Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:21]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClS(O)(=O)=O.C1C(=C(C#N)C#N)C=CC(=C(C#N)C#N)C=1>[Cl:21][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]([OH:20])=[O:19]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=C1CCC(=O)N1Cl
Agent: N#CC(C#N)=c1ccc(=C(C#N)C#N)cc1
Agent: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCC(Cl)C(=O)O
Temperature: 220 °C
Yield: 69.8 %

Procedure:
Into a 50 ml 3-neck round bottom flask fitted with a condenser, thermometer, and magnetic stirrer were placed 11.4 g (0.04 mole) stearic acid, 8.0 g (0.06 mole) N-chlorosuccinimide, 0.1 ml (0.0015 mole) chlorosulfonic acid, and 0.04 g (0.0002 mole) TCNQ. The flask was placed in a heating bath set at 150° C. The mixture was stirred during heating, and a homogeneous liquid phase was formed. The solution temperature continued to rise above that of the heating bath, and a sudden exothermic reaction occurred in which the reaction temperature increased to ca. 220° C. The reaction mixture was cooled and dissolved in chloroform, and the resulting solution was washed thoroughly with dilute aqueous sodium chloride solution. After drying and removal of the chloroform, the residue was recrystallized from acetonitrile to afford 8.9 g (70%) of 2-chlorostearic acid which was equivalent in purity to the product of Example I.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27](B1OC(C)(C)C(C)(C)O1)=[CH:26][CH:25]=2.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([CH3:21])=[CH:30]3)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
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: O
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (850 mg, 2.90 mmol) in DME (20 ml) was added 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.4 g, 5.44 mmol), potassium carbonate (751 mg, 5.43 mmol), Pd(PPh3)4 (157 mg, 0.14 mmol) and water (5 ml) under an inert atmosphere of nitrogen. The resulting solution was stirred for 1 h at 90° C. and then diluted with water (300 ml), extracted with ethyl acetate (3×100 ml), and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue, which was purified by a silica gel column (1%-5% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate as a yellow solid (660 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.[H-].[Na+].I[CH3:15]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]([CH3:15])[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: CI
Reactant: COc1ccc2nc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)ncn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
In an oven dried nitrogen purged 3 neck 50 mL round bottom flask, 5.00 g (37.75 mmol) of 5-methoxybenzimidazole in 20 mL of dry dimethylformamide is reacted with 1.66 g (41.53 mmol) of sodium hydride at room temperature for 4 h. 2.58 mL (41.53 mmol) of iodomethane is added and reaction is allowed to stir at room temperature overnight. Reaction is quenched with water, layers are separated, extracted aqueous 3×50 mL ethyl acetate, dried (MgSO4), and concentrated. The crude mixture is purified by chromatography using dichloromethane: methanol as a solvent system. Product containing fractions are combined to obtain 3.50 g of the title compound which is used as is, 57% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](=[O:23])[CH3:22].Cl>CN(C)C=O.C(OCC)(=O)C>[C:21]([C:22]1[O:10][C:5]2[C:4]([O:11][CH3:12])=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=1)(=[O:23])[CH3:20]
Reactant: CC(=O)CCl
Reactant: COc1cc(Br)cc(C=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Br)cc2cc(C(C)=O)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
10.0 g of 5-bromo-2-hydroxy-3-methoxybenzaldehyde was dissolved in 39 ml of N,N-dimethylformamide, and the resulting solution was mixed with 11.9 g of anhydrous potassium carbonate and stirred at room temperature. 5.0 g of chloroacetone was added dropwise to the above reaction solution at the same temperature, followed by additional 1 hour of stirring at an elevated temperature of 80° C. The resulting reaction solution was diluted with ethyl acetate and adjusted to 2 with concentrated hydrochloric acid, and the resulting organic layer was collected. The organic layer was dried to distill off the solvent, and the resulting residue was purified by silica gel column chromatography, thereby obtaining 4.0 g of 2-acetyl-5-bromo-7-methoxybenzofuran.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1.[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH3:22][O:23][C:24]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[O:30])=[CH:27][CH:26]=1)=[O:34]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(C2CC(OC(C)=O)CCC2N)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC2CCC(OC(C)=O)CC2c2ccc(OC)c(OC)c2)cc1

Procedure:
1.6 g of (±)-acetic acid (1RS,3RS,4RS)-4-amino-3-(3,4-dimethoxyphenyl)cyclohexyl ester (compound B1) are dissolved in 30 ml of dichloromethane. 982 mg (5.45 mmol) of terephthalic acid monomethyl ester and 1.25 g (6.74 mmol) of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride are added successively under stirring. After 3 h further 18 mg (0.1 mmol) of terephthalic acid monomethyl ester are added. After 15 h the reaction is treated with aqueous hydrochloric acid and extracted several times with dichloromethane. After evaporation of the combined organic phases, the crude product is crystallized from ethyl acetate/cyclohexane to give 1.87 g (73% of theory) of the title compound as colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)C#N.[H-].[Na+].[O:19]1CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:19]
Reactant: C1CCOC1
Reactant: N#CC(c1ncccn1)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Product: O=C(c1ncccn1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A mixture of 2-chlorophenyl(2-pyrimidinyl)acetonitile (3.25 g, 0.0142 mol), sodium hydride (60% in mineral oil, 1.07 g, 0.016 mol) and anhydrous tetrahydrofuran is stirred two hours at reflux and cooled to room temperature. Dry air is bubbled into the mixture while stirring three days. The mixture is quenched by dropwise addition of a 3:1 water:methanol mixture and then water. The tetrahydrofuran is removed in vacuo and the aqueous residue filtered to afford the title compound as a brown solid (2.00 g, 64.7%) which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14]C=C[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]#[C:17][NH2:18].C(O)(C(F)(F)F)=O.BrC#N>>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:18]([C:17]#[N:16])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: N#CN
Agent: N#CBr
Solvent: O=C(O)C(F)(F)F
Product: N#CN1CCC(COCc2ccccc2)C1

Procedure:
Following general procedure 12, to a cold (0° C.), stirred solution of the alcohol (26) (188 mg, 1 equiv.) in DMF (9 mL) was added NaH (60% in oil, 56 mg, 1.5 equiv.). The suspension was stirred at 0° C. for 40 minutes followed by the addition of the benzyl chloride (215 uL, 2 equiv.). The suspension was warmed to rt and stirred for 16 h. MeOH was added followed by sat. aq. NH4Cl. The aqueous phase was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (20% EtOAc in hexane) to afford the desired benzyl ether (27). The N-Boc group of the benzyl ether (27) was then converted to the cyanamide (N—CN) following general procedure 3 (i.e. successive treatment with TFA and BrCN). The crude material was purified by flash chromatography (gradient elution: 30% EtOAc in hexane to 50% EtOAc in hexane) to afford the desired product 3-[(benzyloxy)methyl]-1-cyanopyrrolidine (28).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]#[N:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=1.[H-].[Na+].IC.[C:22]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:22][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]([C:16]#[N:17])=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: N#Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(-c2cccnc2)c(C#N)c2ccccc21
Reaction time: 0.5 h

Procedure:
To 2-pyridin-3-yl-1H-indole-3-carbonitrile (1.0 g, 4.56 mmol) in DMF (17 mL) is added 60% sodium hydride in mineral oil (547 mg, 13.68 mmol) and the suspension is stirred for 30 min. Iodomethane (971 mg, 6.84 mmol) is then added to the reaction mixture and stirred at ambient temperature for 1 h. Aqueous NaHCO3 (3 mL) is added and the mixture is concentrated in vacuo. The residue is purified by purified by silica gel flash chromatography (dichloromethane-methanol gradient) to give 1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 3.83 (s, 3H), 7.35 (t, J=7.5 Hz, 1H), 7.40-7.46 (m, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.67-7.74 (m, 2H), 8.16 (dt, J=8.0, 2.0, 1.9 Hz, 1H), 8.76 (dd, J=5.1, 1.5 Hz, 1H), 8.86 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 234.1029 [(M+H)+ Calcd for C15H12N3: 234.1031].
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([N:18]2[CH:22]=[N:21][N:20]=[CH:19]2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH3:23][Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[CH3:23][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([N:18]2[CH:22]=[N:21][N:20]=[CH:19]2)[C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:5]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(-n2cnnc2)cc1C(=O)O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1cc(-n2cnnc2)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of 1.3 g (4.14 mmol) of 2-acetylamino-5-[1,2,4]triazol-4-yl-4-trifluoromethyl-benzoic acid in 15 ml of methanol is treated dropwise with 3.1 ml (6.21 mmol) of a 2M solution of trimethylsilyl diazomethane in hexane. The mixture is stirred for 1 hour at room temperature and another 1.5 ml (3.00 mmol) of a solution of trimethylsilyl diazomethane in hexane (2M) is added. After 1 hour, the reaction is quenched by adding glacial acetic acid until no more gas evolution is observed. The mixture is concentrated in vacuo and the residue taken up in ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, gradient 100% ethyl acetate to ethyl acetate/methanol 9:1) afforded 456 mg (34%) of 2-acetylamino-5-[1,2,4]triazol-4-yl-4-trifluoromethyl-benzoic acid methyl ester as yellow crystals, m.p. 180-184° C.
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:55][S:56]([C:59]1[CH:67]=[CH:66][C:62]([C:63](O)=[O:64])=[CH:61][CH:60]=1)(=[O:58])=[O:57]>C(Cl)Cl>[NH2:55][S:56]([C:59]1[CH:60]=[CH:61][C:62]([C:63]([N:24]2[CH2:25][C@H:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:22]([CH2:21][N:13]([C@@H:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:23]2)=[O:64])=[CH:66][CH:67]=1)(=[O:57])=[O:58]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(S(N)(=O)=O)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A mixture of 100 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate, 53 mg of WSC hydrochloride, 37 mg of HOBt and 1.5 ml of methylene chloride was mixed with 51 mg of 4-(aminosulfonyl)benzoic acid and stirred at room temperature for 3Hours. The reaction solution was washed with water and then concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 120 mg of tert-butyl ({(3R,4S)-1-[4-(aminosulfonyl)benzoyl]-4-phenylpyrrolidin-3-yl}methyl)[(1R)-1-(1-naphthyl)ethyl]carbamate as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](Cl)(=[O:12])[CH2:10][CH3:11].Cl>>[C:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:12])[CH2:10][CH3:11]
Reactant: Oc1ccccc1Cl
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)Oc1ccccc1Cl
Temperature: 100 °C
Yield: 85.4 %

Procedure:
o-Chlorophenol (64 g, 0.5 mole) and propionyl chloride (50 g, 0.55 mole) were mixed at room temperature and then heated at 100° C. (steam bath) for 2-3 hrs. Hydrogen chloride gas was evolved. After 2-3 hrs the reaction mixture was distilled in vacuo and gave 78.8 g (86%) of o-chlorophenyl propionate, bp 11 mm=111° C.
Reaction SMILES: [CH2:1]([S:5]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16](Cl)=[O:17])[CH2:13][CH3:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[O:6])=[N:8]1)=[O:17])[CH2:13][CH3:14]
Reactant: CCCCS(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCS(=O)c1ncn(C(=O)N(CCC)CCC)n1

Procedure:
A mixture of 6.9 g. 3-n-butylsulphinyl-1,2,4-triazole, 8.0 ml. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 10 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give an oily residue which subsequently solidified. This solid product was recrystallized from petroleum ether to give 1-dipropylcarbamoyl-3-n-butylsulphinyl-1,2,4-triazole, m.p. 39° - 40° C. Elemental analysis satisfactory.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13].Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>C1COCC1>[F:3][C:4]1[CH:18]=[C:17]([CH2:19][O:20][C:22]2[CH:23]=[C:24]3[N:31]([CH3:32])[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[N:27]=2)[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cncc(Oc2ccc(CO)cc2F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3cncc(C#N)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using NaH (5.90 mg, 0.246 mmol) in THF (5 mL) was added 5-(2-fluoro-4-(hydroxymethyl)phenoxy)n-icotinonitrile (30 mg, 0.12 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyr-imidin-5(1H)-one (22.8 mg, 0.123 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([Br:17])[CH:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O1CCOCC1>[Br:17][C:12]1[CH:11]=[C:10]([C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:7]=2)=[O:9])[CH:15]=[C:14]([Br:16])[CH:13]=1
Reactant: O=C(c1cc(Br)cc(Br)c1)c1ccnc(Cl)c1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: O=C(c1cc(Br)cc(Br)c1)c1ccnc(N2CCOCC2)c1
Yield: 52.3 %

Procedure:
To (2-chloro-pyridin-4-yl)-(3,5-dibromo-phenyl)-methanone (0.200 g, 0.53 mmol) in 1.0 mL of 1,4-dioxane in a microwave tube was added 0.070 g (0.80 mmol) morpholine. The reaction was subjected to microwave irradiation at 120° C. for 60 minutes. The reaction mixture was cooled and concentrated. The crude product was chromatographed on silica gel using 1:1 hexane:ethyl acetate to give 0.118 g of the (3,5-dibromo-phenyl)-(2-morpholin-4-yl-pyridin-4-yl)-methanone. This compound was converted to [3-(1H-indol-4-yl)-5-(2-morpholin-4-yl-pyridine-4-carbonyl)-phenyl]-carbamic acid methyl ester as described for Example 90. 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J=5.3 Hz, 1H), 8.07 (t, J=1.8 Hz, 1H), 7.95 (s, 1H), 7.76 (t, J=1.6 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.29 (d, J=3.3 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 7.10 (d, J=7.4 Hz, 1H), 7.08 (s, 1H), 6.95 (dd, J=5.1, 1.0 Hz, 1H), 6.62 (d, J=3.1 Hz, 1H), 3.78 (t, J=4.9 Hz, 4H), 3.75 (s, 3H), 3.54 (t, J=4.9 Hz, 4H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[C:20]=1[C:21]([NH2:23])=[O:22].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]3[NH:23][C:21](=[O:22])[C:20]4[C:19](=[CH:27][C:26]([O:28][CH3:29])=[CH:25][C:24]=4[O:30][CH3:31])[N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(C)=O)CC4)cc3)nc2c1
Temperature: 155 °C
Yield: 88.8 %

Procedure:
A mixture of 4-(4-acetylpiperazin-1-yl)benzaldehyde (1.34 g, 5.77 mmol) and 2-amino-4,6-dimethoxybenzamide (1.03 g, 5.24 mmol) in DMA (30 mL) was treated with p-TsOH (0.100 g, 0.524 mmol) and NaHSO3 (0.578 g, 5.55 mmol). The mixture was heated at 155° C. for 6 hours, cooled to room temperature, diluted with water (400 mL), and filtered to give brown solids. The filtrate was extracted with EtOAc (3×100 mL), concentrated, and combined with the brown solids from the filter cake. The combined solids were purified by silica gel chromatography, eluting with 92:7:1 CHCl3/MeOH/concentrated NH4OH to afford 2-(4-(4-acetylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one as a yellow solid (1.9 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:5][C@H:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:7]([OH:11])[CH2:8][CH:9]=[CH2:10].[NH+]1C=C[CH:27]=[CH:26][CH:25]=1.COC(OC)(C)C>C(Cl)(Cl)Cl>[CH2:8]([C@H:7]1[O:11][C:26]([CH3:27])([CH3:25])[N:12]([C:13]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:19])[C@H:6]1[CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:22]=[C:21]([F:23])[CH:20]=1)[CH:9]=[CH2:10]
Reactant: c1cc[nH+]cc1
Reactant: C=CC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Solvent: COC(C)(C)OC
Solvent: ClC(Cl)Cl
Product: C=CC[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1Cc1cc(F)cc(F)c1

Procedure:
Alcohol 13 was stirred in chloroform with pyridinium p-toulenesulfonate and 2,2-dimethoxypropane while heating to afford (14) as a tan solid after workup.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH:6][NH2:7])=[NH:5].C(O)C.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[OH-].[Na+]>O>[ClH:11].[NH2:2][NH:3][C:4]([NH:6][N:7]=[CH:16][C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1)=[NH:5]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: N=C(NN)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N=C(NN)NN=Cc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
The preparation of the subject compound may also be accomplished as follows: 25 g. of 1,3-diaminoguanidine hydrochloride is dissolved in 1800 ml. of boiling ethanol. To this boiling solution, 28 g. of 4-chlorobenzaldehyde in 300 ml. of ethanol is added over a period of 8 hours. The reaction mixture is then cooled at 0° C. overnight, clarified, and the filtrate concentrated to 500 ml. volume and cooled at 0° C. 29 g. of precipitate is obtained. This is slurried in 300 ml.of water, the pH adjusted to 8-8.5 with sodium hydroxide solution, the slurry heated to boiling and filtered. Cooling the filtrate gives 18 g. ofessentially pure product melting at 243°-244° C., as in the previous preparation.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.C[Mg+].[Br-].[CH3:19]COCC>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:19][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1
Reactant: CCOCC
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc2ncc(C)nc2cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound is prepared using an adaptation of the published method of Tamao, et al. Tetrahedron, 1982, 38, 3347-3354. To a THF solution under argon is added 2-Chloro-6,7-dimethoxyquinoxaline (5 g, 26 mmol) and NiCl2(dppp) (0.14 g, 0.26 mmol). The reaction mixture is cooled to 0° C., and a 3 M solution of MeMgBr in Et2O (13 mL, 39 mmol) is added portionwise. The reaction mixture is allowed to warm to room temperature, stirred for 1 hour, then refluxed for 1.5 hours. The mixture is cooled, quenched with 10% HCl, stirred 10 minutes, then made basic with 5% NaOH. CH2Cl2 and H2O are added to the reaction, and the mixture stirred overnight. Additional CH2Cl2, H2O, and NaCl are then added and the mixture is filtered. The resulting solution is poured into a separatory funnel, and the aqueous layers are washed 3× with CH2Cl2. The organic layers are combined, washed with brine, dried (MgSO4), concentrated onto silica gel, and chromatographed (50%-80% EtOAc/hexanes) to provide a orange solid (49% yield).