Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[C:65]1([NH2:68])[CH2:67][CH2:66]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:68][C:65]3([C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=4[C:58]([F:57])([F:69])[F:70])[CH2:67][CH2:66]3)=[O:21])=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1
Reactant: NC1(c2ccccc2C(F)(F)F)CC1
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)NC1(c2ccccc2C(F)(F)F)CC1
Yield: 13.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoic acid (Intermediate-15, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropyl ethyl amine (2.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[2-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-12, 0.082 g, 0.410 mmol) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.27-1.31 (m, 4H), 3.90 (s, 3H), 7.47 (t, J=8.1 Hz, 2H), 7.54-7.69 (m, 6H), 7.87 (t, J=8.4 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.61 (s, 1H); MS (m/z): 547.15 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=4)[CH:15]=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH:15]=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2cnc3ncc(-c4ccc(F)cc4)nc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cn2cnc3ncc(-c4ccc(F)cc4)nc32)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 88.5 %

Procedure:
To a solution of 6-(4-fluoro-phenyl)-1-(4-methoxy-benzyl)-1 H-imidazo[4,5-b]pyrazine (40 mg, 0.12 mmol) in anhydrous dichloromethane (3 mL) at 0° C. was added BBr3 (0.01 mL). The reaction was stirred under nitrogen at 0° C. for 40 minutes, and HPLC showed the presence of 33% of starting material. Another portion of BBr3 (0.01 mL) was added, and the reaction was continued at 0° C. under nitrogen for 2 hours for the completion. The reaction solution was quenched with ice, and partitioned between dichloromethane and water. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified on a silica gel column eluting with EtOAc-Hexane (1:1) to provide 4-[6-(4-fluoro-phenyl)-imidazo[4,5-b]pyrazin-1-ylmethyl]-phenol as a yellow solid (34 mg).
Reaction SMILES: [OH:1][C@H:2]([C:14]1[CH:15]=[CH:16][C:17]([O:32]CC2C=CC=CC=2)=[C:18]([N:20](CC2C=CC=CC=2)[S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=1)[CH2:3][NH:4][C@@H](C1C=CC=CC=1)CO>[Pd].CCO.CC(O)=O.[OH-].[Pd+2].[OH-]>[NH2:4][CH2:3][C@@H:2]([C:14]1[CH:15]=[CH:16][C:17]([OH:32])=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=1)[OH:1]
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1cc([C@@H](O)CN[C@H](CO)c2ccccc2)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reaction time: 19 h

Procedure:
To an evacuated flask containing palladium hydroxide (70.8 mg) and palladium on carbon [50% water by weight] (70.8 mg) was added a solution of N-{5-((1R)-1-hydroxy-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethyl)-2-[(phenylmethyl)oxy]phenyl}-N-(phenylmethyl)methanesulfonamide (354 mg) in EtOH (15 ml) and AcOH (3 ml). The mixture was hydrogenated for 19 h. The catalysts were filtered off and the filtrate concentrated in vacuo. The mixture was purified by column chromatography (Oasis cartridge, 0 to 50% MeOH in water) to afford the title compound. LCMS RT=0.35 min
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[C:10]([Cl:16])[CH:9]=2)=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[Cl:16][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:3])=[O:5])[N:7]2[CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[F:15]
Reactant: CCOC(=O)c1cc2cc(F)c(Cl)cc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: O=C(O)c1cc2cc(F)c(Cl)cc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 6-chloro-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (Lit. 7) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 352.0 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14]O>OS(O)(=O)=O>[CH3:1][C:2]1[C:10]2[O:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1cccc2cc(C(=O)O)oc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2cccc(C)c2o1

Procedure:
A solution of 4.32 g of 7-methylbenzofuran-2-carboxylic acid in 150 ml of methanol and 1 ml of conc. H2SO4 is stirred at reflux over 9 hours. The reaction mixture is cooled and concentrated by evaporation. The residue is dissolved in diethyl ether and washed with water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained as a red-brown oil from the residue. Rf=0.32 (1:6 EtOAc-heptane); Rt=4.51.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]2[O:19][C:18](=[O:20])[C:9]3[CH2:10][N:11]([CH2:14][C:15](=O)[CH3:16])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.[CH2:22]([NH2:24])[CH3:23]>>[Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]2[O:19][C:18](=[O:20])[C:9]3[CH2:10][N:11]([CH2:14][CH:15]([NH:24][CH2:22][CH3:23])[CH3:16])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1
Reactant: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c(Cl)cc23)C1
Reactant: CCN
Product: CCNC(C)CN1CCc2c(c(=O)oc3cc(C)c(Cl)cc23)C1
Yield: 20.9 %

Procedure:
Prepared by the method described for example 51 from 9-chloro-1,2,3,4-tetrahydro-8-methyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (6.2 g, 0.020 moles) and ethylamine (6 ml, 0.092 moles). Recrystallization from ethyl acetate gave the product (1.4 g), mp 162°-163° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17](O)[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]([CH3:3])[C:4]([O:6][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7])=[O:5]
Reactant: CCCCCCCCCCC(C)O
Reactant: CC(N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(C)N
Yield: 110.8 %

Procedure:
To a stirred solution of DL-alanine 1 (5 g, 56.1 mmol) in toluene (100 mL) was added dodecanol 2 (9.42 g, 50.5 mmol) in one lot, followed by pTSA (11.75 g, 61.7 mmol). After addition, the temperature of the reaction mixture was slowly raised to reflux temperature, the water was separated azeotropically, and the reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum, the obtained residue was taken in ethyl acetate (200 mL) and washed with aqueous 5% Na2CO3 (3×50 mL) followed by brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude dodecyl 2-aminopropanoate 3 (14.4 g, yield: 100%) as a liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(C(O)=O)[C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].C1C=CC(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[ClH:38].O1CCOCC1>CC(O)(C)C>[ClH:38].[CH3:1][O:2][C:3]([C:5]1([NH2:28])[C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(=O)O)CC12CCC2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: COC(=O)C1(N)CC12CCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of spiro[2,3]hexane-1,1-dicarboxylic acid methyl ester (660 mg, 3.58 mmol) in 3 mL of anhydrous t-BuOH was added 1.08 g (3.92 mmol) of DPPA and 440 mg (4.35 mmol) of Et3N. The mixture was heated at reflux for 21 h and then partitioned between H2O and ether. The ether phase was dried over magnesium sulfate, filtered and concentrated in vacuo to yield an oil. To this oil was added 3 mL of a 4 M HCl/dioxane solution. This acidic solution was stirred at rt for 2 h and then concentrated in vacuo. The residue was triturated with ether to give 400 mg (58%) of desried prodict as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 8.96 (br s, 3H), 3.71 (s, 3H), 2.41 (m, 1H), 2.12 (m, 4H), 1.93 (m, 1H), 1.56 (q, 2H, J=8 Hz). LC-MS of free amine: MS m/z 156 (M++1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH:38][O:39][CH3:40])=[O:37])=[C:32]([F:41])[CH:31]=2)[CH2:25]1)=[N+]=[N-].O>C1COCC1>[NH2:20][CH2:23][C@@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH:38][O:39][CH3:40])=[O:37])=[C:32]([F:41])[CH:31]=2)[CH2:25]1
Reactant: CONC(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CONC(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Temperature: 40 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
Triphenylphosphine (317 mg, 1.2 mmol) was added to a solution of 5-(S)-azidomethyl-3-[4′-(N-methoxyamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one. (0.335 g, 1.1 mmol) in THF (8 ml) under nitrogen atmosphere. The solution was stirred at 40° C. for 2 h, water (0.24 ml) was added, and the reaction mixture stirred at 40° C. overnight. Solvent was removed under vacuum, and the resulting solid was triturated with ether. Precipitated material was filtered, washed with ether and ethanol and dried under vacuum to afford the product as white crystals (120 mg, 42%). HPLC Rt=3.5 min. MS (m/z): [M+H]+=284.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH3:10][N:11]1[C:15](=O)[CH2:14][CH2:13][CH2:12]1.FC1C=CC=CN=1>CCOC(C)=O>[F:9][C:4]1[CH:3]=[C:2]([NH:1][C:12]2[CH:13]=[CH:14][CH:15]=[CH:10][N:11]=2)[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Nc1ccc(O)c(F)c1
Reactant: CN1CCCC1=O
Agent: Fc1ccccn1
Solvent: CCOC(C)=O
Product: Oc1ccc(Nc2ccccn2)cc1F
Temperature: 120 °C
Reaction time: 9 h

Procedure:
To 4-amino-2-fluorophenol (0.983 g, 7.73 mmol) was added NMP (3 mL) and 2-fluoropyridine (0.670 mL, 7.78 mmol). The reaction mixture was heated to 120° C. for 12.5 h and the temperature was increased to 150° C. After 9 h, the reaction mixture was diluted with EtOAc and the organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (10% to 70% EtOAc in hexanes) gave 2-fluoro-4-(pyridin-2-ylamino)phenol as a pale yellow oil. MS (ESI, pos. ion) m/z: 205.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=O.C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]([CH3:13])=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C=C(C)Nc1ccc(Cl)cc1

Procedure:
A solution of 70 g (0.54 mol) of 4-chloroaniline, 70 ml (0.54 mol) of ethyl acetoacetate, and 0.6 ml acetic acid in 400 ml toluene was heated in a Dean-Stark apparatus for 19 at 130° C. The mixture was evaporated, and the remaining crystalline precipitate stirred with diisopropylether and filtered. The filtrate was concentrated and the residue purified via column chromatography on silica gel with dichloromethane/hexane 4:1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:22]([CH3:29])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[C:19]=S.NC(N)=S>O1CCCC1>[Cl:12][C:11]1[C:2]2[N:1]=[C:19]([NH:18][C:21]3[C:22]([CH3:29])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[N:13]([CH2:14][CH2:15][CH2:16][OH:17])[C:3]=2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: COc1ccc(N=C=S)c(C)n1
Agent: NC(N)=S
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(OC)nc3C)n(CCCO)c12
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a solution of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (2.00 g) in tetrahydrofuran (40.0 mL) was added 3-isothiocyanato-6-methoxy-2-methylpyridine (1.67 g, 9.277 mmol). The reaction mixture was stirred at 70° C. for 14 hrs. The starting material wasn't consumed completely. To the mixture was added 3-isothiocyanato-6-methoxy-2-methylpyridine (1.67 g, 9.277 mmol). The reaction mixture was stirred at 70° C. for 36 hrs. After cooling, the solvent was removed by concentration. The residue was purified by silica gel column chromatography eluting with a 30-80% ethyl acetate/n-hexane gradient mixture to give the mixture contained thiourea and title compound. The mixture was subject to next step without further purification. The mixture was dissolved into tetrahydrofuran (30 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (885.7 mg, 4.62 mmol) and triethylamine (0.71 mL, 5.08 mmol). The reaction mixture was stirred at 50° C. for 2 hrs. After cooling, the mixture was diluted with water, extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless solid (1.50 g, 3.72 mmol, 48% (2 steps)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]([O-:9])=O.[Na+].Cl.N1C=CN=C1.C(=O)=O.Cl.[CH3:21][NH:22][O:23][CH3:24].Cl>C(#N)C.ClCCl.O>[CH3:24][O:23][N:22]([CH3:21])[C:7]([C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:9]
Reactant: O=C([O-])c1ncccn1
Reactant: CNOC
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ncccn1
Temperature: 52 °C
Reaction time: 2 h

Procedure:
Sodium pyrimidine-2-carboxylate (4.00 g, 27.4 mmol), imidazole hydrochloride (3.15 g, 30.1 mmol), and 1-carbonyldiimidazole (5.26 g, 31.5 mmol) was slurried in acetonitrile (30 mL) at room temperature under an N2 atmosphere. The mixture was then warmed to 52° C. over 30 minutes. Evolution of carbon dioxide was seen when the reaction mixture reached approximately 50° C. The mixture was then stirred at 52° C. for approximately 2 hours. The reaction was cooled to room temperature, then N,O-dimethylhydroxylamine hydrochloride (3.54 g, 35.6 mmol) was added slowly, portion wise over approximately 15 minutes and a mild exotherm was seen after each addition. The contents were stirred at room temperature overnight. To the reaction mixture was then added deionized water (25 mL) and dichloromethane (25 mL). 6 M aqueous hydrochloric acid was added dropwise to acidify the aqueous layer to approximately pH 1. The organic phase was then separated and the aqueous phase was extracted twice with dichloromethane. The combined organics were washed with 2 M aqueous hydrochloric acid and the layers separated. The acidic layer was extracted twice with dichloromethane and the organics combined. The organics were washed with a saturated, aqueous NaHCO3 solution, then dried over MgSO4, filtered and the solvent was removed by distillation under reduced pressure to provide the title compound.
Reaction SMILES: C(C1C=C(C=CC=1)C=O)C.[C:11]1([C:17]2[N:21]=[CH:20][N:19]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:41]([C:43]1[CH:44]=[CH:45][C:46]([F:51])=[C:47]([CH:50]=1)[CH:48]=[O:49])[CH3:42]>>[CH2:41]([C:43]1[CH:44]=[CH:45][C:46]([F:51])=[C:47]([CH:48]([C:20]2[N:19]([C:22]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:18]=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:21]=2)[OH:49])[CH:50]=1)[CH3:42]
Reactant: CCc1ccc(F)c(C=O)c1
Reactant: c1ccc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: CCc1cccc(C=O)c1
Product: CCc1ccc(F)c(C(O)c2nc(-c3ccccc3)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 82.5 %

Procedure:
According to the procedure for Intermediate 370.1, 3-phenyl-1-trityl-1H-1,2,4-triazole (250 mg, 0.66 mmol) and 5-ethyl-2-fluorobenzaldehyde (100 mg, 0.66 mmol) afforded 294 mg of Intermediate 384.1 as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.06 (t, J=7.70 Hz, 3H) 2.41 (q, J=7.58 Hz, 2H) 2.89 (d, J=9.05 Hz, 1H) 5.41 (d, J=9.29 Hz, 1H) 6.60 (dd, J=9.90, 8.44 Hz, 1H) 6.82-6.93 (m, 1H) 6.96 (dd, J=7.34, 2.20 Hz, 1H) 7.02-7.09 (m, 6H) 7.09-7.16 (m, 9H) 7.24-7.39 (m, 4H) 7.98-8.10 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17](S(CC)(=O)=O)[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:32])[N:4]([CH3:33])[C:3]1=[O:34].ClC1C=CC([N+]([O-])=O)=CC=1[C:38]#[N:39]>CN(C)C=O>[CH3:1][N:2]1[C:7]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][C:23]=3[C:38]#[N:39])[CH2:12][CH2:13]2)=[CH:6][C:5](=[O:32])[N:4]([CH3:33])[C:3]1=[O:34]
Reactant: CCS(=O)(=O)N(CCCN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1)c1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: CN(C)C=O
Product: Cn1c(N2CCN(CCCNc3ccc([N+](=O)[O-])cc3C#N)CC2)cc(=O)n(C)c1=O
Yield: 154.3 %

Procedure:
0.3 g of Compound 158 obtained beforehand, 0.3 g of 2-chloro-5-nitrobenzonitrile and 0.31 ml of trtiethylamine were stirred at 80° C. for 1 hour in 5 ml of dimethylformamide. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol=40/1, by volume), thereby obtaining 0.4 g of 1,3-dimethyl-6-{4-[3-(2-cyano-4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([Br:14])=[C:7]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:6]=1)C.O.[OH-].[Na+].Cl>O1CCOCC1>[Br:14][C:8]1[C:9]([O:11][CH2:12][CH3:13])=[CH:10][C:5]([C:4]([OH:26])=[O:3])=[CH:6][C:7]=1[O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25]
Reactant: CCOC(=O)c1cc(OCC)c(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1Br
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.21 g (0.47 mmol) of 4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-ethoxy-benzoic acid ethyl ester was dissolved in 6 ml of dioxan. 6 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:14]2[C:9](=[N:10][C:11]([CH3:16])=[C:12]([F:15])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:17]>C(C(C)=O)C.Cl>[F:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][C:6](=[O:17])[N:5]2[CH2:4][CH:3]=[O:2])=[N:10][C:11]=1[CH3:16]
Reactant: COC(Cn1c(=O)ccc2nc(C)c(F)cc21)OC
Agent: Cl
Solvent: CCC(C)=O
Product: Cc1nc2ccc(=O)n(CC=O)c2cc1F
Temperature: 74 °C
Reaction time: 0.83 h
Yield: 91.1 %

Procedure:
To a solution of 0.69 g of 1-(2,2-dimethoxyethyl)-7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-one in 6 mL of methyl ethyl ketone, 0.35 mL of concentrated hydrochloric acid was added, and the temperature was increased to 74° C., and the mixture was stirred for 2 hours 50 minutes. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. To the resultant residue, ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate to obtain 0.52 g of (7-fluoro-6-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([N:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH3:36][O:37][CH2:38][CH2:39]Br>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([N:23]5[CH2:24][CH2:25][N:26]([CH2:39][CH2:38][O:37][CH3:36])[CH2:27][CH2:28]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1N1CCNCC1
Reactant: COCCBr
Product: COCCN1CCN(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[4-(2-methoxyethyl)piperazin-1-yl]-1,3-thiazolidine-2,4-dione was prepared from ((5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperazin-1-yl-1,3-thiazolidine-2,4-dione (Example 351) and 2-bromoethyl methyl ether following General Procedure S.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:9]([C@@:11]1([OH:27])[C@@H:15]([CH2:16][OH:17])[O:14][C@@H:13]([N:18]2[CH:25]=[CH:24][C:22]([NH2:23])=[N:21][C:19]2=[O:20])[C@@H:12]1[OH:26])#[CH:10].N1C=CN=C1>CN(C)C=O>[Si:1]([O:17][CH2:16][C@H:15]1[O:14][C@@H:13]([N:18]2[CH:25]=[CH:24][C:22]([NH2:23])=[N:21][C:19]2=[O:20])[C@H:12]([OH:26])[C@:11]1([C:9]#[CH:10])[OH:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#C[C@@]1(O)[C@@H](CO)O[C@@H](n2ccc(N)nc2=O)[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#C[C@@]1(O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](n2ccc(N)nc2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyldimethylsilylchloride (12.5 g, 82.5 mmol) was gradually added under ice-cooling to a solution of 3′-ethynylcytidine (hereinafter referred to as ECyd) (20 g, 75 mmol) and imidazole (12.8 g, 188 mmol) in N,N-dimethylformamide (hereinafter referred to as DMF) (75 mL), and the mixture was stirred for 5 hours at room temperature. After completion of reaction, the solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with saturated aqueous sodium hydrogen carbonate (100 mL) and saturated brine (100 mL) and dried with magnesium sulfate. Magnesium sulfate was removed through filtration. The filtrate was stirred at room temperature, and precipitated crystals were collected through filtration, to thereby yield Compound 1 (11.5 g, 52%).