Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][OH:11].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: OCc1cc(F)c(F)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=Cc1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To (2-chloro-4,5-difluoro-phenyl)-methanol (120, 2.40 g, 0.0134 mol) in dichloromethane (40.0 mL) was added Dess-Martin periodinane (6.84 g, 0.0161 mol). The reaction was stirred at room temperature for 10 minutes. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a white solid (110, 1.7 g, 71.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([O:36][CH3:37])=[CH:31][CH:30]=2>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:28]3[C:29]4[C:34](=[CH:33][C:32]([O:36][CH3:37])=[CH:31][CH:30]=4)[CH:35]=[C:27]3[CH3:26])=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: COc1ccc2[nH]c(C)cc2c1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Product: COc1ccc2c(c1)cc(C)n2Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1
Yield: 72 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro) benzenesulfonamide (Intermediate 8), and 2-methyl-5-methoxyindole, the title compound was isolated as a yellow solid in 72% yield (98% purity by HPLC).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[CH:12]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:13][CH2:14][CH3:15]
Reactant: C1CCNC1
Reactant: CCCC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC=CN1CCCC1
Temperature: 0 °C

Procedure:
To a dry 500 milliliter (mL) three neck round bottom flask equipped with magnetic stirrer, nitrogen inlet, addition funnel, and thermometer, was charged with pyrrolidine (83.45 mL, 1.0 mmol) and potassium carbonate (34.55 g, 0.25 mol). The mixture was cooled to 0° C. and butanal (30.05 grams (g), 0.42 mol) was added dropwise with stirring under nitrogen at ad rate that maintained the temperature below 15° C. After the addition was complete (˜10 minutes), the cooling bath was taken away and the reaction mixture allowed to warm to room temperature over three hours. The reaction mixture was filtered through a scintered glass filter to remove the solids. The solid was washed thoroughly with ether, and combined with the filtrate, which was concentrated on the rotary evaporator to give the crude 1-but-1-enylpyrrolidine which was purified by vacuum distillation @15 mmHg 65-78° C.; 1H NMR (CDCl3): δ 6.20 (d, 1H), 4.18 (q, 1H), 2.95 (m, 4H), 1.80, (m, 4H), 0.97 (d, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[CH:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[CH:19]=[C:20]=[CH2:21]>>[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:6][CH:5]([CH:7]([CH3:9])[CH3:8])[C:4]([O:3][CH3:2])=[O:10])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[CH:19]=[C:20]=[CH2:21]
Reactant: C=C=CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(N)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: C=C=CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 87.6 %

Procedure:
To a solution of DL-valine methyl ester hydrochloride (527 mg, 3.15 mmol) was added triethylamine (579 mg, 5.72 mmol) followed by product from Example 5 (700 mg, 2.86 mmol) and the resulting mixture was stirred for 10 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave 850 mg (87%) of the product as a solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([O:14]CC1C=CC(OC)=CC=1)[CH:12]=[CH2:13])(=[O:7])=[O:6].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([OH:14])[CH:12]=[CH2:13])(=[O:7])=[O:6]
Reactant: C=C[C@H](OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: C=C[C@H](O)C(C)(C)COS(=O)(=O)CCCCl
Yield: 90.9 %

Procedure:
Following the general procedure for the oxidative cleavage of (4-methoxy)benzyl ethers of Description 19, (3S)-3-[(4-methoxyphenyl)methoxy]-2,2-dimethylpent-4-enyl (3-chloropropyl)sulfonate (13a) (0.50 g, 1.3 mmol), dissolved in a mixture of dichloromethane (DCM) and water (10:1) (10 mL) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.35 g, 1.5 mmol). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) to provide 0.32 g (91% yield) of the title compound (16a) as a colorless oil. Rf=0.48 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=0.95 (s, 3H), 1.00 (s, 3H), 1.75 (d, J=3.6 Hz, 1H), 2.32-2.39 (m, 2H), 3.31-3.35 (m, 2H), 3.70-3.73 (m, 2H), 3.97 (d, J=9.2 Hz, 1H), 4.02-4.04 (m, 1H), 4.26 (d, J=9.2 Hz, 1H), 5.25-5.33 (m, 2H), 5.87-5.96 (m, 1H) ppm. MS (ESI) m/z: 271.08 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([O:27][C:28]1[C:33]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][OH:45])=[CH:37][C:36]=2[O:46][CH3:47])=[C:32]([CH3:48])[N:31]=[C:30]([NH2:49])[N:29]=1)(=[O:26])=[O:25]>C1COCC1.O>[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([O:27][C:28]1[C:33]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][O:45][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:37][C:36]=2[O:46][CH3:47])=[C:32]([CH3:48])[N:31]=[C:30]([NH2:49])[N:29]=1)(=[O:25])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(OCCCO)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCCCOS(C)(=O)=O)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (0.293 mL) was added to a solution of diisopropylethylamine (0.988 mL) and the product from step (vii) (0.95 g) in THF (9.5 mL). The mixture was stirred at RT for 2 h, diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated under reduced pressure to afford the crude product as a pale yellow oil, which was used for next reaction without further purification; 1H NMR (300 MHz, CDCl3); 6.93 (2H, s), 6.73 (1H, d), 6.39 (1H, d), 6.31 (1H, dd), 4.76 (2H, br s), 4.43 (2H, t), 4.03 (2H, t), 3.77 (3H, s), 3.73 (2H, s), 2.98 (3H, s), 2.57 (6H, s), 2.29 (3H, s), 2.25 (3H, s), 2.24-2.16 (2H, m); LC-MS: m/z 580.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=O)(C)(C)C.[ClH:14]>CO>[CH:6]1([N:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)[CH2:12][CH2:11][CH2:10][CH2:9]1.[ClH:14]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: Cl
Solvent: CO
Product: O[C@@H]1CCN(C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(Tert-butoxycarbonyl)-(R)-3-pyrrolidinol (5 g; 26.70 mmol) was diluted in 15 ml of methanol and 5 ml of HCl 37% were added. The reaction mixture was stirred at room temperature overnight, then it was concentrated in vacuo. 2.1 g (17.07 mmol; 63%) of the desired product were obtained as hydrochloride.
Reaction SMILES: [Na].C1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9](CC)=[N:8]2)CCCC1.[CH2:18](OC1C=CC=CC=1C(OCC)=O)C=C.O>C(O)C.CCOCC>[N:7]1[C:11]2=[N:12][CH:18]=[N:15][C:13](=[O:14])[C:10]2=[CH:9][N:8]=1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: C=CCOc1ccccc1C(=O)OCC
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: O=C1N=CN=C2N=NC=C12

Procedure:
Sodium spheres (207 mg) was dissolved in ethanol (15 ml) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1 g, 45 mmol) was added, followed by ethyl 2-(2-propenyloxy)benzoate (1.85 g, 9 mmol). The reaction mixture was refluxed overnight, cooled, the ethanol was stripped and water was added. The pH was adjusted to about 7 and a solid was isolated by filtration. The solid was taken up in ether, washed with dilute HCl, dried over MgSO4, filtered and the solvent was removed and the solid residue was recrystallized from ether to afford 0.56 g of 1-cyclopentyl-3-ethyl-6-[2-(CH2 =CH--CH2O)phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 119-120° C.
Reaction SMILES: [OH:1][C:2]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:5].[CH3:26]O>Cl>[OH:1][C:2]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:26])=[O:15])=[O:5]
Reactant: CO
Reactant: COc1cc(C)c(C(=O)CCCCCCCCC(=O)O)c(O)c1OC
Agent: Cl
Product: COC(=O)CCCCCCCCC(=O)c1c(C)cc(OC)c(OC)c1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
9-(2'-Hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1 wherein R=H3CO, X=H, Y=OH, n=8, in the free form) (0.197 part) was dissolved in methanol saturated with hydrogen chloride gas (7 volume parts) and the solution was stirred at room temperature for 20 minutes. The methanol was distilled off under reduced pressure and the residue was recrystallized from hexane-diethyl ether. The procedure provided methyl 9-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoate (formula II-1 wherein R=H3CO, X=H, Y=OH, n=8, in the form of methyl ester) (0.195 part) as colorless needles melting at 49°-53° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>C(O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(N)cc1
Reactant: FC(F)(F)c1ccc2c(Cl)ncnc2c1
Solvent: CCO
Product: COc1ccc(Nc2ncnc3cc(C(F)(F)F)ccc23)cc1
Yield: 79.2 %

Procedure:
5 ml of ethanol were added to a mixture of 2.3 g of 4-chloro-7-trifluoromethylquinazoline and 1.4 g of p-anisidine. The resulting mixture was heated to dissolve the solids, whereupon the solution solidified immediately. After cooling, the resulting crystals were collected by filtration and washed with, in turn, ethanol, dilute aqueous sodium hydroxide and water. The resulting crystals were recrystallized from ethanol, to give 2.5 g (yield 78%) of the desired Compound No. 51 in the form of colourless needles melting at 190°-194° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]([O:16][CH2:17][CH3:18])=[CH2:15])CCC>CC#N.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([O:16][C:14]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[CH2:15])[CH3:18]
Reactant: Fc1ccc(Br)nc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=C(OCC)c1ccc(F)cn1
Temperature: 80 °C
Yield: 119.6 %

Procedure:
A mixture of 2-bromo-5-fluoropyridine (200 mg, 1 mmol), tributyl(1-ethoxyvinyl)tin (500 mg, 1 mmol), copper(I) iodide (20 mg, 0.1 mmol) and bis(triphenylphosphine)palladium(II) chloride (50 mg, 0.07 mmol) in MeCN (5 mL) was heated to 80° C. for 30 h. The reaction mixture was allowed to cool to room temperature and was diluted with EtOAc, washed with 5% NH4OH, brine, dried over MgSO4, filtered and concentrated to give a crude oil. The product was purified by flash column chromatography on silica gel eluting with a hexane; EtOAc gradient (0-30%) to give 2-(1-ethoxyvinyl)-5-fluoropyridine as a clear oil (0.2 g, 90%). LCMS calc. for C9H11FNO (M+H)+: m/z=168.1. found: 168.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]([CH3:21])[C:12]1[C:13]2[CH:20]=[CH:19][NH:18][C:14]=2[N:15]=[CH:16][CH:17]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[NH:18][CH:19]=[CH:20][C:13]=12
Reactant: CN(c1ccc([N+](=O)[O-])cc1F)c1ccnc2[nH]ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(c1ccc(N)cc1F)c1ccnc2[nH]ccc12

Procedure:
9 mg of 10% palladium-on-carbon are added to a solution of 28 mg (0.08 mmol) of N-(2-fluoro-4-nitrophenyl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine in 10 ml of ethanol, and the suspension is stirred in a hydrogen atmosphere at atmospheric pressure overnight. The suspension is filtered through kieselguhr and the kieselguhr is washed with ethanol. Concentration under reduced pressure gives the target product.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:16][C:6]2[N:7]([CH3:15])[C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH3:23][N:24]=[C:25]=[O:26]>O1CCCC1>[CH3:23][NH:24][C:25](=[O:26])[O:14][C:11]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:15])[C:6]3[CH2:16][CH:3]([CH2:2][OH:1])[CH2:4][C:5]=3[C:13]=2[CH:12]=1
Reactant: Cn1c2c(c3cc(O)ccc31)CC(CO)C2
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)CC(CO)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-2-hydroxymethyl-4-methylcyclopent[b]indol-7-ol (1.7 g, 0.008 mole) in 50 ml of tetrahydrofuran was added milled K2CO3 (2.0 g, 0.015 mole), followed by a solution of methylisocyanate (0.5 ml, 0.008 mole) in 5 ml of tetrahydrofuran. After stirring at ambient temperature for two hours, the mixture was filtered and the filtrate concentrated to a yellow solid. This material was eluted on a silica gel column with ethyl acetate/dichloromethane (1:2) via HPLC. The desired fractions were combined and concentrated to a white solid, 2.1 g, m.p. 134°-8° C. This material was recrystallized from methanol/ether (1:10) to give the product as a white solid, 1.5 g, m.p. 137°-8° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:15]([O:17][C:18](=[O:23])[CH2:19][CH2:20][CH2:21]Br)[CH3:16].Cl>>[CH2:15]([O:17][C:18](=[O:23])[CH2:19][CH2:20][CH2:21][N:11]1[CH2:12][CH2:13][C:14]2=[C:2]([CH3:1])[C:3]3[C:8]([CH:9]2[CH2:10]1)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH3:16]
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: CCOC(=O)CCCBr
Agent: Cl
Product: CCOC(=O)CCCN1CCC2=C(C)c3ccccc3C2C1

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]-pyridine and 4-bromobutyric acid ethyl ester are reacted in accordance with the process described in Example 1. The hydrochloride of the title compound has a M.P. of 186°-188° from ethanol/acetone.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH2:10][CH:9]2[C:12]([O:14]C)=[O:13])[CH2:4][CH2:3]1.O.[OH-].[Li+:19]>>[F:16][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([N:8]2[CH2:11][CH2:10][CH:9]2[C:12]([O-:14])=[O:13])[CH2:6][CH2:7]1.[Li+:19]
Reactant: COC(=O)C1CCN1C1CCC(F)(F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C1CCN1C1CCC(F)(F)CC1

Procedure:
The reaction of methyl 1-(4,4-difluorocyclohexyl)azetidine-2-carboxylate 19B and lithium hydroxide monohydrate yielded lithium 1-(4,4-difluorocyclohexyl)azetidine-2-carboxylate as a light yellow solid (quant). MS ISP (m/e): 220.2 (100) [(M+H)]+, 200.2 (100) [(M−HF+H)]+.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:1]1(=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1
Reactant: O=C1CCCCC1
Product: c1ccc(N=C2CCCCC2)cc1

Procedure:
The dehydrated crude aniline via line 108 can be introduced to and reacted in the reactor 110 to produce a cyclohexanone-reduced product via line 112 that contains less cyclohexanone as compared to the dehydrated crude aniline in line 108. The reactor 110 can be a homogenous reactor where a portion of the cyclohexanone can react within the reactor 110 to produce an imine compound, e.g., cyclohexylidene aniline, as shown in Reaction 2. For example, the cyclohexanone can react with an amine, R—NH2 in the presence of a catalyst, e.g., sulfuric acid, to reduce the cyclohexanone concentration in the dehydrated crude aniline. For example, the concentration of the cyclohexanone in the dehydrated crude aniline can be reduced in an amount from a low of about 10%, and 20%, about 30%, or about 40% to a high of about 50%, about 60%, about 70%, about 80%, or about 90%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:15]([C:23]([OH:25])=O)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[C:28]1([CH2:38][CH2:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.Cl.CNC(NC)CCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:23]([N:45]2[CH2:44][CH2:43][N:42]([CH2:41][CH2:40][CH2:39][CH2:38][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:47][CH2:46]2)=[O:25])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: c1ccc2c(CCCCN3CCNCC3)cccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(C(=O)O)c2ccc(F)cc2)CC1
Agent: CCN=C=NCCC(NC)NC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(O)(C(C(=O)N2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
2.37 g of 1-t-Butoxycarbonyl-4-[carboxy-(4-fluorophenyl)methyl]-4-hydroxypiperidine obtained in Example 11(1) was dissolved in 20 ml of dimethylformamide, and 2.50 g of 1-(4-naphthalen-1-yl-butyl)piperazine dihydrochloride, 1.9 g of 1-(3,3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.9 g of 1-hydroxybenzotriazole monohydrate and 3.5 ml of triethylamine were added, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=3:1) to give 1.96 g of 1-t-butoxycarbonyl-4-{1-(4-fluorophenyl)-2-[4-(naphthalen-1-yl-butyl)piperazin-1-yl]-2-oxoethyl}-4-hydroxypiperidine as an oil.
Reaction SMILES: [CH2:1]([CH:3]1[O:7]C=[N:5][CH:4]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].C(N(CC)CC)C.Cl>O>[NH2:5][CH:4]([CH:3]([OH:7])[CH2:1][CH3:2])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1N=COC1CC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(N)C(O)CC
Yield: 96.9 %

Procedure:
Ethyl 5-ethyl-2-oxazoline-4-carboxylate (10.3 g), water (1.62 ml) and triethylamine (0.086 ml) were stirred at 100° C. for 3 hours. To this mixture was added 5N HCl (26 ml) and the mixture diluted to 100 ml with water, washed twice with methylene chloride and brought to pH 10 with 50% sodium hydroxide solution. The solution was extracted with methylene chloride (6 × 30 ml), dried and evaporated to yield the racemic title compound (e11) (9.4 g).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[N:9]2)C.[OH-].[Li+]>CO>[N:12]1[C:13]2[C:8](=[CH:7][C:6]([CH2:5][C:4]([OH:16])=[O:3])=[CH:15][CH:14]=2)[N:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cc1ccc2nccnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.3 %

Procedure:
To a solution of quinoxalin-6-yl-acetic acid ethyl ester (95 mg, 0.44 mmol) in methanol (2 mL) was added 4 M aqueous lithium hydroxide (0.55 mL, 2.2 mmol). The reaction mixture was stirred at room temperature for 17 h then it was concentrated in vacuo, diluted with water and extracted with diethyl ether (3×). The aqueous layer was treated with 1 N aqueous hydrochloric acid until pH 2 and extracted with ethyl acetate (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 64 mg of product as a beige solid. 1H NMR 500 MHz (DMSO) δ 3.90 (s, 2H), 7.78 (dd, 1H), 7.99 (d, 1H), 8.06 (d, 1H), 8.93 (dd, 2H); MS (m/z) 189 [M+H+]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].S(Cl)([Cl:15])=O>CN(C)C=O.C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([Cl:15])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1ccc(C(=O)O)nc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1ccc(C(=O)Cl)nc1Cl
Yield: 151.6 %

Procedure:
A mixture of 6-chloro-5-methoxypicolinic acid (1.5 g, 8.0 mmol), thionyl chloride (5 g, 8.0×5.25 mmol), a catalytic amount (35 mg) of N,N-dimethylformamide and 5 ml of benzene was refluxed for 1 hour. Then, thionyl chloride and benzene were distilled off, and the residue was distributed with water and dichloromethane. A dichloromethane layer was separated and dried with sodium sulfate. The solvent was then distilled off to obtain 1.64 g of 6-chloro-5-methoxypicolinic acid chloride. It was dissolved again in 5 ml of dichloromethane and the resultant solution was added dropwise to a solution of phenol (0.79 g, 8×1.05 mmol) and triethyl amine (0.89 g, 8×1.1 mmol) in 30 ml of dichloromethane under cooling with ice. After conclusion of the addition, the reaction solution was stirred at room temperature for 2 hours, followed by adding water to separate an organic layer. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried with sodium sulfate. The organic solvent was distilled off to obtain a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[F:20][CH:21]([F:24])[CH2:22][NH2:23].CO>C1COCC1>[F:20][CH:21]([F:24])[CH2:22][NH:23][CH2:15][C:13]1[N:14]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=2)=[O:8])[S:11][CH:12]=1
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Reactant: NCC(F)F
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCc1cccc(F)c1)Nc1nc(CNCC(F)F)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Iodomethyl-thiazol-2-yl)-3-(3-fluorobenzyl)-urea (Intermediate 7, 1 eq.) was taken up in THF (0.3 M) and 2,2-difluoroethanamine (20 eq.) was added. The reaction was stirred overnight at ambient temperature. Some of the starting material, Intermediate 7 remained. Added additional 2,2-difluoroethanamine (10 equivalents). The reaction was complete after 2-4 hours. Removed solvent; coevaporated twice with MeOH. Crude is a 1:1 mixture of title compound and bis addition impurity. (used as is in subsequent step).