Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:4][N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:24][CH2:23]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[C:2]([NH:21][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)[CH2:26][CH2:27]3)=[N:3][N:4]=2)=[CH:15][CH:16]=1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: COc1ccc2c(-c3ccc(Cl)cc3)nnc(Cl)c2c1
Product: COc1ccc2c(-c3ccc(Cl)cc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-(4-chlorophenyl)-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [C:1]([NH:5][C@@H:6]1[C@H:10]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]4[C:27]([Cl:28])=[C:26]([O:29][CH3:30])[CH:25]=[C:24]([O:31][CH3:32])[C:23]=4[Cl:33])[CH:18]=3)[N:13]=2)[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)(=[O:4])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:27]1[C:26]([O:29][CH3:30])=[CH:25][C:24]([O:31][CH3:32])=[C:23]([Cl:33])[C:22]=1[C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([NH:11][C@@H:10]1[CH2:9][NH:8][CH2:7][C@@H:6]1[NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[N:21]=[CH:20]2
Reactant: C=CC(=O)N[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1CNC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1

Procedure:
A solution of tert-butyl (3S,4R)-3-acrylamido-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidine-1-carboxylate (1.26 g, 2.14 mmol) in DCM (8 mL) and TFA (3 mL, 39 mmol) was stirred 3 h at room temperature. The excess solvents were removed under reduced pressure. The yellow oil was dissolved into DCM (˜100 mL) and washed with aqueous saturated sodium bicarbonate solution (˜50 mL). The aqueous layer was then extracted with fresh DCM (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated down, and dried to yield N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidin-3-yl)acrylamide which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[Cl:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Cl:12][C:13]1[C:14]([F:21])=[C:15](/[CH:16]=[C:4](/[C:3]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=2[Cl:1])\[C:5]#[N:6])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1Cl
Yield: 67 %

Procedure:
In a manner similar to the method described in Example 1b, 2,4-dichlorobenzyl cyanide (6 g, 32 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (6 g, 38 mmol), methanolic solution (25 wt %) of sodium methoxide (30 mL, 131 mmol) in methanol (200 mL) at 50° C. for 3 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(2,4-dichloro-phenyl)-acrylonitrile as a white powder (7 g, 67%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][OH:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CO.C(Cl)(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][O:20][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][S:11][CH2:12][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1OC(CO)CN1c1ccc(N2CCSCC2)c(F)c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CN(c3ccc(N4CCSCC4)c(F)c3)C(=O)O2)cc1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
The [3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methanol (1.465 g, 4.69 mmol) was dissolved in pyridine (15 mL) and then cooled to 0° C. (ice bath). This solution was next treated with p-toluenesulfonyl chloride (1.34 g, 7.035 mmol) and allowed to stir at 0° C. under N2 for 7 hours. At this point, the reaction was stoppered and stored in the freezer overnight (16 hours). In the morning, the reaction showed only a trace of starting material by TLC (5% MeOH/CHCl3, UV short wave). The product was precipitated by quenching the reaction mixture with ice water (100 mL). The solid was isolated by suction filtration and washed thoroughly with water. The title compound, 2.02 g (92%), was recovered as a white solid with a melting point of 141° C. and a HRMS (M+) calculated for C21H23N2O5FS2 466.1032, found 466.1036.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=1)=[O:9]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)c1cncc(Br)c1
Product: CC(C)c1ccc(NC(=O)c2cncc(Br)c2)cc1

Procedure:
The intended compound was produced according to the method of Example 92 but using 5-bromonicotinic acid and 4-isopropylaniline as the starting materials.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[NH:16])SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21]N1>CC(O)C>[NH2:1][C:2]1[C:3]([C:10]([N:12]=[C:13]2[N:16]3[CH2:21][CH2:22][CH2:23][CH:19]3[CH2:18][NH:17]2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NC[C@@H]1CCCN1
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)N=C2NCC3CCCN23)nc1Cl
Temperature: 60 °C

Procedure:
1-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (195 mg, 0.5 mmol) is suspended in propan-2-ol (10 ml) and (S)-2-(aminomethyl)pyrrolidine (100 mg, 1 mmol) is added. The mixture is heated at 60° C. for 18 hours, allowed to cool to room temperature and the precipitate is removed by filtration. The filtrate is concentrated in vacuo and the residue purified by chromatography (SiO2, DCM/MeOH) to afford the title compound as a light, yellow gum; [M+H]+ 296
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC(=O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C:26](=[O:25])[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: O=C1CCNC1
Product: CC(C)(C)c1nc(N2CCC(=O)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and pyrrolidin-3-one. MS(m/e): 385.3 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:14]N1C(=O)CCC1=O>C(OC)(C)(C)C.C(#N)C.CCCCCC>[Br:14][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(F)c1C1CCCO1
Solvent: CCCCCC
Solvent: COC(C)(C)C
Solvent: CC#N
Product: Nc1ccc(Br)c(F)c1C1CCCO1
Reaction time: 0.5 h
Yield: 105 %

Procedure:
To a stirring solution of 3-fluoro-2-tetrahydrofuran-2-yl-aniline (16) (131.9 g, 92%, 669.7 mmol) in methyl tert-butyl ether (1.456 L) and acetonitrile (485 mL) cooled to −20° C. was added N-bromosuccinimide (120.4 g, 99%, 669.7 mmol, Aldrich B81255) in 3 portions maintaining a reaction temperature below about −15° C. After complete addition, stirring was continued at −15 to −10° C. for 30 minutes. 1H NMR of a worked-up aliquot showed 96% consumption of starting aniline. Another 4.82 g NBS was added to the reaction mixture and stirred at −10° C. for additional 30 minutes. Aqueous 1 N Na2S2O3 (670 mL) was added to the reaction mixture. The cold bath was removed, the mixture stirred for 20 minutes, then diluted with EtOAc. The layers were separated. The organic phase was washed with saturated aqueous NaHCO3 (2×), water, and brine, dried over Na2SO4, decanted, and concentrated under reduced pressure giving a dark amber oil. The residue was diluted with hexane and eluted through a short plug of silica with 25% EtOAc/hexane to 50% EtOAc/hexane. The desired filtrate was concentrated in vacuo giving 17 as dark amber oil (182.9 g, 90% yield; 86% NMR purity). LCMS (C18 column eluting with 10-90% AcN/water gradient over 5 minutes with formic acid modifier) M+1: 260.12 (3.20 min). 1H NMR (300 MHz, CDCl3) δ 7.15 (dd, J=8.6, 7.6 Hz, 1H), 6.30 (dd, J=8.7, 1.3 Hz, 1H), 5.19-5.12 (m, 1H), 4.58 (s, 2H), 4.16-4.07 (m, 1H), 3.90-3.81 (m, 1H), 2.23-1.99 (m, 4H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:28]([O:30]C)=[O:29])[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:6](/[N:14]=[N:15]/[N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:7]=1[C:8]#[C:9][Si](C)(C)C.[OH-].[Na+].O.Cl>O1CCCC1.CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:28]([OH:30])=[O:29])[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:6](/[N:14]=[N:15]/[N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:7]=1[C:8]#[CH:9]
Reactant: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c(/N=N/N2CCCC2)c1-c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1c(Cl)cc(C(=O)O)c(-c2cccc(F)c2)c1/N=N/N1CCCC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A solution of methyl 4-chloro-3′-fluoro-6-[(E)-pyrrolidin-1-yldiazenyl]-5-[(trimethylsilyl)ethynyl]biphenyl-2-carboxylate (1.0 kg, 2.2 mol) in tetrahydrofuran (3 L) and methanol (0.86 L) was treated with 2.0 M sodium hydroxide in water (3.4 L, 6.7 mol) and heated to 60° C. in 30 minutes and kept at an internal temperature of 60-63° C. for 90 minutes. The reaction mixture was cooled to 1 to 5° C. with an ice bath, treated with 3.0 M hydrogen chloride in water (2.8 L, 8.3 mol) in portions (temperature reached 16° C.) until the pH reached 1-2. The reaction mixture was diluted with ethyl acetate (2 L) and stirred for 20 minutes. The aqueous layer was separated and extracted with ethyl acetate (1 L). The combined organic layers were washed with water (2×3 L) and brine (300 mL), dried over sodium sulfate, filtered, and concentrated to give the desired product as an oil. This material was azeotroped with toluene (1 L) to give the desired product (theoretical yield 830 g) as a dark syrup. This material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19](Br)[C:18]=2[CH3:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:26][C:27]([CH3:32])=[CH:28]B(O)O>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:26]=[C:27]([CH3:32])[CH3:28])[C:18]=2[CH3:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)=CB(O)O
Reactant: CCOC(=O)C1(NC(=O)c2cccc(Br)c2C)Cc2ccccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C=C(C)C)c2C)Cc2ccccc2C1
Temperature: 110 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A suspension of 2-(3-bromo-2-methylbenzoylamino)indan-2-carboxylic acid ethyl ester (293) (402 mg-1 mmol) and 2-methyl-1-propenylboronic acid (200 mg, 2 mmol, 2 eq) in dry DMF (20 mL) and saturated NaHCO3 (5 mL) is degassed for 10 min and then treated with tetrakis(triphenylphosphine)palladium(0) (400 mg). The mixture is stirred at 110° C. for 5 h. The reaction is cooled and the DMF removed in vacuo and the residue diluted with water (80 mL). The aqueous is filtered through celite and extracted with EtOAc (3×50 mL). The organic extracts are washed with water (2×30 mL) and brine (2×30 mL), and dried over MgSO4. The organic phase is then concentrated in vacuo and purified by flash chromatography (120 g silica gel, 30% EtOAc in heptane) to give pale yellow oil (350 mg, 92%).
Reaction SMILES: Cl.Cl.[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:29]1(=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>ClCCCl.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][N:26]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(C3CCCCC3)C2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.3 %

Procedure:
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate dihydrochloride (256 mg) and cyclohexanone (64 mg) in 1,2-dichloroethane (5 mL) was added sodium triacetoxyborohydride (253 mg) and N,N-diisopropylethylamine (0.21 mL), and the mixture was stirred at room temperature for 2 hours. To the resultant was added saturated aqueous ammonium chloride and ethyl acetate, and the mixture was stirred for 20 min. The organic phase was separated, washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol=95/5 v/v) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (338 mg) as a pale yellow foam.
Reaction SMILES: CN(C)C.CN(C=O)C.Cl/[CH:11]=[C:12]1/[C:13](=[N:22]/[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)/[S:14][CH:15]2[CH:20]([CH2:21]/1)[CH2:19][CH2:18][CH:17]=[CH:16]2.[C:30]1([SH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23](/[N:22]=[C:13]2\[S:14][CH:15]3[CH:20]([CH2:21]\[C:12]\2=[CH:11]/[S:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:19][CH2:18][CH:17]=[CH:16]3)=[CH:24][CH:25]=1
Reactant: Cl/C=C1\CC2CCC=CC2S\C1=N/c1ccc(Cl)cc1
Reactant: Sc1ccccc1
Agent: CN(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(/N=C2\SC3C=CCCC3C\C2=C/Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
65 mg of trimethylamine and 1 ml of DMF solution including {3-[1-chloro-(E)-methylidene]-3,4,4a,5,6,8a-hexahydro-thiochromene-(2Z)-ylidene}-(4-chloro-phenyl)-amine were added to 2 ml of DMF solution including 47 mg of thiophenol at 0° C. The resulting solution was stirred at room temperature for an additional 30 minutes, and added with water, and then extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.17 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])(=[O:21])=[O:20])[O:13][C:14]=1[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1C=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(CO)o1
Agent: O=Cc1oc(CNS(=O)(=O)c2ccccc2)cc(=O)c1OCc1ccccc1
Product: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C=O)o1
Yield: 66.9 %

Procedure:
N-(5-Benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-2-methyl-benzenesulfonamide (11-02) (2.8 g, 66.92%) was synthesized as a white solid from N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-2-methyl-benzenesulfonamide (10-02) (4.2 g, 10.12 mmol) following the procedure described for N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (11-01).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:8](=[O:15])[C:9]2[C:10](=[CH:12][S:13][CH:14]=2)[N:11]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O1CCCC1.CN(C)C1C=CN=CC=1>[O:15]=[C:8]1[N:7]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([F:26])([F:25])[F:27])=[CH:20][CH:21]=2)[C:6]([S:5][CH2:4][CH2:3][NH:2][C:35](=[O:37])[CH3:36])=[N:11][C:10]2=[CH:12][S:13][CH:14]=[C:9]12
Reactant: NCCSc1nc2cscc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCSc1nc2cscc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-[(2-Aminoethyl)sulfanyl]-3-[4-(2,2,2-trifluoroethoxy)phenyl]thieno[3,4-d]pyrimidin-4(3H)-one hydrochloride (0.33 g) was suspended in tetrahydrofuran (30 ml), triethylamine (0.31 ml), acetic anhydride (0.28 ml) and 4-dimethylaminopyridine (37 mg) were added successively thereto, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The extract was washed successively with saturated aqueous citric acid solution, water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-yellow solid was purified by silica gel column chromatography (ethyl acetate/hexane) to give a colorless solid. This solid was recrystallized from ethyl acetate/hexane to give the title compound (0.22 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].C1OCCOCCOCCOCCOCCOC1.[C:32]([O:36][CH3:37])(=[O:35])[CH:33]=[CH2:34]>O1CCCC1.CC(C)([O-])C.[K+]>[C:10]([CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:13])[F:1])[CH2:34][CH2:33][C:32]([O:36][CH3:37])=[O:35])#[N:11]
Reactant: C=CC(=O)OC
Reactant: N#CCc1ccccc1C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCC(C#N)c1ccccc1C(F)(F)F
Reaction time: 0.67 h

Procedure:
2-(Trifluoromethyl)phenylacetonitrile (2.0 g) was dissolved in tetrahydrofuran (50 mL). Potassium tert-butoxide (60.6 mg), 18-crown-6 (2.85 g) and methyl acrylate (973 μL) were added at 0° C. and the mixture was stirred at the same temperature for 40 minutes. The reaction was terminated with saturated ammonium chloride, followed by dilution with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. Concentration under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 30%) to obtain the title compound (2.2 g).
Reaction SMILES: [CH2:1]([S:9](Cl)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:13][C:14]1[C:19]2[CH:20]=[C:21]([CH2:23][CH:24]([NH:34]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]3)=[O:26])[S:22][C:18]=2[CH:17]=[CH:16][N:15]=1>>[NH2:13][C:14]1[C:19]2[CH:20]=[C:21]([CH2:23][CH:24]([NH:34][S:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:11])=[O:10])[C:25]([N:27]3[CH2:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH2:32]3)=[O:26])[S:22][C:18]=2[CH:17]=[CH:16][N:15]=1
Reactant: CCCCCCCCS(=O)(=O)Cl
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Product: CCCCCCCCS(=O)(=O)NC(Cc1cc2c(N)nccc2s1)C(=O)N1CCC(C)CC1

Procedure:
This compound was prepared from 0.15 mL of octane sulfonyl chloride and 210 mg of 30a using the procedure described for 58c. Yield: 150 mg; m.p. 101-112° C., (+)-FAB-MS: 495 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6](I)[C:5]2=[O:13].[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][C:15]=1[C:7]1[O:8][C:9]2[C:4]([C:5](=[O:13])[CH:6]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2
Reactant: O=c1c(I)coc2ccc(Cl)cc12
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2nc3ccccc3[nH]2)oc2ccc(Cl)cc12
Temperature: 0 °C
Yield: 13 %

Procedure:
A mixture of 6-chloro-3-iodochromone (153 mg) prepared in Example 28, benzimidazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) was reacted at 80° C. for 2 hours with stirring. The reaction mixture was added to ice water and extracted from chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and recrystallized from benzene/hexane to give the titled compound (19.3 mg; yield=13.0%) as white crystals. Melting point: 248°-250° C. Mass spectrum (M+): 296.5.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.N(CCO)(CCO)CCO.O.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: OCCN(CCO)CCO
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 81.8 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 15.8 g of potassium fluoride in 50 ml of p-xylene, 40 ml of triethanolamine and 10 ml of water were heated to 120° C. At 80° C., a mixture of 24.7 mg of palladium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 17.2 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.F[C:14]1[CH:15]=C(O)C=C(F)[C:19]=1[N+]([O-])=O.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[N+:10]([O-:12])=[O:11])[CH:14]=[CH2:19]
Reactant: O=[N+]([O-])c1c(O)cc(F)cc1F
Reactant: O=[N+]([O-])c1c(F)cc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CC(C)=O
Product: C=CCOc1cc(F)cc(F)c1[N+](=O)[O-]

Procedure:
A solution of 3,5-difluoro-2-nitrophenol and 3,5-difluoro-4-nitrophenol (3.54 g, 20 mmol), allyl bromide (2.9 g, 24 mmol) and potassium carbonate (8.3 g, 60 mmol) in acetone (50 mL) was refluxed for 2 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure at 25° C. The residue was diluted with water extracted with ether. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure at 25° C. The residue obtained was purified by silica gel column chromatography (0-1% ethyl acetate-hexane) to yield 1-(allyloxy)-3,5-difluoro-2-nitrobenzene (934 mg). 1H-NMR (400 MHz, CD3OD): δ 4.72 (2H, d), 5.32 (1H, d J=10.8), 5.42 (1H, d, J=17.2), 5.98-6.02 (1H, m), 6.85 (1H, dt), 6.96 (1H, d).