Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[O:2][CH:3]=[CH:4][C:5]2[C:6]=1[CH:7]=[CH:8][CH:9]=2.C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]([NH:24][C:25]1[CH:37]=[C:36]([CH:38]=[CH2:39])[CH:35]=[CH:34][C:26]=1[C:27]([O:29]C(C)(C)C)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:16]([NH:24][C:25]1[CH:37]=[C:36](/[CH:38]=[CH:39]/[C:9]2[CH:5]=[CH:4][C:3]3[O:2][CH:1]=[CH:6][C:7]=3[CH:8]=2)[CH:35]=[CH:34][C:26]=1[C:27]([OH:29])=[O:28])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1cc2ccocc-2c1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(/C=C/c2ccc3occc3c2)ccc1C(=O)O)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 4 %

Procedure:
61 mg of 5-benzofuran, 0.10 g of cesium carbonate, 15 mg of tetrabutylammonium bromide and 21 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 1.0 mL of toluene solution containing 50 mg of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, 24 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) was added and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 10 mL of trifluoroacetic acid was added to the obtained residue and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 2.4 mg of 2-(benzamido)-4-((E)-2-(benzofuran-5-yl)vinyl)benzoic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=1)[CH3:11]>ClCCl.CCCCCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Sc1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CN(CCOc1ccc(CC(Sc2ccccc2)C(=O)O)cc1)c1nc2ccccc2o1

Procedure:
The title compound, mp 144°-7° C. (dichloromethane-hexane), was prepared from methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(phenylthio)propanoate by a procedure similar to that described for Example 21.
Reaction SMILES: C1C(C(CBr)=[O:8])=CC=C(Br)C=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH3:30])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:16]=[CH:17][C:18]=1[F:19]>C(O)(C)(C)C.C(O)(=O)C.[Zn]>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:22]3[CH2:29][C:28](=[O:8])[N:27]([CH3:30])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Cn1ccc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
PBPB (2.8 g, 7.8 mmol) was added portionwise to the (3-chloro-4-fluoro-phenyl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (1.08 g, 3.9 mmol) suspended in tert-butanol (20 mL) and acetic acid (10 mL). After stirring at room temperature for 18 hours, to the mixture was added zinc dust (760 mg, 11.7 mmol) portionwise and stirring was continued for overnight. The precipitate was filtered off and the filtrate was concentrated. The residue was triturated with little water and the precipitate was collected by vacuum filtration, washed with little ethyl acetate and dried to give 1.12 g (98%) of 4-(3-chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one as a tan colored solid. 1H NMR (DMSO-d6) 9.07 (s, 1H, NH), 8.42 (s, 1H), 8.01 (d, J=2.6 & 7.2 Hz, 1H) 7.56 (m, 1H), 7.34 (t,J=9.1 Hz, 1H), 3.48 (s, 2H, CH2), 3.07 (s, 3H, CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH:13]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C@H:12]2[C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][C@H:13]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
To a solution of p-chlorobenzoyl chloride (247 mg, 1.41 mmol) in CH2Cl2 (4 ml) was added a solution of aminopyrrolidinone of Example S (350 mg, 1.41 mmol) and triethylamine (0.4 ml, 2.82 mmol) in CH2Cl2 (4 ml) and the resulting solution was stirred for 18 h at room temperature. Concentration in vacuo gave an oil which was chromatographed on silica gel eluting with 5/95 EtOH/CH2Cl2 to give the title compound (378 mg, 68%) as a solid. Anal calcd for C20H19N2O4Cl; C, 62.10; H, 4.95; N, 7.24. Found: C, 62.07; H, 5.05; N, 7.18. MS calcd for C20H19N2O4Cl 386, found 386. DSC=215.2°-216.8° C. at 144.3 J/g.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:2]=12.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([O:16][C:13](=[O:15])[CH3:14])[C:2]=12
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cccc2c1CCCCC2
Product: CC(=O)OC1CCCCc2cccnc21
Temperature: 90 °C

Procedure:
The N-oxide was dissolved in acetic anhydride (222 mL) and heated at 90° C. overnight. The mixture was cooled to room temperature and concentrated. Distillation (Kugelrohr, bp 110-140° C.@1 Torr) of the resultant oil provided 53.26 g of acetic acid 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH2:25]1[CH2:32][NH:31][S:28](=[O:30])(=[O:29])[CH2:27][CH2:26]1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:31]2[CH2:32][CH2:25][CH2:26][CH2:27][S:28]2(=[O:30])=[O:29])[CH:7]=1
Reactant: O=S1(=O)CCCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCCCS3(=O)=O)CC2)c(C)c1
Yield: 28857.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using (2-bromo-4-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.19 mg) described in Preparation Example 119 and 1,4-butanesultam (0.394 g), the title compound (0.389 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](/[N:10]=[CH:13]/[N:14]([CH3:16])[CH3:15])=[O:9])=[N:6][CH:7]=1
Reactant: NC(=O)c1ccc(Br)cn1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/C(=O)c1ccc(Br)cn1
Yield: 95 %

Procedure:
A solution of 5-bromopicolinamide (0.500 g, 2.49 mmol) and dimethylformamide dimethylacetal (20 mL), were heated to 85° C. for 3 h. The reaction was concentrated and the product was used directly in the next step (0.604 g, 95% yield). MS (ESI) m/z 257.1 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10])([O-:25])=[O:24]
Reactant: O=C(O)Cc1ccccc1O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 95 °C

Procedure:
A mixture of 2-hydroxyphenylacetic acid (1.52 g, 0.01 mol), 4-fluoro-3-nitrobenzotrifluoride (2.09 g, 0.01 mol), potassium carbonate (2.76 g, 0.02 mol) in dimethylformamide (10 mL) was heated at 95° C. 16 h. The solvent was evaporated, the residue was acidified with dilute HCl, extracted with EtOAc, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane/formic acid). Recrystallization from EtOAc/hexane gave the title compound; mp 165°-167° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15](I)=[C:14]([O:19][CH3:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([C:21]#[N:22])=[C:14]([O:19][CH3:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COc1c(I)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1c(C#N)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 90 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester (490 mg, 1.26 mmol) was added 356 mg (3 mmol) of Zn(CN)2, 140 mg of Pd(PPh3)4 and 4 mL of DMF. The mixture was stirred at 90° C. for 3 h. After cooling to room temperature the reaction mixture was loaded onto a silica gel column and was purified by column chromatography to give 260 mg (72% yield) of desired 5-cyano-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was obtained as a white solid.
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:14]2[O:18][C:17](=[O:19])[NH:16][N:15]=2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O>[Pd].C1COCC1>[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:14]2[O:18][C:17](=[O:19])[NH:16][N:15]=2)=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: [H][H]
Reactant: COc1cc(-c2n[nH]c(=O)o2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(-c2n[nH]c(=O)o2)ccc1N

Procedure:
Hydrogen was introduced under atmospheric pressure into the mixture of 550 mg of 5-(3-methoxy-4-nitrophenyl)-3H-[1,3,4]oxadiazol-2-one, 100 mg of Pd/C and 50 ml of THF up to the theoretical uptake. Afterwards, the catalyst was filtered off with suction and the mixture was concentrated to dryness under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Br[C:25]([CH3:30])([CH3:29])[C:26](Br)=[O:27]>O>[CH3:29][C:25]1([CH3:30])[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=2[O:12]1
Reactant: CC(C)(Br)C(=O)Br
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)OC(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (9.8 g) in a mixed solvent of ethyl acetate (200 ml) and water (200 ml) were added sodium hydrogen carbonate (7.3 g) and 2-bromoisobutyryl bromide (13.7 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (500 ml), to the solution was added potassium carbonate (8.9 g) and the mixture was stirred at room temperature for a day. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 2,2-dimethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (10.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: Cc1ccc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1C
Yield: 45.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3,4-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.032 g (45%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([C:16]3[S:17][C:18]([C:22](O)=[O:23])=[C:19]([CH3:21])[N:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:60]([NH2:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C)C=O>[CH2:60]([NH:67][C:22]([C:18]1[S:17][C:16]([N:9]2[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:27][CH:26]=3)[C:8]2=[O:25])=[N:20][C:19]=1[CH3:21])=[O:23])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(-n2c(=O)n(Cc3ccc(F)cc3)c3ccccc32)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-n2c(=O)n(Cc3ccc(F)cc3)c3ccccc32)sc1C(=O)NCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-4-methylthiazole-5-carboxylic acid in N,N-dimethylformamide is added N,N-diisopropylethylamine, followed by the addition of 1-hydroxybenzotriazole monohydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The resulting mixture is stirred for 10 minutes and followed by the addition of benzylamine at ambient temperature. After stirred at ambient temperature for an additional 17 h, the mixture is concentrated in vacuo. The residue is poured into a saturated aqueous solution of sodium bicarbonate and then extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over sodium sulfate, and filtered. The filtrate is concentrated and purified by column chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[O:19][CH3:20].[C:21](OC(=O)C)(=O)C>CN(CN(C)C)C>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:19][CH3:20])[CH:4]=[CH:5][C:6]=1[C:9](=[O:18])[C:10]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[CH2:21]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(=O)Cc2ccc(Br)cc2)c(Cl)c1Cl
Agent: CN(C)CN(C)C
Product: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2,3-dichloro-4-(4-bromophenyl)acetyl anisole (142.5 g., 0.38 mole) in bis-dimethylaminomethane (325 ml.) under nitrogen is added dropwise acetic anhydride (325 ml.) with cooling to maintain the reaction mixture temperature below 40° C. The reaction mixture is stirred at 25° C. for one hour, then poured into crushed ice-water (4 l.) to precipitate 143 g. of 2',3'-dichloro-4'-methoxy-2-(4-bromophenyl)acrylophenone which melts at 110°-116° C. after crystallization from benzene:hexane, 1:5.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([CH3:13])=[N:4][CH:3]=1.[CH2:14](B(O)O)[CH2:15][CH3:16]>>[CH3:13][C:5]1[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:7][C:2]([CH2:14][CH2:15][CH3:16])=[CH:3][N:4]=1
Reactant: CCOC(=O)c1nc(Cl)cnc1C
Reactant: CCCB(O)O
Product: CCCc1cnc(C)c(C(=O)OCC)n1

Procedure:
The preparation was performed in a similar manner as Reference Example 1.13 (d) from ethyl 6-chloro-3-methylpyrazine-2-carboxylate (Reference Example 1.13 (c)) (1.50 g, 7.48 mmol) and n-propylboronic acid (1.32 g, 15.0 mmol) to give ethyl 3-methyl-6-propylpyrazine-2-carboxylate. MS (APCI): m/z 209 (M+H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1
Reactant: CN1CCN(c2ccc(CO)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(C=O)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A solution of 4-(4-formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.3 g, 4.47 mmol) in THF (50 mL) was mixed with LAH (0.7 g, 17.87 mmol) and stirred at reflux for 14 h. The reaction was quenched at room temperature by adding KOH aqueous (14 N, 20 mL). The supernatant was decanted and combined with DCM washings, then diluted with water (50 mL). The mixture was extracted with DCM (3×50 mL) followed by concentration using a rotary evaporator to give [4-(4-methyl-piperazin-1-yl)-phenyl]-methanol (0.82 g, 89%). To a solution of DMSO (0.56 mL, 7.96 mmol) in DCM (50 mL) at −78° C. was added oxalyl chloride (0.7 mL, 7.96 mmol) and the resulting mixture was stirred at −78° C. for 0.5 h. A solution of [4-(4-methyl-piperazin-1-yl)-phenyl]-methanol (0.82 g, 3.98 mmol) in DCM (20 mL) was slowly added. The reaction was stirred at −78° C. for 1.5 h. Triethylamine (1.7 mL, 11.94 mmol) was added and the reaction was allowed to gradually warm up to room temperature. After stirring for 4 h the reaction was quenched by adding sodium bicarbonate aqueous (1 N, 50 mL). The mixture was extracted with DCM (3×50 mL) followed by concentration to afford a residue, which was further purified by column chromatography to yield 4-(4-methyl-piperazin-1-yl)-benzaldehyde (0.5 g, 61%).
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10](=O)[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=O)[CH:7]=[CH:6][C:5]=12.C([O-])(O)=O.[Na+].CO[C:28]([CH3:31])([CH3:30])[CH3:29]>CO>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[N:1]=[C:5]([CH2:29][C:28]4[CH:31]=[C:11]([CH:10]=[CH:8][CH:30]=4)[C:13]#[N:14])[NH:4][C:11]=3[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)[CH:7]=[CH:6][C:5]=12
Reactant: COC(C)(C)C
Reactant: Cc1cccc(C(=O)C(=O)c2ccc3ncnn3c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(-c2[nH]c(Cc3cccc(C#N)c3)nc2-c2ccc3ncnn3c2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33 %

Procedure:
To a stirred solution of 1-((1,2,4)triazolo(1,5-a)pyridin-6-yl)-2-(6-methylpyridin-2-yl)ethane-1,2-dione (4.00 g, 15.02 mmol) in a mixture of tert-butyl methyl ether (30 mL) and MeOH (30 mL) were added 3-(fomylmethyl)benzonitrile (prepared according to the method described in WO 02/096875 A1) (6.54 g, 45.07 mmol) and NH4OAc (11.58 g, 150.24 mmol), and the mixture was stirred at room temperature for 90 min. The pH of the mixture was adjusted to 8 with saturated aqueous NaHCO3 solution. After removal of solvent, the mixture was extracted with EtOAc (2×150 mL), and the EtOAc solution was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of MeOH and CH2Cl2 (1:19 (v/v)) as eluent to give the titled compound (1.92 g, 33%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.70 (br s, 1H), 9.53 (br s, 1H), 8.49 (s, 1H), 7.96 (dd, 1H, J=9.2, 1.8 Hz), 7.84 (d, 1H, J=2.0 Hz), 7.82 (d, 1H, J=9.2 Hz), 7.74-7.71 (m, 2H), 7.69 (t, 1H, overlapped, J=7.6 Hz), 7.56 (t, 1H, J=7.8 Hz), 7.47 (br s, 1H), 7.15 (d, 1H, J=7.6 Hz), 4.18 (s, 2H), 2.47 (s, 3H); MS (ESI) m/z 392.18 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][N:10](C(OCC)=O)[CH2:9][C@H:8]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)N1CC[C@H](Oc2ccc(Br)cc2)[C@H](c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Product: Brc1ccc(O[C@H]2CCNC[C@H]2c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 7.28 g of cis-4-(4-bromophenoxy)-1-ethoxycarbonyl-3-phenylpiperidine, 48 ml of 20% aqueous sodium hydroxide solution and 90 ml of absolute ethanol is refluxed overnight under nitrogen. The mixture is cooled and partitioned between 50 ml of water and 100 ml of ether. The aqueous phase is extracted with ether (100 ml), and the combined organic phases are concentrated in vacuo. The resulting solid is dissolved in dichloromethane (100 ml) and washed with saturated sodium chloride solution. After drying over anhydrous sodium sulfate, filtration and concentration in vacuo affords a nearly colorless solid. The solid is dissolved in 200 ml of boiling hexane and the solution is reduced after boiling down in volume to about 150 ml. The solution is filtered, allowed to cool to room temperature and refrigerated overnight to afford product as a nearly colorless, crystalline solid, mp 113°-115° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[S:25]([C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1)(=[O:28])(=[O:27])[NH2:26]>>[S:25]([C:29]1[CH:30]=[C:31]([NH:35][C:22]([C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)=[N:10][C:11]=23)=[O:23])[CH:32]=[CH:33][CH:34]=1)(=[O:27])(=[O:28])[NH2:26]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(F)c(F)c3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(F)c(F)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-difluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.21) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 498.2 [(M+H)+]; mp 275° C.