Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]([OH:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26]2[S:39][CH:38]=[CH:37][C:27]=2[N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26]2[S:39][CH:38]=[CH:37][C:27]=2[N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:29]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C(O)c4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C(=O)c4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(hydroxy-phenyl-methyl)-indole-1-carboxylic acid tert-butyl ester [640 mg, 1.17 mmol, Intermediate (12)] in Dichloromethane (25 mL) is added Dess-Martin Periodinane (677 mg, 1.69 mmol) and stirred at room temperature. After 30 minutes water (5 mL) is added and stirred for 10 minutes. The reaction mixture is diluted with dichloromethane (50 mL) and washed twice with a mixture of 10% Na2S2O3/saturated NaHCO3 (5 mL), NaHCO3 (10 mL), water (10 mL), brine and dried over sodium sulfate. The residue is chromatographed on 35 g silica gel cartridge, eluting with 30% ethyl acetate/Heptane to afford 5-benzoyl-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [440 mg, 69%, Intermediate (13)] as a white solid; LC/MS: 544 (M+H). Step 2. A mixture of 5-benzoyl-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [122 mg, 0.224 mmol, Intermediate (13)] in tetrahydrofuran (9 mL) and 1M KOH(aqueous, 2 mL) is heated at 60° C. oil bath overnight. The solvent is removed and added water (5 mL). The water layer is neutralized with 3N hydrochloric acid and extracted three times with ethyl acetate (20 mL). The combined ethyl acetate phases are washed with brine and dried over sodium sulfate. The residue is chromatographed on 10 g silica gel cartridge, eluting with 50 to 100% ethyl acetate gradient in heptane to afford phenyl-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-methanone (58 mg, 75%, Example 25) as a pale yellow solid; 1H NMR [(CD3)2SO)]: δ 13.38 (1H, s), 12.09 (1H, s), 8.05 (1H), 7.78 (8H, m), 7.23 (1H, d, J=5.2 Hz), 6.87 (1H); LC/MS: 344 (M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]=[CH2:17])=[N:5][CH:4]=[C:3]1[C:18]([NH2:20])=O>P(Cl)(Cl)(Cl)=O>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]=[CH2:17])=[N:5][CH:4]=[C:3]1[C:18]#[N:20]
Reactant: C=CCOc1ccccc1-c1ncc(C(N)=O)c(=O)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCOc1ccccc1-c1ncc(C#N)c(=O)[nH]1
Yield: 68.8 %

Procedure:
A solution of 1,6-dihydro-6-oxo-2-(2-allyloxyphenyl)pyrimidine-5-carboxamide (3.58 g.) in phosphorus oxychloride (60 ml.) was heated under reflux for 2 hours. The solution was evaporated to dryness. The residue was cooled in ice and then treated cautiously with ice-water. The mixture was warmed to 25° and then heated on a steam bath for 15 minutes. The solid was collected, washed with cold water, and recrystallized from benzene-Skellysolve B to give the title compound (2.3 g., 69%), m.p. 162°-164°.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:23][S:24][C:25]1[S:29][C:28]([C:30]([OH:32])=O)=[C:27]2[CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:26]=12.C(N(C(C)C)CC)(C)C.[C:47]([O:51][C:52]([N:54]([CH2:62][C:63]1[CH:64]=[C:65]([CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)[CH:66]=[CH:67][CH:68]=1)[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[O:53])([CH3:50])([CH3:49])[CH3:48]>CN(C)C=O>[C:58]([O:57][C:55]([N:54]([CH2:62][C:63]1[CH:64]=[C:65]([CH:69]2[CH2:70][CH2:71][N:72]([C:30]([C:28]3[S:29][C:25]([S:24][CH3:23])=[C:26]4[C:36](=[O:37])[CH2:35][CH2:34][CH2:33][C:27]=34)=[O:32])[CH2:73][CH2:74]2)[CH:66]=[CH:67][CH:68]=1)[C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:53])=[O:56])([CH3:59])([CH3:60])[CH3:61]
Reactant: CSc1sc(C(=O)O)c2c1C(=O)CCC2
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCNCC2)c1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1sc(C(=O)N2CCC(c3cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3)CC2)c2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (120 mg, 0.38 mmol) was added to a room temperature solution of 3-methylsulfanyl-4-oxo-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (88 mg, 0.36 mmol) and diisopropylethylamine (140 mg, 1.08 mmol) in dimethylformamide (2 mL), under nitrogen. The reaction mixture was stirred for 10 minutes at room temperature before adding a solution of 4-[3-(N,N-di-tert-butoxycarbonylaminomethyl)phenyl]piperidine (140 mg, 0.36 mmol) and diisopropylethylamine (140 mg, 1.08 mmol) in dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 16 hours, concentrated to dryness in vacuo, and subjected to dry flash column chromatography on silica with 50:50, dichloromethane:ethyl acetate. 1-{1-[4-(3-(N,N-di-tert -butoxycarbonylaminomethyl)phenyl)-piperidin-1-yl]-methanoyl}-3-methylsulfanyl-6,7-dihydro-5H-benzo[c]thiophen-4-one was isolated as a colorless oil (177 mg). The intermediate was dissolved in dichloromethane (20 mL), cooled at 0° C., and treated with trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature under nitrogen for 2 hours, and concentrated to dryness in vacuo. The residue was dissolved in 20% acetonitrile/water [containing 0.1% trifluoroacetic acid] (9 mL) and purified by preparative reverse-phase HPLC (C-18, 10 micron reverse-phase column), eluting with 10% to 100% acetonitrile/water (containing 0.1% trifluoroacetic acid). The product fractions were combined and the acetonitrile removed in vacuo. The aqueous residue was frozen and lyophilized to give the title compound as an amorphous white solid (122 mg, 64%). 1H NMR [(CD3)2SO]: δ 8.16 (br s, 3H, NH3+); 7.41-7.24 (m, 4H); 4.21 (br d, 2H); 4.03 (q, 2H); 3.18-3.02 (m, 2H); 2.91-2.72 (m, 3H); 2.59 (s, 3H); 2.53-2.41 (m, 2H); 1.98-1.90 (m, 2H); 1.90-1.79 (m, 2H); 1.68-1.50 (m, 2H). MS(Ion spray): 415 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])OC4C=CC=CC=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C([N:33]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][C:35](O)=[O:36])C.O1CCOCC1>CN(C)C1C=CN=CC=1.O>[CH2:38]([N:33]1[CH2:34][C:35](=[O:36])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:10][CH2:11]3)=[CH:16][CH:17]=2)[C:22]1=[O:30])[CH2:39][CH2:40][CH3:41]
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Reactant: CCCCN(CC)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: CCCCN1CC(=O)N(c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)C1=O

Procedure:
A mixture of 24 parts of phenyl [4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]carbamate, 15.9 parts of ethyl N-butylglycine, 2 parts of N,N dimethyl-4-pyridinamine and 200 parts of 1,4-dioxane was stirred and refluxed overnight. Then water was added and stirring was continued for a while. The reaction mixture was cooled, poured onto water and the whole was stirred. The precipitated product was filtered off, washed with water and dissolved in 150 parts of trichloromethane. This solution was stirred for 30 minutes with 3 parts of silica gel. The latter was filtered off and the filtrate was evaporated. The residue was crystallized from butanol. The product was filtered off and dried in vacuo at 60° C., yielding 2.3 parts of 1-butyl-3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2,4-imidazolidinedione; mp. 183.7° C. (39).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[N:20]([CH3:21])[N:19]=[N:18][N:17]=1.C(N(CC)CC)C.C(O)CCC>O>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:16]2[N:20]([CH3:21])[N:19]=[N:18][N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nnnc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCCCO
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1nnnc1N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester (30.0 g, 0.189 mol), 5-chloro-1-methyl-1H-tetrazole (28.8 g, 0.242 mol) and triethylamine (80 mL, 0.573 mol) were added to a mixture of n-butanol (80 mL) and water (80 mL) and the reaction mixture heated to 80° C. for 5 hours. The reaction was cooled to room temperature and stirred at this temperature overnight. The resulting precipitate was filtered off and washed with water (2×25 mL) and then dried to give tert-butyl[1-(1-methyl-1H-tetrazol-5-yl)-piperidin-4-yl]-carbamate as a white powder (41.8 g). 1H NMR (300 MHz, DMSO-d6) ppm 1.39 (s, 9H) 1.44-1.65 (qd, J=12, 4 Hz, 2H) 1.75-1.92)dd, J=13, 3 Hz, 2H) 2.95-3.16 (td, J=13, 3 Hz, 2H) 3.34-3.50 (broad s, 1H) 3.50-3.65 (dt, J=13, 3 Hz, 2H) 3.85 (s, 3H) 6.83-7.04 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCNc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Yield: 78.2 %

Procedure:
A 250 mL round-bottom flask, equipped with a magnetic stir bar, was charged with methyl 4-aminobenzoate (1) (6.04 g, 40 mmol), K2CO3 (11.06 g, 80 mmol) and 85 mL anhydrous DMF. The mixture was cooled to 0° C. and allyl bromide (3.13 mL, 36 mmol) was added dropwise with stirring. After the reaction mixture was heated at 60° C. for 12 hours, DMF was removed under high vacuum. The residual was extracted with CH2Cl2/H2O=150 mL/200 mL, the organic phase was removed and the aqueous phase was then extracted again with CH2Cl2 (150 mL). The combine organic phases were dried over MgSO4. After removal of solvent, the crude product was purified by silica gel chromatography (eluent: Hexane/Ethyl acetate from 100/0 to 100/7) to give compound 2 as a white solid (5.38 g, 78.2% yield). 1H NMR (400 MHz, CDCl3): δ 3.72 (d, 2H), 3.76 (s, 3H), 5.16 (dd, 1H), 5.21 (dd 1H), 5.80-5.85 (m, 1H), 6.50 (d, 2H), 7.80 (d, 2H); 13C NMR (400 MHz, CDCl3): δ 45.89, 51.53, 111.72, 116.80, 118.66, 131.51, 134.29, 144.91, 151.67. MP: 71-73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[CH2:26][C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:20]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=2[Cl:18])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1cc(Cl)ccc1Cl
Product: O=C(Cc1cc(Cl)ccc1Cl)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 27.1 %

Procedure:
Example 13 was prepared in an analogous manner to Example 4 using a mixture of Intermediate 1 (0.055 g) and (2,5-dichlorophenyl)acetic acid (0.041 g) to give the title compound (0.025 g).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:42])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:31][CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:42][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:30]=[CH:31][C:32]([CH2:35][N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:33][CH:34]=2)[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(CN3CCOCC3)cc2)n1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)n(-c2ccc(CN3CCOCC3)cc2)n1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(4-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 550.09 [M-H]+; RTT=2.69 min (HPLC System 3).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[C:19]([CH:20]=2)=[N:18][N:17]([C@H:21]2[CH2:26][CH2:25][C@H:24]([C:27](OC)=[O:28])[CH2:23][CH2:22]2)[CH:16]=3)[CH2:9][CH2:8]1.O.[OH-].[Na+]>C1COCC1>[CH:7]1([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[C:19]([CH:20]=2)=[N:18][N:17]([C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23][CH2:22]2)[CH:16]=3)[CH2:9][CH2:8]1
Reactant: COC(=O)[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1

Procedure:
To a suspension of lithium aluminum hydride (0.462 g) in THF (100 mL) was added dropwise a solution of methyl trans-4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]cyclohexanecarboxylate (4.00 g) in THF (100 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 2 hr, and water (0.462 mL), 5N aqueous sodium hydroxide solution (0.462 mL) and water (0.462 mL) were carefully added successively thereto. The reaction mixture was stirred under ice-cooling for 30 min, and the resulting precipitate was filtered off. The obtained filtrate was concentrated under reduced pressure to give the title compound (3.51 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>C(OCC)C.Cl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c(-c2cccnc2)n(COC(=O)C(C)(C)C)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask is charged with 5-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2, 1.0 g, 3.58 mmol) and THF (20 mL) and cooled to 0° C. KHMDS (0.5 M in toluene, 17.9 mL, 8.95 mmol) is added and the mixture is stirred at room temperature for 30 min, followed by addition of 2,2-dimethyl-propionic acid chloromethyl ester (2.58 mL, 8.95 mmol). The reaction mixture is stirred at room temperature for 3.5 h, then washed with water and extracted with ethyl acetate twice. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to afford an oil, which is taken up in diethyl ether. A few drops of concentrated HCl are added. Evaporation of the solvent and lyophilization give 2,2-dimethyl-propionic acid 5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl ester as a solid. 1H NMR (400 MHz, MeOD) δ ppm (HCl salt) 1.12 (s, 9H), 2.27 (s, 3H), 6.06 (s, 2H), 7.30 (dd, J=8.6, 2.0 Hz, 1H), 7.60 (s, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.74 (dd, J=7.8, 5.1 Hz, 1H), 8.01-8.16 (m, 1H), 8.64-8.79 (m, 2H). HRMS (ESI) m/z 357.1121 [(M+H)+ Calcd for C20H22ClN2O2: 357.1127].
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2.C([BH3-])#N.[Na+].CCCCCC.CC(C)=O>CO.[Cl-].[Na+].O>[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([N:30]3[CH2:35][CH2:34][N:33]([CH:15]4[CH2:16][CH2:17][N:12]([C:3]5[C:2]([F:1])=[C:11]6[C:6]([CH:7]=[CH:8][CH:9]=[N:10]6)=[CH:5][CH:4]=5)[CH2:13][CH2:14]4)[CH2:32][CH2:31]3)[CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2
Reactant: Fc1cc(N2CCNCC2)c2ncccc2c1
Reactant: O=C1CCN(c2ccc3cccnc3c2F)CC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: O
Product: Fc1cc(N2CCN(C3CCN(c4ccc5cccnc5c4F)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(8-fluoroquinolin-7-yl)piperidin-4-one (Step 1, 0.25 g) and 6-fluoro-8-(1-piperazinyl)quinoline (Example B, Step 3; 0.25 g) in anhydrous methanol (10 mL) was added sodium cyanoborohydride (0.11 g). The resulting mixture was stirred at room temperature for 18 hours. An additional aliquot of sodium cyanoborohydride (0.10 g) was added and stirring at room temperature was continued for another 24 hours. The reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator. The crude product was isolated by flash chromatography on silica gel using hexane/acetone to give the desired product as a off-white solid, which was converted to its trihydrochloride salt in CH2Cl2/Et2O diethyl ether using 1M HCl/Et2O to provide 0.11 g as a yellow solid; MS (ES) m/z (relative intensity): 460 (M+H)+ (100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[S:21][N:20]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][CH:27]4[CH2:26][CH2:25][N:24]([C:22]5[S:21][N:20]=[C:19]([CH3:18])[N:23]=5)[CH2:29][CH2:28]4)[N:16]=[C:12]3[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc2cncc(-c3ccc(F)cc3)n2n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3nc4cncc(-c5ccc(F)cc5)n4n3)CC2)n1

Procedure:
Prepared in analogy to example 1h, starting from 5-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine and 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one. The title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:35]S(C)(=O)=O)=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=3)[C:6]=2[CH:34]=1.[C:40](Cl)(=[O:42])[CH3:41].O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:35][C:40](=[O:42])[CH3:41])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:25])=[O:26])=[O:22])=[CH:14][CH:13]=3)[C:6]=2[CH:34]=1
Reactant: CCc1nc2cc(NS(C)(=O)=O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCc1nc2cc(NC(C)=O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a solution of 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine (step 6 of Example 110, 100 mg, 0.3 mmol) in pyridine (7 mL) was added dropwise acetyl chloride (0.03 mL, 0.33 mmol) under nitrogen atmosphere at 0° C., and the reaction mixture was stirred at room temperature for 1.5 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with 2N aqueous NaOH (30 mL), brine (30 mL), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:3) to afford 110 mg (98%) of the title compound as white solids: 1H-NMR (CDCl3) δ 8.66 (1H, s), 7.56 (1H, br.s), 7.45 (2H, d, J=8.2 Hz), 7.29 (2H, d, J=8.2 Hz), 7.12 (1H, s), 3.82 (2H, t, J=7.1 Hz), 3.19 (2H, t, J=7.1 Hz), 2.77 (2H, q, J=7.6 Hz), 2.26 (3H, s), 1.34 (3H, t, J=7.6 Hz).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.O.OC1C2N=NNC=2C=CC=1.[C:29]([O:33][C:34](NC1(C(O)=O)CCCC1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CN1CCNCC1>CN(C=O)C>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:9]([C:4]2([NH:3][C:34](=[O:35])[O:33][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:10])[CH2:12][CH2:13]1
Reactant: CN1CCN(C(=O)C2(N)CCCC2)CC1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Agent: CN1CCNCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)C2(NC(=O)OC(C)(C)C)CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
(1-Aminocyclopentyl)(4-methyl-1-piperazinyl)methanone dihydrochloride ##STR204## 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.49 g, 13.0 mmol) was added portionwise to a cooled (4° C.) solution of hydroxybenzotriazole hydrate (1.49 g, 11.0 mmol) and 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (2.29 g, 10.0 mmol) in DMF (15 ml), and the mixture stirred for 30 min. N-Methylpiperazine (1.10 g, 11.0 mmol) was added, the reaction stirred for 30 min. allowed to warm to room temperature and stirring continued for a further 17 h. The reaction mixture was evaporated in vacuo, and the residual yellow oil partitioned between saturated Na2CO3 solution and EtOAc. The layers were separated, the aqueous phase extracted with EtOAc, and the combined organic solutions dried (MgSO4) and concentrated in vacuo. The residual solid was pre-adsorbed onto silica gel and purified by column chromatography upon silica gel using an elution gradient of CH2Cl2 -MeOH-0.880 NH3 (97.5:2.5:0.25 to 90:10:1) and triturated with Et2O to afford tert-butyl 1-[(4-methyl-1-piperazinyl)carbonyl]cyclopentylcarbamate (2.31 g, 7.4 mmol) as a crystalline solid.
Reaction SMILES: CO.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[C:6]([O:14]CC2CC2)[CH:5]=1.Cl>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:12])[F:13])=[C:6]([OH:14])[CH:5]=1
Reactant: FC(F)Oc1ccc(Br)cc1OCC1CC1
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1cc(Br)ccc1OC(F)F
Yield: 101.9 %

Procedure:
To 60 ml of methanol solution containing 5.80 g (19.7 mmol) of 4-bromo-2-cyclopropylmethoxy-1-difluoromethoxybenzene (see WO 2004033430) was added 60 ml of conc. hydrochloric acid, and the mixture was refluxed for 5 hours. After completion of the reaction, 60 ml of water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 4.80 g of the title compound as a slightly yellowish oil substantially quantitatively.