Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([NH:7][C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:35])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:6])[CH3:3].Cl.Cl[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>C(O)C>[Cl:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:21]([N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:8]3([NH:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:13][CH2:12][N:11]([C:38]4[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=4)[CH2:10][CH2:9]3)[C:16](=[O:35])[CH2:17]1)(=[O:22])=[O:23])[CH:33]=[CH:32]2
Reactant: Clc1ccncc1
Reactant: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1
Yield: 41.6 %

Procedure:
A 4N hydrochloric acid solution in ethyl acetate (30 ml) and ethanol (6 ml) were added to 1-[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (5.21 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, the precipitated crystals were filtered off, washed with ethyl acetate-ethanol, and dried to obtain 1-[4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (3.71 g). A solution of 1-[4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (3.40 g), 4-chloropyridine hydrochloride (1.12 g) and triethylamine (3.48 ml) in ethanol (100 ml) was reacted at 150° C. for 9 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with a 5% aqueous sodium carbonate solution and water, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:10% aqueous ammonia-containing methanol=95:5→80:20), and the precipitated crystals were washed with ethanol-ether to obtain the colorless crystalline title compound (1.52 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1>[Pd].C(O)=O.CO>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1
Reactant: C1=C(c2c[nH]c3ccccc23)CN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: c1ccc2c(C3CCCNC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the 3-(1-benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-indole obtained in Example 28 and 10% palladium on carbon in a mixture of formic acid and methanol is stirred at room temperature for 3 days and filtered through celite. The celite is washed with methanol. The filtrates are combined and concentrated in vacuo to afford the title product, identified by HPLC and mass spectral analyses.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[C:24]#[CH:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[C:28](=[O:34])[CH2:27]2>O.O1CCCC1>[CH2:12]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[C:24]#[C:25][C:28]1([OH:34])[CH:29]2[CH2:32][CH2:33][N:26]([CH2:31][CH2:30]2)[CH2:27]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C#Cc1ccsc1Cc1ccccc1
Reactant: O=C1CN2CCC1CC2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(C#Cc2ccsc2Cc2ccccc2)CN2CCC1CC2
Reaction time: 20 h

Procedure:
0.200 ml of a hexane solution containing 1.8 mol of butyl lithium was added dropwise to a mixture of 45.2 mg of 2-benzyl-3-ethynyl-thiophene and 1 ml of tetrahydrofuran at −78° C., followed by stirring at the same temperature for 20 hours. A solution of 0.5 ml of tetrahydrofuran containing 39.9 mg of 3-quinuclidinone was added dropwise to the reaction solution at the same temperature, followed by stirring and then at room temperature for 4 hours. 0.5 ml of water and NH-silica gel were added to the reaction solution, and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using ethyl acetate, to give 39.5 mg of the target compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].Br[CH2:23][CH2:24]Cl.O>CS(C)=O>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([C:13]2([C:14]([O:16][CH3:17])=[O:15])[CH2:24][CH2:23]2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: ClCCBr
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 0.08 h
Yield: 94 %

Procedure:
The compound (1.76 g) obtained in step 1 was dissolved in DMSO (30 mL), sodium hydride (0.59 g) was added at 0° C., and the mixture was stirred for 5 min. To the reaction mixture was added 2-bromo-1-chloroethane (0.77 mL), and the mixture was stirred at room temperature for 45 min. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (10% ethyl acetate/hexane) to give methyl 1-[3,5-bis(trifluoromethyl)phenyl]cyclopropanecarboxylate (1.80 g, 94%).
Reaction SMILES: C([BH-](CC)CC)C.[Li+].[F:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH2:17][NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[C@:24]12[CH2:33][O:32][C@@H:31]([CH2:34]F)[CH2:30][C@H:29]1[CH2:28][S:27][C:26]([NH:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[N:25]2>O1CCCC1.ClCCl>[F:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH2:17][NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[C@:24]12[CH2:33][O:32][C@@H:31]([CH3:34])[CH2:30][C@H:29]1[CH2:28][S:27][C:26]([NH:36][C:37](=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[N:25]2
Reactant: O=C(NC1=N[C@@]2(c3cc(CNCC(F)(F)F)c(F)cc3F)CO[C@@H](CF)C[C@H]2CS1)c1ccccc1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(CNCC(F)(F)F)c(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.2 %

Procedure:
Lithium triethylborohydride (1.13 mL, 1.13 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C27) (60 mg, 0.11 mmol) in tetrahydrofuran (4 mL). The reaction mixture was allowed to stir at room temperature for 16 hours and then partitioned between ethyl acetate (25 mL) and a saturated aqueous solution of sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted further with ethyl acetate (3×25 mL). The combined organics were then washed sequentially with water (100 mL) and with brine (100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a white solid. The organic crude was re-dissolved in dichloromethane (20 mL) and the resulting solution was washed with 1 N sodium hydroxide (3×25 mL), water (100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the product as an orange solid (60 mg), which was taken directly to the following step. LCMS m/z 514 [M+H+].
Reaction SMILES: [CH:1]1[C:9]2[C:8]3C=CC=C[C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15][CH2:16][CH2:17][CH3:18].[C:19]1(=[O:40])[C:35]2[C:23]([C:24]3[CH:39]=[CH:38][CH:37]=[CH:36][C:25]=3C3[C:34]=2C=C2C=3C=CC=C2)=[CH:22][CH:21]=[CH:20]1>C1COCC1.C(OCC)(=O)C>[CH:15]1[C:8]2[C:9]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:6][C:7]=2[C:18]([C:19]2([OH:40])[C:35]3[CH:34]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]3[C:25]2=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:17][CH:16]=1
Reactant: O=C1C=CC=c2c1c1c(c3ccccc23)=c2ccccc2=C1
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(c2cccc3c2sc2ccccc23)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
Dibenzothiophene (9.21 g, 50 mmol) was dissolved in 100 ml of dry THF and solution was cooled to −50° C. n-BuLi (1.6 molar solution in hexanes, 40 ml, 64 mmol) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 4 hours and cooled to −30° C. Dibenzofluorenone (9.0 g, 50 mmol) in 70 ml THF was added dropwise, reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (75 ml), washed with brine 3 times, dried over MgSO4, filtered and evaporated. The solid residue was purified by column chromatography on silica (hexane/ethyl acetate 7/3) providing 12.0 g of 9-(dibenzo[b,d]thiophen-4-yl)-9H-fluoren-9-ol as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:15]=1>>[N:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:16]2[CH:15]=[C:14]([CH:13]3[C:3]4[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=4[NH:1][C:2]4[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]3=4)[CH:19]=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: COC(OC)c1cccc(OCc2ccncc2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(OCc2ccncc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-(4-pyridylmethoxy)-benzaldehyde dimethyl acetal in an analogous manner to that described in Example 1 gave 9-[3-(4-pyridylmethoxy)-phenyl]-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from methanol/water gave a yellow crystalline solid of melting point 156-158° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH:17][NH2:18])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:19]=1.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C(OC)(OC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[O:16][CH:20]=[N:18][N:17]=4)=[N:8][C:7]=3[C:6]=2[CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NNC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Solvent: COC(OC)OC
Solvent: CCOCC
Product: Brc1ccc2c(c1)-c1nc(-c3nnco3)sc1CCO2
Temperature: 100 °C

Procedure:
To a solution of 9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid hydrazide (400 mg) in trimethyl orthoformate (10 mL) was added p-toluenesulfonic acid (100 mg) and the reaction heated at 100° C. for 16 h. After cooling to room temperature, the solvent was reduced in vacuo and diethyl ether (10 mL) was added. The resulting solid was filtered and air-dried to give 9-bromo-2-[1,3,4]oxadiazol-2-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH:22]([CH2:27][C:28]3[CH:29]=[C:30]4[C:34](=[C:35]([CH3:37])[CH:36]=3)[NH:33][N:32]=[CH:31]4)[C:23]([O:25]C)=[O:24])=[O:20])[CH2:15][CH2:14]1)[CH2:7]2.O1CCCC1.CO.[OH-].[Li+]>O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]([NH:21][CH:22]([CH2:27][C:28]3[CH:29]=[C:30]4[C:34](=[C:35]([CH3:37])[CH:36]=3)[NH:33][N:32]=[CH:31]4)[C:23]([OH:25])=[O:24])=[O:20])[CH2:17][CH2:18]1)[CH2:7]2
Reactant: COC(=O)C(Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3cccc(F)c3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)C(=O)O)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of (±)-methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-(7-methyl-1H-indazol-5-yl)propanoate (0.4 g, 0.79 mmol) in 1:1 tetrahydrofuran/methanol (30 mL) at room temperature was treated with a solution of lithium hydroxide (83 mg, 2.5 equiv) in water (4 mL) and stirred at room temperature overnight. The solvents were evaporated and the pH was adjusted to ca. 1 with 1 N hydrochloric acid. The resulting white suspension was stored at 4° C. overnight and the product was collected by filtration, washed with a small amount of water, and dried in vacuo to afford 0.21 g (74%) as a white powder. Mass spec.: 495.06 (MH)+.
Reaction SMILES: O.C(O)(=O)C.[CH:6]1([N:9]2[C:18]3[C:13](=[C:14]([N+:25]([O-])=O)[C:15]([F:24])=[C:16]([F:23])[C:17]=3[O:19][CH:20]([F:22])[F:21])[C:12](=[O:28])[C:11]([C:29]([O:31]CC)=[O:30])=[CH:10]2)[CH2:8][CH2:7]1>[Fe].C(O)C>[NH2:25][C:14]1[C:15]([F:24])=[C:16]([F:23])[C:17]([O:19][CH:20]([F:21])[F:22])=[C:18]2[C:13]=1[C:12](=[O:28])[C:11]([C:29]([OH:31])=[O:30])=[CH:10][N:9]2[CH:6]1[CH2:8][CH2:7]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1c(F)c(F)c(OC(F)F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
The preparation comprises refluxing mixture of reducing iron powder (2.4 g, 42.8 mmol), water (4.5 mL) and acetic acid (0.3 mL) for 15 min under stirring, adding batch-wise ethyl 1-cyclopropyl-6,7-difluoro-8-difluoromethoxyl-5-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylate (4.3 g, 10.6 mmol), adding ethanol (20 mL), continuously refluxing for 6 h under stirring, hot filtering, distilling off the solvent from the filtrate, adding concentrated hydrochloric acid (5 mL) and acetic acid (10 mL) to react at 100° C. for 1 h, cooling to room temperature, filtering, adding ethanol (10 mL) to the filter cake to reflux for 0.5 h, cooling to room temperature, filtering, and drying obtained filter cake to give a pale yellow solid product 5-amino-1-cyclopropyl-6,7-difluoro-8-difluoromethoxyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (3.1 g, 84.5%).
Reaction SMILES: OS(O)(=O)=O.[C:6]1(=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH:8]=[CH:7]1.[N-:18]=[N+]=[N-].[Na+]>>[NH:18]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9](=[O:16])[CH2:8][CH2:7][C:6]1=[O:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1CCC(=O)c2ccccc2N1
Temperature: 0 °C
Reaction time: 48 h
Yield: 84.9 %

Procedure:
To 10 mL of H2SO4 (97% ) cooled in an ice-bath was added portionwise 1.08 g (6.86 mmol) of 1,4-naphthoquinone and it was stirred to become a solution. To the red solution was added portionwise 0.454 g (6.98 mmol) of NaN3. The mixture was stirred in ice bath for 2 h, then at room temperature for 2 days. It was added dropwise into 100 mL of ice-water and stirred for 1 h and allowed to stand overnight. The mixture was filtered and washed thoroughly by water, dried to leave brown solid 1.02 g. 1H NMR (CDCl3 +DMSO-d6) shows it is more than 80% pure. Portion of the solid was crystallized (DMSO/H2O) to give 32 as a brown solid, mp 225°-226° C. 1H NMR (CDCl3 +DMSO-d6) 6.544 (d, 1, J=12.9), 6.657 (d, 1, J=12.9), 6.978 (t, 1, J=7.5), 7.152 (d, 1, J=8.4), 7.323 (t, 1, J=7.5), 7.812 (d, 1, J=8.1), 10.55 (bs, 1).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[N+](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][O:4][CH:2]([CH3:3])[CH3:1])[CH3:12]
Reactant: CC(C)O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To a solution of 2-propanol (0.776 mL, 10.0 mmol) in dichloromethane (33 mL) is added rhodium (II) acetate dimer (22 mg) followed by ethyl diazoacetate (1.05 mL, 10.0 mmol). The reaction mixture is stirred at RT for 30 min. The reaction mixture is filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 750 mg of the product 405. 1H NMR (CDCl3) δ 4.21 (q, 2 H), 4.06 (s, 2 H), 3.73 (m, 1 H), 1.29 (t, 3 H), 1.22 (s, 3 H), 1.19 (s, 3 H); MS: m/z 147 (M++1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([CH:15]=1)[NH2:14].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:4][CH2:3]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 100 °C
Yield: 110 %

Procedure:
4-Methylpiperidine (172 mg, 1.738 mmol) was added to a solution of 5-chloro-2-nitroaniline (200 mg, 1.159 mmol) in NMP (5 mL) in the presence of triethylamine (0.404 mL, 2.90 mmol). The reaction mixture was heated via microwave irradiation to 100° C. for 1 h, and. Upon cooling, the solvent was removed by vacuum. Purification by flash column chromatography (5% CH3OH/CH2Cl2) afforded the title compound (300 mg) as a solid. 1H NMR: (400 MHz, CDCl3): δ 7.98 (d, 1H, J=10.0 Hz), 6.26 (dd, 1H, J=2.8 and 10.0 Hz), 6.13 (bs, 2H), 5.92 (d, 1H, J=2.0 Hz), 3.85 (m, 2H), 2.89 (m, 2H), 1.72 (m, 2H), 1.62 (m, 1H), 1.23 (m, 2H), 0.96 (d, 3H, J=6.8 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#N)=[CH:16][CH:15]=1.C([O:28][C:29](=O)[C@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:31])(=O)C>>[OH:31][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([N:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)[CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=1)=[O:28]
Reactant: CC(=O)OC(=O)[C@@H](O)c1ccccc1
Reactant: Nc1ccc2ncccc2c1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Product: O=C([C@@H](O)c1ccccc1)N(CCc1ccc(C(F)(F)F)cc1)c1ccc2ncccc2c1

Procedure:
In analogy to example 104 quinolin-6-ylamine, 4-(trifluoromethyl)phenylacetonitrile & (+)-O-Acetyl-L-Mandelic Acid were successively coupled then hydrolysed to give after silica gel chromatography the target compound. MS(m/e): 451.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[NH:13][C@@H:12]([CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:20]([CH2:22][C:23](O)=[O:24])=[CH2:21].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.Cl>C1COCC1.C(OCC)(=O)C>[C:23]([N:13]1[C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][O:10][CH2:11][C@@H:12]1/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])(=[O:24])[CH2:22][CH:20]=[CH2:21].[C:23]([N:13]1[C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][O:10][CH2:11][C@@H:12]1/[CH:14]=[CH:15]\[C:16]([O:18][CH3:19])=[O:17])(=[O:24])[CH2:22][CH:20]=[CH2:21]
Reactant: COC(=O)C=C[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Reactant: C=CCC(=O)O
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC(=O)N1[C@@H](/C=C/C(=O)OC)COC[C@H]1c1ccc(Cl)cc1
Product: C=CCC(=O)N1[C@@H](/C=C\C(=O)OC)COC[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TEA (88.4 μL) was added to a solution of methyl 3-[(3S,5R)-5-(4-chlorophenyl)morpholin-3-yl]acrylate (89 mg), vinylacetic acid (40.4 μL), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (121 mg) in THF (4 mL) at room temperature. The reaction solution was stirred at room temperature for two hours. Then, a 1 N hydrochloric acid solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was sequentially washed with a 1 N sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 52.8 mg of methyl 3-[(3S,5R)-4-(3-butenoyl)-5-(4-chlorophenyl)morpholin-3-yl]-(E)-acrylate and 35.1 mg of methyl 3-[(3S,5R)-4-(3-butenoyl)-5-(4-chlorophenyl)morpholin-3-yl]-(Z)-acrylate. The property values of the isomers are as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH3:15])[CH2:9][N:10]2[C:14]([Br:23])=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: C[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](Cn1ncnc1Br)(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 86.2 %

Procedure:
A mixture of 1.5 g (0.0050 mol) of bis(4-fluorophenyl)(methyl)(1H-1,2,4-triazol-1-ylmethyl)silane, 0.98 g (0.0055 mol) of N-bromosuccinimide and ~1 mg of azobisisobutyltronitrile in 10 mL of CCl4 was warmed to 60°, then illuminated with a high intensity lamp (Roxter Model 5900) for 20 minutes. The mixture was cooled, filtered, and evaporated, and the residue was flash chromatographed (10% ether/methylene chloride) to give 1.7 g of the title compound as an oil: ir (neat) 3030, 2960, 1590, 1498, 1479, 1339, 1265, 1231, 1162, 1108, 1033, 825, 789, 733 cm-1. nmr (CDCl3) δ0.7 (s, 9H), 4.2 (s, 2H, 7.1 (t, 4H), 7.5 (m, 4H), 7.8 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[N:28]=[CH:27][N:26]=[C:25]2[O:40][C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][C:45]([CH3:50])=[CH:44]2.C(=O)([O-])O.[Na+]>C(Cl)Cl.CO>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([CH2:4][CH2:3][O:2][CH3:1])[CH2:36][CH2:35]1)[N:28]=[CH:27][N:26]=[C:25]2[O:40][C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][C:45]([CH3:50])=[CH:44]2
Reactant: COCC=O
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCCN1CCC(COc2cc3ncnc(Oc4ccc5[nH]c(C)cc5c4)c3cc2OC)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.3 %

Procedure:
Methoxyacetaldehyde (368 mg, 3.47 mol) (freshly distilled) followed by sodium triacetoxyborohydride (552 mg, 2.6 mol) were added to a solution of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (726 mg, 1.74 mmol), (prepared as described in Example 70), in a mixture of methylene chloride (15 ml) and methanol (15 ml). After stirring for 1.5 hours at ambient temperature, saturated sodium hydrogen carbonate was added. The volatiles were removed under vacuum and the residue was partitioned between methylene chloride and water. The organic layer, was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (80/20). After removal of the solvent, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum at 60° C. to give 6-methoxy-7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline (392 mg, 47%).