Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:19]3[CH:20]=[C:21](C#N)[CH:22]=[CH:23][C:18]=3[NH:17][C:16]3[N:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:15]=3[CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH3:36][Mg]Br.Cl.[C:40]([O-:43])(O)=O.[Na+]>C1COCC1>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:19]3[CH:20]=[C:21]([C:40](=[O:43])[CH3:36])[CH:22]=[CH:23][C:18]=3[NH:17][C:16]3[N:26]=[C:27]([C:30]([F:31])([F:32])[F:33])[CH:28]=[CH:29][C:15]=3[CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: N#Cc1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reactant: C[Mg]Br
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbonitrile (702 mg, 1.365 mmol) in 5 ml of THF was added a solution of methyl magnesium bromide (4.87 ml, 6.82 mmol) in THF (1.4 M) at 0° C. The solution was heated to reflux for 8 h, then the solution was cooled to room temperature. Excess Grignard reagent was decomposed by the addition of 4 mL of 2N HCl and the solution was stirred for 1 hr at rt. The pH was adjusted to 7-8 with aqueous NaHCO3. The resulting solution was filtered and the solids were washed with CH2Cl2. To the filtrate was added 30 mL of CH2Cl2, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×20 ml), and the combined organic layers were dried with Na2SO4 and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (6:1-4:1) to give the title compound as a white solid; Mass Spectrum: m/e=591 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1)=O)=[O:7])[CH3:2].N12CCCN=C1CCCCC2>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:5]1[C:6](=[O:7])[N:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]=1[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1)=[O:23])[CH3:2]
Reactant: CCOC(=O)CC(=O)N1CCCN1C(=O)c1ccnc(SC)n1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)c1c(-c2ccnc(SC)n2)n2n(c1=O)CCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[2-(2-methylsulfanyl-pyrimidine-4-carbonyl)-pyrazolidin-1-yl]-3-oxo-propionic acid ethyl ester, 12, (9.6 g, 28.4 mmol) in DMF (280 mL) was added 1.8-diazabicyclo[5.4.0]-undec-7-ene (12.7 mL, 85.2 mmol). The reaction solution is stirred for 2 hours at room temperature then diluted with H2O. The aqueous phase is extracted three times with CHCl3. The combined organic phases are washed with aqueous saturated NH4Cl (×3), dried (MgSO4), filtered and concentrated in vacuo. The residue is purified over silica (5% MeOH/CHCl3) to afford 3.1 g of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=5.1 Hz, 1H), 7.61 (d, J=5.1 Hz, 1H), 4.33 (q, J=7.2 Hz, 2H), 4.31 (t, J=7.2 Hz, 2H), 4.09 (t, J=7.2 Hz, 2H), 2.74 (dddd, 7.2, 7.2, 7.2, 7.2 Hz, 2H), 2.61 (s, 3H), 1.35 (t, J=7.2 Hz, 3H); ESI+ MS: m/z (rel intensity) 321.1 (100, M++H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl>[CH2:15]([O:14][C:12](=[O:13])[CH:17]=[CH:7][C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][CH3:11])[CH3:16]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(F)cc1C=O
Solvent: ClCCl
Product: CCOC(=O)C=Cc1cc(F)ccc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.6 %

Procedure:
To a solution of 5-fluoro-2-methoxybenzaldehyde (4.3 g, 28.0 mmol) in dry CH2Cl2 (30 mL) at 0° C. was added carbethoxymethylenetriphenylphosphorane (10.7 g, 30.1 mmol) portion-wise and the reaction was warmed to room temperature and stirred for 12 h. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (EtOAc/hexane, 10:90, v:v, Rf=0.2) to yield the product (6.0 g, 95%) as a 4:1 mixture of trans:cis diastereomers; 1H NMR (CDCl3, 500 MHz): δ 7.93 (d, J=16.2 Hz, 0.8 H), 7.33 (dd, J=3.1, 9.2 Hz, 0.2 H), 7.21 (dd, J=3.1, 9.2, Hz, 0.8 H), 7.08 (d, J=12.5 Hz, 0.2 H), 7.03 (dt, J=3.0, 8.8 Hz, 0.8 H), 6.99 (dt, J=3.0, 8.8 Hz, 0.2 H), 6.84 (dd, J=3.1, 8.6 Hz, 0.8 H), 6.79 (dd, J=3.3, 9.1 Hz, 0.2 H), 6.47 (d, J=16.2 Hz, 0.8 H), 5.99 (d, J=12.5 hz, 0.2 H), 4.25 (q, J=7.1 Hz, 1.6 H), 4.15 (q, J=7.0 Hz, 0.4 H), 3.86 (s, 2.4H), 3.81 (s, 0.6 H), 1.34 (t, J=7.1 Hz, 2.4 H), 1.22 (t, J=7.0 Hz, 0.6 H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:10][CH:9]([C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12]#N)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:27].[OH-:31].[Na+]>>[CH:1]1([NH:7][CH2:8][CH:9]2[CH2:10][O:31][C:12](=[O:27])[C:11]2([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(O)O
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CN(C2CCCCC2)C1
Reactant: [OH-]
Agent: [Na+]
Product: O=C1OCC(CNC2CCCCC2)C1(c1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 20 %

Procedure:
To 41.0 g. (0.12 mole) of α-(1-cyclohexyl-3-azetidinyl)-α,α-diphenylacetonitrile was added 100 g. of a 70% solution of sulfuric acid, and the mixture was stirred and heated at 120° C. for 48 hrs. The solution was then poured over ice and made basic with 50% sodium hydroxide, and extracted with chloroform. The organic layer was dried, filtered, and concentrated in vacuo. The residue was crystallized twice from isopropyl ether, the crystallized material weighed 8.0 g. (20% yield) and melted at 129°-131° C.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6].[CH2:14](O)[CH3:15].S(=O)(=O)(O)O.[C:22]1(C)C=CC=C[CH:23]=1>>[CH2:22]([O:12][C:1](=[O:13])[CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:14][CH3:15])=[O:6])[CH3:23]
Reactant: CCO
Reactant: Cc1ccccc1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccccc1C(=O)OCC
Temperature: 20 °C

Procedure:
A mixture of homophthalic acid [(2-carboxyphenyl)acetic acid] (5 g, 28 mmol), ethanol (23 ml), toluene (12 ml) and concentrated sulphuric acid (0.5 ml) was heated at reflux, using a Dean-Stark apparatus to remove water formed during the reaction, for 6 hrs and then overnight. The mixture was cooled to 20° C., diluted with toluene (˜50 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (˜50 ml). The aqueous layer was separated and extracted with more toluene (˜50 ml) and then the combined toluene washings were washed with saturated aqueous sodium chloride solution and then dried over magnesium sulphate and evaporated. The resulting yellow oil was purified by automated flash silica-gel column chromatography (using a Biotage SP4), eluting with 0-25% gradient of ethyl acetate in hexane (10 column volumes) and then with a 25-50% gradient of ethyl acetate in hexane (2 column volumes), to give ethyl 2-[2-(ethyloxy)-2-oxoethyl]benzoate (5.9 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[O:15][CH2:16][CH2:17][NH:18][C:19]=2[N:20]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C>CCO.O=[Pt]=O>[CH2:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:15][CH2:16][CH2:17][NH:18][C:19]=2[N:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CCC#Cc1ccc2c(n1)NCCO2
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CCCCc1ccc2c(n1)NCCO2
Reaction time: 4 h

Procedure:
A mixture of 4-5 (0.0643 g, 0.223 mmol), triethylamine (0.0169 g, 0.167 mmol), and PtO2 (0.0064 g) in EtOH (3.0 mL) was stirred under a hydrogen balloon for four hours. The reaction was filtered through Celite and concentrated to yield a cloudy, colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([CH:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:7]3[CH:12]=[N:11][CH:10]=[N:9][C:8]=32)=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:23].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([OH:23])[C:7]3[CH:12]=[N:11][CH:10]=[N:9][C:8]=32)=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Clc1ccc(C2c3ccc(Cl)cc3-c3ncncc32)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: OC1(c2ccc(Cl)cc2)c2ccc(Cl)cc2-c2ncncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a stirred solution of 11.0 g of 8-chloro-5-(4-chlorophenyl)-5H-indeno[1,2-d]pyrimidine in 300 ml of acetone were added 6.32 g of potassium permanganate. The mixture was stirred under a nitrogen atmosphere for 2 hours at which time an additional 6.32 g of potassium permanganate were added. The mixture was stirred overnight at room temperature, filtered, and the filtrate concentrated in vacuo. The residue was taken up in a mixture of ethyl acetate and a saturated sodium chloride solution. The layers were separated and the organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was crystallized first from ethyl acetate/isooctane and then from ethyl acetate to provide 3.06 g of the desired title product, m.p. 194°-195.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([O:15][CH3:16])[C:12]#[C:13][CH3:14].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.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:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([O:15][CH3:16])[C:12]#[C:13][CH3:14])[CH:21]=[CH:20][CH:19]=1
Reactant: CC#CC1(OC)C(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cccc(Cl)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: O
Solvent: COCCOC
Product: CC#CC1(OC)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.25 h
Yield: 15 %

Procedure:
5-bromo-3-methoxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (0.56 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol) were stirred at room temperature in dimethoxyethane (22 cm3). After 15 min. 3-chlorophenylboronic acid (0.63 g, 4.0 mmol) and sodium carbonate (1.06 g, 10 mrrol) in water (11 cm3) were added and the mixture heated under reflux. After 16 h, the mixture was cooled, poured into water and extracted with EtOAc (×3). The combined organic layers were washed with sodium hydroxide (1N, ×2), brine, dried (MgSO4) and evaporated. The residue was subjected to column chromatography (SiO2, EtOAc: hexane, gradient elution) and the product triturated with hexane to afford the title compound (0.095 g, 0.30 mmol, 15%) as a solid: mp. >190° C. (decomp.); (CDCl3) δ 1.88 (s, 3H), 3.25 (s, 3H), 3.30 (s, 1H), 6.91 (d, 1H, J=8.1 Hz), 7.29-7.39 (m, 2H), 7.44-7.47 (m, 1H), 7.54-7.57 (m, 2H), 7.74 (d, 1H, J=1.7 Hz); MS (EI) m/z 311 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=2[O:18][CH3:19])[N:3]=1.COC1C(OC)=CC=CC=1CO.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:19][O:18][C:11]1[C:12]([O:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[N:3]=1
Reactant: C1CNCCN1
Reactant: COc1cccc(COc2cncc(Cl)n2)c1OC
Agent: COc1cccc(CO)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(COc2cncc(N3CCNCC3)n2)c1OC

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[(2,3-dimethoxybenzyl)oxy]pyrazine (2.51 g, 8.93 mmol; obtained according to the procedure of example 50, step 1, starting from 2,3-dimethoxybenzyl alcohol), piperazine (2.38 g, 27.7 mmol) and K2CO3 (1.23 g, 8.9 mmol). The yield of the title compound was 1.66 g (56%) which was obtained as an oil. Purity 100% (HPLC). MS m/z 331 (M+H)+. HRMS m/z calcd for C17H22N4O3 (M)+330.1692, found 330.1690.
Reaction SMILES: C=CC=C.O.C(=O)=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28](O)[CH:29]=[CH:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35]>[Pd].C(CC(=O)C)(=O)C.C(CC(=O)C)(=O)C.CN(C)C=O>[CH2:28]=[CH:29][CH:30]([OH:7])[CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35]
Reactant: C=CCCCC=CCO
Reactant: O=C=O
Agent: [Pd]
Agent: C=CC=C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)CC(C)=O
Solvent: CN(C)C=O
Product: C=CCCCC(O)C=C
Yield: 12.4 %

Procedure:
A mixture composed of 0.5 mol of 1,3-butadiene, 1 mol of water, 0.6 mol of carbon dioxide, 0.5 milli-mol of bis(acetylacetone) palladium, 2.0 milli-mol of triphenyl phosphine, and 63 ml of dimethylformamide was placed in an electromagnetic induction rotary type autoclave made of stainless steel having an internal volume of 0.3l, and subjected to reaction for three hours at a temperature of 90° C. Analysis of the resulted liquid reaction product through gas chromatography revealed that 0.153 mol of 2,7-octadien-1-ol, and 0.019 mol of 1,7-octadien-3-ol were produced.
Reaction SMILES: B(F)(F)F.CCOCC.[N+:10](=[CH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N-].C(=O)(O)[O-].[Na+].[Cl:24][CH2:25][C:26]#N>>[Cl:24][CH2:25][C:26]1[O:18][C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][N:10]=1
Reactant: N#CCCl
Reactant: CC(C)(C)C(=O)C=[N+]=[N-]
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)c1cnc(CCl)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2 mL (2.3 g, 16 mmol) of boron trifluoride etherate in 20 mL of chloroacetonitrile at 0° C. was added a solution of 1.33 g (10 mmol) of 1-diazo-3,3-dimethyl-2-butanone in 5 mL of chloroacetonitrile dropwise. The resulting solution was stirred at 0° C. for 0.5 h. The reaction mixture was added to saturated aqueous sodium bicarbonate solution to neutralize the acid and the product was extracted three times with dichloromethane. The combined extracts was dried (sodium sulfate), concentrated and purified by flash column chromatography (Merck silic a, 25×200 mm, dichloromethane) to give 1.1 g of 2-(chloromethyl)-5-t-butyloxazole as a yellow liquid (6.4 mmol, 64% overall from the acid chloride). 1H NMR δ (CDCl3): 1.30 (s, 9 H), 4.58 (s, 2 H), 6.68 (s, 1 H); MS 174 (M+H)+ ; TLC: Rf (silica gel, dichloromethane)=0.33;
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([O-:3])=[O:2].Br[CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:9][CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccc(O)cc1
Reactant: CCOC(=O)C=C(OC)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
A mixture of 4-(2-nitro-4-trifluoromethylphenoxy) phenol (9.36 mm)., ethyl 4-bromo-3-methoxy-2-pentenoate (12 mm.) and K2CO3 (14 mm.) in acetone (20 ml.) is refluxed for 24 hours. After filtration, the filtrate is concentrated and the oily residue chromatographed on silica gel to yield ethyl 4-[4-(2-nitro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoate.
Reaction SMILES: Br[C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[N+:16]([O-:18])=[O:17])[CH:4]=[C:5]([CH3:7])[N:6]=1.[C:19]1([CH3:34])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1OB(C1C=CC=CC=1)O.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:15][O:14][C:10]1[C:9]([N+:16]([O-:18])=[O:17])=[C:8]([N:3]2[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:34])[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-n2cc(C)nc2Br)c1[N+](=O)[O-]
Reactant: Cc1ccccc1OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-n2cc(C)nc2-c2ccccc2C)c1[N+](=O)[O-]
Temperature: 115 °C

Procedure:
Intermediate 1D, method D (0.6 g, 1.9 mmol) and O-tolyl phenyl boronic acid (0.56 g, 3.8 mmol) were dissolved in a solution containing 1,4-dioxane (16 mL) and water (4 mL). To this was then added potassium carbonate (0.56 g, 3.8 mmol). Argon was bubbled into the reaction for 3 min and (triphenylphosphine) palladium (0) (0.1 g, 5% mol) added. The reaction was sealed then heated to 115° C. for 16 hrs, poured into water and extracted with ethyl acetate. The organic layer was separated and washed with water then brined, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the crude purified by flash chromatography on silica gel in 10:1 ethyl acetate/methylene chloride. A white solid (0.5 g) was recovered. MS (ES) m/z 324.1 [M+1]+
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C@H:3]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[CH:29](I)([CH3:31])[CH3:30].C1CCN2C(=NCCC2)CC1>C(#N)C>[OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:29]([CH3:31])[CH3:30])=[O:17])[C@H:3]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCC[C@@H]1[C@@H](C/C=C\CCCCCC(=O)O)[C@@H](O)C[C@H]1O
Reactant: CC(C)I
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCCC[C@@H]1[C@@H](C/C=C\CCCCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O

Procedure:
The compound (27-5) was reacted with isopropyl iodide and DBU in dry acetonitrile and the resultant was purified on silica gel column to give the titled compound (27-6).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH2:30]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH3:31]>CN(C)C=O>[Cl-:1].[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][CH2:13][C:12]([C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N+:32]5([CH2:30][CH3:31])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:4][CH:5]=4)=[O:11])=[CH:18][C:17]=3[CH:19]=2)=[CH:24][CH:25]=1
Reactant: CCN1CCCCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Solvent: CN(C)C=O
Product: CC[N+]1(Cc2ccc(NC(=O)C3=Cc4cc(-c5ccc(C)cc5)ccc4OCC3)cc2)CCCCC1
Product: [Cl-]

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.18g) and 1-ethylpiperidine (0.31ml) in dimethylformamide (5ml) were stirred at 50° C. over night. The solvent was evaporated, and to the residue was added ethyl acetate. Precipitated crude crystal was filtered, which were recrystallized from ethanol-ethyl acetate to give 1-(N-(7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carbonyl)-4-amino-benzyl)-1-ethylpiperidinium chloride (Compound 98) (0.17g) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[C:13]([CH2:17][C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]1([N:36]=[C:37]=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:37]([NH:36][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)=[O:38])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:19])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CC(=O)N3CCOCC3)c2)n1
Reactant: O=C=Nc1cccc2ccccc12
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(CC(=O)N3CCOCC3)c2)n1

Procedure:
A mixture of Example L (0.2 g, 0.58 mmol) and 1-naphthylisocyanate (0.10 g, 0.6 mmol) in dry CH2Cl2 (4 ml) was stirred at RT under N2 for 18 h. The solvent was removed in vacuo and the crude product was purified by column chromatography using ethyl acetate/hexane/CH2Cl2 (3/1/0.7) as the eluent (0.11 g, off-white solid) to yield 1-{3-tert-butyl-1-[3-(2-morpholino-2-oxoethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalene-1-yl)urea. mp: 194–196; 1H NMR (200 MHz, DMSO-d6): δ 9.07 (1H, s), 8.45 (s, 1H), 8.06–7.93 (m, 3H), 7.69–7.44 (m, 7H), 7.33–7.29 (d, 6.9 Hz, 1H), 6.44 (s, 1H), 3.85 (m, 2H), 3.54–3.45 (m, 8H), 1.31 (s, 9H); MS:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13](=[O:28])[CH2:14][C:15]1[C:16]([F:27])=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([O:25][CH3:26])[CH:21]=[CH:20]2.Br[CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41]>C1COCC1>[CH3:11][O:12][C:13](=[O:28])[CH:14]([C:15]1[C:16]([F:27])=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([O:25][CH3:26])[CH:21]=[CH:20]2)[CH2:30][N:31]1[C:35](=[O:36])[C:34]2[C:33](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:32]1=[O:41]
Reactant: COC(=O)Cc1c(F)ccc2ccc(OC)nc12
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1c(F)ccc2ccc(OC)nc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of LiHMDS (1M in THF, 9.6 mL) was added at −78° C. a solution of (7-fluoro-2-methoxy-quinolin-8-yl)-acetic acid methyl ester (2.0 g, 8.0 mmol; prepared as in WO 2007/081597) in THF (16 mL) over 10 min. After stirring the resulting orange mixture for 1 h at −78° C., a solution of N-(bromomethyl)phthalimide (1.2 eq.) in THF (16 mL) was added dropwise over 10 min. The mixture was stirred 1 h at −78° C. and then at rt overnight. The yellow solution was quenched with 1N HCl (80 mL) and then extracted with DCM. The combined org layers were washed with water, dried over MgSO4, concentrated and purified by CC (Hept/EA 1:1) to give 1.89 g of a yellow solid which was recrystallized from EA/MeOH/NH4OH (90:10:1) to afford the title intermediate as a colourless solid (924 mg, 28% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH:12]=[C:11]([C:18]([OH:20])=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22]>C1(C)C=CC=CC=1.S(Cl)(Cl)=O.C(NCC)C>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:17]2[CH:16]=[CH:15][S:14][C:13]=2[CH:12]=1)=[O:20])[CH3:22]
Reactant: COc1ccc(-c2cc(C(=O)O)cc3sccc23)cc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc(-c2ccc(OC)cc2)c2ccsc2c1

Procedure:
The reaction is carried out as in Example 1, starting with 4-(4-methoxyphenyl)benzo[b]thiophene-6-carboxylic acid (2.9 g) in toluene (30 cc) and thionyl chloride (2.3 cc) and triethylamine (4.3 cc) and diethylamine (1.1 cc) in anhydrous toluene (30 cc). After chromatography of the residue on silica gel using a cyclohexane:ethyl acetate (80:20 by volume) mixture as the eluent and recrystallization in isopropyl ether, N,N-diethyl-4-(4-methoxyphenyl)benzo[b]thiophene-6-carboxamide (1.12 g), m.p. 88° C., is isolated.