Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][NH2:36])[CH2:29]1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]>C(#N)C>[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][NH:36][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:29]1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCCN(CCC)CC1CCCN(CCN)C1
Solvent: CC#N
Product: CCCN(CCC)CC1CCCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Yield: 48 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(dipropylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 48% of theory. Colourless crystals, m.p. 153°-155° C. (acetonitrile).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.P(C#N)(OCC)(OCC)=O.[NH2:23][CH:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]([C:35](=[O:52])[C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:51])[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[CH3:50])=[CH:38][CH:37]=2)[CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C)C=O>[NH2:8][CH2:9][C:10]([NH:23][CH:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]([C:35](=[O:52])[C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:51])[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[CH3:50])=[CH:38][CH:37]=2)[CH2:27][CH2:26][CH2:25]1)=[O:11]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)CN)c3ccccc32)cc1
Reaction time: 0.5 h
Yield: 8 %

Procedure:
To a solution of t-butoxycarbonylglycine (0.84 g) in dimethylformamide (20 ml) are added diethyl cyanophosphate (0.73 ml) and 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.74 g), and further thereto is added triethylamine (1.8 ml) under ice-cooling. The mixture is stirred for 30 minutes, and then stirred at room temperature overnight. The reaction solution is concentrated and water is added to the resulting residue. The precipitated crystal is collected by filtration, washed with water, and recrystallized from ethyl acetate to give 5-(2-aminoacetylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (E) (0.16 g). Separately, the filtrate is concentrated and purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from diethyl ether to give 5-[2-(t-butoxycarbonylamino)acetylamino]-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (F) (0.19 g).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]2[CH:20]([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]2([CH3:23])[CH3:22])[NH:10][N:9]=1)=[O:7])C>CO>[CH3:23][C:16]1([CH3:22])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH:15]1[CH2:14][CH2:13][C:11]1[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=1
Reactant: CCOC(=O)c1cc(CCC2C(C)CCCC2(C)C)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CCCC(C)(C)C1CCc1cc(C(=O)O)n[nH]1
Yield: 8.3 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 2.73 mmol) was added to a stirring, room temperature solution of 53 (0.1594 g, 0.5451 mmol) in MeOH (1.36 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (5 min). The reaction was concentrated, redissolved in H2O, and extracted with EtOAc. 10% aq. HCl was added dropwise to the aqueous layer until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.0119 g (8.2%) of 54. An additional 0.0590 g (40.9%) of 54 was obtained, although slightly impure, from the EtOAc layer. 1H (CD3OD, 400 MHz): δ 6.56 (1H, s), 2.64 (2H, t, J=7.8 Hz), 2.03-1.89 (1H, m), 1.69-1.53 (2H, m), 1.55-1.41 (2H, m), 1.39-1.27 (2H, m), 1.20-1.06 (3H, m), 0.97 (3H, s), 0.91 (3H, s), 0.86 (3H, d, J=6.8 Hz) ppm. 13C (CD3OD, 100 MHz): δ 165.07, 149.02, 143.33, 107.26, 50.24, 37.04, 35.11, 31.58, 31.33, 29.00, 28.87, 28.37, 26.30, 22.13, 18.90 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 29.00, 28.87, 18.90; CH2 carbons: 37.04, 31.33, 28.37, 26.30, 22.13; CH carbons: 107.26, 50.24, 31.58 ppm. HPLC: 10.497 min.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][CH:7]=1.C[Al](C)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([N:31]([CH2:33][C:34]2[N:38]=[C:37]([C:39](OCC)=[O:40])[O:36][N:35]=2)[CH3:32])(=[O:30])=[O:29])=[C:23]([CH3:44])[CH:22]=1.ClCCCl>C(Cl)Cl>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][NH:14][C:39]([C:37]2[O:36][N:35]=[C:34]([CH2:33][N:31]([S:28]([C:24]3[C:23]([CH3:44])=[CH:22][C:21]([O:20][CH3:19])=[CH:26][C:25]=3[CH3:27])(=[O:30])=[O:29])[CH3:32])[N:38]=2)=[O:40])=[CH:10][CH:11]=1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: CCOC(=O)c1nc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)no1
Agent: C[Al](C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2noc(C(=O)NCCc3ccc(C4=NCCN4)cc3)n2)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethanamine (bis TFA salt, 108 mg, 0.26 mmol) in DCM (3 mL) at 0° C. was added trimethyl aluminium (2 M in toluene, 0.13 mL, 0.26 mmol) and the mixture was stirred at 0° C. for 15 min. Ethyl 3-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,2,4-oxadiazole-5-carboxylate (50 mg, 0.13 mmol) was added dropwise as a solution in DCM (2 mL), followed by TEA (0.045 mL, 0.32 mmol). The reaction was stirred at ambient temperature for 18 h, after which time TEA (0.110 mL, 0.79 mmol) and DCE (4 mL) were added. The reaction was heated to 60° C. for 18 h, then partitioned between saturated aqueous NH4Cl (20 mL) and EtOAc (2×20 mL). The aqueous layer was extracted with DCM (2×10 mL) and these extracts were dried over MgSO4 and solvents were removed in vacuo. A portion of the product was purified using prep method A.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:29](=[O:30])[C:26]2[C:27]3[C:28]4[C:23](=[CH:24][CH:25]=2)[C:22]2[C:31]5[C:18]([CH:19]=[CH:20][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=5[C:13]=4[CH:12]=[CH:11][C:10]=3[C:8]1=[O:9].[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>N1C=CC=CC=1.O1CCOCC1>[C:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8](=[O:9])[C:10]2[C:27]3[C:28]4[C:13](=[CH:12][CH:11]=2)[C:14]2[C:31]5[C:18]([CH:17]=[CH:16][CH:15]=2)=[CH:19][CH:20]=[CH:21][C:22]=5[C:23]=4[CH:24]=[CH:25][C:26]=3[C:29]1=[O:30])(=[O:36])[C:33]([CH3:35])=[CH2:34]
Reactant: O=C1c2ccc3c4cccc5cccc(c6ccc(c2c36)C(=O)N1CCCCCO)c54
Reactant: C=C(C)C(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCCCN1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
2 g (5 mmol) of N-(5-hydroxypentyl)perylene-3,4-dicarboximide from Example 7, 1. were dissolved in 60 ml of pyridine under nitrogen, with heating at 80° C., and the solution was admixed dropwise at this temperature with a solution of 0.97 ml (10 mmol) of methacryloyl chloride in 30 ml of anhydrous dioxane. Stirring was continued at 80° C. for a further 1.5 h, the solvent was removed by distillation, the residue was taken up in 30 ml of chloroform, a filtration was conducted, the filtrate was admixed with 100 ml of hexane and the precipitated product was isolated by filtration. Chromatographic purification on a short silica gel column using methylene chloride as eluent gave 1.6 g (70%) of the desired product as a brownish red powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:20]2[CH:19]=[C:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:11]=3)[CH:23]=[CH:22][N:21]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)ccn2)s1

Procedure:
5-{4-[4-(4-Chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.5) (0.37 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.25 g), which was subsequently deprotected.
Reaction SMILES: [C:1]1([CH:7]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)=[O:26])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[C:8]([O:10]C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:43]>>[ClH:43].[C:1]1([CH:7]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[CH:34]=[CH:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=4)=[O:26])=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: Cl
Product: O=C(Nc1ccc(N2CCN(C(C(=O)O)c3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of intermediate (3) (0.19 mol) in HCl (36%; 100 ml) was stirred and refluxed for 5 hours, then stirred overnight at room temperature. The precipitate was filtered off and triturated under 2-propanol, filtered off and dried, yielding 5 g of α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-1-piperazineacetic acid monohydrochloride (intermediate 4).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:15])[NH2:14])=[N:6]1.C[O:21][C:22](=O)[C:23]([CH3:30])([CH3:29])[CH:24]([C:27]#[N:28])[C:25]#[N:26]>C(O)(C)(C)C>[NH2:26][C:25]1[C:24]2[C:23]([CH3:30])([CH3:29])[C:22](=[O:21])[NH:28][C:27]=2[N:15]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[F:1])[N:6]=2)[N:14]=1
Reactant: COC(=O)C(C)(C)C(C#N)C#N
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Solvent: CC(C)(C)O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(N)c21

Procedure:
300 mg (1.15 mmol) of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide was dissolved with 2 ml tert.-butanol, 287 mg (1.38 mmol) of methyl-3,3-dicyano-2,2-dimethylpropanoate in 2 ml tert.-butanol and 181 mg (1.61 mmol) of potassium tert.-butylate was added and it was heated under reflux for 72 h. It was evaporated to dryness and the residue was mixed with water/isopropanol (v/v=3:1). The solid was filtered off and dried under high vacuum. 385 mg (80% of theor.) of the target compound was obtained.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([OH:18])=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1.Cl.[OH:20][C:21]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][NH:25][CH2:26]2>>[S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:21]=4[OH:20])[CH2:26]3)=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2cscn2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cscn3)nc3ccccc13)C2
Yield: 9 %

Procedure:
Reaction of 2-(4-thiazolyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 79 (9% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.89 (2t, 2H), 3.47 and 4.02 (2t, 2H), 3.73 and 3.80 (2s, 3H), 4.37 and 4.91 (2s, 2H), 6.31 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.70-7.97 (m, 2H), 8.10-8.18 (m, 2H), 8.66-8.72 (m, 2H), 9.27-9.29 (m, 1H); MS (ESI) m/z 419 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].ClC[CH2:21][O:22][CH2:23][CH3:24]>C1COCC1>[CH3:21][O:22][CH2:23][CH2:24][O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([O:7][CH2:24][CH2:23][O:22][CH3:21])=[CH:8][C:9]=1[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOCCCl
Reactant: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc(C(C)(C)C)c(OCCOC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
2,5-Di-tert-butylhydroquinone (0.2 mmol) was dissolved in anhydrous THF (20 ml). Sodium hydride (0.6 mmol) and 2-chloroethylethylether (0.4 mmol) was then added to the solution. The reaction mixture was then stirred at room temperature overnight. After removal of the solvent, the residue was partitioned between dichloromethane and aqueous NaHCO3 (0.1M). The organic portion was separated and dried over Na2SO4. After solvent removal in vacuo, the crude product was chromatographed (silica, hexanes/DCM from 5:1 to 1:1) to afford 1,4-bis(2-methoxyethoxy)-2,5-di-tert-butyl-benzene in an 81% yield. The product was characterized by 1H NMR (300 MHz, CDCl3, δ/ppm): 7.14 (s, 2H), 4.11 (t, J=4.5 Hz, 4H), 3.80 (t, J=4.5 Hz, 4H), 3.45 (s, 6H), 1.37 (s, 18H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([CH:8]([OH:14])[C:9]([F:13])([F:12])[CH2:10][OH:11])[CH:7]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl.C(OC(=O)C)C.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([CH:8]([OH:14])[C:9]([F:13])([F:12])[CH2:10][O:11][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(F)(F)C(O)c1cc(Br)ccc1F
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC(F)(F)C(O)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled solution of 1-(5-bromo-2-fluorophenyl)-2,2-difluoropropane-1,3-diol (17.0 g, 59.8 mmol) in dry DCM (200 mL) was added imidazole (12.2 g, 179.2 mmol) at 0° C. and stirred for 15 min. tert-butyldimethylsilylchloride (13.5 g, 89.5 mmol) was added to the resultant reaction mixture portion wise for a period of 30 min. and stirring continued for 2 h. Reaction was monitored by TLC analysis. The solids formed in the reaction mixture were separated by filtration and filtrate was concentrated under reduced pressure to obtain crude product which was puirified by column chromatography on silica gel with 2% Ethylacetate in Hexane as eluent to furnish title compound as a colorless liquid. Yield=19 g (80%). TLC (20% ethyl acetate in Hexane): Rf=0.75),
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH3:11])=[O:8])(=O)C.N.C(Cl)Cl.CO.[NH4+].[OH-]>[Zn].CO>[CH2:22]([CH:6]([CH2:5][SH:4])[C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH3:11])=[O:8])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: C[C@H](NC(=O)C(CS)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Treat the product from Step 1 with methanol saturated with ammonia as described in Example 12, Step 3 (before chromatography). Treat the resultant residue with zinc powder as described in Example 17. Chromatograph the product on flash grade silica gel using CH2Cl2 :MeOH:NH4OH (97.5:2.5:0.25) to give the title compound, [α]D26 =-118.2° (MeOH).
Reaction SMILES: [CH2:1]([CH:3]([CH2:27][CH3:28])[CH:4]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[CH2:27]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:23])=[CH:20][CH:19]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:28]
Reactant: CCOC(=O)CCN
Reactant: CCC(CC)C(Nc1ccc(C(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2C)C(CC)CC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
To a mixture of 4-{[2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl]amino}benzoic acid (250 mg) synthesized above, β-alanine ethyl ester hydrochloride (151 mg), 1-hydroxybenzotriazole monohydrate (151 mg), triethylamine (275 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (188 mg), and the mixture was stirred at room temperature for 1 day. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (55% ethyl acetate/hexane) to give the title object compound (85.0 mg, 27%) as a pale-yellow oil.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[Cl-].[Cl-].[Cl-].[Al+3].S(C1C=CC=CC=1)C1C=CC=CC=1.S(Cl)([Cl:32])(=O)=O>ClCCl>[Cl:32][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([O:3][CH:2]([F:11])[F:1])[CH:9]=1
Reactant: Oc1ccccc1OC(F)F
Reactant: O=S(=O)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: ClCCl
Product: Oc1ccc(Cl)cc1OC(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice cold suspension of 2-(difluoromethoxy)phenol (6.54 g, 0.00408 mol), aluminum trichloride (0.0544 g, 0.000408 mol) and 1,1′-thiodibenzene (0.068 mL, 0.000408 mol) was added sulfuryl dichloride (3.61 mL, 0.0449 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction was diluted in dichloromethane (10.0 mL) and purified using silica gel column chromatography eluting with 0-20% EtOAc in heptane. The title compound was isolated as a colourless oil (2.33 g, 0.01195 mol, 29%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]([F:21])([F:20])[F:19])([O-])=O>[Ni].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]([F:21])([F:19])[F:20]
Reactant: O=[N+]([O-])c1ccc(O)nc1Nc1ccccc1OC(F)(F)F
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(O)nc1Nc1ccccc1OC(F)(F)F
Yield: 82.8 %

Procedure:
5-Nitro-6-(2-(trifluoromethoxy)phenylamino)pyridin-2-ol (400 mg, 1.27 mmol) and methanol (370 mL) were stirred at 25° C. for 4 h with excess Raney nickel under an atmosphere of hydrogen. After 4 h the solution was filtered by vacuum filtration through celite. The filtrate was concentrated under reduced pressure to give the title compound as a dark green solid (300 mg). LCMS m/z=286.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.Br[C:23]1[N:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=1.C[Sn](C)(C)[Sn](C)(C)C>O1CCOCC1>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:23]3[CH:24]=[CH:25][C:26]([CH:29]=[O:30])=[CH:27][N:28]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(Br)nc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: C[Sn](C)(C)[Sn](C)(C)C
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 100 °C
Yield: 50.2 %

Procedure:
To a solution of 7-(2-fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine (24) [US 2006/0287343 A1] (6 g, 14.42 mmol) in dioxane (40 mL) were added 6-bromopyridine-3-carbaldehyde (3.22 g, 17.30 mmol), palladium tetrakistriphenylphosphine (0.500 g, 0.433 mmol) and hexamethyldistannane (3.29 mL, 15.86 mmol). The mixture was heated at 100° C. for 20 h. It was then concentrated and adsorbed on silica gel, transferred onto a silica gel column and eluted with DCM/MeOH (100/0, 99/1, 98/2, 97/3) to afford title compound 123 (2.864 g, 50% yield). MS (m/z): 396.1 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17](=[O:19])[NH2:18])=[CH:16][C:10]=2[CH2:9]1)=O)(C)(C)C>CO.Cl>[C:17]([C:15]1[S:14][C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[CH:16]=1)(=[O:19])[NH2:18]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(N)=O)cc2C1
Agent: Cl
Solvent: CO
Product: NC(=O)c1cc2c(s1)CCNC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-t-Butoxycarbonyl-2-carbamoyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (280 mg, 1.0 mmol) was dissolved in hydrochloric acid methanol solution and stirred at room temperature for 18 hours. By evaporating the solvent from the reaction solution under a reduced pressure, crude 2-carbamoyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine was obtained. This compound and triethylamine (0.56 ml, 4.0 mmol) and 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (290 mg, 0.95 mmol) were stirred at room temperature for 22 hours in anhydrous N,N-dimethylformamide (15 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous sodium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 170 mg (0.42 mmol, 44% in yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pt].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(Cl)cc2)CC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)cc2)CC1
Yield: 99.3 %

Procedure:
A solution of 2 g of 4-(4-chloro-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester and 0.5 g of 5% platinum on carbon in 10 mL of ethanol was allowed to stir overnight under 1 atm of hydrogen. The catalyst was filtered off and, the solution concentrated to give 2 g of 4-(4-chloro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester as an oil.