Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([CH2:21][Cl:25])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: ClCc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Yield: 110.9 %

Procedure:
A mixture of 7-chloro-2-(5-hydroxymethylbenzofuran-2-yl)quinoline (0.40 g) and thionyl chloride (0.30 g) in chloroform (20 ml) was stirred under reflux for 1 hour. After being cooled, the resulting mixture was adjusted to pH 7 with aqueous sodium hydrogen carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 7-chloro-2-(5-chloromethylbenzofuran-2-yl)quinoline (0.47 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[BH4-].[Na+].Cl.[OH-].[K+].[CH3:19]I>C1COCC1.O.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]2[C:10]=1[CH:9]([O:11][CH3:19])[CH:8]([CH3:12])[CH2:7]2
Reactant: CI
Reactant: Cc1ccc(Br)c2c1CC(C)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC1c2c(Br)ccc(C)c2CC1C
Temperature: 2.5 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
To a mixture of 74.0 g (0.310 mol) of 7-bromo-2,4-dimethylindan-1-one and 5.86 g (0.155 mol) of NaBH4 in 310 ml of THF 155 ml of methanol was added dropwise by vigorous stirring for 5 h at 0-5° C. This mixture was stirred overnight at room temperature and then added to 1 liter of cold water. The resulting mixture was acidified by 2 M HCl to pH˜5, and then it was extracted with 3×250 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated. The resulting orange oil was dissolved in 600 ml of DMSO, then 70 g (1.25 mol) of KOH and 88 g (0.62 mol) of MeI were added to the resulting solution. This mixture was stirred for 3 h at ambient temperature. Further on, the solution was decanted from an excess of KOH, the latter was washed with 2×200 ml of dichloromethane, and 2000 cm3 of water was added to the combined solution. The organic layer was separated, and the aqueous layer was additionally extracted with 2×100 ml of dichloromethane. The combined organic extract was additionally washed with 5×1500 ml of water, dried over Na2SO4, and evaporated to dryness. Fractional distillation of the residue in vacuum gave 72.3 g (92%) of 7-bromo-1-methoxy-2,4-dimethylindane, b.p. 107-112° C./5 mm Hg.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH:19]1[CH:24]=[C:23]([CH2:25]Br)[C:22]([C:27]#[N:28])=[CH:21][CH:20]=1>CN(C=O)C.C(OCC)(=O)C>[C:27]([C:22]1[CH:21]=[CH:20][CH:19]=[CH:24][C:23]=1[CH2:25][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2])#[N:28]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: N#Cc1ccccc1CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2C#N)CCCC1=O
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
40% Methanolic Triton B (2.18 mL, 4.8 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM) in 10 mL of DMF at 25° C. After 10 minutes, a-bromo-o-tolunitrile (1.0 g, 5.0 mM) was added and the resultant mixture stirred at room temperature for 30 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, 1 N HCl, H2O, sat NaHCO3, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was triturated with diethyl ether and methylene chloride, then dried in vacuo to afford 1.31 g (91%) of the 9-[(2-cyanophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ 7.75 (dd, 1H, J=1 and 8 Hz), 7.5-7.2 (m, 5H), 6.6 (d, 1H, J=8 Hz), 5.55 (s, 2H), 4.05 (s, 3H), 2.85 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.25 (m, 2H). IR (KBr, cm−1) 2222, 1711, and 1650. MS (ES) m/e 357, 359.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9]([C:10]2[O:11][C:12]3[C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:8][C:7]([C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[CH:27]=2)=[CH:6][N:5]=1>CO>[NH2:3][C:4]1[C:9]([C:10]2[O:11][C:12]3[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:8][C:7]([C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)[CH:27]=2)=[CH:6][N:5]=1
Reactant: COC(=O)c1cccc2nc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5cccc(C(=O)O)c5o4)c3)cn2)CC1
Temperature: 50 °C
Yield: 91.4 %

Procedure:
A 3N aqueous solution of sodium hydroxide (0.694 ml) was added to methyl 2-[2-amino-5-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]-3-pyridyl]-1,3-benzoxazole-7-carboxylate (360 mg) dissolved in methanol (5 ml). The resulting solution was heated at 50° C. for 2 hours. The mixture was evaporated to dryness. Water (30 ml) was added and the pH was adjusted to 5 with dilute hydrochloric acid. The resultant solid was filtered, washed with water and dried under reduced pressure to afford 2-[2-amino-5-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]-3-pyridyl]-1,3-benzoxazole-7-carboxylic acid (320 mg) as yellow solid. NMR Spectrum: (DMSOd6) 1.46 (s, 9H), 1.80 (dd, 1H), 1.85 (dd, 1H), 2.00-2.09 (m, 2H), 2.93 (bs, 2H), 3.98-4.12 (m, 2H), 4.35-4.44 (m, 1H), 7.52 (dd, 1H), 7.63 (bs, 2H), 7.83 (s, 1H), 7.92 (d, 1H), 8.06 (d, 1H), 8.27 (s, 1H), 8.33 (d, 1H), 8.52 (d, 1H); Mass spectrum: M+H+ 505.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][C:32]([CH2:35]O)=[CH:31][CH:30]=1>>[N:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:19][C:18]([C:17]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9](=[O:28])[C:10]3[C:15]([C:16]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=3)=[O:20])=[CH:31][CH:30]=1
Reactant: OCc1ccncc1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Product: O=C(OCc1ccncc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and 4-pyridinemethanol. A colorless powder (160 mg).
Reaction SMILES: C(O)(=O)C.[N:5]1([C:14]2([CH2:19][C:20]([NH2:22])=[NH:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[CH:6]1.[C:23]([O:27][C:28](=[O:43])/[C:29](/O)=[C:30](\[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)/[C:31](O)=[O:32])([CH3:26])([CH3:25])[CH3:24].C[O-].[Na+].C(OCC)(=O)C>CO>[C:23]([O:27][C:28]([C:29]1[C:30]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:31]([OH:32])[N:22]=[C:20]([CH2:19][C:14]2([N:5]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:8]4[CH:7]=[CH:6]3)[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:21]=1)=[O:43])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Reactant: N=C(N)CC1(n2ccc3cccnc32)CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a stirred solution of 2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetamidine; compound with acetic acid (402) (800 mg, 2.65 mmol) and (E)-3-benzyloxy-2-hydroxy-4-oxo-pent-2-enoic acid tert-butyl ester (4) (978 mg, 3.18 mmol) in methanol (80 mL) was added sodium methoxide solution (25% in methanol) (1.7 mL, 7.94 mmol) at 0° C. The reaction mixture was allowed to warm slowly to room temperature and was stirred for 16 h (TLC, ethyl acetate, Rf=0.3). After completion of the reaction, methanol was evaporated to get a crude product which was purified by Combi-Flash column (eluted at 60-70% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (403) (1 g, 75%) as a light yellow solid.
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH:19]1[O:23][CH:22]([CH:24]=[C:25]([P:27](=[O:30])([OH:29])[OH:28])[F:26])[CH:21]([OH:31])[CH:20]1[OH:32])(=O)C1C=CC=CC=1>[NH4+].[OH-]>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH:19]1[O:23][CH:22]([CH:24]=[C:25]([P:27](=[O:28])([OH:29])[OH:30])[F:26])[CH:21]([OH:31])[CH:20]1[OH:32]
Reactant: O=C(Nc1ncnc2c1ncn2C1OC(C=C(F)P(=O)(O)O)C(O)C1O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ncnc2c1ncn2C1OC(C=C(F)P(=O)(O)O)C(O)C1O
Reaction time: 8 h
Yield: 55.4 %

Procedure:
Compound 7.5 (50 mg, 0.11 mmol) was dissolved in 5 mL NH4OH and stirred under N2 for overnight. The mixture was concentrated under reduced pressure and the residue was subjected to reverse phase HPLC eluting with 0-25% CH3CN in water to give compound 7.6 (22 mg, 57% yield). 1HNMR (300 MHz, D2O) δ 4.24-4.27 (m, 1H), 4.69-4.71 (m, 1H), 4.96 (m, 1H), 5.54-5.68 (m, 1H), 5.97 (d, 1H, J=4.8), 8.11 (s, 1H), 8.21 (s, 1H). LRMS [M−H]− C11H13FN5O6P requires 361.1. Found 361.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-])=O)[C:18]([C:24]4[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=4)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1>CCO.CC(O)=O.CCOC(C)=O.[Fe]>[NH2:21][C:19]1[C:18]([C:24]2[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][C:11]2[C:12]([C:13](=[O:16])[NH:14][CH3:15])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH:20]=1
Reactant: CCOC(=O)c1cccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N)c1
Reaction time: 1 h
Yield: 88 %

Procedure:
Iron (1.03 g, 18.4 mmol) was added to a stirring solution of ethyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl)benzoate (1.70 g, 3.68 mmol) in EtOH (37 mL) and AcOH (37 mL) at 90° C. The slurry was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl followed by 1M NaOH and sat. NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the titled compound (1.40 g 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.25-8.34 (1H, m), 8.00-8.03 (1H, m), 7.87-7.99 (3H, m), 7.69-7.75 (1H, m), 7.63 (1H, t, J=7.65 Hz), 7.26-7.37 (2H, m), 7.20 (1H, s), 6.98 (1H, s), 5.07 (2H, s), 4.35 (2H, q, J=7.03 Hz), 2.78 (3 H, d, J=4.52 Hz), 1.34 (3H, t, J=7.03 Hz). LC-MS retention time: 1.46 min; m/z (MH+): 433. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](I)[CH3:10]>>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1
Reactant: CCI
Product: CCOc1cccc(F)c1

Procedure:
3-fluoro-phenol and ethyl iodide were reacted to form 3-fluoro-ethoxy benzene with a refractive index of nD25 =1.4823 which was reacted with nitric acid to obtain 2-ethoxy-4-fluoronitro benzene with a melting point of 28°~30° C. which was reacted to obtain 0-(4-nitro-3-ethoxy-phenyl)-hydroxylamine melting at 97°~98° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]([C:13]1[C:21]2[CH:20]=[CH:19][S:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)=[O:12].B(OC(C)C)(OC(C)C)OC(C)C.C([O-])([O-])=O.[Na+].[Na+].[Cl:41][C:42]1[N:47]=[C:46](Cl)[CH:45]=[CH:44][N:43]=1>C1COCC1.ClCCl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][O:10][C:11]([C:13]1[C:21]2[CH:20]=[C:19]([C:44]3[CH:45]=[CH:46][N:47]=[C:42]([Cl:41])[N:43]=3)[S:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: Clc1ccnc(Cl)n1
Reactant: COC(=O)c1cccc2sccc12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cccc2sc(-c3ccnc(Cl)n3)cc12
Reaction time: 1 h
Yield: 50.5 %

Procedure:
Lithium diisopropylamide (5.70 mL, 2 M in THF) is added dropwise to a stirred solution of benzo[b]thiophene-4-carboxylic acid methyl ester (2.00 g, 10.4 mmol) and triisopropyl borate (2.63 mL, 11.4 mmol) in anhydrous THF (20 mL) at −78° C. under nitrogen. Upon the completion of the addition, the mixture is allowed to warm slowly over 1 hour to ambient temperature where it is stirred for another 1 hour. Aqueous Na2CO3 solution (2 M, 15.6 mL) is added to the mixture, followed by the addition of 1,1′-bis(diphenylphosphino)ferrocene (318 mg, 0.570 mmol), palladium(II) acetate (129 mg, 0.570 mmol) and 2,4-dichloropyrimidine (1.46 g, 10.4 mmol). The reaction mixture is heated to reflux for 16 hours. At ambient temperature THF is evaporated off, the aqueous layer is extracted with CHCl3 (100 mL×2) and the combined layers are concentrated to give a dark solid. The solid is dissolved in dichloromethane and purified by chromatography on silica gel, eluting with dichloromethane in hexanes 50-100%, to give the title compound as a yellowish solid (1.60 g, 51% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=[C:3]1[SH:19].Cl[CH2:21][C:22](=[O:24])[CH3:23].C(N(CC)CC)C.CO>CC(C)=O.C(OCC)(=O)C.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:4]=[C:3]1[S:19][CH2:21][C:22](=[O:24])[CH3:23]
Reactant: CC(=O)CCl
Reactant: Cn1c(S)nc(-c2ccccc2)c1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)CSc1nc(-c2ccccc2)c(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 1-methyl-4,5-diphenylimidazol-2-thiol (0.618 g, 0.00255 mol) was dissolved in 150 milliliters of acetone and to it was added with stirring 0.236 gram (0.00255 mol) of chloroacetone and 0.258 g (0.00255 mol) of triethylamine. The mixture was stirred overnight at room temperature. Since the reaction was not complete as determined by TLC, 0.25 gram of chloroacetone and 0.26 gram of triethylamine was added and the mixture refluxed for one hour. The mixture was then allowed to cool and evaporated in vacuo to obtain a residue. The latter was dissolved in ethyl acetate, the ethyl acetate solution was washed with water, 5% sodium hydroxide and brine, the washed solution was dried (MgSO4), and the dried solution evaporated in vacuo to obtain a still impure product. The latter was put over a silica gel column and developed with 1 percent methanol in methylene chloride to recover from the eluate after evaporating off the solvent, 0.561 gram of 1-methyl-4,5-diphenyl-2[(2-oxo-propyl)thio]imidazole. The product after recrystallization from isopropyl alcohol-hexane had a melting point of 179°-182° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1cccc(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1F
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(C)c3F)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 71.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-3-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (35 mg, 0.074 mmol) obtained in step 2 and ethanesulfonamide (33 mg, 0.30 mmol), the title compound (30 mg, 73%) was obtained.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[O:28].O>C(OCC)C>[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]([C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:28]
Reactant: O=Cc1cccc(Br)c1
Reactant: COCOc1cccnc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: COCOc1cccnc1C(O)c1cccc(Br)c1
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-3-methoxymethoxypyridine (9.11 g) in diethyl ether (200 mL) was added, at -78° C., a 1.6M n-butyl lithium hexane solution (29 mL). The mixture was stirred for one hour at the same temperature, to which was further added a solution of 3-bromobenzaldehyde (6.0 mL) in diethyl ether (5 mL), and the mixture was stirred for one hour at the same temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract was washed with a saturated aqueous saline solution, which was then dried (sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromo-α-hydroxybenzyl)-3-methoxymethoxypyridine (10.89 g) (compound A-1). Physical properties and spectrum data of the product are shown in Table 1 and Table 2. In substantially the same manner as above, compounds A-2 to A-4, and A-6 to A-7 shown in Table 1 were produced.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][CH:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8](O)=[O:9].B.C1COCC1.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][CH2:8][OH:9])[CH:11]=[CH:12][CH:13]=1
Reactant: COC1=CC=CC(C=CC(=O)O)C1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc(CCCO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
A solution of dihydro-m-methoxycinnamic acid (90 g, 0.5 mole) and tetrahydrofuran (250 mL) was stirred under N2 at 0° as BH3.THF (1M solution, 525 mL) was added slowly. The reaction mixture was stirred at room temperature for 2 hours. After cooling to -5° C., 1N HCl was added. THF was evaporated and water was added to the residue. The aqueous layer was extracted with ether. The combined extracts were washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (MgSO4), filtered and evaporated to yield 70.0 g white solid, M+ 166.
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[N:20][CH:21]=1.C1C[O:26][CH2:25]C1>>[Br:15][C:16]1[CH:17]=[C:18]([CH:25]=[O:26])[C:19]([F:22])=[N:20][CH:21]=1
Reactant: C1CCOC1
Reactant: Fc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a stirred solution of DIPEA (44.1 mL, 312 mmol) in dry THF (500 mL) at −78° C. was added dropwise n-BuLi (2.5M in hexanes, 125 mL, 313 mmol). The temperature was warmed to rt and stirred for 10 minutes. The solution was cooled to −78° C. and a solution of 5-bromo-2-fluoro-pyridine (1) (50.0 g, 284 mmol) in THF (500 mL) added dropwise. The reaction mixture was stirred at −78° C. for 45 minutes then quenched with 10% citric acid in THF (250 mL) at −78° C. The solution was warmed to rt then diluted with H2O (250 mL). The solution was extracted with EtOAc (3×250 mL) and the combined organics washed with saturated brine solution (250 mL), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by column chromatography (100-200 mesh silica gel, 20% EtOAc-pet ether) to provide the title compound as a white solid (36.0 g, 62%); Rf: 0.7 (10% EtOAc-pet ether).
Reaction SMILES: C([O:4][CH2:5][C:6]#[C:7][CH2:8][N:9]1[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[C:12](=[O:22])[N:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C:10]1=[O:31])(=O)C>C(O)C.Cl>[Cl:30][C:25]1[CH:24]=[C:23]([N:11]2[C:12](=[O:22])[C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)([CH3:14])[N:9]([CH2:8][C:7]#[C:6][CH2:5][OH:4])[C:10]2=[O:31])[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: CC(=O)OCC#CCN1C(=O)N(c2ccc(Cl)c(Cl)c2)C(=O)C1(C)c1ccc(O)cc1
Agent: Cl
Solvent: CCO
Product: CC1(c2ccc(O)cc2)C(=O)N(c2ccc(Cl)c(Cl)c2)C(=O)N1CC#CCO
Yield: 88 %

Procedure:
500 mg 4-[1-(3,4-dichlorophenyl)-2,5-dioxo-4-(4-hydroxyphenyl)-4-methylimidazolidin-3-yl]-2-butynyl acetate (the product of Example 223) are dissolved in 10 mL of a 2 N ethanol/HCl mixture (70/30). The mixture is stirred under reflux for 3 hours then concentrated and dried under vacuum. 400 mg of a white solid are obtained (Yd=99%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:16]([NH:17][C:18](=O)[CH2:19][CH:20]([CH3:22])[CH3:21])=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[C:9](=[O:10])[C:11]2[C:16](=[N:15][CH:14]=[CH:13][N:12]=2)[N:17]=[C:18]1[CH2:19][CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(=O)Nc1nccnc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cc1nc2nccnc2c(=O)n1Cc1ccccc1
Yield: 33.5 %

Procedure:
Formula 104 where R2 and R3 are H; R5 is Benzyl; R6 is Isopropyl; R6′ is H; X and Y are —C═; and W and Z are —N═: A solution of DMF (100 mL), 3-(3-methyl-butyrylamino)-pyrazine-2-carboxylic acid benzylamide (3.0 g, 9.60 mmol) and sodium carbonate (1.30 g, 12.3 mmol) was stirred at 120° C. overnight. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography using hexane-EtOAc (2:1) as eluent to obtain the desired pyrazopyrimidinone product of Formula 104, 3-benzyl-2-isobutyl-3H-pteridin-4-one (0.948 g, 33.0%). MS (Cl) M/E: 295.1.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:8]([CH:20]=1)[C:9]([O:11]CC1C=CC(F)=CC=1)=[O:10]>O.O1CCCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[C:8]([CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccc(F)cc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1
Reaction time: 8 h

Procedure:
Lithium hydroxide (0.43 g, 18.14 mmol) was added to a solution of (4-fluorophenyl)methyl 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoate (may be prepared as described in Description 86) (2.62 g, 6.05 mmol) in water (5 ml) and tetrahydrofuran (20 ml). The mixture was stirred overnight and the solvent removed in vacuo. The residue was redissolved in water (30 ml) and acidified to pH=2 using 1N HCl and then extracted with ethyl acetate (3×25 ml). The combined organic layers were dried (MgSO4) and the solvent removed in vacuo to yield the titled compound as a white solid. 1.97 g.