Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[H-].[Na+].Cl[C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=1>CN(C=O)C.CO>[F:20][C:2]([F:1])([F:19])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([O:18][C:24]4[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: N#Cc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cn1
Temperature: 50 °C
Reaction time: 18 h
Yield: 27.2 %

Procedure:
A solution of 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (150 mg, 0.52 mmol) and sodium hydride (60% dispersion in oil, 22.98 mg, 0.57 mmol) in DMF (5 mL) was stirred for 30 minutes at ambient temperature under nitrogen. 5-Chloropicolinonitrile (80 mg, 0.57 mmol) was added to the reaction mixture. The resulting solution was stirred at 50° C. for 18 hours. The reaction mixture was diluted with a few drops of MeOH. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 5-[[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]oxy]pyridine-2-carbonitrile (55.0 mg, 27%) as a solid.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[NH:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:25]=[C:24]2[C:19]([C:20](=[O:31])[C:21]([C:28]([OH:30])=[O:29])=[CH:22][N:23]2[CH2:26][CH3:27])=[CH:18][C:17]=1[F:32]>N1C=CC=CC=1>[CH2:26]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([F:32])=[C:16]([N:11]3[CH2:12][CH2:13][NH:14][CH:9]([CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:10]3)[CH:25]=2)[C:20](=[O:31])[C:21]([C:28]([OH:30])=[O:29])=[CH:22]1)[CH3:27]
Reactant: c1ccc(OCC2CNCCN2)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COc4ccccc4)C3)cc21
Temperature: 130 °C
Yield: 46.9 %

Procedure:
A mixture of 2 g of 3-phenoxymethylpiperazine and 701 mg of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of pyridine was heated under argon in a pressure bottle at 130° C. for 18 hours. The solvents were removed and the residue chromatographed on silica gel, eluting with chloroform:methanol (9:1). The appropriate fractions were combined, evaporated, triturated with methanol and ether, then dried, giving 519 mg of the desired compound, mp 198°-200° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[CH:21][CH:22]=2)[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CC(CCc1ccc(N)cc1)c1cccc(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)CC(CCc1ccc(NS(=O)(=O)c2ccccc2)cc1)c1cccc(C#N)c1
Reaction time: 1 h
Yield: 41 %

Procedure:
Part A. methyl 3-(3-cyanophenyl)-5-(4-aminophenyl)pentanoate (0.100 gm, 0.325 mmol) was dissolved in dioxane and 0.5 mL of 1 N NaOH was added, followed by benzenesulfonyl chloride. The solution was stirred for 1 hour, quenched in 1 N HCl and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over MgSO4. The solvent was removed under vacuum and the residue was chromatographed on silica gel eluting ethyl acetate:toluene (20:80, v:v) to give methyl beta-[3-(cyano)phenyl]-4-[(phenylsulfonyl)amino]benzenepentanoate as an oil 0.060 gm (41%). MS: (M+NH4)+ 466; 1H NMR (CDCl3): 1.9 (m, 2H), 2.35 (m, 2H), 2.6 (m, 2H), 3.15 (m, 1H), 3.55 (s, 3H), 6.95 (s, 4H), 7.45 (m, 5H), 7.55 (m, 2H), 7.75 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O>ClCCl>[Br:11][C:7]1[C:5]([NH2:6])=[CH:4][C:3]([O:9][CH3:10])=[C:2]([F:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(N)ccc1F
Solvent: ClCCl
Product: COc1cc(N)c(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 4-fluoro-3-methoxyaniline (9.87 g, 70 mmol) and N-bromosuccinimide (12.46 g, 70 mmol) in dichloromethane (150 ml) was stirred at room temperature for 1 h (exothermic). The reaction mixture was evaporated in vacuo to give a dark slurry which was chromatographed on silica gel (˜350 g) using a gradient elution 20-50% ethyl acetate in hexane to give the title compound as a brown solid (12.70 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[O:4].[C:26]([Cu])#[N:27]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:26]#[N:27])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(Br)c2c(Oc3ccccc3OC)cccc2c1O
Product: COC(=O)c1nc(C#N)c2c(Oc3ccccc3OC)cccc2c1O

Procedure:
The title compound was synthesized from 1-bromo-4-hydroxy-8-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester and CuCN in analogy to example 3a; MS-(+)-ion: M+1=351.4.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:24]#[CH:25]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[N:26]1([CH2:23][C:24]#[C:25][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)=[CH:12][CH:11]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C#CCN1CCCC1
Reactant: O=C(c1ccc(I)cc1)c1ccc(OC2CCCCO2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(c1ccc(C#CCN2CCCC2)cc1)c1ccc(OC2CCCCO2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
A 25 mL Schlenk flask was charged with (4-iodophenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (408 mg, 1 mmol), Pd(PPh3)2Cl2 (18 mg, 0.025 mmol), CuI (10 mg, 0.05 mmol), Et3N (10 ml) and 1-(prop-2-ynyl)pyrrolidine (165 mg, 1.5 mmol). The flask was flushed with argon three times and the mixture was stirred at 90° C. for 3 h. The solvent was evaporated under vacuum and the residue was purified by columnchromatography to give the desired product (312 mg, 80% yield)
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10](=[O:12])[CH2:11][CH:5]2[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH3:25]>CN(C)C=O>[CH2:24]([N:3]1[CH2:2][CH2:1][N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10](=[O:12])[CH2:11][CH:5]2[CH2:4]1)[CH3:25]
Reactant: CCBr
Reactant: O=C1CC2CNCCN2c2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN2c3ccccc3NC(=O)CC2C1
Temperature: 60 °C

Procedure:
To a solution of Example 1D (30 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (57 mg, 0.41 mmol) and bromoethane (10.3 μl, 0.14 mmol). The reaction was warmed to 60° C. for 14 hours. Excess potassium carbonate was filtered off. The solution was passed through a PS-isocyanate cartridge (Silicycle, 2 g) to trap leftover starting material. The solution was concentrated and purified by preparative HPLC with a gradient of acetonitrile and 0.1% trifluoroacetic acid in water to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.19-7.24 (m, 1H), 7.14-7.18 (m, 1H), 7.09-7.13 (m, 1H), 7.01 (dd, J=7.78, 1.37 Hz, 1H), 3.52-3.64 (m, 3H), 3.32-3.39 (m, 2H), 3.19-3.27 (m, 2H), 2.97-3.10 (m, 2H), 2.66 (dd, J=13.73, 7.02 Hz, 1H), 2.09 (d, J=13.12 Hz, 1H), 1.27 (t, J=7.32 Hz, 3H); MS (ESI) m/z 246.0 (M+H)+.
Reaction SMILES: [S:1]([CH2:4][S:5][C:6]1[S:7][C:8](=[CH2:13])[C:9]([CH3:12])([CH3:11])[N:10]=1)[C:2]#[N:3].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]Cl)=[CH:17][CH:16]=1>ClCCl>[S:1]([CH2:4][S:5][C:6]1[S:7][C:8](=[CH:13][S:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[C:9]([CH3:11])([CH3:12])[N:10]=1)[C:2]#[N:3]
Reactant: ClSc1ccc(Cl)cc1
Reactant: C=C1SC(SCSC#N)=NC1(C)C
Solvent: ClCCl
Product: CC1(C)N=C(SCSC#N)SC1=CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Thiocyanomethylthio-4,4-dimethyl-5-methylenethiazoline, 4.0 gm (prepared in a manner consistent with Examples 1 and 2) was added to 100 ml of dichloromethane. 3.11 gm of 4-chlorophenylthiochloride was added to the system. The system was stirred at room temperature for 48 hours. The product precipitated from solution. The product was filtered and air-dried to give 4.7 gm of the 2-thiocyanomethylthio-4,4-dimethyl-5-(4-chlorophenylthio)methylenethiazoline as an off-white solid, m.p. 122°-131° C. Listed as compound number 1 in Table I.
Reaction SMILES: [OH:1][CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].CCN(CC)CC.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C1COCC1>[OH:1][CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCCCCc1ccc(OCC(O)CC#CCCCC(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(OCC(O)CCCCCCC(=O)O)cc1

Procedure:
A mixture of 3.5 g of 8-hydroxy-9-(4-pentylphenoxy)-5-nonynoic acid, 0.3 g of Lindlar's catalyst, 2.5 ml of Et3N and 80 ml of THF was hydrogenated under 1 atm of hydrogen until the uptake hydrogen ceased. The solvent and catalyst were removed. The crude product was recrystallized in toluene to yield the title compound, mp 105.0°-105.5°. CI-MS (high resolution) (M+1=337.2298).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[O:18]1[CH2:23][CH2:22][CH:21]([N:24]2[CH:28]=[C:27]([NH2:29])[CH:26]=[N:25]2)[CH2:20][CH2:19]1>COCCO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[C:6]3[N:7]=[C:2]([NH:29][C:27]4[CH:26]=[N:25][N:24]([CH:21]5[CH2:22][CH2:23][O:18][CH2:19][CH2:20]5)[CH:28]=4)[N:3]=[CH:4][C:5]=3[N:10]=[N:9]2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(-n2nnc3cnc(Cl)nc32)cc1
Reactant: Nc1cnn(C2CCOCC2)c1
Solvent: COCCO
Product: Fc1ccc(-n2nnc3cnc(Nc4cnn(C5CCOCC5)c4)nc32)cc1
Temperature: 25 °C

Procedure:
A solution of 74.9 mg (0.30 mmol) 5-chloro-3-(4-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 60.2 mg (0.36 mmol) 1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-ylamine in 0.5 ml 2-methoxy-ethanol is stirred for 4 hours at 90° C. The reaction mixture is cooled to room temperature. The solvent is partially removed under vacuum and the residue is purified by preparative HPLC yielding “A20” as brown amorphous solid; HPLC/MS (B): 2.1 min, [M+H] 381;
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](O)=[O:36]>>[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:36]
Reactant: O=C(O)c1cccs1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CN(C(=O)c1cccs1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 2-thiophenecarboxylic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(2-thiophenecarbonyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 474 (M-H)-.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH2:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[CH3:30].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH3:30])=[CH:32][CH:33]=1)[CH3:28]
Reactant: CCc1ccc(O)cc1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2ccc(CC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 67.4 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 4-ethylphenol (0.34 g), 8 M potassium hydroxide solution (0.34 mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12 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 and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.59 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Reactant: Oc1ccc(-c2ncc(Cl)cn2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(Cl)cn3)cc2)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyrimidin-2-yl)-phenol (Preparation 19) and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a pale yellow solid (103 mg, 43.1%)
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[C:16]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[CH:15][C:14]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[N:13]3)[CH2:9]2)C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:16]2[N:12]([CH:10]3[CH2:9][NH:8][CH2:11]3)[N:13]=[C:14]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:15]=2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)nn2C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Fc1ccc(Cc2cc(-c3ccncc3)nn2C2CNC2)cc1
Temperature: 57 °C

Procedure:
To a flask charged with NH4CO2H (6.2 g, 98.4 mmol) was added MeOH (50 mL) and stirred to a solution, followed by addition of a solution of 4-[1-[1-(diphenylmethyl)azetidin-3-yl]-5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine (2.3 g, 4.85 mmol) in EtOAc (50 mL), and the mixture stirred to a homogenous solution. This was added to a second flask containing 10% Pd/C (0.84 g) in MeOH (100 mL) under N2, and the reaction mixture was heated to 57° C. under N2 for 5 hours. The mixture was cooled to room temperature and the solids removed by filtration through a GF/F filter set. The filtrate was concentrated and diluted with water (50 mL) and then saturated with NaOH. The emulsion was then extracted with CH2Cl2 (3×100 mL) followed by Et2O (4×100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (90:10:1 CH2Cl2/MeOH/NH4OH) to yield the title compound as a white solid, 0.892 g, 60%. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.61 (d, 2 H), 7.69 (d, 2 H), 7.06-7.14 (m, 2 H), 6.95-7.05 (m, 2 H), 6.42 (s, 1 H), 4.91-5.08 (m, 1 H), 4.29 (t, 2 H), 3.98 (s, 2 H), 3.61 (t, 2 H); m/z (APCI+) for C18H17N4F 309.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[CH3:15][CH:16]([CH3:22])[C:17](=O)[CH2:18][CH:19]=O>>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:17]([CH:16]([CH3:22])[CH3:15])[CH:18]=[CH:19][N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CC(C)C(=O)CC=O
Product: CC(C)c1ccn2nc(SCc3ccccc3)nc2n1
Yield: 96 %

Procedure:
This material was prepared in 96% yield from 3-amino-5-benzylthio-1,2,4-triazole and 4-methyl-3-oxopentanal following the general procedure described in Example 7. The desired product was isolated as a solid, m.p. 65°-66° C. IR and 1H NMR were in agreement with the assigned structure.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:6]=1[C:7]#[N:8])([CH3:3])[CH3:2].Cl>CO.[Fe]>[NH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[C:6]=1[C:7]#[N:8]
Reactant: CC(C)Nc1cccc([N+](=O)[O-])c1C#N
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CC(C)Nc1cccc(N)c1C#N
Temperature: 90 °C
Yield: 106.3 %

Procedure:
To a solution of 2-(isopropylamino)-6-nitrobenzonitrile (Example 90c) (0.21 g, 1.02 mmol) in MeOH (9 mL) was added concentrated HCl (2 mL). Then Fe (0.17 g, 3.07 mmol) was added portionwise, and the reaction mixture was refluxed at 90° C. for 15 minutes. After cooling to room temperature, dilution with H2O (50 mL) and extraction with DCM (3×50 mL), the combined organic phases were washed with brine, dried over MgSO4 and the solvents were evaporated to give 2-amino-6-(isopropylamino)benzonitrile (0.19 g, 100%) as a brown oil which was used in the next step without any further purification. MS 176 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][CH2:20][CH2:21]Cl)[S:10](=[O:18])(=[O:17])[C:11]3[C:12]=2[C:13]=1[CH:14]=[CH:15][CH:16]=3)(=[O:3])[CH3:2].[C:23]1([C:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][CH2:20][CH2:21][N:32]3[CH2:31][CH:30]=[C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:34][CH2:33]3)[S:10](=[O:18])(=[O:17])[C:11]3[C:12]=2[C:13]=1[CH:14]=[CH:15][CH:16]=3)(=[O:3])[CH3:2]
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: CC(=O)Nc1ccc2c3c(cccc13)S(=O)(=O)N2CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Nc1ccc2c3c(cccc13)S(=O)(=O)N2CCCN1CC=C(c2ccccc2)CC1
Temperature: 20 °C
Yield: 32.1 %

Procedure:
5-Acetylamino-2-(3-chloropropyl)naphto[1,8-cd]isothiazole 1,1-dioxide (0.8 g), 4-phenyl-1,2,3,6-tetrahydropyridine (0.4 g), potassium carbonate (4 g) and acetonitrile (25 cc) are heated at boiling point for 20 hours. The reaction mixture is cooled to a temperature of about 20° C. The solution is filtered and then concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by chromatography on a silica column with a mixture of ethyl acetate and methylene chloride (70-30 vol) as eluant, then recrystallized from boiling ethanol (20 cc). 5Acetylamino-2-[3-(4-phenyl 1,2,3,6-tetrahydro-1-pyridyl)-propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (0.35 g) is obtained, m.p. 178° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[OH:12])[CH:3]=1.[H-].[Na+].[CH3:15]I.O>CN(C)C=O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH3:15])[CH:3]=1
Reactant: CI
Reactant: Nc1ccc2c(O)cccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2cc(N)ccc12
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
A solution of commercially available 2-amino-5-hydroxynaphthalene (5.16 g, 31.48 mmol) in dimethylformamide (125 ml) was cooled with ice in an inert nitrogen atmosphere. Subsequently, NaH (1.39 g dispersion in a mineral oil at 60%, 34.6 mmoles) was added keeping the temperature below 10° C. and was shaken during 15 min. at ≈5° C. Subsequently methyl iodide (4.47 g, 31.48 mmol) solved in dimethylformamide (5 ml) was added and was left stirring at room temperature during 20 hrs. Water was added and it was evaporated to dryness in a rotavapor. To the remaining residue, water and ethylic ether were added. The aqueous phase was newly extracted with ether and the collection of organic phases was dried over Na2SO4, filtered, and evaporated to dryness. To the resulting crude slurry, a mixture of isopropylic alcohol/petroleum ether 1/1 was added, stirred during a few minutes and the insoluble precipitate was filtered. 4.21 g (77%) of 2-amino-5-methoxynaphthalene were obtained, with a purity determined by HPLC of 99%.
Reaction SMILES: [C:1]1([C:7]#[C:8][C@@H:9]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC1C=CC=CC=1[S:43]([NH2:46])(=[O:45])=[O:44]>>[NH2:46][S:43]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:7]#[C:8][C@@H:9]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:19]=1)(=[O:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])(=[O:45])=[O:44]
Reactant: NS(=O)(=O)c1ccccc1I
Reactant: O=C(O)C[C@@H](C#Cc1ccccc1)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1
Product: NS(=O)(=O)c1ccccc1C#C[C@H](CC(=O)O)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1

Procedure:
The procedure for the preparation of the product of EXAMPLE 18 was repeated using 2-iodobenzene-1-sulfonamide (Maybridge) in the place of iodobenzene to provide the title product. 1H (CD3OD): δ 7.88 (2H, m); 7.81 (1H, d); 7.52 (1H, d); 7.44 (4H, m); 7.11 (1H, d); 7.05 (2H, m); 6.87 (1H, t); 4.68 (1H, t); 4.01 (2H, m); 3.37 (2H, m); 2.84 (2H, m); 1.82 (4H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.C(Cl)(=O)C([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:14][C:7]1[CH2:9][C:2]([CH3:10])([CH3:1])[CH2:3][C:4](=[O:5])[CH:6]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)C=C(Cl)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared using the method of Clark and Heathcock. J. Org. Chem., 1976, 41, 636. To a suspension of dimedone (15.0 g, 107 mmol) in chloroform (40 ml) was added slowly oxalyl chloride (27.2 g, 214 mmol). The addition was accompanied by vigorous evolution of gas. After stirring at room temperature for 10 minutes, the slurry was refluxed for 20 minutes to give a yellow solution which was evaporated and distilled to give 15.7 g (92%) of chloroenone as a colorless liquid, bp 72° (5 mm). ##STR5##