Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][O:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:6]=2[CH:34]=1.O.NN>C(O)C>[NH2:17][O:16][CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][C:6]=3[C:7]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 70 °C

Procedure:
A stirred suspension of 8-chloro-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine (9.4 g., 0.02 mole) in absolute ethanol (100 ml.) was treated with hydrazine hydrate (1.45 ml.) and warmed, under nitrogen, at a bath temperature at 70° C. for 3 hours. The mixture was cooled in an ice bath and filtered. The solid was washed with ethanol and methylene chloride. The combined filtrate was concentrated in vacuo; the residue was mixed with water and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in chloroform-ethyl-acetate and filtered through a small pad of silica gel. The filtrate was crystallized from methanol-ethylacetate to give 1-[(aminooxy)methyl]-8-chloro-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in three crops: 1.95 g. of melting point 190°-191.5° C.; 0.89 g. of melting point 183°-186° C.; 0.285 g. of melting point 183°-186° C. The analytical sample had a melting point 191°-192° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23]COC)=[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.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][OH:23])=[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: COCOCCc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: OCCc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Yield: 24.2 %

Procedure:
To a solution of 1.0 g of 1-benzyl-4-[4-[2-(methoxymethoxy)ethyl]phenyl]piperidin-4-ol in 30 ml of toluene was added 2.0 g of p-toluenesulfonic acid. Then the resulting mixture was heated under reflux for 1 hour while eliminating the water thus formed with a Dean Stark trap. Then the reaction mixture was brought back to room temperature and a saturated aqueous solution of sodium bicarbonate was added thereto. Then it was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.2 g of the title compound as a brown oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[NH+:3]1[O-:13]>C(O)C.O=[Pt]=O>[OH:13][N:3]1[C:2]([CH3:14])([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1([CH3:12])[CH3:11]
Reactant: CC1(C)c2ccccc2C(C)(C)[NH+]1[O-]
Agent: O=[Pt]=O
Solvent: CCO
Product: CC1(C)c2ccccc2C(C)(C)N1O
Yield: 77.7 %

Procedure:
6.6 g (0.035 mol) of 1,1,3,3-tetramethyl-1,3-dihydroisoindole N-oxide are hydrogenated to saturation in 66 ml of ethanol over 0.12 g of PtO2 at atmospheric pressure. The catalyst is filtered off and the solvent is evaporated on a rotary evaporator, after which the crystalline residue is recrystallized from a little dichloromethane. This gives 5.2 g (78%) of N-hydroxy-1,1,3,3-tetramethyl-1,3-dihydroisoindole which is obtained in the form of colourless crystals; melting point: 128-130° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][CH:19]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4].[NH:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:35]1([CH2:2][C:3]([NH:5][CH:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([C:17](=[O:34])[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[CH:20][CH:19]=3)[CH2:9][CH2:8][CH2:7]2)=[O:4])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)CCl)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)Cn3ccnc3)c3ccccc32)cc1
Yield: 23.4 %

Procedure:
A mixed solution of 5-(2-chloroacetylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g), imidazole (0.1 g) and potassium carbonate (0.19 g) in acetonitrile (30 ml) is refluxed for 8 hours. The reaction solution is concentrated and the resulting residue is washed with water and separated by decantation. The remainder is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1→15:1), and recrystallized from ethanol/n-hexane to give 5-[2-(1-imidazolyl)acetylamino]-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.15 g) as colorless needles, m.p. 250°-252° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:16][C:17]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:29](=[O:31])[NH2:30])[CH:25]=2)[CH:20]1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:18])[CH2:8][C:9]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.Cl.CCOC(C)=O>CCOC(C)=O>[CH:32]1([CH:20]2[C:21]3[C:26](=[CH:25][C:24]([C:29]([NH2:30])=[O:31])=[CH:23][CH:22]=3)[CH2:27][CH2:28][N:19]2[C:17](=[O:18])[CH2:16][NH:7][CH2:8][C:9]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N(CC(=O)N1CCc2cc(C(N)=O)ccc2C1C1CCCCC1)CC1(O)CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc2c(c1)CCN(C(=O)CNCC1(O)CCCCC1)C2C1CCCCC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 40.1 %

Procedure:
Tert-butyl[2-(6-carbamoyl-1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl][(1-hydroxycyclohexyl)methyl]carbamate (357 mg) was dissolved in EtOAc (8 mL). 4 M HCl/EtOAc (0.85 mL) was added to the reaction liquid under ice-cooling, followed by stirring at 60° C. for 5 hours. The solvent was evaporated and water was added to the resulting residue, followed by washing with chloroform. Saturated aqueous sodium bicarbonate was added to the aqueous layer which was then adjusted to a pH of around 8, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate to obtain 1-cyclohexyl-2-{N-[(1-hydroxycyclohexyl)methyl]glycyl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (116 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](N)[CH:8]=2)[CH:3]=[N:2]1.F[B-](F)(F)F.[H+].N([O-])=[O:18].[Na+]>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:18])[CH:8]=2)[CH:3]=[N:2]1
Reactant: O=N[O-]
Reactant: Nc1ccc2cn[nH]c2c1
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Oc1ccc2cn[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Indazol-6-amine (24.33 g; manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in water (100 mL) and a 48 wt % aqueous solution of tetrafluoroboric acid (242 mL; manufactured by Sigma-Aldrich Co.), and the solution was cooled to 0° C. Subsequently, an aqueous solution of sodium nitrite (20 mL (sodium nitrite (13.87 g; manufactured by Kanto Chemical Co., Inc.) was dissolved in water (20 mL)) was added dropwise to the solution over 10 minutes, and the resulting mixture was stirred for 30 minutes at 0° C. Precipitates of the reaction solution were filtered, and were washed with chloroform. The obtained precipitates were dissolved in acetic acid (250 mL), and the solution was stirred for 10 minutes at 50° C., for 10 minutes at 110° C., and for 10 minutes at 130° C. The reaction solution was cooled, a saturated aqueous solution of sodium carbonate was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in ethanol (240 mL). A 2 mol/L aqueous solution of sodium hydroxide (365 mL) was added to the solution, and the mixture was stirred for one hour at room temperature. The reaction solution was concentrated under reduced pressure, and 2 mol/L hydrochloric acid (200 mL), water and a saturated aqueous solution of ammonium chloride were added to the residue to adjust the pH to about 7. The mixture was then extracted with ethyl acetate. The organic layer was washed with brine, and was dried over anhydrous magnesium sulfate. Subsequently, the solvent was evaporated under reduced pressure, and chloroform was added to the residue. Insoluble matters were filtered, and were washed with chloroform. Thus, a crude product (13.5401 g) of the title compound was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C:3]1([CH2:18][CH3:19])[CH3:17]>CO.[H][H].[OH-].[OH-].[Pd+2]>[NH2:1][CH:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][NH:5][CH2:4][C:3]1([CH2:18][CH3:19])[CH3:17]
Reactant: [H][H]
Reactant: CCC1CN(Cc2ccccc2)CC(C)(CC)C1N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1CNCC(C)(CC)C1N

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.3 g) and 4-amino-1-benzyl-3,5-diethyl-3-methylpiperidine (2.1 g, 8.07 mmol) in methanol (50 ml) was stirred in hydrogen atmosphere (4 atm.) at 45° C. for 4 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-amino-3,5-diethyl-3-methyl-piperidine as an oil.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21](O)=[O:22]>>[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:22]
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: Cc1cc(C(=O)O)cc(Br)n1
Agent: Cl
Product: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(Br)n1
Yield: 29 %

Procedure:
The title compound is prepared in 29% yield (182 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (200 mg, 0.78 mmol, Amine-1, single enantiomer) and 2-bromo-6-methylisonicotinic acid (269 mg, 1.95 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:38][C:39]([C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][N:45]=[CH:44]2)=[NH:40]>CN(C=O)C>[NH:46]1[C:47]2[C:43](=[CH:42][C:41]([C:39]3[N:38]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:40]=3)=[CH:49][CH:48]=2)[CH:44]=[N:45]1
Reactant: N=C(NO)c1ccc2[nH]ncc2c1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1C#N
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 32 %

Procedure:
3-Cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (1.52 g), EDAC (2.14 g) and HOBt (1.51 g) were dissolved in DMF (30 ml) and then stirred for 5 minutes. N-hydroxy-1H-indazole-5-carboximidamide (D2) (1.3 g) was added and the reaction was heated to 80° C. for 6 hours and left to cool overnight. The solvent was removed in vacuo and the crude was partitioned between EtOAc and aq. sodium bicarbonate. The organic layer was separated, dried and evaporated to dryness in vacuo. The resulting solid was triturated with ether and ethyl acetate, washed with methanol and ether to give the title compound (816 mg) as a pink solid. MS (ES): C19H15N5O2 requires 345; found (MH+) 346
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=O)[CH:25]=2)[CH:20]=[CH:19]1>>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:27]([C:24]5[CH:25]=[C:26]6[C:21]([CH:20]=[CH:19][NH:18]6)=[CH:22][CH:23]=5)=[O:29])=[CH:13][CH:12]=3)[N:6]=[CH:5]4)=[O:29])[CH:25]=2)[CH:20]=[CH:19]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Product: O=C(Nc1ccc(-n2ncc3cc(NC(=O)c4ccc5cc[nH]c5c4)ccc32)cc1)c1ccc2cc[nH]c2c1

Procedure:
Compound 523 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 1H-indole-6-carboxylic acid. [M+H]+ calcd for C31H22N6O2: 511.18; found: 511.02.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH:20]=[CH2:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([N:29]([CH2:35]OC)[CH2:30][Si](C)(C)C)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:22]([N:29]1[CH2:35][CH2:21][CH:20]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])=[CH:19]3)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=Cc1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1cnc2c(C3CCN(Cc4ccccc4)C3)cccc2c1
Yield: 32.9 %

Procedure:
3-(Phenylsulfonyl)-8-vinylquinoline (210 mg, 0.71 mmol, prepared according to WO2007039219) was reacted with benzyl methoxymethyl trimethylsilylmethyl amine (253 mg, 1.07 mmol) in dichloromethane (2 ml) in the presence of trifluoroacetic acid for 20 minutes. The solution was washed with a saturated aqueous solution of NaHCO3 solution, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography (100% dichloromethane) to give the title compound as a colourless oil (100 mg, 33%).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:37])([CH3:36])[CH2:4][C:5]1[N:6]=[C:7]([CH:16]([OH:35])[C:17]2([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:25][CH:24]=3)[S:22][CH2:21][CH2:20][CH2:19][S:18]2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>O1CCCC1>[CH3:2][C:3]([CH3:37])([CH3:36])[CH2:4][C:5]1[N:6]=[C:7]([CH:16]([C:17]2([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:25][CH:24]=3)[S:18][CH2:19][CH2:20][CH2:21][S:22]2)[OH:35])[NH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(O)C1(c2ccc(-c3ccccn3)cc2)SCCCS1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)Cc1c[nH]c(C(O)C2(c3ccc(-c4ccccn4)cc3)SCCCS2)n1
Temperature: 70 °C

Procedure:
Step C, 1.5 N Hydrochloric acid (1 mL) was added to a solution of 4-(2,2-dimethylpropyl)-2-{hydroxy[2-(4-pyridin-2-ylphenyl)-1,3-dithian-2-yl]methyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide in tetrahydrofuran (1 mL). After heating in a sealed tube at 70° C. for a few minutes until no further reaction (LCMS), the reaction mixture was cooled to 0° C., quenched with 10% aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Preparatory plate chromatography eluting with 10% methanol/ethyl aceate afforded the title compound. LCMS: 440 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](O)[CH2:9][N:10]([CH2:17][CH2:18]O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:33]([NH2:36])[CH:34]=[CH2:35].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:17][CH2:18][N:36]2[CH2:33][CH:34]=[CH2:35])=[CH:4][CH:3]=1
Reactant: OCCN(C[C@H](O)c1ccc(Cl)cc1)c1ccccc1
Reactant: C=CCN
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCN1CCN(c2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To (R)-1-(4-chlorophenyl)-2-[(2-hydroxyethyl)(phenyl)amino]-1-ethanol (1.68 g, 4.94 mmol) produced in Example 11, ethyl acetate (10 mL) and triethylamine (1.75 g, 3.5 equivalents) were added. The mixture was cooled to 5° C. Methanesulfonyl chloride (1.81 g, 3.2 equivalents) was added dropwise thereto, and then allylamine (1.69 g, 6.0 equivalents) was added dropwise thereto. The mixture was stirred at 5° C. for 1 hour and then at 25° C. for 2 hours. The reaction mixture was transferred in an autoclave, and stirred at 50° C. for 18 hours. The mixture was cooled to room temperature, and then 10 wt % aqueous solution of sodium carbonate (8.38 g) was added to the mixture. After the organic layer and aqueous layer were separated, the organic layer was washed twice with distilled water (10 mL). The obtained organic layer was concentrated to give 1.11 g of a concentrate as yellow oil (chemical purity: 30.2 area %). The concentrate was purified by column chromatography (gel: silica gel, solvent: ethyl acetate/hexane=1/9), and the obtained fractions were concentrated and dried under vacuum, to obtain 307 mg of the title compound as colorless oil (yield: 19%, chemical purity: 98.1 area %). The retention time in the chemical purity analysis method was 56.6 min.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([CH3:11])=[CH:7][C:8]=1[C:9]#[N:10].[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16](F)=[CH:15][C:14]=1[F:23].Cl>C1COCC1>[F:12][C:13]1[C:14]([F:23])=[CH:15][C:16]([NH:3][C:4]2[S:5][C:6]([CH3:11])=[CH:7][C:8]=2[C:9]#[N:10])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1
Reactant: Cc1cc(C#N)c(N)s1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C#N)c(Nc2cc(F)c(F)cc2[N+](=O)[O-])s1
Temperature: 2.5 °C
Yield: 43.9 %

Procedure:
Add sodium hydride, 60% dispersion in mineral oil (55.0 g×60%=33.0 g, 1.38 mol) to THF (950 mL) with stirring at 0-5° C. under nitrogen. Add a solution of 2-amino-5-methyl-thiophene-3-carbonitrile (95.0 g, 0.687 mol) and 1,2,4-trifluoro-5-nitro-benzene (121.7 g, 0.687 mol) in THF (1325 mL) dropwise over ˜1 hour, keeping the temperature below 10° C. Allow the reaction to warm to ambient temperature and stir for 8-20 hours. Cool to 10-15° C. and add aqueous 1N HCl (550 mL) dropwise over 10-15 minutes to adjust the pH to 7.0-7.2, keeping the pot temperature below 15° C. Remove most of the organic portion under reduced pressure, and then filter and rinse with water. Dry at 50-60° C. to obtain the crude product. Purify by flash chromatography, eluting with 1:1/methylene chloride:heptane to give 89.1 g (44%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.77 (bs, 1H), 8.33 (m, 1H), 7.09 (s, 1H), 7.07 (m, 1H), 2.47 (s, 3H). HRMS (ES) exact mass M+H calcd for C12H7F2N3O2S 318.0125; found 318.0133.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]([C:30]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:39]1[CH2:40][CH2:41][CH:36]([C:33]2[CH:34]=[CH:35][C:30]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: O=C(CCCCCBr)Nc1ccccc1Cc1ccccc1
Product: O=C(CCCCCN1CCC(c2ccc(Oc3ccccc3)cc2)CC1)Nc1ccccc1Cc1ccccc1

Procedure:
The compound (12) synthesized in Reference Example 12 and the compound (4) synthesized in Reference Example 4 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[O-].[Na+].C[C:42](O)=[O:43]>CO>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([O:43][CH3:42])[N:21]=1
Reactant: CC(=O)O
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)F
Temperature: 50 °C
Yield: 68.3 %

Procedure:
To a suspension of 4 (500 mg, 0.951 mmol) in MeOH (10 ml) was added NaOMe in MeOH (25%, 0.90 ml). The mixture was heated to 50° C. for 3 h. Then, it was neutralized with AcOH. It was concentrated and EtOAC (30 ml) was added. The insoluble solid was filtered off The filtrate was concentrated and purified by flash column chromatography on silica gel using 0 to 15% MeOH in CH2Cl2 as eluents. Compound 7 (203 mg, 68.3%) was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 6.61 (s, 2H), 6.05 (d, J=17.6 Hz, 1H), 5.67 (d, J=7.2 Hz, 1H), 5.25 (t, J=4.8 Hz, 1H), 4.18 (dt, J=25.6, 8.0 Hz, 1H), 3.96 (s, 3H), 3.91 (dm, J=9.2 Hz, 1H), 3.85 (ddd, J=2.0, 5.2, 12.8 Hz, 1H), 3.69 (ddd, J=2.8, 3.2, 12.0 Hz, 1H), 1.06 (d, J=22.8 Hz, 3H); tR=0.52 (99.1%); LRMS (ESI) [M+H]+ calculated for C12H17FN5O4 314.3, found 314.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1Br.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:28]([OH:29])[CH:25]1[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Fc1ccc(F)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2cc(F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
To a solution of 2,5-difluoro-1-bromobenzene (24.5 g, 127 mmol) in anhydrous tetrahydrofuran (400 ml) at −78° C. was added n-butyllithium (1.6M, 80 ml, 128 mmol). The solution was stirred for 15 minutes tert-butyl-4-formyl-piperidine-1-carboxylate (27.0 g, 127 mmol) added slowly in THF (50 ml). The mixture was allowed to warm to room temperature and stirred for 16 hours, quenched with water (200 ml) and extracted with ethyl acetate (3×150 ml). The combined organics were washed with water (50 ml), dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 3 to 10% ethyl acetate in iso hexanes to yield (RS)-tertbutyl 4-[(2,5-difluorophenyl)-hydroxymethyl]-piperidine-1-carboxylate as a colourless oil (14 g, 34%).
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[CH:3][C:4]#[N:5].[C:19](OCC)(=[O:26])[CH2:20][C:21](OCC)=[O:22]>>[OH:26][C:19]1[C:3]([C:4]#[N:5])=[C:2]([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:7]=2)[NH:1][C:21](=[O:22])[CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N#CC=C(N)c1ccc(Oc2ccccc2)cc1
Product: N#Cc1c(O)cc(=O)[nH]c1-c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
3-Amino-3-(4-phenoxyphenyl)acrylonitrile (720 mg, 3.05 mmol) in diethyl malonate (9 mL, 59.3 mmol) was microwaved at 250° C. for 10 min. After cooling to room temperature, the solid was collected by filtration, washed with 20% isopropanol in heptanes and dried under vacuum to give 4-hydroxy-6-oxo-2-(4-phenoxyphenyl)-1,6-dihydropyridine-3-carbonitrile (688 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (1H, br. s), 7.67 (2H, δ, J=8.53 Hz), 7.48 (2H, t, J=7.91 Hz), 7.25 (1H, t, J=7.40 Hz), 7.11 (4H, dd, J=19.70, 8.16 Hz), 5.52-5.74 (1H, m); MS (ES+) m/z: 305 (M+H); LC retention time: 3.546 min (analytical HPLC Method A).