Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[NH:6][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:8][C:4]=2[CH:3]=[CH:2]1.Br[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[CH3:12][O:11][C:9]([C:7]1[N:6]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[CH:8]=1)=[O:10]
Reactant: Fc1ccc2cccc(CBr)c2c1
Reactant: COC(=O)c1cc2ccsc2[nH]1
Product: COC(=O)c1cc2ccsc2n1Cc1cccc2ccc(F)cc12

Procedure:
Using general procedure B, methyl 6H-thieno[2,3-b]pyrrole-5-carboxylate was coupled with 1-bromomethyl-7-fluoro-naphthalene (from Example 49.3.) to give 6-(7-fluoro-naphthalen-1-ylmethyl)-6H-thieno[2,3-b]pyrrole-5-carboxylic acid methyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 324.5 ([M−H]−).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C)C=O>[OH:33][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1ccccc1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-[4-(4-Oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) (0.15 g, 0.5 mmol) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) (0.12 g, 0.75 mmol) were mixed in N,N-dimethylformamide (15 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N NaOH and then poured into a saturated aqueous NaHCO3. The aqueous solution was extracted with 1-butanol and the combined organic layers were concentrated. The residue was purified by preparative thin layer chromatography (10% MeOH/CH2CH2) to give the title compound as a pale yellowish solid; mp 218-220° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.30-1.60 (m, 2H), 1.80-2.00 (m, 2H), 2.50-3.00 (m, 5H), 3.00-3.50 (m, 3H), 3.50-3.70 (m, 2H), 3.85-4.00 (m, 3H), 4.48 (dd, J=9.8, 3.8 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 6.90-6.97 (m, 3H), 7.04 (d, J=8.6 Hz, 2H), 7.25-7.38 (m, 3H); MS (ES) m/z: 456.0 (MH+); HRMS Calcd. for C24H29N3O4S(M+): 455.1878. Found: 455.1880.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[I:9]I.CCCCCC>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Br:1][C:2]1[N:7]=[C:6]([I:9])[C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nc1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CCCCCC
Product: Nc1ccc(Br)nc1I
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a stirred solution of 6-bromo-pyridin-3-ylamine (10.2 g, 0.0580 mol) and Ag2SO4 (18.1 g, 0.0580 mol) in EtOH (150 mL) was added I2 (7.59 g, 0.0580 mol) and the reaction was allowed to stir overnight. At this time hexane (200 mL) was added and the resultant mixture was filtered through Celite. The solvent was removed in vacuo, dissolved in CHCl3 (200 mL), washed with aqueous saturated Na2S2O3 (100 mL), water (1×100 mL), and dried (Na2SO4). The solvent was concentrated in vacuo and the residue was dissolved in hot EtOAc (100 mL), filtered and treated with hexanes (100 mL). Filtration gave 11.2 g (65%) of the title compound as a white crystalline material. 1H-NMR (CDCl3; 400 MHz): δ 7.10 (d, 1H, J=8.2 Hz), 6.74 (d, 1H, J=8.2 Hz), 4.06 (br s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]#[N:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=[O:19].[OH-].[Na+].OO>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15](=[O:19])[NH2:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Temperature: 50 °C

Procedure:
To a solution of 4-cyano-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (2.24 g, 10 mmol) in methanol (25 mL) was added DMSO (1mL), aqueous 1N NaOH (12mL, 12 mmol) and H2O2 (4 mL) at room temperature. The mixture was heated at 50° C. for 3 hours. After cooling to room temperature, the mixture was partitioned between EtOAc and H2O. The organic layer was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed to afford the desired product.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O=[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](OCC)=[O:18]>S(=O)(=O)(O)O>[OH:2][C:1]1[C:9]2[C:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:17](=[O:18])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: Oc1cc(O)cc(O)c1
Agent: O=S(=O)(O)O
Product: O=c1oc2cc(O)cc(O)c2c2c1CCCC2
Temperature: 0 °C

Procedure:
Phloroglucinol (1 g) and ethyl 2-oxocyclohexane carboxylate (1.32 g) were stirred in 75% sulfuric acid (10 ml) overnight, the mixture poured into ice water and filtered Yield: 1.55 g.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1.[C:25]([O-:28])(=[O:27])[CH3:26].[Na+]>CN(C=O)C>[C:25]([O:28][CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)[O-]
Reactant: ClCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 100 °C
Yield: 51.9 %

Procedure:
A suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxy-phenyl)quinazoline (159 mg, 0.5 mmol) in DMF (2 mL) was treated with sodium acetate (104 mg, 1.2 mmol). The mixture was heated at 100° C. for 2 h, than it was poured into ice-water. The precipitated solid was collected by filtration, washed with water, and dried. The crude product was crystallized from EtOAc-hexane to give the title compound as colorless needles (95 mg); mp 144-147° C.; 1H NMR (CDCl3) 7.37 (s 1H), 7.33 (s, 1H), 7.19-7.24 (m, 2H), 6.97 (d, J=8.5, 1H), 6.15 (s, 2H), 6.07 (s, 2H), 5.41 (s, 2H), 2.24 (s, 3H). Anal. calcd. for C19H14N2O6: C, 62.30; H, 3.85; N, 7.65. Found: C, 62.12; H, 3.92; N, 7.65.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([NH:24][C:25](=[O:33])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[Cl:32])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:34]([NH2:36])=[O:35])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C1COCC1.CN(C1C=CN=CC=1)C>[C:44]([NH:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([NH:24][C:25](=[O:33])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[Cl:32])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:34]([NH2:36])=[O:35])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3])(=[O:46])[CH3:45]
Reactant: NC(=O)c1nn(-c2ccc(S(N)(=O)=O)cc2)c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a stirring solution of 1-[4-(aminosulfonyl)phenyl]-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (2967 mg, 5.7 mmol) in THF (120 mL) was added DMAP (348 mg, 2.8 mmol), then tri-ethyl amine (0.95 mL, 6.8 mmol), followed by acetic anhydride (1.62 mL, 17.1 mmol). The reaction mixture was stirred at room temperature for overnight and then concentrated. To the residue was added 5% aq. NaHCO3 (100 mL). All compounds were dissolved. The aq. Layer was washed with EA (100 mL×2), CH2Cl2 (100 mL). The aq. layer was separated. To the aq. Layer was added 1N HCl to pH=6. A white precipitate was formed. It was filtered and washed with ether to give a white solid. The solid was dried under reduced pressure at 45° C. to give 1-{4-[(acetylamino)sulfonyl]phenyl}-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (2255.4 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:21]([O:23][CH2:24][CH2:25]Br)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[ClH:28].[C:29]1([C:35]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:28].[CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:21]([O:23][CH2:24][CH2:25][N:38]2[CH2:39][CH2:40][C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:36][CH2:37]2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCBr)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 41.5 %

Procedure:
2.35 g of 3-methyl 5-(2-bromoethyl) (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 1.46 g of 4,4-diphenylpiperidine hydrochloride and 1.55 g of finely powdered potassium carbonate in 15 ml of anhydrous dimethylformamide are stirred for 6 h at 80° C. After the mixture has cooled, 100 ml of water are added and the mixture is then extracted with ether. The ether phase is washed twice with water, dried over sodium sulphate and then evaporated in vacuo. The residue is chromatographed over a silica gel column using a 95:5 chloroform/ethanol as the mobile phase. The chromatographically pure fractions are collected and evaporated. The residue is dissolved in ether and 2 ml of a saturated solution of hydrogen chloride in ether are added to the solution, crystallisation occurring. The product is filtered off under suction, washed with ether and dried. 1.4 g of the title compound of m.p. 155°-158° C. (decomp.) and [α]22D =+68.4° (c=1, methanol) are obtained.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N+:20]([O-])([OH:22])=[O:21].C(O)(=O)C.N([O-])=O.[Na+]>O>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([S:7]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[CH:13][C:12]=2[CH3:18])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)Nc2c(C)cccc2C)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)Nc2c(C)cc([N+](=O)[O-])cc2C)cc1

Procedure:
The sulfonamide intermediate of Example 4 (6.9 g, 0.025 mole) was added to a solution of 6.3 ml of concentrated nitric acid in 50 ml of water, followed by addition of 50 ml of glacial acetic acid and 0.18 g of sodium nitrite. The mixture was heated at reflux for one hour, then poured into 100 ml of water. The crude product thus isolated was recrystallized from ethanol to give 6.5 g of the title compound. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:26])[CH:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:12](=O)[CH3:13].CS(O)(=O)=O>C([O-])(=O)C.[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]2[C:3]=1[NH:9][C:10](=[O:26])[C:11]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1)=[C:12]2[CH3:13]
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)Nc1cc(O)ccc1Cl
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Product: Cc1c(Cc2ccc(S(C)(=O)=O)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Temperature: 100 °C

Procedure:
A mixture of N-(2-chloro-5-hydroxyphenyl)-2-(4-methanesulfonylbenzyl)-3-oxo-butyramide (0.25 g) and methanesulfonic acid (1.1 g) was heated at 100° C. for 10 minutes. The mixture cooled to room temperature and poured into a saturated aqueous solution of sodium acetate (20 mL). The resulting precipitate was collected by filtration, washed with water and dried to afford title compound as a pale pink solid, 0.21 g.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[C:7]1=[O:24].[O:26]1[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[N:27]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:25][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][N:20]([C:31]([C:28]5[CH:29]=[CH:30][O:26][N:27]=5)=[O:32])[CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[C:7]1=[O:24]
Reactant: O=C(O)c1ccon1
Reactant: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CNCC4C3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CN(C(=O)c5ccon5)CC4C3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-[(2,2-Difluorocyclopropypmethyl]-5-(1,2,3,3a,4,6a-hexahydrocyclopenta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (14-2, 50 mg, 0.14 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 24.4 mg, 0.21 mmol, 1.5 equiv), DIPEA (0.076 mL, 0.43 mmol, 3.0 equiv) and HATU (82 mg, 0.21 mmol, 1.5 equiv) were added to anhydrous acetonitrile (3 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 14-3 as a white solid. MS m/z (M+H): calculated=442.1688; observed=442.1703.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:22]1[N:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1)#[N:21]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:25]3[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[N:27][CH:26]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: N#Cc1ccc(C(=O)Cl)cn1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: N#Cc1ccc(C(=O)NCCCCn2cnc3c(N)nc4ccccc4c32)cn1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 6-cyanopyridine-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-cyanonicotinamide as an off white powder, m.p. 125.0-129.0° C. 1H NMR (300 MHz, DMSO-d6) δ 9.05 (dd, J=2.1, 0.8 Hz, 1H), 8.88 (t, J=5.6 Hz, 1H), 8.31 (dd, J=8.1, 2.1 Hz, 1H), 8.21 (s, 1H), 8.14 (dd, J=8.1, 0.8 Hz, 1H), 8.03 (m, 1H), 7.62 (dd, J=8.3, 1.1 Hz, 1H), 7.42 (m, 1H), 7.20 (m, 1H), 6.59 (broad s, 2H), 4.64 (t, J=6.9 Hz, 2H), 3.30 (m, 2H), 1.93 (m, 2H), 1.59 (m, 2H); MS (EI) m/e 385.1648 (385.1651 calcd for C21H19N7O).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:32]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:32]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][N:27]([CH2:29][CH2:30][O:31][S:41]([CH3:40])(=[O:43])=[O:42])[CH:28]=5)[N:18]4[N:17]=3)=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OCCn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-pyrazol-1-yl)-ethanol (0.55 g, 1.28 mmol) in dichloromethane (5 ml) was added triethylamine (450 μl, 3.20 mmol) followed by methanesulfonyl chloride (200 μl, 2.56 mmol). The mixture was stirred for 18 hours at room temperature, and partitioned between ethyl acetate and ammonium chloride. The aqueous phase was extracted multiple times with ethyl acetate, and the combined organic phases dried over magnesium sulfate, filtered and concentrated in vacuo to provide a white fluffy solid. No further purification was required. Yield: 0.34 g, 52%; LCMS method: 2, RT: 2.25 min, MI: 512 [M+1].
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[N:28]=[C:29]([CH3:35])[S:30][C:31]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:27]2[N:28]=[C:29]([CH3:35])[S:30][C:31]=2[C:32]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:33])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Cc1nc(-c2cccc(F)c2)c(C(=O)O)s1
Product: Cc1nc(-c2cccc(F)c2)c(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic Acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 4-(3-Fluoro-phenyl)-2-methyl-thiazole-5-carboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][O:13][CH3:14])[CH:6]=1)=[O:4].Br.[C:16]1([CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([CH2:2][N:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:4])=[CH:6][C:7]=1[CH2:12][O:13][CH3:14]
Reactant: COCc1cc(C(=O)CBr)ccc1O
Reactant: c1ccc(CCCOCCCCCCNCc2ccccc2)cc1
Agent: Br
Solvent: ClCCl
Product: COCc1cc(C(O)CN(CCCCCCOCCCc2ccccc2)Cc2ccccc2)ccc1O
Yield: 18.3 %

Procedure:
A solution of 2-bromo-1-[4-hydroxy-3-(methoxymethyl)phenyl]ethanone (700 mg), N-[6-(3-phenylpropoxy)hexyl]benzenemethanamine hydrobromide (1.1 g) and DEA (0.95 ml) in dichloromethane (10 ml) was kept at room temperature overnight. ER (50 ml) was added and the suspension was washed twice with water, brine, dried and concentrated to an oil which was dissolved in ethanol (20 ml) and treated with sodium (400 mg). The solution was stirred and refluxed refluxed overnight, water (30 ml) was added and the mixture was extracted with ER (3×25 ml). The organic extracts were washed with brine, dried and concentrated to a red oil which was purified by FCC eluting with System E (80:20:1→66:33:1) to give the title compound as an oil (250 mg), t.l.c. (System E 66:37:1) Rf 0.22.
Reaction SMILES: [CH2:1]([C:5]1[C:13]([C:14]([C:16]2[CH:23]=[CH:22]C(C#N)=[CH:18][CH:17]=2)=[O:15])=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[C:29]([OH:32])(=[O:31])[CH3:30]>O>[CH2:1]([C:5]1[C:13]([C:14]([C:16]2[CH:23]=[CH:22][C:30]([C:29]([OH:32])=[O:31])=[CH:18][CH:17]=2)=[O:15])=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCc1nn2ccccc2c1C(=O)c1ccc(C#N)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCc1nn2ccccc2c1C(=O)c1ccc(C(=O)O)cc1

Procedure:
A mixture of 845 mg of the product of Example 2 and 15 ml of a mixture in equal proportions of sulfuric acid, acetic acid and water was refluxed for 2 hours and the mixture was cooled down, taken up in water, filtered, washed with water and dried at 80° C. under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1ccc2c(ccn2-c2ccc(F)c(F)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(ccn2-c2ccc(F)c(F)c2)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 100.3 %

Procedure:
A mixture of methyl 1-(3,4-difluorophenyl)-indole-5-carboxylate 24c (3.0 g, 10.4 mmol) and LiOH (1.0 g, 41.8 mmol) in THF (120 mL) and H2O (60 mL) was stirred at room temperature for 5 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 24d (2.85 g).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:34]1([CH2:37]Br)[CH2:36][CH2:35]1>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:37][CH:34]3[CH2:36][CH2:35]3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: BrCC1CC1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2CC1CC1)N1CCN(C2CCC2)CC1
Yield: 80 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (80%).
Reaction SMILES: [NH2:1][CH:2]([OH:24])[C@H:3]([CH3:23])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1.[BH4-].[Na+].O.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30]>CO>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH2:1][CH:2]([OH:24])[C@H:3]([CH3:23])[CH2:4][CH2:5][C:6]1[S:7][C:8]([CH:11]([OH:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:10]=1
Reactant: C[C@H](CCc1ccc(C(=O)CCCCc2ccccc2)s1)C(N)O
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H](CCc1ccc(C(O)CCCCc2ccccc2)s1)C(N)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
(2R)-Amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol (130 mg, 0.38 mmol) obtained in Example 50 was dissolved in methanol (3 ml), and sodium borohydride (17 mg, 0.45 mmol) was added thereto in an ice bath followed by stirring for 1 hour at room temperature. To the reaction solution was added water in the ice bath, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol, and oxalic acid (34 mg, 0.38 mmol) was added thereto, and the solvent was evaporated in vacuo. To the residue was added ethanol (3 ml), and the resulting precipitate was filtered off to give the title compound (95 mg, 58% yield) as a white crystalline solid.