Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:17]=[CH:16][C:13]=1[C:14]#N.C[OH:38]>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:38]
Reactant: CO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#N)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Di-isobutylaluminum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of the 2-fluoro-4-(hexadecylamino)benzonitrile under a nitrogen atmosphere. The temperature rises to 40° C. during the addition which takes 30 minutes and the reaction is then stirred for 1 hour. A solution of methanol in toluene (50 ml., 1:1) is added during 30 minutes and the mixture is poured into vigorously stirred ice-cold aqueous sulfuric acid (500 ml., 5%). After 10 minutes, diatomaceous earth (30 g.) is added, the mixture filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. Recrystallization from hexane affords 2-fluoro-4-(hexadecylamino)benzaldehyde as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:21])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:8][CH:7]=2)[CH3:2].CC1[C:24](=O)[NH:25][C:26]2[C:31](N=1)=[CH:30][C:29](OCCCCC(O)=O)=[CH:28][CH:27]=2.CNC1CCCCC1.C(NC1CCCCC1)C>>[CH2:1]([C:3]1[C:4](=[O:21])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([N:25]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:24])=[O:20])=[CH:8][CH:7]=2)[CH3:2]
Reactant: CCc1nc2cc(OCCCCC(=O)O)ccc2[nH]c1=O
Reactant: Cc1nc2cc(OCCCCC(=O)O)ccc2[nH]c1=O
Agent: CCNC1CCCCC1
Solvent: CNC1CCCCC1
Product: CCc1nc2cc(OCCCCC(=O)N(C)C3CCCCC3)ccc2[nH]c1=O
Yield: 77.4 %

Procedure:
In Example 72 the compound 1013 was replaced by compound 1037 and N-methylcyclohexylamine was replaced by N-ethylcyclohexylamine 0.77 ml to obtain the compound 1035.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([OH:48])[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:33]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[O:48][C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][N:39]=[C:38]2[NH:37][C:34]1[CH:35]=[CH:36][N:32]([CH3:31])[N:33]=1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CN(C)CCN(C)S(=O)(=O)c1cnc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)CCN(C)S(=O)(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 59.9 %

Procedure:
5,6-Dichloro-N-[2-(dimethylamino)ethyl]-N-methylpyridine-3-sulfonamide (104 mg, 0.33 mmol) and potassium tert-butoxide (58 mg, 0.52 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (50 mg, 0.21 mmol), and stirred under a nitrogen atmosphere at 100° C. for 2.5 hours. The reaction solution was cooled with ice, saline water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate:chloroform=2:5:1 to 2:5:2) to obtain the entitled compound (65 mg, yield: 61%) as a pale orange amorphous solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[N:25]=3)[C:16]=2[CH:32]=1.CC(C1C=C(C(C)C)C(S([N:48]=[N+:49]=[N-:50])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C>>[N:48]([CH:19]1[N:18]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[N:25]=2)[C:16]2[CH:32]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[N:21]([CH3:22])[C:20]1=[O:23])=[N+:49]=[N-:50]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: COc1cccc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Product: COc1cccc(C2=NC(N=[N+]=[N-])C(=O)N(C)c3ccc(Cl)cc32)n1
Yield: 62.3 %

Procedure:
As illustrated in the scheme above and following General Procedure 6, KHMDS (0.19 mL of 0.5 M in toluene, 0.095 mmol), 7-chloro-1,3-dihydro-5-(6-methoxy-2-pyridinyl)-1-methyl-2H-1,4-benzodiazepin-2-one (0.0290 g, 0.0918 mmol), trisyl azide (0.0710 g, 0.229 mmol) and acetic acid (0.023 mL, 0.40 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (49:1 CH2Cl2:EtOAc) provided the title compound (0.0204 g, 62%). 1H-NMR (CDCl3): δ 7.95 (d, J=7.2 Hz, 1H), 7.78-7.70 (m, 2H), 7.54 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 4.64 (s, 1H), 3.80 (s, 3H), 3.44 (s, 3H). MS (ESI) (M+H)+=357.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8](Br)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].Cl.[CH3:22][NH:23][CH3:24].CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:23]([CH3:24])[CH3:22])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(Br)COc1ccc(Br)cc1-2
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1nc2c(s1)C(N(C)C)COc1ccc(Br)cc1-2
Temperature: 60 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (200 mg, 0.477 mmol) in THF (6 mL) were added Dimethylamine Hydrochloride (77.8 mg, 0.954 mmol), DIPEA (308 mg, 2.38 mmol). The reaction mixture was stirred in autoclave at 60° C. overnight. Then the mixture was cooled to room temperature and partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 9-Bromo-4-dimethylamino-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (120 mg, 65%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH2:7])=[O:6].[NH:14]1[CH2:16][CH2:15]1>CC#N>[N:14]1([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[N+:11]([O-:13])=[O:12])[C:5]([NH2:7])=[O:6])[CH2:16][CH2:15]1
Reactant: C1CN1
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CC#N
Product: NC(=O)c1ccc([N+](=O)[O-])c(N2CC2)c1
Yield: 41.1 %

Procedure:
A stirred solution of the above benzamide (100 mg, 0.54 mmol) in dry MeCN (4 mL) was treated with aziridine (168 μL, 3.24 mmol) at room temperature for 4 h. The resulting precipitate was collected, washed with cold water, and crystallized twice from EtOAc to give 9 (46 mg, 41%). mp 223-224° C.;; 1H NMR [(CD3)2SO] δ8.21 (br s, 1H, NHH), 7 99 (d, J=8.5 Hz, 1H, H-5), 7.69 (d, J=1.8 Hz, 1H, H-2), 7.67 (br s, 1H, NHH), 7.56 (dd, J=8 5, 1.8 Hz, 1H, H-6), 2.30 (s, 4H, (CH2)2). Anal. Calcd for C9H9N3O3: C, 52.17;H, 4.38, N, 20.28. Found C, 52 10;H, 4.30, N, 20.07%.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1.[Li][CH2:14][CH2:15][CH2:16][CH3:17].BrCCCC>C1COCC1>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:12][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1
Reactant: [Li]CCCC
Reactant: Cc1cc(C)c2c(n1)N(C)CC2
Solvent: C1CCOC1
Solvent: CCCCBr
Product: CCCCCc1cc(C)c2c(n1)N(C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 225 mg (1.39 mmol) of 1,4,6-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 4 mL of THF was added 1.39 mL (2.22 mmol, 1.6 M in hexanes) of n-BuLi followed by 157 μL (1.46 mmol) of 1-bromobutane at −78° C. The reaction mixture was slowly warmed to room temperature and stirred for another 16 h. The reaction mixture was quenched by the addition of 10 mL of sat aq NH4Cl at 0° C. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel column (25 3.2 cm). Elution with 10:1 hexanes/ethyl acetate gave the product as a yellow oil: yield 0.20 g (66%); silica gel TLC Rf 0.15 (8:1:1 hexanes/ethyl acetate/MeOH); 1H NMR (CDCl3) δ 0.88 (t, 3H, J=7.2 Hz), 1.30-1.36 (m, 4H), 1.66 (quint, 2H, J=7.6 Hz), 2.08 (s, 3H), 2.55 (t, 2H, J=8.0 Hz), 2.81 (t, 2H, J=8.0 Hz), 2.88 (s, 3H), 3.38 (t, 2H, J=8.0 Hz) and 6.13 (s, 1H); 13C NMR (CDCl3) δ 14.1, 18.0, 22.6, 24.4, 29.6, 31.8, 33.3, 38.0, 52.5, 112.4, 118.2, 141.1, 159.1 and 163.7; mass spectrum, m/z 218.2 (M+) (theoretical 218.3); mass spectrum (APCI), m/z 219.1864 (M+H)+ (C14H23N2 requires 219.1861).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C.[NH:51]1[CH:55]=[CH:54][N:53]=[C:52]1[CH:56]=O.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:56][C:52]3[NH:51][CH:55]=[CH:54][N:53]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: O=Cc1ncc[nH]1
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ncc[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(31), where 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione was substituted in place of 6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and imidazole-2-carboxaldehyde was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of that example.
Reaction SMILES: Cl.[NH:2]([CH2:9][C:10]1[C:11](=[O:36])[C:12]2[C:17]([C:18](=[O:35])[C:19]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:37](Cl)([Cl:39])=[O:38].C1(C)C=CC=CC=1>ClCCl.C(N(C(C)C)CC)(C)C>[C:3]1([N:2]([CH2:9][C:10]2[C:11](=[O:36])[C:12]3[C:17]([C:18](=[O:35])[C:19]=2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:37]([Cl:39])=[O:38])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCCCCCCC1=C(CNc2ccccc2)C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC1=C(CN(C(=O)Cl)c2ccccc2)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Anilinomethyl-3-pentadecyl-1,4-naphthoquinone hydrochloride (9.25 g, 18.1 mmol) was dissolved in dichloromethane (100 ml). A 12 percent solution of phosgene in toluene (45 ml, 54.4 mmol) and diisopropylethylamine (50 ml) were added and the resulting solution was stirred at room temperature for about 15 minutes. The solution was then concentrated under reduced pressure and the residue was taken up in dichloromethane. The solution was washed with 2N hydrochloric acid, dried over anhydrous magnesium sulfate, filtered, and concentrated. The product was used as a crude oil in the preparation of the above PRDR.
Reaction SMILES: [Cl:1][C:2]1[C:3](Br)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:10]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.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>[Br:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[N:4][CH:5]=1
Reactant: Clc1cc(Br)cnc1Br
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cc2Cl)cc1
Yield: 67.6 %

Procedure:
10.0 g (37.0 mmol) of 3-chloro-2,5-dibromopyridine, 11.11 g (44.4 mmol) of 4-octyloxybenzeneboronic acid, 7.85 g (74.0 mmol) of sodium carbonate and 0.46 g (0.4 mmol) of tetrakis(triphenylphosphine)palladium(0) are heated at 80° C. for 18 hours in 125 ml of toluene, 60 ml of ethanol and 60 ml of water. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether, the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate and evaporated, and the product is purified by chromatography (silica gel, dichloromethane:hexane =4:1), giving 9.93 g of 5-bromo-3-chloro-2-(4-octyloxyphenyl)pyridine. ##STR16##
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH3:35])[C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][OH:33])[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1.O[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=[CH:39][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CCOC(C)=O.CO>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH3:35])[C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:37]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:40]=[CH:39][CH:38]=4)[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1
Reactant: Oc1ccnc2ccccc12
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2ccc(C)nc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)N(C)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
Diethyl azodicarboxylate (DEAD) (139 μL, 0.88 mmol) was added dropwise to a solution of 5,11-dihydro-2,5-dimethyl-11-ethyl-8-(2-hydroxyethyl)-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one (110 mg, 0.35 mmol), 4-hydroxyquinoline (128 mg, 0.88 mmol) and Ph3P (231 mg, 0.88 mmol) in THF (3.5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted in EtOAc (60 mL) and the solution was successively washed with 1 N aqueous NaOH (3×10 mL) and brine (15 mL) then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc then EtOAc:MeOH, 9.5:0.5) to give the title compound (57 mg, 37% yield) as a white solid: MS (ESI) m/z 440 (MH)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]([O:20]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]1([CH2:28][CH2:29][CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([NH2:40])=[CH:37][CH:38]=3)[CH:33]=[CH:32]2)[CH:27]=[CH:26][N:25]=[CH:24]1.C[O-].[Na+].C1(C)C=CC=CC=1>CO>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]([NH:40][C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][CH2:29][CH2:28][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH:32]=[CH:33]2)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2ccc(Cl)cc2n1Cc1ccccc1
Reactant: Nc1ccc2c(ccn2CCCn2ccnc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2c(ccn2CCCn2ccnc2)c1)c1nc2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
A mixture of 27.9 g of ethyl 1-benzyl-6-chlorobenzimidazol-2-carboxylate, 17.8 g of 1-[3-(imidazol-1-yl)propyl]-5-aminoindole, 8 g of sodium methylate and 600 ml of toluene was stirred at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, the crystals being separated were collected by filtration and washed with toluene. Thus obtained crystals were dissolved in 500 ml of chloroform, then 100 ml of water was added and the mixture was filtrated with Celite. The chloroform layer was taken by separation, after washed with water, the chloroform portion layer was dried with anhydrous magnesium sulfate, and the solvent was removed by distillation to obtain brown oily product. This oily product was dissolved in methanol, further added n-hexane and the crystals being separated were collected by filtration, recrystallized from methanol and dried. There was obtained 31.8 g of 1-benzyl-6-chloro-2-{1-[3-(imidazol-1-yl)propyl]indol-5-ylamino-carbonyl}benzimidazole.
Reaction SMILES: C(C1N2C=CN=CC2=NC=1)#C.I[C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][C:33]=1C)[C:16]([NH:18][NH:19]C(=O)C1C(Cl)=CC(Cl)=CC=1Cl)=[O:17].C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:16]([NH:18][NH2:19])(=[O:17])[C:15]1[CH:31]=[CH:32][CH:33]=[CH:13][CH:14]=1
Reactant: Cc1ccc(C(=O)NNC(=O)c2c(Cl)cc(Cl)cc2Cl)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#Cc1cnc2cnccn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-ethynylimidazo[1,2-a]pyrazine (0.09 g, 0.6 mmol), N′-(3-iodo-4-methylbenzoyl)-2,4,6-trichlorobenzohydrazide (0.3 g, 0.6 mmol), Pd(PPh3)4 (0.036 g, 0.03 mmol), CuI (0.008 g, 0.03 mmol) and diisopropylethylamine (0.75 ml, 0.9 mmol) in DMF (10 ml) was stirred at ambient temperature for 12 hrs under an atmosphere of nitrogen. The reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (elution with 10% methanol in dichloromethane) to provide 2,4,6-trichloro-N′-[3-[2-(2-imidazo[1,2-a]pyrazin-3-yl)ethynyl)]]-4-methylbenzoyl]benzohydrazide.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:16][C:15](=[O:17])[NH:14][N:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[N+:18]1([O-])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2=[N:13][NH:14][C:15](=[O:17])/[C:16]/2=[C:19]2\[NH:18][C:27]3[C:22]([CH:21]=[CH:20]\2)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccc(C2=NNC(=O)C2)cc1
Reactant: [O-][n+]1cccc2ccccc21
Product: CNS(=O)(=O)c1ccc(C2=NNC(=O)/C2=C2/C=Cc3ccccc3N2)cc1

Procedure:
The title compound was synthesized using N-methyl-4-(5-oxo-4,5-dihydro-1H-pyrazol-3-yl)benzenesulfonamide and quinoline N-oxide according to the procedure described in Example 23. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.49 (s, 3H) 7.09 (s, 1H) 7.48-7.60 (m, 2H) 7.76-7.81 (m, 3H) 7.83-7.90 (m, 4H) 8.25 (d, J=9.09 Hz, 2H) 11.90 (s, 1H); ESI-MS: m/z calc'd for C19H16N4O3S 380.42. found 381.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([O:27][C:28]3[CH:41]=[CH:40][C:31]4[C:32]([C:36]([NH:38][CH3:39])=[O:37])=[C:33]([CH3:35])[O:34][C:30]=4[CH:29]=3)=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:39][NH:38][C:36]([C:32]1[C:31]2[CH:40]=[CH:41][C:28]([O:27][C:21]3[C:20]4[C:25](=[CH:26][C:17]([O:16][CH2:2][CH2:3][N:4]5[CH2:9][CH2:8][O:7][CH2:6][CH2:5]5)=[CH:18][CH:19]=4)[N:24]=[CH:23][CH:22]=3)=[CH:29][C:30]=2[O:34][C:33]=1[CH3:35])=[O:37]
Reactant: ClCCN1CCOCC1
Reactant: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(O)ccc34)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCCN5CCOCC5)ccc34)ccc12
Temperature: 120 °C
Yield: 19.6 %

Procedure:
A solution of 4-(2-chloroethyl)morpholine (10.7 g, 57.4 mmol) and Cs2CO3 (46.3 g, 143.5 mmol) in DMF (100 mL) was stirred for 1 hour at room temperature. To the solution was added a solution of 6-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide (10 g, 28.7 mmol). The mixture was heated to 120° C. for 15 hr. The solution was cooled to room temperature and extracted with EtOAc. The concentrated residue was purified by a silica gel column chromatography (using 5 to 10%) MeOH/CH2Cl2) to give 2.6 g of free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinolin-4-yloxy]benzofuran-3-carboxamide as a solid. The solid free base was identified as Form 1 as characterized by powder X-ray diffraction as shown in FIG. 11. Note, Form 1 can also be prepared by slurrying any of Forms 3, 5, or 6 in water at room temperature for 24 hours.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>C1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][C:16]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:17]
Reactant: C1CCNC1
Reactant: O=C(Cl)CCCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCCl)N1CCCC1
Reaction time: 0.25 h

Procedure:
A solution of pyrrolidine (35 grams; 0.5 mol) and triethylamine (50 grams; 0.5 mol) in benzene (500 ml) is placed in a glass reaction flask equipped with a mechanical stirrer and reflux condenser. β-Chloropropionyl chloride (64 grams; 0.5 mol) is then slowly added with stirring over a period of about 15 minutes. Stirring is continued for a period of about 30 minutes. After this time the reaction mixture is first filtered to remove triethylamine hydrochloride nd is the stripped of benzene to yield 1-(β-chloropropionyl) pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.CCCCCC.[Cl:15][C:16]1[CH:17]=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:19]=[C:20]([Cl:23])[C:21]=1F.O>C1C=CC=CC=1.C([Li])CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:21]2[C:20]([Cl:23])=[CH:19][C:18]([C:24]([F:25])([F:27])[F:26])=[CH:17][C:16]=2[Cl:15])[CH:3]=1
Reactant: Clc1cccc(I)c1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: FC(F)(F)c1cc(Cl)c(-c2cccc(Cl)c2)c(Cl)c1
Yield: 36.7 %

Procedure:
To 10.0 g (41.9 mmol) of 1-chloro-3-iodobenzene in 50 ml of dry benzene, 32.0 ml of a n-butyllithium solution in hexane (1.56 mol/1) was added dropwise in a nitrogen stream at room temperature with stirring. After another 2 hours of stirring at room temperature, 9.9 g (42.5 mmol) of 3,5-dichloro-4-fluorobenzotrifluoride was added dropwise at 10° C. After another 12 hours of stirring at room temperature, the reaction mixture was poured into 500 ml of water for separation. The organic layer was washed with 200 ml of water twice and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 5.0 g of 1-chloro-3-(2,6-dichloro-4-trifluoromethylphenyl)benzene (yield 35.0%).