Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23](Cl)=[O:24]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:23](=[O:24])[CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH2:8]2
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCCN[C@H]1CCc2cccc(OC)c2C1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN(C(=O)Cc1cccs1)[C@H]1CCc2cccc(OC)c2C1

Procedure:
Synthesis worked according to the preparation of A4-1 when using 310 mg (1.4 mmol) enantiomerical pure (S)-N-(8-methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R=OMe) and 0.35 mL (2.8 mmol) 2-thienyl acetic acid chloride. Flash chromatography was done with hexane/ethyl acetate 20/1.
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].C[O-].[Na+].[CH:11]([CH:13]([CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:14](OCC)=O)=[O:12]>CO>[N+:1]([NH:4][C:5]1[NH:7][C:11](=[O:12])[C:13]([CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[CH:14][N:6]=1)([O-:3])=[O:2]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCOC(=O)C(C=O)Cc1ccc(OC)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1

Procedure:
Nitroguanidine (4.7 g) was added to a solution of sodium methoxide (prepared from 1.15 g sodium) in methanol (50 ml) and the mixture was refluxed for 45 minutes. Ethyl 2-formyl-3-(6-methoxy-3-pyridyl)propionate (10.7 g) was added and the mixture was refluxed for 34 hours and evaporated to a residue. This residue was dissolved in water and the solution was extracted with chloroform (subsequently discarded). The aqueous solution was adjusted to pH 5 with acetic acid, and the solid which precipitated out was filtered off to give 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone m.p. 183.5°-186°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:26][N:27]([CH3:31])[C:28](=[O:29])[O:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[C:4]([F:25])=[CH:3][C:2]=1[Cl:1]
Reactant: CN(C)C(=O)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCO)c(Cl)cc2F)c1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)OCCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-[4-chloro-2-fluoro-5-(2-hydroxyethoxy)-phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione with N,N-dimethylcarbamoyl chloride and triethylamine in toluene there is obtained 2-[2-chloro-5-[3,6-dihydro-2,6 -dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4 -fluorophenoxy]-ethyl N,N-dimethylcarbamate, 1H-NMR (CDCl3, 400 MHz): 7.31 ppm (d,1H), 6.81 ppm (d,1H), 6.36 ppm (s,1H), 4.40°-4.47 ppm (m,2H), 4.16°-4.22 ppm (m,2H), 3.56 ppm (d,3H), 2.92 ppm (s,3H), 2.89 ppm (s,3H);
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C:17]3([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C(N(CC)CC)C.[CH3:30][NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35](O)=[O:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C:17]3([NH:22][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][N:40]=[C:32]([NH:31][CH3:30])[CH:33]=4)[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1
Reactant: CNc1cc(C(=O)O)ccn1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OCC3(N)CCCC3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNc1cc(C(=O)NC2(COc3cccc4c3C(N)=NS(=O)(=O)N4)CCCC2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.9 %

Procedure:
To a stirred suspension of 4-amino-5-((1-aminocyclopentyl)methoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (200 mg, 0.577 mmol) in DMF (5 mL) was added triethylamine (0.32 mL, 2.31 mmol). After being stirred at room temperature for 10 min., a mixture of 2-(methylamino)isonicotinic acid (88 mg, 0.577 mmol), EDCI (122 mg, 0.635 mmol) and HOBt (86 mg, 0.635 mmol) in 10 ml of DMF were added, and the reaction mixture was then stirred at room temperature overnight and at 55° C. for 2 hrs. The resulting solution was purified by preparative HPLC (10-90% CH3CN in water). The clean fractions were collected and re-crystallized from ethanol/water, dried at 60° C. under vacuum to provide the title compound (87 mg) in 34% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.62-1.84 (m, 6H), 2.15-2.21 (m, 2H), 2.76 (J=4.8 Hz, 3H), 4.40 (s, 2H), 6.59-6.64 (m, 3H), 6.70-6.72 (m, 1H), 6.77 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.8 Hz, 1H), 7.88 (s, 1H), 8.00 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 8.38 (s, 1H), 10.97 (s, 1H). MS 445 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[CH2:7]1)=[O:5])[CH3:2].O.NN>C(O)C>[NH2:13][CH2:12][CH:8]1[O:9][CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]1
Reactant: CCOC(=O)N1CCOC(CN2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1CCOC(CN)C1
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
A mixture of N-[(4-ethoxycarbonyl-2-morpholinyl)methyl]phthalimide (10.0 g), 85% hydrazine hydrate (2.9 g), and ethanol (10 ml) is refluxed with stirring for 10 minutes. The reaction mixture is filtered and the filtrate is extracted with chloroform. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. Removal of the solvent under reduced pressure gives the title compound (5.8 g) as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1)=O.[CH3:23][NH2:24].CO>O1CCCC1.CO>[CH3:23][NH:24][CH2:1][C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1
Reactant: O=Cc1cc(NC(=O)c2ccccc2)n(-c2ccccc2)n1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc(NC(=O)c2ccccc2)n(-c2ccccc2)n1
Reaction time: 18 h

Procedure:
N-(3-Formyl-1-phenyl-1H-pyrazol-5-yl)benzamide (303 mg) was dissolved in tetrahydrofuran (5 mL) and methanol (3 mL), and 40% methylamine-methanol solution (1.1 mL) was added at room temperature. After stirring for 18 hr, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (3 mL), sodium borohydride (118 mg) was added under ice-cooling and the mixture was further stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→ethyl acetate) to give a free base of the title compound as a pale-yellow amorphous form (yield 248 mg). The obtained free base was dissolved in tetrahydrofuran (5 mL), and the mixture was added to a solution of fumaric acid (94 mg) in ethanol (10 mL). The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 137 mg, yield 37%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH3:20]C1C=CC=C2C=1C=CN2>>[CH3:20][C:5]1[CH:4]=[CH:3][CH:2]=[C:10]2[C:6]=1[CH:7]=[C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)[NH:9]2
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: Cc1cccc2[nH]ccc12
Product: Cc1cccc2[nH]c(B3OC(C)(C)C(C)(C)O3)cc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole using 4-methyl-1H-indole.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[F:11].F[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]>C1COCC1>[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[N+:19]([O-:21])=[O:20])=[CH:6][C:5]=1[F:11]
Reactant: Nc1ccc(Cl)c(F)c1
Reactant: O=[N+]([O-])c1ccncc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccncc1Nc1ccc(Cl)c(F)c1
Reaction time: 18 h
Yield: 22 %

Procedure:
NaH (422 mg, 60% dispersion in mineral oil, 10.6 mmol) was suspended in THF (20 mL) and 4-chloro-3-fluoroaniline (1.54 g, 10.6 mmol) and 3-fluoro-4-nitropyridine (500 mg, 3.52 mmol) were added. The reaction mixture was stirred for 18 h, quenched with sat aq NH4Cl (2 mL), and concentrated in vacuo. The residue was partitioned between water (50 mL) and DCM (50 mL) and the organic fraction was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (207 mg, 22.0%) as an orange solid. LCMS (ES+): 268.0 [MH]+.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:18])([CH3:17])[CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[N:1]1([CH2:6][C:7]2([C:34](=[O:35])[CH2:33][C:30]3[CH:29]=[CH:28][C:27]([C:26]([F:37])([F:25])[F:38])=[CH:32][CH:31]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:18])([CH3:17])[CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CNC(CN2CCCC2)c2ccccc21
Reactant: O=C(Cl)Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC1(C)CNC(CN2CCCC2)(C(=O)Cc2ccc(C(F)(F)F)cc2)c2ccccc21

Procedure:
Prepared as Ex. No. 1, from 2.44 g (10.0 mmoles) of 1-(pyrrolidin-1-yl)methyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline, 3.04 g (22.0 mmoles) of anhydrous potassium carbonate and 2.45 g (11.01 mmoles) of 4-trifluoromethylphenylacetyl chloride in 40 ml of dry chloroform.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH:11]2[CH2:13][CH2:12]2)=[N:9]/[OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:17][C:18]1[C:19]([F:31])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([F:24])=[CH:22][CH:23]=1.CN(C)C=O>C1(C)C=CC=CC=1>[F:31][C:19]1[C:18]([CH2:17][O:10]/[N:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)\[CH:11]2[CH2:12][CH2:13]2)=[CH:23][CH:22]=[C:21]([F:24])[C:20]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O/N=C(/c1ccc(Cl)cc1)C1CC1
Reactant: Fc1ccc(CCl)c(F)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Fc1ccc(CO/N=C(/c2ccc(Cl)cc2)C2CC2)c(F)c1-c1ccccc1

Procedure:
In a manner similar to Example 2, the reaction of 0.59 g (0.003 mole) of (E)-(4-chlorophenyl)(cyclopropyl)methanone oxime with 0.072 g (0.003 mole) of sodium hydride and 0.72 g (0.003 mole) of 3-chloromethyl-2,6-difluoro[1,1'-biphenyl] in 25 ml of a 20% solution of N,N-dimethylformamide in toluene produced (E)-(4-chlorophenyl)(cyclopropyl)methanone O-[(2,6-difluoro[1,1'-biphenyl]-3-yl)methyl]oxime as an oil.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]#[N:29])[CH2:24][CH2:23]1>CS(C)=O.O>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]#[N:29])[CH2:24][CH2:23]3)=[N:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: N#CC1CCNCC1
Reactant: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Solvent: O
Solvent: CS(C)=O
Product: N#CC1CCN(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Reaction time: 8 h

Procedure:
In a 50 mL round-bottomed flask was placed N-(4-(3-chloropyrazin-2-yloxy)-phenyl)pyridin-2-amine (0.2376 g, 0.7954 mmol) in DMSO. Piperidine-4-carbonitrile (0.4363 g, 3.977 mmol) was added and the temperature was brought to 80° C. to stir overnight. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (3×10 mL), satd sodium chloride solution (3×10 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (25M), eluting with a gradient of 1% to 5% methanol in DCM, to provide 1-(3-(4-(pyridin-2-ylamino)-phenoxy)pyrazin-2-yl)piperidine-4-carbonitrile. MS (ESI, pos. ion) m/z: 373.1 (M+1). IC50 (uM) 0.006048.
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=1[NH:22][C:23](=O)[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:3][C:4](=[O:11])[NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.O1CCCC1>CN(C)C1C=CN=CC=1.O>[OH:1][C:2]1[C:12]2[C:13](=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:16][CH:17]=2)[N:22]=[C:23]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[C:3]=1[C:4]([NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Yield: 93.9 %

Procedure:
7.3 g of the product of Step B, 140 ml of tetrahydrofuran and 2.4 g of 4-dimethylamino-pyridine were stirred for 1 hour at ambient temperature and the solvent was eliminated under reduced pressure. The residue was taken up in 100 ml of water and 20 ml of N hydrochloric acid and the solution was extracted with a mixture of ethyl acetate and tetrahydrofuran. After washing the organic phase with water and drying and concentrating the filtrate under reduced pressure, 7 g of crude product were obtained which was triturated in ether, separated, washed with ether and dried under reduced pressure at 60° C. to obtain 6.6 g of 1,1-dimethylethyl N-[[4-hydroxy-8-(trifluoromethyl)-3-[(2-thiazolylamino)-carbonyl]quinolin-2-yl]-methyl]-carbamate melting at 238° C.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:8]1[C:13]([O:14][SiH:15]([CH3:17])[CH3:16])=[C:12]([Br:18])[C:11]([O:19][CH3:20])=[CH:10][C:9]=1[CH2:21][CH:22]1[C:27](=[O:28])[CH:26]=[CH:25][CH2:24][C:23]1([CH3:30])[CH3:29])([CH3:7])([CH3:6])[CH3:5]>CCOCC.[Cu]I>[C:4]([C:8]1[C:13]([O:14][SiH:15]([CH3:16])[CH3:17])=[C:12]([Br:18])[C:11]([O:19][CH3:20])=[CH:10][C:9]=1[CH2:21][C@H:22]1[C:23]([CH3:30])([CH3:29])[CH2:24][C@@H:25]([CH3:1])[CH2:26][C:27]1=[O:28])([CH3:7])([CH3:5])[CH3:6]
Reactant: COc1cc(CC2C(=O)C=CCC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Reactant: C[Mg]Br
Agent: [Cu]I
Solvent: CCOCC
Product: COc1cc(C[C@@H]2C(=O)C[C@H](C)CC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of copper(I) iodide (2 mg) in 1 mL of anhydrous ether at 0°C. was added methylmagnesium bromide (0.106 mL of a 3.0 M solution in ether, 0.319 mmol, 1.00 equiv). Then enone 13 (149 mg, 0.319 mmol) in 2 mL of anhydrous ether was added slowly to the stirring cuprate mixture at a temperature maintained below 5° C., and upon completion of the addition, the reaction mixture was stirred at 0° C. for 3 h before quenching with a 4:1 mixture of saturated aqueous NH4Cl/NH4OH. The resultant biphasic mixture was extracted with ether, dried over Na2SO4, and concentrated under diminished pressure. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 9:1) afforded 36 mg (30%) of the desired conjugate addition product as a white solid. 1H NMR (400 MHz, CDCl3) δ0.22 (s, 6H, Si(CH3)2), 1.00 [m, 18H, 3,3,5-CH3 and SiC(CH3)3 ], 1.50 (dd, 2H, J=15.1, 6.5 Hz, 4-Hz, 4-H), 2.02 (m, 1H, 5-H), 2.14 and 2.23 (ABq, 2H, JAB =12.0 Hz, 6-H), 2.42 (dd, 1H, J=10.4, 6.4 Hz, 2-H), 2.88 and 2.89 (d of ABq, 2H, JAB =12.0 Hz, JA =10.4 Hz, JB =6.3 Hz, benzylic-CH2), 3.82 (s, 3H, OCH3), 6.65 (s, 1H, 6'-H), 6.92 ppm (s, 1H, 3'-H).
Reaction SMILES: [CH:1]([OH:3])=[O:2].C([N:11](CC1C=CC=CC=1)[C@@H:12]([CH3:20])[C@H:13]([CH:15]1[CH2:17][C:16]1([CH3:19])[CH3:18])[OH:14])C1C=CC=CC=1>[Pd].C(O)C>[CH3:19][C:16]1([CH3:18])[CH2:17][CH:15]1[CH:13]([OH:14])[C@@H:12]([NH:11][C:1](=[O:3])[O:2][C:15]([CH3:17])([CH3:16])[CH3:13])[CH3:20]
Reactant: C[C@@H]([C@@H](O)C1CC1(C)C)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=CO
Agent: [Pd]
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)C(O)C1CC1(C)C
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Formic acid (2.4 ml) and 10% Pd/C (0.4 g) were added to an ethanol solution (60 ml) containing (1S,2S)-2-(dibenzylamino)-1-(2,2-dimethylcyclopropyl)propan-1-ol (2.4 g) obtained in the 5th step, followed by stirring at 90° C. for 5 hours. The reaction solution was filtered through Celite and the filtrate was distilled away under reduced pressure. Diisopropyl ethylamine (1.5 ml) and di-tert-butyl carbonate (1.75 g) were added to a THF (5 ml) solution containing the obtained residue, followed by stirring at room temperature for 40 minutes. Water and a 10% citric acid aqueous solution were added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with water and saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:0.2). A yellow liquid of tert-butyl ((2S)-1-(2,2-dimethylcyclopropyl)-1-hydroxypropan-2-yl)carbamate (0.45 g) was thus obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=[C:9]1[CH:17]([N:21]1[CH:25]=[C:24]([CH2:26][CH2:27][N:28]2C(=O)C3C(=CC=CC=3)C2=O)[N:23]=[C:22]1[C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=1)[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:28][CH2:27][CH2:26][C:24]1[N:23]=[C:22]([C:39]2[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[N:21]([CH:17]([C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=2)[CH:18]([CH3:20])[CH3:19])[CH:25]=1
Reactant: Cc1ccc(-c2nc(CCN3C(=O)c4ccccc4C3=O)cn2C(c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc(CCN)cn2C(c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.9 %

Procedure:
To 2-(2-{1-[1-(1-Benzyl-4,5-dimethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-2-methyl-propyl]-2-p-tolyl-1H-imidazol-4yl}-ethyl)-isoindole-1,3-dione (0.371 g, 0.619 mmol) in EtOH (14 mL) was added hydrazine monohydrate (0.138 g, 2.48 mmol) and the reaction was stirred at room temperature for 72 h. The reaction was filtered and the filtrate was concentrated to dryness. The residue was purified by flash chromatography on silica gel (90:9:1 CH2Cl2:MeOH:NH4OH) to give the title compound as a white solid (0.209 g, 72%). MS(ES)+m/e 470 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+].O>C(O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(I)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(-c2cn3cc(I)ccc3n2)cc1
Yield: 81 %

Procedure:
2-Amino-5-iodopyridine (1.0 g) and 2-bromo-4′-cyanoacetophenone (1.02 g) were dissolved in ethanol (30 mL), and sodium hydrogencarbonate (382 mg) was added to the solution, followed by refluxing for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was left to cool. The precipitated matter was recovered through filtration and dried, to thereby yield the title compound (1.27 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.C1COCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:11]=[CH:12][CH:13]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(CO)c1
Temperature: 0 °C
Yield: 42.4 %

Procedure:
To an ice-cold solution of 3-(methylsulfonyl)benzoic acid (1.4 g, 7.1 mmol) in 2:1 Et2O/THF (60 mL) was added LiAlH4 (8.5 mL of 1.0 M solution in THF, 8.5 mmol), and the reaction mixture was heated at reflux for 1 h. The reaction mixture was cooled to 0° C., and the reaction was quenched with water (15 mL) and 15% NaOH in water (35 mL). The reaction mixture was filtered, concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with water and then brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 1:2 to 3:1 EtOAc/hexanes) provided (3-methanesulfonyl)phenyl methanol as a clear oil (0.56 g, 42%): 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.83 (d, J=7 Hz, 1H), 7.64 (d, J=7 Hz, 1H), 7.53 (t, J=7 Hz, 1H), 4.78 (d, J=6 Hz, 2H), 3.05 (s, 3H), 2.61 (br s, 1H). Step 2. Preparation of 1-Chloromethyl-3-methanesulfonylbenzene.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>O1CCCC1>[CH2:34]([NH:36][C:37]([NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([C:14]2[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=3)=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH:21]=1)=[O:38])[CH3:35]
Reactant: Nc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 24.5 %

Procedure:
A mixture of [3-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]amine hydrochloride (Example 212, 100 mg, 0.26 mmol) and triethylamine (0.05 mL, 0.36 mmol) in tetrahydrofuran (2 mL) was cooled to 0° C. and ethyl isocyanate (0.08 mL, 0.31 mmol) added. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica, eluting with 40% ethyl acetate/isohexane, followed by trituration with diethyl ether to give the title compound as a white solid (27 mg, 24%). δH (500 MHz, d6 DMSO): 8.85 (1H, s), 8.15 (1H, s), 7.86 (2H, d, J=8.4 Hz), 7.79 (2H, d, J=8.4 Hz), 7.67 (2H, dd, J=5.7, 8.5 Hz), 7.50-7.48 (1H, m), 7.43-7.40 (3H, m), 7.27 (1H, d, J=16.5 Hz), 7.22 (2H, t, J=8.8 Hz), 6.20 (1H, t, J=5.4 Hz), 3.12-3.06 (2H, m), 1.03 (3H, t, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH:17][S:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=1)(=[O:29])=[O:28])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: COc1ccc(S(=O)(=O)NCC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)cc1

Procedure:
Following the procedure described in the preceeding examples but using 2-(2,4-dichlorophenyl)-3-amino-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and ρ-methoxybenzenesulfonylchloride, the title compound was obtained in a similar yield: