>[CH2:4]1[C:3]2=[CH:6][CH:7]=[CH:8][CH:9]=[CH:10][C:11]3=[C:2]2[N:1]([C:13](=[O:15])[CH2:12]3)[C:5]1=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CC1=CC=CC=Cc2cc[nH]c21
Product: O=C1CC2=CC=CC=CC3=C2N1C(=O)C3
Temperature: 25 °C

Procedure:
A solution of ±1H-cycloocta[b]pyrrole-9-acetic acid, decahydro-2-oxo-, (3aα, 9β, 9aα)-; ±1H-cyloocta[b]pyrrole-9-acetic acid,decahydro-2-oxo, (3aα, 9α, 9aα)-; ±1H-cycloocta[b]pyrrole-9-acetic acid, decahydro-2-oxo-, (3aα, 9β, 9aβ) (2.8 g, 0.012 mol) in acetic anhydride is heated at reflux for 30 minutes and allowed to cool to room temperature overnight. The solution is concentrated at reduced pressure and the resulting solid is triturated with anhydrous diethyl ether. Sublimation (120° C., 0.1 mm) yields cycloocta[gh]pyrrolizine-2,4-(1H, 5H)-dione, octahydro-, (5aα, 10a α, 10bα)-; ±cycloocta[gh]pyrrolizine-2,4(1H,5H)-dione, octahydro-, (5aβ, 10aβ, 10bα)-; cycloocta[gh]pyrrolizine-2,4(1H,5H)dione,octahydro-, (5aα, 10aβ, 10bα)- with mp 121°-124° and 132°-134° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[Cl:22].[S:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[CH2:2][C:25]1[CH:26]=[CH:27][S:23][CH:24]=1)[O:10][CH:9]([C:13]([F:16])([F:15])[F:14])[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]2
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C1=Cc2cc(Cl)c(Cc3ccsc3)cc2OC1C(F)(F)F
Temperature: 65 °C

Procedure:
The ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 16, Step 3 (2.0 g, 5.0 mmole) was dissolved in DME (10.8 mL). The thien-3-ylboronic acid (127.96 mg, 5.0 mmole) was added to above solution and followed by addition of Pd(PPh3)4 (40 mg). After addition of 2M Na2CO3 (5.0 mL), the reaction was heated to 60-70° C. The color of the reaction changed from yellow to red and back to yellow. The solution was heated to reflux for 2 hrs. Additional 107 mg of thien-3-ylboronic acid and Pd(PPh3)4 (8 mg) were added to above mixture. After 2 hsr, the reaction was diluted with 5 ml of water and extracted with EtOAc. The organic layer was washed with NaHCO3 (sat.) and dried over MgSO4 and filtered. The filtrate was concentrated to afford the title ester. The ester (dark oil) was purified by chromatography eluted with 5 to 10% EtOAc in Hexane to give 620 mg, which had suitable purity to use without further purification.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:14])([F:13])[S:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([S:5][C:4]([F:13])([F:3])[F:14])=[CH:11][CH:10]=1
Reactant: Cc1ccc(SC(F)(F)F)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)Sc1ccc(CBr)cc1

Procedure:
Bromine (20.5 g, 0.13 mol) in 20 ml of carbon tetrachloride is added slowly to a solution of 4-trifluoromethylthiotoluene (29 g, 0.15 mol) in 90 ml of carbon tetrachloride heated to gentle reflux under a 275 W sunlamp. When the addition is complete, the solution is maintained at reflux for one hour. Most of the solvent is removed at atmospheric pressure, then the residue is vacuum distilled. The 15.5 g cut with boiling point 64°-77° C./0.6-0.8 mm is 92% monobromo compound by glc.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH:11]([CH3:13])[CH2:10][N:9](C(=O)C(F)(F)F)[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[NH:22][CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+].CO>O>[Cl:1][C:2]1[C:12]2[CH:11]([CH3:13])[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[NH:22][CH2:23][CH3:24]
Reactant: CCNc1c(OC)nc2c(c1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCNc1c(OC)nc2c(c1Cl)C(C)CNCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (99.0 mg, 0.30 mmol) in MeCN (5 ml) was added NCS (44.0 mg, 0.33 mmol) at room temperature and the mixture was refluxed for 30 minutes. The reaction was quenched with excess of sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 40 mg (36%) of 4-chloro-N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 4.39 (0.5H), 4.04 (0.5H), 3.94 (3H), 3.83 (1H), 3.78 (1H), 3.72 (1H), 3.45 (1H), 3.35 (2H), 3.25 (1H), 3.09 (1H), 1.19 (6H) ppm. A mixture of 4chloro-N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (37.0 mg, 0.10 mmol), K2CO3 (40 mg), MeOH (1.5 ml) and H2O (0.3 ml) was stirred for 16 h at room temperature. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to give 27 mg (93%) of 4-chloro-N-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 3.85 (s, 3H), 3.47 (m, 1H), 3.23 (m, 2H), 3.16 (m, 2H), 3.08 (m, 1H), 2.89 (dd, 2H), 2.69 (dd, 1H), 1.22 (d, 3H), 1.09 (t, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH:25][CH2:26][C:27]#[CH:28])=[N:22][CH:21]=[CH:20][CH:19]=2)([O-:14])=[O:13].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[C:27]([CH2:26][NH:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][N:22]=4)[N:17]=[CH:16][C:15]=3[N+:12]([O-:14])=[O:13])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCNc1c([N+](=O)[O-])cnc2cccnc12
Reactant: ON=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Temperature: 40 °C
Reaction time: 18 h
Yield: 31.9 %

Procedure:
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (44.6 g, 257 mmol) was added to a mixture of 3-nitro-N-prop-2-ynyl[1,5]naphthyridin-4-amine (29.34 g, 129 mmol) and anhydrous triethylamine (39.5 mL, 283 mmol) in anhydrous dichloromethane (1 L). The reaction was stirred at 40° C. for 18 hours and then concentrated under reduced pressure. The residue was triturated with water; the resulting solid was isolated by filtration, washed sequentially with isopropanol and a small amount of diethyl ether, and then dried under vacuum to provide 15.02 g of N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-3-nitro[1,5]naphthyridin-4-amine as a brownish-green solid.
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4]1.[CH:10](=[O:12])[CH3:11]>C(O)C.O>[S:3]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:11][CH:10]=[O:12])=[CH:4]1
Reactant: CC=O
Reactant: O=Cc1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=CC=Cc1ccsc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of sodium hydroxide (1.0 g, 25 mmol) in a mixture of ethanol (6 ml) and water (12 ml) was added thiophen-3-carbaldehyde (4.5 g, 40.1 mmol), and the mixture was stirred at 0° C. for 10 minute. To the mixture was dropwise added 40% acetaldehyde (10 g, 90.8 mmol) over 3 hours at the same temperature, and the mixture was further stirred for 30 minutes. The reaction mixture was treated in a similar manner to that in Reference 6 to give compound B4 (3.58 g, 64.6%) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:17]=[C:16]3[C:10]([CH:11]=[CH:12]O[C:14]3=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:17]=[C:16]3[C:10]([CH:11]=[CH:12][N:20]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[C:14]3=[O:15])=[CH:9][CH:8]=2)=[CH:18][CH:19]=1
Reactant: NCc1cccnc1
Reactant: O=c1occc2ccc(Oc3ccc(Cl)cc3)cc12
Product: O=c1c2cc(Oc3ccc(Cl)cc3)ccc2ccn1Cc1cccnc1
Temperature: 180 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
A mixture of 100 mg of 7-(4-chlorophenoxy)isocoumarin and 377 mg of 3-aminomethylpyridine was heated at 180° C. without solvent under stirring for 5 hours. After finishing the reaction, the mixture was chromatographed on a column of silica gel, eluting with ethyl acetate to give 97 mg of the titled compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)=[O:10])[N:12]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(C(F)(F)F)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Trifluoromethyl-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([OH:17])=O.[C:22]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([NH:31][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])=[O:17]
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1cc2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
A solution of N-(3,4-dichlorobenzyl)indole-2-carboxylic acid (0.23 g), benzenesulphonamide (129 mg), dimethylaminopyridine (0.22 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.19 g) in dichloromethane was allowed to stir for 24 hours at room temperature. 2N HCl was added and the reaction stirred vigorously for 2 hours, then extracted with dichloromethane. Combined organic extracts were dried (MgSO4) and concentrated to yield the desired end product as a white crystalline solid (122 mg, 32%); NMR δ(CD3SOCD3) 5.65 (s, 2H), 6.73 (dd, 1H), 7.12 (m, 2H), 7.30 (t, 1H), 7.38 (d, 1H), 7.56 (m, 4H), 7.70 (m, 2H), 7.91 (d, 2H); M/z (−) 457 (M−H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13][CH2:14][C:15]([O:17]CC)=O)[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:20][CH2:21][C@@H:22]([OH:34])[CH2:23][N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1>CCO>[CH2:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33][N:24]1[CH2:23][C@H:22]([OH:34])[CH2:21][NH:20][C:15](=[O:17])[CH2:14][O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2
Reactant: NC[C@@H](O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1cccc2ccc(OC)nc12
Solvent: CCO
Product: COc1ccc2cccc(OCC(=O)NC[C@@H](O)CN3CCc4ccccc4C3)c2n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
Ethyl 2-((2-methoxyquinolin-8-yl)oxy)acetate (100 mg, 0.383 mmol), (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (79.0 mg, 0.383 mmol) and EtOH (1 mL) were combined in a sealed tube. The mixture was stirred at 120° C. for 30 min in a microwave. The EtOH was evaporated and the residue was purified by pre-HPLC to give the desired product (77 mg, yield 48%). 1H NMR (MeOD-d4, 400 MHz) δ: 8.36 (br. s., 1H), 8.16 (d, J=8.8 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.28-7.15 (m, 4H), 7.12 (d, J=6.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.82 (s, 2H), 4.23-4.16 (m, 3H), 4.10 (s, 3H), 3.54-3.48 (m, 1H), 3.47-3.40 (m, 1H), 3.38-3.33 (m, 2H), 3.13-2.98 (m, 4H). LCMS (m/z): 422.2 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][CH:7]=1.C([O-])(=[O:18])C.[Na+]>CN(C)C=O>[C:10]1(/[CH:9]=[CH:8]/[C:5]2[O:6][CH:7]=[C:3]([CH2:2][OH:18])[N:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)[O-]
Reactant: ClCc1coc(/C=C/c2ccccc2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCc1coc(/C=C/c2ccccc2)n1
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 91.3 %

Procedure:
A mixture of 4-chloromethyl-2-[(E)-2-phenylethenyl]oxazole (5.0 g), sodium acetate (7.48 g) and N,N-dimethylformamide (50 ml) was stirred at 90° C. for 4.5 hours. The reaction mixture was poured onto ice-water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water dried (MgSO4), and concentrated under reduced pressure. To the residue was added potassium carbonate (4.73 g), water (25 ml) and methanol (50 ml) and then the resultant was stirred for 2 hours at room temperature. The reaction mixture was concentrated, to which was added brine, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give 2-[(E)-2-phenylethenyl]-4-oxazolylmethanol (4.18 g, 91%). Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 94-95° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH:10]([CH3:15])[C:9]1=[C:16]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:29])CBr.CN(C=O)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH3:14])[N:11]([C:26]([O:25][CH3:24])=[O:29])[CH:10]([CH3:15])[CH:9]1[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CBr
Reactant: CC1CN(C(=O)OC(C)(C)C)C(=C=O)C(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N1C(C)CN(C(=O)OC(C)(C)C)C(C)C1C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 3,5-dimethyl carbonyl piperazine-1-carboxylic acid t-butyl ester (18.7 g), potassium carbonate (14.5 g), bromo acetic acid methyl ester (14.7 g), DMF (90 mL) was stirred at 60° C. for 3 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give the title compound. This compound was provided to the next reaction without further purification.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[I:5][C:6]1[C:7]([OH:16])=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([CH:13]=1)[CH:11]=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:16][C:7]1[C:6]([I:5])=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[O:14][CH3:15])[CH:2]=[CH2:3]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1c(I)cc(C=O)cc1OC
Reaction time: 1 h

Procedure:
Allyl bromide (27.5 ml, 0.32 mol) was added to a solution of 5-iodovanillin (50.0 g, 0.18 mol) in DMF (200 ml) containing potassium carbonate (48 g, 0.35 mol) at 80° C. The mixture was stirred at this temperature for 1 hour, filtered, and the filtrate was evaporated to a residue, which was purified by HPLC (hexane-ethyl acetate, 4:1, v/v) to give 4-allyloxy-5-iodo-3-methoxybenzaldehyde.