Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:3].[S:15]1[CH:19]=[C:18]([C:20]2[NH:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[N:17]=[CH:16]1>N1C=CC=CC=1>[CH2:11]([O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][C:2]([N:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[C:18]1[N:17]=[CH:16][S:15][CH:19]=1)=[O:3])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOCCOCCOC(=O)Cl
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Solvent: c1ccncc1
Product: CCCCOCCOCCOC(=O)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
32.9 G. (146 mmoles) of 2(2-n-Butoxyethoxy)-ethyl chloroformate is added dropwise to a stirred suspension of 24.9 g. (124 mmoles) of 2-(4-thiazolyl)-benzimidazole in 200 ml. of pyridine. The addition is complete in 40 minutes whereupon all of the starting material had dissolved. The reaction mixture is stirred for 16 hours at room temperature and filtered to remove pyridine hydrochloride which is washed with additional pyridine. The combined filtrate and washing are evaporated to dryness in vacuo affording a residual oil which is triturated with 300 ml. portions of ice water. The water is decanted and the residue extracted with 300 ml. of methylene chloride, filtered and the methylene chloride filtrates washed with 300 ml. of ice water, 250 ml. of 0.25 N HCl containing ice and 200 ml. of saturated sodium bicarbonate solution containing 50 ml. of ice. The organic fraction is dried, filtered and evaporated to dryness in vacuo affording 51.7 g. of a residual oil. The oil is extracted with petroleum ether whereupon a dark oil remains. The petroleum ether solution is decanted and the product separates therefrom as an oil. The petroleum ether is decanted and the remaining solvent is removed in vacuo affording 17.4 g. of a light yellow residual oil. Thin layer chromatography revealed a single spot which is confirmed by elemental analysis.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[CH3:21][C:22]1[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=1.C(/C(O)=O)=C\C(O)=O.N.N>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]3[C:4]=2[CH2:3][N:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[C:23]2=[O:28])=[CH:15][CH:16]=1
Reactant: Cc1ccc[nH]c1=O
Reactant: Fc1ccc2nc(-c3ccc(Cl)cc3)c(CCl)n2c1
Agent: Cl
Agent: N
Agent: O=C(O)/C=C/C(=O)O
Product: Cc1cccn(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)c1=O

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridine hydrochloride and 3-methylpyridin-2(1H)-one. 1H-NMR (CDCl3, 400 MHz, δ) 8.43 (dd, J=2.4, 4.1 Hz, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.58 (dd, J=5.0, 9.6 Hz, 1H), 7.45 (d, J=8.6 Hz, 2H), 7.17 (m, 1 h), 7.13 (m, 1H), 6.65 (dd, J=1.4, 6.9 Hz, 1H), 5.93 (t, J=6.8 Hz, 1H), 5.63 (s, 2H), 2.16 (s, 3H) ppm; m/e368 (M+H)+
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4](=[O:12])[C:5]1[C:10]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:14]
Reactant: CCN(CC)C(=O)c1ccccc1Cl
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Product: CCN(CC)C(=O)c1c(Cl)cccc1[Si](C(C)C)(C(C)C)C(C)C

Procedure:
The title compound was prepared according to General Method A from the compound of Example e and 1.1 eq triisopropylsilyl chloride. Purification by HPLC using 1:19 ethyl acetate/hexanes gave 5.5 g of the desired product as of a clear oil, a 75% yield.
Reaction SMILES: N1(C2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[S:13][C:14]4[N:15]=[C:16]([Cl:27])[N:17]=[C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:19]=4[N:20]=3)[CH2:7][CH2:6]2)CCC1.[C:28]([O:32][C:33]([N:35]1CCNCC1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]2[S:13][C:14]3[N:15]=[C:16]([Cl:27])[N:17]=[C:18]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:19]=3[N:20]=2)[CH2:9][CH2:10]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCC4)CC3)sc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Prepared according to the method used in the preparation of 2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine using piperazine-1-carboxylic acid tert-butyl ester in place of 4-azetidin-1-ylpiperidine. The title compound was obtained as a white solid (129 mg, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:19]3[CH:20]=[CH:21][C:16]([S:13]([CH3:12])(=[O:15])=[O:14])=[CH:17][CH:18]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Brc1ccc2ncc(I)n2c1
Product: CS(=O)(=O)c1ccc(-c2cnc3ccc(Br)cn23)cc1

Procedure:
The title compound, brown solid (0.53 g, 69%), MS (ISP) m/z=353.4 [(M+H)+], mp 194° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 4-methanesulfonyl-phenylboronic acid (0.48 g, 2.38 mmol).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[CH:27]([C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[NH:37][C:38]([NH2:40])=[S:39])([CH3:29])[CH3:28]>>[CH:27]([C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[NH:37][C:38]([NH:40][C:2]([NH:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=3)[N:12]=2)[CH:6]=1)=[O:3])=[S:39])([CH3:29])[CH3:28]
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: Cc1ccc(NC(N)=S)c(C(C)C)c1
Product: Cc1ccc(NC(=S)NC(=O)NCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c(C(C)C)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(2-isopropyl-4-methylphenyl)thiourea and isolated as an off-white solid (0.216 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:15])[NH2:14])=[N:6]1.C([N:22](CC)CC)C.O.NN>C(O)C>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:14])[NH:15][NH2:22])=[N:6]1
Reactant: CCN(CC)CC
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Agent: NN
Solvent: CCO
Solvent: O
Product: N=C(NN)c1nn(Cc2ccccc2F)c2c1CCC2
Temperature: 0 °C
Reaction time: 72 h

Procedure:
200 mg (0.77 mmol) of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide were initially charged in 4 ml of ethanol and cooled to 0° C. 310 mg (3.07 mmol) of triethylamine and 48 mg (0.77 mmol) of 80% hydrazine hydrate were added, and the mixture was stirred at room temperature for 72 h. The mixture was concentrated on a rotary evaporator, taken up in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, concentrated on a rotary evaporator and dried under high vacuum. 209 mg (100% of theory) of the target compound were obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]([CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:13]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=2)[C:2]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:3]([C:16]#[N:17])[C:4]1=[O:15])[CH3:14]
Reactant: CCn1c(=O)c(C#N)c(Cl)c2ccc(C)nc21
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCn1c(=O)c(C#N)c(N2CCCC2)c2ccc(C)nc21

Procedure:
A stirred mixture of 7.41 g. (0.03 mole) of 4-chloro-1-ethyl-1,2-dihydro-7-methyl-2-oxo-1,8-naphthyridine-3-carbonitrile, 2.13 g. (0.03 mole) of pyrrolidine and 3.18 g. (0.03 mole) of sodium carbonate in 100 ml. of ethanol was heated under reflux for 1 hour. The mixture was filtered and the filter cake was triturated with 200 ml. of water. The insoluble material was collected, air dried and was recrystallized from 2-ethoxyethanol to give 7.4 g. of the title product, m.p. 211°-213° C.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=O)[CH2:6][CH3:7].O.[NH2:17]N>CCO>[CH2:6]([C:5]1[NH:17][N:2]=[CH:3][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]
Reactant: NN
Reactant: CCC(=O)C(=CN(C)C)c1ccccc1
Solvent: CCO
Solvent: O
Product: CCc1[nH]ncc1-c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a mixture of 1-(dimethylamino)-2-phenylpent-1-en-3-one (3.32 g, 16.33 mmol) in EtOH (80.0 mL) was added hydrazine hydrate (1.58 mL, 32.66 mmol). The resulting mixture was stirred at 80° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated to give a solid. The solid was re-crystallized, using 20% ethanol in water to give the title compound as a white solid (2.81 g). LCMS m/z=173 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.31 (t, J=7.58 Hz, 3H), 2.88 (q, J=7.58 Hz, 2H), 7.22-7.30 (m, 1H), 7.35-7.42 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17].Cl>O.CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:10][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(O)cc1
Reactant: O=C(O)C(=O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1csc(-c2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Hydroxybenzenecarbothioamide (1.53 g, 10 mmol) and potassium hydroxide (1.50 g, 26.8 mmol) were dissolved in a mixture of 60 ml of water and 15 ml of methanol. A solution of bromopyruvic acid (1.67 g, 10 mmol) in 10 ml of methanol was added dropwise at room temperature. The resulting mixture was heated to reflux for 1.5 h, cooled to room temperature, poured into 100 ml of water and adjusted with 0.2N HCl solution to pH2. The mixture was placed in a refrigerator for 15 h. The title compound was obtained by filtration as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.82 (d, 2H), 7.78 (d, 2H), 8.37 (s, 1H), 10.05 (s, 1H), 13.00 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.C([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]2[CH:22]=[N:23][C:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[C:14]2[C:13]1=[O:32])(C)(C)C>C(Cl)Cl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:23]=[CH:22][N:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:12][C:13](=[O:32])[C:14]=23)=[CH:26][CH:27]=1
Reactant: CC(C)(C)n1c(=O)c2c(-c3ccc(F)cc3)ncn2c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2ccccc2n2cnc(-c3ccc(F)cc3)c12
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (50.0 ml) is added to a solution of 5-tert-butyl-3-(4-fluorophenyl)-4,5-dihydroimidazo[1,5-a]quinoxalin-4-one (XXXIV, EXAMPLE 245, 4.01 g) and methylene chloride (50.0 ml) at 0°. The solution is stirred for 1 hr at 0° and is concentrated. The residue is triturated with water, filtered, washed with water (2×100 ml), ether (2×100 ml), and dried under reduced pressure to give the title compound, mp >300°; IR (mineral oil) 2955, 2922, 2868, 2855, 1667, 1499, 1377 and 1366 cm-1 ; NMR (d6 -DMSO) 11.45, 9.16, 8.3-8.45, 8.21 and 7.2-7.45 δ; MS (EI, m/z) 279, 251 and 223.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:22]([C:31]#[C:32][Si](C)(C)C)[CH:21]=1>C(Cl)Cl.O>[C:31]([C:22]1[CH:21]=[C:20]([F:19])[CH:25]=[CH:24][C:23]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28])#[CH:32]
Reactant: COC(=O)Cc1ccc(F)cc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: C#Cc1cc(F)ccc1CC(=O)OC

Procedure:
A solution of TBAF (1.0 M in THF; 2.0 mL, 2.0 mmol) was added to a stirred solution of methyl 2-(4-fluoro-2-((trimethylsilyl)ethynyl)phenyl)acetate (A49) (0.212 g, 0.802 mmol) in DCM (5 mL). After 2 minutes the resulting mixture was diluted with water (100 mL) and DCM (50 mL). The organic fraction was separated and adsorbed onto silica gel then purified using column chromatography (Biotage Isolera, 12 g SiO2 Cartridge, 0-20% EtOAc in petroleum benzine 40-60° C.) to give the title compound A50 as a brown oil (0.106 g, 69%); 1H NMR (400 MHz, CDCl3) δ 7.37-7.26 (m, 1H), 7.23 (dd, J=9.0, 2.8 Hz, 1H), 7.06 (m, 1H), 3.84 (s, 2H), 3.73 (s, 3H), 3.33 (s, 1H). LCMS-A: rt 5.838 min; m/z 193 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[C:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([OH:24])=[O:23]>>[C:22]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:27][CH:26]=1)([OH:24])=[O:23]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1
Yield: 19.6 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4-carboxyphenylboronic acid (73 mg, 0.44 mmol, 1.50 equiv) as reactants. Purification by prep-TLC yielded 21 mg (19%) of 3-(4-carboxyphenyl)-2-phenylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: C(S([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]2[CH:18]=[C:19]([C:22]3[C:23]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[N:24][N:25]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[CH:20]=[CH:21][C:8]=2[N:7]=1)(=O)=O)C.[H-].[Na+].[CH3:55][C:56]1[C:61]([OH:62])=[CH:60][CH:59]=[CH:58][N:57]=1.O>CN(C)C=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:9]3[CH:18]=[C:19]([C:22]4[C:23]([C:46]5[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=5)=[N:24][N:25]([C:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:26]=4)[CH:20]=[CH:21][C:8]=3[N:7]=[C:6]2[O:62][C:61]2[C:56]([CH3:55])=[N:57][CH:58]=[CH:59][CH:60]=2)=[CH:12][CH:13]=1
Reactant: CCS(=O)(=O)c1nc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1
Reactant: Cc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1nc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
40 mg 2-(ethylsulfonyl)-1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-1H-benzo[d]imidazole obtained in Example 138 was dissolved in 2 mL N,N-dimethylformamide, then 6.8 mg sodium hydride was added thereto and stirred for 20 minutes, and 3 mL 2-methyl-3-pyridinol was added thereto and stirred at 80° C. for 3 hours. Water was added thereto, and the reaction solution was extracted with ethyl acetate, and the organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give 1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-2-[(2-methyl-3-pyridyl)oxy]-1H-benzo[d] imidazole. This product was subjected to deprotection of the trityl group by the same method as in Example 84 and then purified by NAM silica gel chromatography (ethyl acetate/methanol), to give 6 mg of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].Br[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[S:17][C:16]([S:18]([N:21]3[CH:25]=[CH:24][CH:23]=[CH:22]3)(=[O:19])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: CCc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1
Yield: 81 %

Procedure:
N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrole was prepared, in the same manner as described in Example 32C, from 4-ethylphenylboronic acid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by column chromatography using 10% ethyl acetate/hexanes gave the pure sulfonamide as a tan solid in 81% yield.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH2:3][CH2:2]1>ClCCl.[O-2].[O-2].[Mn+4]>[O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH2:3][CH2:2]1
Reactant: OCc1cc2c(cn1)OCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2c(cn1)OCC2
Reaction time: 18 h
Yield: 69.4 %

Procedure:
2,3-Dihydrofuro[2,3-c]pyridin-5-ylmethanol (1.31 g, 8.7 mmol) was dissolved in dichloromethane (100 ml) and treated with manganese dioxide (6 g, 69 mmol) at ambient temperature with vigorous stirring for 18 h. The mixture was filtered through kieselguhr and the filtrate evaporated to dryness to provide the desired compound (0.9 g, 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:10]=1[CH:11]([C:14]1[CH:15]=[CH:16][C:9]([O:8][CH3:1])=[CH:10][CH:13]=1)[OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c(F)cccc1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2c(F)cccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 170.1 %

Procedure:
To a THF solution (50 mL) of 2-benzyloxy-6-fluoro-benzaldehyde (2.25 g, 9.8 mmol) as described in International Publication WO 04/048335, a 4-methoxyphenyl-magnesium bromide THF solution (0.5 M, 21.5 mL) was added dropwise in a nitrogen stream at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours, and then a saturated ammonium chloride aqueous solution was added thereto under cooling with ice and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (2.82 g, 85%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1N[C:10](=O)[CH2:9]2.IC.[CH3:16][N:17]([CH:19]=[O:20])[CH3:18]>>[CH3:16][N:17]1[C:18]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:10])[C:4]([CH3:12])([CH3:3])[C:19]1=[O:20]
Reactant: Cc1cccc2c1NC(=O)C2
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cc1cccc2c1N(C)C(=O)C2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.00 g (50.0 mmol) sodium hydride (55%, suspension in mineral oil) were added at 0° C. to 2.34 g (3.58 mmol) 7-methyl-1,3-dihydro-indol-2-one in 20 mL DMF and the mixture was stirred for 30 min. Then 3.00 mL (48.2 mmol) iodomethane were added and the mixture was stirred for 2 h at RT. Ice water was added to the reaction mixture, then it was extracted with DCM and aqueous sodium hydrogen carbonate solution. The organic phase was dried on sodium sulphate, filtered and evaporated down i. vac. The residue was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:21])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH3:23][O:24][NH2:25]>>[CH3:23][O:24][N:25]=[C:18]([CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH3:21])[CH3:19]
Reactant: CC(=O)CCCn1c(C)nc2c(N)nc3ccccc3c21
Reactant: CON
Agent: Cl
Product: CON=C(C)CCCn1c(C)nc2c(N)nc3ccccc3c21

Procedure:
By the general method described in Part F of Example 30, 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one was reacted with O-methylhydroxylamine hydrochloride to provide 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-methyloxime in about a 5.25 to 1 mixture of E and Z isomers as white needles after recrystallization from toluene, mp 158-161° C.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][NH:24][CH2:23][CH2:22]2)=[O:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][N:24]([CH2:2][CH:3]1[O:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][CH2:4]1)[CH2:23][CH2:22]2)=[O:16]
Reactant: COC(=O)c1cccc2c1CNCC2
Reactant: BrCC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1CN(CC1COc3ccccc3O1)CC2
Temperature: 140 °C

Procedure:
To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (0.2 g, 0.88 mmol) and 1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid methyl ester (0.14 g, 0.88 mmol) in DMF (10 ml) was added K2CO3 (0.61 g, 4.41 mmol). The reaction mixture was heated under microwaves at 140° C. for 10 min. Water was then added and the mixture extracted with DCM (3×5 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 95:5).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH2:32][CH2:33][C:34](OC)=[O:35])=[CH:16][N:17]3[CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C)C1C=CN=CC=1.O>[CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH2:32][CH2:33][C:34]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[O:35])=[CH:16][N:17]3[CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:13][CH:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: COC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2OC)c2cc(CC(=O)NCC3CCCC3)ccc12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cn1cc(CCC(=O)N2CCOCC2)c2ccc(CC(=O)NCC3CCCC3)cc21
Yield: 75 %

Procedure:
A solution of 4-[6-(cyclopentylmethylcarbamoyl)methyl-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoic acid (0.40 g) and 4-dimethylaminopyridine (0.10 g) in morpholine (3 ml) was heated at 80° for 52 hr. The reaction was diluted with water and acidified to pH 1 with 10% (v/v) hydrochloric acid to form a precipitate which was collected by filtration to give 4-[6-(cyclopentylmethylcarbamoyl)methyl-3-(2-morpholinocarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoic acid (0.34 g, 75%) as an ivory solid; partial NMR (250 MHz, CDCl3): 2.72(t, 2H, COCH2), 3.35-3.60(8H, morpholino), 3.66(s, 2H, COCH2Ar), 3.95(s, 3H, OCH3), 5.29(s, 2H, NCH2Ar). (It will be recognized that this compound is also an example of the invention.)