Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[CH3:24]C(C)=O>>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[C:6]([O:8][C:9]([CH3:10])([CH3:18])[CH3:24])(=[O:7])[CH2:5][C:4]([CH3:3])=[O:21]
Reactant: CC(C)=O
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: CC(=O)CC(=O)OC(C)(C)C

Procedure:
Sucrose and glycerin acetoacetates were prepared using 2,2,6-trimethyl-4H-1,3-dioxan-4-one (structure below) as a starting material. A 2 L flask equipped with a Dean-Stark trap, reflux condenser and thermometer, was charged with 100.3 g of sucrose and 335 g of 2,2,6-trimethyl-4H-1,3-dioxan-4-one (TDO). The reaction mixture was brought to 96° C. at which point the evolution of acetone commenced. Acetone was collected over the next 1.5 hours until distillation stopped. The quantity of acetone collected showed that ˜98 mol % of the available hydroxyl groups had reacted. The product was then tested as per the material obtained from the t-butyl acetoacetate synthesis. It per formed the same according to the previous Examples. This synthetic route provides for synthesis of the product at lower temperature and at higher conversion levels.
Reaction SMILES: CC([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]1([CH2:28]O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])(C)C.[H-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[O:5]=[C:6]1[N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][C:9]2([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:28][O:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CO)(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)OCC2(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
Bis(1,1-dimethylethyl)2-(hydroxymethyl)-2-(phenylmethyl)piperazine-1,4-dicarboxylate (3.6 g, 8.9 mmol) was dissolved in N,N-dimethylformamide (40 mL). 60% Sodium hydride (0.43 g, 11 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added a 0.5 M aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added diethyl ether, and the precipitated crystals were collected by filtration to obtain the title compound (2.6 g, yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C@@H:6]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:29])=[C:16]([C@:18]4([CH3:28])[C:24]([F:26])([F:25])[CH2:23][O:22][CH2:21][C:20](=S)[NH:19]4)[CH:17]=3)[CH2:7][CH2:8][C:9]=2[CH:10]=1.CO.C(OO)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[NH3:44]>>[NH2:44][C:20]1[CH2:21][O:22][CH2:23][C:24]([F:26])([F:25])[C@:18]([C:16]2[CH:17]=[C:12]([NH:11][C@@H:6]3[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[CH2:8][CH2:7]3)[CH:13]=[CH:14][C:15]=2[F:29])([CH3:28])[N:19]=1
Reactant: C[C@]1(c2cc(N[C@H]3CCc4cc(Cl)cnc43)ccc2F)NC(=S)COCC1(F)F
Reactant: N
Agent: CC(C)(C)OO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@]1(c2cc(N[C@H]3CCc4cc(Cl)cnc43)ccc2F)N=C(N)COCC1(F)F
Temperature: 23 °C
Reaction time: 22 h
Yield: 45 %

Procedure:
To a solution of (R)-5-[5-((S)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-6,6-difluoro-5-methyl-[1,4]oxazepane-3-thione (intermediate A20Ab) (16 mg, 36.2 μmol) in 7 M ammonia in methanol (0.4 mL, 2.8 mmol) at 23° C. was added tert-butyl hydroperoxide (70% in water, 16.3 mg, 17.4 μL, 181 μmol) and the mixture stirred at 23° C. for 22 hours. Poured into aqueous 2 M Na2CO3 solution, extracted with ethyl acetate, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a light brown solid, which was purified by flash chromatography (silica gel (amine)) with n-heptane/ethyl acetate to give the title compound as a yellow solid (7 mg, 45%). MS (ISP): m/z=425.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:11]1[CH:16]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:14][CH2:13][CH:12]1[C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=1.O.[OH-].[Na+:34]>CO>[Na+:34].[CH3:30][C:29]1[C:24]([CH:12]2[CH2:13][CH2:14][CH2:15][CH:16]([C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)[N:11]2[CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O-:31])=[O:2])=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1C(=O)[O-]
Temperature: 25 °C
Yield: 108.6 %

Procedure:
To a solution of 2-(3,3″-Dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (0.723 g, 1.74 mmol) in MeOH (5 mL) was added water (5 mL) and solid NaOH (0.757 g, 18.93 mmol). The resultant mixture was heated to reflux overnight then cooled to room temperature. The mixture was extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated and provided 0.80 g (97%) of COMPOUND 63 as a while solid. 1H NMR (D2O) δ 1.58-1.73 (m, 3H), 1.88-2.04 (m, 3H), 2.36 (s, 6H), 3.66 (s, 2H), 4.12 (d, 2H, J=10.2 Hz), 6.82 (t, 1H, J=7.2 Hz), 6.92-7.03 (m, 4H), 7.40-7.47 (m, 3H), 8.13 (d, 2H, J=3.9 Hz). 13C NMR (D2O) δ 16.66, 24.13, 32.40, 56.97, 65.27, 122.76, 125.65, 127.27, 128.10, 130.45, 132.60, 136.88, 139.70, 146.15, 159.77, 177.12; ES-MS m/z 402 (M+H), 424 (M+Na). Anal. Calcd. For C25H26N3O2Na.2.7H2O: C, 63.60; H, 6.70; N, 8.90. Found: C, 63.60; H, 6.78; N, 8.55.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO.CCCCCC>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([O:12][CH3:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCC
Product: C=CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a stirred solution of (2R)-2-[(tert-butoxycarbonyl)amino]pent-4-enoic acid (2.15 g, 10.0 mmol) in CH2Cl2 (20 mL) and MeOH (1.5 mL) was added a 2.0 M solution of trimethylsilyldiazomethane in hexane (10 mL) dropwise. After the yellow color persisted and gas evolution ceased, the solution was stirred for 15 min, and then quenched with two drops of HOAc. The reaction mixture was washed with sat. NaHCO3, the aqueous layer extracted with CH2Cl2, the combined organic layers dried over Na2SO4, treated with activated carbon and concentrated at reduced pressure to give 2.2 g of methyl (2R)-2-[(tert-butoxycarbonyl)amino]pent-4-enoate as a yellow oil. This material was dissolved in 20 mL ether, and treated with a solution of diazomethane (prepared by the portionwise treatment of a stirred mixture of 35 mL ether and 10 mL 25% KOH at 0° C. with 3.32 g (22.5 mmol) 1-methyl-3-nitro-1-nitrosoguanidine). The resulting cold (0° C.) stirred solution was treated with a very small portion of Pd(OAc)2 which caused vigorous gas evolution. The cold bath was removed, and stirring continued for 1 h. The reaction mixture was filtered through a 1 cm pad of SiO2 and eluted with ether. The filtrate was concentrated to give a yellow oil that was chromatographed on a 110 g Redi-Sep column using a 0–40% EtOAc-hexane gradient over 40 min, 40 mL/min. The pure fractions were combined and concentrated at reduced pressure to give 1.0 g of the title compound as a colorless oil: 1H NMR (300 MHz, CDCl3): δ 5.10–5.20 (br d, J=6.1 Hz, 1H), 4.34–4.43 (m, 1H), 3.74 (s, 3H), 1.66 (t, J=6.5 Hz, 2H), 1.45 (s, 9H), 0.65–0.75 (m, 1H), 0.4–0.55 (m, 2H), 0.01–0.14 (m, 2H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.O[CH2:13][P+:14]([CH2:19]O)([CH2:17]O)[CH2:15]O.[CH3:21][NH:22][C:23]([NH:25][CH3:26])=[O:24]>C1(C)C=CC=CC=1>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH3:21][N:22]([CH2:19][P+:14]([CH2:13][N:22]([CH3:21])[C:23]([NH:25][CH3:26])=[O:24])([CH2:15][N:22]([CH3:21])[C:23]([NH:25][CH3:26])=[O:24])[CH2:17][N:22]([CH3:21])[C:23]([NH:25][CH3:26])=[O:24])[C:23]([NH:25][CH3:26])=[O:24]
Reactant: OC[P+](CO)(CO)CO
Reactant: CNC(=O)NC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)C[P+](CN(C)C(=O)NC)(CN(C)C(=O)NC)CN(C)C(=O)NC
Yield: 89.7 %

Procedure:
Reaction of tetrakis(hydroxymethyl)phosphonium p-toluenesulfonate (16.31 g, 0.05 mol) with 1,3-dimethylurea (17.62 g, 0.2 mol) in toluene (200 ml), following Example 1, gave 27.21 g (89.7%) of tetrakis(1,3-dimethylureidomethyl)phosphonium p-toluenesulfonate (I, R=R'=CH3, R"=H, X=SO3C6H4CH3 -p) as a white, crystalline solid, mp 130°-131° C. after two recrystallizations from acetonitrile. The analytical sample was dried under vacuum for 2 hr at 100° C.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10](=[O:20])[CH:9]=1)(C)(C)C>CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10](=[O:20])[CH:9]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccn(-c2ccccc2)c(=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1cc(CO)ccn1-c1ccccc1
Reaction time: 16 h

Procedure:
4-(Tert-butyl-dimethyl-silyloxymethyl)-1-phenyl-1H-pyridin-2-one from Step 3 (1.3 g) was dissolved in TBAF in 1M THF (15 mL). The clear reaction mixture was stirred for 16 hours. The reaction mixture was concentrated and purified on a column of silica eluting with 10% MeOH/EtOAc to yield 4-hydroxymethyl-1-phenyl-1H-pyridin-2-one as a tan solid. 1H NMR (400 MHz, CDCl3) δ 7.5-7.47 (m, 2H); 7.43 (d, 1H); 7.38-7.36 (m, 2H); 7.32-7.30 (d, 1H) 6.67 (s, 1H); 6.23 (d, 1H) 4.57 (d, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[CH:26][CH:27]=[C:28]3[CH:32]=[CH:31][O:30][C:29]=23)[CH2:20][CH2:19]1)[C:13](=O)OCC.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[O:30]1[C:29]2=[C:24]([N:21]3[CH2:20][CH2:19][CH:18]([N:12]([CH3:13])[CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH2:23][CH2:22]3)[N:25]=[CH:26][CH:27]=[C:28]2[CH:32]=[CH:31]1
Reactant: CCOC(=O)N(Cc1ccc2ccccc2c1)C1CCN(c2nccc3ccoc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccc2ccccc2c1)C1CCN(c2nccc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 700 mg of the product obtained in Step A in 20 ml of tetrahydrofuran is added at 0° C. to a suspension of 123 mg of LiAlH4 in 20 ml of tetrahydrofuran. The whole is stirred for 3 hours at ambient temperature and then hydrolysed with 0.17 ml of water, 0.5 ml of 20% sodium hydroxide solution and 0.70 ml of water. The whole is filtered, evaporated and purified by chromatography on silica gel (dichloromethane/ethanol: 95/5), enabling the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]#C.BrCC#[N:21].CN(C=O)C>>[Cl:1][C:2]1[N:3]=[C:4]2[C:10]([N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]#[N:21])=[CH:11][N:12]=1
Reactant: C#CCN1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: N#CCBr
Solvent: CN(C)C=O
Product: CN1C(=O)CCN(CC#N)c2nc(Cl)ncc21

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 154, on a 0.31 mmol scale, utilising bromoacetonitrile (Aldrich; 33 μL, 0.47 mmol), as an amber gum containing 0.6 equivalents of DMF (97 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH3:39]>>[CH3:34][O:35][CH2:36][CH2:37][N:38]([CH3:39])[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: CNCCOC
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCCN(C)c1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide with cesium carbonate and N-(2-methoxyethyl)methylamine. ES-MS m/e (%): 457 (M+H+, 100).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH3:39])=[O:37]>O.O1CCCC1>[NH2:4]/[C:2](=[N:3]\[C:36](=[O:37])[O:38][CH3:39])/[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1
Reactant: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/N=C(\N)c1ccc(CNC(=O)c2cc(C)n(-c3ccc(F)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
75 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 78 mg of potassium carbonate were dissolved in 0.95 ml of water and 4.75 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.016 ml of methyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-])=O.Cl.[NH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)C(C)C)(C)C>C(#N)C.[Zn]>[NH2:1][CH2:4][CH:5]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: [Zn]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(CN)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 148.3 %

Procedure:
trans-β-Nitrostyrene (4.04 g, 27.1 mmol) was added to a solution of ethyl 3-aminopropanoate hydrochloride (4.16 g, 27.1 mmol), and N,N-diisopropylethylamine (9.43 mL, 54.2 mmol) in acetonitrile (70 mL). After 15 min, anhydrous hydrochloric acid gas was bubbled into the solution until acidic. The mixture was concentrated, redissolved in ethanol (60 mL) and aqueous hydrochloric acid (12M; 30 mL), and cooled to 0° C. Zinc dust (8.80 g, 134 mmol) was added in portions over 5 min. After 0.5 h, the mixture was concentrated to remove ethanol and saturated aqueous sodium carbonate was added. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give the title compound (9.5 g). MS 237 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:22])([F:21])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].Cl>CCCCCC.ClCCl>[CH3:24][C:23]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:6]([F:21])([F:22])[F:5])[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:25]
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Yield: 90 %

Procedure:
To a mixture of 2.43 moles (324 g.) of aluminum chloride in 648 ml. of dichloromethane is added a solution of 0.88 mole (274 g.) of 1,4-bis(2,2,2-trifluoroethoxy)benzene and 0.97 mole (92 ml.) of acetic anhydride in 880 ml. of dichloromethane over a 3 hour period while maintaining the temperature at above 0° C. The reaction mixture is then heated to its reflux temperature and stirred at reflux for 5 hours. The progress of the reaction is followed using thin-layer chromatography. The reaction mixture is placed in an ice bath and ice and 10 percent hydrochloric acid are added slowly to decompose the aluminum chloride complex. The temperature of the reaction mixture is not allowed to exceed 25° C. The organic phase is separated and washed once with 2 liters of 10 percent hydrochloric acid and then with 2 liters of water. The combined aqueous phase is extracted with several liters of dichloromethane. The organic phase is dried over magnesium sulfate, then evaporated to provide a moist residue. Hexane is added to the residue and the resulting solid is collected by filtration and washed with hexane. Upon drying, 250 g. of light yellow crystalline 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is obtained. The yield is 90 percent, the m.p. is 84° to 86° C.
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2ncccc2F)C[C@@H]1C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2ncccc2F)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64.1 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-4-[(3-fluoro-2-pyridinyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 72) (111.6 mg, 0.214 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 45 min then concentrated in vacuo. The residue was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined and concentrated in vacuo to give a residue which was dissolved in DCM (5 mL). The resulting solution was treated with HCl (1M in Et2O, 0.2 mL, 0.2 mmol) then concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-N-(3-fluoro-2-pyridinyl)-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (67.4 mg, 0.137 mmol, 64.1% yield) as a light orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11]1[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1.[H-].[Na+].Cl[CH2:22][C:23]1[CH:44]=[CH:43][C:26]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[C:31]([F:42])[CH:30]=2)=[CH:25][CH:24]=1.[OH-].[Na+].Cl>CN(C)C=O.C(O)C.O>[F:42][C:31]1[CH:30]=[C:29]([O:28][CH2:27][C:26]2[CH:43]=[CH:44][C:23]([CH2:22][N:10]([CH2:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:11]3[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=3)=[CH:24][CH:25]=2)[CH:34]=[CH:33][C:32]=1[CH2:35][CH2:36][C:37]([OH:39])=[O:38]
Reactant: CC(C)c1csc(NCCc2ccccc2F)n1
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)c1csc(N(CCc2ccccc2F)Cc2ccc(COc3ccc(CCC(=O)O)c(F)c3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of N-[2-(2-fluorophenyl)ethyl]-4-isopropyl-1,3-thiazole-2-amine (139 mg) in N,N-dimethylformamide (2 mL) was added sodium hydride (20 mg), and the mixture was stirred at room temperature for 1 hr. Ethyl 3-(4-{[4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate (175 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:1 in volume ratio) to give a yellow oil. This oil was dissolved in ethanol (5 mL), 2N aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.) and concentrated to give the title compound (206 mg, yield 71%) as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N+:20]=1[O-:25]>>[O-:25][N+:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: [O-][n+]1ccccc1S
Product: O=C1CCc2cc(OCCCCSc3cccc[n+]3[O-])ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril and 2-mercapto-pyridine-N-oxide.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=1)[C:15](Cl)=O.N>>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][N:20]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Clc1cc(-c2nc(-c3cccnc3)no2)ccn1

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Aldrich) and 2-chloroisonicotinoyl chloride (Maybridge). 1H NMR (300 MHz, DMSO-d6) δ 7.68 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 8.16 (dd, J=5.1, 1.4 Hz, 1H), 8.23 (dd, J=1.5, 0.8 Hz, 1H), 8.42-8.54 (m, 1H), 8.77 (dd, J=5.1, 0.7 Hz, 1H), 8.84 (dd, J=4.7, 1.7 Hz, 1H), 9.28 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 259 (M+H)+, 261 (M+H)+.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[CH2:49]([NH-:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:49]([NH-:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [NH-]Cc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 88 mg of Z-Phe-His-OH, 65 mg of H-Leu-Val-benzyl amide, 31 mg of Hobt and 54 mg of DCCI, the title compound is obtained after flash chromatography (100 g of silica gel 60, 40-63 μm, system B3). Rf (B2)=0.60, Rf(S10)=0.68.