Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[C:3]=1[CH3:24].[CH3:25][O:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[C:27]([O:26][CH3:25])=[N:28][CH:29]=[CH:30][CH:31]=5)[C:3]([CH3:24])=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(Cl)c1C
Reactant: COc1ncccc1B(O)O
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: CCOC(C)=O
Product: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)cc(C)c1C
Temperature: 80 °C
Yield: 93 %

Procedure:
To N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (100 mg, 0.29 mmol), 2-methoxypyridin-3-ylboronic acid (67 mg, 0.44 mmol) and tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol) in 1,2-dimethoxyethane (3.0 mL), 2 M Na2CO3 (438 μL, 0.88 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 68 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide as a pale yellow solid (112 mg, 92.4%). ESI-MS m/z calc. 415.5. found 416.5 (M+1)+. Retention time 1.68 minutes.
Reaction SMILES: C(O/[CH:4]=[C:5](/[C:11](=O)[C:12]([F:15])([F:14])[F:13])\[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[NH:18]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[NH2:19]>C(O)C>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([N:18]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=[N:19]2)=[CH:21][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(NN)cc1
Reactant: CCO/C=C(\C(=O)OCC)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(C#N)cc2)c1C(F)(F)F
Temperature: -10 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
A solution of (Z)-ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (2.41 g, 10.03 mmol) in ethanol (10 mL) was added dropwise to a stirred solution of 4-hydrazinylbenzonitrile hydrochloride (1.702 g, 10.03 mmol), in ethanol (50 mL) cooled to −10° C. The resulting solution was allowed to stir at room temperature for 16 hours. The reaction mixture was evaporated to dryness and the residue redissolved in EtOAc (100 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica (120 g) chromatography, elution gradient 10 to 60% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.400 g, 77%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>>[CH:19]1([C:22]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:23])[CH2:21][CH2:20]1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)C1CC1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)C4CC4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.068 mMol) cyclopropanecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.C(=O)([O-])[O-:20].[Na+].[Na+]>C(O)C>[CH:14]1[CH:15]=[CH:16][C:11]([CH:9]2[O:10][CH:8]2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:20])=[CH:12][CH:13]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: O=C(c1ccccc1)C1OC1c1ccccc1
Reaction time: 3 h
Yield: 22 %

Procedure:
1.040 g (5 mmol) of chalcone was dissolved in 15 ml of ethanol and to the solution was added 2 ml of 25% hydrogen peroxide and 2 ml of an aqueous solution of 1 M sodium carbonate. The precipitate which was formed after stirring for 3 h was isolated and recrystallized from DMSO-water to give 250 mg (22%) of chalcone epoxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[N:3]=[C:4]([CH2:8][C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cccc(Cl)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2cccc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.22 ml of 2-chloro-6-methylpyridine in 12.5 ml of tetrahydrofuran was added 1.4 ml of a hexane solution containing 1.58 M n-butyl lithium at 0° C., followed by stirring the reaction mixture at 0° C. for 30 minutes. After cooling down to −78° C., a solution of 403.7 mg of tert-butyl 4-oxo-1-piperidinecarboxylate in 1 ml of tetrahydrofuran was added to the solution, followed by gradually warming up the reaction mixture to −40° C. To the reaction mixture was added saturated aqueous ammonium chloride solution, followed by extracting with chloroform. The resulting chloroform layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1−3/2) to give the title compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O.[Cl-].[NH4+].C1C[O:30]CC1>CCCCCC>[OH:30][C:21]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1
Reactant: CN1CCCCC1=O
Reactant: C1CCOC1
Reactant: Brc1cccc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: CN1CCC(O)(c2cccc3ccccc23)CC1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 1-bromonaphthalene (2.7 g, 13 mmol) in THF (40 mL) was added dropwise a 1.63 M solution of n-butyllithium (7.3 mL, 12 mmol) in hexane at −78° C. over 10 minutes. The reaction mixture was then stirred for 30 minutes and a solution of N-methylpiperidone (1.1 g, 10 mmol) in THF (2 mL) was added dropwise to the reaction mixture. After stirring the reaction mixture for 2 hours, a saturated aqueous ammonium chloride(10 mL) was added to the reaction mixture, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated, and the resulting crude crystals were recrystallized from chloroform/hexane to afford the title compound (1.5 g, yield: 63%) as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=O)=[CH:16][N:15]=1>N1C=CC=CC=1>[F:13][C:14]1[N:15]=[CH:16][C:17]([C:18]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)=[CH:21][CH:22]=1
Reactant: N#Cc1cccc(C(N)=NO)c1
Reactant: O=C(Cl)c1ccc(F)nc1
Solvent: c1ccncc1
Product: N#Cc1cccc(-c2noc(-c3ccc(F)nc3)n2)c1
Temperature: 25 °C

Procedure:
3-Cyano-N′-hydroxybenzimidamide (0.322 g, 1 mmol) was dissolved in pyridine 10 mL and 6-fluoronicotinoyl chloride (Frontier Scientific, 0.160 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-d6) δ 7.56-7.52 (m, 1 H), 7.85 (t, J=7.9 Hz, 1 H), 8.15-8.12 (m, 1 H), 8.43-8.41 (m, 1 H), 8.49 (m, 1 H), 8.8-8.74 (m, 1 H), 9.11-9.0 (m, 1 H) ppm; MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)OC(C2C=CC=CC=2)[CH:12]2[CH:16](O)[CH2:15][N:14](C(=O)CCCCC[N:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])[CH2:13]2)=CC=1.C1(C)C=CC=CC=1.C(CC[O:61][P:62]([N:70](C(C)C)C(C)C)N(C(C)C)C(C)C)#N.C(OCC)(=[O:79])C>CCCCCC>[NH:14]1[CH2:15][CH2:16][CH2:12][CH2:13]1.[P:62]([NH2:70])([O-:61])[O:79][N:24]1[C:32](=[O:33])[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:26]2[C:25]1=[O:34]
Reactant: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCN3C(=O)c4ccccc4C3=O)CC2O)c2ccc(OC)cc2)cc1
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Reactant: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C1CCNC1
Product: NP([O-])ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Compound 77 (1.5 g, 2.26 mmol) was coevaporated with anhydrous toluene (25 mL). To the residue N,N-tetraisopropylammonium tetrazolide (0.127 g, 1.13 mmol) was added and the mixture was dried over P2O5 in a vacuum oven for overnight at 40° C. The reaction mixture was dissolved in acetonitrile/dichloroethane (10 mL) and 2-cyanoethyl-N,N,N′,N′-tetraisopropylphosphorodiamidite (1.362 g, 1.49 mL, 4.52 mmol) was added. The reaction mixture was stirred at ambient temperature for overnight. The completion of the reaction was ascertained by TLC (Rf=0.4 in 1:1 ethyl acetate:hexane). The reaction mixture was concentrated undervacuum and the residue was dissolved in ethyl acetate (100 mL). The organic layer was washed with 5% NaHCO3 (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4 filtered and concentrated under reduced pressure. The residue was purified over silica gel (50:49:1, EtOAc:Hexane:triethlyamine) to afford compound 78 as white solid (1.66 g, 85%).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=[O:14]>CO.[Pd]>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)Cn1c(=O)ccc2cnccc21
Agent: [Pd]
Solvent: CO
Product: O=C(O)CN1C(=O)CCc2cnccc21
Reaction time: 18 h

Procedure:
A suspension of 2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetic acid (150 mg, 0.734 mmol) and Pd/C (20 mg) in methanol was shaken under a 40 psi atmosphere of H2 for 18 h. The suspension was filtered through Celite and the filtrate was concentrated under vacuum to give 2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetic acid. Retention time (min)=0.343, method [3], MS (ESI) 207.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1C=[C:4]([Cl:24])[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[Cl:25]NC(=O)CCC(N)=O.N.[CH2:35]([Cl:37])Cl>>[NH2:1][C:2]1[C:35]([Cl:37])=[C:4]([Cl:24])[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[C:23]=1[Cl:25]
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(N)cc(Cl)c21
Reactant: NC(=O)CCC(=O)NCl
Reactant: ClCCl
Agent: N
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2c(Cl)c(N)c(Cl)c(Cl)c21

Procedure:
4.75 g (0.014 mol) of 7-amino-9-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one are dissolved in 100 ml of dry methylene chloride and treated with 4.2 g of N-chlorosuccinamide. The reaction mixture is heated at reflux for 40 hours, treated with 25 percent aqueous ammonia and extracted several times with methylene chloride. After drying and evaporating the organic phase, the residue is chromatographed on 250 g of silica gel with methylene chloride/ethyl acetate (20:1) as the elution agent. There is obtained 7-amino-6,8,9-trichloro-1,3-dihydro-5-(o-fluorophenyl)-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 165°-166° (ether/n-hexane).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Cl.[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH:1]2[CH2:2][CH2:3]2)[CH:9]=1
Reactant: Clc1ccncc1
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: C1CCOC1
Product: Clc1ccnc(C2CC2)c1

Procedure:
The title compound is prepared according to a modification of a procedure described in the literature [Comins, D. L.; Mantlo, N. B., Journal of Organic Chemistry, (1985), 50, 4410-4411]. Cyclopropylmagnesium bromide (0.5M in THF, 100 mL, 50 mmol, 2.2 eq) is added in one portion to a cold (−78° C.) suspension of 4-chloropyridine hydrochloride (3.4 g, 22 mmol) in THF (68 mL).
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[C:5]=1[O:6]/[CH:7]=[CH:8]/[C:9]([O:11]CC)=[O:10])([CH3:3])[CH3:2].[OH-].[K+]>O.C(O)C>[CH:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[C:5]=1[O:6]/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/Oc1c(C(C)C)cccc1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1O/C=C/C(=O)O
Yield: 66.4 %

Procedure:
Ethyl (E)-3-(2,6-diisopropylphenoxy)acrylate (250 mg, 0.91 mmol) was combined with 0.5 g of solid KOH in 10 mL of a mixture of water/ethanol (20:80), and the mixture was refluxed overnight. The solvent was removed under reduced pressure. The residue was acidified with 5% HCl solution and then extracted with three 25 mL portions of ethyl acetate. The ethyl acetate solution was extracted with saturated sodium chloride solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 150 mg (60%) of (E)-3-(2,6-diisopropylphenoxy)acrylic acid 30b. 1H NMR (400 MHz, CDCl3) 1.17-1.19 (d, 12H), 2.98-3.05 (m, 2H), 5.05-5.08 (d, 1H, J=12.4 Hz), 7.14-7.22 (m, 3H), 7.81-7.85 (d, 1H, J=12.4 Hz). MS (ESI): 271 [M+Na].
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH:2](C)C.C(N(CC)CC)C.[N:25]([CH2:28][CH2:29][CH3:30])=[C:26]=[O:27]>C(Cl)Cl>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([NH:17][C:26]([NH:25][CH2:28][CH2:29][CH3:30])=[O:27])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH3:2]
Reactant: CCCN=C=O
Reactant: CC(C)CN1CCN(c2ccc(N)cn2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)Nc1ccc(N2CCN(CC)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.2 %

Procedure:
A mixture of 20 mg (0.1 mmol) 6-(4-isobutyl-piperazin-1-yl)-pyridin-3-ylamine, 15 mg (0.15 mmol) triethylamine and 9.4 mg (0.11 mmol) 1-isocyanato-propane in 1 ml DCM was stirred at room temperature for 16 h. After evaporation the residue was taken up in 1 ml methanol/acetonitrile 1/1 and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 15.5 mg (53%) of the title compound. (m/e): 292.3 (MH+; 100%).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.C[Mg]Br.O1CCCC1.[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:25]=[O:26])[CH:24]=1>>[Br:18][C:19]1[CH:24]=[C:23]([CH:25]([OH:26])[C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)[CH:22]=[N:21][CH:20]=1
Reactant: Ic1ncn2ccsc12
Reactant: O=Cc1cncc(Br)c1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: OC(c1cncc(Br)c1)c1ncn2ccsc12
Yield: 89.3 %

Procedure:
7-[(5-Bromopyridin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole (2.77 g) was prepared in substantially the same manner as in step a) of Synthesis Example 1, except that 2.50 g of 7-iodoimidazo[5,1-b]thiazole, 12.2 ml of a 0.93 M methylmagnesium bromide/tetrahydrofuran solution, and 2.05 g of 3-bromo-5-formylpyridine were used as the starting materials.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[S:13][CH:12]=[N:11][CH:10]=1.CCCCCC.C([Li])CCC.CN(C)[CH:27]=[O:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[S:13][C:12]([CH:27]=[O:28])=[N:11][CH:10]=1
Reactant: c1ncc(COC2CCCCO2)s1
Reactant: CN(C)C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ncc(COC2CCCCO2)s1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole (7.44 g) in tetrahydrofuran (100 mL) was slowly added a 1.6M n-butyllithium hexane solution (25.6 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 30 min and N,N-dimethylformamide (8.0 g) was added. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (6.91 g, yield 82%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). MS: 228 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[H-].[Na+].Br[CH2:17]COC1CCCCO1>CN(C=O)C>[Cl:12][C:7]1[CH:6]=[C:5]([CH:4]2[CH2:17][CH2:1][O:2][C:3]2=[O:13])[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 58.4 %

Procedure:
A mixture of 30 g (137 mmol) (3,4-Dichloro-phenyl)-acetic acid methyl ester (commercially available), 6.47 g (151 mmol) NaH (55%) and 35.8 g (171 mmol) 2-(2-Bromo-ethoxy)-tetrahydro-pyran in 100 mL DMF was stirred at room temperature for 17 h. The mixture was evaporated to dryness and partitioned between water and ethyl acetate. The combined organic phases were washed with NaCl aq., dried with Na2SO4 and evaporated. The residue was treated with 400 mL 4N HCl in dioxane in 250 mL methanol and stirred for 16 h at room temperature. The mixture was evaporated to dryness and subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The combined product fractions were evaporated to yield 18.5 g (58%) of the title compound as yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[C:26]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]>CO.C(Cl)Cl>[C:26]([N:29]1[CH2:34][CH2:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=3)=[O:10])=[C:4]([C:18]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=3)[CH:3]=2)([OH:35])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CC(=O)N1CCC(=O)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCC(O)(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1
Yield: 64 %

Procedure:
The title compound was prepared by the procedure of Example 11 using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g), 80.0 mg, 0.200 mmol) and 1-acetyl-piperidin-4-one (123 μL, 1.00 mmol). Silica gel chromatography (2-5% MeOH/DCM) afforded the title compound (59.1 mg, 64%) as a colorless oil. 1H-NMR (CD3OD; 400 MHz): δ 8.18 (d, 1H, J=8.6 Hz), 8.00 (s, 1H), 7.39 (dd, 1H, J=8.6, 2.3 Hz), 7.35 (d, 1H, J=2.3 Hz), 5.74 (m, 1H), 4.45 (m, 1H), 3.84 (m, 1H), 3.60 (m, 1H), 3.11 (m, 1H), 2.28-2.35 (m, 2H), 2.15 (s, 3H), 1.91-2.10 (m, 4H), 1.76 (m, 2H), 1.59 (t, 2H, J=6.3 Hz), 1.09 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H31N5O3, 462.2 (M+H). found 462.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:3][CH2:2]1.[Cl:16][CH2:17][CH2:18][CH2:19][CH:20]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[ClH:16].[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH:20]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:19][CH2:18][CH2:17][N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[S:9][N:8]=3)[CH2:5][CH2:6]2)=[CH:26][CH:25]=1
Reactant: c1ccc2c(C3CCNCC3)nsc2c1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: Fc1ccc(C(CCCN2CCC(c3nsc4ccccc34)CC2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
A mixture of 5.0 g of 3-(4-piperidinyl)-1,2-benzisothiazole, 7.70 g of 4-chloro-1,1-bis(4-fluorophenyl)butane, 7.0 g of potassium carbonate, 0.25 g of potassium iodide and 120 ml of dimethylformamide was stirred at 90° for 8.0 hrs and overnight at ambient temperature. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The product was purified by high-pressure liquid chromatography using dichloromethane:methanol (2%) as the eluent. The eluent was evaporated, the residue was dissolved in ether and a saturated hydrogen chloride/ether solution was added dropwise to yield a solid. The solid was recrystallized from ethyl acetate/ether to give 2.0 g (21%) of product, mp 198°-199°.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH3:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C([O-])(=O)C.[Na+].[H][H]>[Pd].C(O)(=O)C>[NH:14]1[CH2:15][CH2:16][CH2:17][CH:12]([CH:10]([N:6]2[C:5]3[CH:18]=[CH:19][CH:2]=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])[CH3:11])[CH2:13]1
Reactant: CC(c1cccnc1)n1c(=O)[nH]c2cc(Cl)ccc21
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C1CCCNC1)n1c(=O)[nH]c2ccccc21
Yield: 100 %

Procedure:
A mixture of 24 parts of 5-chloro-1,3-dihydro-1-[1-(3-pyridinyl)ethyl]-2H-benzimidazol-2-one, 10 parts of sodium acetate and 400 parts of acetic acid is hydrogenated at normal pressure and at a temperature of 60° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and the whole is alkalized with concentrated ammonium hydroxide. The product is extracted three times with 300 parts of trichloromethane. The combined extracts are dried, filtered and evaporated, yielding 22 parts (100%) of 1,3-dihydro-1-[1-(3-piperidinyl)ethyl]-2H-benzimidazol-2-one as an oily residue.