Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][O:25]S(C)(=O)=O)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:50]1[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][O:25][C:50]2[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=2)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOS(C)(=O)=O
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1
Reaction time: 0.08 h

Procedure:
To a solution of 1.2 g of methyl 8-(p-chlorophenylsulfonamido)-4-(2-hydroxyethyl)-octanoate (example 28) in 12 ml methylene chloride is added 1.14 g triphenylphosphine followed by 0.336 g 3-hydroxypyridine. After stirring for 5 min, 0.55 ml diethyl azodicarboxylate is added slowly. After 1 h, solvent is evaporated and the residue subjected to flash chromatography to obtain methyl 8-(p-chlorophenylsulfonamido)-4-[2-(3-pyridyloxy)ethyl]-octanoate, m.p. 57°-58°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]3[C:19]4[C:14](=[CH:15][C:16]([C:20]5[N:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=5)=[CH:17][CH:18]=4)[CH2:13][N:12]([CH3:27])[CH2:11]3)[CH:8]=[CH:9][C:2]1=2.O.NN>CO.[Pd]>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]3[C:19]4[C:14](=[CH:15][C:16]([C:20]5[N:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:17][CH:18]=4)[CH2:13][N:12]([CH3:27])[CH2:11]3)[CH:8]=[CH:9][C:2]1=2
Reactant: CN1Cc2cc(-c3ccc(Cl)nn3)ccc2C(c2ccc3sccc3c2)C1
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: CN1Cc2cc(-c3cccnn3)ccc2C(c2ccc3sccc3c2)C1
Yield: 70.6 %

Procedure:
To a solution of the product obtained in Step B (2.02 g, 5.15 mmol) and hydrazine hydrate (8 mL) in MeOH (100 mL), was added 10% Pd/C (0.25 g). The reaction mixture was heated to reflux 8 h, then, the reaction mixture was filtered through a short pad of celite. The filtrate was concentrated to dryness under reduced pressure. The residue was diluted with CH2Cl2 (60 mL), then, washed with H2O (1×40 mL). The aqueous phase was extracted with additional amount of CH2Cl2 (3×20 mL). The combined organic phases were dried (Na2SO4) and concentrated to dryness under reduced pressure. The residue was purified using medium pressure chromatography (eluent: EtOAc/MeOH 9:1) to afford (+/−)-4-benzo[b]thiophen-5-yl-2-methyl-7-pyridazin-3-yl-1,2,3,4-tetrahydroisoquinoline (1.3 g, 71%, >99% AUC HPLC) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.14 (dd, J=1.6, 4.9 Hz, 1H), 7.94 (d, J=1.5 Hz, 1H), 7.84-7.79 (m, 2H), 7.71-7.67 (m, 2H), 7.51 (dd, J=8.6, 4.9 Hz, 1H), 7.44 (d, J=5.4 Hz, 1H), 7.28-7.26 (m, 1H), 7.20 (dd, J=8.3, 1.6 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.46 (m, 1H), 3.90 (d, J=14.6 Hz, 1H), 3.76 (d, J=14.6 Hz, 1H), 3.15-3.10 (m, 1H), 2.71-2.65 (m, 1H), 2.48 (s, 3H); ESI-MS m/z 358 [M+H]+.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:20](=[O:22])C)[CH:11]=[CH:12][C:13]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCOCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[C:20]([OH:22])=[O:2]
Reactant: CC(=O)c1ccc(C2CCCCC2)c(Cl)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C2CCCCC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
An aqueous alkaline solution of potassium permanganate (2.94 g, 0.0186 mol; in 22 mL 12% aqueous sodium hydroxide) is added to solution of 1-(3-chloro-4-cyclohexylphenyl)ethanone (2.2 g, 0.0093 mol) in dioxane (11 mL). The reaction mixture is stirred at 80° C. temperature for 2 hrs. It is then filtered and the filtrate is washed with diethyl ether (2×10 mL). The pH of the aqueous layer is adjusted to 1-2 by using 6N hydrochloric acid. It is extracted in ethyl acetate (3×15 mL). Combined organic layer is dried over sodium sulfate and concentrated to get the crude, which is purified using column chromatography (230-400 mesh; ethyl acetate:n-hexane, 1:3) to yield 3-chloro-4-cyclohexyl benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:13][C:14]#[N:15].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:13][C:14]#[N:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S)cc1OC
Reactant: N#CCCl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(SCC#N)cc1OC
Temperature: 80 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
To a solution of 3,4-dimethoxythiophenol (5.0 g, 29.4 mmol) in dry DMF (150 ml), were added chloroacetonitrile (1.85 ml, 29.4 mmol), anhydrous K2CO3 (6.09 g, 44.1 mmol) and DMAP (358 mg, 2.9 mmol). The reaction mixture was stirred at 80° C. for 20 h under nitrogen. After cooling, the mixture was filtered and concentrated in vacuo. The residue was combined with H2O, extracted with CH2Cl2, the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (AcOEt) gave the title product (5.16 g, 84%).
Reaction SMILES: [Br:1][C:2]1[N:10]2[C:5]([C:6](Cl)=[N:7][C:8]([Cl:11])=[N:9]2)=[N:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][NH:20][CH2:21][CH3:22])=[CH:17][CH:16]=1>C1COCC1>[Br:1][C:2]1[N:10]2[C:5]([C:6]([N:20]([CH2:21][CH3:22])[CH2:19][C:18]3[CH:23]=[CH:24][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[N:7][C:8]([Cl:11])=[N:9]2)=[N:4][CH:3]=1
Reactant: Clc1nc(Cl)c2ncc(Br)n2n1
Reactant: CCNCc1ccc(OC)cc1
Solvent: C1CCOC1
Product: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(Br)cnc12
Reaction time: 1 h
Yield: 106.8 %

Procedure:
(I10A): A solution of 7-bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine (Intermediate I9F) (10 g, 37.3 mmol) in anhydrous THF (300 ml) was treated with N-(4-methoxybenzyl)ethanamine (8.01 ml, 46.7 mmol), resulting in the immediate precipitation of a solid. The reaction was stirred for 1 hour; the mixture was concentrated in vacuo. To the residue was added EtOAc (100 ml) and the mixture stirred 10 min. The salts were filtered off and the filtrate was washed with 0.5M citric acid, sat. NaHCO3, water and brine. The solution was dried over Na2SO4 and solvents removed to afford 7-bromo-2-chloro-N-ethyl-N-(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (15.8 g).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=O)[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:28][C:29]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:30]=1[C:31](=[S:34])[NH:32][NH2:33]>CCO.C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH:33][N:32]=[C:31]([C:30]3[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:29]=3[F:28])[S:34]2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NNC(=S)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)NCCCC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC1(c2cccc(O[Si](C)(C)C(C)(C)C)c2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 4-(3-(tert-butyldimethylsilyloxy)phenyl)-4-oxobutylcarbamate (1.400 g, 3.55 mmol) in 20 mL of a 3:1 EtOH/DCM mixture was added 2,5-difluorobenzothiohydrazide (0.704 g, 3.74 mmol). The reaction was stirred overnight at room temperature, then heated to 45° C. for 10 hours. The reaction mixture was then concentrated in vacuo, loaded directly to Biotage (45), followed by flash column chromatography (20-50% ethyl acetate/hexanes), yielding the desired product as a yellow semi-solid (1.742 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].Cl.[NH2:19][CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:20][NH2:19])[CH:26]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: NCc1cccc(B(O)O)c1
Agent: Cl
Product: NCc1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-aminomethyl-phenylboronic acid hydrochloride gives “A76”; method 1: HPLC/MS: 0.94 min, [M+H]=320;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]1)=[O:16])[CH2:7][CH2:6]2.[ClH:30]>C(OCC)(=O)C>[ClH:30].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1)=[O:16])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)CN(C(=O)C1CCCN(C(=O)OC(C)(C)C)C1)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)CN(C(=O)C1CCCNC1)CC2

Procedure:
A conventional amidation reaction was carried out using a dichloromethane solution (40 ml) of 2.53 g of (±)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 3.0 g of N-(tert-butyloxycarbonyl)nipecotic acid, 3.0 g of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 0.89 g of 1-hydroxybenztriazole to give 3.77 g of (±)-6,7-dimethoxy-2-{[1-(tert-butyloxycarbonyl)-3-piperidyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline. Deprotection of 3.77 g of (±)-6,7-dimethoxy-2-{[1-(tert-butyloxycarbonyl)-3-piperidyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline was further carried out using 10 ml of an ethyl acetate solution containing 4N hydrochloric acid to give 2.30 g of (±)-6,7-dimethoxy-2-[(3-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14]>C(Cl)Cl.Cl>[CH:13]([NH:16][C:17]([NH:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])=[O:18])([CH3:15])[CH3:14]
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: ClCCl
Product: CC(C)NC(=O)N[C@@H](CC(=O)O)c1ccccc1
Reaction time: 3 h

Procedure:
To a stirred suspension of (S)-3-amino-3-phenylpropionic acid (1.22 g, 7.3 mmol) and TEA (1.24 mL, 8.86 mmol) in CH2Cl2 (30 mL) at ambient temperature was added isopropyl isocyanate (0.798 mL, 8.12 mmol). The reaction mixture was stirred for 3 h, diluted with 1M HCl (25 mL), and extracted with CH2Cl2 (3×25 mL). The combined CH2Cl2 extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=251 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][C:11]([CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])=[CH:10][C:9]3=2)[CH2:3][CH2:2]1.[H-].[Na+].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C1COCC1>[C:30]([Si:27]([O:23][C:21]([CH3:24])([CH3:22])[CH2:20][C:11]1[CH:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]3[C:8]([C:9]=2[CH:10]=1)=[CH:7][C:6]([O:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)=[CH:19][CH:18]=3)([CH3:29])[CH3:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(O)Cc1ccc2ccc3ccc(OCC4CC4)cc3c2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(Cc1ccc2ccc3ccc(OCC4CC4)cc3c2c1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of crude 1-[6-(cyclopropylmethoxy)-3-phenanthryl]-2-methylpropan-2-ol from Step 4 above in THF (10 mL), was added sodium hydride (60% dispersion in oil, 0.27 g, 6.79 mmol). The mixture was heated at reflux for 2 minutes, then cooled to room temperature. Tert-butyldimethylsilylchloride (0.512 g, 3.39 mmol) was added and the reaction mixture heated at reflux for 2 h. After usual workup of the reaction, tert-butyl(2-[6-(cyclopropylmethoxy)-3-phenanthryl]-1,1-dimethylethoxy)dimethylsilane (0.5 g) was obtained, which was used as crude material for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6]2.[Br:15]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>ClCCl>[Br:15][C:4]1[C:3]([O:2][CH3:1])=[CH:11][C:10]([O:12][CH3:13])=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(c(OC)c1)C(=O)CC2
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c2c(c1Br)CCC2=O
Yield: 86.4 %

Procedure:
845 mg of 5,7-dimethoxyindan-1-one was dissolved in 40 ml of dichloromethane. Thereafter, 822 mg of N-bromosuccinimide was added to the reaction solution. After completion of the reaction, chloroform was added to the reaction solution. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was suspended in acetone, and the suspension was filtered, so as to obtain 1.03 g of 4-bromo-5,7-dimethoxyindan-1-one. The obtained product was suspended in a mixed solution consisting of 30 ml of methanol, 10 ml of tetrahydrofuran, and 20 ml of chloroform. Thereafter, 952 mg of methoxylamine hydrochloride and 935 mg of sodium acetate were added to the reaction solution, and the obtained mixture was stirred at room temperature. Approximately 4 hours later, 952 mg of methoxylamine hydrochloride and 935 mg of sodium acetate were further added to the reaction solution. After completion of the reaction, the reaction solution was concentrated. A saturated sodium bicarbonate aqueous solution and ethyl acetate were added to the resultant product, so as to separate an organic layer. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was suspended in t-butyl methyl ether, and the suspension was filtered, so as to obtain 896 mg of the subject compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C@H:9]([CH2:14][CH3:15])[C:10](OC)=[O:11])[C:5]([N+:21]([O-])=O)=[CH:4][N:3]=1.[H][H]>C(O)(=O)C.[Ni]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:21][C:10](=[O:11])[C@@H:9]([CH2:14][CH3:15])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1
Reactant: CC[C@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(=O)O
Product: CC[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Temperature: 77.5 °C
Reaction time: 12 h
Yield: 66.5 %

Procedure:
Methyl (2R)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]butanoate 1m (1 g, 3 mmol) was dissolved in 10 mL of acetic acid followed by the addition of Raney nickel (0.50 g), filled with hydrogen three times, then heated to 75-80° C. and stirred for 12 hours. The reaction mixture was filtered, washed with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure, added with 100 mL ethyl acetate, washed with water (50 mL×3) and saturated sodium chloride solution (50 mL×3) successively. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one 1n (0.56 g, yield: 66.7%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4]1.[CH2:13]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)/C=C\C(O)=O.CN[C@@H]1CC2C(=CC=CC=2)NC1>C1(C)C=CC=CC=1>[CH3:1][N:2]([C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4]1)[C:21](=[O:22])[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN[C@H]1CNc2ccccc2C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C(O)/C=C\C(=O)O
Solvent: Cc1ccccc1
Product: CN(C(=O)OCc1ccccc1)[C@H]1CNc2ccccc2C1
Reaction time: 0.5 h

Procedure:
A mixture of (R)-1,2,3,4-tetrahydro-N-methyl-3-quinolinamine of crude material prepared above (V, EXAMPLE 4, 15.0 g), approximately 84.4 mmol) in toluene (50 ml) is stirred at −40° while N-(benzyloxycarbonyloxy)succinimide (24.2 g, 97.1 mmol) in toluene (150 ml) is added over one hr. After 30 min at −40°, GLC analysis indicated that all of (V) had been consumed. The mixture is quenched by the addition of sodium bicarbonate (10% aqueous solution, 300 ml) and warmed to 0°, followed by the addition of methanol (100 ml). This is stirred overnight and then extracted with ethyl acetate. Drying over magnesium sulfate and solvent removal gives a liquid which is purified by flash chromatography (230-400 mesh silica gel; hexane/ethyl acetate, 4/1) which crystallized from ethyl acetate/hexane to give the title compound, mp=80°; NMR (CDCl3) 2.88, 2.80-3.04, 3.30, 3.83, 4.57, 5.16, 6.51, 6.64, 6.96-7.02 and 7.35 δ; [a]25D=−50.1° (CH3OH, c=0.816); IR (mineral oil) 1680 and 1606 cm−1.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][C@H:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([O:39][CH3:40])[CH:33]=2)[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)[C@H:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([O:39][CH3:40])[CH:33]=2)[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2)ccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled suspension of (3R)-1-benzyl-3-(3-methoxy-4-methylbenzyl)piperazine-2,5-dione (1.35 g) in tetrahydrofuran (22 ml) was added lithium aluminum hydride (0.378 g) at 5° C. or below under a nitrogen atmosphere. The mixture was stirred under reflux for 3 hours. After cooling the mixture to 5° C. or below, 2N sodium hydroxide was added to the mixture. After stirring the mixture for 30 minutes, insoluble matters were collected by filtration and washed with tetrahydrofuran. The filtrate and the washings were combined and the solvent was evaporated under reduced pressure to give (3R)-1-benzyl-3-(3-methoxy-4-methylbenzyl)piperazine in the form of an oily substance. A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.80 ml) in dichloromethane (1 ml) was added dropwise to an ice-cooled solution of (3R)-1-benzyl-3-(3-methoxy-4-methylbenzyl)-piperazine obtained by the above process and triethylamine (0.84 ml) in dichloromethane (10 ml) at 5° C. or below over 5 minutes. After stirring at the same temperature for 30 minutes, the reaction mixture was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate (4:1). Fractions containing the desired compound were collected and the solvent was evaporated under reduced pressure to give (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-methoxy-4-methylbenzyl)-piperazine (1.92 g) in the form of an oily substance.
Reaction SMILES: [N:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20](Cl)=[O:21])=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:23]([NH:27][C:20]([C:18]1[CH:17]=[N:16][C:12]2[O:13][CH2:14][CH2:15][N:10]([S:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)(=[O:9])=[O:8])[C:11]=2[CH:19]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)N1CCCCC1)CCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cnc2c(c1)N(S(=O)(=O)N1CCCCC1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
To a biphasic mixture of 1-(piperidin-1-ylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (38 mg, 0.110 mmol) in DCM (2 mL) and saturated aqueous NaHCO3 (2 mL) was added tert-butylamine (50 μL, 0.472 mmol). The reaction was stirred at room temperature for 16 h. The biphasic mixture was extracted with DCM (3×2 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution of hexanes with 10-70% EtOAc to provide N-tert-butyl-1-(piperidin-1-ylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide (27.7 mg, 0.072 mmol, 65.2% yield over 2 steps) as a white solid. LCMS (+ESI) m/z=383.1 [M+H]+; 1H-NMR (CDCl3) δ 8.27. (d, 1H), 8.17 (d, 1H), 5.86 (br s, 1H), 4.49 (dd, 2H), 3.78 (dd, 2H), 3.29 (dd, 4H), 1.67-1.53 (m, 6H), 1.46 (s, 9H).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:36])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=CC=1)([O-])=O.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH:38]=1>O1CCCC1>[F:24][C:22]([F:25])([F:23])[C:18]1[CH:17]=[C:16]([C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:35])[F:34])[CH:27]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:47][CH2:46][CH2:45][CH2:44][CH2:43][C:39]2[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH:21]=[CH:20][CH:19]=1
Reactant: NCCCCc1cccnc1
Reactant: O=C(/C=C/C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1)NCCCCc1cccnc1
Yield: 65.2 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis[3-(trifluoromethyl)phenyl]-2,4-pentadienoic acid 4-nitrophenyl ester (4.8 g) and 3-pyridinebutanamine (1.5 g) in tetrahydrofuran (20 mL) was stirred for 2 hours at room temperature and was then worked up in the usual manner. The crude product was purified by HPLC (ethyl acetate) and then crystallized from ether-hexane to afford 3.2 g of (E)-5,5-bis[3-(trifluoromethyl)phenyl]-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 89°-90° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14](O)(=[O:18])[C:15]([CH3:17])=[CH2:16].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)O
Reactant: OCCCCCCCCCCCBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 19 h
Yield: 79.1 %

Procedure:
19.2 g (76.4 mmol) 11-bromo-1-undecanol, 7.2 g (84.1 mmol) methacrylic acid and 1.03 g (8.4 mmol) 4-dimethylaminopyridine were dissolved in 157 ml dichloromethane. The solution was subsequently cooled to 0° C. and then a solution of 17.4 g (84.2 mmol) dicyclohexylcarbodiimide in 80 ml dichloromethane was added dropwise, in the course of 45 minutes at 0° C. The reaction was allowed to warm to room temperature, stirred for 19 hours and filtered. The filtrate was concentrated by evaporation. Chromatography of the residue on 170 g silica gel using toluene yielded 19.3 g (98.4%) 2-methylacrylic acid 11-bromoundecyl ester.