Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][C@@H:18]([OH:20])[C@@H:17]([OH:21])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1.N1([C:27]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[NH:37][C:36]3=[O:44])[CH2:31][CH2:30]2)=[O:28])C=CN=C1.CC(C)([O-])C.[K+]>O1CCCC1>[O:44]=[C:36]1[NH:37][C:38]2=[N:39][CH:40]=[CH:41][CH:42]=[C:43]2[N:35]1[CH:32]1[CH2:31][CH2:30][N:29]([C:27]([O:21][C@H:17]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH2:10][C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:19][C@H:18]2[OH:20])=[O:28])[CH2:34][CH2:33]1
Reactant: O=C(N1CCC(n2c(=O)[nH]c3ncccc32)CC1)n1ccnc1
Reactant: O[C@@H]1C[C@@H](c2cccc(F)c2F)Cc2cccnc2[C@@H]1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O[C@H]1c2ncccc2C[C@H](c2cccc(F)c2F)C[C@H]1O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.3 %

Procedure:
In an oven-dried 100 mL round-bottom flask was dissolved (6S,8R,9S)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-8,9-diol (61 mg, 0.209 mmol) (azeotroped with dry benzene) and 1-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (65.4 mg, 0.209 mmol) in tetrahydrofuran (2 mL) to give a colorless solution under nitrogen. After cooling to 0° C. (ice bath), potassium t-butoxide (1M in tetrahydrofuran, 0.754 mL, 0.754 mmol) was added dropwise, and the tan suspension was warmed up to room temperature with stirring. After 2 h some SM remained. Another 20 mg of 1-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one was added, and the mixture was left stirring overnight. After 18 h the reaction was quenched with sodium bicarbonate solution and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated to give a yellow oil. Purification by FCC up to 10% methanol/methylene chloride afforded the desired product (last peak, 16 mg, 14%) as a light yellow foam. MS(ESI)[M+H+]=536.26, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27-8.59 (m, 1H) 8.08 (dd, J=5.29, 1.26 Hz, 1H) 7.54 (d, J=2.52 Hz, 1H) 7.31-7.51 (m, 1H) 7.22 (dd, J=7.30, 5.04 Hz, 1H) 6.93-7.19 (m, 4H) 5.39-5.63 (m, 1H) 5.18 (br. s., 1H) 4.45-4.64 (m, 1H) 4.37 (br. s., 1H) 3.10-3.40 (m, 3H) 2.92 (d, J=13.85 Hz, 1H) 2.11-2.88 (m, 5H) 1.75-1.95 (m, 2H) 1.55-1.71 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[O:25])=[N:13][CH:14]=1.[CH3:33][CH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=O.C([BH3-])#N.[Na+].Cl>>[ClH:8].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][N:29]([CH:35]3[CH2:36][CH2:37][CH2:38][CH:34]3[CH3:33])[CH2:28]2)=[O:25])=[N:13][CH:14]=1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNC1
Reactant: CC1CCCC1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCC1N1CCC(OC(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)C1
Yield: 158.2 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(pyrrolidin-3-yloxycarbonyl)amino]benzamide trifluoroacetate (100 mg, 0.211 mmol), 2-methylcyclopentanone (0.112 mL, 1.05 mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded, after treatment with HCl, 80 mg (80%) of the title compound as the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br-:10].[Na+].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: [Br-]
Reactant: Cc1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(CBr)c(Cl)c1
Temperature: 80 °C

Procedure:
To a 500 mL round bottom flask fitted with a Teflon magnetic stirrer was added 2,4-dichlorotoluene (Aldrich) (14.4 g, 90 mmol) in 300 mL glacial acetic acid. To this was added sodium bromide (9.4 g, 92 mmol) and anhydrous ceric ammonium nitrate (100 g, 182 mmol) and the reaction mixture was heated at 80° C. for 2.5 h. The reaction mixture was then poured into 1000 g of ice and water. The slurry was extracted with ether (3×200 mL) and the combined ether layers were washed with saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was chromatographed by flash column chromatography on silica gel (eluted with 100% hexanes) and the desired product obtained. 1H-NMR 500 MHz (CDCl3): δ 4.58 (s, 2H), 7.28 (m, 1H), 7.43 (m, 2H),
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH:16]=[CH:17][CH2:18][O:19][C:14]=3[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=2)=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH:16]=[CH:17][CH2:18][O:19][C:14]=3[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=2)=[CH:4][N+:3]=1[O-:32]
Reactant: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OCC=C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Product: COc1cc(Cc2c[n+]([O-])c(N)nc2N)c2c(c1OC)OCC=C2
Reaction time: 18 h

Procedure:
To a solution of 2,4-diamino-5-(7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl)pyrimidine (0.993 g, 3.16 mmol) in DMF (80 mL) was added a solution of m-chloroperbenzoic acid (0.641 g, 3.16 mmol as 85%) in DMF (10 mL) dropwise over 30 min. After 18 hr, the solvent was evaporated and the residue chromatographed on silica gel eluted with 10-15% methanol-methylene chloride. Recovered starting material eluted first (0.40 g) followed by title compound as a white power (0.47 g). Recrystallization from absolute ethanol gave white crystals, mp 233°-234° dec.; assignment of N-1 oxide based on 13C-NMR: C-4 shifts from 154.40 to 161.28 ppm on acidification. Anal. Calcd for C16H18N4O4 : C, 58.17; H, 5.49; N, 16.96. Found: C, 57.81; H, 6.11; N, 16.84.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>C1(C)C=CC=CC=1.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:18]1[N:17]=[C:16]([C:12]2[N:11]([CH2:10][C:3]3[C:2]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:7][C:6]([O:8][CH3:9])=[CH:5][N:4]=3)[CH:15]=[CH:14][N:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COc1cnc(Cn2ccnc2-c2cccc(F)n2)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cnc(Cn2ccnc2-c2cccc(F)n2)c(-c2ccccn2)n1
Temperature: 110 °C
Yield: 86.1 %

Procedure:
A mixture of 3-chloro-2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-methoxy-pyrazine (80 mg, 0.25 mmol), 2-tributylstannylpyridine (138 mg, 0.37 mmol), and PdCl2(PPh3)2 (18 mg, 0.026 mmol) in toluene (10 mL) is heated at 110° C. in a sealed tube for 16 hours. On cooling, the mixture is diluted with DCM (20 mL) and filtered. After the solvent is removed, the residue is purified by PTLC (silica gel; 5% MeOH in DCM) to give 78 mg of 2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-methoxy-3-pyridin-2-yl-pyrazine. 1H NMR (CDCl3) 8.59 (d, 1H), 8.15 (d, 1H), 8.08 (s, 1H), 8.02 (d, 1H), 7.85(t, 1H), 7.72 (dd, 1H), 7.32 (dd, 1H), 7.10 (s, 1H), 7.15 (s, 1H), 6.65 (dd, 1H), 6.31 (s, 2H), 4.01 (s, 3H). G. 2-[1-(3-Chloro-5-methoxy-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine (Compound 8) 1. Synthesis of 2-(1H-imidazol-2-yl)-pyrimidine hydrochloride
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[NH3:27]>CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH2:27])=[O:26])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: N
Solvent: CO
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(N)=O)c2n1
Yield: 38 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K) and 7N NH3 in MeOH. The combined organic extracts were concentrated and the residue was purified by reverse phase HPLC (0-80% acetonitrile/water) to provide the title compound (15 mg, 38% yield). MS (apci) m/z=357.0 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][O:11][CH3:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:20][CH:21]([F:31])[C:22]1[C:26]([C:27](Cl)=[O:28])=[CH:25][N:24]([CH3:30])[N:23]=1>ClCCl.O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]([N:10]([O:11][CH3:12])[C:27]([C:26]2[C:22]([CH:21]([F:31])[F:20])=[N:23][N:24]([CH3:30])[CH:25]=2)=[O:28])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CONC(C)c1cccc(I)c1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of N-[1-(3-iodo-phenyl)-ethyl]-O-methyl-hydroxylamine (3 g, 10.8 mmol), prepared as described in example P11, in dichloromethane (30 ml), was added triethylamine (2.5 ml, 26.3 mmol) followed by a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (2.2 g, 11.3 mmol) slowly at 0° C. After complete addition of acid chloride, the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×60 ml). The combined dichloromethane layer was washed with 2N HCl, sat. NaHCO3 and brine, dried over anh. sodium sulfate and concentrated. The crude mass was purified by column chromatography using 35% ethyl acetate in hexane to yield 2.7 g (60% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [1-(3-iodo-phenyl)-ethyl]methoxy-amide in form of a solid. Mp 136-138° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N+:9]([C:5]1[C:6]([NH2:8])=[CH:7][C:2]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([F:33])([F:32])[F:21])=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Nc1cc(Br)ncc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Nc1cc(-c2ccccc2C(F)(F)F)ncc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 18 h

Procedure:
2-Bromo-5-nitropyridin-4-amine (561 mg, 2.57 mmol), Cs2CO3 (2.52 g, 7.72 mmol), (dppf)PdCl2.DCM (113 mg, 0.154 mmol), and 2-(trifluoromethyl)phenylboronic acid (636 mg, 3.35 mmol) were combined and flushed with Ar and anhydrous DME (24 mL) was added. H2O (8 mL) was added via syringe and the resulting mixture was stirred at 85° C. for 18 h. The resulting mixture was cooled to room temperature and diluted with EtOAc (30 mL) and the resulting solution was washed with brine (30 mL). The aqueous phase was extracted with EtOAc (3×25 mL) and the combined extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was chromatographed on a 40-g SiO2 pre-packed column eluting with 0:1-2:3 EtOAc/hexanes to yield 5-nitro-2-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine. 1H-NMR (400 MHz, CDCl3) δ: 9.17 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.56 (t, J=7.1 Hz, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.00 (br. s., 2H), 6.71 (s, 1H). Mass Spectrum (LCMS, ESI pos.): Calculated for C12H8F3N3O2: 284.1 (M+H). Measured: 284.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.C1(O)C=CC=CC=1>CN(C=O)C>[F:37][C:19]1[CH:18]=[C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[CH2:12][CH2:13]2)=[O:15])[CH:22]=[CH:21][C:20]=1[O:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:46][CH2:47][CH2:48][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1O
Reactant: ClCCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C

Procedure:
To a mechanically stirred slurry of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (16.6 g, 32.8 mmol) and potassium carbonate (13.6 g, 98.6 mmol) in DMF (250 mL) was added 4-(3-chloropropyl)-morpholine hydrochloride (13, 7.92 g, 39.6 mmol). The resulting mixture was heated at 90° C. for 5 hours (until phenol completely consumed). The reaction mixture was allowed to cool to room temperature, then dumped into water (900 mL), followed by extraction with EtOAc (3×). The combined extracts were washed with 5% LiCl (aq.) (3×) and brine (1×) followed by drying over MgSO4 and concentration in vacuo. The crude (18.8 g) obtained as brown solid was further purified by flash chromatography [silica gel, 4-stage gradient system: 1) EtOAc; 2) EtOAc:MeOH:7N N3/MeOH (95:5:0.5); 3) DCM:MeOH:7N N3/MeOH (95:5:0.5); 4) DCM:MeOH:7N N3/MeOH (93:8:1)], affording N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin 4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide was obtained as an off white solid (15.0 g, 72% yield). 1H NMR (400 MHz, DMSO-d6): 10.41 (s, 1H), 10.02 (s, 1H), 8.47 (d, 1H), 7.91 (dd, 1H), 7.65 (m, 2H), 7.53 (m, 2H), 7.42 (t, 1H), 7.40 (s, 1H), 7.16 (m, 2H), 6.42 (d, 1H), 4.20 (t, 2H), 3.96 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (br, s, 4H), 1.98 (m, 2H), 1.48 (m, 4H). LC/MS Calcd for [M+H]+ 633.3. found 633.0.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:31](=O)[CH:32]([CH3:34])[CH3:33].C([BH3-])#N.[Na+]>CO>[CH2:31]([N:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH2:3][CH:4]([CH3:9])[CH3:5])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)C=O
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)CN(Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1)CC(C)C

Procedure:
Prepared analogously to Example 159 from (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride, isobutyraldehyde and sodium cyanoborohydride in methanol.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:7][C:8]2[CH:13]=[C:12]([C@H:14]3[C@H:19]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@@H:18]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C@H:17]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:16]([CH2:44][O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[O:15]3)[CH:11]=[CH:10][C:9]=2[Cl:53])=[N:5][N:6]=1.[CH3:54][S-:55].[Na+]>O1CCCC1>[Cl:53][C:9]1[CH:10]=[CH:11][C:12]([C@H:14]2[C@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@@H:18]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C@H:17]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:16]([CH2:44][O:45][CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[O:15]2)=[CH:13][C:8]=1[CH2:7][C:4]1[S:3][C:2]([S:55][CH3:54])=[N:6][N:5]=1
Reactant: C[S-]
Reactant: Clc1nnc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)s1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nnc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 2-chloro-5-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzyl)-1,3,4-thiadiazole (419 mg, 0.55 mmol) from Step 2 in tetrahydrofuran (10 mL) was added sodium methanethiolate (77 mg, 1.1 mmol). The resulting mixture was stirred at ambient temperature overnight. After cooling to 0° C., the reaction was quenched with hydrochloric acid (1.0 M) and diluted with ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on Biotage® purification apparatus (silica gel, 10 to 60% ethyl acetate in hexanes) to yield the title compound (331 mg, 0.42 mmol, 77%) as a yellow oil. MH+ 779.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C:15]([CH:16]2[CH2:18][CH2:17]2)=[CH:14][C@H:13](O)[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27]([O:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29].C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO[Si](C(C)(C)C)(C)C)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:27]([O:30][N:31]([C@H:13]1[CH2:12][N:11]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C:15]([CH:16]2[CH2:17][CH2:18]2)=[CH:14]1)[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29]
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C=C(C2CC2)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C2CC2)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-cyclopropyl-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 238, 2.74 g, 7.14 mmol) and N-(allyloxy)-2-nitrobenzenesulfonamide (Intermediate 9, 1.85 g, 7.14 mmol) following the procedure described for Intermediate 10. The desired product was obtained as a light yellow oil (3.19 g, 71%).
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[O:19][CH2:18][CH2:17][C:16]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH:32]5[CH2:37][CH2:36][C:35]6(OCC[O:38]6)[CH2:34][CH2:33]5)[CH3:31])=[CH:25][CH:24]=4)=[O:21])=[CH:15][C:14]=3[CH:42]=2)=[CH:6][CH:5]=1)[CH3:2].Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][C:16]([C:20]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([CH2:29][N:30]([CH3:31])[CH:32]5[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]5)=[CH:27][CH:28]=4)=[O:21])=[CH:15][C:14]=3[CH:42]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCC5(CC4)OCCO5)cc2)CCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCC(=O)CC4)cc2)CCO3)cc1
Reaction time: 22 h
Yield: 74.1 %

Procedure:
To a solution of 7-(4-ethoxyphenyl)-N-[4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]phenyl]-2,3-dihydro-1-benzoxepine-4-carboxamide (151.5 mg) in THF (10 ml) was added at room temperature 3N hydrochloric acid (2 ml), and the mixture was stirred for 22 hours. To the mixture was added saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated to give colorless solid, which was recrystallized from ethyl acetate/diisopropylether to give colorless crystals of 7-(4-ethoxyphenyl)-N-[4-[N-methyl-N-(4-oxocyclohexyl)aminomethyl]phenyl]-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 288) (103.5 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[N:13])[C:5](OC)=[O:6].C(S)CS>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][C:11]=1[C:12]#[N:13]
Reactant: COC(=O)c1ccc(C#N)c(Cl)c1C
Agent: SCCS
Solvent: C1CCOC1
Product: Cc1c(CO)ccc(C#N)c1Cl
Temperature: 70 °C
Yield: 66.5 %

Procedure:
To a pressure reaction flask containing compound 7A (1.5 g, 7.2 mmol) in THF (30 mL) were added 1,2-ethanedithiol (2.4 g, 28.6 mmol) and NaBH (812 mg, 21.5 mmol). It was sealed, and heated at 70° C. for 2 hr, and cooled to RT. The reaction mixture was concentrated, dissolved in EtOAc, washed with water, dried over Na2SO4, and concentrated. Recrystallization in EtOAc/hexanes give the title compound (870 mg). (ES) m/z 182 [M+H]+; 204 [M+Na]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:13]([C:14]([O:16]C)=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:27]1[CH2:32][CH2:31][O:30][C:28]1=[O:29]>CC(C)=O>[C:14]([C:13]1[CH:18]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[CH:11][C:12]=1[O:19][CH:27]1[CH2:32][CH2:31][O:30][C:28]1=[O:29])([OH:16])=[O:15]
Reactant: O=C1OCCC1Br
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1cc(OCc2ccccc2)ccc1OC1CCOC1=O

Procedure:
To a mixture of 32 g of methyl 5-benzyloxysalicylate, 17 g of anhydrous potassium carbonate and 500 ml of acetone was added 30.7 g of α-bromo-γ-butyrolactone under cooling with ice and, then, the mixture was refluxed for 15 hours. After cooling, the acetone was distilled off and 10% methanolic sodium hydroxide was added to the residue for hydrolysis. The reaction mixture was made acidic with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was dissolved in dioxane (300 ml)-benzene (200 ml) and the solution was refluxed in the presence of p-toluenesulfonic acid (30 g), with the resultant water being continuously distilled off. The solvent was distilled off and the residue was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to remove the solvent. The residue was recrystallized from ethyl acetate. By the above procedure there was obtained α-[(2-carboxy-4-benzyloxyphenyl)oxy]-γ-butyrolactone as colorless needles, m.p. 120°-122° C.
Reaction SMILES: [CH2:1]([N:3]([C:5]1[CH:6]=[C:7]([OH:13])[C:8](=[CH:11][CH:12]=1)[CH:9]=O)[CH3:4])[CH3:2].[C@@H:14]1([NH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH2:20]>>[CH2:1]([N:3]([C:5]1[CH:6]=[C:7]([OH:13])[C:8](=[CH:11][CH:12]=1)[CH:9]=[N:20][C@@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[N:21]=[CH:9][C:8]1[C:7](=[CH:6][C:5]([N:3]([CH3:4])[CH2:1][CH3:2])=[CH:12][CH:11]=1)[OH:13])[CH3:4])[CH3:2]
Reactant: CCN(C)c1ccc(C=O)c(O)c1
Reactant: N[C@@H]1CCCC[C@H]1N
Product: CCN(C)c1ccc(C=N[C@@H]2CCCC[C@H]2N=Cc2ccc(N(C)CC)cc2O)c(O)c1

Procedure:
Synthesis and working up are carried out as in Example 9, starting from 500 mg (2.79 mmol) of 4-(N-ethyl-N-methylamino)salicylaldehyde and 152 mg (1.33 mmol) of trans-1,2-cyclohexanediamine. Yield: 569 mg (98%), yellow solid.