Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:31])[C:7]([C:29]#[N:30])=[N:8][NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([S:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][N:19]=2)=[C:12]([Cl:28])[CH:11]=1)C.C([O-])(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[Cl:28][C:12]1[CH:11]=[C:10]([N:9]2[C:4](=[O:3])[NH:5][C:6](=[O:31])[C:7]([C:29]#[N:30])=[N:8]2)[CH:15]=[C:14]([Cl:16])[C:13]=1[S:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][N:19]=1
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1cc(Cl)c(Sc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)c1cc(Sc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Temperature: 120 °C
Yield: 103.2 %

Procedure:
A solution of (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (86) (2.98 g, 5.99 mmol) in glacial acetic acid (60 mL) was treated with sodium acetate (2.46 g, 29.95 mmol). The resulting mixture was heated to 120° C. for 3 h. At this time, LCMS indicated complete consumption of the starting material and conversion to product. The reaction was cooled to 25° C., poured onto water (200 mL) and was extracted with ethyl acetate (2×150 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×150 mL), dried with magnesium sulfate, filtered and concentrated under vacuum to give an orange solid. This solid was dissolved in a 1:1 methylene chloride:hexanes mixture and concentrated in vacuo three times. It was then dissolved in a 1:1 methylene chloride:methanol mixture and concentrated under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (87) (2.79 g) as an orange solid. The material was used without further purification; ES(+)-HRMS m/e calcd for C17H12Cl2N6O3S (M+H)+ 451.0142, found 451.0143. Exact Mass=450.0069; Molecular weight=451.29
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([CH3:27])[CH:26]=1)[NH:23][C:22](=[O:28])[C:21]2=[O:29].N1C=CC=C(C)C=1.CS(Cl)(=O)=[O:39]>C(#N)C.O>[N:23]1[CH:22]=[CH:21][CH:27]=[C:25]([CH3:26])[CH:24]=1.[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:23][C:24]2[C:25]([CH3:27])=[CH:26][C:18]([Cl:17])=[CH:19][C:20]=2[C:21](=[O:29])[C:22]([OH:39])=[O:28])=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Cl)cc2c1NC(=O)C2=O
Solvent: CC#N
Solvent: O
Solvent: Cc1cccnc1
Product: Cc1cc(Cl)cc(C(=O)C(=O)O)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 03/015519 for preparation) (97.6% purity, 3.25 g, 10.5 mmol) and 5-chloro-7-methylindoline-2,3-dione (K. Tsuji et al., Bioorg. Med. Chem. Letters, 2002, 12(17), pp 2427-2430) (1.96 g, 10.0 mmol) in dry acetonitrile (12 mL) was added 3-picoline (2.60 g, 28 mmol). The mixture was cooled to 0° C., and then methanesulfonyl chloride (1.48 g, 12.9 mmol) was added dropwise at 0-10° C. After stirring 5 minutes at this temperature, the mixture was warmed to room temperature for 2 hours. Then additional quantities of 3-picoline (0.37 g, 4.0 mmol) and methanesulfonyl chloride (0.24 g, 2.1 mmol) were added, and stirring was continued at room temperature for 3 hours. The mixture was cooled to 0° C., water (6 mL) was added dropwise, and stirring at 0-5° C. was continued for 1 hour. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), and dried under nitrogen to afford the 3-picoline salt of the title compound as a light green solid, 1.23 g.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:13][C:3]1[C:2]([Br:1])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:4]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Nc1n[nH]c(-c2ccccc2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(-c2ccccc2)c1Br

Procedure:
Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=3/7) afforded the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): 7.74-7.78 (m, 2H), 7.24-7.36 (m, 3H), 6.86-6.92 (m, 2H), 6.74-6.78 (m, 2H), 4.9 (s, 2H), 4.22 (s, 2H), 3.64-3.74 (m, 4H), 2.86-3.04 (m, 4H). 13C NMR (400 MHz, CDCl3): 164, 146.2, 144.8, 128, 126.8, 118, 114.8, 60, 50.2, 50, 48.8, 46, 42, 20.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:17][C:16]=2[F:32])[CH2:10]1)=[N+:7]=[N-:8].C(N(CC)CC)C>ClCCl>[N:6]([CH:9]1[CH:13]([O:14][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:17][C:16]=2[F:32])[CH2:10]1)=[N+:7]=[N-:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CC(O)C(N=[N+]=[N-])C3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC(N=[N+]=[N-])C(OS(C)(=O)=O)C3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (8 μL, 0.10 mmol) was added to a solution of N-({(5S)-3-[4-(3-azido-4-hydroxypyrrolidin-1-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (30 mg, 0.08 mmol) and triethylamine (16 μL, 0.12 mmol) in dichloromethane (0.5 mL) at 0° C. After 1 h, the solution was diluted with more dichloromethane, washed with dilute NaHCO3, brine and dried (MgSO4), filtered and concentrated to give the title compound as an oil. This material was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:30][C:31]#[N:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.[NH2:37][OH:38]>CS(C)=O>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:30][C:31](=[N:37][OH:38])[NH2:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CC#N)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Reactant: NO
Solvent: CS(C)=O
Product: CC(C)(C)C(CC(N)=NO)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 140 °C

Procedure:
To a solution of racemic 3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]-4,4-dimethyl-pentanenitrile, 124a, (0.059 g, 0.116 mmol) in DMSO (0.500 mL) was added hydroxylamine (0.031 g, 0.470 mmol). The mixture was heated in a microwave at 140° C. for 30 minutes. The residue was purified on a C18 column (acetonitrile/0.1% formic acid) to afford the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=1.58 minutes (M+H) 390.06.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[C:7](F)=[C:6]([F:12])[CH:5]=1)=[O:3].[CH3:13][S-:14].[Na+]>C(#N)C>[F:12][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH3:1])[CH:9]=[C:8]([F:10])[C:7]=1[S:14][CH3:13]
Reactant: C[S-]
Reactant: CC(=O)c1cc(F)c(F)c(F)c1
Agent: [Na+]
Solvent: CC#N
Product: CSc1c(F)cc(C(C)=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
The 3,4,5-triflouroacetophenone (9.50 g, 54.6 mmol) and sodium thiomethoxide (4.60 g) were mixed together in acetonitrile (80 mL). The solution was stirred for 2 hour at ambient temperature. Solvent was removed in vacuo and the residue dissolved in ethyl acetate. The solution was extracted with water (2×100 mL), saturated ammonium chloride (2×100 mL) and dried over sodium sulfate. Solvent was removed in vacuo to yield 1-[3,5-difluoro-4-(methyl-thio)phenyl]ethanone as a yellow oil (8.08 g, 73%). 1H NMR (CDCl3/300 MHz) 7.46-7.43 (m, 2H), 2.58 (s, 3H), 2.56 (t, 3H, J=1). ESHRMS m/z 203.0357 (M+H+, Calcd 203.0342).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([O:12][CH2:13][CH2:14]O)[CH:11]=1.O1CCCC1.[OH-].[K+]>C(O)(C)(C)C>[Cl:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([O:12][CH:13]=[CH2:14])[CH:11]=1
Reactant: OCCOc1cncc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: C=COc1cncc(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (58.6 g, 493 mmol) was added to a mixture of 3-chloro5-(2-hydroxyethoxy)pyridine (14.5 g, 82.1 mmol) and tetrahydrofuran (100 ml). The mixture was stirred for 1 h at 50° C. The mixture was evaporated. Potassium hydroxide (9.0 g, 164 mmol) and tert-butanol (100 ml) were added and the mixture was stirred for 3 days at 100° C. The solvent was evaporated. Water (150 ml) was added and the mixture was extracted twice with diethyl ether (100 ml). Yield 6.77 g, 53%.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:23][CH2:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O[CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>ClCCl.CN(C)C1C=CN=CC=1>[C:16]([NH:23][CH2:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([O:30][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:29])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCOC(=O)CCC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
A solution of N,N′-dicyclohexylcarbodiimide (DCC, 3.34 g; 16.2 mmol) in dry dichloromethane (20 mL) was added using a syringe to a stirred mixture of 5-(Boc-amino)-4-oxopentanoic acid (3.70 g; 16.0 mmol), t-butyl 3-hydroxypropanoate (2.31 g; 15.8 mmol), and 4-dimethylaminopyridine (DMAP, 50 mg) in dichloromethane (40 mL) at ambient temperature under argon. The mild exothermic reaction was moderated with an ice-water bath. After stirring 2 days at ambient temperature, the mixture was suction-filtered on a glass-sinter filter. The residue was washed with dichloromethane (3×20 mL). The combined filtrates were evaporated and the residue was purified by flash chromatography on a 45×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (500 mL), collecting 7×50 ml fractions. After evaporation of fractions 2-4, 5.45 g (96%) product was obtained (pale yellow oil).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.Br[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]>>[CH2:28]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]2=[N:3][C:2]=3[NH2:1])=[C:15]([CH3:21])[CH:16]=1)[CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)CCBr
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCC(C)C)cc3C)cc12

Procedure:
2-(4-(Isopentyloxy)-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) following the procedure described for Example 136, but using 1-bromo-3-methylbutane. 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.72 (s, 1H), 8.29 (d, 1H), 7.43 (s, 1H), 7.17 (D, 1H), 7.10 (d, 1H), 6.76 (d, 1H), 6.68 (d, 1H), 6.56 (br, 2H), 4.00 (t, 2H), 3.17 (t, 2H), 3.07 (t, 2H), 2.48 (s, 3H), 1.76-1.91 (m, 1H), 1.60-1.71 (m, 2H), 0.96 (s, 6H). LRMS [M+H]=414.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][C:10]([CH3:12])=O.CC(O)=O.[BH3-]C#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH:10]([CH3:12])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Nc1cncc(Br)c1
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromopyridin-3-amine (XXV) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 μL, 4.02 mL) The pH was adjusted to 4 using HOAc and stirred for 30 min. NaCNBH3 (272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% hexane→90:10 hexane:EtOAc) to produce 5-bromo-N-isopropylpyridin-3-amine (XLVI) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.12 (d, J=6.3 Hz, 6H), 3.55-3.59 (m, 1H), 6.03 (d, J=7.9 Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J=2 Hz, 1H), 7.90 (d, J=2 Hz, 1H); ESIMS found C8H11BrN2 m/z 215 (M+H).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.IC1C=CC=CC=1.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].C(#N)C>CN(C=O)C>[C:1]1([CH3:8])[C:6]([O:7][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1O
Reactant: Cc1ccccc1I
Solvent: CN(C)C=O
Solvent: Ic1ccccc1
Solvent: CC#N
Product: Cc1ccccc1Oc1ccccc1C

Procedure:
Example 3.1 was repeated, replacing the phenol with 206 μl of o-cresol (2 mmoles) and the iodobenzene with 383 μl of 2-iodotoluene (3 mmoles), the acetonitrile with DMF, and with the nucleophile and the arylation agent being added at the same time as the solvent.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:9]=[N:10][C:4]=2[C:3]1=[O:11].C1C(=O)N([Br:19])C(=O)C1>CC#N>[Br:19][C:6]1[C:5]2[O:8][CH:9]=[N:10][C:4]=2[C:3](=[O:11])[N:2]([CH3:1])[CH:7]=1
Reactant: Cn1ccc2ocnc2c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cn1cc(Br)c2ocnc2c1=O
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To the title compound of step 4 (100 mg, 0.7 mmol) in CH3CN (5 mL) was added NBS (154 mg, 0.8 mmol) at 20° C. After 2 h, the mixture was concentrated in vacuum at 45° C. Purification by silica gel chromatography (PE:EA=5:12:1) to gave the title compound (70 mg, yield: 45%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.04 (s, 1H), 7.52 (s, 1H), 3.69 (s, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1.FC1C=CC=C(F)C=1C(NC1C=NC(N2C3C=CC(OC)=CC=3N=C2C(F)(F)F)=CN=1)=O.[CH3:55][C:56]1[CH:63]=[CH:62][CH:61]=[CH:60][C:57]=1[CH2:58][NH2:59].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I.CCOC(C)=O>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:5]3[N:6]=[CH:7][C:2]([NH:59][CH2:58][C:57]4[CH:60]=[CH:61][CH:62]=[CH:63][C:56]=4[CH3:55])=[N:3][CH:4]=3)[C:9]([C:19]([F:22])([F:21])[F:20])=[N:10][C:11]=2[CH:16]=1
Reactant: Cc1ccccc1CN
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(Br)cn1
Agent: [Cu]I
Agent: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NCc2ccccc2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
Into a 50 mL roundbottom flask, was placed a solution of 1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) (50 mg, 0.13 mmol) in DMSO (5 mL) (1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) was prepared as described for Compound 1 above). To this was added 2-methyl-benzylamine (40 mg, 0.33 mmol) followed by CuI (10 mg, 0.05 mmol). To the mixture was added L-proline (20 mg, 0.17 mmol). The resulting solution was held at 50° C. for 1 hr while the reaction progress was monitored by TLC (EtOAc/PE=1:2). After completion, the reaction mixture was allowed to cool to room temperature, then washed twice with H2O (30 mL each). After removal of the volatile components under vacuum, the residue was purified by eluting through a silica gel column with a 1:10 EtOAc/PE solvent system. This resulted in 25 mg (44%) of the product [5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-benzyl)-amine (Compound 46) as a white solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:5]=2[C:6]=1[CH3:7].[CH:13]([Sn](CCCC)(CCCC)CCCC)=[CH2:14].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1C(=O)CCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:12][C:9]1[CH:10]=[CH:11][C:4]2[S:3][C:2]([CH:13]=[CH2:14])=[C:6]([CH3:7])[C:5]=2[CH:8]=1
Reactant: Cc1c(Br)sc2ccc(Cl)cc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: C=Cc1sc2ccc(Cl)cc2c1C

Procedure:
A solution of 2-bromo-5-chloro-3-methylbenzthiophene (5 g, 19.1 mmol), vinyltributylstannane (5.59 mL, 19.1 mmol), Pd2dba3 (525 mg, 0.57 mmol), and tri(2-furyl)phosphine (532 mg, 2.29 mmol) in NMP (70 mL) at 90° C. was stirred for 18 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with hexanes to provide the desired product. MS (ESI(−)) m/e 207 (M−H)−.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18]C)=O)[N:11]=2)[N:9]=1)[NH2:3].O.[NH2:21][NH2:22].C(OCC)(=O)C>C(O)C>[NH2:3][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH:21][NH2:22])=[O:18])[N:11]=2)[N:9]=1)[NH2:1]
Reactant: COC(=O)c1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-(6-methoxycarbonylpyridin-2-yl)thiazole (4.0 g) and 100% hydrazine monohydrate (1.05 ml) in ethanol (40 ml) was heated under reflux for 8 hours. To the reaction mixture was added ethyl acetate (60 ml) under stirring at ambient temperature. The isolated precipitate was collected by filtration to give 2-(diaminomethyleneamino)-4-(6-hydrazinocarbonylpyridin-2-yl)thiazole (3.19 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.O.[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:1]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:4])=[O:2]
Reactant: c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccccc1

Procedure:
The reaction Was carried out in the same reactor as that described above in Examples 3 and 4 which are representative of the present invention. Benzene in 7% stoichiometric excess is metered into a nitrating acid consisting of 2.3 wt. % of nitric acid, 68.0 wt. % of sulfuric acid and 29.7 wt. % of water. The amount of benzene was chosen so as to give a space-time yield of nitrobenzene of 4.3 t/m3h, based on the reactor volume. The mixture obtained was introduced into a reactor at a start temperature of 99.8° C. After 13.4 vol. % of the reaction space, the temperature of the reaction mixture was 113.6° C. The reaction end temperature was 123.6° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][OH:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1>[CH2:25]([O:24][C:22]([O:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][OH:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: OCC1COc2c(O)cccc2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cccc2c1OCC(CO)C2
Yield: 100.2 %

Procedure:
23.95 g of 3,4-dihydro-8-hydroxy-3-hydroxymethyl-2H-1-benzopyran was dissolved in 270 ml of tetrahydrofuran, and 14.8 g of triethylamine was added. With stirring under ice cooling, a solution of 15.9 g of ethyl chloroformate in 135 ml of tetrahydrofuran was added dropwise over 1.5 hours. The mixture was stirred at 2° C. for 1.5 hours. After the reaction, the insoluble matter was removed by filtration, and the mother liquor was distilled under reduced pressure. To the residue was added 500 ml of ethyl acetate to form a solution. The solution was washed successively with 2 N hydrochloric acid and a saturated aqueous solution of sodium chloride, and dried. The solvent was distilled off to give 33.6 g (yield 100%) of 3,4-dihydro-8-ethoxycarbonyloxy-3-hydroxymethyl-2H-1-benzopyran.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][C:11]#N)=[CH:7][S:8][CH:9]=1.[OH-:18].[Na+].[OH2:20]>CO>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][C:11]([OH:20])=[O:18])=[CH:7][S:8][CH:9]=1
Reactant: N#CCc1cscc1Nc1c(Cl)cccc1Cl
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)Cc1cscc1Nc1c(Cl)cccc1Cl

Procedure:
31 g (0.11 mole) of 4-(2,6-dichloroanilino)-3-thiophenacetonitrile are boiled in a solution of 110 g of sodium hydroxide in 450 ml of water and 220 ml of methanol for 4 hours. The mixture is diluted with 2 liters of warm water and extracted with toluene, the aqueous phase is acidified and the precipitate of 4-(2,6-dichloroanilino)-3-thiophenacetic acid, which has formed, is filtered off. The precipitate is boiled up with diisopropyl ether and dried; it then melts at 179° to 180°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4]([CH:12]=O)=[C:3]1Cl.C([O-])([O-])=O.[K+].[K+].[SH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[CH3:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]1[S:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:12][C:4]2=1
Reactant: Cc1ccc2c(c1)c(C=O)c(Cl)n2C
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3cc(C)ccc3n(C)c2s1
Yield: 14.4 %

Procedure:
Prepared from (46) (0.80 g), K2CO3 (1.5 g) and methyl 2-mercaptoacetate (0.60 ml) yielding (52) 0.144 g (14.4%). M.p. 152°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]([OH:13])=O)[CH2:9][CH2:8][N:7]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:6]1)=[O:4].CN(C)C=O.Cl.Cl.[CH3:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:35]#[N:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[C:35]([C:34]1[CH:37]=[CH:38][C:39]([N:40]2[CH2:45][CH2:44][N:43]([C:11]([C@H:10]3[CH2:9][CH2:8][N:7]([C:14]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:15])[CH2:6][C@@H:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:13])[CH2:42][CH2:41]2)=[C:32]([CH3:31])[CH:33]=1)#[N:36]
Reactant: COC(=O)[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1C(=O)O
Reactant: Cc1cc(C#N)ccc1N1CCNCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of (3R,4S)-piperidine-1,3,4-tricarboxylic acid 1-benzyl ester 3-methyl ester (0.554 g, 0.00172 mol) in N,N-dimethylformamide (8.500 mL, 0.1098 mol) was added 3-methyl-4-piperazin-1-ylbenzonitrile dihydrochloride (0.6146 g, 0.002241 mol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.017 g, 0.001896 mol), and, N,N-diisopropylethylamine (1.509 mL, 0.008620 mol). The reaction mixture was stirred overnight at room temp. Reaction quenched with KH2PO4(sat solution). Layers separated and aq layer extracted with ethyl acetate 3×. Organic layers were washed with brine and dried over magnesium sulfate. Filtered and concentrated. The residue was purified by Combiflash with 40-70% EtOAc/Hex to give the product (75% in yield). MS (ESI): (M+H)+=505.