Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:14][O-:15].[Na+]>CO.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:15][CH3:14])=[N:7]2
Reactant: C[O-]
Reactant: Fc1ccc(Br)c2ccc(Cl)nc12
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(Br)ccc(F)c2n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-bromo-2-chloro-8-fluoroquinoline (1.08 g, 4.2 mmol) in anhydrous methanol (10 mL) at 50° C. was added NaOMe (30% w/w, 0.9 g, 5.0 mmol). The resulting mixture was stirred at 50° C. for one hour, then allowed to cool to room temperature. The mixture was diluted with water, then extracted with EtOAc. The combined organics were washed with water then saturated Nael (aq), dried over MgSO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 0-5% EtOAc/hexanes to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 8.33 (dd, J=9.1, 1.6 Hz, 1H); 7.55 (dd, J=8.4, 4.4 Hz, 1H); 7.22 (dd, J=10.2, 8.4 Hz, 1H); 7.04 (d, J=9.2 Hz, 1H); 4.13 (s, 4H). LC4 2.37 min. (M+H) 256.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[Na+].Cl.[C:9]([NH2:14])(=[NH:13])[CH2:10][CH2:11][CH3:12].C(Cl)Cl>O>[CH3:5][O:4][C:2]([NH:14][C:9](=[NH:13])[CH2:10][CH2:11][CH3:12])=[O:3]
Reactant: CCCC(=N)N
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCC(=N)NC(=O)OC
Yield: 95 %

Procedure:
222 parts of methyl chloroformate and 337 parts of 50% strength sodium hydroxide solution are added via two inlets to a mixture of 286 parts of butyramidine hydrochloride in 1,300 parts of methylene chloride and 500 parts of water, at from 10° to 15° C., in the course of 25 minutes, while stirring. The mixture is stirred at room temperature for 2 hours, and the organic phase is separated off and concentrated on a rotary evaporator to give 320 parts (95% of theory) of N-methoxycarbonylbutyramidine of nD25 1.4763.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1.O.[NH2:23][NH2:24].C(#N)C>CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=3)=[CH:15][CH:14]=2)[NH:24][N:23]=1
Reactant: NN
Reactant: CC(C)(C)Nc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: O
Solvent: CCO
Solvent: CC#N
Product: CC(C)(C)Nc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 95 °C
Reaction time: 22 h

Procedure:
Into a 25 mL sealable tube under nitrogen were combined 4-{2-amino-6-[(1,1-dimethylethyl)amino]-4-pyrimidinyl}-2-fluorobenzonitrile (500 mg, 1.25 mmol) and hydrazine monohydrate (1.22 mL) in EtOH (8 mL). The vial was sealed, and the reaction mixture was stirred at 95° C. for 22 hours. The solution was concentrated, partitioned between EtOAc and water, and extracted with EtOAC (2×) and CH2Cl2. The organic layer was separated, washed with NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The resulting solid was dissolved in a mixture of CH3CN/water/CH3OH/DMSO and purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA). Fractions were evaporated, aqueous potassium carbonate was added to the residue and the solution was stirred at room temperature for 2 hrs. The aqueous mixture was extracted with EtOAc (×2) and DCM (×2). The organic layer was separated, washed with brine, dried (MgSO4), filtered, concentrated and azeotroped with CH3CN to give a brown solid. Minimum amount of acetonitrile was added to the solids, and the resulting mixture was sonicated. A white precipitate crashed out which was filtered and washed with hexanes and Et2O to afford the title compound (102 mg) as a white solid. LC-MS (ES) m/z=298 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.42 (s, 9H), 5.36 (s, 2H), 5.90 (s, 2H), 6.31 (s, 1H), 6.53 (s, 1H), 7.36 (dd, J=8.6, 1.3 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.80 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1
Reactant: CCCCCI
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Product: CCCCCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
5-(4,4-Dimethyl-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrrole-carbonitrile (1.94 g, 7.3 mmol) was reacted, according to General Method A, with 1-iodopentane (1.5 g, 7.6 mmol) to afford the title compound, m.p. 128–131° C. (0.2 g, 8%); 1H-NMR (DMSO-d6) δ 0.73 (t, J=7.3 Hz, 3H), 1.05 (m, 2H), 1.14 (m, 2H), 1.57 (m, 2H), 1.63 (s, 6H), 4.04 (t, J=7.5 Hz, 2H), 6.28 (d, J=4 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 7.04 (d, J=4.5 Hz, 1H), 7.33 (dd, J=8.9, 2.0 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 10.41 (s, 1H), MS (APCI (−)) m/z 336 (M−H)−
Reaction SMILES: [CH2:1]([Mg]Cl)C(C)C.C(Cl)C(C)C.[Mg].[F:13][C:14]([F:26])([F:25])[CH:15]([OH:24])[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CI>CCOCC.[CH-]1[C-]=[C-][C-]=[C-]1.[CH-]1[C-]=[C-][C-]=[C-]1.Cl[Ti]Cl>[F:13][C:14]([F:25])([F:26])[CH:15]([OH:24])/[CH:16]=[C:17](\[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)/[CH3:1]
Reactant: CC(C)C[Mg]Cl
Reactant: OC(C#Cc1ccccc1)C(F)(F)F
Agent: Cl[Ti]Cl
Agent: [Mg]
Agent: [c-]1[c-][c-][cH-][c-]1
Solvent: CI
Solvent: CCOCC
Solvent: CC(C)CCl
Product: C/C(=C/C(O)C(F)(F)F)c1ccccc1
Reaction time: 4 h
Yield: 63 %

Procedure:
In an isobutylmagnesium chloride solution that was prepared by reacting isobutyl chloride (3.74 g, 40 mmol) and magnesium (0.97 g, 40 mmol) in dry ether (40 ml) at 0° C., dichlorobis(π-cyclopentadienyl)titanium (0.22 g, 0.9 mmol) and 1,1,1-trifluoro-4-phenyl-3-butyne-2-ol (2 g, 10 mmol) were slowly added at 0° C. After 4 hour agitation of the mixture at room temperature, solvent was removed under heating for 30 min. Next, dry tetrahydrofuran (20 ml) was put into the reaction vessel and further methyl iodide (12.7 g, 90 mmol) was slowly added. After 12 hour agitation, the reaction mixture was treated by a method similar to the one in the above Examples to obtain (Z)-1,1,1-trifluoro-4-phenyl-3-pentene-2-ol (b.p.: 84°-86° C./2 mmHg) at a yield of 63%. The above product gave the following analytical data:
Reaction SMILES: [CH3:1][C:2]([O:10][CH3:11])([CH2:4][CH2:5][CH:6]=C(C)C)[CH3:3].[O:12]=[O+][O-].O=O.CSC>CO.C(Cl)Cl>[CH3:11][O:10][C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][CH:6]=[O:12]
Reactant: COC(C)(C)CCC=C(C)C
Reactant: O=[O+][O-]
Agent: O=O
Solvent: ClCCl
Solvent: CO
Solvent: CSC
Product: COC(C)(C)CCC=O
Reaction time: 16 h

Procedure:
A stirred, cooled (-65~C) mixture of 2,6-dimethyl-2-methoxyhept-5-ene (125 g, 1.25 mol), methylene chloride (500 mL) and methanol (500 mL) was treated with a gas stream enriched with ozone. Upon the appearance of a blue color pure oxygen was passed through the mixture followed by nitrogen. Dimethyl sulfide (88 mL, 1.4 mol) was added and the mixture was allowed to stand 16 hours at 25~C. Upon workup 4-methoxy-4-methylpentanal was obtained, bp30 85-87~C (64.4 g); NMR(CDC13) 1.2(s,6H), 1.9(t,2H), 2.5(m,2H), 3.2(s,3H), 9.8(t,1H); IR(neat) 2975, 2825, 2725, 1730, 1470, 1370, 1090 cm-1 ; MS(m/e) 43, 73, 83, 115.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([CH2:12][O:13][CH2:14][O:15][CH3:16])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:23][CH:24]=O>CO.O.C(Cl)Cl>[CH3:16][O:15][CH2:14][O:13][CH2:12][C:4]1[N:3]2[CH:23]=[CH:24][N:1]=[C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: O=CCCl
Reactant: COCOCc1ccc(C(=O)OC)c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COCOCc1ccc(C(=O)OC)c2nccn12
Reaction time: 16 h
Yield: 70.4 %

Procedure:
To a stirred suspension of methyl 2-amino-6-({[(methyloxy)methyl]oxy}methyl)-3-pyridinecarboxylate (496 mg, 2.192 mmol) and sodium bicarbonate (193 mg, 2.302 mmol) in a mixture of methanol (15 mL) and water (7.5 mL) was added chloroacetaldehyde (50% wt. solution in water, 0.311 mL, 2.412 mmol). The mixture was heated to reflux for 2 hours when LCMS indicated that no reaction has occurred. More chloroacetaldehyde (0.311 mL, 2.412 mmol) was added and heating continued for 16 hours when LCMS indicated the reaction to be complete. The mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic phase was separated and the aqueous phase back extracted with ethyl acetate (50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give crude product (450 mg). This material was dissolved in DCM and purified on silica (50 g) using a 0-25% methanol-DCM gradient over 60 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an orange oil (386 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([NH:24][CH3:25])=[O:23].ClC1C=CN=NN=1.[NH2:36][CH2:37][CH2:38][CH2:39][OH:40]>CN(C=O)C>[OH:40][CH2:39][CH2:38][CH2:37][NH:36][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([NH:24][CH3:25])=[O:23])[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: NCCCO
Reactant: CNC(=O)c1cccc(N)c1
Agent: Clc1ccnnn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Nc2ncnc(NCCCO)n2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (0.300 g, 2.000 mmol) in DMF (6670 μL) was added N-ethyl-N-isopropylpropan-2-amine (1048 μL, 6.000 mmol). The reaction vessel was cooled in an ice-water bath prior to the addition of 3-amino-N-methylbenzamide (300 mg, 2.000 mmol). The reaction mixture was stirred for 3 h at 0° C. at which time LC-MS revealed complete conversion to the desired chloro-triazine intermediate. To this yellow solution was added 3-aminopropan-1-ol (150 mg, 2.000 mmol). The reaction mixture was allowed to stir and warm slowly to RT over 18 h. Solids had precipitated out of the solution. The solid was filtered off, washed with water, and very little methanol to obtain 3-(4-(3-hydroxypropylamino)-1,3,5-triazin-2-ylamino)-N-methylbenzamide (516 mg, 1.707 mmol, 85%) as a white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]1([SH:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.Cl[C:18]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=2)[N:21]=[CH:20][C:19]=1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>CN(C=O)C.CCOC(C)=O>[CH:11]1([S:16][C:18]2[N:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=3)[N:21]=[CH:20][C:19]=2[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: SC1CCCC1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2SC2CCCC2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
Sodium bis(trimethylsilyl)amide (7.13 mL, 7.13 mmol) was added dropwise to cyclopentanethiol (0.761 mL, 7.13 mmol) in DMF (25 mL) under nitrogen. The resulting solution was stiffed at 20° C. for 30 minutes. A solution of tert-butyl 5-chloro-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate (Intermediate#9) (2 g, 5.94 mmol) in DMF (10 mL) was then added dropwise and the resulting mixture was stirred at 20° C. for 2 hours. The reaction mixture was diluted with EtOAc (200 mL), and washed sequentially with water (4×50 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 chromatography, elution gradient 0 to 25% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate (1.380 g, 57.7%) as a colourless oil which crystallised on standing.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)([O-])O.[Na+].ClCCl>O>[C:16]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)(=[O:18])[CH3:17]
Reactant: CCOC(=O)CNc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CNc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of 2.7 parts of ethyl 2-[(4-aminophenyl)amino]-acetate hydrochloride, 1.1 parts of acetic acid anhydride, 0.98 parts of sodium hydrogen carbonate, 65 parts of dichloromethane and 50 parts of water was stirred for 30 minutes at room temperature. The organic phase was separated, washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 1.9 parts (68%) of ethyl 2-[[4-(acetylamino)phenyl]amino]acetate; mp. 119.5° C. (12).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[N:11][C:10]=2[CH:9]=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1.CN1CCN(C(=O)C=C[C:36]2[C:44]3[N:43]([C:45]4C=CC=C[CH:46]=4)C=N[C:40]=3C=C(C(F)(F)F)C=2)CC1>>[CH2:45]([N:43]([CH:44]([CH3:36])[CH3:40])[C:3](=[O:2])[CH:4]=[CH:5][C:6]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[N:11][C:10]=2[CH:9]=[C:8]([C:21]([F:23])([F:22])[F:24])[CH:7]=1)[CH3:46]
Reactant: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Product: CCN(C(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12)C(C)C
Yield: 6 %

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one. The oily residue was purified by preparative LCMS to afford the title compound as a white solid (7.2 mg, 6%), m/z 402.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:48]=[CH:47][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[NH:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][C@H:21]2[CH2:25]C[N:23](C(OC(C)(C)C)=O)[CH2:22]2)=[O:19])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>ClCCl.ClCCCl>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[NH:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH:21]2[CH2:25][NH:23][CH2:22]2)=[O:19])=[O:11])=[CH:47][CH:48]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CCCNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCCNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC1CNC1
Reaction time: 0.17 h

Procedure:
To a solution of the compound (1.90 g), which had been obtained in (1), in anhydrous dichloromethane (20 ml), trifluoroacetic acid (10 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 10 minutes and then at room temperature for 10 minutes. The reaction mixture was diluted with 1,2-dichloroethane and concentrated by evaporation under reduced pressure. The residue was washed successively with hexane and diethyl ether by decantation and the solvent was distilled off, whereby a crude 3-[4-[2,3-di(4-nitrobenzyloxycarbonyl)guanidino]-butanoylamino]azetidine trifluoroacetate (1.93 g) was obtained. The product was provided for use in the subsequent reaction without isolation.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:9].CC1(C)COB([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=2[C:36]([N:38]2[CH2:47][CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39]2)=[O:37])OC1>>[CH2:11]([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([C:3]1[N:4]=[CH:5][N:6]([CH3:7])[C:2]=1[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[C:36]([N:38]1[CH2:47][CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])=[O:9])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN(CCCC)C(=O)c1ncn(C)c1Br
Reactant: COC(=O)c1ccc(B2OCC(C)(C)CO2)c(C(=O)N2CCc3ccccc3C2)c1
Product: CCCCN(CCCC)C(=O)c1ncn(C)c1-c1ccc(C(=O)OC)cc1C(=O)N1CCc2ccccc2C1
Yield: 39.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 264I, 5-bromo-N,N-dibutyl-1-methyl-1H-imidazole-4-carboxamide (600 mg, 1.9 mmol) and methyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 264H, 1.55 g, 3.8 mmol) were converted to the title compound (400 mg, 40%). MS(ESI+) m/z 531.6 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[CH:10][C:9]3[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:8]=3[O:7][C:6]=2[CH:17]=1.CO/[CH:20]=[CH:21]/[C:22]([O:24][Si](C)(C)C)=[CH2:23].C1COCC1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:20]=[CH:21][C:22](=[O:24])[CH2:23][CH:10]3[C:9]3[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:8]=3[O:7][C:6]=2[CH:17]=1
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Reactant: Cc1cccc2c1C=Nc1ccc(Br)cc1O2
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cccc2c1C1CC(=O)C=CN1c1ccc(Br)cc1O2
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of 7-bromo-1-methyldibenz[b,f][1,4]oxazepine (25.05 g, 86.98 mmol) and Ytterbium(III) triflate (2.8 g, 4.5 mmol) in toluene (0.21 L) at 0° C., (E)-1-methoxy-3-trimethylsilyloxy-1,3-butadiene (18 mL, 95.7 mmol) was added dropwise. THF (0.1 L) was added to dissolve the formed precipitate and the solution was stirred for 15 min. 1N hydrochloric acid (50 mL) was added and the resulting mixture was stirred for an additional 15 min, after which it was diluted with ethyl acetate and washed with brine. After drying (Na2SO4) the solvent was evaporated under reduced pressure to yield the crude compound which was triturated in methanol to give the title compound (25.4 g, 82%). Data: 1H-NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), 2.43 (m, 1H), 3.00 (m, 1H), 5.23 (m, 1H), 5.41 (m, 1H), 6.99-7.52 (m, 7H). (m/z)=356+358 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[N:39][CH:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[N:39][CH:38]=[N:37]2)[CH:31]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J34) (313 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (390 mg, 74%).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([O:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].[CH2:38](Cl)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[C:1]1([S:7]([N:10]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:11]2[CH:12]=[C:13]([O:25][C:26](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: ClCc1ccccc1
Reactant: O=C(Oc1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(OCc2ccccc2)c(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1)c1ccccc1
Temperature: 70 °C
Yield: 60.1 %

Procedure:
To a stirred solution of benzoic acid 3-benzenesulfonylamino-4-benzyloxy-phenyl ester(which was obtained in Example 17) (2.88 g, 7.27 mmol) in DMF (20 mL) was added 60% sodium hydride (0.32 g, 8 mmol). After hydrogen evolution had subsided the stirred mixture was heated at 70° C. for 15 minute, and then it was cooled down to room temperature and a solution of benzyl chloride (1.01 g, 8 mmol) in 5 mL of DMF was added dropwise. The mixture was then heated at 85–90° C. for 2 hours, then it was cooled down to room temperature, poured into ice-water. The aqueous layer was extracted with ethyl acetate and the organic layer was dried and concentrated. The product was purified by flash silica gel chromatography eluting with ethyl acetate and hexanes to give the title compound as a white solid (2.40 g, 70%); 1H NMR (300 MHz, CDCl3) δ 4.74(s, 2 H), 4.83(s, 2 H), 8.83(d, J=8.9 Hz, 1 H), 8.10–8.50(m, 2 H); HRMS Calcd. for C33H28NO5S(MH+): 550.1688. Found: 550.1680.
Reaction SMILES: O=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6]CC)=O.C1(NN)CCCCC1.[CH:19]1([C:22]2[N:26]([CH:27](C)C)[N:25]=[CH:24][C:23]=2C=O)[CH2:21][CH2:20]1>>[CH:24]1([N:25]2[C:2]([CH2:9][CH3:10])=[C:3]([CH:4]=[O:6])[CH:27]=[N:26]2)[CH2:20][CH2:21][CH2:19][CH2:22][CH2:23]1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Reactant: CCOC(=O)CC(=O)CC
Agent: NNC1CCCCC1
Product: CCc1c(C=O)cnn1C1CCCCC1

Procedure:
1-Cyclohexyl-5-ethyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl 3-oxo-pentanoate and cyclohexyl hydrazine (TCI) in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:16])[C:9](=[O:15])[N:10]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:5]2=[CH:4][CH:3]=1.[CH3:17]C(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Br-].[C:52]([CH2:54][CH2:55][CH2:56][Zn+])#[N:53].C1COCC1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:17][C:12]([CH3:13])([CH3:14])[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([CH2:56][CH2:55][CH2:54][C:52]#[N:53])=[CH:3][CH:4]=2)[N:8]([CH3:16])[C:9]1=[O:15]
Reactant: N#CCCC[Zn+]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Reactant: Cn1c(=O)n(CC2CC2)c2ccc(Cl)nc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCC#N)nc21

Procedure:
To a stirred solution of 1-4 (0.40 g, 1.58 mmol), Pd(OAc)2 (0.02 g, 0.08 mmol), xphos (0.074 g, 0.16 mmol) in dioxane (12 mL) was added 3-cyanopropylzinc bromide 0.5M solution in THF (12.6 mL, 6.3 mmol) and the resulting mixture was microwave irradiated for 30 minutes at 100° C. The reaction was allowed to cool and partitioned between ethyl acetate and water. The organic phase was concentrated and flash column separation using a 0-60% ethyl acetate/hexane gradient gave 38-1. (0.42 g, 94%). LRMS (ES) (M+H)+: observed=287.2, calculated=287.4.