Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:13]1[CH:14]=[CH:15][C:10]([S:9][C:5]2[N:4]=[C:3]([C:1]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16](=[O:24])[N:2]=3)[CH:8]=[CH:7][CH:6]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(Sc2ccncc2)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(Sc3ccncc3)n2)sc2ccccc12
Yield: 2.1 %

Procedure:
2-Cyano-6-(4-pyridylthio)pyridine (1.54 g, 7.22 mmol) and methyl thiosalicylate (1.34 g, 7.94 mmol) were dissolved in toluene (50 ml), and triethylamine (1.52 ml, 10.83 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.053 g, 2%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[Cl:11][C:4]1[S:3][C:2]([NH:1][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)sc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1sc(Cl)cc1C(=O)OC)C(=O)OCC

Procedure:
Reaction of methyl 2-amino-5-chlorothiophene-3-carboxylate with diethyl ethoxymethylenemalonate in a similar manner to that used in Reference Example 10 yields diethyl (5-chloro-3-methoxycarbonylthienyl)aminomethylenemalonate as crystals melting at 89.5°-90.5° C.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].[OH:10][C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]>O1CCCC1>[CH2:8]([O:7][C:5]([CH2:4][NH:1][C:2]([O:10][C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])=[O:3])=[O:6])[CH3:9]
Reactant: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1
Reactant: CCOC(=O)CN=C=O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)Oc1cc(C=CC(=O)c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 20 °C
Reaction time: 72 h
Yield: 16.6 %

Procedure:
1.5 g of ethyl isocyanatoacetate was added to a solution containing 0.54 g of the product obtained in Example 8 in 10 ml of tetrahydrofuran and the solution was stirred for 3 days at 20° C. The solvent was evaporated in reduced pressure and the raw product was purified in a silica gel column using toluene-dioxane-acetic acid (8:1:1) as an eluent. Crystallization from acetone-petroleum ether yielded 0.13 g (17%) of the desired product desired, m.p 155°-158° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:5][CH2:4]1)[CH3:2]>Cl.O1CCOCC1>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:6]([CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCC(CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCN1CCC(CC2CCNCC2)CC1
Yield: 87.4 %

Procedure:
1,1-Dimethylethyl 4-[(1-ethyl-4-piperidinyl)methyl]-1-piperidinecarboxylate (may be prepared as described in Description 7) (2.5 g) was stirred in a solution of HCl-Dioxane (70 ml, 4M) for 2 h. The solvent was evaporated and the resultant hydrochloride salt was dissolved in saturated potassium carbonate (25 ml). The solution was extracted into DCM (3×50 ml) and the combined organics dried (MgSO4) and evaporated to give the title compound (D8) (1.48 g).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])(C)=C.[H-].[Na+].CI.Cl>CN(C=O)C>[CH3:1][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)[nH]c2ccccc21
Temperature: 45 °C
Yield: 74.6 %

Procedure:
A solution of 1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one (30 g, 0.172 moles) in DMF (180 ml) was added dropwise over 30 minutes to a suspension of 80% sodium hydride (5.42 g, 0.181 moles) in DMF (60 ml). The reaction mixture was heated at 45° C. for 45 minutes then a solution of methyl iodide (16.1 ml, 0.258 moles) in DMF (50 ml) was added dropwise. The reaction mixture was heated at 80° C. to 90° C. for 45 minutes, cooled at room temperature and adjusted to pH 3 to 4 with 37% HCl and heated at 80° C. for 30 minutes. The reaction mixture was cooled at room temperature and poured into ice/water. The solid residue separated was filtered and dried to give 19 g of the title compound, m.p. 188° C.-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].Br[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:15]([CH3:14])[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)cc1O
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cl)cc1OC(C)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.6 %

Procedure:
A solution of methyl 4-chlorosalicylate (5.0 g) in dimethyl formamide (10 ml) was treated sequentially with methyl 3-bromopropionate (4.0 g) and potassium carbonate (6.0 g). The mixture was stirred at room temperature for 18 hrs and diluted with water. The mixture was extracted with ether and the organics were washed with water. The organic layer was dried and evaporated to give the desired material (6.7 g) as a low melting solid. NMR: 7.8 (d, 1H), 7.2 (m 1H), 6.9 (m, 1H), 4.8 (q, 1H), 3.9 (s, 3H), 3.8 (s, 3H), 1.7 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(N(CC)C(C)C)(C)C.[C:23](Cl)(=[O:25])[CH3:24].CO.ClCCl>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][C:23](=[O:25])[CH3:24])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: CC(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(NC(C)=O)ccc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Alternately, combine methyl 2-methoxy-5-aminobenzoate (1.5 g, 8.3 mmol) and dichloromethane (25 mL). Cool in an ice bath. Add N,N-diisopropylethylamine (3.2 mL, 18.2 mmol), and acetyl chloride (0.62 mL, 9.7 mmol). Warm to ambient temperature. After 4 hours, dilute the reaction mixture with dichloromethane and extract three times with half saturated aqueous ammonium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 3% methanol/dichloromethane/0.1% concentrated aqueous ammonia to give methyl 2-methoxy-5-acetamidobenzoate: mp; 132-134° C. Elemental Analysis calculated for C11H13NO4: C, 59.19; H, 5.87. Found C, 59.04; H, 5.86.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([OH:6])=O.[CH3:13][C:14]([NH2:17])([CH3:16])[CH3:15].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[C:14]([NH:17][C:4](=[O:6])[C:3]1[C:7]([F:12])=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[F:1])([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(F)c(C(=O)O)c1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(C(=O)NC(C)(C)C)c1F
Reaction time: 2 h
Yield: 55.3 %

Procedure:
To a stirred solution of 2,6-difluoro-3-methylbenzoic acid (8.75 mmol, 1.5 g), 2-methylpropan-2-amine (9.43 mmol, 1 mL, 0.690 g) and triethylamine (28.7 mmol, 4 mL, 2.90 g) in dichloromethane (20 mL) was added 1-propanephosphonic acid cyclic anhydride (13.50 mmol, 8 mL, 8.59 g, 50% solution In ethyl acetate). The reaction was stirred for 2 hours before being diluted with dichloromethane and aqueous sodium hydrogen carbonate. The organic layer was separated, dried and concentrated under vacuum to yield the title compound (1.1 g). MS (ESI) m/z 228.4 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1([O:11][CH3:12])[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20])(=[O:15])[CH3:14].SCC(SC)C(N1[C@H](C(O)=O)CC2(C(=O)CCC2=O)C1)=O>>[C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([N:6]1[CH2:7][C:3]([O:11][CH3:12])([O:2][CH3:1])[CH2:4][C@H:5]1[C:8]([OH:10])=[O:9])=[O:20])(=[O:15])[CH3:14]
Reactant: COC1(OC)CN[C@H](C(=O)O)C1
Reactant: CC(=O)SCC(C)(C)C(=O)Cl
Agent: CSC(CS)C(=O)N1CC2(C[C@H]1C(=O)O)C(=O)CCC2=O
Product: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(C)(C)CSC(C)=O)C1

Procedure:
4,4-Dimethoxy-L-proline is reacted with 3-acetylthio-2,2-dimethylpropionyl chloride according to the procedure of Example 3 (d) to give 1-[3-(acetylthio)-2,2-dimethyl-1-oxopropyl]-4,4-dimethoxy-L-proline.
Reaction SMILES: CO.[C:3]([NH:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]([F:22])=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[C:14]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[N:13]=2)[CH2:8]1)(=[O:5])[CH3:4].[OH-].[Na+]>O.C(OCC)(=O)C>[C:3]([NH:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]([F:22])=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[C:14]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[N:13]=2)[CH2:8]1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(=O)NC1CCN(c2nc(Nc3ccc(F)cc3F)c(C(=O)O)cc2F)C1
Yield: 93 %

Procedure:
In a mixture of 30 ml of tetrahydrofruran, 10 ml of methanol and 4 ml of water was suspended 980 mg of methyl 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate, and 5.3 ml of 1N aqueous sodium hydroxide solution was added thereto, after which the resulting mixture was subjected to reaction at 65° C. for 3 hours. Subsequently, the reaction mixture was added to a mixture of 50 ml of ethyl acetate and 50 ml of water, and the aqueous layer was separated, after which the pH thereof was adjusted to 2.0 with 1N hydrochloric aicd. The crystals thus deposited were collected by filtration and washed successively with 2 ml of water and 2 ml of ethanol to obtain 880 mg (yield 93.0%) of 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinic acid having a melting point of 232°-234° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH:8]=[O:9])[CH3:7])C.O.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:4]([CH2:5][N:6]([CH3:7])[CH:8]=[O:9])=[O:3])[NH2:13]
Reactant: NN
Reactant: CCOC(=O)CN(C)C=O
Solvent: O
Solvent: CCO
Product: CN(C=O)CC(=O)NN
Yield: 84 %

Procedure:
As described for example 112a, (formyl-methyl-amino)-acetic acid ethyl ester (Hay, Michael P.; Wilson, William R.; Denny, William A. Tetrahedron (2000), 56(4), 645-657) in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 96 h. The mixture was concentrated and chromatographed (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 50:10:1) to afford the title compound as a colorless oil (yield: 84%). MS: m/e=100.1 [M+H−N2H4]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[C:39](O)=[O:40])(=[O:13])=[O:12].ON1C=CC=CC1=O.CCN=C=NCCCN(C)C.[NH2:61][CH2:62][C:63]1[NH:67][N:66]=[N:65][N:64]=1>C(Cl)Cl.CN(C=O)C>[NH:64]1[C:63]([CH2:62][NH:61][C:39]([C@@H:15]2[CH2:16][C@@H:17]([S:19][C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18][N:14]2[S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:12])=[O:13])=[O:40])=[N:67][N:66]=[N:65]1
Reactant: NCc1nnn[nH]1
Reactant: O=C(O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: O=c1ccccn1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1nnn[nH]1)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
A solution of 200 mg (0.34 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid and 42 mg (0.38 mmol) N-hydroxy-2-pyridone in 15 ml CH2Cl2 were treated at 0° C. with 72 mg (0.38 mmol) of EDCI. After 3.5h at RT, it was cooled (0° C.) and treated with 37 mg (0.38 mmol) of 5-aminomethyl-tetrazol. The reaction was stirred over night at RT, 2 ml DMF were added and after 4 h at RT the reaction was extracted with EtOAc/aqueous saturated NaHCO3. The organic phase was washed with aqueous 10% KHSO4, dried over Na2SO4 and purified by flash-chromatography on silicagel (CH2Cl2/MeOH 9:1) to give 100 mg (44%) of (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid (1H-tetrazol-5-ylmethyl)-amide, mp: 135-145 slow dec, MS: 661 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13]>>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: N#CCCCCCCl
Product: N#CCCCCCN1CCCC1

Procedure:
Using pyrrolidine and 6-chloro-hexanenitrile as substrates. MS (ion spray) m/z 167 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].C([Sn](CCCC)(CCCC)[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])=[CH:3][C:2]=1[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ncccn2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
Tris(dibenzylideneacetone)-dipalladium(0) (1 mg) was added to 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide (20 mg, 0.034 mmol), 2-(tributyl-stannyl)pyrimidine (25 mg, 0.068 mmol) and triphenylphosphine (1.9 mg, 0.007 mmol) in toluene (1.6 ml) under argon and the mixture was stirred at 100° C. overnight. After cooling, the mixture was filtered through celite and evaporated. The residue was purified by preparative HPLC. Pure fractions were freeze-dried to give the title compound (5 mg, 27%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]1[CH:40]=[CH:39][C:25]2/[C:26](=[C:35](/[CH3:38])\[C:36]#[N:37])/[C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[O:29][CH2:30][C:24]=2[CH:23]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([C:3]1[N:4]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]3/[C:26](=[C:35](/[CH3:38])\[C:36]#[N:37])/[C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[O:29][CH2:30][C:24]=3[CH:23]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2]
Reactant: C/C(C#N)=C1/c2ccc(CCl)cc2COc2ccccc21
Reactant: CCc1nc(-c2ccccc2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc(-c2ccccc2)cn1Cc1ccc2c(c1)COc1ccccc1/C2=C(\C)C#N
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
[step 1] 2-Ethyl-4-phenylimidazole (Tetrahedron Lett. 2001, p 7079; 192 mg, 1.12 mmol) was dissolved in DMF (4.8 mL), potassium carbonate (0.700 g, 5.07 mmol) was added, and the mixture was stirred for 15 min. To this mixture was added (E)-2-(8-chloromethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiononitrile (300 mg, 1.01 mmol) obtained in Reference Example B5, and the mixture was stirred at 60° C. for 3 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 6/4) to give (E)-2-[8-(2-ethyl-4-phenylimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (434 mg, 99%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)O1.[NH2:19][C:20]1[C:29]2[C:24](=[C:25](Br)[C:26]([CH2:30][CH3:31])=[CH:27][CH:28]=2)[N:23]=[N:22][C:21]=1[C:33]([NH2:35])=[O:34]>>[NH2:19][C:20]1[C:29]2[C:24](=[C:25]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][N:13]=[CH:12]4)[C:26]([CH2:30][CH3:31])=[CH:27][CH:28]=2)[N:23]=[N:22][C:21]=1[C:33]([NH2:35])=[O:34]
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: CCc1ccc2c(N)c(C(N)=O)nnc2c1Br
Product: CCc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2[nH]ncc2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole and 4-amino-8-bromo-7-ethylcinnoline-3-carboxamide. ESI-MS m/z [M+H]+ 333.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[CH3:30][C:31]1([CH3:41])[CH2:35][C:34]2[CH:36]=[CH:37][CH:38]=[C:39]([NH2:40])[C:33]=2[O:32]1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:40][C:39]3[C:33]4[O:32][C:31]([CH3:41])([CH3:30])[CH2:35][C:34]=4[CH:36]=[CH:37][CH:38]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CC1(C)Cc2cccc(N)c2O1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cccc4c3OC(C)(C)C4)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 99.9 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.15 g, 0.36 mmol) obtained in Example 19, step 4 and 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-amine (0.088 g, 0.54 mmol), the title compound (0.194 g, 99%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].F[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].O.[OH-].[Li+].[NH4+].[Cl-]>CS(C)=O>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[C:11]([NH:1][C:2]2[S:3][C:4]([CH3:9])=[CH:5][C:6]=2[C:7]#[N:8])[CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: Cc1cc(C#N)c(N)s1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C#N)c(Nc2cc(Cl)ccc2[N+](=O)[O-])s1
Yield: 34.6 %

Procedure:
Dissolve 2-amino-5-methyl-thiophene-3-carbonitrile (0.79 g, 5.7 mmol) and 2-fluoro-4-chloronitrobenzene (1 g, 5.7 mmol) in dimethylsulfoxide (15 ml) and stir under nitrogen. Add lithium hydroxide monohydrate (250 mg, 6 mmol) and heat the mixture in an oil bath at 60° C. overnight. Pour the mixture into sat. NH4Cl(aq), extract into ethyl acetate, dry (MgSO4) and concentrate under reduced pressure. Chromatography on silica gel (eluent cyclohexane/ethylacetate) gives 2-(5-chloro-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile as a yellow solid (0.58 g, 35%): NMR (1H, 300 MHz, CDCl3): δ 9.6 (1H broad), 8.21 (1H,d), 7.09 (1H, s), 6.92 (1H,d), 6.80 (1H, s), 2.49 (3H,s).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[C:13]([CH3:22])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[O:18])=[C:13]([CH3:22])[CH:12]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CN1CCNCC1
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCC(=O)O
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCC(=O)N1CCN(C)CC1
Yield: 91.1 %

Procedure:
2-(4-(adamantan-1-yl)-2-methylphenoxy)acetic acid (0.2 g, 0.66 mmol) and 1-methylpiperazine (0.06 g, 0.66 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-methylphenoxy)-1-(4-methylpiperazin-1-yl)ethanone as a white solid (0.23 g, 90.5% yield).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 39.4 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-methoxyphenylboronic acid (available from Frontier Scientific, Inc.; 61 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-methoxy-biphenyl-2-carboxylic acid (36 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ 12.75 (br s, 1H), 8.45 (s, 1H), 8.31-8.37 (m, 2H), 8.21 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.27 (d, J=7.5 Hz, 1H), 7.04 (d, J=7.3 Hz, 2H), 3.69 (s, 3H).
Reaction SMILES: [CH3:1][C@@H:2]([NH:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[C:3]([F:6])([F:5])[F:4].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[CH3:1][C@@H:2]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=1)[C:3]([F:5])([F:6])[F:4]
Reactant: C[C@@H](NCc1ccc(C#N)cc1)C(F)(F)F
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H](NCc1ccc(CN)cc1)C(F)(F)F
Yield: 56.6 %

Procedure:
Add cobalt(II) chloride hexahydrate (1.45 g, 6.09 mmol) to a solution of (R)-4-[(1-methyl-2,2,2-trifluoro-ethylamino)-methyl]-benzonitrile (695 mg, 3.045 mmol) in methanol (20 mL). Add sodium borohydride (1.15 g, 30.45 mmol) in small batches and stir at room temperature for 3 h. Quench with water, add chloroform and filter the mixture through Celite®. Separate layers and extract the aqueous phase twice with chloroform. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with a gradient of DCM to 19:1 and 9:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the title compound as an oil (0.4 g, 57%). MS (ES+) m/z: 233 (M+H)+.