Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][CH:3]=1.[CH3:20][N:21]=[C:22]=[O:23]>C1C=CC=CC=1>[CH3:20][NH:21][C:22]([N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]([CH3:1])=[CH:3][N:4]=1)=[O:23]
Reactant: Cc1cnc(Nc2ccccc2)n1-c1ccccc1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N(c1ccccc1)c1ncc(C)n1-c1ccccc1
Yield: 59.4 %

Procedure:
A mixture of 6.25 g (0.025 mol) of 5-methyl-1-phenyl-2-phenylamino imidazole (derivative No. 1), 1.44 g of methyl isocyanate (0.025 mol) and 20 ml of benzene are refluxed for 6 hours. After the solvent has been evaporated in vacuo, the residue is taken up in ether, filtered, and recrystallized from a mixture of isopropanol/isopropyl ether. 4.55 g of greyish-beige crystals are obtained in a yield of 59.5%, melting point 147° C measured by Koefler's block.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:12]([C:17]1[CH:18]=[CH:19][C:20]([C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:7])=[CH:21][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCc1ccc(C(=O)CCC(=O)O)cc1

Procedure:
Succinic anhydride (8.6 g; 0.1 mole) is reacted with pentylbenzene (100 ml) and aluminum chloride (29 g; 0.22 mole) and the product isolated by the manner described in Example 3. Recrystallization from aqueous ethanol gives 3-(4-n-pentylbenzoyl)propanoic acid (17 g) as colorless crystals, m.p. 98°-100° C.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:13]1([C:19]2[O:23][N:22]=[CH:21][C:20]=2[CH2:24][CH2:25][C:26](O)=[O:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH:10][C:26](=[O:27])[CH2:25][CH2:24][C:20]3[CH:21]=[N:22][O:23][C:19]=3[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: Nc1ccc(-n2ccnc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A mixture of 4-(1-imidazolyl)aniline (0.51 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.60 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.75 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-(1-imidazolyl)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide (0.95 g, yield 83%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 176–177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)=[CH:8][C:7]=1[F:14]
Reactant: OCc1ccc(Oc2ccc(F)c(Cl)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)c(Cl)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3-chloro-4-fluorophenoxy)-3-fluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [I:1][C:2]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH3:27]>CS(C)=O.O>[CH2:24]([N:7]1[C:6]2[CH:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:3]=[C:2]([I:1])[C:11]=2[O:10][CH2:9][C:8]1=[O:12])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCBr
Reactant: COC(=O)c1cc(I)c2c(c1)NC(=O)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCN1C(=O)COc2c(I)cc(C(=O)OC)cc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of Methyl 8-iodo-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (2.64 g) and potassium carbonate (5 g) in DMSO (20 mL) was added bromobutane (5 g), and the reaction mixture was stirred for 1 h at 80° C. The mixture was cooled to room temperature, diluted with 1:1 ethyl acetate/hexanes (100 mL) and water (160 mL), and separated. The organic layer was washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:10 ethyl acetate/hexanes) afforded 2.24 g of the title compound: 1H NMR (300 MHz, CDCl3) δ 8.13, 7.63, 4.74, 3.96, 3.92, 1.64, 1.42, 0.97.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1SC(CN3CCN(C4C=CC=CC=4)CC3)=C(C(OC)=O)N=1)[CH2:19][CH2:18]2)=O.C(C1SC(N2CCC3C(=C(C(=O)/N=C4/SC5C=CC=CC=5N/4COCC[Si](C)(C)C)C=CC=3)C2)=NC=1C(OC)=O)=O.[NH2:94][C:95]1[CH:100]=[CH:99][C:98]([OH:101])=[CH:97][CH:96]=1.CN1CCC(=O)CC1>>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([NH:94][C:95]2[CH:100]=[CH:99][C:98]([OH:101])=[CH:97][CH:96]=2)[CH2:18][CH2:19]1
Reactant: Nc1ccc(O)cc1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CN1CCN(c2ccccc2)CC1
Agent: CN1CCC(=O)CC1
Agent: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1C=O
Product: CN1CCC(Nc2ccc(O)cc2)CC1

Procedure:
The compound 104A was prepared in a similar manner to the synthesis of compound 62A by substituting 1-phenylpiperazine and compound 45C with 4-aminophenol and 1-methylpiperidin-4-one, respectively: ESI (+)/LC/MS: 207 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][CH2:7][C:8]([NH:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([C:18]#[N:19])=[CH:13][C:12]=1[Cl:20])=[O:9]>>[Cl:20][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][C:8](=[O:9])[CH2:7][Cl:6])[C:18]([NH2:19])=[O:2]
Reactant: N#Cc1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
16.8 Parts of concentrated sulfuric acid were stirred and cooled to 0° C. and there were added portionwise 4.2 parts of 2-chloro-N-(2,6-dichloro-4-cyanophenyl)acetamide. Upon completion, stirring was continued for 3 hours in an ice-bath. The reaction mixture was allowed to stand overnight at room temperature and poured onto ice-water. The precipitated product was filtered off, washed with water, dried and boiled in acetonitrile. The product was filtered off and dried, yielding 2.7 parts of 3,5-dichloro-4-[(2-chloroacetyl)amino]benzamide; mp. +260° C. (intermediate 71).
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C:7]#[N:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[Br:16]Br.O>O1CCOCC1>[Br:16][C:4]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[C:2]([Br:1])[NH:6][C:5]=1[C:7]#[N:8]
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(Br)[nH]1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1[nH]c(Br)c(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A sample of 5-bromo-4-(p-chlorophenyl)pyrrole-2-carbonitrile (2.2 g., 0.0078 mol) is dissolved in 30 mL of dry dioxane. The solution is heated with bromine (1.3 g., 0.008 mol) in dioxane (20 mL) and then stirred overnight at room temperature. The reaction mixture is poured into water precipitating a tan solid (2.6 g., 92%). A portion (1.6 g) is purified by flash chromatography using 75/25 hexane/ethyl acetate to give 0.8 g of grey solid with m.p. 191°-194° C.
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[Br:13].OS(O)(=O)=O.[N+:22]([O-])([O-:24])=[O:23].[K+]>>[C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:22]([O-:24])=[O:23])[C:6]([C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:5][C:4]=1[Br:13]
Reactant: COC(=O)Oc1ccc(C(C)(C)C)cc1Br
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
2-Bromo-4-tert-butylphenyl methyl carbonate (5.0 g, 17.4 mmol) was added portion-wise to H2SO4 (9.3 mL, 174.1 mmol) to generate a colorless homogeneous solution. This solution was then cooled to 0° C. and treated with KNO3 (2.1 g, 20.9 mmol) portion-wise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured on ice water. The aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic extracts was dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10% ethyl acetate/hexane) provided 2-bromo-4-tert-butyl-5-nitrophenyl methyl carbonate (4.4 g, 76% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.92 (s, 1H), 3.90 (s, 3H), 1.34 (d, J=5.4 Hz, 9H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4].[CH3:20][O:21][C:22]1[C:31]([CH2:32][CH:33]=O)=[C:30]2[C:25]([C:26](=[O:37])[CH2:27][C:28]([CH3:36])([CH3:35])[O:29]2)=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:20][O:21][C:22]1[C:31]([CH2:32][CH2:33][N:17]2[CH2:18][CH2:19][CH:14]([N:11]3[C:12]4[C:8](=[CH:7][CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:13]=4)[CH:9]=[CH:10]3)[CH2:15][CH2:16]2)=[C:30]2[C:25]([C:26](=[O:37])[CH2:27][C:28]([CH3:36])([CH3:35])[O:29]2)=[CH:24][CH:23]=1
Reactant: CNC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Reactant: COc1ccc2c(c1CC=O)OC(C)(C)CC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c4OC(C)(C)CC5=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
120 mg of N-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide and 120 mg of (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde were dissolved in 8 ml of methylene chloride. Thereafter, 0.05 ml of acetic acid and 0.15 g of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then filtered. The filtrate was then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate), so as to obtain 210 mg of the subject compound.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[CH:3]1[CH2:8][CH:6]2[CH2:5][CH2:4]1.O.S(=O)(=O)(O)[OH:11]>CC(C)=O>[OH:11][CH:2]1[CH:7]([OH:1])[CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2
Reactant: O=S(=O)(O)O
Reactant: C1CC2CC1C1OC21
Solvent: O
Solvent: CC(C)=O
Product: OC1C2CCC(C2)C1O

Procedure:
Into a four-neck flask (200 ml) were fed 20.3 g (185 mmol) of 2,3-epoxynorbornane, 50 ml of water, 25 ml of acetone, and 50 μl of sulfuric acid, and the reaction mixture was refluxed at 40° C. for 6 hours. After complete reaction, an object compound was extracted with each 40 ml of diethylether five times, and the resultant extract was washed with saturated salt solution (braine), and was dried with sodium sulfate to obtain 2,3-dihydroxynorbornane.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([C:17]([OH:19])=[O:18])[N:3]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH2:25]([O:18][C:17]([C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:19])[CH3:26]
Reactant: CCO
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C(=O)O)n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared from the compound of Example 73 by refluxing in ethanol in the presence of concentrate sulphuric acid, mp. 177.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:20])[C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][N:38]=[C:37]2Cl)=[O:31]>C(#N)C>[CH3:28][O:29][C:30]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][N:38]=[C:37]2[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([C:10](=[O:19])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH3:20])[CH:4]=1)=[O:31]
Reactant: COC(=O)c1cccc2c(Cl)ncnc12
Reactant: COc1ccc(C(=O)N(C)c2cccc(CN)c2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cccc2c(NCc3cccc(N(C)C(=O)c4ccc(OC)cc4)c3)ncnc12
Reaction time: 8 h

Procedure:
101 mg (0.37 mmol) N-(3-Aminomethyl-phenyl)-4-methoxy-N-methyl-benzamide were dissolved in 3 ml acetonitrile and 260 μl (1.87 mmol) triethylamine. 130 mg (0.37 mmol) 4-Chloro-quinazoline-8-carboxylic acid methyl ester were added and the mixture was stirred overnight. The solvent was removed, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O1CCCC1.O>[O:29]1[CH2:30][CH2:31][N:26]([CH2:2][C:3](=[O:25])[C@@H:4]2[C@:21]3([CH3:22])[C@H:7]([C@H:8]4[C@H:18]([C:19](=[O:23])[CH2:20]3)[C@:16]3([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]3)[CH2:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:27][CH2:28]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCl)[C@@]3(C)CC(=O)[C@@H]12
Reactant: C1COCCN1
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 72 h

Procedure:
21-Chloro-5α-pregnane-3,11,20-trione (200 mg.) in dry tetrahydrofuran (4 ml.) was treated with morpholine (0.20 ml.), and the solution was refluxed for 21/2 hours, and then left at room temperature for 3 days. The solution was diluted with water and extracted with chloroform. The organic solution was washed with water, dried over sodium sulphate and evaporated to a white foam (210 mg.), which was purified by preparative TLC in ethyl acetate to give 21-morpholino-5α-pregnane-3,11,20-trione (88 mg.) as a white foam, [α]D + 99°, (c 0.59). Treatment of this product in similar manner to that described in Example 50 gave title compound.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1.O>CS(C)=O>[OH:19][CH:16]1[CH2:17][CH2:18][N:13]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:15]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: OC1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A solution of ethyl 4-fluorobenzoate (16.5 g, 98.1 mmol) and piperidin-4-ol (10.0 g, 98.8 mmol) in DMSO (20 mL) was heated at 120° C. under nitrogen for 48 hours. The mixture was cooled to room temperature, poured into water (400 mL), and the solids were filtered off, washed with water, followed by hexane, to afford ethyl 4-(4-hydroxypiperidin-1-yl)benzoate (20.0 g, 82%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@H:40]([NH2:43])[CH2:41][CH3:42].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@H:40]([NH:43][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])[CH2:41][CH3:42]
Reactant: CC[C@@H](N)c1ccccn1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with (R)-1-(2-pyridyl)-propylamine hydrochloride (40 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 112 mg of the title compound as a light yellow solid. Optical Rotation: [α]D=−66.8° (c=0.40 mg/ml; CH3OH).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:26])[CH2:17][C:18]2[C:23]([Br:24])=[CH:22][N:21]=[C:20]([Cl:25])[CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13]([CH:16]([OH:26])[CH2:17][C:18]2[C:23]([Br:24])=[CH:22][N:21]=[C:20]([Cl:25])[CH:19]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2cc(Cl)ncc2Br)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(O)Cc2cc(Cl)ncc2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (240 mg) is added to an ice-cooled solution of 4-[2-(5-bromo-2-chloro-pyridin-4-yl)-acetyl]-piperidine-1-carboxylic acid tert-butyl ester (1.65 g) in a mixture of tetrahydrofuran (40 mL) and water (10 mL). The resulting mixture is stirred for 0.5 h at room temperature. 2 N Aqueous citric acid is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with aqueous NaHCO3 solution and brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 65:35) to give the title compound. LC (method 3): tR=1.48 min; Mass spectrum (ESI+): m/z=419, 421 [M+H]+.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=2)=[CH:27][CH:26]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(Cl)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 4-chlorophenylboronic acid (156 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (74 mg, yield 91%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][C:38](Cl)=[O:39])[N:33]=[N:32]1>C(Cl)Cl>[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][C:38]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[CH:14]=3)=[O:10])[CH2:5][CH2:4]2)=[O:39])[N:33]=[N:32]1
Reactant: N#Cc1cc(Cl)cc(COC(=O)N2CCC(N)CC2)c1
Reactant: O=C(Cl)CCc1c[nH]nn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(COC(=O)N2CCC(NC(=O)CCc3c[nH]nn3)CC2)c1
Reaction time: 1 h

Procedure:
To a suspension of 3-chloro-5-cyanobenzyl 4-aminopiperidine-1-carboxylate HCl salt (Example 64, step 3) (234 mg, 0.709 mmol) in DCM (5 mL) at RT under nitrogen was added Huenig's Base (0.248 mL, 1.418 mmol). 3-(1H-1,2,3-Triazol-4-yl)propanoyl chloride (113 mg, 0.709 mmol) in DCM (2 mL) was then added and the mixture stirred for 1 hour. The reaction mixture was diluted with DCM and washed with a 10% solution of citric acid, a saturated solution of brine and then the organic portion was dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH in DCM as eluent to afford the title product;
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[O:22][C:2]1[C:7]2=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Cc1ccn2ncnc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a mixture of 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (3.37 g, 20.11 mmol, PCT Appl. WO 2000/071129, U.S. pat. application 2003/0186982, the disclosure of which is herein incorporated by reference) and 2-fluoro-4-nitrophenol (3.48 g, 22.12 mmol) in anhydrous DMF (100 mL), stirred for 5 minutes under a nitrogen atmosphere, was added anhydrous potassium carbonate (6.11 g, 44.24 mmol). The mixture was heated at 60° C. for 15 h before 2-fluoro-4-nitrophenol (1.00 g, 6.37 mmol) was added and stirring continued at 60° C. for 4.5 h. The mixture was cooled to room temperature, diluted with dichloromethane, washed sequentially with water and 10% aqueous lithium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a tan solid. Purification by silica gel (Merck KGaA, 230-400 mesh particle size) flash chromatography, eluting with chloroform, afforded the title compound (4.19 g, 72%) as a pale yellow solid. 1H NMR (CDCl3) δ 8.20-8.13 (m, 2H), 7.83 (s, 1H), 7.73 (d, 1H, J=2.6 Hz); 7.58-7.53 (m, 1H), 6.69 (d, 1H, J=2.4 Hz), 2.62 (s, 3H); HRMS(ESI), 289.0737 (M+H)+ calc, 289.0733 (M+H)+ found.