Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[N:17]1([S:14]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([O:1][CH2:30][CH2:31][CH3:32])[CH:3]=3)[NH:7][C:6]=2[C:11]([NH2:13])=[O:12])(=[O:16])=[O:15])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CCCI
Reactant: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 50 (29 mg, 0.089 mmol) in 1 mL of dimethylformamide was added cesium carbonate (86 mg, 0.27 mmol) and 1-iodopropane (0.0094 mL, 0.096 mmol). After one hour, another portion (0.005 mL) of 1-iodopropane was added. After an additional hour, 0.5 mL of water was added to solubilize the material, and the resulting mixture was purified by preparative reversed phase HPLC to provide the titled product as a white solid. HRMS (ES) exact mass calculated for C16H22N3O5S (M+H+): 368.1275. Found 368.1291.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:10][C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>CC(N(C)C)=O>[Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:10][C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=1[F:25]
Reactant: Cc1cnc(Cn2c(C)cc(O)c(Cl)c2=O)cn1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-chloro-4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one (2.48 g, 9.3 mmol) in DMA (7 mL)was added K2CO3 (1.54 g, 11.0 mmol) followed by 2,4-difluorobenzyl bromide (1.2 mL, 9.3 mmol). The reaction mixture stirred at room temperature under nitrogen for 1.5 hours. The solvent was distilled in vacuo. The resulting residue was diluted in dichloromethane and washed with water. The organic extracts were concentrated and the resulting residue was purified by flash column chromatography (ethyl acetate). The appropriate fractions were combined, and concentrated. 1H NMR (CD3OD, 400 MHz) δ 8.49 (d, 1H, J=1.2 Hz), 8.40 (s, 1H), 7.59 (m, 1H), 7.04 (m, 2H), 6.54 (s, 1H), 5.41 (s, 2H), 5.28 (s, 2H), 2.54 (s, 3H), 2.40 (s, 3H); ES-HRMS m/z 392.1014 (M+H calculated for C19H17N3O2ClF2 requires 392.0972).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH2:26][CH2:27][O:28]C4CCCCO4)=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.Cl.O>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:11])=[O:12])[CH2:3][CH2:2]1
Reactant: O=C(Nc1cnc(CCOC2CCCCO2)cn1)[C@H](CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cnc(CCO)cn1)[C@H](CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A mixture of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)-N-{5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyrazin-2-yl}propanamide (118 mg) in THF (10 mL) was added 1 M hydrochloric acid (10 mL) at room temperature, followed by stirring for 2 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After concentration, the obtained crude product was purified by silica gel column chromatography (wetting with hexane:ethyl acetate=1:1, chloroform:methanol=1:0-10:1) to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(2-hydroxyethyl)pyrazin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamide (94 mg) as a white amorphous substance.
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[NH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]O)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[I:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(CO)cc1
Reactant: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2I)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2nc(-c3ccc(OC)cc3)c(I)c3ccc(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 25-mL flask under argon, 4-iodo-7-methoxy-3-(4-methoxyphenyl)isoquinolin 1(2H)-one (500 mg, 1.23 mmol) is dissolved in 15 mL of anhydrous THF. 4-methoxybenzyl alcohol (217 μl, 1.84 mmol), triphenylphosphine (482 mg, 1.84 mmol) and diisopropyl azodicarboxylate (261 μl, 1.84 mmol) are added to the previous solution. After stirring overnight at ambient temperature, the medium is hydrolyzed with 20 mL of water and extracted with 3×20 mL of dichloromethane. The organic phases are washed with 3×10 mL of water, dried over MgSO4 and concentrated under vacuum. Compound 69 is obtained by recrystallization from ether (358 mg, 55%). 1H NMR CDCl3 δ 7.94 (s, 1H), 7.89 (d, 1H), 7.34 (d, 1H), 6.98 (d, 2H), 6.91 (d, 2H), 6.81 (d, 2H), 6.72 (d, 2H), 5.19 (s, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.74 (s, 3H);
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9](C(OC(C)(C)C)=O)[C:8]=2[C:19]([O:21]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:24][NH2:25]>O>[C:1]1([C:7]2[CH:11]=[CH:10][NH:9][C:8]=2[C:19]([NH:24][NH2:25])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(-c2ccccc2)ccn1C(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Product: NNC(=O)c1[nH]ccc1-c1ccccc1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A solution of 1-tert-butyl 2-methyl 3-phenyl-1H-pyrrole-1,2-dicarboxylate (7.00 g, 23.0 mmol) in hydrazine monohydrate (30.0 mL, 617 mmol) was heated at 100° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The solid precipitated was filtered through a Büchner funnel and dried under reduced to pressure to yield 3-phenyl-1H-pyrrole-2-carbohydrazide (3.80 g, 81.0%) as a white solid. LCMS method B-3: retention time 1.54 min, [M+1]=202.0. 1H NMR (400 MHz, DMSO-d6) δ ppm: 4.32 (s, 2H), 6.23 (d, J=2.8 Hz, 1H), 6.88 (d, J=2.8 Hz, 1H), 7.21-7.26 (m, 1H), 7.32-7.36 (m, 2H), 7.44-7.47 (m, 2H), 8.37 (s, 1H), 11.40 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][CH:6]=[C:7]([CH:9]=O)[N:8]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12][NH2:13]>>[CH2:16]([O:15][C:11](=[O:14])[NH:12][N:13]=[CH:9][C:7]1[N:8]=[C:4]([CH2:3][O:2][CH3:1])[NH:5][CH:6]=1)[CH3:17]
Reactant: CCOC(=O)NN
Reactant: COCc1nc(C=O)c[nH]1
Product: CCOC(=O)NN=Cc1c[nH]c(COC)n1

Procedure:
A 19.60 gm. portion of 2-(methoxymethyl)-4-imidazolecarboxaldehyde and 16.02 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 186°-190° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:38]3[CH:39]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:32]#[N:33])[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)c1
Yield: 20 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (20%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[C:8]([NH:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:9].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:45]=[O:46])C>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][CH:20]=[C:7]2[C:6]=1[CH:45]([OH:46])[N:10]([C:11]([CH3:19])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:8]2=[O:9]
Reactant: CN(C)C=O
Reactant: COCOc1cccc(C(=O)NC(C)(C)c2ccccc2)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1cccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 96.2 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (8.07 g, 27.0 mmol) was dissolved in THF (320 mL), and the solution was treated with TMEDA (13.0 mL, 85.4 mmol), sec-butyllithium-hexane solution (0.99 mol/L, 87.1 mL, 86.3 mmol) and DMF (4.60 mL, 59.3 mmol), followed by purification by slurry using hexane to obtain 4-methoxymethoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (8.50 g, yield 96%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:10]1[CH:22]=[CH:21][C:13]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[CH:12][CH:11]=1>C1COCC1>[C:1]([C:10]1[CH:22]=[CH:21][C:13]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[CH:12][CH:11]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CCCCCCC
Reactant: O=C1CCCC1Cc1ccc(I)cc1
Solvent: C1CCOC1
Product: CCCCCCC#Cc1ccc(CC2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.1 g (10 mmol) of 1-Octyne was added to a flame dried 25 mL flask charged with a 10 mL THF solution of 1.49 g (5 mmol) of 2-(4′-iodobenzyl)cyclopentanone (3). After degassing for 30 minutes, 2 mL triethylamine, 5 mg of CuI and 10 mg of Pd(PPh3)4 were added under N2 protection. The reaction was stirred at room temperature for 6 hrs, then the solvent removed in vacuo and residue chromotographed with chloroform eluent to give 1.25 g (93%) as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:39])[CH:15]([C:30]2[CH:35]=[CH:34][C:33]3[O:36][CH2:37][O:38][C:32]=3[CH:31]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=2[CH2:27][CH2:28][CH3:29])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:40][Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].IC>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:39])[C:15]([C:30]2[CH:35]=[CH:34][C:33]3[O:36][CH2:37][O:38][C:32]=3[CH:31]=2)([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=2[CH2:27][CH2:28][CH3:29])[CH3:40])(=[O:12])=[O:11])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CCCc1cc(C(=O)OC)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Reactant: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCc1cc(C(=O)OC)ccc1OC(C)(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 0.516 g (0.93 mmol) of the product of Example 57 dissolved in 1.0 mL of anhydrous THF was added 2.80 mL (2.80 mmol) of a 1.0M solution of lithim bis(trimethylsilylamide) in THF at -78° C. under a nitrogen atmosphere. The reaction mixture was magnetically stirred at -78° C. for 1 hour, then 174 μL (2.80 mmol) of iodomethane was added via syringe. The reaction was allowed to warm to room temperature and was stirred an additional 14 hours. The reaction was next quenched with excess 10% aqueous NaHSO4 and partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with CHCl3 --MeOH--NH4OH (90:10:1). Evaporation of the purified fractions and drying in vacuo afforded 0.293 g (55%) of the title compound as an amorphous solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C-]#N.[Na+].[N:30]12CCN(CC1)C[CH2:31]2.O>CS(C)=O>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:12][CH:11]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:31]#[N:30])[N:7]=1
Reactant: CC(C)(C)CN(Cc1ccc(Cn2cncn2)cc1)c1ccnc(Cl)n1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)CN(Cc1ccc(Cn2cncn2)cc1)c1ccnc(C#N)n1
Temperature: 70 °C
Reaction time: 5 h
Yield: 69167.1 %

Procedure:
(2-Chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-(4-[1,2,4]triazol-1-ylmethyl-benzyl)-amine (160 mg, 0.43 mmoles) and sodium cyanide (0.1 g, 2.2 mmoles) are dissolved in 5 ml of DMSO and 1,4-diaza bicyclo[2,2,2]octane (23 mg, 0.2 mmoles) is added at rt. The mixture is stirred at rt for 5 h at 70° C. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 50 g of desired 4-[(2,2-dimethyl-propyl)-(4-[1,2,4]triazol-1-ylmethyl-benzyl)-amino]-pyrimidine-2-carbonitrile in 32% yield.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[CH:8][C:7]2=[O:17])[CH2:3][CH2:2]1.N1C=CC=CC=1.S(OC)(O[C:28](SC)([S:31][CH3:32])[S:29][CH3:30])(=O)=O>O1CCOCC1>[CH3:30][S:29][C:28]([S:31][CH3:32])=[C:8]1[C:9](=[O:16])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([NH:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:7]1=[O:17]
Reactant: COS(=O)(=O)OC(SC)(SC)SC
Reactant: O=c1cc(O)c2ccccc2n1NCC1CC1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CSC(SC)=C1C(=O)c2ccccc2N(NCC2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To the suspension of 1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (984.4 mg, 4.28 mmol) in 1,4-dioxane (40 mL) was added pyridine (2.8 mL, 34.6 mmol) and tris(methylthio)methyl methyl sulfate (prepared using the procedures in SYNTHESIS, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi) (2.26 g, 8.55 mmol) at room temperature. The suspension was put in a preheated oil bath at 55° C. and stirred for 15 minutes. To the solution was added another portion of tris(methylthio)methyl methyl sulfate (2.26 g, 8.55 mmol) and the mixture was stirred at 55° C. for 15 minutes and cooled to room temperature. The mixture was concentrated in vacuo and the residue was diluted with dichloromethane and loaded on a silica gel column and eluted with dichloromethane, 2% ethyl acetate/dichloromethane and then 5% ethyl acetate/dichloromethane to give 3-[bis(methylthio)methylene]-1-[(cyclopropylmethyl)amino] quinoline-2,4(1H,3H)-dione (852.1 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ 0.15 (m, 2 H) 0.42 (m, 2 H) 0.98 (m, 1 H) 2.61 (s, 6 H) 2.73 (t, J=6.43 Hz, 2 H) 6.05 (t, J=5.88 Hz, 1 H) 7.15 (m, 1 H) 7.64 (m, 1 H) 7.76 (d, J=8.09 Hz, 1 H) 7.98 (m, 1 H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.Br[Zn][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([C:2]2[C:10]3[O:9][C:8]([C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=4)=[N:7][C:6]=3[CH:5]=[C:4]([OH:19])[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: Br[Zn]C1CCCC1
Product: Oc1ccc(-c2nc3cc(O)cc(C4CCCC4)c3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 35, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole, and bromo(cyclopentyl)zinc. The desired product was obtained as a white solid, m.p. 220–222° C.; MS m/e 296 (M+H)+.
Reaction SMILES: [Br-].[C:2]([O-:5])(=[O:4])[CH3:3].[Na+].[Cl:7][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[CH:10][C:11]([CH3:16])=[C:12]([CH:15]=1)[C:13]#[N:14]>CN(C=O)C.O>[C:2]([O:5][CH2:16][C:11]1[CH:10]=[C:9]([N+:17]([O-:19])=[O:18])[C:8]([Cl:7])=[CH:15][C:12]=1[C:13]#[N:14])(=[O:4])[CH3:3]
Reactant: CC(=O)[O-]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1C#N
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1cc([N+](=O)[O-])c(Cl)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
The above partially purified bromide was dissolved in DMF (300 mL) and cooled to 0° C. Sodium acetate (18.0 g, 0.22 mol) was added. The mixture was stirred at 60° C. for 30 min. After cooling, the mixture was diluted with H2O and extracted with EtOAc. The EtOAc extract was washed with H2O (2×), dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel and elution with hexanes:EtOAc (9:1) yielded a front fraction containing 5-chloro-4-nitro-2-methylbenzonitrile and dibromide. Further elution with hexanes:EtOAc (2:1) gave the title compound (19.5 g, 47%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:35]=[CH:34][C:26]2[O:27][CH:28]([C:31](O)=[O:32])[CH2:29][O:30][C:25]=2[CH:24]=1>>[OH:22][C:23]1[CH:35]=[CH:34][C:26]2[O:27][CH:28]([C:31]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:32])[CH2:29][O:30][C:25]=2[CH:24]=1
Reactant: O=C(O)C1COc2cc(O)ccc2O1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Product: O=C(C1COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 80 %

Procedure:
That compound is obtained a yield of 80% starting from 1-[bis(4-fluorophenyl)methyl]piperazine and 6-hydroxy-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]#[CH:21]>C(#N)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:21][C:20]#[CH:19])=[C:3]([S:9]([NH2:12])(=[O:10])=[O:11])[CH:4]=1
Reactant: C#CCBr
Reactant: Cc1ccc(O)c(S(N)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccc(C)cc1S(N)(=O)=O
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
A mixture of 24.3 g of 2-hydroxy-5-methylphenylsulfonamide, 36.0 g of potassium carbonate, 16.7 g of propargyl bromide and 500 ml of acetonitrile is stirred at 50° C. for 4.5 hours. The reaction mixture is then filtered, and concentrated by evaporation. The yield after recrystallisation from ethyl acetate is 23.9 g of 5-methyl-2-propargyloxyphenylsulfonamide, m.p. 169°-170° C.
Reaction SMILES: CO[CH:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:9]1([C:4](=[CH:3][S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC=C(C(=O)OC)c1ccccc1
Reactant: Sc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(=CSc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2.0 g (10.4 mmol) of methyl 3-methoxy-2-phenyl-2-propenoate 1.26 g (11.4 mmol) of thiophenol and 10 mg of p-toluenesulfonic acid monohydrate in 28 ml of toluene was stirred at 90° C. for 9 hours. The reaction mixture was cooled to room temperature and then concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 1.75 g of methyl 2-phenyl-3-(phenylthio)-2-propenoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:16][CH2:17][CH:18](Br)[CH2:19][CH3:20]>>[CH2:17]([CH:18]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[N:8]=[N:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:19][CH3:20])[CH3:16]
Reactant: COc1ccc(NC(=O)C(C)(C)C)nn1
Reactant: CCC(Br)CC
Product: CCC(CC)c1cc(OC)nnc1NC(=O)C(C)(C)C
Yield: 65.5 %

Procedure:
Using a procedure analogous to Example 17B, from N-(6-methoxy-pyridazin-3-yl)-2,2-dimethyl-propionamide (6.09 g, 29.14 mmol) and Grignard reagent prepared from 3-pentyl bromide (18.1 mL, 160.3 mmol) and Mg (3.84 g, 160.26 mmol) gives the title compound (5.32 g, 19.1 mmol, 65%). 1H NMR (CDCl3): δ. 0.84 (t, J=7.5 Hz, 6H), 1.36 (s, 9H), 1.50-1.72 (m, 4H), 3.50-3.70 (m, 1H), 4.07 (s, 3H), 6.96 (s, 1H) ppm. ES-MS (m/z): calcd for C15H25N3O2 (M+H)+: 280.4. found: 280.2.
Reaction SMILES: FC(F)(F)CO[C:5]1[CH:10]=[CH:9][N:8]2[N:11]=[C:12]([S:14]([NH:17][C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])(=[O:16])=[O:15])[N:13]=[C:7]2[N:6]=1.[CH3:28][NH:29][CH3:30].Cl>O>[CH3:28][N:29]([CH3:30])[C:5]1[CH:10]=[CH:9][N:8]2[N:11]=[C:12]([S:14]([NH:17][C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])(=[O:16])=[O:15])[N:13]=[C:7]2[N:6]=1
Reactant: O=S(=O)(Nc1c(Cl)cccc1Cl)c1nc2nc(OCC(F)(F)F)ccn2n1
Reactant: CNC
Agent: Cl
Solvent: O
Product: CN(C)c1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
The starting 5-(2,2,2-trifluoroethoxy)-N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide (1.5 g, 3.4 mmol) was dissolved in 5 ml (44 mmol) of 50% aqueous dimethylamine. After stirring for 48 hours at room temperature the solution was diluted with water and acidified with 6N aqueous HCl. The solid which separated was collected by filtration and treated with 0.5N aqueous NaOH and filtered to remove insoluble material. The filtrate was acidified to precipitate a solid. The solid was collected and dried to yield 1.0 g (60%) of the desired product as a solid, mp >310° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: Cl[C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](Cl)=[N:4][N:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][CH2:18][NH:17][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([NH:17][CH2:18][CH2:19][CH2:20][OH:21])=[N:4][N:3]=1
Reactant: NCCCO
Reactant: Clc1nnc(Cl)c2cc3ccccc3cc12
Product: OCCCNc1nnc(NCCCO)c2cc3ccccc3cc12
Temperature: 130 °C

Procedure:
A mixture of 1,4-dichloro-2,3-diaza-anthracene (4.84 g) and dry 1-amino-3-propanol (48 ml) is heated at 130° C. for 24 hours in an autoclave. After cooling to room temperature and dilution of the reaction mixture with a solution of potassium carbonate (96 g) in water (240 ml) a crystalline solid separates which is filtered and recrystallized from aqueous ethanol to give 6.09 g of 1,4-bis[N-(3-hydroxypropyl)amino]-2,3-diaza-anthracene, m.p. 225°-228° C.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)(=[O:5])=[O:4])[CH3:2].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>>[CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[C:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH:19]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Nc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Product: CCS(=O)(=O)Nc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Yield: 113.3 %

Procedure:
Beginning with 1.45 gm (6.5 mMol) 5-ethanesulfonylamino-1H-indole and 1.03 mL (3.4 mMol) 1-methyl-4-piperidone, 1.23 gm (59.7%) of the title compound were recovered as pale orange crystals.