Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)(O)[C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[CH:17]=3)[N:12]([CH3:34])[C:11](=[O:35])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:38])=O>>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([Cl:38])([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[CH:17]=3)[N:12]([CH3:34])[C:11](=[O:35])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: O=S(Cl)Cl
Agent: Cl
Product: Cn1cncc1C(Cl)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 22 °C
Reaction time: 0.25 h

Procedure:
A 1 liter reaction vessel was charged with 105.4 g of 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone hydrochloric acid salt (compound (III) and 400 ml of N,N-dimethylimidazolidinone added at 22° C. The mixture was stirred vigorously for 15 minutes at 22° C. and became homogeneous. 32.1 ml of thionyl chloride was added over 10 minutes to the reaction mixture, the reaction temperature rising from 22° C. to 40° C. After addition of the thionyl chloride, the reaction mixture was cooled from 40° C. to 22° C. and stirred for three hours at the latter temperature to provide a solution of 4-(3-chlorophenyl)-6-[chloro-(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone (compound (IV).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[CH:4][N:3]=1.O.[NH2:18][NH2:19]>>[NH:18]([C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[CH:4][N:3]=1)[NH2:19]
Reactant: COc1ccc(F)c(-c2cnc(Cl)cn2)c1
Reactant: NN
Solvent: O
Product: COc1ccc(F)c(-c2cnc(NN)cn2)c1

Procedure:
An ethanolic solution of 2-chloro-5-(2-fluoro-5-methoxyphenyl) pyrazine and hydrazine monohydrate (10 equiv.) was refluxed under a N2 atmosphere for 6 h. The ethanol was removed under reduced pressure and the residue was partitioned between 5% HCl and CH2Cl2. The CH2Cl2 layer was extracted several times with 5% HCl and the combined aqueous portions were washed (1×) with CH2Cl2. The aqueous solution was made basic with 10N NaOH and then extracted (4×) with CH2Cl2. The combined CH2Cl2 portions were washed (1×) with brine, dried (Na2SO4), treated with decolorizing charcoal and filtered through celite. Evaporation of the solvent under reduced pressure yielded 2-hydrazino-5-(2-fluoro-5-methoxyphenyl)-pyrazine as a beige oil. ##STR38##
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>ClCCl>[C:24]([O:23][C:21]([N:15]1[CH2:20][CH2:19][N:18]([S:2]([C:5]2[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:17][CH2:16]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(F)c(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
5-Chlorosulfonyl-2-fluorobenzoic acid (2 g) was dissolved in dichloromethane (20 mL) under nitrogen atmosphere and cooled to 0° C. tert-Butyl 1-piperazinecarboxylate (3.12 g) was added portionwise to the solution at 0° C. and stirred for 3 hours at ambient temperature. The organic solvent was evaporated in vacuo, and the residue was dissolved in 1N-sodium hydroxide solution. The aqueous solution was washed with diethyl ether and acidified with 1N-hydrochloric acid. The precipitates were collected by filtration and washed with water to give 5-[4-(tert-butoxycarbonyl)piperazin-1-ylsulfonyl]-2-fluorobenzoic acid (2.26 g) as a colorless solid substance.
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.NC1[C:19]([Br:20])=[CH:18][NH:17][N:16]=1>C(O)(=O)C>[Br:20][C:19]1[CH:18]=[N:17][N:16]2[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:13]=12
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: Nc1n[nH]cc1Br
Solvent: CC(=O)O
Product: Brc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one and 0.01 mole of 3-amino-4-bromopyrazole in glacial acetic acid is heated at reflux temperature for 8 hours. The solvent is removed to give the product of the example, m.p. 243°-244° C.
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[C:4]([OH:24])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH:7]=1)[CH3:5].C(=O)(O)[O-].[Na+].[CH3:32][C:33]([CH3:35])=[O:34]>S(=O)(=O)(O)O>[CH3:32][C:33]1([CH3:35])[O:24][C:4]([CH3:5])([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)[CH:7]=2)[CH:3]([O:2][CH3:1])[O:34]1
Reactant: CC(C)=O
Reactant: COC(OC)C(C)(O)c1cccc(OCc2ccc3ccccc3c2)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC1OC(C)(C)OC1(C)c1cccc(OCc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
Concentrated sulphuric acid (5 drops) was added to a solution of 2-hydroxy-2-[3-(naphth-2-ylmethoxy)phenyl]propionaldehyde dimethyl acetal (1.5 g) in acetone (30 ml) and the mixture was stirred at ambient temperature for 5 hours. A saturated aqueous sodium bicarbonate solution (30 ml) was added and the bulk of the acetone was evaporated. The residue was partitioned between diethyl ether and water. The organic phase was washed with water and with a saturated sodium chloride solution, dried (MgSO4) and evaporated. The residue, comprising a mixture of diastereoisomers, was purified by column chromatography using increasingly polar mixtures of petroleum ether (b.p. 40°-60° C.) and methylene chloride as eluent. There was thus obtained the less polar diastereoisomer, (4SR,5RS)-2,2,4-trimethyl-5-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]-1,3-dioxolane (0.39 g, 31%), m.p. 100°-103° C.; the 4-methyl and 5-methoxy groups being in a cis-relationship.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O=S(Cl)Cl.Cl.[CH3:20][NH:21][O:22][CH3:23].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:21]([O:22][CH3:23])[CH3:20])=[O:5]
Reactant: CNOC
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
1.04 g (5 mmol) of 2-fluoro-3-(trifluoromethyl)benzoic acid (compound of formula (III)) 3 ml of SOCl2 were dissolved and the mixture was refluxed for 2 hrs. Remaining SOCl2 was removed in vacuo and the residue (crude acid chloride derivative) was dissolved in 5 ml of CH2Cl2. N,O-Dimethyhydroxylamine hydrochloride (585 mg, 6 mmol) in 8 ml of CH2Cl2 was added followed by 0.5 ml of pyridine. The reaction mixture was stirred for 1.5 hrs., quenched with aq. NH4Cl solution and the product was extracted twice with CH2Cl2, and the combined organic phases were washed with brine and dried over sodium sulfate. Evaporation of solvents in vacuo gave 1.02 g of product as an oil which was pure enough to be used in the next step without further purification.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28](Br)[CH:29]=2)(=[O:23])=[O:22])[CH:11]=1)C)(C)(C)C.[CH3:32][N:33](C)C=O.C(OCC)(=O)C.[ClH:43]>C(O)C.[C-]#N.[Zn+2].[C-]#N>[ClH:43].[CH3:6][NH:7][CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:29]=2)[C:32]#[N:33])(=[O:22])=[O:23])[CH:11]=1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(Br)c2)c1)C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(C#N)c2)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 42 %

Procedure:
A mixture of tert-butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate (112 mg), zinc cyanide (50 mg) and N,N-dimethylformamide (4 mL) was degassed with argon gas. Tetrakis(triphenylphosphine)palladium (46 mg) was added, and the mixture was stirred at 100° C. for 1.5 hr. After cooling the reaction mixture to room temperature, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→3:2) to give a colorless oil. The obtained oil was dissolved in ethanol (2 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 1 hr, the mixture was concentrated under reduced pressure, and recrystallized from ethanol to give the title compound as a solid (yield 32.7 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[CH:10]([C:18]2[S:22][C:21]([C:23]([O:25]CC)=[O:24])=[CH:20][CH:19]=2)[N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[CH:10]([C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)[N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C(C(=O)Nc2ccc(Cl)cc2)N2CCN(C)CC2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1CCN(C(C(=O)Nc2ccc(Cl)cc2)c2ccc(C(=O)O)s2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 5-[2-[(4-chlorophenyl)amino]-1-(4-methylpiperazin-1-yl)-2-oxoethyl]thiophene-2-carboxylate (0.56 g, 1.33 mmol) was made 0.5 M in dioxane and to this stirring solution was added 3 equivalents 3M LiOH (1.33 mL, 3.98 mmol). The resulting mixture was stirred at ambient temperature for 3 hours. The mixture was adjusted to pH 6 with 1 M HCl then concentrated in vacuo to give the desired product. MS: cal'd 394, 396 (MH+), exp 394, 396 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][CH:3]=1.[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>C(Cl)Cl>[OH:22][CH:21]([CH2:23][N:34]1[CH2:33][CH2:32][N:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[OH:24])[CH2:36][CH2:35]1)[CH2:20][N:10]1[C:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][C:12]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[N:9]1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(I)cc3)nn2CC2CO2)C1
Reactant: Oc1ccccc1N1CCNCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3ccc(I)cc3)nn2CC(O)CN2CCN(c3ccccc3O)CC2)C1
Reaction time: 72 h

Procedure:
1-[3-(4-Iodo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (62 mg, 0.15 mmol) and 4-(2-hydroxyphenyl)-piperazine (34 mg, 0.19 mmol) were combined in CH2Cl2 (0.5 mL) and the solution treated with Yb(OTf)3.H2O (44 mg, 0.071 mmol). The mixture was shaken for 72 h then diluted with CH2Cl2 (1 mL). Purification by preparative TLC (silica, 10% MeOH/CH2Cl2) grave 45 mg (51%) of an off-white powder. TLC (silica, 8% MeOH/CH2Cl2): Rf=0.2. MS (electrospray): m/z calculated for C27H33IN5O3 [M+H]+ 602.15, found 602.2. 1H NMR (CDCl3, 500 MHz, a mixture of amide rotamers): 7.76 (d, J=8.6 Hz,1H), 7.72 (d, J=8.6 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.14 (m, 1H), 7.80 (t, J=7.7 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.86 (t, J=7.7 Hz, 1H), 4.83 and 4.72 (A and B of AB quartet, Jab=15.6 Hz, 1H), 4.61 (s, 1H), 4.22-4.15 (m, 2H), 4.02 (m, 2H), 3.88 (m, 1H), 3.76 (m, 3H), 3.00-2.49 (m, 11H), 2.20 (s, 1.5H), 2.15 (s, 1.5H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:26])[C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][CH:13]=1.C(O)(C)C>[H][H].[C].[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:26])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: COc1ccc(CCNCC(O)c2ccc(OCc3ccccc3)cc2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(CCNCC(O)c2ccc(O)cc2)cc1OC
Yield: 85 %

Procedure:
A mixture of 0.62 g of α-(3,4-dimethoxyphenethylaminomethyl)-4-benzyloxybenzylalcohol hydrochloride, 0.2 g of 10% palladium-carbon and 200 ml of isopropanol is shaken at room temperature in hydrogen gas under atmospheric pressure. After hydrogen uptake is completed, the mixture is filtered to remove the catalyst. Then, the filtrate is concentrated to dryness, and the residue obtained is recrystallized from a mixture of isopropanol and isopropylether. 0.42 g of α-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzylalcohol hydrochloride is thereby obtained. M.p. 164° - 167° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:10]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=1[Cl:23].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:23][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:10]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:7][CH:2]=1
Reactant: Cc1ccc(Nc2cnc(Br)c(Cl)c2)c(C(=O)OC(C)(C)C)c1
Reactant: OB(O)c1ccccc1
Product: Cc1ccc(Nc2cc(Cl)cnc2-c2ccccc2)c(C(=O)OC(C)(C)C)c1

Procedure:
Obtained (0.008 g, 3% of yield) following the procedure described in Example 8 (step A) starting with Intermediate 20B (0.58 mmol, 0.230 g) and phenylboronic acid (0.87 mmol, 0.106 g).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[O:3]1.[H-].[Na+].I[CH2:24][C:25]#[N:26]>CN(C=O)C>[C:25]([CH2:24][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]2[CH:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)#[N:26]
Reactant: N#CCI
Reactant: Cc1cc(O)cc2c1C(CC(=O)OC(C)(C)C)OB2O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC#N)cc2c1C(CC(=O)OC(C)(C)C)OB2O
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a solution of tert-butyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (500 mg, 1.80 mmol) in DMF (10 mL) was added 60% NaH (215.8 mg, 5.40 mmol) in DMF (5 mL) at 0° C. The reaction mixture was stirred for 30 min, followed by addition of 2-iodoacetonitrile (450.5 mg, 2.70 mmol). The reaction mixture was stirred for an additional 5 h at room temperature, quenched by water (15 mL) at 0° C., and acidified by 1N HCl to pH=7. The resulting mixture was extracted by EtOAc (3×10 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by prep HPLC to give the title compound as a white solid (120 mg, yield: 21%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1.[CH3:21][S-:22].[Na+]>CN(C=O)C>[I:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:12][C:4]1[N:3]=[C:2]([S:22][CH3:21])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH3:11]
Reactant: C[S-]
Reactant: Cn1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(NCc2cccc(I)c2)c2ncn(C)c2n1
Temperature: 110 °C
Yield: 51.8 %

Procedure:
A mixture of compound 6 (24.4 mg, 0.061 mmol) and sodium thiomethoxide (8 mg, 0.1 mmol) in DMF (1.5 mL) was heated for 22 h at 110° C. After cooling, the reaction mixture was concentrated to dryness and the residue was purified by a silica gel column chromatography (chloroform-methanol, 20:1) to give compound 16 (13 mg, 52.0%) as a colorless solid. 1H NMR (DMSO-d6) δ 3.06 (s, 6 H, N(CH3)2), 3.56 (s, 3 H, CH3), 4.58 (br s, 2 H, CH2), 7.10 (pseudo t, J=7.9 and 7.6 Hz, 1 H, H-16), 7.38 (d, J=7.6 Hz, 1 H, H-17), 7.56 (d, J=7.9 Hz, 1 H, H-15), 7.76 (s, 1 H, H-13), 7.69 (s, 1 H, H-8), 7.90 (br s, 1 H, exchangeable with D2O, NH).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Br[CH2:10][C:11]#[N:12].[Cl-].[NH4+]>O1CCCC1>[F:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]#[N:12])[CH:8]=1
Reactant: Fc1cn[nH]c1
Reactant: N#CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#CCn1cc(F)cn1
Temperature: 0 °C
Reaction time: 12 h
Yield: 68.8 %

Procedure:
Sodium hydride (306 mg, 12.78 mmol, 60% oil dispersion) was suspended in tetrahydrofuran and the suspension was cooled to 0° C. A solution of 4-fluoro-1H-pyrazole (1.0 g, 11.62 mmol) and 2-bromoacetonitrile (1.39 g, 11.62 mmol) in tetrahydrofuran at 0° C. was added dropwise over a period of 40 min. The reaction mixture was stirred at room temperature for 12 h, and then a saturated aqueous solution of ammonium chloride was added. The mixture was extracted with diethyl ether, and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 5-10% ethyl acetate in petroleum ether) to afford 2-(4-fluoro-1H-pyrazol-1-yl)acetonitrile (1 g).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]1[CH:12]=[C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=[CH:15][C:16]=1[C:17]1[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=1.O>C1COCC1.CCCCCC>[F:10][C:11]1[CH:12]=[C:13]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:14]=[CH:15][C:16]=1[C:17]1[C:18]2=[N:23][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:19]2[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ncccc1-c1ccc(-c2ccccc2)cc1F
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3F)C2=N1
Yield: 79.1 %

Procedure:
To a suspension of 60% sodium hydride (0.76 g) in THF (20 mL) was added 2-chloroethanesulfonyl chloride (1.85 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 5 min, and a solution of 3-(3-fluorobiphenyl-4-yl)pyridin-2-amine (1.0 g) in THF (20 mL) was added. The reaction mixture was stirred at room temperature overnight, and water and hexane were added under ice-cooling. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give the title compound (1.06 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[Mg].CN([CH:15]=[O:16])C.Cl>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:9])[C:7]=1[F:8])[CH:15]=[O:16]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Mg]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)c(F)c(F)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
In a nitrogen atmosphere, a solution prepared by dissolving 50 g of 3,4,5-trifluorobromobenzene in 50 mL of THF was added dropwise at a rate that caused gentle reflux to a mixed solution of 6.34 g of magnesium and 60 mL of THF. After dropwise addition, the mixture was stirred at 40° C. for 1 hour. Then, a solution prepared by dissolving 34.64 g of DMF in 60 mL of THF was added dropwise under ice cooling at such a rate that the inside temperature did not exceed 20° C., followed by stirring at room temperature for 1 hour. Then, 10% hydrochloric acid was added until the reaction system became acidic, and the mixture was stirred at room temperature for 1 hour. Then, hexane was added to the mixture to separate an organic layer, and an aqueous layer was subjected to extraction with hexane. The hexane extract was combined with the organic layer and washed with a saturated aqueous sodium bicarbonate solution and saturated brine. The resultant mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure to yield 37.91 g of 3,4,5-trifluorobenzaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:26]([OH:28])=O)=[N:11][N:12]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC.[F:50][C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:26]([NH:56][CH2:55][C:54]2[CH:57]=[CH:58][C:51]([F:50])=[CH:52][CH:53]=2)=[O:28])=[N:11][N:12]2[CH:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CC(c2ccccc2)n2nc(C(=O)O)c(OCc3ccccc3)c2C1=O
Reactant: NCc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CC(c2ccccc2)n2nc(C(=O)NCc3ccc(F)cc3)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-5-methyl-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (20 mg, 0.053 mmol) in anhydrous DMF were added HOBT (11 mg, 0.079 mmol), EDC (15 mg, 0.079 mmol), Et3N (7 μL, 0.053 mmol), and 4-fluorobenzylamine (7 μL, 0.064 mmol). The reaction mixture was stirred at room temperature for 1 hour. Purification was achieved by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions yielded the title product as a white solid. ES MS (M+1)=485.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:32])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:21]4)=[CH:14][CH:13]=3)=[C:9]([C:33]3[CH:38]=[CH:37][C:36]([O:39]C)=[CH:35][CH:34]=3)[S:8][C:7]=2[CH:41]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:32])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:21]4)=[CH:16][CH:17]=3)=[C:9]([C:33]3[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=3)[S:8][C:7]=2[CH:41]=1
Reactant: CCCCCCN1CCCC(COc2ccc(C(=O)c3c(-c4ccc(OC)cc4)sc4cc(OC)ccc34)cc2)C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CCCCCCN1CCCC(COc2ccc(C(=O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)C1
Yield: 19 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-[(1-hexylpiperidin-3-yl)methoxy]benzoyl)benzo[b]thiophene (1.24 g, 2.17 mmol), ethane thiol (10.8 mmol), and aluminum chloride (1.73 g, 13.0 mmol) were converted to 224 mg (19%) of the title compound by the procedure of Example 16. MS(FD) 544(M+). EA calculated for C33H37NO4S: C, 72.90; H, 6.86; N, 2.58. Found: C, 73.14; H, 7.04; N, 2.52.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([CH:18]([OH:20])C)[N:7]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[Br:9].I[CH3:22]>C1COCC1>[Br:3][C:4]1[N:5]=[C:6]([CH2:18][O:20][CH3:22])[N:7]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[Br:9]
Reactant: CI
Reactant: CC(O)c1nc(Br)c(Br)n1COCC[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1nc(Br)c(Br)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
NaH (0.016 g of a 60% dispersion in mineral oil, 0.41 mmol) was added to a 0° C. solution of [4,5-dibromo-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-2-yl]ethanol (0.15 g, 0.39 mmol) in THF (2 mL). The solution was stirred at RT for 30 mins, recooled to 0° C. and iodomethane was added (0.052 mL, 0.78 mmol). After 2 h at RT, the reaction mixture was quenched by addition of sat'd NaHCO3 and extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-30% EtOAc/hex) to afford the title compound (0.084 g, 54%) as clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.39 (s, 2H), 4.55 (s, 2H), 3.57 (t, J=8.19 Hz, 2H), 3.35 (s, 3H), 0.91 (t, J=8.15 Hz, 2H), −0.01 (s, 9H).