Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:4]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)#[N:25].N1C=CC=CC=1.Cl>C(Cl)Cl>[C:20]([C:4]1[CH:3]=[C:2]([NH:1][S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[C:7]([CH3:8])=[CH:6][C:5]=1[S:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(N)cc2C(C)(C)C)cc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(NS(=O)(=O)c3ccc(C#N)cc3)cc2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of toluene-4-thiosulfonic acid S-(4-amino-2-tert-butyl-5-methyl-phenyl) ester obtained from Example HHHH (0.20 g, 0.57 mmol), 4-cyanobenzenesulfonyl chloride (0.15 g, 0.74. mmol), pyridine (7 mL) and CH2Cl2 (1 mL) was stirred at room temperature under nitrogen overnight. 1N HCl was then added and the mixture was extracted with EtOAc. The organic phase was washed with 1N HCl and brine, dried (Na2SO4), filtered and concentrated. The resulting residue was flash chromatographed on silica gel, eluting with 19:1 CHCl3 :EtOAc to afford the title compound. 1H NMR (CDCl3) δ 1.16 (s, 9 H), 1.98 (s, 3 H), 2.43 (s, 3 H), 6.49 (s, 1 H), 7.23 (s, 1 H), 7.27 (d, partially obscured by CDCl3, 2 H), 7.48 (d, 2 H), 7.78 (d, 2 H), 7.87 (d, 2 H).
Reaction SMILES: O.[CH2:2]([O:9][C:10](Cl)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([O:9][C:10]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCCC1CCNCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(CCCO)CC1
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a stirred mixture of methylene chloride (400 ml) and water (40 ml) are added dropwise benzyloxycarbonyl chloride (100 g) and a solution of 3-(4-piperidyl)propanol (84 g) and triethylamine (65 g) in methylene chloride (100 ml) for 45 minutes at room temperature. After addition is completed, stirring is continued for further 1 hour. The methylene chloride layer is separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Vacuum distillation of the oily residue is carried out to remove the low boiling material (50°-60° C./5 mmHg). 3-(1-Benzyloxycarbonyl-4-piperidyl)propanol (110 g) is obtained as a yellow oily residue.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[CH2:17][CH2:18][I:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1[CH:25]=[CH:24][C:23]([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[I-:19].[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[CH2:17][CH2:18][P+:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23]1[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(CCI)c(OCc2ccccc2)cc1F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Fc1cc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(OCc2ccccc2)cc1F
Product: [I-]
Temperature: 140 °C
Yield: 79.3 %

Procedure:
To a solution of 1-(benzyloxy)-4,5-difluoro-2-(2-iodoethyl)benzene (630 mg, 1.684 mmol) in xylene (10 mL) was added Ph3P (883 mg, 3.37 mmol) and the mixture was heated at 140° C. for 16 h. The mixture was cooled to rt (The product solidified). Solids were then filtered off and washed with ether and hexane, dried under high vacuum to afford (2-(benzyloxy)-4,5-difluorophenethyl)triphenylphosphonium iodide salt (850 mg, 1.336 mmol, 79% yield) as white solid. 1H NMR (500 MHz, CDCl3)) δ 7.87-7.61 (m, 15H), 7.44-7.33 (m, 6H), 6.74 (dd, J=11.6, 6.4 Hz, 1H), 5.00 (s, 2H), 3.94-3.83 (m, 2H), 3.06-2.91 (m, 2H). LCMS (M+H)=510.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15]N(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)O.[NH2:23][C:24]([NH2:26])=[NH:25].O.O.O.C([O-])(=O)C.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:25]=[C:24]([NH2:26])[N:23]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: N=C(N)N
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Yield: 55 %

Procedure:
A solution of 1-t-Butoxycarbonyl-3-(dimethylamino)methylene-4-piperidone, Intermediate 4 (7.64 g, 30.04 mmol) in methanol (190 mL) was treated with guanidine carbonate (21.65 g, 120.16 mmol), followed by sodium acetate trihydrate (32.70 g, 240.32 mmol). The reaction mixture was heated at reflux for 17 hours and the solvent was removed in vacuo. The residue was diluted with water and the mixture was swirled for a few minutes. The undissolved white solid was collected and washed with water, followed by a small amount of cold ethyl acetate to give the title compound (4.10 g, 55%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2)[CH2:2][CH3:3].[F:15]C(F)(F)S([O-])(=O)=O.[Na+].Cl>ClCCl.O>[F:15][C:10]1[C:11]2[C:6](=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:14]
Reactant: CCCc1ccc2cc(O)ccc2c1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCc1ccc2c(F)c(O)ccc2c1
Reaction time: 8 h
Yield: 800.3 %

Procedure:
To a solution of 20 g of 6-propyl-2-naphthol and 1.8 g of sodium trifluoromethanesulfonate in 80 ml of dichloromethane was added 23.7 g of N,N′-difluoro-2,21′-dipyridinium bistetrafluoroborate. The reaction mixture was then stirred for 8 hours. The reaction solution was then poured in water. To the reaction mixture was then added diluted hydrochloric acid. The resulting organic phase was then separated. The resulting aqueous phase was extracted with toluene. The organic phase and the material thus extracted were together washed sequentially with water and saturated brine, and then dehydrated and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain an oily matter which was then purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 17.1 g of 1-fluoro-6-propyl-2-naphthol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([NH2:11])[CH2:6][CH2:5]2.Cl[CH2:13][C:14]1([CH:27]=O)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([N:11]1[CH2:13][C:14]3([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[CH2:27]1)[CH2:6][CH2:5]2
Reactant: N[C@@H]1CCc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(CCl)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(Br)ccc31)C2
Temperature: 50 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a solution of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine (1835 g, 8.66 mol) in anhydrous methanol (24 L) was added tert-butyl 4-(chloromethyl)-4-formylpiperidine-1-carboxylate (2310 g, 8.83 mol). The mixture was stirred at 50° C. for 16 h, and cooled to rt. Sodium cyanoborohydride (1000 g, 15.9 mol) in THF (15 L) was added via a syringe pump over 2 hours. The mixture was stirred at 60° C. for 24 hours under nitrogen with a vent into a bleach bath. The reaction was cooled to 20° C. and transferred via a cannula into a vessel containing 24 L of 2.5M sodium hydroxide, and 30 L of DCM. The layers were separated and the aqueous layer was extracted with DCM (2×5 L). The aqueous layer was treated to destruct residual sodium cyanoborohydride. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude material was slurried in MTBE (7 L) by stirring at 40° C. for 1 h and at rt for 1 h. The solid was filtered, and washed with MTBE (2×500 mL) and dried under vacuum oven at 50° C. to give the title product as a white crystals (3657 g, 90%). MS (ES+) 422.3 (M+H)+. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.67 (dd, 4H), 1.84-1.93 (m, 1H), 2.07-2.16 (m, 1H), 2.72-2.81 (m, 1H), 2.95-3.15 (m, 5H), 3.31 (dd, 4H), 3.85 (br s, 1H), 7.12 (d, 1H), 7.28 (br s, 1H), 7.35 (br s, 1H). [α]D20=+39.6 deg (c=1.06 mg/mL, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([OH:12])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[NH2:17]>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[OH:12])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: COc1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: COc1ccc(O)c(C(=O)Nc2cc(Cl)cc(Cl)c2)c1
Yield: 29.8 %

Procedure:
Using 5-methoxysalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[CH2:2].[CH3:12][C@@H:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OC1C=CC(C(O)=O)=CC=1)C=C.C1([C@@H](N)C)C2C(=CC=CC=2)C=CC=1>>[CH3:12][C@@H:13]([NH:20][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:11][CH:10]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: C=Cc1ccc(C(=O)O)cc1
Agent: C=CCOc1ccc(C(=O)O)cc1
Agent: C[C@H](N)c1cccc2ccccc12
Product: C=Cc1ccc(C(=O)N[C@H](C)c2ccccc2)cc1

Procedure:
(R)-N-α-Methylbenzyl-4-vinylbenzamide was prepared as above in Example 1 except 2.5 g (0.017 mole) of 4-vinylbenzoic acid and 2.13 g (0.018 mole) of (R)-α-methylbenzylamine (Aldrich) were used rather than the 2.0 g of 4-allyloxybenzoic acid and 2 g of (S)-1-(1-naphthyl)ethylamine in Example 1. The product was recrystallized from absolute ethanol to give 1.85 g (44%) of white crystals; mp 162°-163° C.; [α]D25 -25.49° (c=0.404, CHCl3); IR (KBr): 3390 and 1640 cm-1 ; NMR (δ): 1.64 (3H, d, J=7.4 Hz); 5.32 (1H, q, J=7.4 Hz); 5.44-5.94 (2H, m); 6.48-6.92 (2H, m), 7.24-7.82 (9H, m). Anal. for C17H17NO: Calcd: C, 81.27; H, 6.77. Found: C, 81.24; H, 6.79.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].[NH3:15].CO>>[NH2:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cc(CBr)cc(C(F)(F)F)c1
Reactant: N
Solvent: CO
Product: N#Cc1cc(CN)cc(C(F)(F)F)c1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
3-Bromomethyl-5-trifluoromethyl-benzonitrile (which is prepared in Reference Example 12) (15.9 g) is dissolved in 7M-ammonia/methanol (550 ml), and the mixture is stirred at 50-60° C. for 30 minutes. The reaction solution is concentrated under reduced pressure. To the resulting residue are added a saturated aqueous sodium bicarbonate solution and chloroform, and the mixture is separated, and the organic layer is dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1→chloroform:methanol:ammonium hydroxide solution=19:1:0.1) to give 3-aminomethyl-5-trifluorometyl-benzonitrile (10.4 g). MS (m/z): 201 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][CH2:25][CH2:26][N:27](C)[C:28](=O)OC(C)(C)C)[CH2:19]4)[C:14]([F:36])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.O1CCOCC1>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][CH2:25][CH2:26][NH:27][CH3:28])[CH2:19]4)[C:14]([F:36])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(CCN[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CNCCN[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a flask containing tert-butyl 2-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexylamino)ethyl(methyl)carbamate, 47b, (0.02 g, 0.04 mmol) in dichloromethane/MeOH mixture was added HCl in Dioxane (3.86 mL of 4 M solution, 15.44 mmol). The solution was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure and used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>>[CH:22]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:10]1)([CH3:24])[CH3:23]
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C(C)C)c3c(C)cccc23)cc1
Yield: 40.7 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.115 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.057 g) as a white solid.
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[C:5]1[CH:6]=[CH:7][C:8](/[C:13](/[C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:14]/[C@@H:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[C:18](=[O:31])[CH2:17][CH2:16]2)=[N:9][C:10]=1[O:11][CH3:12].O>CN(C)C=O>[C:38]([C:35]1[CH:36]=[CH:37][C:32](/[C:13](/[C:8]2[CH:7]=[CH:6][C:5]([S:2][CH3:1])=[C:10]([O:11][CH3:12])[N:9]=2)=[CH:14]\[C@@H:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[C:18](=[O:31])[CH2:17][CH2:16]2)=[CH:33][CH:34]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(Br)c(OC)n2)c(OC)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(SC)c(OC)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34 %

Procedure:
Sodium thiomethoxide (44 mg) was added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-42(1) (150 mg) in N,N-dimethylformamide (1.5 mL), and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:10) to give (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[6-methoxy-5-(methylsulfanyl)pyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (53 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:18][NH:19][O:20][CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:19]([O:20][CH3:21])[CH3:18])=[O:9]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
A mixture of 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid (2.0 g, 7.8 mmol, Step-1), N,O-dimethylhydroxylamine hydrochloride (0.916 g, 9.39 mmol), HBTU (3.56 g, 9.39 mmol) and triethylamine (5.45 mL, 39.1 mmol) in dichloromethane (39 mL) is stirred at room temperature for 3 hours. The reaction mixture is poured into water (100 mL) and extracted with dichloromethane (200 mL). The organic layer is washed with water (100 mL) and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (4:1) to give 2.2 g (94% yield) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[C:34]=1[N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>O.ClCCl>[Cl:32][C:33]1[C:34]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[C:35]([CH2:39][N:40]2[CH2:45][CH2:44][N:43]([C:12]([O:8][CH:3]([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1])=[O:14])[CH2:42][CH2:41]2)[CH:36]=[CH:37][CH:38]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Clc1cccc(CN2CCNCC2)c1N1CCOCC1
Reactant: OC(C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2cccc(Cl)c2N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A 50 mL round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan-2-ol (168 mg, 1.00 mmol, 1.02 equiv), triphosgene (99.0 mg, 0.330 mmol, 0.33 equiv), dichloromethane (10 mL). N,N-Diisopropylethylamine (471 mg, 3.64 mmol, 3.72 equiv) was added dropwise. The mixture was stirred at room temperature for 2 hours. 4-[2-Chloro-6-(piperazin-1-ylmethyl)phenyl]morpholine (290 mg, 0.980 mmol, 1.00 equiv) was added dropwise. The resulting solution was stirred for 2 hours at room temperature and diluted with water (20 mL). The resulting solution was extracted with dichloromethane (3×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1). The crude product (313 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 134 mg (27% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[3-chloro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.27 (d, J=3.0 Hz, 2H), 7.06-7.11 (m, 1H), 5.71-5.84 (m, 1H), 3.87-3.90 (m, 2H), 3.53-3.78 (m, 10H), 2.78 (d, J=10.8 Hz, 2H), 2.48-2.49 (m, 4H). LCMS (ESI, m/z): 490 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([CH:23]1[CH2:25][CH2:24]1)[C:20]([NH2:22])=[O:21].CO>CCCCCCC>[C:20]([CH:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH:23]1[CH2:25][CH2:24]1)(=[O:21])[NH2:22]
Reactant: NC(=O)C(N)C1CC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Solvent: CCCCCCC
Solvent: CO
Product: NC(=O)C(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-amino-cyclopropaneacetamide (CAN 1100749-41-4) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/20% 2-propanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 330.1806 (M+H)+; αD20 (MeOH)=−40.1°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:22]=[CH:21][C:10]3[C@:11]4([CH3:20])[C@@H:16]([CH2:17][CH2:18][C:9]=3[CH:8]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]4)[S:5][CH:6]=1.[C:23](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:23][N:15]1[C@H:16]2[C@@:11]([CH3:20])([C:10]3[CH:21]=[CH:22][C:7]([C:4]4[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=4)=[CH:8][C:9]=3[CH2:18][CH2:17]2)[CH2:12][CH2:13][C:14]1=[O:19]
Reactant: CC(C)(C)O
Reactant: Cc1csc(-c2ccc3c(c2)CC[C@H]2NC(=O)CC[C@]32C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: Cc1csc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-methylthiophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (20 mg, 0.06 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (20 mg, 0.18 mmol). Methyl iodide (0.011 mL, 0.18 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 15 mg (72%) of the title compound as a white solid. mp 115°-117°. FDMS: m/e=351.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=O.Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4](=[N:20][OH:21])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1
Reactant: O=C(c1cccc(F)c1)c1ccc(O)c(Cl)c1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1cccc(F)c1)c1ccc(O)c(Cl)c1Cl

Procedure:
To a solution of 5 g of 2,3-dichloro-4-hydroxy-3'-fluorobenzophenone in 50 ml of pyridine, 1.58 g of hydroxylamine hydrochloride is added. The mixture is refluxed for 18 hours. The pyridine is evaporated in vacuo and the residue is partitioned between 5% HCl and ethylacetate. The ethylacetate is washed with water, dried over Na2SO4 and evaporated to give 2,3-dichloro-4-hydroxy-3'-fluorobenzophenone oxime as a mixture of isomers, mp 178°-185° C.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=1[OH:15].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:13]([C:11]1[CH:10]=[CH:9][C:8]2[O:15][CH2:2][C:3](=[O:4])[NH:6][C:7]=2[CH:12]=1)#[N:14]
Reactant: O=C(Cl)CCl
Reactant: N#Cc1ccc(O)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(c1)NC(=O)CO2
Temperature: 0 °C
Yield: 60.5 %

Procedure:
Chloroacetyl chloride (3.12 ml, 38 mmol) was added dropwise to a solution of 2-amino-4-cyanophenol (4.96 g, 37 mmol), triethylamine (10.98 ml, 78 mmol) and 4-(dimethylamino)pyridine (0.09 g, 0.74 mmol) in dry dichloromethane (40 ml) maintained at 0° C. The solution refluxed for 24 h. The reaction mixture was cooled, and the organic layer was washed with phosphoric acid (0.5 M), saturated sodium bicarbonate, water and brine, then dried with anhydrous magnesium sulfate. The organic layer was filtered, then evaporated to dryness. The residue was recrystalized from ethanol to afford 3.9 g (60%) of the titled compound. (mp 243–245° C.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:10]1[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=1)[CH3:9]>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13](=[O:16])[N:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=1)[CH3:9]
Reactant: CCc1ccc(=O)[nH]c1
Reactant: Ic1ccccc1
Product: CCc1ccc(=O)n(-c2ccccc2)c1
Yield: 84 %

Procedure:
Iodobenzene when caused to react with 5-ethyl-2-(1H)-pyridone following the general procedure outlined in Example 1, an 84% yield of 5-ethyl-1-phenyl-2-(1H)-pyridone is obtained.