Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f14) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>>[F:24][C:25]1[C:30]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: OB(O)c1cccnc1F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cccnc3F)ccc1-2
Yield: 20 %

Procedure:
Following the procedure for 128, 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and 2-fluoropyridin-3-ylboronic acid were reacted to give 487 (0.226 g, 20%). 1H NMR (400 MHz, DMSO) δ 8.48 (d, J=8.3, 1H), 8.33-8.18 (m, 2H), 8.12 (s, 1H), 7.54-7.45 (m, 2H), 7.37 (d, J=1.5, 1H), 5.96-5.75 (m, 1H), 4.44 (t, J=5.0, 2H), 3.49 (t, J=5.0, 2H), 1.90-1.28 (m, 6H). MS (ESI(+)): m/z 408.12 (M+H)
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:42][CH:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]1>CN(C)C=O>[C:52]([O:51][C:49]([N:46]1[CH2:45][CH2:44][CH:43]([NH:42][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:48][CH2:47]1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a mixture of 0.25 g (0.56 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.30 mL (1.7 mmole) of ethyldiisopropyl amine and 0.12 g (0.62 mmole) of 4-amino-1-Boc-piperidine in 4.0 mL of dimethylformamide was added 0.27 g (0.62 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with hexane-ethylacetate (gradient, 70:30-0:100) gave 0.21 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-71) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:18]C(=O)OCC2C=CC=CC=2)[C:12]2[O:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:2]1>O1CCCC1.[Pd]>[NH2:18][C@H:11]([C:12]1[O:13][C:14](=[O:17])[NH:15][N:16]=1)[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)c1n[nH]c(=O)o1)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: N[C@@H](Cc1c[nH]c2ccccc12)c1n[nH]c(=O)o1
Reaction time: 24 h

Procedure:
A solution of (S)-benzyl 2-(1H-indol-3-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl-carbamate (1.41 g, 3.73 mmol) in anhydrous tetrahydrofuran (100 mL) was mixed with 10% palladium on activated carbon (160 mg) and hydrogenated for 24 h at room temperature and at 3 bar. A further portion of 20% palladium on activated carbon (160 mg) was added and the mixture hydrogenated for a further 24 h at 3 bar and 40° C. The catalyst was then filtered off, the filtrate concentrated to low volume in a vacuum and the residue (1.24 g) purified by flash chromatography (100 g, 20×4.0 cm) with chloroform/methanol (95:5).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][P:15]([O-:24])[O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1.[ClH:25]>C(Cl)Cl.CCOCC>[ClH:25].[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[P:15]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)(=[O:24])[O:14][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=1
Reactant: [O-]P(Oc1ccc(F)cc1)Oc1ccc(F)cc1
Reactant: C1CCNCC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=P(Oc1ccc(F)cc1)(Oc1ccc(F)cc1)C1CCCCN1
Yield: 54 %

Procedure:
A mixture of piperidine trimer (4.5 g, 54 mmole) and di(4-fluorophenyl)phosphite (14.8 g, 55 mmole) was heated at 90°-100° C. for 3 h under nitrogen. The resulted oil was cooled and dissolved in a mixture of 50 mL CH2Cl2 and 50 mL ether. The solution was saturated with dry HCl, the oil was separated and solidified after several hours. The solid was filtered, washed with ether and dried. The hygroscopic material was stirred in 200 mL dry ether for several hours and the yellowish solid was filtered and dried. The product was obtained in 54% yield (11.6 g) and used for subsequent reaction: mp. 155°-165° C. (dec); 1H NMR (D2O) δ7.2-6.8 (m, 8H), 3.6-2.9 (m, 3H), 2.2-1.4 (m, 6H); MS (FAB) m/e 354 (M-Cl)+. Anal. (exact mass, HRMS) calcd. for C17H19N1O3P1Cl2 m/e 354.1070, found 354.1098.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1.[O-]S(C(F)(F)F)(=O)=O.[Li+].[O:27]1[CH2:33][C@@H:28]1[C:29]([O:31][CH3:32])=[O:30]>C(#N)C>[O:17]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH:12][CH2:33][C@@H:28]([OH:27])[C:29]([O:31][CH3:32])=[O:30])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1
Reactant: Nc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Reactant: COC(=O)[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: COC(=O)[C@H](O)CNc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 56.5 %

Procedure:
A solution of 4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluoroaniline (EXAMPLE 15, Step 3, 1.30 g, 5.0 mmol) in acetonitrile (7.5 mL) is treated with lithium triflate (0.60 g, 5.0 mmol) and methyl (2R)-2,3-epoxypropanoate (0.51 g, 0.46 mL, 5.0 mmol) and heated to 70° C. for 2 h. At this time an additional amount (1.5 mmol each) of the two reagents is added and the mixture stirred for another 7 h at 70° C. The reaction mixture is then cooled to room temperature, concentrated, and purified by column chromatography (50→60% ethyl acetate-hexane) to provide the title compound (1.03 g, 57%), MS (m/z): [M+H]+=365; 1H NMR (300 MHz, CDCl3): δ 3.04 (d, 1H), 3.15 (m, 4H), 3.31-3.46 (m, 2H), 3.47-3.56 (m, 4H), 3.83 (s, 3H), 4.20 (t, 1H), 4.40 (m, 1H), 6.17 (d, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:34][CH2:35][C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].[S:48]1[CH:52]=[CH:51][C:50]2[CH:53]=[C:54](O)[CH:55]=[CH:56][C:49]1=2.C(N(CC)CC)C>ClCCl>[S:48]1[CH:52]=[CH:51][C:50]2[CH:53]=[C:54]([O:34][CH2:35][C@@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:55]=[CH:56][C:49]1=2
Reactant: Oc1ccc2sccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Polystyrene supported triphenylphosphine (2.9 mmol/g, 1.70 g, 4.95 mmol) was treated with diisopropylazodicarboxylate (0.779 mL, 3.96 mmol) at 0° C. in anhydrous dichloromethane. A mixture of (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.5 g, 3.3 mmol), benzo[b]thiophen-5-ol (0.5 g, 3.3 mmol) and triethylamine (0.689 mL, 4.95 mmol) in dichloromethane (5 mL) was then added to the reaction. The mixture was then allowed to warm up to room temperature and stirred overnight. The reaction was then filtered off and the filtrate purified by column chromatography on silica gel using a gradient of 15 to 50% ethyl acetate in hexanes to obtain a clear oil that solidied into an off-white solid on standing. Yield=0.48 g. MS (M+H)+ 334.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([O:49][Si:50]([CH:57]([CH3:59])[CH3:58])([CH:54]([CH3:56])[CH3:55])[CH:51]([CH3:53])[CH3:52])=[C:45]([Cl:60])[CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([O:49][Si:50]([CH:54]([CH3:56])[CH3:55])([CH:57]([CH3:58])[CH3:59])[CH:51]([CH3:53])[CH3:52])=[C:45]([Cl:60])[CH:44]=2)[N:36]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1Cl)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5C)n4c3)c3ccccc32)cc1Cl)(C(C)C)C(C)C
Yield: 89 %

Procedure:
A mixture of Intermediate E (145 mg, 0.40 mmol) and [5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporated herein by reference, 251 mg, 0.420 mmol) in 1,4-dioxane (4 mL) and DIPEA (110 μL, 0.63 mmol) was stirred at 90° C. for 5.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-12% MeOH in DCM, to give the title compound (288 mg, 89%). LCMS (Method 3): Rt 3.85 min, m/z 811 [MH+].
Reaction SMILES: [Na].[Cl:2][C:3]1[C:12](Cl)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.[CH3:16][OH:17]>>[Cl:2][C:3]1[C:12]([O:17][CH3:16])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1
Reactant: CO
Reactant: COc1ccc2nc(Cl)c(Cl)nc2c1
Agent: [Na]
Product: COc1ccc2nc(Cl)c(OC)nc2c1
Temperature: 50 °C

Procedure:
In a flame-dried reaction flask under a dry nitrogen atmosphere, there was slowly added a solution consisting of 850 mg. of sodium dissolved in 80 ml. of methanol to a slurry of 7.1 g. of 2,3-dichloro-6-methoxyquinoxaline in 60 ml. of methanol at 50° C. over a period of seven hours. The resulting mixture was then heated at 50° C. overnight and finally cooled to room temperature. Upon completion of this step, the spent reaction mixture was concentrated in vacuo and the residue subsequently dissolved in chloroform, followed by washing with water and drying over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, the resulting residue was subsequently chromatographed on a column of 400 ml. of silica gel, followed by elution with toluene. The good fractions were combined and concentrated in vacuo to ultimately afford a white solid consisting of 6.1 g. (88%) of pure 2-chloro-3,6-methoxyquinoxaline. m.p. 79°-81° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][OH:29])=[C:23]([F:30])[CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].N1(C(=O)CC2C(F)=C[C:40]([OH:44])=CC=2F)CCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:44][CH3:40])=[O:29])=[C:23]([F:30])[CH:22]=3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CCO)c(F)c3)CC2)nc1
Reactant: O=C(Cc1c(F)cc(O)cc1F)N1CCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[4-(2-{(1S,2R)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]ethanol (0.200 g, 0.726 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of 1-(azetidin-1-yl)-2-(2,6-difluoro-4-hydroxyphenyl) ethanone (0.160 g, 0.871 mmol) in 5 ml anhydrous dichloromethane. Triphenylphosphine, polymer-bound (0.571 g, 1.90 mmol), and di-tert-butyl azodicarboxylate (0.334 g, 1.45 mmol) was added and the slurry stirred at RT for 3 hours. The mixture was filtered through Celite and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica gel (Biotage column, 50 g) using a gradient eluent of 0-50% ethyl acetate in hexanes (700 ml) to afford the title compound. LC/MS (m/z) 442.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>CCOCC>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1cc(Cl)cnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 2,5-dichloronicotinic acid (20.2 g, 0.105 mol, Aldrich) in methanol (500 mL) was cooled to 0° C. and neat thionyl chloride (38 mL, 63 g, 0.525 mol) was added over ˜30 min. The reaction mixture was stirred at 0° C. for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to room temperature, and the reaction was allowed to stir for an additional 2 days at room temperature. The solvent was removed under reduced pressure to give an off-white residue. The residue was dissolved in ether (˜500 mL) and the resulting solution was washed successively with saturated aqueous sodium bicarbonate solution (˜300 mL), water (˜300 mL), and brine (˜300 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. Removal of the solvent under reduced pressure yielded methyl 2,5-dichloronicotinate (21.0 g, 97% yield) as a white solid.
Reaction SMILES: C([Li])CCC.[C:6]1([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(N(C2C=CC=CC=2)C([O:25][C:26](=O)[C:27]2[CH:32]=[CH:31][C:30]([CH2:33][N:34]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([NH:43][C:44](=[O:52])[CH:45]([CH2:50][CH3:51])[CH2:46][CH2:47][CH2:48][CH3:49])[CH:41]=4)[CH:36]=[CH:35]3)=[C:29]([O:53][CH3:54])[CH:28]=2)=O)C=CC=CC=1.P([O-])(O)(O)=O.[K+]>O1CCCC1>[CH2:50]([CH:45]([CH2:46][CH2:47][CH2:48][CH3:49])[C:44]([NH:43][C:40]1[CH:41]=[C:42]2[C:37]([CH:36]=[CH:35][N:34]2[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:26](=[O:25])[CH2:15][S:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:14])=[O:13])=[CH:28][C:29]=2[O:53][CH3:54])=[CH:38][CH:39]=1)=[O:52])[CH3:51]
Reactant: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)OC(=O)N(c4ccccc4)c4ccccc4)cc3OC)c2c1
Reactant: CS(=O)(=O)c1ccccc1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)CS(=O)(=O)c4ccccc4)cc3OC)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
A solution of butyllithium (0.86 ml of a 2.3M solution in hexanes) was added to a solution of methyl phenyl sulphone (312 mg) in dry tetrahydrofuran (THF) (5 ml.) at -78° C. After 15 minutes a white suspension formed. To this mixture was then added a solution of 4-[6-(2-ethylhexanamido)indole-1-yl-methyl]-3-methoxybenzoic N,N-diphenylcarbamic anhydride (A) (500 mg) in THF (4 ml). After two hours, the mixture was allowed to warm to ambient temperature and an excess of a saturated solution of potassium dihydrogen phosphate was added. The solvent was removed by evaporation and the residue was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The residual gum was purified by chromatography on silica gel (20 g), using 2:98 v/v ether:methylene chloride as eluent, to give the title compound as a white solid (200 mg, 44%); mp 131°-133° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([C:32]#[N:33])[N:23]=1>CN1C(=O)CCC1>[C:32]([C:24]1[N:23]=[C:22]([O:1][CH2:2][C@H:3]2[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:31]2[C:26]([CH:25]=1)=[CH:27][CH:28]=[CH:29][CH:30]=2)#[N:33]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: N#Cc1cc2ccccc2c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1nc(C#N)cc2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (444 mg, 2.206 mmol) and Cs2CO3 (719 mg, 2.206 mmol) in NMP (4 mL) were stirred at 0° C. for 1 hour. Next, 1-chloroisoquinoline-3-carbonitrile (400 mg, 2.121 mmol) was added and the reaction mixture was heated at 140° C. for 15 minutes in a microwave reactor. Additional Cs2CO3 (719 mg, 2.206 mmol) was added. The reaction mixture heated at 140° C. for 1 hour to give the title compound, which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:28])[C:25](O)=[O:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC>[CH2:11]([CH:18]1[CH2:19][CH2:20][N:21]([C:24](=[O:28])[C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[O:26])[CH2:22][CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCCCCC
Product: O=C(Nc1ccc2[nH]ccc2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-aminoindole (Aldrich) and (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) according to the method described in Example 1c. Melting Point: 68-72° C. (hexane)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.BrN1C(=[O:21])CCC1=O.C1N2CN3CN(C2)CN1C3>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(C)cc2)cc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 120 °C
Yield: 24 %

Procedure:
Into CCl4 solvent, 2.4 g(13.3 mmol) of the compound produced in Example 1 (Compound 1) and 0.536 g(3.0 mmol) of N-bromosuccinimide were added and refluxed for 24 hours. After cooled down, the reactant was suction-filtrated and the resultant solution was washed with distilled water and then was dried with anhydrous magnesium sulfate. The dried product was dissolved again in chloroform together with 5.34 g(51.2 mmol) of hexamethylenetetraamine and refluxed for 5 hours. After the reactant was cooled down, the solvent was distilled off under reduced pressure and the residue was refluxed severely in acetic acid/H2O(17 mL/17 mL) at 120° C. for 2 hours. Finally, 7 mL of HCl was added to be refluxed. After cooled down, the reactant was extracted with methylene chloride. The solution was distilled off under reduced pressure and the residue was purified through the column chromatography (silica gel, ethyl acetate/n-hexane=1:3) to be dried. Yield; 24%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CC(C)(C)C(=O)Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C(C)(C)C)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2,2-dimethyl-propionamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and pivaloyl chloride (109 μl, 0.89 mmol). The title compound was obtained as brown powder (171 mg, 53%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[CH2:10]([S:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)[CH3:11]>>[CH2:10]([S:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[F:9])[CH:16]=[CH:15][CH:14]=1)[CH3:11]
Reactant: CCSc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)c(F)c1
Product: CCSc1cccc(-c2ccc(N)cc2F)c1
Yield: 108.7 %

Procedure:
The title compound (430 mg) was prepared from 4-bromo-3-fluoroaniline (300 mg, 1.6 mmol) and 3-(ethylthio)phenylboronic acid (370 mg, 2.0 mmol) as a yellow liquid.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C)C=O>[CH2:37]([O:36][C:34]([CH2:33][O:23][C:20]1[CH:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:9]2[N:10]([CH3:14])[C:11]3[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH2:24][CH3:25])[C:7]=3[N:8]=2)=[CH:22][CH:21]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)CCl
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)cc3)n2C)n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(/C=C/c2nc3c(c(=O)n(CC)c(=O)n3CC)n2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
Compound 175 (300 mg, 0.88 mmol) obtained in Reference Example 114 was dissolved in 10 ml of dimethyl formamide. To the solution were added 731 mg (5.29 mmol) of potassium carbonate and 0.47 ml (4.41 mmol) of ethyl chloroacetate, and the mixture was stirred at room temperature for 2 hours. Water was added thereto to dissolve potassium carbonate and the deposited crystals were collected by filtration. The collected crude crystals were dissolved in chloroform, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give 341 mg (yield 91%) of Compound 180 as pale yellow needles.