Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[NH2:17][C:18]([C:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1)=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:23]([C:20]2([C:18]([NH2:17])=[O:19])[CH2:22][CH2:21]2)=[O:24])=[CH:11][CH:12]=1
Reactant: Nc1ccc(COc2cccc(F)c2)cc1
Reactant: NC(=O)C1(C(=O)O)CC1
Product: NC(=O)C1(C(=O)Nc2ccc(COc3cccc(F)c3)cc2)CC1
Yield: 42 %

Procedure:
The title compound is prepared in analogy to example 2 from 4-(3-Fluoro-phenoxymethyl)-phenylamine and 1-(aminocarbonyl)-1-cyclopropane-carboxylic acid. Yield=42%. Colorless solid. MS: m/e=329.3 (M++H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[F:14])[N:10]([CH2:17][CH2:18][F:19])[CH:9]=[C:8]([C:20]([O:22]CC)=[O:21])[C:7]2=[O:25].Cl>CO>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[F:14])[N:10]([CH2:17][CH2:18][F:19])[CH:9]=[C:8]([C:20]([OH:22])=[O:21])[C:7]2=[O:25]
Reactant: CCOC(=O)c1cn(CCF)c2c(OC)c(F)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(CCF)c12
Reaction time: 5 h
Yield: 73 %

Procedure:
5 ml of a 4% w/v aqueous solution of sodium hydroxide were added to a solution of the whole (0.0005 mole) of the ethyl 6,7-difluoro-1-(2-fluoroethyl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (X, R9' =2-fluoroethyl) prepared as described in Step (C5) dissolved in 15 ml of methanol. The mixture was then allowed to stand at room temperature for 5 hours, after which it was acidified by adding concentrated hydrochloric acid to precipitate crystals. These crystals were collected by filtration to give 0.11 g of 6,7-difluoro-1-(2-fluoroethyl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IIa, R9' =2-fluoroethyl) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([N:36]1[CH2:41][CH2:40][N:39]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:29])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:38][CH2:37]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)N1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
2-(4-tert-Butyl-piperazin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-tert-butyl-piperazine following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:18])[N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1c(=O)cnc2ccc(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)cnc2ccc(Cl)cc21
Reaction time: 4 h
Yield: 92.5 %

Procedure:
To a mixture of ethyl (7-chloro-2-oxoquinoxalin-1(2H)-yl)acetate (2.21 g) and THF (25 mL) was added a 1 M aqueous NaOH solution (9.0 mL) at room temperature, followed by stirring at the same temperature for 4 hours. The reaction mixture was acidified by the addition of 1 M hydrochloric acid solution and then concentrated under reduced pressure. To the residue was added water, followed by stirring and collecting by filtration. The obtained solid was washed with water to obtain (7-chloro-2-oxoquinoxalin-1(2H)-yl)acetic acid (1.83 g).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[O:4][C:5]3[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=3[CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cccc2cc(C(Cl)C3CCCCC3)oc12
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: COc1cccc2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)oc12
Yield: 7.3 %

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-7-methoxy-1-benzofuran (401 mg) synthesized in Example A20(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (360 mg) synthesized in Example 2(2) and in the same manner as in Example A7(3), the title object compound (48.7 mg, 7%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([CH3:15])=[N:8]1)([CH3:6])[C:3]([NH2:5])=[O:4].[H][H]>CO.[Pd]>[NH2:12][C:10]1[C:9]([CH3:15])=[N:8][N:7]([C:2]([CH3:1])([CH3:6])[C:3]([NH2:5])=[O:4])[CH:11]=1
Reactant: [H][H]
Reactant: Cc1nn(C(C)(C)C(N)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1nn(C(C)(C)C(N)=O)cc1N
Yield: 93.8 %

Procedure:
To a solution of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide (2.5 g, 11.7 mmol) in MeOH (50 mL) was added Pd/C (1 g), exchanged with nitrogen for three times then with hydrogen, and the reaction was stirred at hydrogen atmosphere (1 atm) for 1 h at ambient temperature. The solution was filtered and the filtrate was concentrated under reduced pressure to give crude 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanamide (2.0 g, 93%) which was used in the next step without further purification.
Reaction SMILES: [C:1](=[O:9])([O:5][CH2:6][CH2:7][CH3:8])[O:2][CH2:3]I.[Na].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][NH:20][C:21]([C:23]1[C:24](=[O:41])[C:25]([OH:40])=[C:26]2[C:31](=[O:32])[N:30]3[CH2:33][C@H:34]4[CH2:38][CH2:37][CH2:36][N:35]4[C@@H:29]3[CH2:28][N:27]2[CH:39]=1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1](=[O:9])([O:5][CH2:6][CH2:7][CH3:8])[O:2][CH2:3][O:40][C:25]1[C:24](=[O:41])[C:23]([C:21]([NH:20][CH2:19][C:13]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=2[F:11])=[O:22])=[CH:39][N:27]2[CH2:28][C@H:29]3[N:35]4[CH2:36][CH2:37][CH2:38][C@@H:34]4[CH2:33][N:30]3[C:31](=[O:32])[C:26]=12
Reactant: CCCOC(=O)OCI
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C[C@H]3CCCN3[C@@H]1C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Product: CCCOC(=O)OCOc1c2n(cc(C(=O)NCc3ccc(F)cc3F)c1=O)C[C@@H]1N(C[C@H]3CCCN31)C2=O

Procedure:
The title compound was prepared from iodomethyl 2-(methyl)ethyl carbonate (92 mg, 0.354 mmol), (4aS,13aR)-N-[(2,4-difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide sodium salt (80 mg, 0.177 mmol), potassium carbonate (73 mg, 0.531 mmol), and tetrabutylammonium hydrogen sulfate (60 mg, 0.177 mmol), using a similar process to that described in example 1. 1H NMR (CDCl3) δ 10.23 (m, 1 H), 8.39 (s, 1 H), 7.30 (m, 1 H), 6.77 (m, 2 H), 5.89 (d, J=6.4 Hz, 1 H), 5.78 (d, J=6.4 Hz, 1 H), 4.56-4.48 (m, 3 H), 4.34-4.15 (m, 4 H), 3.86 (m, 1 H), 3.69-3.55 (m, 3 H), 3.31 (s, 3 H), 3.11-2.95 (m, 2 H), 2.78 (m, 1 H), 2.04-1.84 (m, 3 H), 1.63 (m, 1 H). ES+ MS: 563 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C(C)=CC=CC=1>[CH2:10]([O:9][C:1](=[S:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:11]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ccccc1
Solvent: Cc1ccccc1C
Product: CCOC(=S)c1ccccc1
Yield: 115.3 %

Procedure:
Prepare a solution of ethyl benzoate (10 g, 66.5 mmol) in xylene (100 mL). Add Lawesson's reagent (14.5 g, 36 mmol). Reflux the reaction for 5 hours, then concentrate in vacuo to an oil. Chromatograph (silica gel, 100% Hexane) to afford thiobenzoic acid O-ethyl ester (6.9 g). 1H NMR (CDCl3) δ 8.20 (d, J=8 Hz, 2H), 7.52 (t, J=7 Hz, 1H), 7.39 (t, J=7 Hz, 2H), 4.69-4.78 (m, 2H), 1.55 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([C:8]1(O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:11])O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[CH2:1]([C:8]12[NH:22][CH2:19][CH2:20][N:21]1[C:10](=[O:11])[C:12]1[C:17]2=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(O)(Cc2ccccc2)c2ccccc21
Reactant: NCCN
Product: O=C1c2ccccc2C2(Cc3ccccc3)NCCN12

Procedure:
Condense 3-benzyl-3-hydroxyphthalide (15 g.) and ethylenediamine (30 ml.) by the procedure of Example 1 to obtain 9b-benzyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, m.p. 115°-117° C. (elemental analysis confirms the empirical formula C17H16N2O), reduce with lithium aluminum hydride and treat with hydrogen chloride as described in Example 1 to obtain 1-benzyl-1,2,3,4,5,6-hexahydro-2,5-benzodiazocine dihydrochloride, m.p. 238°-40° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[N:26]=[N:25][C:24](=[S:27])[N:23]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[O:11]COCCOC)([CH3:4])[CH3:3]>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[CH3:21][C:18]([C:9]1[CH:8]=[C:7]([C:22]2[N:26]=[N:25][C:24](=[S:27])[N:23]=2)[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:19])[CH3:20]
Reactant: COCCOCOc1c(C(C)(C)C)cc(C2=NC(=S)N=N2)cc1C(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)(C)c1cc(C2=NC(=S)N=N2)cc(C(C)(C)C)c1O

Procedure:
Anhydrous zinc bromide (6.6 g, 0.0292 mole) is added to a suspension of 5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-3H-1,2,4-triazole-3-thione (2.4 g, 0.0058 mole) in methylene chloride (6.0 ml). After 18 hours the mixture is diluted with methylene chloride (30 ml), washed with water (15 ml), saturated aqueous NaHCO3 (15 ml), saturated aqueous NaCl (10 ml), and dried over MgSO4. Filtration and concentration gives a solid which is recrystallized from ethyl acetate/isopropyl ether to provide 0.8 g (1.8 g theor., 44%) of product, mp >250° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[N+:25](=[CH2:27])=[N-:26].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[OH-].[K+].C(OCCOCCO)C>O1CCCC1.C(OCC)C.O.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:16])[CH:27]=[N+:25]=[N-:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)C=[N+]=[N-]
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.0 g in a mixture of 26 mL dry tetrahydrofuran and 26 mL dry diethyl ether) at -10° C. was added 1.91 mL of triethylamine followed by the dropwise addition of 1.78 mL isobutyl chloroformate. The reaction was stirred at -10° C. for 30 minutes then warmed to 0° C. Over the next hour, 26 mL of a solution of diazomethane in diethyl ether was added (prepared from: 8.0 g Diazald® in 70 mL diethyl ether; 4g potassium hydroxide; 20 mL 2-(2-ethoxyethoxy)ethanol; 6 mL water and 12 mL diethyl ether using a mini Diazald Kit) and the mixture allowed to stir at room temperature for an additional 2 hours. At this time the reaction was quenched by the addition of 3 mL acetic acid at 0° C. This was then diluted with 100 mL water and 100 mL diethyl ether, the layers separated and the aqueous portion extracted with (2×75 mL) diethyl ether. The combined organics were washed with water (75 mL), saturated sodium bicarbonate (2×75 mL) and brine (75 mL) then dried over magnesium sulfate. Removal of the solvent in vacuo and purification of the residue by flash chromatography on silica gel (hexane:ethyl acetate, 8:2) gave the title compound (2.99 g).
Reaction SMILES: COC1C=CC(C[S:8][C@H:9]2[CH2:13][N:12]([S:14]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)(=[O:16])=[O:15])[C@H:11]([C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[O:28])[CH2:10]2)=CC=1.C[Si](Cl)(C)C.CS(C)=O.C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+].C(S)[C@@H](O)[C@H](O)CS.OS([O-])(=O)=O.[K+]>C(O)(C(F)(F)F)=O.CO>[SH:8][C@H:9]1[CH2:13][N:12]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[C@H:11]([C:27]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)c3ccc(OC)cc3)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CS(C)=O
Product: COc1ccc(C(=O)[C@@H]2C[C@@H](S)CN2S(=O)(=O)c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.5 %

Procedure:
140 mg (0.26 mmol) (2S,4R)-[4-(4-methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-(4-methoxy-phenyl)-methanone in 2 ml TFA were treated with 0.45 ml (6 mmol) trimethylsilyl chloride and 0.3 ml (6 mmol) DMSO for 2 h at RT, added to a sat. solution of Na2CO3 and extracted with EtOAc, washed with brine and dried. The crude product was dissolved in 6 ml acetonitrile, a sat. solution of K2CO3 in MeOH and 100 mg (0.65 mmol) DTT were added. The solution was stirred at RT for 1.5 h, the solution was acidified with 1M aq KHSO4 and the inorganic phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated. Flash chromatography yielded 89.5 mg (81%) (2S,4R)-[4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-(4-methoxy-phenyl)-methanone as light yellow solid, MS: 292 (M-C5H9O)+, 135 (C5H9O)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][O:16][C:17](=O)[CH:18]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[C:17]([Cl:3])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(-c2cc(=O)o[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(Cl)on2)cc1
Reaction time: 4 h

Procedure:
To 30 g of phosphorus oxychloride were added 7.4 g (39 mmol) of 3-(4-methoxyphenyl)isoxazol-5-one, followed by the dropwise addition of 4 g (40 mmol) of triethylamine. After completion of the dropwise addition, the reaction mixture was stirred at 120°-125° C. for 4 hours. The solvent was then distilled off under reduced pressure. Ice water (100 ml) was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried. Purification by silica gel column chromatography (solvent: hexane/ethyl acetate=10/1) gave the title compound as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:12]4[N:13]([CH:20]=[N:21][CH:22]=4)[CH:14]=[CH:15][C:16]=3[C:17]([OH:19])=O)=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH2:55][O:56][CH2:57][C@@H:58]([OH:60])[CH3:59]>CN(C=O)C>[OH:60][C@@H:58]([CH3:59])[CH2:57][O:56][NH:55][C:17]([C:16]1[CH:15]=[CH:14][N:13]2[CH:20]=[N:21][CH:22]=[C:12]2[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]=1[F:23])=[O:19]
Reactant: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Reactant: C[C@H](O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CONC(=O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.2 %

Procedure:
A suspension of 8-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (0.11 g, 0.35 mmol), EDCI (0.081 g, 0.42 mmol), HOBt (0.057 g, 0.42 mmol), DIPEA (0.085 mL, 0.88 mmol) and (S)-1-aminooxy-propan-2-ol hydrochloride (0.05 g, 0.39 mmol) in DMF (1.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM (5 mL) and saturated aqueous NaHCO3 (5 mL). The organic layer was washed with water (5 mL), followed by brine (5 mL), then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 60%, ethyl actetate in DCM) to give a yellow sticky solid, which was further purified by preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes) to afford the title compound as a yellow solid (38 mg, 27%). LCMS (method A): RT=6.87 min, [M+H]+=385. 1H NMR (DMSO-d6) 10.54 (1H, s), 8.27 (1 H, s), 7.76 (1H, dd, J=7.37, 0.93 Hz), 7.14 (1H, t, J=8.37 Hz), 6.98 (1H, dd, J=11.87, 1.95 Hz), 6.95-6.89 (1H, m), 6.76 (1H, d, J=7.33 Hz), 6.27 (1H, s), 3.89-3.79 (1H, m), 3.72-3.62 (2H, m), 1.99-1.90 (1H, m), 1.04 (3H, d, J=6.34 Hz), 0.99-0.93 (2H, m), 0.76-0.67 (2H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[C-:12]#[N:13].[Na+].C([O-])(O)=O.[Na+]>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:12]#[N:13])[N:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution 2-chloro-4-(trifluoromethyl)pyrimidine (5.00 g, 27.4 mmol) in dimethyl sulfoxide (25 mL) was added sodium cyanide (1.68 g, 34.2 mmol). The reaction was stirred at room temperature for 30 minutes and poured into cold saturated aqueous NaHCO3 solution. The mixture was transferred to a 100 mL separatory funnel and extracted with ethyl ether (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound, 4-trifluoromethyl-pyrimidine-2-carbonitrile, as a brown oil, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ9.16 (d, J=5.1 Hz, 1H), 7.88 (d, J=5.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=3)[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A solution of Compound 35 (3 g, 16.57 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 729 mg, 18.22 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat 4-fluorobenzyl bromide (2.28 mL, 18.23 mmol) was added and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 3.23 g (67%) of white solids. M.P. 107° C. 1H NMR (DMSO-d6): δ 5.27 (s, 2H), 7.19 (m, 2H), 7.29 (dd, J=3.9, 9.0 Hz, 1H), 7.47 (m, 2H), 7.65 (td, J=5.5, 9.0 Hz, 1H), 7.81 (dd, J=2.9, 7.9 Hz, 1H). Anal. (C15H9F2NO3) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:20][CH2:21]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(C(=O)N2CCN(Cc3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
4-Amino-3-fluorobenzoic acid (28.4 mmol, 4.40 g), 1-benzylpiperazine (28.4 mmol, 4.93 mL, 5 g) and triethylamine (85 mmol, 11.86 mL, 8.61 g) were stirred in dichloromethane at room temperature. 1-Propanephosphonic acid cyclic anhydride (42.6 mmol, 25.2 mL, 27.1 g, 50% solution in ethyl acetate) was added and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and concentrated under reduced pressure to afford the title compound (7.51 g). MS (ESI) m/z 314.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5]2.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:7]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2cc1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2nc(Cl)c(-c3ccccc3)cc2c1
Temperature: 0 °C

Procedure:
6-Chloro-3-phenylquinolin-2-one (6.7 gm.) and phosphorus oxychloride (100 ml.) were heated together under reflux for 2 hr. The reaction mixture was then poured into ice water (1000 ml.) and extracted with ethyl acetate (3×100 ml.). The ethyl acetate extract was washed with water (3×50 ml.) and dried (Na2SO4), and the solvent was evaporated. The resulting solid was crystallised from ethanol to give 2,6-dichloro-3-phenylquinoline, m.p. 147°-9°.
Reaction SMILES: [CH2:1]([OH:12])[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.OO>>[CH:1](=[O:12])[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: COc1ccc(CO)cc1OC
Agent: OO
Product: COc1ccc(C=O)cc1OC

Procedure:
With veratryl alcohol, if hydrogen peroxide is added to the above reaction medium, approximately 3 times less veratraldehyde is obtained.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[B:32](OC)([O:35]C)[O:33]C.[Cl-].[NH4+]>C(OCC)(=O)C.C1COCC1>[Si:5]([O:8][C:9]1[CH:10]=[C:11]([O:17][CH3:18])[C:12]([B:32]([OH:35])[OH:33])=[C:13]([O:15][CH3:16])[CH:14]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: COB(OC)OC
Reactant: COc1cc(OC)cc(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(O[Si](C)(C)C(C)(C)C)cc(OC)c1B(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a mixture of tert-butyl(3,5-dimethoxyphenoxy)dimethylsilane (4.97 g, 18.5 mmol) and THF (50.0 mL) were added N,N,N′,N′-tetramethylethylenediamine (3.35 mL, 22.2 mmol) and n-butyllithium (2.77 M solution in n-hexane: 8.01 mL, 22.2 mmol) in that order at room temperature, and the mixture was stirred for 1 hour at room temperature. The mixture was then cooled to −78° C. (internal temperature), and then trimethyl borate (2.48 mL, 22.2 mmol) was added and the temperature was raised to room temperature while stirring. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and then ethyl acetate was added, while cooling on ice. After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (mixture of n-heptane and ethyl acetate: n-heptane/ethyl acetate=4/1) to obtain the title compound (3.50 g, 11.2 mmol).