Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH2:20])=[S:19])=[CH:16][C:3]1=2.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClCCl.CO>CN(C=O)C>[CH2:21]([S:19][C:18](=[NH:20])[NH:17][C:15]1[CH:14]=[CH:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[NH:8][C:2](=[O:1])[C:3]=2[CH:16]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: N=C(Nc1ccc2c(c1)C(=O)Nc1ccccc1N2)SCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-2-yl)-thiourea (Example 9, 50 mg, 0.18 mmol) in DMF (1 mL) was added benzyl bromide (21 μL, 0.18 mmol). The solution was stirred at room temperature for 2 hr then heated at 60° C. for 1 hr. The solvent was removed under vacuo. The residue was dissolved in a mixture of tetrahydrofuran (5 mL) and diethyl ether (5 mL) and treated with 2 mL of saturated sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and evaporated to give an oily residue which was subjected to silica gel column chromatography (98% dichloromethane: 2% methanol). H1 NMR (acetone d6) δ: 8.91 (bs, 1H), 7.42-7.21 (m, 5H), 7.09-6.89 (m, 7H), 5.93 (bs, 1H), 4.31 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[C:14]#[N:15].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=2[C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 99.1 %

Procedure:
To a solution of 15.2 g (0.105 moles) of 4-chlorothiophenol dissolved in 150 ml of DMSO was added 4.2 g (0.105 moles) of NaOH. The mixture was heated to 60° C. and 18.3 g (0.100 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 60° C. for 21/2 hrs. The mixture was cooled and poured into a solution of 100 ml of 2 N aqueous NaOH and 600 ml of water. The product was collected by filtration, washed well with water and dried to obtain 28.8 g of product (99% yield). Recrystallization from ethanol afforded purified 2-((4-chlorophenyl)thio)-5-nitrobenzonitrile, mp 162°-164.5° C.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-])=O.[Na+].[NH2:15][C:16]1[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19].C[Si](OP(=O)=O)(C)C.CCOC(C)=O>O>[Br:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18]([OH:19])=[N:20][C:3]([C:2]([F:13])([F:1])[C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=3)=[N:15]2)=[CH:21][CH:22]=1
Reactant: NC(=O)c1ccc(Br)cc1N
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(Br)ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a mixture of sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (2.05 g, 9.62 mmol) and 2-amino-4-bromobenzamide (1.89 g, 8.75 mmol) was added trimethylsilyl polyphosphate (˜15 mL) and the mixture was stirred overnight at 120° C. Equal volumes of EtOAc and water were added and the resulting solution was stirred for 1 h. The EtOAc layer was washed with brine, dried over Na2SO4 and then concentrated under reduced pressure. Et2O was added and evaporated. Trituration of the residue with hexanes, followed by collection of the solid by filtration afforded 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (2.49 g, 77%). 1H NMR (300 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.76 (s, 1H), 7.97-8.07 (m, 2H), 7.88 (d, J=8.3 Hz, 1H), 7.69-7.81 (m, 2H);
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33]>C1COCC1>[O:20]=[C:12]1[C:11](=[C:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH:10]=3)[CH2:6][O:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Reactant: CCCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added butyryl chloride (19.6 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was filtered and rinsed with MEOH and EtOAc/hexanes (1:1) to afford the title compound (46.2 mg, 73%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2][C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])CS.C(N(CC)CC)C>C(O)C>[CH2:16]([O:15][C:11]([C:1]1[S:2][C:3]([S:4][CH3:5])=[C:6]([C:9]#[N:10])[C:7]=1[NH2:8])=[O:14])[CH3:17]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: CCOC(=O)CS
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1sc(SC)c(C#N)c1N
Temperature: 65 °C

Procedure:
Stir a slurry of bis(methylthio)methylenepropanedinitrile, prepared in preparation 34, (69.29 g, 407 mmol) in ethanol (1.1 L) under nitrogen at rt then add ethyl thioglycolate (44.9 mL, 407 mmol) followed by triethylamine (56.7 mL, 407 mmol). Heat the resulting mixture at 65° C. for 30 min. Cool slowly to 35° C. over 45 min, then cool to 3° C. over 20 min and maintain at that temperature for 20 min. Collect precipitate by filtration, wash with cold ethanol and ether to afford the title compound: 1H NMR (CDCl3) δ 5.77 (bs, 2H), 4.28 (q, J=7.1, 2H), 2.64 (s, 3H), 1.33 (t, J=7.1, 3H); TLC (25% hexanes/ethyl acetate) Rf=0.25).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][C@H:2]1[CH2:7][N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9]
Reactant: Brc1ccccn1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H]1CN(c2ccccn2)CCN1C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 48 h
Yield: 46.9 %

Procedure:
To a solution of tert-butyl (2S)-2-methylpiperazine-1-carboxylate (8 g, 39.94 mmol) in DMSO (25 ml) was added 2-bromopyridine (6.594 g, 41.74 mmol), and DIEA (15.48 g, 119.78 mmol). After stirring 2 days at 120° C., the resulting solution was quenched by the addition of DCM (200 ml), washed with water (3×300 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified via silica gel chromatography (3% ethyl acetate in petroleum ether) to afford (S)-tert-butyl 2-methyl-4-(pyridin-2-yl)piperazine-1-carboxylate as a red oil (5.2 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 105 %

Procedure:
To a solution of the methyl 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate from step 1 (3.75 g, 8.6 mmol) in methanol (10 mL) and tetrahydrofuran (30 mL) was added 10% aqueous sodium hydroxide (10 mL). The solution was stirred for 20 hours at ambient temperature. The resulting slurry was concentrated to half volume and acidified to a pH of about 2 with 1M hydrochloric acid. The resulting solid was collected by vacuum filtration to provide the title compound largely present as (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (yellow solid, 3.79 g, quantitative yield). LC/MS on 4.6×50 mm C-18 column, tR=6.74 minutes (10 to 90% acetonitrile/water over 8 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 420 (M+H); HRMS Calculated for C24H22ClN3O2: 420.1473 (M+H)+. Found: 420.1449; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.55 (m, 6H), 1.64-1.75 (m, 2H), 1.75-1.87 (m, 1H), 1.99-2.09 (m, 1H), 2.15-2.23 (m, 1H), 2.78-2.91 (m, 2H), 3.00 (d, J=16.11 Hz, 1H), 4.89 (dd, J=9.26, 5.77 Hz, 1H), 7.14 (dd, J=9.00, 1.75 Hz, 1H), 7.34 (d, J=1.88 Hz, 1H), 7.63 (d, J=8.86 Hz, 1H), 7.73 (s, 1H), 7.76 (s, 1H), 7.94 (d, J=7.79 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:21])[C:13]([NH:15][N:16]=[CH:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH3:2].[CH3:22]C(C)=O.[C:26](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1.O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:21])[C:13]([N:15]([CH3:22])[N:16]=[CH:17][CH:18]([CH3:19])[CH3:20])=[O:14])[CH3:2].[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:21])[C:13](=[N:15][N:16]=[CH:17][CH:18]([CH3:19])[CH3:20])[O:14][CH3:26])[CH3:2]
Reactant: CC(C)=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=CC(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Product: CCc1cc(C)cc(CC)c1C(=O)C(=NN=CC(C)C)OC
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=CC(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a 50 mL volume three-necked flask, 5.0 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(2-methyl-1-propylidene)hydrazine ((40-a)-(14)-4), 19 ml of acetone, 7.19 g of potassium carbonate and 2.13 ml of dimethyl sulfate were added and the mixture was stirred at room temperature for 6 hours. Water and toluene were added to the reaction mixture and the resultant was extracted. Further, aqueous layer was extracted with toluene two times. The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant was subjected to column chromatography (hexane:ethyl acetate=6:1 to 2:1) to give 2.99 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(2-methyl-1-propylidene)hydrazine ((40-b)-(15)-4) and 0.28 g of methyl 2-(2,6-diethyl-4-methylphenyl)-N-(2-methyl-1-propylidene)-2-oxoethanehydrazonate (x-2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5])[CH3:2].N1C=CC=CC=1.B(O)(O)[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:8]=[C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:10]=1)=[O:5])[CH3:2]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
To a round bottom flask containing 5-tert-Butyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.5 g, 2.6 mmol) stirring in 25 mL DCM was added Pyridine (0.95 mL, 11.7 mmol), p-tolylboronic acid (1.1 g, 8.1 mmol), Cu(OAc)2 (0.75 g, 4.1 mmol) and 4 A molecular sieves (0.75 g). The reaction stirred at room temperature for 14 h under air. The resulting mixture was filtered through a pad of diatomaceous earth and the filtrate concentrated in vacuo to afford a light green solid. The crude material was purified by Flash chromatography to afford (0.64 g, 83%) the desired product as a clear oil (0-50% EtOAc:hexanes on silica gel). Expected mass=286. Observed mass=287.
Reaction SMILES: [C:1]1([PH:7](=[O:15])[O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1>[C:1]1([P:7](/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:15])[O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[PH](OC1CCCCC1)c1ccccc1
Reactant: C=CCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCC/C=C/P(=O)(OC1CCCCC1)c1ccccc1
Yield: 98 %

Procedure:
In toluene (2 ml)under a nitrogen atmosphere at 100° C. for 20 hours, 1 mmol of cyclohexyl phenylphosphinate and 1 mmol of 1-octene were allowed to react using 3 molar % of Rh(PPh3)3Br as a catalyst to give cyclohexyl phenyl[(E)-1-octen-1-yl]phosphinate in a yield of 98%.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=1.[CH:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=2)=[O:25])=[CH:27][CH:28]=1)([CH3:19])[CH3:18]
Reactant: CCN(CC)CCSc1nnc(N)s1
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCSc1nnc(NC(=O)c2ccc(C(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole (2.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Isopropylbenzoic acid (1.6 g) and carbonyldiimidazole (1.8 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 3.5 g of the aimed compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=1.C1OCCOCCOCCOCCOCCOC1.[F-].[K+]>CS(C)=O.CCOCC>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCN(CC)CCCCOc1ccc2[nH]ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCN(CC)CCCCOc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
260 mg (1 mmol) Diethyl-[4-(1H-indol-5-yloxy)-butyl]-amine in 2 ml DMSO were treated with 175 mg (1 mmol) 1-bromo-4-fluorobenzene and 26.4 mg (0.1 mmol) 18-crown-6 and 182 mg (1 mmol) KF on alox. The suspension was stirred at 120° C. for 2 h, additional 175 mg (1 mmol) 1-bromo-4-fluorobenzene, 26.4 mg (0.1 mmol) 18-crown-6 and 182 mg (1 mmol) KF on alox were added. The suspension was stirred for 1 h, cooled to RT and diluted with ether and filtered. The solution was washed with 1M NaOH and water, and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 4:1 yielded 205 mg (48%) {4-[1-(4-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine as light yellow oil, MS: 415 (MH+, 1Br). (analogously to William J. Smith III, J. Scott Sawyer, Tetrahedron Letters 1999, Vol.37, No.3, 299-302.)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1.[C:17](O)(=[O:19])[CH3:18]>C(OCC)(=O)C>[C:17]([O:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1)(=[O:19])[CH3:18]
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc2c3ccccc3[nH]c(=O)n2n1

Procedure:
Three grams (0.014 mole) of the product of Example 3 [2-(hydroxymethyl)pyrazolo[1,5-c]quinazolin-5(6H)-one] is refluxed with 250 ml of glacial acetic acid for 20 hours under nitrogen. The solution is cooled and stripped to a solid residue which is dissolved in a mixture of ethyl acetate-absolute ethanol. The volume of solution is reduced and the concentrated solution set aside at 5°. The precipitate is filtered off to give 3.5 g of product. Recrystallization from ethyl acetate-absolute ethanol gives 3.1 g of analytically pure title compound, m.p. 177°-179°.
Reaction SMILES: Cl[C:2]1[N:21]=[CH:20][C:19](Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:5].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C1(CNCC2CCCCC2)CCCCC1.[CH3:47][C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[C:52]([CH3:54])[CH:53]=1>CO.O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH2:7][NH:6][C:4]([C:3]1[C:2]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[N:21][CH:20]=[C:19]([C:50]2[CH:51]=[C:52]([CH3:54])[CH:53]=[C:48]([CH3:47])[CH:49]=2)[CH:18]=1)=[O:5]
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: COc1ccc(CNC(=O)c2cc(Cl)cnc2Cl)cc1OC
Reactant: OB(O)c1cccnc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C1CCC(CNCC2CCCCC2)CC1
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)cnc2-c2cccnc2)cc1OC
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 2,5-dichloro-N-(3,4-dimethoxybenzyl)nicotinamide (3-2, 0.100 g, 0.293 mmol) and 3-pyridyl boronic acid (0.172 g, 1.17 mmol) in methanol (1 mL) was added N,N-dicylohexylmethylamine (0.070 mL, 0.322 mmol), and bis(tri-t-butylphosphine)palladium (0.030 g, 0.058 mmol) and the system was stirred at 75° C. in an oil bath overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford a yellow oil. This oil (0.035 g, 0.091 mmol) was re-dissolved in dioxane (0.2 mL) and to it was added 3,5-dimethylphenyl boronic acid (0.075 g, 0.502 mmol), N,N-dicylohexylmethylamine (0.022 mL, 0.100 mmol), and bis(tri-t-butylphosphine)palladium (0.009 g, 0.018 mmol) and the system was stirred overnight at 90° C. in an oil bath. The reaction was then cooled to room temperature, partitioned between ethyl acetate and water and dried over magnesium sulfate. The reaction mixture was filtered and purified via normal phase chromatography (0→10% MeOH in DCM) followed by reverse phase chromatography (10%→65% 0.1% TFA in water: 0.1% TFA in ACN) and free based with saturated sodium carbonate to afford the title compound (1-3) as a white powder. ESI+ MS [MH]+ C28H27N3O3=454.34.
Reaction SMILES: ClC1C=C(C(C2C=CC=C(Cl)C=2)N2CCNCC2)C=CC=1.C1([NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:28])=[O:27])CC1>C(N(C(C)C)C(C)C)C>[CH2:29]([S:26]([NH2:25])(=[O:28])=[O:27])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Agent: Clc1cccc(C(c2cccc(Cl)c2)N2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCS(N)(=O)=O
Yield: 270.4 %

Procedure:
1-[Bis(3-chlorophenyl)methyl]piperazine (5.00 g, 15.5 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (4.15 g, 17.30 mmol) were refluxed in N-ethyldiisopropylamine (25 ml) for 7 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[bis(3-chlorophenyl)methyl)]-1-piperazinyl]hexanesulfonamide (7.73 g) as an oil (yield based on 1-[bis(3-chlorophenyl)methyl]piperazine: 94.7%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH2:8]>>[C:4]1(=[O:5])[O:6][C:1](=[O:7])[CH:2]=[CH:3]1.[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:8])=[O:5].[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:8])=[O:5]
Reactant: O
Agent: O=C1C=CC(=O)O1
Product: O=C(O)/C=C/C(=O)O
Product: O=C(O)/C=C\C(=O)O

Procedure:
In a process for stripping low-boiling impurities from crude maleic anhydride produced by the vapor phase oxidation of a hydrocarbon feedstock; the improvement which comprises, passing the lights stripper overhead vapor containing, by volume, about 1 to 30 percent maleic anhydride and about 10 to 70 percent water, through a condenser system maintained at a temperature in the range of from about 25° C. to 40° C. at less than about 50 millimeters of mercury pressure thereby to obtain solid maleic anhydride having less than 300 ppm of maleic acid and fumaric acid impurities.
Reaction SMILES: [SH:1][CH:2]([CH3:10])[C:3]([NH:5][CH2:6][C:7](O)=[O:8])=[O:4].C(N(CC)CC)C.ClC(OCC)=O>C(Cl)Cl>[CH3:10][CH:2]1[S:1][C:7](=[O:8])[CH:6]=[N:5][C:3]1=[O:4]
Reactant: CC(S)C(=O)NCC(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1SC(=O)C=NC1=O
Temperature: 25 °C
Yield: 33.8 %

Procedure:
A solution of N-(2-mercaptopropanoyl) glycine (5 g, 0.031 mole) in methylene chloride (250 ml) was chilled in an ice bath and triethylamine (3.1 g, 0.031 mole) was added. Ethyl chloroformate (3.4 g, 0.031 mole) in methylene chloride (25 ml) was added dropwise over 15 minutes. The resulting solution was then stirred for two and a half hours at room temperature. The methylene chloride was washed with water, saturated aqueous sodium chloride, and dried over magnesium sulfate. Filtration and evaporation of the solvent afforded the crude product as a yellow oil which was chromatographed on silica-gel (CHCl3) to yield colorless crystals of 6-methyl[1,4]thiazine-2,5-dione (1.5 g, 30%) after crystallization from ether-hexane, m.p. 81°-83°.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1.C(N(CC)CC)C.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][OH:44])=[CH:38][CH:37]=1>C(#N)C>[OH:44][CH2:43][CH2:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:24]2[CH2:25][CH2:26][C:20]3([O:19][CH2:18][CH2:17][N:16]([C:14]([C:12]4[N:13]=[C:9]([CH3:8])[S:10][CH:11]=4)=[O:15])[CH2:21]3)[CH2:22][CH2:23]2)=[CH:37][CH:38]=1
Reactant: OCCc1ccc(CBr)cc1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4ccc(CCO)cc4)CC3)C2)cs1
Reaction time: 8 h

Procedure:
To a solution of (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.791 g) and triethylamine (0.697 mL) in acetonitrile (10 mL) was added 2-(4-(bromomethyl)phenyl)ethanol (example 16, step a) and the resulting mixture stirred overnight. The solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (25 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was separated and extracted with ethyl acetate (2×25 mL). The combined organic solutions were washed with brine (25 mL), dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a yellow oil. Yield 0.76 g.