Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[OH:4].Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[F:1][C:2]([F:15])([F:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=1)=[O:4]
Reactant: OC(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(C(F)(F)F)cc1)C(F)(F)F

Procedure:
25.4 g (0.1 mol) of 2,2,2-trifluoro-1-(4-trifluoromethylphenyl)ethanol and 1.76 g (0.005 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 350 ml of methylene chloride at room temperature. 108 ml (0.125 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 20 minutes with vigorous stirring and the mixture is stirred for a further 5 hours at room temperature. The reaction mixture is added to 400 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product (18 torr, 60°-61° C.), 16.74 g (66.5% of theory) of 4-trifluoroacetyltrifluoromethylbenzene are obtained, which, according to GC, is 96.7% pure. nD20 : 1.4146.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([O:27]C)=[O:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]([CH3:32])=[CH2:31])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]([CH3:32])=[CH2:31])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2OCC(=O)OC)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2OCC(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Yield: 18 %

Procedure:
Racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-methoxycarbonylmethoxy-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (80 mg, 0.164 mmol) was dissolved in THF (10 mL). Then aqueous solution (1 mL) of NaOH (20 mg) was added. The mixture was refluxed for 1 h. After cooled to room temperature, the solution was concentrated and acidified to “pH” 2-3. The mixture was extracted with ethyl acetate. The organic layer was separated, dried and concentrated. The crude product (50 mg) was purified by Prep-HPLC to give the title compound as a white solid (14 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])O)=[CH:4][CH:3]=1.[OH-:13].[Na+].Cl.[Cl-].[Na+]>C(OCC)(=O)C.CCCCCC.O>[CH2:9]([CH:7]1[C:2]([OH:6])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: [OH-]
Reactant: CCCCC(O)c1ccc(C)o1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CCCCC1C(=O)C=CC1(C)O
Temperature: 40 °C

Procedure:
In a reaction vessel, water (40 ml) and 5-methyl-2-furyl-n-butylcarbinol (0.5 g) were charged, and the pH value was regulated to 5 with an aqueous 1 N NaOH solution and an aqueous 1 N HCl solution. The temperature was elevated up to 100° C. to reflux, and the mixture was stirred under reflux for 30 hours while maintaining a pH value of 5 to 5.5 by the addition of an aqueous 1 N NaOH solution and an aqueous 1 N HCl solution. After cooling to 40° C., the reaction mixture was neutralized with an aqueous 1 N NaOH solution, and sodium chloride (12 g) was added thereto. The mixture was extracted with toluene (40 ml) five times. From the extract, toluene was removed by distillation at 60° C. under reduced pressure to give an oily substance (0.48 g), which was subjected to a thin layer chromatography on silica gel with a mixture of ethyl acetate-n-hexane (1:2 by volume) as the developing solvent. The objective part of the silica gel layer was collected by scraping and eluted with ethyl acetate. The silica gel was eliminated by filtration, and the filtrate was concentrated to obtain 2-n-butyl-3-hydroxy-3-methyl-4-cyclopentenone (3.5 g). Yield, 70%. NMR spectrum (CCl4, internal standard TMS, δ ppm, 60 MHz): 7.25 (d, 1H, 4-H); 5.85 (d, 1H, 5-H); 3.63 (broad s, 1H, 3--OH); 2.20 (m, 1H, 2-H); 1.25 (s, 3H, 3-CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[O:14]=[C:15]1[C@@H:19]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17][N:16]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:15]2([OH:14])[C@@H:19]([O:20][Si:21]([CH:25]([CH3:26])[CH3:27])([CH:28]([CH3:29])[CH3:30])[CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17][N:16]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)c1
Reactant: CC(C)[Si](O[C@H]1CCN(C(=O)OC(C)(C)C)C1=O)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](O[C@H]1CCN(C(=O)OC(C)(C)C)C1(O)c1cccc(F)c1)(C(C)C)C(C)C
Temperature: -22 °C
Reaction time: 2 h

Procedure:
In step 3-2, a solution of 3-fluoro-1-bromo benzene (4.0 g, 22.9 mmol) in THF (10 mL) was cooled to −60° C. To this solution n-BuLi in hexanes solution (1.6 M hexanes, 14.3 ml, 22.9 mmol) was added over 12 minutes allowing for a gradual temperature ramp (2° C./minute) until a net internal temperature of −40° C. was obtained and all the n-BuLi was added. The reaction mixture was then allowed to warm over a 30 minute period until an internal temperature of −22° C. was reached, then the resulting solution (dark in color) was cooled to −45° C. and then a solution of (S)-tert-butyl 2-oxo-3-(triisopropylsilyloxy)pyrrolidine-1-carboxylate (2.0 grams, 5.6 mmoles) in THF (10 mL) was added over 6 minutes (do not allow the internal temperature to exceed −40° C. during this addition event). The mixture was then allowed to warm to −20° C. over a 35 minute period and the temperature was then held at −20° C. for 2 hours. The reaction mixture was then quenched with cold saturated ammonium chloride aqueous solution (150 mL), warmed to room temperature and extracted with ethyl acetate (3×150 mL). The organic extracts were combined, concentrated using a rotary evaporator and purified using flash chromatography (5% ethyl acetate in hexanes to 10% ethyl acetate in hexanes over a 30 minute gradient) yielding the racemate of (3S)-tert-butyl 2-(3-fluorophenyl)-2-hydroxy-3-(triisopropylsilyloxy)pyrrolidine-1-carboxylate (3-2) as an oil. 1H NMR (400 MHz, D6 acetone) δ ppm 7.92-7.23 (m, 4H), 5.80 (br s, 1H), 5.10 (app t, J=8.2, 1H), 3.20-2.95 (m, 2H), 2.05-1.95 (m, 2H), 1.35 (s, 9H), 1.21-0.99 (m, 21H). LCMS observed m/z 737.5 major ion.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].N1CCC[CH2:14]1.CC(O)=O.[OH-].[Na+]>O1CCOCC1.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:14][NH:9]2
Reactant: C1CCNC1
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Fc1cc(Br)c2cc[nH]c2c1
Temperature: 100 °C
Yield: 27 %

Procedure:
To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (4.69 g, 20 mmol) in 1,4-dioxane (25 mL) at RT was slowly added DMF dimethylacetal (13.3 mL) and pyrrolidine (1.7 mL). The solution was heated at 100° C. for 18 h, then concentrated in vacuo to give a dark residue. To the residue was added HOAc (30 mL) and iron powder (11 g, 200 mmol) then the mixture was heated to reflux for 1 h, cooled to RT, neutralized by addition of 50% aq. NaOH and extracted with EtOAc (2×200 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with an EtOAc/petroleum ether gradient (5 to 30% EtOAc) to afford 1.16 g (27%) of 4-bromo-6-fluoro-1H-indole (224)—as brown solid: MS (ESI) m/z=213.9 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[C:22]1([S:28]([N:6]2[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]2=[O:8])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: O=c1[nH]c(=O)n(S(=O)(=O)c2ccccc2)cc1F
Temperature: 80 °C
Reaction time: 7 h
Yield: 54.6 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil and 1.38 g (0.01 mole) of anhydrous potassium carbonate were suspended in 70 ml. of dioxane. 3.5 g (0.02 mole) of benzenesulfonyl chloride in 10 ml. of dioxane was dropwise added thereto and stirred at 80°C. for 7 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and a resinous residue was obtained. The residue was dissolved in a small amount of ethanol and allowed to stand at 5°C. overnight. There was obtained 2.95 g (54.6% yield) of 1-benzenesulfonyl-5-fluorouracil. The product was recrystallized from dioxane-ethanol and gave granular crystals melting at 256°-257°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows:
Reaction SMILES: Cl.C([NH:9][CH2:10][C:11]1([OH:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:9][CH2:10][C:11]1([OH:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc2c(c1)C(O)(CNCc1ccccc1)CCC2
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: COc1ccc2c(c1)C(O)(CN)CCC2
Yield: 99.8 %

Procedure:
A suspension of 1-benzylaminomethyl-7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol hydrochloride (45.00 g), ammonium formate (25.50 g), and 10% palladium on carbon (50% wet, 4.5 g) in methanol was refluxed for 40 minutes. After cooling, the catalyst was removed by filtration and the filtrate was evaporated in vacuo. Water (45 ml), 1N hydrochloric acid (90 ml) and diethyl ether (120 ml) were added to the residue and the aqueous layer was separated. The aqueous layer was made alkaline with 5N aqueous sodium hydroxide (45 ml), and extracted with ethyl acetate (600 ml×6 times). The organic layers were combined, dried over sodium sulfate, and evaporated in vacuo to give 1-aminomethyl-7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol (27.89 g) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3](S(C2C=CC=CC=2)(=O)=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([Mg]Br)=[C:24]([F:32])[CH:23]=1>C1COCC1>[Cl:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=2)=[C:24]([F:32])[CH:23]=1
Reactant: COc1cc([Mg]Br)c(F)cc1Cl
Reactant: O=S(=O)(c1ccccc1)c1ncc(C(F)(F)F)cc1Cl
Solvent: C1CCOC1
Product: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Yield: 84 %

Procedure:
3-Chloro-2-phenylsulfonyl-5-trifluoromethylpyridine was stirred with 4-chloro-2-fluoro-5-methoxyphenylmagnesium bromide for 2.5 hours at room temperature in THF. Working-up by distillation gave the coupling product 2-(4-chloro-2-fluoro-5-methoxyphenyl)-3-chloro-5-trifluoromethylpyridine in a yield of 84%, which is outstanding.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:15][C:16]3[C:17]([F:27])=[C:18]4[C:23](=[CH:24][C:25]=3[F:26])[N:22]=[CH:21][CH:20]=[CH:19]4)[N:13]=[N:14][C:9]2=[N:8][CH:7]=1)=[CH2:5])C>C(O)(=O)C.Cl>[F:27][C:17]1[C:16]([CH2:15][N:12]2[C:10]3=[N:11][C:6]([C:4](=[O:3])[CH3:5])=[CH:7][N:8]=[C:9]3[N:14]=[N:13]2)=[C:25]([F:26])[CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2
Reactant: C=C(OCC)c1cnc2nnn(Cc3c(F)cc4ncccc4c3F)c2n1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1cnc2nnn(Cc3c(F)cc4ncccc4c3F)c2n1
Reaction time: 2 h
Yield: 2.3 %

Procedure:
To a solution of the 6-((6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline (6.0 mg, 0.45 mmol) in acetic acid, 3N HCl (0.1 mL) was added. The solution stirred at it for 2 h. Solvents were removed under reduced pressure. The residue was diluted with water, treated with aqueous NaHCO3 solution, extracted with DCM. The organic layer was washed sequencially with NaHCO3 (aq.) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography with Hexane:ethyl acetate to give yellow solid 1-(1-((5,7-difluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (3.5 mg), yield 63%. LCMS (method B): [MH]+=340.9, tR=2.09 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:18]=[C:19]([C:23]4[O:24][C:25]([C:28]5[CH:29]=[N:30][N:31]([CH:33]6[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]6)[CH:32]=5)=[CH:26][N:27]=4)[CH:20]=[CH:21][CH:22]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:46]>O1CCOCC1.CO>[ClH:46].[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[O:24][C:25]([C:28]5[CH:29]=[N:30][N:31]([CH:33]6[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]6)[CH:32]=5)=[CH:26][N:27]=4)[CH:18]=3)[N:10]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(Cn5nc(-c6cc(F)cc(F)c6)ccc5=O)c4)o3)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(-c2ncc(-c3cnn(C4CCNCC4)c3)o2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 90.4 mg (0.147 mmol) of tert-butyl 4-[4-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}oxazol-5-yl)pyrazol-1-yl]piperidine-1-carboxylate in a mixture of 0.22 ml of 4 N hydrogen chloride in dioxane and 0.23 ml of methanol is stirred at room temperature for 16 hours. The solution is evaporated and dried in vacuo, giving 6-(3,5-difluorophenyl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)oxazol-2-yl]benzyl}-2H-pyridazin-3-one hydrochloride as colourless crystals; ESI 515.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[NH2:11][C:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17](=O)[N:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15]=2[S:14][C:13]=1[C:32]([O:34][CH3:35])=[O:33].[OH-].[Na+]>O1CCCC1.CCOCC>[NH2:11][C:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17][N:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15]=2[S:14][C:13]=1[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)c1sc2c(c1N)c1ccccc1c(=O)n2-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1sc2c(c1N)-c1ccccc1CN2c1ccccc1
Reaction time: 0.67 h
Yield: 17.9 %

Procedure:
To a suspension of 0.34 g of lithium aluminum hydride in 30 ml of tetrahydrofuran was added a solution of 1.20 g aluminium chloride in 60 ml of ether for 10 minutes. To the mixture was added a solution of 1.05 g of methyl 1-amino-4,5-dihydro-5-oxo-4-phenyl-thieno[2,3-c]isoquinoline-2-carboxylate in 60 ml of tetrahydrofuran for 50 minutes, which was prepared by Example 1, and the mixture was stirred for 40 minutes. To the reaction mixture was added 30 ml of a 5% sodium hydroxide aqueous solution, and the mixture was stirred. The aqueous layer was extracted with 30 ml of tetrahydrofuran twice. The organic layers were combined together, and dried over anhydrous magnesium sulfate. The dried solution was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/chloroform=1/1) to obtain amorphous product in orange-yellow. The amorphous product obtained was triturated with n-hexane to obtain 180 mg of the desired product.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].OS(O)(=O)=O.[CH2:13](O)[CH3:14]>>[C:1]([O:7][CH2:13][CH3:14])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: C#CCCC(=O)OCC
Temperature: 50 °C
Yield: 70 %

Procedure:
In analogy to the method as described in Tetrahedron, 2000, 56, 5735-5742, a mixture of the 4-pentynoic acid (10 g, 102 mmol) and H2SO4 98% (0.338 mL, 6.12 mmol) in ethanol (113 mL) was heated at 50° C. overnight. The reaction mixture was concentrated and the crude product was dissolved in ethyl acetate, washed with NaHCO3 1M and water. The solvent was removed under reduced pressure to afford 9.04 g of ethyl pent-4-ynoate (Yield: 70%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:17])[CH:6]=[CH:7][C:8]=2[O:15][CH3:16])[N:3]=1.C(O)(=[O:20])C>>[CH:12]([C:11]1[C:2](=[O:20])[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:15][CH3:16])[CH:7]=[CH:6][C:5]=2[CH3:17])([CH3:14])[CH3:13]
Reactant: CC(=O)O
Reactant: COc1ccc(C)c2nc(Cl)c(C(C)C)cc12
Product: COc1ccc(C)c2[nH]c(=O)c(C(C)C)cc12
Temperature: 120 °C
Reaction time: 15 h

Procedure:
2-Chloro-3-isopropyl-5-methoxy-8-methylquinoline (2.65 g, 10.6 mmol) was dissolved in acetic acid (70 ml), and the solution was stirred at 120° C. for 15 hours. The reaction solution was condensed under reduced pressure, and the resultant residue was recrystallized from chloroform-ethyl acetate. 2.10 g of the title compound was obtained as pale yellow powdery crystals (85.6%).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13](OS(C)(=O)=O)[CH2:14]2)[N:11]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:9])#[N:2].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C)C=O>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:14]2)[N:11]1[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OS(C)(=O)=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2N2CCCC2)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 80 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-[(methylsulfonyl) oxy]-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 12-1 (153 mg) in dimethylformamide (2.0 mL), was added pyrrolidine (79 mg). The mixture was stirred at 80° C. for 1 hr. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with chloroform and methanol (19:1) to give the target compound (91 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[N:17][C:16]=2Cl)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:24][NH2:25]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[N:17][C:16]=2[NH:24][NH2:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nnc2Cl)CC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nnc2NN)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
4-(3,6-Dichloro-pyridazin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (9.73 g; 28.03 mmol) was dissolved in 20 ml EtOH and treated with Hydrazine Hydrate (14.03 g; 280.33 mmol). It was stirred at 70° C. for 16 hours. Two peaks with product mass detected via HPLC-MS. The reaction mixture was extracted with aqueous NaHCO3 solution and DCM. The organic phase was dried and evaporated to dryness. The crude product was purified by using reversed phase chromatography under acid conditions.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:43]([CH2:44][CH3:45])=[CH:42][N:41]=[C:40]([CH3:46])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:43]([CH2:44][CH3:45])=[CH:42][N:41]=[C:40]([CH3:46])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)ncc3CC)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(5-ethyl-2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K19) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (310 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[BH4-].[Na+].[OH-].[Na+]>ClCCl.O.C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][C:8]([F:11])=[CH:9][N:10]=1
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: OCc1cc(F)cnc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 34.3 %

Procedure:
2-Chloro-5-fluoronicotinic acid (4.50 g, 25.6 mmol) was dissolved in dichloromethane (100 mL) and dry dimethylformamide (1 mL) and cooled in an ice bath. Thionyl chloride (20 ml, 274 mmol) was added slowly and the reaction stirred for 20 minutes then it was removed from the ice bath. After another 15 minutes the solution was evaporated to dryness under reduced pressure. The crude acid chloride was further dried under high vacuum then dissolved in dry tetrahydrofuran (20 mL) and slowly added to an ice cooled solution of sodium borohydride (2.5 g, 66.1 mmol) in water (100 mL with about 80 mL of ice) over 40 minutes. The reaction was stirred for an additional 15 minutes. Ethyl acetate (400 mL) and additional water (100 mL) were added and the phases stirred. Sodium hydroxide (5 N, 40 mL) was added to make the aqueous layer basic. The mixed phases were stirred for 2 hours then the layers were separated. The organic layer was dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired (2-chloro-5-fluoropyridin-3-yl)methanol (1.42 g, 8.79 mmol, 34.3% yield) as a brown oil that solidified on standing.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[CH:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: O
Product: Fc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1

Procedure:
After weighing 80 g (0.28 mol) of 1-benzyl-4-(4-fluorophenyl)-4-hydroxypiperidine and 69.0 g (0.364 mol) of p-toluenesulfonic acid monohydrate to 400 ml of chlorobenzene under stirring, the reaction mixture is boiled under reflux for 3 hours while distilling out water introduced as crystal water and the water formed in the reaction. After termination of the reaction, 100 ml of chlorobenzene are additionally distilled out under atmospheric pressure. After cooling the mixture obtained to 0° C., the precipitated title product is filtered, twice washed with 10 ml of cold acetone each and dried on the air to give a yield of 90.5 g (73%), m.p.: 180-182° C.