Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[OH-].[Na+].Cl[C:12](=[CH:17][C:18]([F:21])([F:20])[F:19])[C:13]([F:16])([F:15])[F:14]>CN(C)C=O>[F:14][C:13]([F:16])([F:15])[CH2:12][C:17]1([C:18]([F:21])([F:20])[F:19])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
11 g of pyrocatechol were dissolved in 200 ml of dimethylformamide, and 18 g of 45% by weight aqueous sodium hydroxide solution were added. 20 g of 2-chloro-1,1,1,4,4,4-hexafluorobut-2-ene were added dropwise to the mixture at 75° C. The reaction mixture was subsequently stirred for 30 minutes at 75° C. and then poured into 500 ml of ice-water and extracted with diethyl ether. The organic phase was washed with water, dried over magnesium sulphate and concentrated. The product was finally distilled under high vacuum. The yield was 15 g (=56%) and the boiling point was 60° C. at 10 mbar. The NMR spectra showed the following characteristic absorptions: 19F NMR: -59.0 and -84.6 ppm. 1H NMR: 3.02 ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:18]=3[N:19]=2)[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(Nc3nc4cc([N+](=O)[O-])ccc4o3)CC2)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc(CN2CCC(Nc3nc4cc(N)ccc4o3)CC2)ccc1OC
Temperature: 60 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To a solution of [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(5-nitro-benzooxazol-2-yl)-amine (1.0 g, 2.35 mmol, 1.0 equiv; example 225) in ethanol (10 mL) was added palladium on activated charcoal 10% (0.1 g, 0.10 mmol, 0.04 equiv), the reaction vessel filled with hydrogen (3.5 bar) and stirred at 60° C. for 18 h. The catalyst was removed by filtration over celite and the solvent removed under reduced pressure yielding 0.79 g (85%) of the title compound which was used directly without further purification. MS (ESI): 397.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[C:12]1[S:16][C:15](=[S:17])[NH:14][C:13]1=[O:18])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:19]CN(C(C)C)C(C)C.IC>CO>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[C:12]1[S:16][C:15]([S:17][CH3:19])=[N:14][C:13]1=[O:18])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1[nH]c2ccccc2c1C=C1SC(=S)NC1=O
Solvent: CO
Solvent: CI
Product: CSC1=NC(=O)C(=Cc2c(C)[nH]c3ccccc23)S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a room temperature suspension of (Z) 5-[(2-methyl-1H-indol-3-yl)methylene]-2-thioxo-4-thiazolidinone (1.502 g, 5.48 mmols) in 50 mL of methanol is added Hunig's base (1.15 mL, 6.61 mmols) followed by iodomethane (0.500 mL, 8.03 mmols). The thick suspension is stirred for 2 hours at room temperature. Filtration washing with 1:1 hexane:ether provides 1.201 g of an orange solid. This material is suspended in 100 mL of hot ethyl acetate and filtered to provide 943 mg (60%) of (Z)-5-[(2-methyl-1H-indol-3-yl)methylene]-2-(methylthio)-4(5H)-thiazolone; mp 253-255° C. dec.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([CH2:39][C:40]2[S:41][CH:42]=[CH:43][N:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([CH2:39][C:40]2[S:41][CH:42]=[CH:43][N:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2nccs2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2nccs2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A mixture of hydroxylammonium chloride (2.2 g), sodium hydrogen carbonate (3.5 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-6-oxo-1-(1,3-thiazol-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.96 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.41 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.47 g, 44%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][N:9]([CH2:18][C:19]([O:21]CC)=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:26](CCN)CC)C.C(N(C(C)C)CC)(C)C>CCOCC>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][N:9]([CH2:18][C:19]([NH2:26])=[O:21])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: NC(=O)Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 18 h

Procedure:
A mixture of 10 g (0.033 mol) of ethyl 3,4-diphenyl-1H-pyrazole-1-acetate, 6.9 mL (0.049 mol) of diethylaminoethylamine and 39 mL of diisopropylethylamine was stirred on a steam bath under nitrogen for 18 hours. The reaction was stripped, the residue taken up in about 300 mL of ether and washed twice with water. The ether layer was extracted twice with a total of 150 mL of cold water containing 20 mL of 10% HCl. The combined water extracts were washed once with ether, colled, made basic with solid sodium carbonate, extracted several times with methylene dichloride, dried over sodium sulphate, treated with decolorizing carbon, filtered and stripped. The oily red residue was crystallized from ether to yield 6.86 g of N-[2-diethylamino)ethyl]-3,4-diphenyl-1H-pyrazole-1-acetamide, mp 80°-83° C.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9](O)=[O:10])=[O:6].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9]([Cl:17])=[O:10])=[O:6]
Reactant: O=C(O)CNC(=O)OCC(Cl)(Cl)Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CNC(=O)OCC(Cl)(Cl)Cl

Procedure:
N-(2,2,2-Trichloroethyloxycarbonyl)-glycine (0.75 g, 3 mMol) is suspended in CH2Cl2 (30 ml) and the mixture is stirred under N2 with ice-bath cooling. Oxalyl chloride (0.28 ml, 3.3 mMol) and DMF (0.023 ml, 0.3 mMol) are added thereto, and the mixture is stirred for 1 hour in the cold. The resulting solution is washed with ice-cold water and ice-cold brine, dried briefly over Na2SO4, and filtered. This solution of N-(2,2,2-trichloroethyloxycarbonyl)glycyl chloride is used immediately in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5](N(OC)C)=[O:6].CON(C)C(=O)C1C=CN=CC=1.ClC1C(C2C=CC=CC=2)=C(Cl)C2C(=CC=C(C([C:52]3[N:56]([CH3:57])[CH:55]=[N:54][CH:53]=3)(C3C=CN=CC=3)O)C=2)N=1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([C:55]2[N:56]([CH3:57])[CH:52]=[CH:53][N:54]=2)=[O:6])[CH:11]=[CH:12][N:13]=1
Reactant: Cn1cncc1C(O)(c1ccncc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: CON(C)C(=O)c1ccnc(F)c1
Agent: CON(C)C(=O)c1ccncc1
Product: Cn1ccnc1C(=O)c1ccnc(F)c1

Procedure:
The title compound was prepared using 2-fluoro-N-methoxy-N-methylisonicotinamide (Intermediate 28: step a) in place of N-methoxy-N-methylisonicotinamide (Intermediate 25: step a) according to the procedure described in Intermediate 25: step b.
Reaction SMILES: [Br:1]Br.[CH3:3][Si:4]([CH3:21])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1CCO)[C:5]([CH3:10])([CH3:9])[CH:6]([CH3:8])[CH3:7].N1[CH:27]=[CH:26]C=CC=1>C1(C)C=CC=CC=1.CCCCCC>[CH3:21][Si:4]([CH3:3])([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:26][CH2:27][Br:1])=[CH:16][CH:17]=1)[C:5]([CH3:9])([CH3:10])[CH:6]([CH3:7])[CH3:8]
Reactant: c1ccncc1
Reactant: BrBr
Reactant: CC(C)C(C)(C)[Si](C)(C)Oc1ccccc1CCO
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)C(C)(C)[Si](C)(C)Oc1ccc(CCBr)cc1
Temperature: 18 °C

Procedure:
To a 0° C. solution of 19.7 g (75 mmol) in 350 mL of toluene was added dropwise over 5 minutes 3.8 mL (74 mmol) of bromine. This was stirred for 50 minutes at which time a solution of 21.0 g (75 mmol) of dimethyl [2-(hydroxy)ethylphenoxy] (1,1,2-trimethylpropyl) silane and 6.1 mL (75 mmol) of pyridine in 100 mL of toluene was added dropwise over 10 minutes. The reaction mixture was allowed to warm slowly to 18° C. over 4.3 hours. The mixture was cooled to 0° C. and diluted with 500 mL hexane. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with 500 mL hexane, chilled and passed through a silica gel column. Elution with hexane gave 11.7 g of pure title A bromide.
Reaction SMILES: [CH3:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: Cc1c(N)cccc1F
Reactant: S=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1c(F)cccc1N=C=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Into a solution of 2-methyl-3-fluoroaniline (1.0 g, 8.0 mmol) in 30 mL of toluene at room temperature, thiophosgene (0.94 mL, 12 mmol) and triethylamine (1.34 mL, 12 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The combined organic layer was then concentrated to give the desired product (1.1 g, 82%). EI-MS m/z 168.2 (M+).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60][CH:61]=[CH:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:60][CH:61]=[CH:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: N=C(OCC=Cc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg in 3 ml 33% methylene chloride in cyclohexane), cinnamyl trichloroacetimidate (54 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 30 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (45 mg).
Reaction SMILES: [ClH:1].C(O/[CH:5]=[C:6]1\[C:7](=O)[C:8]2[C:13]([O:14][C:15]3\1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2)C.[CH3:22][NH:23][NH2:24]>C(O)C>[ClH:1].[CH3:22][N:23]1[CH:5]=[C:6]2[C:15]3([O:14][C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:7]2=[N:24]1)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3
Reactant: CNN
Reactant: CCO/C=C1\C(=O)c2ccccc2OC12CCNCC2
Agent: Cl
Solvent: CCO
Product: Cn1cc2c(n1)-c1ccccc1OC21CCNCC1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
(Z)-3-(Ethoxymethylene)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (2.46 g, 7.94 mmol) in ethanol (24.6 mL) was treated with methylhydrazine (423 μL, 7.94 mmol). The reaction mixture was heated at 70° C. for 1 h and then at 100° C. for 10 min. The mixture was allowed to cool to room temperature overnight. The yellow solid was filtered off and was washed with ethanol to give 2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] hydrochloride (1.20 g, 74%). ESI-MS m/z calc. 255.1, found 256.3 (M+1)+; Retention time: 0.65 minutes. 1H NMR (400 MHz, DMSO) δ 9.01 (s, 2H), 7.75 (s, 1H), 7.61 (dd, J=7.5, 1.2 Hz, 1H), 7.28-7.20 (m, 1H), 7.10-6.99 (m, 2H), 3.89 (s, 3H), 3.28-3.18 (m, 4H), 2.18-2.02 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[C:29](Cl)(Cl)=[O:30].O>C1COCC1>[Cl:1][C:2]1[N:11]2[C:29](=[O:30])[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Clc1nc(NNc2ccccc2)c2ccccc2n1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1n(-c2ccccc2)nc2c3ccccc3nc(Cl)n12
Reaction time: 0.08 h

Procedure:
To a mixture of 2-chloro-4-phenylhydrazinoquinazoline (2 g, 7.4 mmol) and N,N-diisopropylethylamine (2 ml, 11.4 mmol) in THF was added phosgene (6 ml, 20% in Toluene) slowly, then stirred for additional 5 min. The reaction mixture was poured into water and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine and dried over Na2SO4 and evaporated under reduced pressure. The residue was triturated with ethanol and filtered to afford 5-chloro-2-phenyl-1,2,4-triazolo[4,3-c]quinazolin-3-one (1.8 g) as a yellow solid. m.p. 167°-168° C.
Reaction SMILES: C(=O)=[O:2].[S:4](=[O:6])=[O:5].C(=O)(O)[O-:8].[Mg+2:11].C(=O)(O)[O-:13]>>[S:4](=[O:8])([OH:6])[O-:5].[Mg+2:11].[S:4](=[O:13])([OH:6])[O-:5].[S:4]([O-:2])([O-:6])=[O:5].[Mg+2:11]
Reactant: O=C([O-])O
Reactant: O=C=O
Reactant: O=S=O
Agent: [Mg+2]
Product: O=S([O-])O
Product: O=S([O-])[O-]

Procedure:
contacting at least a portion of the particles of combusted oil shale with an aqueous leaching agent containing sufficient dissolved carbon dioxide and sulfur dioxide for forming an enriched solution containing dissolved magnesium bicarbonate, and insufficient sulfur dioxide for forming magnesium bisulfite or magnesium sulfite; and
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[CH:20]=1>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:21]3[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=3)[C:18]([OH:27])=[O:17])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COc1ccc(-c2ccc(O)cc2)cc1
Product: COc1ccc(-c2ccc(OCc3cccc(C(=O)O)c3)cc2)cc1

Procedure:
3-(4′-Methoxy-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4-hydroxy-4′-methoxybiphenyl (available from TCI America, Portland, Oreg.) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd. Morcambe, Lancashire, UK). Yield: 73 mg. Mass spectrum (ES) MH+=335.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.[C:8]([C:12]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:20][CH2:19]2)[CH:15]=[C:14]([CH:28]2[CH2:31][CH2:30][CH2:29]2)[N:13]=1)([CH3:11])([CH3:10])[CH3:9]>>[ClH:27].[C:8]([C:12]1[N:13]=[C:14]([CH:28]2[CH2:29][CH2:30][CH2:31]2)[CH:15]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][S:7][C:5]3[S:6][C:2]([CH3:1])=[N:3][N:4]=3)[CH2:20][CH2:19]2)[N:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: Cc1nnc(S)s1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCl)CC2)n1
Product: Cc1nnc(SCCCN2CCN(c3cc(C4CCC4)nc(C(C)(C)C)n3)CC2)s1
Product: Cl

Procedure:
Using the method of example 1, the title compound was prepared by reacting of 5-methyl-[1,3,4]thiadiazol-2-thiol with 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine and converting the isolated compound into its hydrochloride salt.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:7]=[C:8]([N:20]2[CH2:24][C@H:23]([CH2:25]OS(C)(=O)=O)[O:22][C:21]2=[O:31])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]1>CN(C=O)C.C(OCC)(=O)C>[N:1]([CH2:25][C@@H:23]1[O:22][C:21](=[O:31])[N:20]([C:8]2[CH:9]=[CH:10][C:11]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]3)=[C:6]([F:5])[CH:7]=2)[CH2:24]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CN1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1=O
Temperature: 75 °C

Procedure:
Sodium azide (924 mg) was added to a solution of (5R)-3-(3-fluoro-4-{4-methyl-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (950 mg) in dry DMF (50 ml), and the mixture heated at 75° C. for 2 hours. The mixture was diluted with ethyl acetate and washed with three portions of water. The aqueous layer was then back-extracted with two portions of ethyl acetate, and the combined organic extracts dried over MgSO4. Evaporation gave (5R)-5-azidomethyl-3-(3-fluoro-4-{4-methyl-3-oxopiperazin-1-yl}phenyl)oxazolidin-2-one product which was used without further purification.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:16]=[CH:15][C:11]2[CH2:12][CH2:13][O:14][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:8]2[C:16](=[CH:15][C:11]3[CH2:12][CH2:13][O:14][C:10]=3[CH:9]=2)[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCC2
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCC3

Procedure:
A solution of 8.0 g. of 1-Isopropyl-1-(2,3-dihydro-6-benzofuranyl)urea, 3.6 ml. of benzaldehyde, 5 drops of methanesulfonic acid and 200 ml. of toluene is stirred and refluxed under a water separator for 20 hours. The resulting solution is cooled and the cooled solution is washed twice with 150 ml. water, dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is dissolved in a minimum amount of chloroform and chromatographed on silica gel (200 g.) using chloroform as an eluent to give an oil of 1-isopropyl-4-phenyl-3,4,6,7-tetrahydro-furo[3,2-g] quinazolin-2(1H)-one and an oil of 6-isopropyl -9-phenyl-2,3,8,9-tetrahydro-furan[2,3-f]quinazolin-7(6H)-one.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:10](=[O:22])[C@@H:9]1[CH2:23][C:24]([OH:26])=[O:25])=O)(C)(C)C.[CH2:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)[Cl:36].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CCOCC>[ClH:36].[CH2:27]([O:26][C:24]([CH2:23][C@@H:9]1[NH:8][CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=[O:16])[C:10]1=[O:22])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCc1ccccc1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)CN1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)O)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: Cl
Product: O=C(O)CN1CCN[C@@H](CC(=O)OCc2ccccc2)C1=O
Reaction time: 1 h

Procedure:
To a mixture of 8.6 g of (S)-4-t-butoxycarbonyl-1-t-butoxycarbonylmethyl-2-oxopiperazine-3-acetic acid, 2.5 g of benzyl alcohol, 50 mg of 4-dimethylaminopyridine and 30 ml of methylene chloride was added, at 0 C, 6.2 g of dicyclohexylcarbodiimide. The mixture was stirred for one hour. Insolubles were filtered off. To the filtrate was added 30 ml of trifluoroacetic acid, and the mixture was left standing for one hour. The reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in a 4N HCl-ethyl acetate solution, and the solution was stirred for 30 minutes at room temperature, then subjected to evaporation to dryness. This procedure was repeated to give a crude product, which was processed with ether to afford 3.7 g of the title compound as amorphous powder.
Reaction SMILES: [CH2:1]([N:8]([CH3:32])[C:9]1[C:10]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][N:27]=[CH:26]3)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[CH2:1]([N:8]([CH3:32])[C:9]1[C:10]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][N:27]=[CH:26]3)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)Cc3ccccc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(Cc1ccccc1)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of methyl 3-(benzyl(methyl)amino)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylate (70 mg, 0.17 mmol) in methanol (20 ml) was added sodium hydroxide (33 mg, 0.82 mmol) in water (5 ml). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum to give a residue, which was dissolved in water (20 ml), and adjusted to pH 4 with HCl (3N). The solids were collected by filtration to afford 3-(benzyl(methyl)amino)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylic acid as a yellow solid (64.1 mg, 89%).