Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2].Cl[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].C(OC(C1C(=O)N(CC2C=CC(F)=CC=2)C2C=CSC=2C=1N1CCN(C(C2OC=CC=2)=O)CC1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:30][C:31](=[O:32])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2]
Reactant: O=C(CCl)c1ccccc1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2[nH]c1=O
Agent: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2n(Cc2ccc(F)cc2)c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 7-[4-(furan-2-carbonyl)-piperazin-1-yl]-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (10) and 2-chloroacetophenone by applying similar method as described for 4-(4-fluoro-benzyl)-7-[4-(furan-2-carbonyl)-piperazin-1-yl]-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (11). MP 246° C. 1H-NMR (DMSO-d6) δ 1.25 (t, J=7.2 Hz, 3H), 3.85 (m, 4H), 4.23 (q, J=6.8 Hz, 2H), 5.75 (s, 2H), 6.66 (m, 1H), 7.07 (d, J=3.2 Hz, 1H), 7.34 (d, J=5.6 Hz, 1H), 7.61 (t, J=7.6 Hz, 2H), 7.73 (t, J=7.6 Hz, 1H), 7.88 (d, J=0.8 Hz, 1H), 8.01 (d, J=5.6 Hz, 1H), 8.10 (d, J=7.6 Hz, 2H); EIMS m/z 520 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].CO[CH2:11][N:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:7][O:6][C:4]([C:3]1([O:2][CH3:1])[CH2:8][CH2:11][N:12]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:13]1)=[O:5]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(OC)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(OC)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a stirred solution of methyl 2-methoxyacrylate (20.8 g, 179 mmols) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (55 ml, 215 mmols) in dichloromethane (160 ml) was added at 0 C a solution of trifluoroacetic acid (2 ml) in dichloromethane (10 ml). The resulting solution was warmed to room temperature and stirred overnight. After concentration, the crude product was purified by column chromatography on silica gel eluting with a solution of ethyl acetate/hexanes/Et3N (1000:3000:4 to 1000:1000:3) to give the title compound (17.7 mg, 40%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[C:30]([F:29])=[CH:37][CH:36]=[CH:35][C:34]=3[F:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c(F)cccc1F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1cccc(F)c1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,6-difluorobenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 505.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[C:5](O)(=O)C.C(O)(=O)C.C(O)(=O)C.[CH:17]1([CH2:28][N+]([O-])=O)O[C@H:24]([CH2:26]O)[C@@H:22](O)[C@H:20](O)[C@H:18]1O.[C:32]1(N=C=O)[CH:37]=[CH:36]C=[CH:34][CH:33]=1.ClCCCl.C(N(CC)CC)C>>[C:17]1([CH:28]=[CH:5][C:1]([C:2]2[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=2)=[O:4])[CH:26]=[CH:24][CH:22]=[CH:20][CH:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=[N+]([O-])CC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 78 °C
Reaction time: 15 h

Procedure:
To a solution of 44 mg (0.11 mmol) a D-glucopyranosylnitromethane tetra-acetate (alpha anomer) and 24 μL (0.22 mmol) phenyl isocyanate in 0.80 mL 1,2-dichloroethane containing 30 mg (0.016 mmol) Rink Amide Resin bound compound 1, 2 mL (0.016 mmol) triethylamine was added under argon. The mixture was refluxed and shaken at 78° C. for 15 hours. It was allowed to cool down to room temperature. The resin bound compound 2 was collected in a 3 mL filtering column and was washed with N,N-dimethylformamide (3×2 mL), methylene chloride (3×2 mL) and dried under vacuum. The dried Resin bound compound 2 was treated with 2 mL 20% trifluoroacetic acid in methylenechloride for 20 minutes. The solid was filtered off and washed 3 times with 1.5 mL methylene chloride. The combined washings were concentrated and dried under vacuum to give 12 mg product 3 of ca. 95% purity. The spectral data consisted of: Electrospray MS m/z 884 (M+ +1). ##STR60##
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:11].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[C:8]([CH3:9])([CH3:10])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:11]
Reactant: [H][H]
Reactant: CC1(C)CCCNC(=O)C1(Cl)Cl
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CCCNC(=O)C1Cl
Yield: 94.9 %

Procedure:
3.8 g (0.018 moles) of 3,3-dichloro-4,4-dimethyl-2-oxoperhydroazepine were dissolved in 300 ml of glacial acetic acid and shaked at 40 psi of hydrogen with 1.9 g of 10% Pd/C. When the theoretical amount of hydrogen was consumed the catalyst was filtered off and the filtrate evaporated in vacuo to give 3 g of the title compound sufficiently pure for the following step.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[S:4](=[O:15])(=[O:14])[NH:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:36](=[O:37])[C:35]2[CH:38]=[CH:39][CH:40]=[C:33]3[C:34]=2[C:29](=[CH:30][CH:31]=[CH:32]3)[C:28]1=[O:41]>CN(C=O)C>[O:41]=[C:28]1[C:29]2[C:34]3[C:33](=[CH:40][CH:39]=[CH:38][C:35]=3[C:36](=[O:37])[N:27]1[CH2:26][CH2:25][CH2:24][CH2:23][N:3]1[C:2](=[O:1])[C:6]3[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=3[S:4]1(=[O:15])=[O:14])[CH:32]=[CH:31][CH:30]=2
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)NC2=O
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)N(CCCCN1C(=O)c3cccc4cccc(c34)C1=O)C2=O
Temperature: 25 °C

Procedure:
To a stirred mixture of 3-oxo-2,3-dihydrobenzo[d]isothiazole-6-carboxylic acid 1,1-dioxide (8) (1 mmol) and anhydrous K2CO3 (5 mmol) in DMF was added 2-(4-bromobutyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (3b) (3 mmol). The reaction mixture was gently refluxed for overnight, cooled to room temperature and poured into the crushed ice. The resulted solution was acidified with con. HCl and extracted with ethylacetate. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated under vacuum to get the crude product. The Crude residue was purified by flash column chromatography using MeOH—CHCl3 (2:8) to obtain the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54-8.34 (m, 6H), 7.91-7.77 (m, 3H), 4.41-4.37 (m, 2H), 4.14-4.08 (m, 2H), 1.89-1.71 (m, 4H). MS (ES−) m/z 477 (M−H)−.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12](=[O:20])[NH:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)=O)(C)(C)C.[ClH:21]>CO.C1COCC1.O1CCOCC1>[ClH:21].[CH3:19][O:18][C:16](=[O:17])[CH2:15][CH2:14][NH:13][C:12]([CH:10]1[CH2:9][NH:8][CH2:11]1)=[O:20]
Reactant: COC(=O)CCNC(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)CCNC(=O)C1CNC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
A solution of 3-(2-Methoxycarbonyl-ethylcarbamoyl)-azetidine-1-carboxylic acid tert-butyl ester (0.55 g, 1.92 mmol) in MeOH (4 mL) and THF (2 mL) was treated with 4.0N HCl in 1,4-dioxane (4 mL) and stirred at 0° C. for 30 minutes and at room temperature for 5 hours. The solvent was removed in vacuo to yield the title compound as a gum (100%).
Reaction SMILES: [N:1]([CH:4]([CH3:11])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].N>C(Cl)Cl>[CH3:11][CH:4]1[NH:1][C:2](=[O:3])[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5]1
Reactant: CC(Cc1cccs1)N=C=O
Agent: N
Solvent: ClCCl
Product: CC1Cc2sccc2C(=O)N1
Yield: 22 %

Procedure:
To PPA (15 ml) a solution of 2-(2-isocyanatopropyl)-thiophene in CH2Cl2 (15 ml) was added. The reaction mixture was stirred under reflux for 3 h, cooled, poured into ice and alkalified with concentrated ammonia. Then, the mixture was extracted with chloroform, dried over Na2SO4 and concentrated on rotary evaporator. The residue was purified by flash column chromatography on silica gel (eluent: chloroform/acetone—0→30%) to give 0.5 g of the target compound as a white solid.
Reaction SMILES: C(OC1N=NC(C(C2C=CC=CC=2)=C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:31]([O:38][C:39]1[N:40]=[N:41][C:42](Cl)=[CH:43][C:44]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[F:54][C:55]([F:78])([F:77])[C:56]1[CH:57]=[C:58](/[CH:66]=[CH:67]/B2OC(C)(C)C(C)(C)O2)[CH:59]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:61]=1>>[CH2:31]([O:38][C:39]1[N:40]=[N:41][C:42](/[CH:67]=[CH:66]/[C:58]2[CH:59]=[C:60]([C:62]([F:63])([F:65])[F:64])[CH:61]=[C:56]([C:55]([F:54])([F:77])[F:78])[CH:57]=2)=[CH:43][C:44]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: CC1(C)OB(/C=C/c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC1(C)C
Agent: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)c1cc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc(C(F)(F)F)c1
Yield: 77 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine (Intermediate 25) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 2-[(E)-2-[3,5-bis(trifluoromethyl)phenyl]ethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 77% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:16]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([O:7][CH3:16])=[O:6]
Reactant: Nc1cc(C(=O)O)ccc1I
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(I)c(N)c1

Procedure:
3-Amino-4-iodobenzoic acid (13.35 g, 50.8 mmol) was added to MeOH (150 mL) and SOCl2 (4.8 mL, 65.8 mmol, 1.3 equivalent) was added. The mixture was refluxed for 3 h and then volatiles were removed under reduced pressure. The residue was co-evaporated three times with MeOH and dried in vacuo (15.23 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1>CO.[Pd]>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])[N:3]=1
Reactant: Cc1nn(COCC[Si](C)(C)C)c2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CO
Product: Cc1nn(COCC[Si](C)(C)C)c2cc(N)ccc12
Yield: 88.9 %

Procedure:
A solution of 3-methyl-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2.37 g, 7.70 mmol) and Pd/C (10 weight %) (0.082 g, 0.77 mmol) in MeOH (35 mL) was stirred under an atmosphere of H2 at about 25° C. for about 12 h. The hydrogen source was removed and the flask was purged with N2. The catalyst was removed by filtration and the filtrate was concentrated to give 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine (1.9 g, 84%): LC/MS (Table 2, Method h) Rt=2.09 min; MS m/z: 278 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([CH2:18][CH:19]=[CH2:20])=[C:4]([OH:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:28]([O:21][C:4]1[CH:3]=[C:2]([OH:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8]([O:7][C:6]=2[C:5]=1[CH2:18][CH:19]=[CH2:20])=[C:9]([O:17][CH2:18][C:5]1[CH:6]=[CH:15][CH:2]=[CH:3][CH:4]=1)[CH:10]=[CH:11][CH:12]=3)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C=CCc1c(O)cc(O)c2c(=O)c3cccc(O)c3oc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1c(OCc2ccccc2)cc(O)c2c(=O)c3cccc(OCc4ccccc4)c3oc12
Temperature: 110 °C
Yield: 160.7 %

Procedure:
To a solution of xanthone 5 (48 g, 168 mmol) in dry DMF was added potassium carbonate (46 g, 336 mmol) and benzyl bromide (90 g, 526 mmol) and the mixture was heated to 110° C. for 8 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (1.4L) and the remaining potassium carbonate was destroyed with 2M Sulfuric acid. The organic layer was washed with brine (2×500 mL), dried over magnesium sulfate and concentrated in vacuo to afford the xanthone 6 as a solid (63 g, 135 mmol, 81%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][C:24]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:31]([O:33][CH3:34])=[O:32])[CH3:10].[CH3:35][N:36]1[CH2:41][CH2:40][CH:39](O)[CH2:38][CH2:37]1.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>C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH:39]2[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][C:24]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:25][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:31]([O:33][CH3:34])=[O:32])[CH3:10]
Reactant: COC(=O)c1sc(-n2cnc3cc(OC(F)(F)F)ccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(OC(F)(F)F)ccc32)cc1O[C@H](C)c1cccc(OC2CCN(C)CC2)c1Cl
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a slurry of methyl 3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{5-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate (Intermediate 25, 0.18 g, 0.35 mmol) and 1-methyl-4-piperidinol (0.12 g, 1.1 mmol) in DCM (10 mL) was added triphenylphosphine (0.18 g, 0.70 mmol) and di-tert-butyl azodicarboxylate (0.16 g, 0.70 mmol). The clear, yellow solution was stirred for 1 h, and then silica gel (3 g) was added. The volatiles were evaporated under reduced pressure and the residue was purified by flash column chromatography (0 to 100% 80/20/1 DCM/MeOH/ammonium hydroxide:DCM) to give 0.20 g (0.34 mmol) of methyl 3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-{5-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate which was then dissolved in a solution of 7 N ammonia in MeOH (10 mL). The mixture was heated in a sealed tube to 80° C. for 40 h and then cooled to rt. Silica (1 g) was added, the volatiles were evaporated under reduced pressure and the residue was purified by flash column chromatography (0 to 100% 80/20/1 DCM/MeOH/ammonium hydroxide:DCM) to afford 0.18 g (86%) of the title compound as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ 8.45 (s, 1H), 7.63 (s, 1H), 7.45 (d, J=8.79 Hz, 1H), 7.31 (m, 2H), 7.17 (d, J=7.51 Hz, 1H), 7.10 (d, J=8.24 Hz, 1H), 6.97 (s, 1H), 6.05 (q, J=6.29 Hz, 1H), 4.56 (m, 3H), 2.72 (br m, 2H), 2.47 (br m, 2H), 2.33 (s, 3H), 1.95 (br m, 4H), 1.77 (d, J=6.41 Hz, 3H): MS (ESI): 595 [M+H]+.
Reaction SMILES: [F:1][C:2]1([CH3:16])[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[CH:8][CH:3]1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1([CH3:16])[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[CH:8][CH:3]1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C1C=CC(S(C)(=O)=O)=CC1(C)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(F)C=C(S(C)(=O)=O)C=CC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
53.8 g of crude methyl 2-fluoro-2-methyl-4-(methylsulfonyl)benzoate were initially charged in 500 ml of THF, and 10.5 g NaOH dissolved in 500 ml of H2O were added. The mixture was stirred at RT for 3 h, and most of the THF was then removed under reduced pressure. The residue was washed with diethyl ether and the aqueous phase was then acidified with 10% strength H2SO4. The precipitated crystals were filtered off with suction, washed with cold water and dried. This gave colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH2:18]([CH:20]([CH2:26][CH3:27])[C:21](=O)[CH2:22][C:23]#[N:24])[CH3:19]>>[CH2:18]([CH:20]([C:21]1[C:22]([C:23]#[N:24])=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]2[C:2](=[CH:7][C:6]([O:8][CH3:9])=[CH:5][CH:4]=2)[N:1]=1)[CH2:26][CH3:27])[CH3:19]
Reactant: COc1ccc(C(=O)c2ccccc2)c(N)c1
Reactant: CCC(CC)C(=O)CC#N
Product: CCC(CC)c1nc2cc(OC)ccc2c(-c2ccccc2)c1C#N

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-4-methoxy-phenyl)-phenyl-methanone and 4-ethyl-3-oxo-hexanenitrile (prepared as described in example 101 step A). Colorless oil. MS (ESI): 331.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:17]1[C:25]2[C:20](=[C:21]([CH2:26][NH2:27])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.CCN(C(C)C)C(C)C.CCCCO.[C:42](O)([C:44]([F:47])([F:46])[F:45])=[O:43]>>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:27][CH2:26][C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[C:20]=4[C:19]([C:42](=[O:43])[C:44]([F:47])([F:46])[F:45])=[CH:18][NH:17]5)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: O=C(O)C(F)(F)F
Reactant: NCc1cccc2[nH]ccc12
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C(c1c[nH]c2cccc(CNc3nccc(Nc4cc(C5CC5)[nH]n4)n3)c12)C(F)(F)F
Temperature: 70 °C

Procedure:
A vial was charged with 53 (300 mg, 1.27 mmol), (1H-indol-4-yl)methanamine (279 mg, 1.903.20 mmol, CASRN 3468-18-6), DIPEA (0.67 mL) and n-BuOH (3 mL), sealed and heated at 140 C for 72 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and H2O. The aqueous layer was extracted once with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude produce was directly dissolved in TFA (3 mL), and the mixture was heated at 70° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to afford 38.3 mg (7%) of I-37.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[C:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: BrCCCOc1ccccc1-c1ccccc1
Product: c1ccc(-c2ccccc2OCCCN2CCOCC2)cc1

Procedure:
2-(3-Bromo-propoxy)-biphenyl (1.0 g) was reacted with morpholine (5 mL) at 50° C. for 1 hour to form 4-[3-(biphenyl-2-yloxy)-propyl]-morpholine. The excess morpholine was evaporated and water was added, followed by extraction with ethyl acetate. Removal of ethyl acetate afforded 900 mg of 4-[3-(biphenyl-2-yloxy)-propyl]-morpholine (t) as an oil which was used without further purification: m/e: 297.17, MS (ES+): 298.2; 1H NMR (500 MHz, CDCl3): 7.8-7.0 (m, 9H), 4.0 (m, 2H), 3.7 (m, 4H), 2.5 (m, 6H) and 1.8 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([NH:5][CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]3[CH2:29][C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[CH2:22]3)=[O:20])=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)=[O:4]>CO>[CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C@@H:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([N:21]3[CH2:29][C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[CH2:22]3)=[O:20])=[CH:16][CH:17]=2)=[CH:8][CH2:7]1)=[O:4]
Reactant: CC(C)C(=O)NC1CC=C(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1
Solvent: CO
Product: CC(C)C(=O)N[C@H]1CC=C(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1

Procedure:
A racemic mixture of N-(4-{4-[(2-methylpropanoyl)amino]cyclohex-1-en-1-yl}phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (250 mg) was dissolved in methanol and separated using SCF-LC with a ChiralPak AD-H 21×250 mm column to provide N-(4-{(4R)-4-[(2-methylpropanoyl)amino]cyclohex-1-en-1-yl}phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.41 (s, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.56-7.48 (m, 2H), 7.43 (d, J=5.1 Hz, 1H), 7.37-7.29 (m, 2H), 6.02 (bs, 1H), 4.84-4.77 (m, 4H), 3.89-3.73 (m, 1H), 2.44 (ddd, J=12.7, 8.7, 4.6 Hz, 2H), 2.41-2.26 (m, 2H), 2.14-1.97 (m, 1H), 1.93-1.81 (m, 1H), 1.67-1.49 (m, 1H), 1.00 (dd, J=6.8, 2.4 Hz, 6H); MS (ESI(+)) m/e 405 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([O-:8])=[O:7])=[CH:2]1.[Na+].Br[C:11]1[CH:19]=[CH:18][C:17]2[N:16]([CH3:20])[C:15]3[CH2:21][CH:22]4[NH:26][CH:25]([C:14]=3[C:13]=2[C:12]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:23]4>>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([C:11]2[CH:19]=[CH:18][C:17]3[N:16]([CH3:20])[C:15]4[CH2:21][CH:22]5[NH:26][CH:25]([C:14]=4[C:13]=3[C:12]=2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:23]5)(=[O:8])=[O:7])=[CH:2]1
Reactant: O=S([O-])c1ccsc1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccsc4)ccc31)C1CCC(C2)N1
Yield: 31 %

Procedure:
Intermediate 25 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, hexane/ethyl acetate 55:45) to give tert-butyl 2-(3-thienyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (130 mg, 31%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.20 (s, 1H), 8.02-8.53 (m, 1H), 7.66-7.74 (m, 1H), 7.28-7.37 (m, 3H), 5.26 (br s, 1H), 4.70 (br s, 1H), 3.61 (s, 3H), 3.38 (br s, 1H), 2.50 (d, J=15.9 Hz, 1H), 2.12-2.41 (m, 2H), 1.89-2.00 (m, 1H), 1.57-1.68 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:17]1[N:21]([C:22]2[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=2)[C:20]2[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:19]=2[N:18]=1)[CH3:16])(C)(C)C>C(Cl)Cl>[F:32][C:29]1[CH:30]=[CH:31][C:19]2[N:18]=[C:17]([C@@H:15]([NH2:14])[CH3:16])[N:21]([C:22]3[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=3)[C:20]=2[CH:28]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccnn1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccnn1C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
TFA (20 mL) was added to a solution of {(S)-1-[6-fluoro-1-(2-methyl-2H-pyrazol-3-yl)-1H-benzoimidazol-2-yl]-ethyl}carbamic acid tert-butyl ester (0.96 g, 2.67 mmol) in DCM (10 mL) and stirred for 15 min. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM (×3) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) to give the title compound as a colourless oil (0.69 g, 51%). LCMS (Method C): RT 1.55, 1.72 min [M+H]+ 260.1.