Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:55]6[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCN(C)CC4)c3)ccc2OC)c1
Yield: 59.6 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM, 1-methylpiperazine (12 mg, 13.3 uL, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 μL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky white solid [36.2 mg (60%)]. LC-MS m/z 759.5 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:13]([C@:15]12[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][C@@H:20]1[NH:19][CH2:18][CH2:17][CH2:16]2)[CH3:14]>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:19]3[C@@H:20]4[C@:15]([CH2:13][CH3:14])([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[CH2:22][CH2:21]4)[CH2:16][CH2:17][CH2:18]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: CC[C@@]12CCCN[C@H]1CCc1ccccc12
Solvent: CO
Solvent: ClCCl
Product: CC[C@@]12CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CCc1ccccc12
Yield: 44 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-10b-ethyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 44% of theory; TLC: rf=0.42 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=360 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](F)[CH:17]=2)[C:12](=[O:21])[N:11]([OH:22])[C:10]1=[O:23])[CH3:8].C(N(CC)CC)C>C(#N)C>[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:17]=2)[C:12](=[O:21])[N:11]([OH:22])[C:10]1=[O:23])[CH3:8]
Reactant: CCn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCCC3)cc21
Yield: 48.8 %

Procedure:
Piperidine (0.025 mL, 0.22 mmol) was added to a solution of 1-ethyl-6,7-difluoro-3-hydroxy-1H-quinazoline-2,4-dione (Example D, 0.05 g, 0.2 mmol) and triethylamine (0.06 mL, 0.4 mmol) in 20 mL of acetonitrile. The solution was heated to reflux for 23 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, water, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.03 g of the title compound as a solid, mp 173-175° C.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[C:37]([O:44][CH3:45])[CH:36]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[CH2:42]([O:41][C:38]1[CH:39]=[CH:40][C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)=[CH:36][C:37]=1[O:44][CH3:45])[CH3:43]
Reactant: CCOc1ccc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc1OC
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc1OC
Temperature: 85 °C
Reaction time: 20 h
Yield: 32.8 %

Procedure:
After adding 102 mg of 2-hydrazinopyrimidine and 129 μl of triethylamine to a solution of 435 mg of {2-(4-ethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 15 ml of DMF, the mixture was stirred at 85° C. for 20 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 20 ml of a methanol:THF=1:1 mixed solvent. Next, 186 μl of acetic acid and 292 mg of sodium cyanotrihydroborate were added to the solution and the mixture was stirred at room temperature for 2 hours and 30 minutes. After adding ethyl acetate to the reaction mixture, it was filtered through a small amount of NAM silica gel, and the silica gel was washed with ethyl acetate-methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (152 mg).
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]#[C:15][CH3:16])[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:23]([NH2:26])([CH3:25])[CH3:24]>COC(C)(C)C>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([NH:26][CH:23]([CH3:25])[CH3:24])[N:7]=[CH:8][N:9]=1)[C:14]#[C:15][CH3:16]
Reactant: CC(C)N
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: CC#CCOc1cc(NC(C)C)ncn1
Temperature: 70 °C
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To 4 ml of dimethylsulfoxide were added 365 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 332 mg of potassium carbonate, and 591 mg of isopropylamine, followed by stirring at 70° C. for 6 hours. The reaction mixture was then left for cooling to room temperature, diluted with tert-butyl methyl ether, and washed twice with an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 339 mg of 4-(2-butynyloxy)-6-(isopropylamino)pyrimidine (the present compound (106)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](O)=[C:8]([CH3:14])[C:9]([CH3:13])=[N:10]2)=[CH:5][C:4]=1[CH3:16].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH3:16])[CH:5]=2)[N:10]=[C:9]([CH3:13])[C:8]=1[CH3:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nc(C)c(C)c(O)c2cc1C
Product: COc1cc2nc(C)c(C)c(Cl)c2cc1C

Procedure:
Prepared according to procedure S using 7-methoxy-2,3,6-trimethylquinolin-4-ol (444.7 mg, 2.0 mmol) and POCl3 (2.0 mL, 21.5 mmol) to give 4-chloro-7-methoxy-2,3,6-trimethylquinoline. Mass Spectrum (ESI), m/e=236.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)[CH:10]=[CH:11][CH:12]([OH:22])[CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+].CO>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)[CH:10]=[CH:11][CH:12]([OH:22])[CH2:13][CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Temperature: -80 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
The reduction was carried out following the procedure described in Example 9. A solution of 180 mg (0.38 mmole) of ethyl 9,9-bis(4-fluorophenyl)-5-hydroxy-8-(1 H-tetrazol-1-yl)-3-oxo-6,8-nonadienoate in 10 mL of tetrahydrofuran at 0° C. was treated with triethylborane (0.9 mL, 1 M in tetrahydrofuran). After 2 hrs., the solution was cooled to -80° C. and treated with 30 mg of sodium borohydride followed by 200 μL of methanol. The crude product was purified by silica gel chromatography to yield 111.2 mg (62%) of the title compound.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH3:26][C:27]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:28]=1[CH:29]=O.CC(C)([O-])C.[K+].O>O1CCCC1>[CH3:26][C:27]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:28]=1[CH:29]=[CH:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C=O)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C=CCC(=O)O)c(C)c1
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
(2-Carboxyethyl)triphenylphosphonium bromide (150 g, 361 mmol) was suspended in tetrahydrofuran (500 mL) and 2,4-dimethylbenzaldehyde (55.4 mL, 397 mmol) was added thereto. A solution of potassium t-butoxide (81.1 g, 722 mmol) in tetrahydrofuran (300 mL) was added thereto under nitrogen atmosphere over 10 minutes and the mixture was stirred under ice-cooling for 3 hours. Water was added to the reaction mixture to stop the reaction and the temperature of the liquid was returned to room temperature. The mixture was concentrated under reduced pressure, a 8N aqueous sodium hydroxide solution was added thereto to bring pH to 11 and ether was added thereto to separate it. A 12N aqueous hydrochloric acid solution was added to an aqueous phase to bring pH to 2 and ethyl acetate was added thereto to separate it. The thus obtained organic phase was separated, washed with water and a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1-6:1) to obtain 4-(2,4-dimethylphenyl)-3-butenoic acid (37.0 g, yield: 54%). 10% Palladium-carbon (7.96 g, 50% hydrous) was added to a solution of the obtained 4-(2,4-dimethylphenyl)-3-butenoic acid (37.0 g, 195 mmol) in methanol (400 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. After the palladium-carbon in the reaction mixture was Celite-filtered, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1) to obtain the title compound (64.4 g, yield: 84%).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1.N1C=CC=CC=1>ClCCl>[CH2:4]([O:3][C:1](=[O:2])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1)[CH:5]=[CH2:6]
Reactant: Nc1ccc(CO)cc1
Reactant: C=CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)Nc1ccc(CO)cc1
Reaction time: 2 h
Yield: 28.9 %

Procedure:
Alloc-Cl (537 g) in dichloromethane (5 ml) was added dropwise to a solution of (4-amino-phenyl)-methanol (500 mg) and pyridine (5 ml) in dichloromethane (5 ml). After stirring for 2 h, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The title compound (243 mg) was obtained by recrystallization from dichloromethane. The mother liquor was chromatographed on silica gel in heptane/ethyl acetate=1/1 (v/v) as eluent which yielded another 245 mg of the title compound. Yield: 488 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH2:36](I)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:36][CH3:37])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: CCI
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: CCOc1ccc(OC)c2c1CCN(CC(=O)NCc1ccccn1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with ethyl iodide
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][NH:15][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NN=C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=S(=O)(NN=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A four neck flask (2 liters) equipped with a thermometer, a reflux condenser and a stirrer was charged with 78.4 g (0.4 mol) of benzophenone hydrazone, 64.6 g (0.64 mol) of triethylamine and 1 liter of ether, and 105.6 g (0.6 mol) of benzenesulfonic acid chloride was dropwise added thereto in one hour while stirring at room temperature and then heated under reflux for 72 hours. The reaction liquid was cooled down to 20° C. and then washed (separated) twice with 500 ml of deionized water. The ether layer was dried over anhydrous magnesium sulfate and filtered off, and then the mother liquid was concentrated by means of a rotary evaporator to obtain reddish yellow crystal. This crude crystal was added to 1 liter of diethyl ether and heated under reflux for 30 minutes, and then the crystal was filtered off at 30° C. This was dried under reduced pressure to thereby obtain white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[N:20])=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.ClC1C(C#N)=CC(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2Cl)N=1.C(N)CC.C[Mg+].[Br-].[C:59](Cl)(=[O:62])[CH2:60][CH3:61]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH2:16][CH2:17][CH3:18])[C:59](=[O:62])[CH2:60][CH3:61])[C:12]([C:19]#[N:20])=[CH:11][C:10]=1[C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1
Reactant: CCCNc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Reactant: CCC(=O)Cl
Agent: C[Mg+]
Agent: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: [Br-]
Solvent: CCCN
Product: CCCN(C(=O)CC)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N

Procedure:
6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-(propylamino)pyridine-3-carbonitrile (prepared by reaction of the product of Step C Example 1 with propylamine using the procedure of Step D EXAMPLE 26) was reacted with MeMgBr followed by propionyl chloride using the procedure of EXAMPLE 42 Step A to afford the title compound. HPLC/MS: 472.1 (M+1), 474.1 (M+3); Rt=4.40 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([CH3:12])=O.Cl.[NH2:14][OH:15].C(=O)([O-])O.[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](=[N:14][OH:15])[CH3:12]
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=NO)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Twenty six grams (g) (162 millimoles (mmol)) of commercially available 2-benzofuranylmethylketone was dissolved in 300 milliliters (ml) of methanol, and 16.9 g (243 mmol) of hydroxylamine hydrochloride and 20.4 g (243 mmol) of sodium hydrogencarbonate were added thereto. The resulting mixture was stirred at room temperature for 8 hours. Then, φml of water was added and the methanol was distilled away under reduced pressure. Precipitated crystals were filtered off and washed with water to yield 27.8 g of 2-benzofuranylmethylketone oxime having the following formula (yield, 98%). ##STR26##
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(OC(=O)C)(=[O:14])C.N1C(C)=CC=CC=1C>C(OCC)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH:7]([OH:14])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=S1CCC2(CC1)OCCO2
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: OC1CC2(CCS1)OCCO2
Temperature: 150 °C

Procedure:
A mixture of 0.88 g of product from Example 393, 5.0 ml of acetic anhydride and 2.0 ml of lutidine is heated at 110°-115° C. for 2.5 hours, followed by increasing the temperature to 150° C. and then heated for 3 hours. The reaction mixture is diluted with ethyl acetate, washed 2× with 1N hydrochloric acid, water, saturated sodium chloride, dried and concentrated in vacuo. The residue is dissolved in methylene chloride, filtered through a pad of hydrous magnesium silicate and reconcentrated in vacuo to give 0.569 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C.O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1ccccc1
Reaction time: 0.67 h
Yield: 87.7 %

Procedure:
4-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole (530 mg, 2.2 mmol) was added to 88 mg (2.2 mmol) of 60% NaH/mineral oil in 20 mL of DMF and the mixture stirred for 0.67 hours. Then, 0.21 mL (2.2 mmol) of methyl bromoacetate was added and stirring maintained for 17 hours. The mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4), and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 597 mg (88% yield) of [[2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester, 140°-143° C.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1([C:27](=[O:32])C(=NO)C)CCCCC1.C(=O)C1C=CC=C(OC)C=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:32][CH3:27])[CH:15]=2)[O:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: CC(=NO)C(=O)C1CCCCC1
Agent: COc1cccc(C=O)c1
Product: COc1cccc(-c2nc(CI)c(C3CCCCC3)o2)c1

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 1-cyclohexyl-1,2-propanedione-2-oxime and m-anis-aldehyde gave 4-iodomethyl-5-cyclohexyl-2-(3-methoxyphenyl)oxazole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([CH3:14])[CH3:13])=[C:4]([C:7]([OH:11])=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.C([O-])([O-])=O.[K+].[K+].[F:21][C:22]([F:31])([F:30])/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH:12]([CH3:14])[CH3:13])=[C:4]2[C:7](=[C:8]([CH3:10])[CH:9]=1)[O:11][CH:23]([C:22]([F:21])([F:31])[F:30])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: Cc1cc(Cl)c(C(C)C)c(C=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2c(c(C)cc(Cl)c2C(C)C)OC1C(F)(F)F
Temperature: 90 °C
Yield: 67.3 %

Procedure:
A mixture of 3-chloro-6-hydroxy-2-isopropyl-5-methylbenzaldehyde (1.83 g, 8.6 mmole), K2CO3 (2.38 g, 17.3 mmole) and ethyl 4,4,4-trifluorocrotonate (2.17 g, 12.9 mmole) in anhydrous DMF (10.0 mL) was heated to 90° C. under a dry N2 atmosphere for 18 hrs. The mixture was then cooled, poured into 0.5 N HCl (50 ml) and extracted with EtOAc (2×50 mL). The combined extracts were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to give a dark oil which was subject to flash chromatography (silica gel) and eluted with 50% CH2Cl2/hexanes to give a yellow oil (2.1 g, 68%): GCMS m/z 362.0 (M+). 1H NMR (CDCl3/400 MHz) 8.07 (s, 1H), 7.02 (s, 1H), 5.64 (q, 1H, J=7.0 Hz), 4.23 (m, 2H), 3.39 (s, 3H), 3.23 (m, 1H), 1.26 (m, 3H), 1.12 (m, 6H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:15][N:14]=1>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:15]1)=[O:11]
Reactant: Oc1nsc(-c2ccccc2)n1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)n1sc(-c2ccccc2)nc1=O
Temperature: 20 °C

Procedure:
0.5 ml of triethylamine and 10 ml of methyl isocyanate were added to a solution of 9 g of 3-hydroxy-5-phenyl-1,2,4-thiadiazole in 100 ml of tetrahydrofuran and the mixture was stirred at 20° C for an hour and then was vacuum filtered. The crystals recovered were crystallized from acetic acid to obtain 10 g of 2-(N-methylcarbamoyl)-5-phenyl-1,2,4-thiadiazole-3-one melting at 210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].C(OO)(=[O:23])C.S(=O)(=O)(O)[O-].[Na+].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])(=[O:23])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(CS(=O)c2cccc[n+]2[O-])ccc1Cl
Reactant: CC(=O)OO
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(CS(=O)(=O)c2cccc[n+]2[O-])ccc1Cl
Temperature: 70 °C

Procedure:
To a mixture of 14.0 g (0.0426 mole) of 2-[[(4-chloro-3-nitrophenyl)methyl]sulfinyl]-pyridine-N-oxide in 35 ml of acetic acid was added 10.1 g of peracetic acid (40% in acetic acid) dropwise over one hour. The temperature of the reaction mixture rose to 27° C. before a water bath was placed on the flask to hold the temperature at 25° C. After addition, the mixture was heated to 70° C. for five hours. The mixture was cooled, and 20 ml additional acetic acid and solid sodium bisulfate and water were added to destroy the excess peracetic acid. The aqueous mixture was neutralized with potassium carbonate and chilled in an ice bath to precipitate an almost white solid. The precipitate was filtered off, washed with water, dried under vacuum overnight, and found to have a melting point of 162–164° C. Infrared and NMR spectra were both consistent with the proposed structure. The product was recrystallized from ethanol to give needle-like white crystals, melting point 168–170° C. C,H,N calculated for C12H9ClN2O5S: C=43.85%; H=2.76%; N=8.52%. Found: C=43.27%; H=2.65%; N=8.21%