Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]([N:8]=[CH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1OC)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH:22]([Li])([CH3:24])[CH3:23]>C1COCC1>[CH:22]([C:11]1[CH:12]=[C:13]([O:18][CH3:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=1[CH:9]=[N:8][CH:4]([CH:1]([CH3:2])[CH3:3])[CH:5]([CH3:6])[CH3:7])([CH3:24])[CH3:23]
Reactant: COc1cc(OC)c(OC)cc1C=NC(C(C)C)C(C)C
Reactant: [Li]C(C)C
Solvent: C1CCOC1
Product: COc1cc(C=NC(C(C)C)C(C)C)c(C(C)C)cc1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-isopropyl-2-methyl-propyl)-(2,4,5-trimethoxy-benzylidene)-amine (1.024 g, 3.5 mmol) in 35 ml THF at −78° C. was added isopropyllithium (6.0 mL, 0.7 M in pentane) drop-wise over 5 minutes. The solution was allowed to stir 30 min at −78° C. After warming to room temperature over 45 minutes the mixture was quenched by the addition of 5 mL of 10% NH4Cl and concentrated in vacuo. 100 mL of H2O was added and the mixture was extracted with ethyl acetate, washed with H2O and then brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give (2-isopropyl-4,5-dimethoxy-benzylidene)-(1-isopropyl-2-methyl-propyl)-amine as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[OH:11])[S:7][C:6]=2[C:14]=1[Cl:15].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[Cl:1][C:2]1[C:3]([O:16][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:11])([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cc2cc(C(C)(C)O)sc2c(Cl)c1Cl

Procedure:
To a mixture of 6,7-dichloro-5-hydroxy-α,α-dimethylbenzo[b]thiophene-2-methanol in 250 ml of 2-butanone is added a solution of 7.7 g of t-butyl bromoacetate in 50 ml 2-butanone and the resultant mixture is placed in a preheated oil-bath at 95°. To the mixture is added 6.7 g of potassium carbonate and 3 ml of dimethylformamide and the reaction mixture is refluxed at 95° for 21/2 hrs. The cooled mixture is filtered and 100 ml of water is added. The layers are separated and the aqueous phase is extracted two times with ethyl ether. The organic extracts are washed, dried over anhydrous magnesium sulfate, filtered and concentrated to give a solid. Recrystallization from ethyl ether and pentane gives 11.5 g of t-butyl [[6,7-dichloro-2-(1-hydroxy-1-methylethyl)benzo[b]thien-5-yl]oxy]acetate, mp 137°-138°.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:16](C(OC(C)(C)C)=O)[C:9]2=[N:10][C:11]([Cl:15])=[C:12]([CH3:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH2:2]([O:3][C:4]([C:6]1[NH:16][C:9]2=[N:10][C:11]([Cl:15])=[C:12]([CH3:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C)c(Cl)nc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(C)c(Cl)nc2[nH]1

Procedure:
A solution of 0.53 g (1.56 mmol) 6-chloro-5-methyl-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 8 mL dichloromethane was cooled to 0° C., 1.44 mL (2.14 g, 18.8 mmol) trifluoroacetic acid was added and the cooling bath removed. After 2 h the volatile components were removed and the residue was poured into saturated aqueous sodium bicarbonate solution and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The resulting off-white solid (91.1%) was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]([CH3:20])=[CH2:19]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:19][C:18](=[CH2:17])[CH3:20]
Reactant: C=C(C)CCl
Reactant: Cc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1cc(C)ccc1C

Procedure:
To a solution 122.2 g of 2,5-dimethylphenol in 300 ml of acetone was added 83 g of anhydrous potassium carbonate and 150 ml of 3-chloro-2-methylpropene. After refluxing for 65 hours, the reaction mixture was filtered and concentrated under reduced pressure and diluted with 200 ml diethyl ether. The mixture was washed three times with 100 ml of 10% aqueous solution of sodium hydroxide. The combined organic extracts were washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under the reduced pressure to afford 168 g of methallyl 2,5-dimethylphenyl ether as colorless oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH3:16][Si:17]([CH3:21])([CH3:20])[CH2:18][NH2:19].Cl.CN(C)CCCN=C=NCC.O>ClCCl>[Br:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:19][CH2:18][Si:17]([CH3:21])([CH3:20])[CH3:16])=[O:15])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)c2ccccc12
Reactant: C[Si](C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CNC(=O)c1ccc(CBr)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
4-(bromomethyl)naphthalen-1-carboxylic acid (7 g), 1-(trimethylsilyl)methylamine (2.7 g), N,N-dimethylaminopyridine (0.1 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (6.6 g) were dissolved in dichloromethane (30 ml), and stirred for 5 hours at room temperature. Water was added to the reaction mixture, and then organic layers, were separated and dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 4-(bromomethyl)-N-[(trimethylsilyl)methyl]naphthalene-1-carboxamide (3 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=2[F:14])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:14][C:8]1[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[S:3][CH:4]=1
Reactant: Fc1cccc(-c2csc(Br)n2)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(F)c3F)cs2)CC1
Yield: 45.1 %

Procedure:
A solution of 2-bromo-4-(2,3-difluorophenyl)-1,3-thiazole (6.74 g, 24.4 mmol), tert-butyl piperazine-1-carboxylate (9.09 g, 48.4 mmol) and potassium carbonate (3.37 g, 24.4 mmol) in dimethylformamide (80 ml) was stirred at 120° C. for 13 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and crystals were collected by filtration to give 4.20 g (45.1%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:32][CH2:33][N:28]([C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: Cc1cccc(C)c1N1CCNCC1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2c(C)cccc2C)CC1
Yield: 67 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 67%). 1H NMR (300 MHz, CDCl3): δ 2.33-2.40 (m, 6H), 3.14-3.22 (m, 4H), 3.69-3.76 (m, 3H), 4.06-4.18 (m, 4H), 6.97-7.04 (m, 3H), 7.20-7.85 (m, 4H).
Reaction SMILES: [CH2:1]([S:8](Cl)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14](=[O:26])[N:15]([CH2:23][CH:24]=[CH2:25])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1>N1C=CC=CC=1>[CH2:1]([S:8]([NH:12][C:13]1[C:14](=[O:26])[N:15]([CH2:23][CH:24]=[CH2:25])[C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCn1c(C(F)(F)F)ccc(N)c1=O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCn1c(C(F)(F)F)ccc(NS(=O)(=O)Cc2ccccc2)c1=O
Yield: 96.7 %

Procedure:
Benzylsulfonyl chloride (103 mg, 0.542 mmol) was added to a stirred solution of 3-amino-6-trifluoromethyl-1-allyl-2-pyridinone (106.5 mg, 0.488 mmol) in pyridine (1 ml) at 0° C. After 1 h the reaction was evaporated in vacuo and the residue was partitioned between methylene chloride and 10% potassium hydrogen sulfate solution, dried (Na2 SO4), and evaporated in vacuo to give the title compound (175.8 mg): 1H NMR (CDCl3) selected signals at δ4.42 (s, 2H), 4.74 (d, J=5.5 Hz, 2H), 5.16-5.31 (m, 2H), 5.86-5.96 (m, 1H), 6.55 (d, J=7.7 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.27-7.33 (m, 5H), 7.70 (br s, 1H, NH).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>ClCCl>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:30](=[O:31])[CH2:29][Cl:28])[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)C1CCC(Oc2ccc3c(c2)CCN3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CCN3C(=O)CCl)CC1
Reaction time: 4 h

Procedure:
A solution of 5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-1H-indole (0.55 g, 2 mmol), triethylamine (0.56 mL, 4 mmol) in dichloromethane (8 mL) was added chloroacetyl chloride (0.2 mL, 2.6 mmol) at 0° C. The solution was stirred from 0° C. to room temperature for 4 hrs. The solution was diluted with dichloromethane and washed with 5% aqueous citric acid, aqueous sodium biocarbonate, and water, dried over MgSO4 and concentrated. The residue was purified with silica gel column eluted with ethyl acetate in hexane to give product 90.37 g, yield: 52%). ESI-MS: 350.2 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([CH2:17][CH3:18])[C:6]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=O)C.C[O-].[Na+].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CO.C1COCC1>[CH2:17]([C:7]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]([OH:4])[C:14]2[C:9]([CH:8]=1)=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH3:18]
Reactant: CCc1cc2cc(OC)ccc2c(OC(C)=O)c1-c1ccccc1
Agent: C[O-]
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of 3-ethyl-6-(methyloxy)-2-phenyl-1-naphthalenyl acetate (56) (0.61 g, 1.90 mmol) in MeOH (20 mL) and THF (20 mL) was added NaOMe (0.5M in MeOH, 10 mL). The mixture was stirred at room temperature for 3 h. Cooled to room temperature, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.74 g, 7.50 mmol) was added. Most of the solvent was removed and the residue was diluted with water (20 mL) and acidified with 5 N HCl. The mixture was extracted with CH2Cl2. The extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (10:1) to give 0.52 g (98%) of compound 57 as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.08 (t, J=7.5 Hz, 3H), 2.49 (q, J=7.5 Hz, 2H), 3.93 (s, 3H), 5.14 (s, 1H), 7.05-7.10 (m, 2H), 7.24 (s, 1H), 7.32-7.38 (m, 2H), 7.42-7.48 (m, 1H), 7.50-7.56 (m, 2H), 8.05-8.10 (m, 1H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([CH3:21])[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[C:14]([CH3:21])[CH:13]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: COc1ccc(B(O)O)c(C)c1
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: COc1ccc(-c2cc(C=O)c(C)o2)c(C)c1
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.5 g), 4-methoxy-2-methylphenylboronic acid (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.5 g), 2N aqueous sodium carbonate solution (10 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.7 g, 94%) as a pale-yellow solid.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.CO>CO>[CH3:3][CH:2]([CH3:4])[C:1]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CC(C)C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 132.9 %

Procedure:
To a stirred mixture of tert-butyl 4-isobutyrylpiperazine-1-carboxylate (6.8 g, 26.5 mmol) in methanol (15 mL) was added hydrochloride/methanol (30 mL, 3M)) at 0° C. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was concentrated to give 2-methyl-1-(piperazin-1-yl)propan-1-one (5.5 g, yield: 100%) as an off-white solid. 1H-NMR (400 MHz, CDCl3) δ: 3.82 (brs, 1H), 5.19 (s, 3H), 6.91-6.95 (m, 1H), 7.32-7.36 (m, 2H); LC-MS (ESI) m/z: 157(M+1)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[C:14](B(O)O)=[CH:13][CH:12]=[CH:11][N:10]=1.Br[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:32][CH:33]=1)[C:22]#[N:23]>O1CCOCC1.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>[CH2:35]([O:34][C:31]1[N:30]=[CH:29][C:28]([O:27][C:26]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[C:14]2[C:9]([O:8][CH3:7])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:33][CH:32]=1)[CH:36]([CH3:38])[CH3:37]
Reactant: COc1ncccc1B(O)O
Reactant: CC(C)COc1ccc(Oc2ccc(C#N)cc2Br)cn1
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: [K+]
Solvent: C1COCCO1
Product: COc1ncccc1-c1cc(C#N)ccc1Oc1ccc(OCC(C)C)nc1
Temperature: 60 °C
Yield: 79.2 %

Procedure:
Potassium carbonate (0.239 g, 1.73 mmol) and (2-methoxypyridin-3-yl)boronic acid (0.162 g, 0.950 mmol) were added to a solution of 3-bromo-4-[(6-isobutoxypyridin-3-yl)oxy]benzonitrile (Preparation 6, 0.300 g, 0.864 mmol) in dioxane (10 mL). The reaction was degassed three times. Tetrakis(triphenylphosphine)palladium(0) (0.010 g, 0.009 mmol) was added and the mixture was degassed three times more. The mixture was heated at 60° C. for 24 hours, then allowed to cool to room temperature and filtered through arbocel, washing with DCM/MeOH (1/1, 50 mL). The combined filtrates were concentrated in vacuo. The residue was absorbed onto silica and purified by silica gel chromatography (Biotage®, SNAP cartridge 50 g, gradient from 5 to 10% EtOAc in heptane 6, then 10% EtOAc in Heptane) to yield the title compound as a solid (0.257 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N:15]=[CH:16][N:17]([CH2:19][CH3:20])[CH3:18])=[C:10]([CH3:21])[CH:9]=2)=[N:4][C:3]=1[CH:22]=O.Cl.[NH2:25][O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CO>O>[C:27]([O:26][N:25]=[CH:22][C:3]1[N:4]=[C:5]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N:15]=[CH:16][N:17]([CH2:19][CH3:20])[CH3:18])=[C:10]([CH3:21])[CH:9]=2)[S:6][C:2]=1[Cl:1])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)ON
Reactant: CCN(C)C=Nc1cc(C)c(Oc2nc(C=O)c(Cl)s2)cc1C
Agent: Cl
Solvent: O
Solvent: CO
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(C=NOC(C)(C)C)c(Cl)s2)cc1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 74 %

Procedure:
A solution of 0.23 g (0.50 mmol) of N′-{4-[(5-chloro-4-formyl-1,3-thiazol-2-yl)oxy]-2,5-dimethylphenyl}-N-ethyl-N-methylimidoformamide and 63 mg (0.50 mmol) of 2-(aminooxy)-2-methylpropane hydrochloride in a solvent mixture of 10 ml of methanol and 3 ml of water was stirred at ambient temperature for 5 days. Evaporation of the solvents and column chromatography of the crude mixture (gradient cyclohexane->ethyl acetate) yielded 130 mg (0.37 mmol) 61% of N′-[4-({4-[(tert-butoxyimino)methyl]-5-chloro-1,3-thiazol-2-yl}oxy)-2,5-dimethylphenyl]-N-ethyl-N-methylimidoformamide. Log P (pH 2.3)=2.65
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[Li]CCCC.[C:22](=[O:24])=[O:23]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([F:14])([F:15])[F:16])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[C:8]=1[C:22]([OH:24])=[O:23]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 1-methoxy-3,5-bis(trifluoromethyl)benzene (48, 0.56 g, 2.33 mmol) in anhydrous ether (5 mL) was slowly added n-BuLi (1.6 M solution in hexanes, 3 mL, 4.66 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. Dry ice was added into the yellow suspension until the starting material was completely consumed as monitored by TLC. The reaction was quenched with H2O (3 mL) and organic layer was separated. The aqueous layer was acidified with concentrated HCl, and then extracted with Et2O (3×5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-methoxy-4,6-bis(trifluoromethyl)benzoic acid (49, 0.38 g, 50%): 1H NMR (300 MHz, DMSO-d6) δ 13.94 (s, 1H), 7.76 (s, 1H), 3.97 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:33].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:33])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(OC(F)(F)F)cc1
Reactant: ClCCl
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(OC(F)(F)F)cc1

Procedure:
Subsequent chlorination (70° C.; 4h30) of 3-ethyl-8-[2-(4-trifluoromethoxy-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.200 g; 2.731 mmol), and purification by FC (DCM/MeOH=50/1) afforded 1-chloro-3-ethyl-8-[2-(4-trifluoromethoxy-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (0.810 g; 63%). LC-MS: tR=1.08 min.; [M+H]+=473.97 g/mol.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][C:12]3[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.O>[CH2:21]([N:18]([CH2:19][CH3:20])[C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[CH:24][CH:23]=1)[CH3:22]
Reactant: CCN(CC)C(=O)c1ccc(CN2CCC3(CC2)OCCO3)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)c1ccc(CN2CCC(=O)CC2)cc1
Reaction time: 72 h
Yield: 100.5 %

Procedure:
4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-ylmethyl)-N,N-diethylbenzamide (63.9 g, 192 mmol) is dissolved in 193 mL of tetrahydrofuran and treated with a solution of concentrated sulfuric acid (77 mL) in water (309 mL). The solution is allowed to stir for three days and then refluxed for 17 hours. It is neutralized with 2.5N NaOH and extracted with 400 mL, 200 mL and then 100 of methylene chloride. The pooled extracts are dried over Na2SO4 and concentrated in vacuo affording 58.74 g (193 mmol, 100% yield) of product as a yellow oil: IR (thin film) 3500, 2980, 2810, 1720, 1630 cm-1 ; 1H NMR (Me2SO-d6, 400 MHz) δ7.4 (d,J=8.1 Hz, 2H), 7.3 (d,J=8.2 Hz, 2H), 3-3.6 (m, 8H), 2.68 (t,J=6.1 Hz, 2H), 2.34 (t,J= 6.0 Hz, 2H), 1.1 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([C@@H:9]([NH2:16])[CH2:10][C:11]3[N:12]=[CH:13][NH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[C:29]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:30])[C:23](O)=[O:24].ClCl>ClCCl.CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([C@@H:9]([NH:16][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:28]([C:29]([N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[O:30])=[C:20]([CH3:19])[CH:21]=3)[CH2:10][C:11]3[N:12]=[CH:13][NH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: N[C@@H](Cc1c[nH]cn1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C(=O)N[C@@H](Cc2c[nH]cn2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 55 %

Procedure:
Prepared analogously to Example 10d from (S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-(1H-imidazol-4-yl)ethylamine and 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid. Yield: 55% of theory. Rf value: 0.72 (silica gel; dichloromethane/methanol=4:1); C25H25ClN6O2 (476.97); mass spectrum: (M+H)+=477/479 (chlorine isotope).
Reaction SMILES: [CH2:1](C([Sn])=C(CCCC)CCCC)[CH2:2]CC.Br[C:17]1[CH:22]=[C:21]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1[NH:36][C:37](=[O:45])[C@:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40]>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.[Pd].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]>[CH:1]([C:17]1[CH:22]=[C:21]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1[NH:36][C:37](=[O:45])[C@:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH2:2]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc1Br)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)ccc1NC(=O)[C@@](C)(O)C(F)(F)F
Reaction time: 7 h

Procedure:
Tributylvinyltin (0.28 ml) was added to a deoxygenated suspension of (R)-N-[2-bromo-4-(4-mesylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 140) (0.50 g) and tris(dibenzylideneacetone)dipalladium(O) (0.05 g) in anhydrous toluene (10 ml). The mixture was heated under reflux with stirring. After 14 hours a further portion of tris(dibenzylideneacetone)dipalladium(0) (0.05 g) and tributylvinyltin (0.28 ml) was added and heating was continued for a further 7 hours. The reaction mixture was allowed to cool and volatile materials were removed by evaporation. The residue was purified on a silica gel Mega Bond Elut column eluting with 5-50% ethyl acetate/hexane to give the title compound (0.146 g) as a solid. NMR (CDCl3) 1.74 (s, 3H), 3.06 (s, 3H), 5.65-5.82 (dd, 2H), 6.67-6.77 (dd, 1H), 7.86-7.89 (dd, 1H), 7.95 (s, 1H), 8.06-8.16 (m, 4H), 8.35 (d, 1H), 8.79 (s, 1H); MS (ESP−): 477.