Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCCc1cccc(OCc2c(C)cccc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(CCCC(=O)O)c1
Reaction time: 3 h

Procedure:
A solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)butanoate (Step B, 3.26 g, 10 mmol) in abs ethanol (60 ml) was treated with 1N NaOH (20 ml) at room temperature. The reaction mixture was stirred for 3 hours, or until all the starting material is gone, concentrated and diluted with chloroform and acidified by 1M HCl to bring the pH to 3.5-4. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([OH:25])=O)[C:14]3=[O:29])[CH:10]=[N:9]2)=[C:5]([CH3:30])[O:4][N:3]=1.[CH2:31]([N:33](CC)CC)C.C(Cl)CCl>C(#N)C.Cl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH:33][CH3:31])=[O:25])[C:14]3=[O:29])[CH:10]=[N:9]2)=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C(=O)O)c3)C2=O)cn1
Agent: Cl
Solvent: CC#N
Solvent: ClCCCl
Product: CNC(=O)c1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 24.7 %

Procedure:
3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzoic acid (100 mg, 0.24 mmol) (example 10-8), methylamaine hydrochloride (67 mg, 1 mmol), triethylamine (155 mg, 1.5 mmol), and EDC (57 mg, 0.3 mmol) in acetonitrile (3 mL) were irradiated in the microwave reactor at 80° C. for 10 minutes. The reaction was cooled, diluted with aqueous 1N HCl (100 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in MeOH (3 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 25 minute gradient) to afford 3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)-N-methylbenzamide (25 mg, 25%) as white solid. MS M+H calculated 423.17; found 423.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:23])[N:16]([CH3:22])[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>C(O)(=O)C.[Pd]>[CH3:20][N:18]1[CH:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15](=[O:23])[N:16]([CH3:22])[C:17]1=[O:21]
Reactant: Cn1cc(N2CCN(Cc3ccccc3)CC2)c(=O)n(C)c1=O
Agent: [Pd]
Solvent: O=CO
Solvent: CC(=O)O
Product: Cn1cc(N2CCNCC2)c(=O)n(C)c1=O
Temperature: 100 °C
Yield: 56.7 %

Procedure:
2.6 g (8.26 mmol) of compound 13a are placed in the presence of 1.3 g of palladium and of 130 mL of formic acid in 300 mL of acetic acid at room temperature for 4 h. The mixture is heated to 100° C.° for 2 h 30 min. After neutralization with a 10% soda solution, the reaction medium is extracted with CHCl3. The organic phase is washed with water and then with a saturated NaCl solution. After drying on MgSO4, the organic phase is concentrated. The obtained residue is purified by flash chromatography (CH2Cl2-MeOH—NH4OH, gradient 90-10-0 to 90-9-1 over 30 min). 1.05 g of intermediate 13b is obtained as a beige solid (yield: 56%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1>[Pd].O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(N2CCCC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N2CCCC2)ncc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
A mixture of 4-methyl-5-nitro-2-pyrrolidin-1-ylpyridine (2.08 g, 10.0 mmol) and 10% palladium on carbon (208 mg) in tetrahydrofuran (10 mL) was stirred under hydrogen atmosphere at room temperature for 16 hr. Catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound (1.76 g, 9.89 mmol, 99%) as a purple solid.
Reaction SMILES: [CH3:1][C:2](C)=[CH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:27])[C:14]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:8][CH2:7]1.Cl.Cl.N[CH:32]1[CH2:37]CN(CC2CCCCCC2)C[CH2:33]1>>[CH:4]1([CH2:5][N:6]2[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:27])[C:14]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)([OH:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:8][CH2:7]2)[CH2:37][CH2:32][CH2:33][CH2:1][CH2:2][CH2:3]1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2ccccn2)C2CCCC2)CC1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1ccccn1)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Sept 4 of Example 22 using 2-cyclopentyl-2-hydroxy-2-(2-pyridyl)acetic acid obtained in Example 52 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.[ClH:54].C(N=C=NCCCN(C)C)C>ClCCl>[ClH:54].[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[O:9])[CH2:24][CH2:25]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccccn3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
0.28 g of picolic acid (2.32 mmol) and 0.8 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.32 mmol) were dissolved in 30 ml of dichloromethane. After addition of 1.19 g of diisopropylethylamine (9.26 mmol), 0.155 g of hydroxybenzotriazole (HOBt, 1.15 mmol), and 0.487 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 2.54 mmol) at 0° C., the reaction mixture was stirred for 16 h at room temperature. 0.24 g of N-Ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added and the reaction mixture was stirred for 5 h. 100 ml of dichloromethane were added. The organic layer was washed twice with water. The dichlormethane phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate as eluent. The residue was re-dissolved in 15 ml of diethylether and treated with 1 N hydrochloric acid in diethyl ether. The precipitate was collected by filtration to yield 0.95 g of the title compound as a hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=2)[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c[nH]nc1Nc1nc(Cl)ncc1Cl

Procedure:
The mixture ethyl 3-amino-1H-pyrazole-4-carboxylate (80 mg, 0.50 mmol), 2,4,5-trichloropyrimidine (57 μL, 0.5 mmol), and sodium carbonate (53 mg, 0.5 mmol) in 3 mL of EtOH is heated at 40° C. over night. The precipitate is filtered, washed by cold EtOH, and dried in vacuo to afford ethyl 3-(2,5-dichloropyrimidin-4-ylamino)-1H-pyrazole-4-carboxylate; ESMS m/z 302.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)[C:4]=2[O:3]1.[OH:17][C:18]1([C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:21]3[CH2:22][CH2:23][C:18]([OH:17])([C:24]4[CH:25]=[N:26][C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:19][CH2:20]3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(OCCCCl)c2O1
Reactant: OC1(c2cnc3ccccc3c2)CCNCC1
Product: CC1(C)Cc2cccc(OCCCN3CCC(O)(c4cnc5ccccc5c4)CC3)c2O1
Yield: 46.6 %

Procedure:
Beginning with 0.316 gm (1.3 mMol) 3-chloropropyl 2,2-dimethyl-2,3-dihydrobenzofur-7-yl ether and 0.300 gm (1.3 mMol) 4-hydroxy-4-(quinolin-3-yl)piperidine, 0.262 gm (46%) of the title compound were recovered as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13](=O)[CH2:14][CH2:15][CH:16]=[CH2:17].[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:17][CH2:16][CH2:15][CH:14]=[CH2:13])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCCC=O
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCCCNCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
0.44 ml of 4-tert-butylbenzylamine (2.5 mmol) and 0.414 ml of pent-4-enal (3.75 mmol) were dissolved in 7.5 ml methanol at rt and then refluxed for 1.5 h. After cooling down to rt, 114 mg (3 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was then refluxed for 2¼ h. After cooling down to rt again 114 mg of sodium borohydride were added and the mixture was again refluxed for additional 1¼ h. After cooling down to rt, the reaction mixture was treated with 5 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:1) to give 172 mg light yellow oil (29%). MS (ISP) 232.3 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7]1.[NH:16]1[CH2:21][CH:20]=[C:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1>>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:19]2[CH2:20][CH2:21][N:16]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:14](=[O:15])[N:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]4=[N:7]3)[CH2:17][CH:18]=2)=[CH:23]1
Reactant: O=c1n(CCCCCl)nc2ccccn12
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Product: O=c1n(CCCCN2CC=C(c3c[nH]c4ccccc34)CC2)nc2ccccn12

Procedure:
2-{4-[4-(1H-Indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one was prepared by reacting 2-(4-Chloro-butyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (225 mg, 1 mmol) and 3-(1,2,3,6-Tetrahydro-pyridin-4-yl)-1H-indole (198 mg, 1 mmol) by adopting the procedure as outlined in Experimental 24. Yield: 87 mg (22%) compound was isolated as pale yellow solid. Mp: 123.2° C.; M+388.1
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]#[CH:10])[N:6]=[N:5][C:4]2=[C:11]([C:14](=[S:16])[NH2:15])[N:12]=[CH:13][N:3]12.Br[CH2:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=O.C(N(CC)CC)C>CC#N>[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[C:19]1[N:15]=[C:14]([C:11]2[N:12]=[CH:13][N:3]3[C:2](=[O:1])[N:7]([CH2:8][C:9]#[CH:10])[N:6]=[N:5][C:4]=23)[S:16][CH:18]=1
Reactant: O=C(CBr)c1nccs1
Reactant: C#CCn1nnc2c(C(N)=S)ncn2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#CCn1nnc2c(-c3nc(-c4nccs4)cs3)ncn2c1=O
Yield: 38 %

Procedure:
4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide (0.43 mmol) and 2-bromo-1-(1,3-thiazol-2-yl)ethanone (0.43 mmol) were stirred in MeCN (2 mL) overnight at room temperature. The reaction mixture containing a newly formed precipitate was then treated with sufficient triethylamine to solubilise before evaporating to dryness and purifying by column chromatography, eluting with 10% MeCN/DCM, to give the title compound. Yield 38%. δH (DMSO-d6) 9.00 (1H, s) 8.44 (1H, s), 7.97 (1H, d, J=3.2), 7.85 (1H, d, J=2.8), 5.16 (2H, d, J=2.4), 3.55 (1H, t, J=2.4).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][C:14]=1[C@H:26]([OH:29])[CH2:27][OH:28].Cl.C(OCC)C>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][C:14]=1[C@H:26]([OH:29])[CH2:27][O:28][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CCc1ccc(Cl)c([C@H](O)CO)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)CCc1ccc(Cl)c([C@H](O)COS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
p-Toluenesulfonyl chloride (1.08 g, 5.69 mmol) in pyridine (15 mL) was added drop wise over 30 min to a cooled (0° C.) solution of ethyl 3-{4-chloro-3-[(1S)-1,2-dihydroxyethyl]phenyl}propanoate (1.41 g, 5.17 mmol) in pyridine (20 mL) under N2. The solution slowly warmed to rt overnight. After 16 h, 1N HCl and ethyl ether were added. The organic layer was isolated and the aqueous layer washed with ethyl ether (2×). The combined organic fractions were washed with 1N HCl, 10% aqueous Cu2SO4, brine, dried (Na2SO4), and concentrated. The crude product was purified by Biotage chromatography (0%-10% EtOAc/Hexanes) to afford 1.77 g of product as an oil (80%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.81 (d, J=8.08 Hz, 2 H) 7.43 (d, J=2.27 Hz, 1 H) 7.36 (d, J=8.34 Hz, 2 H) 7.22 (d, J=8.08 Hz, 1 H) 7.10 (dd, J=8.21, 1.89 Hz, 1 H) 5.34 (td, J=5.62, 2.91 Hz, 1 H) 4.28 (dd, J=10.61, 2.53 Hz, 1 H) 4.14 (q, J=7.24 Hz, 2 H) 3.98 (dd, J=10.61, 8.34 Hz, 1 H) 2.93 (t, J=7.71 Hz, 2 H) 2.60 (t, J=7.83 Hz, 2 H) 2.47 (s, 3 H) 1.25 (t, J=7.07 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:22]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]1=O)=[O:26])[CH3:23].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1>[C:7]([O:6][C:4]([C:3]1[CH:11]=[CH:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:14][C:2]=1[NH:1][CH:30]1[CH2:31][CH2:32][N:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:28][CH2:29]1)=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Reactant: CCOC(=O)N1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)N1CCC(Nc2cc(N3CCN(C)CC3)ccc2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
tert-Butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate (1.5 g, 5.15 mmol) was dissolved in dry dioxane (25 mL) under a nitrogen atmosphere. N-ethoxycarbonylpiperidone (1.06 g, 0.932 mL, 6.18 mmol, 1.2 eq) was added, followed by trifluoroacetic acid (1.03 mL, 13.39 mmol, 2.6 eq) and sodium triacetoxyborohydride (1.72 g, 7.73 mmol, 1.5 eq). The mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of NaHCO3 was then added, the mixture was concentrated under reduced pressure and extracted with dichloromethane (3×40 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. After purification by chromatography over silica gel (DCM/EtOH 93:7) 2.187 g of title compound were obtained as a white solid (95% yield).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[CH:10]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:13][OH:14].C([O-])([O-])=O.[Na+].[Na+]>CCO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[CH:10]=[N:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C[C@@H]1C[C@H]1c1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: ON=C[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
A solution of trans-2-phenylcyclopropanecarbaldehyde rac-I-6B (0.89 g, 6.1 mmol) in EtOH (12 mL) and cooled to 0°C. was treated with hydroxylamine hydrochloride (0.43 g, 6.1 mmol) and Na2CO3. The reaction mixture was allowed to warm to rt and stir fo(12 h. The volatiles were removed in vacuo and extracted with EtOAc. The organics were collected, dried over Na2SO4 filtered, and concentrated to afford trans-2-Phenylcyclopropanecarbaldehyde oxime which was used without further purification.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:6]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][C:8]([NH:15][C:16]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11].C(Cl)(Cl)Cl>CO>[CH3:3][O:4][C:5]1[C:6]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][C:8]([NH:15][C:16]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])=[C:9]([CH:14]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc(OC)c(-c2ccccc2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)O)c(NC(=O)c2cncc(-c3ccccc3)c2)cc1-c1ccccc1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (1.3 mL) was added to a methanol (2.2 mL) suspension of the obtained methyl 5-methoxy-4-phenyl-2-(5-phenylpyridine-3-carboxamido)-benzoate (0.11 g) at room temperature, followed by stirring at the same temperature for 30 minutes. Chloroform (3 mL) and methanol (2 mL) were added to the reaction mixture, followed by stirring at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and ethanol and water were added to the obtained residue. After adjusting the pH to 1 with 6 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 88 mg of 5-methoxy-4-phenyl-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18].Cl>ClCCl.C1(C)C=CC=CC=1>[C:17]([C:6]1[CH:5]=[CH:4][C:3]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:2]([CH3:1])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1NS(C)(=O)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2-methylphenyl)methanesulfonamide (1.84 g, 10 mmol) in dichloromethane (2 mL) was added aluminum chloride (3.3 g, 25 mmol) carefully at 0° C. Then acetyl chloride (1.07 ml, 15 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hours, the reaction was monitored by using TLC and 1H-NMR, and after completion of the reaction, the reaction mixture was diluted with toluene and poured into 2N HCl aqueous solution with stirring at 0° C. The precipitate solid was filtered, washed with H2O, and dried to give a mixture of the title compound and by-product (N-acetylated product) (2.31g, ratio; title compound: by-product=81:19 (ratio was determined by 1H-NMR)) as a flesh color powder.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=1)[CH2:10][CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[O:16][CH:11]([C:12]([F:13])([F:14])[F:15])[CH2:10][N:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])[CH:19]=3)[C:3]=2[CH:4]=1
Reactant: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cc(F)ccc1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)N(Cc1cccc(OC(F)(F)C(F)F)c1)CC(C(F)(F)F)O2
Temperature: 145 °C
Yield: 45.2 %

Procedure:
The 3-[(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (200 mg, 0.45 mmol) product from EX-661B was dissolved in anhydrous dimethylformamide (20 mL), and powdered K2CO3 (180 mg) was added. The mixture was stirred and heated to 145° C. for 15 h. The mixture was diluted with water (60 mL) and extracted into ether (2×40 mL), which was washed with brine and water. The ether solution was dried over anhydrous MgSO4, and the ether was removed in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:15) to give 86.9 mg (48%) of the desired 6-fluoro-3,4-dihydro-4-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2-(tri-fluoromethyl)-2H-1,4benzoxazine product as a yellow oil, 98% pure by HPLC analysis. 1H NMR (CDCl3) δ7.39 (t, 1H), 7.17 (m, 3H), 6.88 (m, 1H), 6.41 (m, 2H), 5.92 (tt, 1H), 4.54 (m, 1H), 4.45 (s, 2H), 3.44 (m, 2H). 19F NMR (CDCl3) δ−77.7 (d, 3F), −88.6 (m, 2F), −120.28 (m, 1F), −137.2 (dt, 2F). HRMS calcd. for C18H13F8NO2: 428.0899 [M+H]+, found: 428.0910.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[N:33]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][N:35]=[CH:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:41]5[CH2:40][CH2:39][CH:38]([N:33]6[CH:37]=[CH:36][N:35]=[CH:34]6)[CH2:43][CH2:42]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:30])[F:31])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: c1cn(C2CCNCC2)cn1
Product: O=C1N=C(N2CCC(n3ccnc3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-imidazol-1-yl-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-Imidazol-1-yl-piperidine following General Procedure B.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[OH-].[Na+].C1(C)C=CC=CC=1>[CH2:8]([O:15][C:16]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(NCCS(=O)(=O)O)OCc1ccccc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Taurine (1 g; 8 mmol) was dissolved in 2N NaOH (4.3 mL) and, after cooling on ice/water bath, 4N NaOH (2.14 mL) and a solution of benzyloxycarbonyl chloride (3.27 mL; 8 mmol) in toluene (3 mL) were dropped at same time. After the additions, the mixture was left stirring at T=0-5° C. for 1 h. The reaction was quenched by adding diethyl ether. The mixture was debated and the phases were separated. The aqueous one was cooled to 0-5° C. and 37% HCl was added to pH=2. The acidic phase was extracted with ethyl acetate (3×10 mL) and the collected organic extracts were washed with water (2×15 mL) and brine (15 mL), dried over Na2SO4 and evaporated under vacuum to give 2-(N-benzyloxycarbonylamino)ethanesulfonic acid as crude product purified by trituration in diethyl ether to give the pure product as white solid (1.46 g; 5.64 mmol Yield=70.5%)