Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[C:21]1[CH:22]=[C:23]([CH:38]=[CH:39][N:40]=1)[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[O:25])=[O:7].[NH:44]1[CH2:49][CH2:48][CH:47]([CH2:50][CH2:51][OH:52])[CH2:46][CH2:45]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:52][CH2:51][CH2:50][CH:47]1[CH2:48][CH2:49][N:44]([CH2:2][C:3]2[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=2)[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[C:21]2[CH:22]=[C:23]([CH:38]=[CH:39][N:40]=2)[C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:25])=[O:7])[CH2:45][CH2:46]1
Reactant: OCCC1CCNCC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CN3CCC(CCO)CC3)c2)c1
Reaction time: 12 h

Procedure:
A mixture of 20 mg of 2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 8.1a, 5.2 mg of 2-(piperidin-4-yl)ethanol, and 9.1 mg of K2CO3 in 2 mL of DMF was stirred for 12 h. The product was isolated by reverse phase chromatography eluting with 0.05% TFA in a water/acetonitrile gradient. MS (ES, m/z) 700.27 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[Br:16]C1CC(C(C)C)CCC1=O>>[Br:16][CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][C:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:8]#[N:9])[CH2:6]1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Product: N#CC1(c2ccccc2)CCC(=O)C(Br)C1

Procedure:
The bromination of 4-oxo-1-phenyl-cyclohexanecarbonitrile takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[CH3:13])=[N:4][C:3]=1[C:14](=[O:16])[CH3:15].C([O-])(=O)C.[Na+].Cl.[NH2:23][OH:24]>O>[OH2:16].[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[CH3:13])=[N:4][C:3]=1[C:14](=[N:23][OH:24])[CH3:15]
Reactant: CC(=O)c1nc(-c2ccncc2C)[nH]c1C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=NO)c1nc(-c2ccncc2C)[nH]c1C
Temperature: 25 °C

Procedure:
To a 1.0 g (0.005 mole) amount of 1-[5-methyl-2-(3-methyl-4-pyridinyl)-1H-imidazol-4-yl]ethanone (prepared as described in Example 27) dissolved in 200 ml of boiling water, were added 1.0 g (0.012 mole) of sodium acetate and 0.7 g (0.01 mole) of hydroxylamine hydrochloride. The mixture was stirred and heated for 3 hours, then cooled at room temperature. The resulting precipitate was collected by filtration and when dried at 60° C. for 18 hours gave 0.6 g of the desired product as its hydrate, a yellowish powder, mp 195°-197° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[N:4][C:5]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:42]OC(OC)OC.O>>[F:27][CH:25]([F:26])[C:15]1[N:14]([C:5]2[N:4]=[C:3]3[C:2]([N:1]=[CH:42][N:28]3[CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[C:7]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:6]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c(N2CCOCC2)n1
Reactant: COC(OC)OC
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2ncn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of tert-butyl 4-{[5-amino-2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4-pyrimidinyl]amino}-1-piperidinecarboxylate (Example 96) (250 mg, 0.435 mmol), trimethylorthoformate (5 mL), and p-TSOH.H2O (8.3 mg, 0.0436 mmol) was heated at 95-100° C. for 3 hrs. The mixture was cooled to room temperature and the solvent was removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 99:1), gave tert-butyl 4-[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-9H-purin-9-yl]-1-piperidinecarboxylate (193 mg, 76%): mp (CH2Cl2/MeOH) 213-215° C.; 1H NMR (CDCl3) δ 7.82 (s, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.44 (t, JHF=53.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 4.57 (tt, J=12.0, 4.0 Hz, 1H), 4.38 (m, 6H), 4.06 (s, 3H), 3.88 (t, J=4.9 Hz, 4H), 2.95 (t, J=12.6 Hz, 2H), 2.19 (dd, J=12.1, 2.0 Hz, 2H), 2.05 (dq, J=12.3, 4.2 Hz, 2H), 1.49 (s, 9H); Anal. Calcd. for C28H34F2N8O4: C, 57.5; H, 5.9; N, 19.2. Found: C, 57.3; H, 5.8; N, 19.1%.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH:16]([NH2:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:19][CH:16]([CH3:18])[CH3:17])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 1.00 g of Boc-Pro-OH, 0.40 ml of isopropylamine, 0.71 g of HOBt and 1.06 g of EDC hydrochloride were added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 28 (Process 2) to give 654 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N12CCCN=[C:32]1[CH2:31][CH2:30][CH2:29]CC2.BrCC1CC1.O>C(O)C.C(OCC)(=O)C>[CH:31]1([CH2:32][O:1][C:2]2[CH:3]=[C:4]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]4[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])[N:14]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:29][CH2:30]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Agent: BrCC1CC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OCC1CC1

Procedure:
A 0.3 g quantity of 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained in Example 136 and 0.4 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 5 ml of ethanol, 0.24 g of (bromomethyl)cyclopropane was added thereto, and the mixture was heated and refluxed for 4.5 hours. After standing to cool, water was added to the reaction mixture, and ethyl acetate extraction was performed. The extract was washed twice with water, the organic layer was then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), thereby yielding 0.2 g of white powdery 3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methyl pyridin-2-yl)propan-1-one.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[C:8]([CH2:12][CH2:13][CH3:14])O[C:10](=[O:11])[C:5]=2[S:4][N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>Cl>[CH2:15]([N:22]1[C:10](=[O:11])[C:5]2[S:4][N:3]=[C:2]([CH3:1])[C:6]=2[N:7]=[C:8]1[CH2:12][CH2:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CCCc1nc2c(C)nsc2c(=O)o1
Agent: Cl
Product: CCCc1nc2c(C)nsc2c(=O)n1Cc1ccccc1
Temperature: 200 °C

Procedure:
3-Methyl-5-propyl-isothiazolo[4,5-d][1,3]oxazin-7-one (method 58) (200 mg, 1.02 mmol) was taken in a 10 mL microwavable pyrex tube and benzyl amine (1 g, 9.34 mmol) was added to it. The resulting mixture was heated in a microwave synthesizer (CEM's Discoverer) at 200° C. for 20 min. The MS of the reaction mixture showed the complete disappearance of the starting material and the presence of the product peak at 286 (MH+). The reaction mixture was diluted with 1N HCl (10 mL) and extracted with EtOAc (2×30 mL). The combined EtOAc layers were washed with water, brine, dried and concentrated. The thus obtained crude product was purified by column chromatography to isolate the pure product as a white solid. Yield 208 mg (71%). 1H NMR (300 MHz) δ 0.98 (t, 3H), 1.76-1.88 (m, 2H), 2.68 (s, 3H), 2.74 (t, 2H), 5.42 (s, 2H), 7.10-7.19 (m, 2H), 7.28-7.39 (m, 3H).
Reaction SMILES: C[Al](C)C.[I:5][C:6]1[C:7]([S:12]([NH2:15])(=[O:14])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:16][O:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27](=O)[O:28]C)[N:19]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:25][O:24][C:22]1[N:23]=[C:18]([O:17][CH3:16])[N:19]=[C:20]([NH:26][C:27](=[O:28])[NH:15][S:12]([C:7]2[C:6]([I:5])=[CH:11][CH:10]=[CH:9][N:8]=2)(=[O:13])=[O:14])[N:21]=1
Reactant: NS(=O)(=O)c1ncccc1I
Reactant: COC(=O)Nc1nc(OC)nc(OC)n1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc(NC(=O)NS(=O)(=O)c2ncccc2I)nc(OC)n1
Temperature: 0 °C

Procedure:
9.0 ml (18 mmol) of a 2M solution of trimethylaluminum in toluene are added dropwise at room temperature to 4.3 g (15 mmol) of 3-iodo-2-pyridinesulfonamide in 150 ml of dichloromethane. After evolution of gas has ceased, 3.85 [lacuna] (18 mmol) of methyl 4,6-dimethoxy-1,3,5-triazin-2-yl-carbamate in 20 ml of dichloromethane is added dropwise and the resulting solution is refluxed for 24 hours. The mixture is cooled and poured into 150 ml of ice-cold 1N hydrochloric acid. The organic phase is separated off and the aqueous phase is extractd 2× using dichloromethane. The organic phase is dried and evaporated. After triturating the crude product with diethyl ether, 3.1 g (44% of theory) of 3-(4,6-dimethoxy-1,3,5-triazin-2-yl)-1-(3-iodo-2-pyridylsulfonyl)urea of melting point 155 ° C. (dec.) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20]CC3C=CC=CC=3)=[O:19])=[C:16]([CH3:28])[C:15]([CH:29]([OH:31])[CH3:30])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CO.O.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:28])[C:15]([CH:29]([OH:31])[CH3:30])=[CH:14][CH:13]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1c(C(C)O)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Cc1c(C(C)O)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)O
Reaction time: 16 h
Yield: 65.6 %

Procedure:
A mixture of Example 272A (79 mg, 0.22 mmol) in methanol (8 mL) and water (1.0 mL) was treated with 10% Pd/C (160 mg) and stirred under hydrogen for 16 hours. Filtration and solvent evaporation gave the desired compound (51 mg). 1H NMR (DMSO-d6) δ 1.23 (s, 3H), 2.21 (s, 3H), 4.87 (m, 1H), 5.06 (br s, 1H), 6.82 (d, 1H), 7.36-7.41 (m, 3H), 7.78-7.82 (m, 2H), 10.4 (s, 1H), 13.2 (br s, 1H); MS (ESI(−)) m/e 352 (M−H)−.
Reaction SMILES: N1C=CN=C1.CC1N(CCCN)C=CN=1.C(C1N(CCCN)C=CN=1)C.C[C:28]1[N:29]([CH2:34][CH2:35][CH2:36][NH2:37])[CH:30]=[C:31]([CH3:33])[N:32]=1.C1(C2N(CCCN)C=CN=2)C=CC=CC=1.C1(C2N=CN(CCCN)C=2)C=CC=CC=1>>[CH3:33][C:31]1[N:32]=[CH:28][N:29]([CH2:34][CH2:35][CH2:36][NH2:37])[CH:30]=1
Reactant: Cc1cn(CCCN)c(C)n1
Agent: CCc1nccn1CCCN
Agent: Cc1nccn1CCCN
Agent: NCCCn1ccnc1-c1ccccc1
Product: Cc1cn(CCCN)cn1

Procedure:
By substituting the appropriate imidazole starting material in the above procedure, the following intermediates were prepared: 2-methyl-1H-imidazole-1-propanamine; 2-ethyl-1H-imidazole-1-propanamine; 2,4-dimethyl-1H-imidazole-1-propanamine; 2-phenyl-1H-imidazole-1-propanamine; and 4-phenyl-1H-imidazole-1-propanamine.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3]C(C)(C)C)=O.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1C(Cl)=O.C(N(CC)CC)C>ClCCl>[N:8]1([C:1]([C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[C:15]([F:26])([F:25])[F:14])=[O:3])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-Boc-piperazine (1.96 g, 10.5 mmol) in dichloromethane (50 mL) was added 2-trifluoromethylbenzoyl chloride (2.09 g, 10.0 mmol) as a dichloromethane solution in the presence of triethylamine (3 mL) at 0° C. The resulting mixture was stirred at ambient temperature for 18 hours and then quenched with water (25 mL). The organic phase was washed with water, saturated NaCl, dried over MgSO4 and then concentrated in vacuo to afford the desired product as a pall yellow solid used for next step reaction without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:13][NH2:14])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[Br:22][CH:23]([CH3:27])[C:24](O)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[Cl:2][C:3]1[C:4]([CH2:13][NH:14][C:24](=[O:25])[CH:23]([Br:22])[CH3:27])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CC(Br)C(=O)O
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Br)C(=O)NCc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (1.0 g) in tetrahydrofuran (5 ml) and triethylamine (0.41 g) which had been stirred at room temperature for 30 minutes, was added a mixture of 2-bromopropionic acid (0.62 g) and carbonyldiimidazole (0.65 g) in tetrahydrofuran (5 ml) which had also been stirred at room temperature for 30 minutes. The combined mixture was stirred at room temperature for 12 hours and then the solvent was removed. The residue was partitioned between diethyl ether and water and the layers separated. The organic phase was dried (MgSO4) and the solvent removed to give the title product.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([F:24])=[CH:19][CH:18]=3)=[O:14])[C@H:8]([NH:25][C:26]([C:28]2[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=2)=[O:27])[CH2:7]1)=O)C.[ClH:38].[CH3:39][NH2:40]>>[ClH:38].[F:24][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:13]([NH:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([C:4](=[O:3])[NH:40][CH3:39])[CH2:7][C@H:8]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:14])=[CH:23]2
Reactant: CCOC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(F)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Reactant: CN
Agent: Cl
Product: CNC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(F)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
(1S,2R,4S)-4-Ethoxycarbonyl-N1-[(5-fluoroindol-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine was hydrolyzed and then subjected to a condensation reaction with monomethylamine hydrochloride in a similar manner to Example 157 to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[Cl:21])[CH2:10][C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C1COCC1.O>[Cl:21][C:15]1[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=1[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11][OH:12]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)c1cccc(Cl)c1Cl
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCO)c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 82A, 430 mg (1.29 mmol) were suspended in 5 ml of THF and cooled to 0° C., and the suspension was admixed with 179 μl (1.29 mmol) of triethylamine and also with 184 μl (1.42 mmol) of isobutyl chloroformate and stirred at 0° C. for 1 hour. The suspension was then filtered through a Seitz frit into a cooled flask, and the retained solid was washed with a little THF. The filtrate was added slowly dropwise, with ice cooling, to a solution of 146 mg (3.86 mmol) of sodium borohydride in 0.5 ml of water and stirred at 0° C. for 1 h. For work-up, the reaction mixture was admixed with about 10 ml of saturated aqueous sodium hydrogen carbonate solution and extracted with 50 ml of ethyl acetate. The organic phases were washed once with saturated aqueous sodium hydrogen carbonate solution and once with saturated aqueous sodium chloride solution. They were then dried over sodium sulphate, filtered and concentrated on a rotary evaporator. This gave 419 mg (95% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22](O)=[O:23])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][CH:5]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH2:37]1[CH2:56][O:55][C:39]2([CH2:44][CH2:43][CH:42]([N:45]([CH2:47][C:48]3[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=3)[CH3:46])[CH2:41][CH2:40]2)[O:38]1>C1COCC1.O.C(N(CC)CC)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:20])(=[O:21])[CH2:18][CH2:17][C:16]([C:22]([NH:52][C:51]4[CH:50]=[CH:49][C:48]([CH2:47][N:45]([CH:42]5[CH2:41][CH2:40][C:39]6([O:38][CH2:37][CH2:56][O:55]6)[CH2:44][CH2:43]5)[CH3:46])=[CH:54][CH:53]=4)=[O:23])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCC2(CC1)OCCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCC5(CC4)OCCO5)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.4 %

Procedure:
To a solution of 7-(4-ethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (180 mg) in THF (10 ml) were added at room temperature oxalyl chloride (0.09 ml) and a drop of DMF, and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure, and the residue was dissolved in THF (10 ml). The solution was added dropwise at 0° C. to a solution of 4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]aniline [0.153 g (0.553 mmol)] and triethylamine (0.14 ml) in THF (5 ml), and the mixture was stirred at room temperature for 16 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give crude crystals, which were recrystallized from ethanol/diisopropylether to give colorless crystals of 7-(4-ethoxyphenyl)-N-[4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 18) (187 mg).
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:4][CH2:5]O)[CH3:2].S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:4][CH2:5][Cl:18])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCN(CCO)c1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Product: CCN(CCCl)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 91.7 %

Procedure:
To a solution of 3.0 g (14.3 mmol) of 4-[N-ethyl,N-(2-hydroxyethyl)amino]nitrobenzene in 20 ml of chloroform, 2.1 ml (28.8 mmol) of thionyl chloride were added. After the resultant mixture was stirred under heat at 80° C. for 2 hours, the solvent was distilled out under reduced pressure. The residue was purified by chromatography on a silica gel column (ethyl acetate/n-hexane=1/1), whereby 3.0 g of yellow powder were obtained (yield: 92%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]([CH2:24][C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[C:7]2[C:12]([C:13]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:11][CH:10]=[C:9]([C:20]([O:22]C)=[O:21])[CH:8]=2)=O.[C:33]([NH:37][C:38]([NH2:40])=[S:39])([CH3:36])([CH3:35])[CH3:34].[OH-].[Na+].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>CS(C)=O>[C:33]([NH:37][C:38]1[S:39][CH:2]=[C:3]([C:5]2[N:6]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[C:7]3[C:12]([C:13]=2[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:11][CH:10]=[C:9]([C:20]([OH:22])=[O:21])[CH:8]=3)[N:40]=1)([CH3:36])([CH3:35])[CH3:34].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]
Reactant: CC(C)(C)NC(N)=S
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(C(=O)CBr)n(CC(=O)N3CCOCC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)Nc1nc(-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2CC(=O)N2CCOCC2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The bromomethylketone of example 11 (39.6 mg, 0.078 mmol, 1 equiv.) was dissolved in DMSO (1 mL) and N-tertbutylthiourea (12.4 mg, 0.094 mmol, 1.2 equiv.) was added. The mixture was stirred for 2 h at room temperature. 10 N NaOH (24 μL) was added and after stirring for 4 h at room temperature, another portion of 10 N NaOH (24 μL) was added and the mixture stirred 24 h at room temperature to complete the hydrolysis. The reaction mixture was then neutralized by addition of TFA and the title product of example 12 isolated directly from the reaction mixture by preparative HPLC as a white amorphous TFA salt (21 mg).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH:4]1[CH2:5][C:6](=[N:12]O)[CH2:7]2.[OH-].[NH4+].[H][H]>[Rh].CO>[NH2:12][CH:6]1[CH2:5][CH:4]2[N:3]([CH3:2])[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7]1
Reactant: [H][H]
Reactant: CN1C2CCCC1CC(=NO)C2
Agent: [Rh]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CN1C2CCCC1CC(N)C2
Temperature: 50 °C
Yield: 92.4 %

Procedure:
A mixture of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one oxime hydrochloride (0.670 g, 3.27 mmol), rhodium on carbon (0.610 g, 5% rhodium), methanol (18 mL), and concentrated ammonium hydroxide (8.0 mL, 120 mmol) was shaken under a 50 psi hydrogen atmosphere and warmed to 50° C. for 19 h. The mixture was then filtered through a pad of diatomaceous earth and the pad rinsed with additional methanol (3×20 mL). The filtrate was then concentrated to dryness, and residue was partitioned between 10% aqueous sodium carbonate (25 mL) and chloroform (25 mL). The layers were separated, and the aqueous layer was extracted with additional chloroform (2×25 mL). The combined organic extracts were dried over anhydrous potassium carbonate, filtered, and concentrated to afford 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (0.466 g, 92% yield) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 3.20 (m, 1H), 3.01 (d, J=11.1 Hz, 2H), 2.46 (s, 3H), 2.32-2.25 (m, 2H), 1.99-1.89 (m, 3H), 1.50-1.42 (m, 1H), 1.14-10.9 (m, 2H), 1.07 (br s, 2H), 0.98-0.91 (m, 2H); MS (ESI) m/z 155 [M+H]+. This material was converted to the corresponding dihydrochloride salt in quantitative yield by treatment with excess 4M hydrogen chloride gas in dioxane: mp 232-235° C. 1H NMR (300 MHz, DMSO-d6) δ 11.28 (br s, 1H), 10.31 (br s, 1H), 8.46 (br s, 2H), 3.85 (br s, 2H), 3.61 (br s, 1H), 3.07 (dd, J=18.1, 6.6 Hz, 1H), 2.96 (d, J=4.6 Hz, 2H), 2.76 (d, J=4.6 Hz, 1H), 2.46 (d, J=17.0 Hz, 1H), 2.30-2.18 (m, 2H), 2.02 (br d, J=7.8 Hz, 1H), 1.88-1.72 (m, 2H), 1.70-1.19 (m, 3H).