Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:17]([F:20])([F:19])[F:18])=[O:14])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([NH:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1)=[O:32].ClS([N:43]=[C:44]=O)(=O)=O.CN(C)C=O>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:44]#[N:43])=[C:7]([C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[C:17]([F:18])([F:20])[F:19])=[O:14])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([NH:33][C:34]1([C:37]#[N:38])[CH2:35][CH2:36]1)=[O:32]
Reactant: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)NC3(C#N)CC3)c(Cl)cc21
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)c(C#N)c2cc(C(=O)NC3(C#N)CC3)c(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
6-Chloro-N5-(1-cyanocyclopropyl)-1-ethyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide (0.100 g, 0.18 mmol) is initially charged in dry acetonitrile (2 ml) under argon and cooled to 0° C., and chlorosulphonyl isocyanate (0.028 g, 0.19 mmol) is added dropwise. After 30 min, N,N-dimethylformamide (0.015 g, 0.19 mmol) is added and the mixture is stirred at 0° C. for a further 30 min and at room temperature overnight. Then the mixture is cooled again to 0° C. and chlorosulphonyl isocyanate (0.028 g, 0.19 mmol) is added dropwise, N,N-dimethylformamide (0.015 g, 0.19 mmol) is added after 30 min, and the mixture is stirred at room temperature for a further 48 h. The reaction mixture is then concentrated under reduced pressure, and the residue is admixed with sodium hydrogencarbonate and extracted with dichloromethane. The organic phase is dried with sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by means of preparative HPLC (Kromasil100, C18 250×20; eluent: acetonitrile in water, gradient: 10-100%) to obtain 0.006 g (5% of theory) of 6-chloro-3-cyano-N5-(1-cyanocyclopropyl)-1-ethyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.[CH3:12][CH:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14]>CN(C=O)C>[CH:13]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:12]
Reactant: CC(=O)Nc1ccnc(Cl)c1
Reactant: CC(C)N1CCNCC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccnc(N2CCN(C(C)C)CC2)c1
Temperature: 150 °C

Procedure:
A mixture of 4.6 g (27 mmol) N-(2-chloropyridin-4-yl)acetamide (commercially available) and 5.2 g (41 mmol) 1-(2-propyl-)-piperazine in 2 ml DMF was heated to 150° C. for 4 h. Purification of the crude mixture with flash column chromatography on silica eluting with a gradient formed from DCM (1% NEt3) and methanol yielded after evaporation of the product fractions 3.38 g (47%) of the title compound as white solid. MS: (m/e): 263.4 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([NH:10][C:11]([C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[C:19](Br)[CH:20]=3)[NH:15][N:14]=1)=[O:12])[CH2:6]2.[O:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:23]1[CH:27]=[CH:26][C:25]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:11]([NH:10][CH:5]2[CH2:4][CH:3]3[N:2]([CH3:1])[CH:7]([CH2:8][CH2:9]3)[CH2:6]2)=[O:12])=[CH:24]1
Reactant: OB(O)c1ccoc1
Reactant: CN1C2CCC1CC(NC(=O)c1n[nH]c3ccc(Br)cc13)C2
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Product: CN1C2CCC1CC(NC(=O)c1n[nH]c3ccc(-c4ccoc4)cc13)C2
Yield: 4 %

Procedure:
In a 5 mL microwave reaction vessel was added N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-bromo-1H-indazole-3-carboxamide (0.286 mmol), furan-3-boronic acid (0.588 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.0289 mmol), tri-tert-butylphosphine tetrafluoroborate (0.0579 mmol), and potassium carbonate (0.810 mmol). The vessel was evacuated, back-filled with argon gas, and the contents diluted with N,N-dimethylformamide (5.0 mL). The vessel was sealed and subjected to microwave irradiation at 200° C. for 600 s. The contents of the reaction were filtered through Celite (methanol wash) and loaded on a 5 g SCX column. The column was washed with methanol (50 mL) and the product was eluted with 2 M ammonia in methanol and concentrated. The residue was purified by chromatography [1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] followed by preparative HPLC, thus providing the product in 4% yield. 1H NMR (CD3OD) δ 8.51 (s, 1H), 8.35 (s, 1H), 7.93 (s, 1H), 7.70-7.58 (m, 3H), 6.87 (s, 1H), 4.56-4.52 (m, 0.5H), 4.28-4.26 (m, 0.5H), 3.97-3.93 (m, 2H), 2.84 (s, 3H), 2.49-2.12 (m, 8H); LC/MS (EI) tR 4.20 min, m/z 351 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=[C:5]2[O:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[O:11][C:7]1[C:6]2[C:2]([NH2:1])=[N:3][O:4][C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1noc2cccc(O)c12
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1noc2cccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
94.37 mg (0.63 mmol) of 3-amino-1,2-benzisoxazol-4-ol (from example V), 100 mg (0.63 mmol) of 3,4-difluoronitrobenzene and 95.56 mg (0.69 mmol) of potassium carbonate are suspended in 3 ml of anhydrous dimethylformamide and stirred at room temperature for 16 hours. The reaction solution is then diluted with water, and the precipitate is filtered off. The product is dried under high vacuum.
Reaction SMILES: CS(O[CH2:6][C:7]1([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)(=O)=O.[C-:20]#[N:21].[K+]>CN(C)C=O.O.CCOCC>[CH2:13]([O:12][CH2:11][C:7]1([CH2:6][C:20]#[N:21])[CH2:10][CH2:9][CH2:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1(COCc2ccccc2)CCC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: N#CCC1(COCc2ccccc2)CCC1
Temperature: 130 °C
Yield: 63 %

Procedure:
To a solution of 16.75 g (59.0 mmol) of {1-[(benzyloxy)methyl]cyclobutyl}methyl methanesulfonate in 150 mL of N,N-dimethylformamide and 15 mL of water was added 4.97 g (88.5 mmol) of potassium cyanide and the contents heated at 130° C. for 5 h. The reaction mixture was cooled, diluted with ether and water, and the layers separated. The organic phase was dried using magnesium sulfate and concentrated under vacuum to afford the crude product, which was purified by silica gel chromatography using ethyl acetate/hexane (1:3) as the eluent to afford 8.0 g (88%) of {1-[(benzyloxy)methyl]cyclobutyl}acetonitrile as a colorless oil. 1H NMR (300 MHz, CDCl3). 1H NMR (300 MHz, CDCl3) δ 7.43-7.29 (m, 5H), 4.59 (s, 2H), 3.5 (s, 2H), 2.6 (s, 2H), 2.08-1.92 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N+:15]([O-])=[CH:14][C:13]3[N:20]=[C:21]([CH2:36][O:37][CH2:38][CH3:39])[N:22]([CH2:23][C:24]([NH:27][C:28]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:29])([CH3:26])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:44]=C=O)=O>ClCCl>[NH2:44][C:14]1[C:13]2[N:20]=[C:21]([CH2:36][O:37][CH2:38][CH3:39])[N:22]([CH2:23][C:24]([NH:27][C:28]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:29])([CH3:25])[CH3:26])[C:12]=2[C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCOCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Reaction time: 1 h
Yield: 62.7 %

Procedure:
N-{2-[8-(benzyloxy)-2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide (2.41 g, 4.55 mmol) was suspended in dichloromethane (75 mL) and trichloroacetyl isocyanate (0.70 mL, 5.92 mmol) was added dropwise. After stirring for 1 hour, the volatiles were removed under reduced pressure. The resulting orange residue was dissolved in methanol (75 mL) and 6 mL of sodium methoxide (21% in methanol) was added. The reaction was stirred overnight and then the methanol was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with water followed by brine. The organic fraction was dried over sodium sulfate, filtered and concentrated under reduced pressure to give an orange foam. The residue was purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used eluting with a gradient of 10-20% CMA in chloroform to yield 1.51 g of N-{2-[4-amino-8-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide as a tan solid.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH2:19]([C:26]1[CH:27]=[C:28]([NH2:31])[NH:29][N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([C:26]1[CH:27]=[C:28]([NH:31][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[NH:29][N:30]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cc(Cc2ccccc2)n[nH]1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1cc(Cc2ccccc2)n[nH]1

Procedure:
The named compound is prepared by substituting 5-benzyl-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.231 gms. 5-benzyl-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL) overnight.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:28])[CH2:25][CH2:26]Br)[C:3]=1[F:29].Cl.[CH3:31][NH:32][CH3:33].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:28])[CH2:25][CH2:26][N:32]([CH3:33])[CH3:31])[C:3]=1[F:29]
Reactant: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CCBr)c(F)c3o2)cc1F
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
130 mg (0.276 mmol) of Compound 160 obtained in EXAMPLE 160 was dissolved in 5 mL of dimethylformamide, 112 mg (1.38 mmol) of dimethylamine hydrochloride and 0.24 mL (1.38 mmol) of diisopropylethylamine were added, and the mixture was stirred at 50° C. for 30 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1), to give 122 mg of Compound 162 (yield: 86%), which was converted to a hydrochloride according to the same manner as that in EXAMPLE 161.
Reaction SMILES: [ClH:1].CC1(C)[O:7][C@@H:6]2[CH:8]=[CH:9][C@@H:10]([N:11]3[C:19]4[C:18]([F:20])=[CH:17][N:16]=[C:15]([NH2:21])[C:14]=4[N:13]=[CH:12]3)[C@@H:5]2[O:4]1>CO>[NH2:21][C:15]1[C:14]2[N:13]=[CH:12][N:11]([C@H:10]3[C@H:5]([OH:4])[C@H:6]([OH:7])[CH:8]=[CH:9]3)[C:19]=2[C:18]([F:20])=[CH:17][N:16]=1.[ClH:1]
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(N)ncc(F)c43)C=C[C@H]2O1
Agent: Cl
Solvent: CO
Product: Nc1ncc(F)c2c1ncn2[C@@H]1C=C[C@@H](O)[C@H]1O

Procedure:
Concentrated HCl (3 mL) was added to 1-[(3aS,4R,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-7-fluoro-1H-imidazo[4,5-c]pyridin-4-amine (2-3) (158 mg, 0.54 mmol, 1 equiv) in methanol (10 mL). After disappearance of the starting material, as monitored by LC-MS analysis, the mixture was concentrated to afford (1S,2R,5R)-5-(4-amino-7-fluoro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-3-ene-1,2-dial (2-5) as a yellow solid of the bis-HCl salt. 1H NMR (2-5) (500 MHz, DMSO): δ 8.57 (s, 2H); 8.52 (s, 1H); 8.03 (d, J=5.3 Hz, 1H); 6.23 (d, J=5.9 Hz, 1H); 6.09 (d, J=6.2 Hz, 1H); 5.53 (d, J=5.5 Hz, 1H); 4.51 (s, 1H); 4.13 (t, J=5.7 Hz, 1H). HRMS m/z (M+H) 251.0939 found, 251.0939 required. 1H NMR (2-6) (500 MHz, DMSO): δ 8.53 (s, 1H); 8.24 (s, 2H); 8.08 (d, J=4.5 Hz, 1H); 6.32 (d, J=5.9 Hz, 1H); 6.21 (d, J=6.2 Hz, 1H); 5.71 (s, 1H); 4.54 (d, J=5.7 Hz, 1H); 4.08 (m, 1H). HRMS m/z (M+H) 251.0938 found, 251.0939 required.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][N:17]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=2)[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([Cl:29])[C:20]=2[F:30])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([CH2:32][N:17]([CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[C:21]([Cl:29])[C:20]=2[F:30])=[CH:38][CH:37]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1ccc(CN(CCc2cccc(OCc3ccccc3)c2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(O)c2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)cc1
Yield: 80.2 %

Procedure:
A solution of 1.1 g of N-[2-(3-benzyloxy-phenyl)-ethyl]-N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-5-trifluoromethyl-benzamide (1.84 mmol) in 50 ml ethyl acetate was hydrogenated over 0.33 g Pd/C-5%. After completion of the reaction the suspension was filtered off and concentrated in vacuo to give 0.75 g of a colorless amorphous material. MS: 508.4 [ISP (M+H)+].
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH2:10][NH+:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2].[I-].[C:29]([Mg]Br)([CH3:31])=[CH2:30].O1CCCC1>C(OCC)C>[CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH:10]([C:29]([CH3:31])=[CH2:30])[N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2]
Reactant: C=C(C)[Mg]Br
Reactant: CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Agent: [I-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)C1c2c(ccc(OC)c2OC)C(CC)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a suspension of 13-ethyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (300 mg, 0.61 mmol) in anhydrous diethyl ether (100 mL) at 0° C. was added a solution of isopropenylmagnesium bromide in tetrahydrofuran (0.5 M, 18.4 mL, 9.2 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 13-ethyl-8-isopropenyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (32 mg, 12%). LC/MS m/e calcd for C25H27NO4 (M+H)+: 406.50, observed: 406.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.20 Hz, 3 H) 1.53 (s, 3 H) 2.57-2.64 (m, 1 H) 2.64-2.71 (m, 1 H) 2.64-2.71 (m, 1 H) 2.71-2.78 (m, 1 H) 2.95-3.04 (m, 1 H) 3.15-3.22 (m, 1 H) 3.72 (s, 3 H) 3.81 (s, 3 H) 4.60 (s, 1 H) 4.72 (s, 1 H) 5.08 (s, 1 H) 6.04 (d, J=4.55 Hz, 2 H) 6.86 (s, 1 H) 6.89 (s, 1 H) 6.96 (s, 2 H).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:13]N1C(=O)CCC1=O.[C:21]([O:28][CH3:29])(=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24]>C(OC(=O)C)C.CCCCCC>[CH3:26][O:25][C:23](=[O:24])[CH:22]([Br:13])[C:21]([O:28][CH3:29])=[O:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(Br)C(=O)OC

Procedure:
p-Toluene sulfonic acid monohydrate (11.0 g, 0.057 mol) and N-bromosuccinimide (1.74 g, 0.009 mol) were slowly added to a stirred solution of dimethyl malonate (5.0 g, 0.037 mol) in CH3CH (30 mL). The resulting mixture was heated at reflux for 2 hours, evaporated and dissolved in dichloromethane. The organic layer was washed with H2O, dried over MgSO4 and concentrated. An analytically pure sample was to obtained by column chromatography on silica gel using a 1:4 mixture of ethylacetate/hexane. Yield: 6.0 g (76.0%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:19]([N:28]3[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34]C(=O)OC(C)(C)C)[CH2:29]3)=[C:20]3[CH2:26][CH2:25][C:24](=[O:27])[C:21]3=[N:22][CH:23]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:42].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C@H:30]1[CH2:31][CH2:32][CH2:33][N:28]([C:19]2[C:18]([NH:17][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:42])=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[N:14]=3)=[O:16])=[CH:23][N:22]=[C:21]3[C:24](=[O:27])[CH2:25][CH2:26][C:20]=23)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3=O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.7 %

Procedure:
A mixture of tert-butyl {(3S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (6.0 mg, 0.010 mmol) in DCM (0.05 mL) and TFA (0.052 mL, 0.68 mmol) was stirred at room temperature for 20 min. The solution was then concentrated under reduced pressure. The residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a white powder (2.2 mg, 44%). LCMS calc. for C25H23F3N5O2 (M+H)+: m/z=482.2. Found: 482.3.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21].O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCC1CCc2ccc(NC(=O)C(C)C)c(O)c21
Reaction time: 3 h
Yield: 105.1 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), isobutyryl chloride (42.5 μL, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 3 hr. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (118 mg, yield 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17](O)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([N:28]4[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]4)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: OC1CCNCC1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(N1CCC(O)CC1)C12CC(c3ccccc31)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
To a solution of 2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (described in example 1j) (6.51 g, 24.1 mmol) in toluene (70 mL) was added thionyl chloride (2.28 mL, 31.3 mmol, 1.3 eq). The reaction was heated to reflux monitoring gas evolution with a mineral oil bubbler. The system reached a steady state within 40 min at which time it was slightly cooled and 4-hydroxypiperidine (6.08 g, 60.3 mmol, 2.5 eq) was added portionwise. A significant amount of heat is evolved and the reaction becomes dark. The suspension was heated to reflux for 2 h, cooled to room temperature and stirred for 18 h. The reaction was diluted with ethyl acetate (200 mL) and washed with 3 N HCl (2×100 mL), 2.5 N NaOH (2×100 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The procedure yielded 6.95 g (82%) of the title compound as a viscous oil. No addition purification was required. 1H NMR (D6 -DMSO, 250 MHz) 7.63 (m, 1H), 7.21 (m, 6H), 4.41 (s, 1H), 4.18 (m, 1H), 3.65 (m, 2H), 3.25 (m, 2H), 2.76 (m, 2H), 1.90 (m, 2H), 1.38 (m, 2H) MS (CI, CH4) m/z 354 (M+1,100), 356 (36), 382 (M+29,19), 336 (27), 318 (9)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].Cl[C:16]1[CH:21]=[N:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:23][C:22]([F:25])([F:24])[C:19]1[N:20]=[CH:21][C:16]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: FC(F)(F)c1cnc(Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 1 g, 4.99 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 1.09 g, 5.99 mmol) and DIPEA (2.62 ml, 14.98 mmol) in DMSO (17 ml) was subjected to microwave irradiation at 140° C. for 1 hour. The reaction was partitioned between ethyl acetate and water, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:16](=[O:18])[NH2:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]([N:24]1[C:28](=[O:29])[CH:27]=[C:26](Cl)[S:25]1(=[O:32])=[O:31])([CH3:23])([CH3:22])[CH3:21]>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:16](=[O:18])[NH2:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:26]2[S:25](=[O:31])(=[O:32])[N:24]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:28](=[O:29])[CH:27]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)C(N)=O

Procedure:
This compound was prepared according to the procedure of Example 1.1, Step 4, using (S)-2-phenyl-1-carbamoyl-ethyl-carbamic acid tert-butyl ester and 9-A as the starting materials. LCMS found for C21H29N3O6SNa (M+Na)+: m/z=474.