Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](OCC)=[O:24])=[C:17]([CH3:28])[C:16]=2[CH3:29])=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[S:10][N:9]=1>>[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[C:17]([CH3:28])[C:16]=2[CH3:29])=[C:11]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[S:10][N:9]=1
Reactant: CCOC(=O)CCc1ccc(OCc2c(Cl)nsc2-c2ccc(OC)cc2)c(C)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(-c2snc(Cl)c2COc2ccc(CCCO)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 156 following Step 2 by LAH reduction of ethyl 3-(4-((3-chloro-5-(4-methoxyphenyl)isothiazol-4-yl)methoxy)-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CDCl3) δ: 7.50 (d, J=9.0 Hz, 2H), 6.97 (m, 3H), 6.78 (d, J=8.4 Hz, 1H), 5.45 (s, 2H), 3.86 (s, 3H), 3.73 (t, J=6.0 Hz, 2H), 2.71 (t, J=7.8 Hz, 2H), 2.25 (s, 3H), 2.19 (s, 3H), 1.81-1.88 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C22H24ClNO3S, 418.1[M+H]. found 418.1.
Reaction SMILES: O1CCCC1.[CH2:6]([C:8]1([C:18](=[O:24])[C:19]([O:21]CC)=[O:20])[CH:13]=[C:12]([CH2:14][CH3:15])[CH:11]=[C:10]([CH2:16][CH3:17])[CH2:9]1)[CH3:7].[OH-].[Na+]>O>[CH2:6]([C:8]1([C:18](=[O:24])[C:19]([OH:21])=[O:20])[CH:9]=[C:10]([CH2:16][CH3:17])[CH:11]=[C:12]([CH2:14][CH3:15])[CH2:13]1)[CH3:7]
Reactant: CCOC(=O)C(=O)C1(CC)C=C(CC)C=C(CC)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC1=CC(CC)(C(=O)C(=O)O)CC(CC)=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a 3 L volume four-necked flask, tetrahydrofuran (750 ml) and ethyl 2-(1,3,5-triethylphenyl)-2-oxoacetate (9-b) (261.0 g) were added, and sodium hydroxide (88 g) dissolved in water (237 g) was added dropwise thereto at about 15-20° C. The resulting mixture was stirred at room temperature for 1 hour and 30 minutes. The solid was removed by decantation. The liquid part was concentrated under reduced pressure. The residue was extracted with toluene and water. After the organic layer was removed, the aqueous layer was washed with toluene. The pH of the aqueous layer was adjusted to 1 with dilute sulfuric acid under cooling, and then the aqueous layer was extracted with toluene. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered to remove the insolubles. The filtrate was concentrated under reduced pressure to give 214.8 g of 2-(1,3,5-triethylphenyl)-2-oxoacetic acid (8-b).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:18][CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:19]([C@@H:21]([OH:24])[CH2:22][CH2:23][C@@:9]34[OH:25])[O:20][C:4]([C:5]=25)=[C:3]([OH:26])[CH:2]=1.C(N(CC)CC)C.[C:34]([O:38]C(=O)CC)(=[O:37])[CH2:35][CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:18][CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:19]([C@@H:21]([OH:24])[CH2:22][CH2:23][C@@:9]34[OH:25])[O:20][C:4]([C:5]=25)=[C:3]([OH:26])[CH:2]=1.[C:34]([O-:38])(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)OC(=O)CC
Agent: O=C([O-])[O-]
Agent: Oc1ccc2c3c1O[C@H]1[C@@H](O)CC[C@@]4(O)[C@@H](C2)N(CC2CCC2)CC[C@]314
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)[O-]

Procedure:
75 mL of methylene chloride and 3.75 g (0.01 mole) of nalbuphine were added to a 250-mL round-bottomed flask. The flask was placed in an ice bath to keep it cool. The content was then stirred and then gradually a 20 mL of methylene chloride solution containing 0.16 mole of triethylamine was added. With rapid stirring, another 20 mL of methylene chloride solution containing 0.011 mole of dry propionic anhydride was added drop by drop. Afterward, the mixture was stirred at room temperature for 1 hour. 20 mL of 10% sodium carbonate solution was added to neutralize the residual acid and remove the water soluble impurities. Sodium sulfate was used to dehydrate the solution. After drying under vacuum, a nalbuphine propionate solid was obtained. The product was purified by column chromatography. The physical data are shown in Table 1 and FIGS. 4 and 5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:8])[CH2:3][CH2:2]1.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][C:11]=3[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)=[O:20])=[O:8])[CH2:3][CH2:2]2)=[O:36])[CH:31]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)C1CCNCC1
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)C1CCN(C(=O)c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
3-[(Piperidin-4-yl)carbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in Example 228 is dissolved in N,N-dimethylformamide (3 ml), and thereto are added successively nicotinic acid (34 mg), 1-hydroxybenzotriazole (37 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg), and the mixture is stirred at room temperature for 4 hours. To the reaction solution are poured a saturated aqueous sodium hydrogen carbonate solution and water, and the precipitates are collected by filtration, washed with chloroform, and dried to give 3-[1-((pyridin-3-yl)carbonyl)piperidin-4-ylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (103 mg). This product is treated with hydrogen chloride in dioxane to give the title compound (115 mg).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[CH2:25]([CH:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:42])[C:39](Cl)=[O:40])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:25]([CH:32]1[CH2:33][CH2:34][N:35]([C:38](=[O:42])[C:39]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][CH2:9][CH2:10]3)=[O:40])[CH2:36][CH2:37]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Cl)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc2c(c1)CCN2)C(=O)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a stirred solution of 0.5 g (2.25 mmol) of 5-amino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester and 0.4 ml (2.8 mmol) of triethylamine in 20 ml of chloroform 0.7 g (2.6 mmol) of (4-benzyl-piperidin-1-yl)-oxo-acetyl chloride in 10 ml of chloroform is added dropwise at 0° C. The reaction mixture is stirred at room temperature for 1 hour, then washed with water and the organic layer is concentrated. The residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent to yield 0.9 g (88.7%) of the title compound as solid. The crude product is used in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([N+:29]([O-:31])=[O:30])=[C:19]([C:23](N(OC)C)=[O:24])[NH:20]2)=[CH:16][CH:15]=1.[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>C(OCC)C.C1COCC1>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([N+:29]([O-:31])=[O:30])=[C:19]([C:23]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[O:24])[NH:20]2)=[CH:16][CH:15]=1
Reactant: Brc1ccccn1
Reactant: CON(C)C(=O)c1[nH]c2cc(Cl)ccc2c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(c1ccccn1)c1[nH]c2cc(Cl)ccc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
To a solution of 2-bromopyridine (548 mg, 3.47 mmol) in diethyl ether (8 ml) cooled to −70° C. was added dropwise 1.66 M n-BuLi (2.1 ml in hexane). After stirring for 30 min, a solution of 6-chloro-2-(N-methoxy-N-methylamino)carbonyl-3-nitroindole (step 2, 328 mg, 1.16 mmol) in THF (8 ml) was added. The mixture was allowed to warm to ambient temperature and stirring continued for 5 h. Saturated ammonium chloride (20 ml) was then added and the mixture basified with saturated sodium bicarbonate (50 ml). The mixture was extracted with ethyl acetate (150 ml) and the extract was washed with brine (80 ml) and dried (Na2SO4). After removal of solvent by evaporation, the residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1:3) to afford 150 mg (43%) of the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[O:16][N:15]=1)=O)(C)(C)C.F[C:30](F)(F)[C:31](O)=O>ClCCl>[CH3:26][O:25][C:23]1[CH:22]=[C:21]([CH:20]=[C:19]([C:17]2[O:16][N:15]=[C:14]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][N:8]3[CH2:6][C:31]3[CH:30]=[CH:11][CH:10]=[CH:9][N:8]=3)[N:18]=2)[CH:24]=1)[C:27]#[N:28]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(C#N)cc(-c2nc(C3CCCCN3C(=O)OC(C)(C)C)no2)c1
Solvent: ClCCl
Product: COc1cc(C#N)cc(-c2nc(C3CCCCN3Cc3ccccn3)no2)c1

Procedure:
To a solution of 2-[5-(3-cyano-5-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (162 mg, 0.42 mmol) in dichloromethane (4 mL) cooling in an ice-bath was added trifluoroacetic acid (2 mL). The ice-bath was removed after 30 min. and then left stirring for an additional hour. After the solvent was removed in vacuo, the residue was dissolved in ethyl acetate and then washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo 113 mg (94%) of the title compound as a white solid. 1H NMR (CDCl3), δ(ppm): 7.99 (s, 1H), 7.84 (d, 1H), 7.35 (s, 1H), 5.56 (bs, 1H), 4.06 (m 1H), 3.93 (s, 3H), 3.01 (m, 1H), 2.84 (m, 1H), 1.92 (m, 1H), 1.70 (m, 2H), 1.49 (m 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].Cl.[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH2:29].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:29][CH2:28][C:27]([O:26][CH3:25])=[O:30])=[O:19])=[C:5]2[OH:23]
Reactant: COC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Temperature: 80 °C
Yield: 74.3 %

Procedure:
A mixture of ethyl 6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.810 g, 2.41 mmol), glycine methyl ester hydrochloride (0.39 g, 3.11 mmol, 1.3 eq.), 1,4-dioxane (7.0 mL) and DIPEA (1.3 mL, 7.46 mmol) was heated at 80° C. for 6 hours. The mixture was then cooled to room temperature and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with 2N HCl and brine. The solution was dried (MgSO4) and concentrated under reduced pressure to give a pale yellow solid. The product was recrystallized from EtOAc to give a colorless solid (0.68 g). MS m/e=380.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:39]=[O:40]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH3:8][C:6]1[C:5]([CH:9]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:4][N:3]=[C:2]([CH:39]=[O:40])[CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ncc1C(Sc1ccccc1)c1c(F)ccc(F)c1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)ncc1C(Sc1ccccc1)c1c(F)ccc(F)c1F
Temperature: -40 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of 2-bromo-4-methyl-5-[(phenylthio)(2,3,6-trifluorophenyl)meth yl]pyridine (2.00 g, 4.40 mmol) in toluene (40 ml), a hexane solution of n-butyllithium (1.58 M, 3.3 ml, 5.28 mmol) was added in an argon atmosphere at −75° C. The reaction mixture was stirred for 1 hour at −40° C., and then cooled again to −75° C., and N,N-dimethylformamide (0.68 ml, 8.80 mmol) was added. After Completion of dropwise addition, the reaction mixture was allowed to warm to 0° C., and water was added to the same temperature. Ethyl acetate was added to the reaction mixture, the organic layer was separated, and then the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate was concentrated under reduced pressure to obtain the title compound (1.03 g, 2.76 mmol, 63%) as a pale yellow oily substance.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)COCCO>[CH2:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)c1
Agent: NN
Solvent: O
Solvent: OCCOCCO
Product: c1ccc(Cc2cccc(Cc3ccccc3)c2)cc1
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 94.7 %

Procedure:
In a 4 neck, 1 liter flask fitted with thermocouple, mechanical stirrer, Barrett trap with condenser, nitrogen line, and stopper, 1,3-dibenzoylbenzene (197 g) and hydrazine monohydrate (280 g) were heated in diethyleneglycol (540 ml) at 100° C. for 4 hours. The mixture was then heated to 160° C. while collecting water and excess hydrazine hydrate in a Barrett trap. Potassium hydroxide (43.7 g) was slowly added over 0.5 hour while the temperature was slowly increased to 200° C. The temperature was maintained at 200° C. for 1 hour. The reaction was cooled to room temperature and 1 L of water was added and stirred for 20 minutes. The contents were transferred to a separatory funnel. The reactor was rinsed with 250 ml dichloromethane and the rinse added to the water layer. The water was extracted three times with dichloromethane (250 ml each) and the combined organic phases were backwashed with 1 L water. The organic phases were dried over magnesium sulfate, filtered and the solvent removed on a rotary evaporator to give 1,3-dibenzylbenzene as a pale yellow liquid (168.3 g, 94.7% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:6][C:7]2[C:12]([C:13]=1[N+:14]([O-])=O)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]>CO.O1CCCC1.[Pd]>[NH2:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: CCNc1c(N2CCOCC2)nc2ccccc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1c(N2CCOCC2)nc2ccccc2c1N

Procedure:
The 3-ethylamino-2-morpholino-4-nitroquinoline (0.7 g, 0.0023 mol) was dissolved in a mixed solvent of methanol and tetrahydrofuran (15 ml) and subjected to catalytic reduction in the presence of 10g palladium-on-carbon (0.3 g), thereby obtaining 4-amino-3-ethylamino-2-morpholinoquinoline in an amount of 0.5 g (yield, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2)cc1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(-c2ccccc2)ccc1CBr
Yield: 97.2 %

Procedure:
A mixture of 6.00 g of 3-fluoro-4-methylbiphenyl, 5.73 g of N-bromosuccinimide, 0.075 g of 2,2′-azobisisobutylonitrile and 120 ml of carbon tetrachloride was heat-refluxed for 5 hours. The reaction solution was washed with water, and the organic layer was concentrated. The resulting residue was purified through silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 9:1) to give 8.30 g of oily 4-bromomethyl-3-fluorobiphenyl.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH3:26].S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([O:11][CH3:12])[CH:7]=3)[N:1]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: COc1ccc(N)c(C(N)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc2nc(-c3cc(C)c(OCCO)c(C)c3)[nH]c(=O)c2c1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-amino-5-methoxy-benzamide (2.62 g, 15.80 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (3.23 g, 16.60 mmol) in N,N-dimethyl acetamide (20 mL), were added sodium hydrogen sulfite (58.5 wt %, 3.44 g, 19.00 mmol) and p-toluenesulfonic acid monohydrate (0.60 g, 3.20 mmol) and the reaction mixture was stirred at 115° C. for 16 hours. Solvent was evaporated in vacuo, water (50 mL) was added, and the separated solid was filtered. The solid was triturated with ether to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-one as a white solid. Yield: 3.56 g (66%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]#[N:36]>>[Cl:1][C:2]1[CH:26]=[CH:25][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:32]([CH3:31])[CH2:33][CH2:34][C:35]#[N:36])=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:28])[F:29])[CH:3]=1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCCC#N
Product: CN(CCC#N)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
3-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-propionitrile was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and 3-methylamino-propionitrile following General Procedure B.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[N:24]1([C:28]([C:30]2[CH:35]=[CH:34][C:33](Br)=[CH:32][N:31]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[N:24]1([C:28]([C:30]2[N:31]=[CH:32][C:33]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH:16]=3)[C:5]([NH:7][C:8]3[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=3)=[O:6])=[CH:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC3CCOCC3)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(OC3CCOCC3)c2)n1
Temperature: 200 °C
Yield: 21.6 %

Procedure:
3-Hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide (200 mg, 0.63 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (184 mg, 0.76 mmol), bromotris(triphenylphosphine)copper (186 mg, 0.2 mmol) and caesium carbonate (411 mg, 1.26 mmol) were dissolved/suspended in DMA (3.5 mL). The reaction mixture was heated in a microwave reactor for 1 hour at 200° C. then allowed to cool, filtered and reduced in vacuo. Water (25 mL) was added and the product extracted with ethyl acetate (2×25 mL), the organics dried (MgSO4) then purified by chromatography on silica, eluting with 0-10% methanol in DCM, to give the desired compound as a pale yellow foam (65 mg). 1H NMR δ (d6-DMSO): 1.57-1.67 (m, 2H), 1.97-2.05 (m, 2H), 2.23-2.34 (m, 2H), 3.51 (t, 2H), 3.78 (s, 3H), 3.83-3.90 (m, 2H), 4.08 (t, 2H), 4.59 (t, 2H), 4.69-4.76 (m, 1H), 6.56 (d, 1H), 7.00 (t, 1H), 7.29 (t, 1H), 7.49 (t, 1H), 7.54-7.58 (m, 1H), 7.60 (d, 1H), 8.00 (d, 1H), 8.41 (d, 1H), 10.83 (s, 1H); m/z 478 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[N:23][C:24]([C:27](=[O:29])[CH3:28])=[N:25][CH:26]=2)=[N:6][CH:7]=1.[CH3:30][Mg]Br>C1COCC1.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[N:23][C:24]([C:27]([OH:29])([CH3:30])[CH3:28])=[N:25][CH:26]=2)=[N:6][CH:7]=1
Reactant: CC(=O)c1ncc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ncc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cn1
Yield: 47.4 %

Procedure:
A solution of 1-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidin-2-yl)ethanone (Example 73) (12 mg, 0.03 mmol) in THF (5 mL) was treated with methylmagnesium bromide (0.09 mL, 0.3 mmol, 3.0 M in THF) at it. Upon completion of the reaction as judged by TLC analysis, the solution was diluted with saturated aq NH4Cl solution and extracted with EtOAc. The organic layer was removed, dried over MgSO4, filtered and concentrated giving rise to an oil. The oil was purified on silica gel to afford the title compound (6.3 mg). LC/MS: m/e 443.0 (M+H)+. 1H NMR (500 MHz, Acetone-d6): δ 1.54 (s, 6H), 4.56 (s, 1H), 7.39 (m, 2H), 7.47 (d, J=8.5 Hz, 1H), 7.82 (m, 1H), 8.25 (m, 2H), 8.45 (d, J=2.5 Hz, 1H), 9.39 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[N:15]=[CH:14][NH:13][N:12]=1)([O-:3])=[O:2].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:16]([N:18]([CH2:22][CH3:23])[C:19]([N:13]1[CH:14]=[N:15][C:11]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[N:12]1)=[O:20])[CH3:17]
Reactant: O=[N+]([O-])c1ccccc1Sc1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCN(CC)C(=O)n1cnc(Sc2ccccc2[N+](=O)[O-])n1

Procedure:
3-(2-Nitrophenylthio)-1,2,4-triazole (4 g) and diethyl carbamoyl chloride (2.71 g) are dissolved in acetone (50 ml) and potassium carbonate (5.5 g) is added, followed by reaction for 5 h under reflux with stirring. After cooling, water (100 ml) is added to the reaction solution, whereupon the crystal of the end product precipitates. After drying, the crystal is recrystallized from ethyl acetate/n-hexane to produce the titled compound, 1-(diethylcarbamoyl)-3-(2-nitrophenylthio)-1,2,4-triazole, in an amount of 5.08 g; yield, 87.8%; m.p. 101°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:19])[C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(Cl)cc(Cl)c3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2cc3cc(Cl)cc(Cl)c3o2)cc1
Temperature: 200 °C
Yield: 74.6 %

Procedure:
A mixture of 85 (0.7 g, 2.4 mmol) and Pyridine HCl (10 g) was heated to 200° C. After 1 Hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried and concentrated to give a solid which was triturated with MeOH, filtered to give a solid (0.5 g, 75%): Mp=184-186° C.; 1H NMR (DMSO-d6) δ 10.04 (s, 1 H), 7.77 (d, 2 H, J=8.3 Hz), 7.67 (t, 1 H, J=0.8 Hz), 7.48-7.46 (m, 1 H), 7.26 (s, 1 H), 6.90 (d, 2H, J=8.2 Hz); MS 277/279 [M−H]−