Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCC(NC(=O)OC(C)(C)C)C1.[O:15]=[C:16]1[C:24]2[C:23]([NH:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)=[N:22][C:21]([N:33]3[CH2:38][CH2:37][CH2:36][CH:35]([NH:39]C(=O)OC(C)(C)C)[CH2:34]3)=[N:20][C:19]=2[CH2:18][NH:17]1.Cl.O1CCOCC1.[OH-].[Na+]>>[NH2:39][CH:35]1[CH2:36][CH2:37][CH2:38][N:33]([C:21]2[N:22]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[C:24]3[C:16](=[O:15])[NH:17][CH2:18][C:19]=3[N:20]=2)[CH2:34]1
Reactant: Cc1cccc(Nc2nc(N3CCCC(NC(=O)OC(C)(C)C)C3)nc3c2C(=O)NC3)c1
Agent: CC(C)(C)OC(=O)NC1CCCNC1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cccc(Nc2nc(N3CCCC(N)C3)nc3c2C(=O)NC3)c1
Yield: 64.2 %

Procedure:
The above compound was prepared in a manner similar to EXAMPLE 10 using tert-butyl piperidin-3-ylcarbamate in place of cyclohexylamine. Following cyclization, tert-butyl 1-(5-oxo-4-(m-tolylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)piperidin-3-ylcarbamate (20.00 mg, 0.046 mmol) was treated with 4M HCl in dioxane (2 mL, 8.00 mmol) at RT for 5 h to deprotect the Boc group. The mixture was subsequently basified with 2N NaOH, extracted with EtOAc, washed with brine, dried over MgSO4, and evaporated. The residue was purified by recrystallization (EtOH-Hexane) to give the title compound as white solid (10 mg, 64.8% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.99-2.03 (m, 4 H), 2.30 (s, 3 H), 2.57-3.07 (m, 3 H), 4.16 (s, 2 H), 4.26-4.86 (m, 2 H), 6.88 (d, J=5.6 Hz, 1 H), 7.23 (s, 1 H), 7.42-7.55 (m, 1 H), 7.59 (s, 1 H), 8.08 (s, 1 H), 8.55 (s, 1 H). [M+H] calc'd for C18H22N6O, 339; found, 339.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[S:25]>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[S:25]
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: S=C=Nc1ccccc1Cl
Solvent: CN(C)C=O
Product: S=C(NCC(c1ccccc1)c1ccccc1)Nc1ccccc1Cl

Procedure:
The compound was prepared substantially in accordance with the procedure detailed in Example 1, using 2,2-diphenylethylamine (1.61 g, 8.1 mmol) and 2-chlorophenyl isothiocyanate (1.1 ml, 8.2 mmol) in 30 ml of DMF. The crude material was purified by recrystallization (hexanes/EtOAc).
Reaction SMILES: C(O[C:4]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([C:12]#[N:13])[S:6](=[O:15])(=[O:14])[N:5]=1)C.[NH3:16]>C(O)C>[NH2:16][C:4]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([C:12]#[N:13])[S:6](=[O:15])(=[O:14])[N:5]=1
Reactant: CCOC1=NS(=O)(=O)C(C#N)=C1OCC
Reactant: N
Solvent: CCO
Product: CCOC1=C(C#N)S(=O)(=O)N=C1N
Reaction time: 2 h

Procedure:
To a suspension of 3,4-diethoxy-5-cyanoisothiazole-1,1-dioxide (0.85 g, 0.0037 mol) in 40 ml of ethanol was added 2.6 ml of 1.7M ammonia in ethanol (0.0044 mol) with stirring. A clear yellow solution formed and a white precipitate separated in 5 minutes. After 2 hours at room temperature, the title compound (0.61 g, 82%, mp 232°-233.5°) was collected and a sample recrystallized from ethanol to give analytically pure material, mp 236°-238.5°, Rf 0.26 (10% methanol-chloroform, silica gel).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[C:21]([O:25][C:26](=[O:35])[NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[C:21]([O:25][C:26](=[O:35])[NH:27][CH2:28][CH:29]1[CH2:30][CH2:31][N:32]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:33][CH2:34]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=[N+]([O-])c1cc2cccnc2cc1Cl
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2cc3ncccc3cc2[N+](=O)[O-])CC1
Temperature: 100 °C
Yield: 23 %

Procedure:
To a solution of 7-chloro-6-nitro-quinoline (974 mg, 4.67 mmol) in N,N-dimethylformamide (25 mL) were added potassium carbonate (1.93 g, 14.01 mmol) and piperidin-4-ylmethyl-carbamic acid tert-butyl ester (1.00 g, 4.67 mmol) and the resulting mixture was heated at 100° C. overnight. The reaction mixture was cooled and partitioned between water (500 mL) and ethyl acetate (300 mL). The organic layer was separated, washed twice with water (500 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified twice by flash chromatography to afford 415 mg of [1-(6-nitro-quinolin-7-yl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester as an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(ethoxycarbonylmethyl)piperidine (0.011 mol) and 1-fluoro-4-nitrobenzene (0.011 mol) in DMSO (20 ml) was stirred in the presence of Na2CO3 (0.044 mol) during 2 hours at a temperature of 60° C. The reaction mixture was cooled to room temperature and poured into an ice/water mixture. The resulting precipitate was filtered and washed with water. The reaction product was purified by recrystallisation from a mixture of ethyl acetate and hexane, yielding [1-(4-nitro-phenyl)-piperidin-4-yl]-acetic acid ethyl ester (intermediate 3, mp. 83-85° C.).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[OH:12])=[O:3].[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=O>>[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]1[O:12][C:5]2[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=2[C:2](=[O:3])[CH:1]=1
Reactant: COc1ccc(C(C)=O)c(O)c1
Reactant: O=C(Cl)c1ccccc1Cl
Product: COc1ccc2c(=O)cc(-c3ccccc3Cl)oc2c1

Procedure:
2 is prepared from 2-hydroxy-4-methoxyacetophenone and 2-chlorobenzoyl chloride by the procedure of Example 1. Material is purified by flash chromatography (gradient elution using 25% ethyl acetate in hexane and 10% ethyl acetate in chloroform; material is loaded on column in methylene chloride), yielding 2 with a melting point of 148.5°-149.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26].CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C1COCC1>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([NH:8][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:10]([OH:26])[C@H:11]2[OH:25])=[C:19]([Cl:23])[N:18]=1
Reactant: N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1S,2R,3S,5R)-3-amino-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol trifluoroacetate (0.304 g, 1.0 mmol) in THF (10 mL) is treated with DIPEA (0.387 g, 3.0 mmol) followed by propionyl chloride (0.093 g, 1.0 mmol). After stirring at room temperature for 2 hours, the solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water-0.1% TFA). MS (ES+) m/e 360 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])NC(CC1C=C(F)C=C(F)C=1)C(O)CNC1(C2C=CC=C(C#C)C=2)CC1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCO[CH2:37][CH2:36]1>CO>[C:6]([C:36]#[CH:37])([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:33]
Reactant: C#Cc1cccc(C2(NCC(O)C(Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)CC2)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: C#CC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 360 %

Procedure:
[1-(3,5-difluorobenzyl)-3-[1-(3-ethynylphenyl)cyclopropylamino]-2-hydroxypropyl]-carbamic acid tert-butyl ester (2.34 g, 5.13 mmol) was treated with 4N HCl in dioxane (15.8 mL, 63.3 mmol). The resulting heterogeneous mixture was treated with methanol (10 mL) whereupon it became homogeneous over 30 min. The volatiles were evaporated in vacuo. Dioxane (20 mL) was added and the mixture was evaporated in vacuo to produce a white solid (2.33 g, 106%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:25])(=O)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[N:6]([CH3:25])[N:7]([CH2:17][CH:18]2[CH2:19][CH2:20]2)/[C:8](=[N:10]/[C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])/[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)c1cc(NC(=O)C(F)(F)F)n(CC2CC2)n1
Solvent: Cc1ccccc1
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)C(F)(F)F)n1CC1CC1
Yield: 54.4 %

Procedure:
A mixture of Example 27D (11.6 g, 40 mmol) and dimethyl sulfate (20.2 g, 160 mmol) in toluene (10 mL) was heated in a microwave at 150° C. for 30 min. The mixture was concentrated and purified by flash chromatography (silica gel, MeOH/Et3N (10:1)/EtOAc in 10-60% gradient) to yield 6.6 g (54.4%) of the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 0.41-0.53 (m, 4H), 1.15-1.27 (m, 1H), 1.38 (s, 9H), 3.98 (s, 3H), 4.20 (d, J=7.12 Hz, 2H), 6.70 (s, 1H); MS (ESI) m/z 304 [M+H]+, 302 M−H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[N:12]1([CH2:18][C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[CH:20]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: Nc1cccc(CN2CCOCC2)c1
Product: O=[N+]([O-])c1cc(Br)cnc1Nc1cccc(CN2CCOCC2)c1

Procedure:
N-(5-Bromo-3-nitropyridin-2-yl)-N-[3-(morpholin-4-ylmethyl)phenyl]amine was prepared from 5-bromo-2-chloro-3-nitropyridine and 3-(morpholin-4-ylmethyl)phenylamine as described in Example 3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])[C:6]=1[Cl:7].Cl[C:14]1[N:15]=[C:16]([O:41][CH:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[C:17]2[C:22]([C:23]3[CH:32]=[CH:31][C:26]4[N:27]=[C:28]([CH3:30])[O:29][C:25]=4[CH:24]=3)=[CH:21][N:20]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]=2[N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:7][C:6]1[N:5]([CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])[N:4]=[CH:3][C:2]=1[NH:1][C:14]1[N:15]=[C:16]([O:41][CH:42]2[CH2:43][CH2:44][CH2:45][CH2:46]2)[C:17]2[C:22]([C:23]3[CH:32]=[CH:31][C:26]4[N:27]=[C:28]([CH3:30])[O:29][C:25]=4[CH:24]=3)=[CH:21][N:20]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]=2[N:19]=1
Reactant: CC(C)(O)Cn1ncc(N)c1Cl
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Nc5cnn(CC(C)(C)O)c5Cl)nc(OC5CCCC5)c34)cc2o1
Temperature: 100 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a degassed mixture of 1-(4-amino-5-chloro-1H-pyrazol-1-yl)-2-methylpropan-2-ol (1 equiv), 6-(2-chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1.01 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.1 equiv) in 1,4-dioxane (0.08 M) was added palladium acetate (0.1 equiv) and cesium carbonate (3 equiv). The reaction was stirred at 100° C. for 2 h. Upon completion, the reaction mixture was cooled to room temperature and concentrated to give the title compound which was used directly in next step without further purification (97% yield). MS (ESI) m/z 652.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:28]=[CH:29][C:30]6[N:34]=[C:33]([NH:35]C(=O)OC)[NH:32][C:31]=6[CH:40]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.Cl>CO.[OH-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:28]=[CH:29][C:30]6[N:34]=[C:33]([NH2:35])[NH:32][C:31]=6[CH:40]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(c3ncnc(C)c3Cc3ccc(F)cc3)CCO4)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncnc(N2CCOc3ccc(-c4ccc5nc(N)[nH]c5c4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 65 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
A mixture of methyl [6-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamate (example 2) (60 mg, 0.11 mmol) in methanol and 2M potassium hydroxide (1:1, 2 mL) was stirred at 65° C. for 18 hours. The reaction mixture was cooled, adjusted to pH 10 with 2M hydrochloric acid, concentrated, diluted with ethyl acetate (10 mL), washed with brine solution (5 mL), dried over sodium sulfate, filtered, concentrated. The residue was purified by preparative reverse phase HPLC to give 6-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-amine (29 mg, 54% yield). 1H NMR (400 MHz, Methanol-d4): 8.44 (1H), 7.37 (dd, 1H), 7.31 (s, 1H), 7.29 (s, 1H), 7.14 (dd, 1H), 7.07-7.01 (m, 2H), 6.99 to 6.91 (m, 3H), 6.70 (br, 1H), 4.49 (s, 2H), 4.26 (m, 2H), 3.95 (s, 2H), 3.86 (m, 2H), 2.19 (s, 3H), MS (EI) for C28H25FN6O: 481 (MH+).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[N:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:34]5[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=5[Cl:45])=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)=[O:23])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=CC=1>C(Cl)Cl.CO>[N:11]1([CH2:14][C:15]2[N:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:34]4[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=4[Cl:45])=[C:28]4[C:33]=3[N:32]=[CH:31][CH:30]=[CH:29]4)=[O:23])=[CH:17][CH:16]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)cn3)CC2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNCC4)nc3)c3ncccc23)c1Cl
Temperature: 120 °C
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 105 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (6-piperazin-1-ylmethyl-pyridin-3-yl)-amide (Example 170) and stirring the reaction mixture for 1 h at 120° C. Title compound: ESI-MS: 552.0 [M+H]+; tR=3.57 min (System 1); TLC: Rf=0.12 (DCM/MeOH, 9:1).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]([CH3:17])=[CH:5][CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14].[OH-].[Na+]>CO.O>[CH3:17][C:4](=[CH:5][CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:3]([OH:18])=[O:2]
Reactant: COC(=O)C(C)=CC=CCC(C)CCC=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)=CCCC(C)CC=CC=C(C)C(=O)O
Temperature: 0 °C

Procedure:
22.8 g. of 2,7,11-trimethyl-2,4,10-dodecatrienoic acid methyl ester is dissolved in 150 ml of methanol and mixed with 22.8 g. of sodium hydroxide dissolved in 35 ml of water. The mixture is boiled under reflux for 3 hours, poured on to ice-water and extracted with diethyl ether. The ether extracts are discarded and the aqueous phase acidified with dilute sulphuric acid. The acidic aqueous solution is extracted with diethyl ether and the ether extract is washed repeatedly with aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated on a rotary evaporator. There is obtained 2,7,11-trimethyl-2,4,10-dodecatrienoic acid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([C:33](=O)[CH3:34])=[N:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:37][NH3+:38].C([O-])(=O)C.[Na+]>CO>[Si:1]([O:18][CH2:19][C:20]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[C:23]([C:33](=[N:38][OH:37])[CH3:34])=[N:22][CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH3+]O
Reactant: CC(=O)c1ncc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)n1COCC[Si](C)(C)C
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1ncc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)n1COCC[Si](C)(C)C
Temperature: 50 °C
Reaction time: 7 h
Yield: 21.9 %

Procedure:
1-[5-(tert-Butyldiphenylsilyloxymethyl)-1-(2-trimethylsilylethoxymethyl)-1H-imidazol-2-yl]ethanone (60.0 g) was dissolved in methanol (600 mL), and at room temperature hydroxylammonium chloride (16.4 g) and sodium acetate (24.2 g) were added, which mixture was subsequently warmed at 50° C., followed by stirring for 7 hours. After the reaction solution was cooled to room temperature, the insolubles were removed by filtration, and the mother liquor was concentrated to obtain the residue, which was purified by flash chromatography (ethyl acetate/hexane=10%→60%) using silica gel column (product name: Hi-Flash Column 5 L, manufactured by Yamazen Corporation) to afford the title compound (13.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2ccccc12
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(=O)O)c2ccccc2c1
Reaction time: 5 h
Yield: 95.5 %

Procedure:
3-Nitro-1-naphthoic acid (1.77 g, 0.008 mole) was dissolved in a minimum of warm MeOH. 10% Pd/C (300 mg) was added and the reaction shaken on a Parr shaker under 50 psi H2 for 5 hours. The catalyst was filtered through celite and the solvent was removed under vacuum. The residue was dried to yield 3-amino-1-naphthoic acid (1.43 g) as a pink colored solid.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:16])[CH3:15].[OH-].[Na+]>CO>[C:14]([NH:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:17])=[O:2])(=[O:16])[CH3:15]
Reactant: COC(=O)Cc1ccc(OC)cc1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CC(=O)O)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-acetylamino-4-methoxy-phenyl)-acetic acid methyl ester (49 mg, 0.21 mmol) in 1.5 mL of methanol was added aqueous 1N NaOH (1.5 mL, 1.5 mmol). The mixture was stirred for 3 h at room temperature. and the pH was adjusted to ˜4 by the addition of Amberlyst 15 ion-exchange resin. After filtration, the filtrate was concentrated to give 46 mg (100%) of 2-acetylamino-4-methoxy-phenyl)-acetic acid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[CH3:10][NH:9][C:8](=[O:11])[C:6]1[CH:5]=[CH:4][C:3]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:2]([CH3:1])[CH:7]=1
Reactant: CNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(N2CCNCC2)c(C)c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To tert-butyl 4-(2-methyl-4-(methylcarbamoyl)phenyl)piperazine-1-carboxylate (1.90 g, 5.70 mmol) was added Hydrochloric acid solution (17.10 ml, 68.4 mmol) in dioxane at 23° C. The reaction was stirred at 23° C. for 30 min. The resulting suspension was diluted with Et20 (20 mL), filtered, rinsed with Et20 (3×10 mL), and the resulting solid was dried in vacuo to provide N,3-dimethyl-4-(piperazin-1-yl)benzamide dihydrochloride (1.70 g, 5.55 mmol, 97% yield) as an off-white, hygroscopic solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 3H) 2.72-2.79 (m, 3H) 3.05-3.14 (m, 4H) 3.17-3.28 (m, 4H) 7.06 (d, J=8.34 Hz, 1H) 7.64-7.68 (m, 1H) 7.68-7.70 (m, 1H) 8.29-8.39 (m, 1H) 9.36 (br. s., 2H). ESI-MS: m/z 234.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][SH:23])=[C:14]([Br:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[C:30]([N+]1C=CC=CC=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][S:23][C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[C:14]([Br:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)[n+]2ccccc2)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CS)nc3N21
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CSC(c4ccccc4)(c4ccccc4)c4ccccc4)nc3N21
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 0.25 g of the product of step 1 in 5 ml dichloromethane was added 0.25 g tritylpyridinium tetrafluoroborate at room temperature and the mixture was stirred at this temperature for 2 h. The reaction mixture was purified by chromatography on silica gel with dichlorometha:ethyl aceate=19:1 to yield 0.39 g of the title compound as colorless foam (MS: 656.3 and 658,4 (M+H+)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:6]=[CH:7][C:8]=1[O:9]CC1C=CC(OC)=CC=1.C1(S)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(COc2ccc(-c3cnc4[nH]cc(-c5ccccc5OC)c4c3)cc2OC)cc1
Agent: O=C([O-])O
Agent: Sc1ccccc1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc3[nH]cc(-c4ccccc4OC)c3c2)ccc1O
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a 50 ml round bottomed flask were added 5-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (48 mg, 0.10 mmol), methylene chloride (2.5 ml) and 396 mg (0.28 mmol) PS-thiophenol (1.41 mmol·g−1; Argonaut Technologies). Trifluoroacetic acid (500 μl) was added and the suspension was shaken in a orbital shaker for 1 hour. The yellow reaction mixture was filtered, and the resin was washed three times with dichloromethane and ether, then twice with dichloromethane. The combined filtrate was concentrated to obtain a yellow residue, which was distributed between ethyl acetate and saturated aqueous solution of sodium bicarbonate. The layers were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate and hexanes gave 31 mg (86%) of 2-methoxy-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenol as a light yellow powder. 1H-NMR (d6-DMSO) δ=11.87 (br.s, 1H), 9.04 (br.s, 1H), 8.48 (d, 1H), 8.07 (d, 1H), 7.68 (dd, 1H), 7.57 (dd, 1H), 7.27 (t, 1H), 7.20 (d, 1H), 7.13 (d, 1H), 7.08 (dd, 1H), 7.02 (t, 1H), 6.85 (d, 1H), 3.85 (s, 3H), 3.82 (s, 3H); MS m/z: 347 [MH]+.