Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[CH3:12][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:51])[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35](C#CC4N5C=CN=CC5=NC=4)[CH:34]=3)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:14][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:51])[C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[C:37]([C:2]#[C:1][C:3]4[N:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:38]=3)[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: C#Cc1cnc2ccccn12
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-ethynylimidazo[1,2-a]pyridine (0.032 g, 0.22 mmol) in anhydrous DMF (1.26 mL) was added N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide (prepared as in Example 3), Pd(PPh3)4 (0.013 g, 0.011 mmol), CuI (0.0032 mg, 0.0165 mmol) and DIPEA (0.064 mL, 0.44 mmol). The solution was degassed with argon for 15 minutes then stirred overnight at rt. The solvent was removed and the resultant residue was chromatographed over silica gel eluting initially with EtOAc and then with methanol/methylene chloride (5:95) to furnish the desired product: (0.07 g, 59%) MS (M+H)+542.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[CH:8]=2)[N:3]=1.[NH2:22][C:23]([CH2:28][CH3:29])([CH2:26][OH:27])[CH2:24][OH:25].O>CN1C(=O)CCC1>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][C:23]([CH2:28][CH3:29])([CH2:26][OH:27])[CH2:24][OH:25])[N:11]=[CH:10]2
Reactant: CCC(N)(CO)CO
Reactant: Nc1nc(Cl)nc2ccc(Oc3ccc(F)cc3F)cc12
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(CO)(CO)Nc1ncc2cc(Oc3ccc(F)cc3F)ccc2n1
Temperature: 25 °C
Yield: 47 %

Procedure:
Compound (1G) (250 mg, 0.85 mmol) and 2-amino-2-ethyl-1,3-propanediol (298 mg, 2.5 mmol) in NMP (0.25 mL) were stirred at 120° C. for 4 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (2×25 mL). The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The crude product was purified by chromatography (silica gel, CH2Cl2:MeOH, 95:5) to afford 150 mg of the above-titled compound (Example 1). Mp=110-112.9° C. MW (M+H)+=376.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][S:12][C:11]3[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:10]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C.C([O-])(O)=O.[Na+]>[N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][S:12][C:11]3[CH:15]=[C:16]([NH:19][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])[CH:17]=[CH:18][C:10]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)SCCN2CCCN1CCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)SCCN2CCCN1CCCC1)c1cccs1
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A solution of 4-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (0.43 g, 1.550 mmol) in dry ethanol (15 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.884 g, 3.10 mmol) at room temperature, and the resulting mixture was stirred overnight (18 hours). The reaction was diluted with saturated NaHCO3 solution (30 mL), and the product was extracted into CH2Cl2 (3×20 mL). The combined CH2Cl2 layers were washed with brine (20 mL) and then dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (5:95 (2 M NH3 in MeOH):CH2Cl2,) to obtain the title product 21 (0.51 g, 85%) as a solid. 1H NMR (DMSO-d6) δ 7.68 (d, 1H, J=4.5 Hz), 7.55 (d, 1H, J=5.1 Hz), 7.06 (dd, 1H, J=3.6, 4.9 Hz), 6.70 (d, 1H, J=8.7 Hz), 6.52-6.44 (m, 2H), 6.32 (brs, 2H), 3.51-3.48 (m, 2H), 3.27 (t, 2H, J=7.2 Hz), 3.04-3.00 (m, 2H), 2.48-2.40 (m, 6H), 1.80-1.60 (m, 6H); ESI-MS (m/z, %): 387 (MH+, 68), 276 (100), 194 (75); HPLC purity: 98.32% by area.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[S:13][CH:14]=[CH:15][N:16]=3)O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl.CCOC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OC(c1ccc2occc2c1)c1nccs1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: c1csc(Cc2ccc3occc3c2)n1

Procedure:
Under argon at 24° C., crude benzofuran-5-yl(thiazol-2-yl)methanol (2.50 g, 10.8 mmol) was dissolved in 1,2-dichloroethane (40 mL), treated with triethylsilane (3.14 g, 27.0 mmol) and trifluoroacetic acid (1.25 mL, 16.2 mmol), and heated to reflux for 20 h. The mixture was diluted with EtOAc and ice, washed 1× with saturated aqueous NaHCO3, brine, dried over MgSO4, and evaporated. Purification by flash chromatography (hexanes to hexanes/EtOAc=3:2) gave 2-(benzofuran-5-ylmethyl)thiazole as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (d, J=3.3 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.55 (br. s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.27-7.24 (m, 1H), 7.19 (d, J=3.3 Hz, 1H), 6.74-6.73 (m, 1H), 4.44 (s, 2H). MS (ESI) m/z: Calculated: 215.0; Observed: 216.1 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>[Cu]I.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>[CH3:31][Si:30]([CH3:33])([CH3:32])[CH2:29][CH2:28][O:27][CH2:26][N:23]1[C:19]2[N:20]=[CH:21][N:22]=[C:17]([C:15]3[CH:14]=[N:13][N:12]([CH:8]([C:4]4[CH:5]=[N:6][CH:7]=[C:2]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:3]=4)[CH2:9][C:10]#[N:11])[CH:16]=3)[C:18]=2[CH:25]=[CH:24]1
Reactant: C#C[Si](C)(C)C
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: C[Si](C)(C)C#Cc1cncc(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (from Example 429) (0.080 g, 0.00015 mol) in TEA (0.300 mL, 0.00215 mol) was degassed with nitrogen, and then copper(I) iodide (0.005 g, 0.00003 mol), (trimethylsilyl)acetylene, and bis(triphenylphosphine)palladium(II) chloride were added. The reaction mixture was sealed in a tube and stirred at room temperature overnight. The resulting black solution was partitioned between water (10 mL) and ethyl ether. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-{5-[(trimethylsilyl)ethynyl]pyridin-3-yl}propanenitrile as a yellow oil (60 mg, 72.6), LCMS (M+1)+: 542).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:30][NH2:31]>C(#N)C>[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:30][NH:31][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)cc1F

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 3,4-difluorobenzylamine and acetonitrile essentially as described above in example 48. Purity by LC/MS (APCI)=98%, [M+H]+=401.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[CH:13]([NH:15][NH2:16])=O>C(O)CCC.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:13]=[N:15][N:16]=[C:7]1[CH2:6][CH2:5]2
Reactant: S=C1CCc2cc(Br)ccc2N1
Reactant: NNC=O
Solvent: CCCCO
Solvent: O
Product: Brc1ccc2c(c1)CCc1nncn1-2
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 6-bromo-3,4-dihydroquinoline-2(1H)-thione (74-4; 0.17 g, 0.0007 mol) in n-butanol (2 mL) was added formic hydrazide (0.105 g, 0.0017 mol) at room temperature. Reaction mass was allowed to stir at 140° C. for 1 h under microwave irradiation conditions. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford title compound. MS (M+3): 252.2.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:2].[CH3:16][NH:17][CH3:18].[BH4-].[Na+].[CH3:21]O>C(Cl)(Cl)Cl.[Cl-].[Na+].O>[NH3:5].[CH3:1][OH:2].[CH3:15][O:14][C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:3]([N:17]([CH3:18])[CH3:16])=[CH:4][N:5]2[CH3:21])=[CH:10][CH:9]=1)=[O:13]
Reactant: CNC
Reactant: COC(=O)c1ccc2c(C=O)c[nH]c2c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(N(C)C)cn(C)c2c1
Product: N
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 99 %

Procedure:
A solution of methyl 3-formylindole-6-carboxylate (8.0 g, 39.3 mmol) in 270 ml methanol is treated with dimethylamine (40% aqueous; 267 ml, 2.56 mol) at ambient temperature. After 45 minutes, NaBH4 (4.45 g, 118.1 mmol) is added, and the resulting mixture is heated at 55° C. for 3 hours. The reaction mixture is allowed to cool then is diluted with CHCl3 (200 ml) and brine (I 50 ml). The organic layer is washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue is purified by flash chromatography (SiO2; 100% ethyl acetate then 20% 2M NH3/methanol in CHCl3) to give 9.07 g of 3-dimethylamino-methyl-1H-indole-6-carboxylic acid methyl ester(99%). Amine 61 is prepared from 3-dimethylaminomethyl-1H-indole-6-carboxylic acid methyl ester by essentially following the procedures detailed in Amine 49, 1 paragraph; and Amine 51, 3rd paragraph.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[C:7]([Br:18])[CH:6]=2.[CH2:19](OC(OCC)OCC)C>Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:18][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][C:14]([CH3:15])([OH:16])[CH3:17])[CH:19]=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Br)ccc12
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(O)Cn1cnc2cnc3cc(Br)ccc3c21
Yield: 95 %

Procedure:
A 2-L round bottom flask was charged with 1-[(3-amino-7-bromoquinolin-4-yl)amino]-2-methylpropan-2-ol (25.5 g, 82.2 mmol), toluene (1 L), pyridine-HCl (0.1 g, 0.82 mmol, 0.01 eq) and triethylorthoformate (13.4 g, 90.4 mmol, 1.1 eq), and the reaction was heated at reflux for 2 hours. The reaction mixture was concentrated to dryness. The resulting pale yellow solid was slurried in 1% aqueous sodium carbonate solution (250 mL), collected by vacuum filtration, and air-dried on the funnel overnight to provide 25 g of 1-(7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>C(Cl)Cl>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: c1c[nH]cn1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Solvent: ClCCl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCn2ccnc2)c1OCCC(C)c1ccc(F)cc1
Yield: 45 %

Procedure:
Example 8a (50 mg, 0.10 mmol) was reacted with imidazole (8.0 eq.) as described under General Procedure G and the crude mixture was dissolved in DCM and HCl gas was bubbled through it for 3 minutes. Then, solvent was removed under vacuum and the residue was suspended in dry ether and triturated to afford the title compound as a off-white solid (22 mg, 45%). 1H NMR (300 MHz, CDCl3) δ 9.57 (bs, 1H), 7.33 (bs, 1H) 7.19-7.14 (m, 3H), 7.02-6.96 (m, 2H), 4.60 (bs, 2H), 4.37 (bs, 2H), 3.89-3.76 (m, 5H), 2.88-2.93 (m, 1H), 2.32 (s, 3H), 2.16 (s, 3H), 1.94-1.96 (m, 2H), 1.27 (d, J=6.6 Hz, 3H). MS (ES+) m/z 475.2 (M+H+).
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[C:10]([C:11]#[N:12])=[C:9]([F:13])[C:8]([F:14])=[C:7](F)[C:6]=1[F:16]>CO>[CH3:1][O:2][C:7]1[C:6]([F:16])=[C:5]([F:4])[C:10]([C:11]#[N:12])=[C:9]([F:13])[C:8]=1[F:14]
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(F)c(F)c(C#N)c(F)c1F
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A solution of 44.8 g (0.83 mole) of sodium methoxide in 1.6 liters of methanol was added dropwise at room temperature to a solution of 160.0 g (0.83 mole) of pentafluorobenzonitrile (XVIII) in 2.5 liters of methanol, whilst stirring. When the addition was complete, the mixture was allowed to stand at room temperature overnight. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the residue was shaken with a mixture of water and toluene. The toluene layer was separated, washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure. The residual solid was washed with hexane to afford 160.7 g of 4-methoxy-2,3,5,6-tetrafluorobenzonitrile (XIX) as colorless needles.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:30])[C:15]2[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:17][NH:18][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([N+:31]([O-:33])=[O:32])[CH:9]=1>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:15]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:18][NH:17][C:16]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:30])=[C:10]([N+:31]([O-:33])=[O:32])[CH:9]=1
Reactant: CCOC(=O)c1n[nH]c(C(=O)OCC)c1C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Chromium (VI) oxide (17.48 g, 174.8 mmol) was added over 37 minutes to a solution of pyridine (27.6 mL, 349.5 mmol) in dichloromethane (400 mL). Diethyl 4-[(4-chloro-2-nitro-phenyl)hydroxymethyl]-1H-pyrazole-3,5-dicarboxylate (11.56 g, 29.1 mmol) was added as a solid over 9 minutes. The reaction mixture was allowed to stir at room temperature 44 is hours. The solution was filtered and the organic layer was washed with aqueous hydrochloric acid (500 mL, 3N). The aqueous layer was extracted with ethyl acetate (3×250 mL) and dichloromethane (3×250 mL). The resulting organic extracts were combined and concentrated on the rotary evaporator to give a crude solid (10.92 g). The product was purified by chromatography eluting with dichloromethane:2-propanol (98:2, 96:4, and 94:6). The desired product was obtained from the mixed fractions by recrystallization from toluene (250 mL). Clean fractions from chromatography were combined with recrystallized product to give the title compound as a white solid (9.85 g, 86%, mp 168° C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[N:12]=1)(C)(C)C.[BrH:30]>C(O)(=O)C.CCOCC>[BrH:30].[BrH:30].[BrH:30].[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:20][CH2:21]2)=[O:15])[N:12]=1
Reactant: CN1CCC(N2CCN(C(=O)Cc3csc(NC(=O)OC(C)(C)C)n3)CC2)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CN1CCC(N2CCN(C(=O)Cc3csc(N)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
47.2 To a stirred suspension of 3.9 g (4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-carbamic acid tert-butyl ester was added 40 ml of 33% HBr in acetic acid. The reaction mixture was stirred at r.t. for 4 h. The mixture was left overnight in the fridge. Then it was concentrated to leave an off-white solid which was suspended in 50 ml Et2O, triturated and stirred at r.t. for 3 h. The product was collected by filtration, washed with Et2O and dried to give 5.6 g 2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanone trihydrobromide. Off-white solid. MS 324.4 ([M+H]+)
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1>CC(C)=O.CN(C=O)C>[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][N:20]1[C:16]1[S:15][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[N:17]=1
Reactant: N#C[S-]
Reactant: O=C(O)c1cccnc1Cl
Reactant: c1ccc2c(c1)CCNC2
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=c1nc(N2CCc3ccccc3C2)sc2ncccc12
Yield: 49.1 %

Procedure:
The reaction procedure of Example 57 was followed except that 1.718 g (10.90 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 872 mg of ammonium thiocyanate, 15 ml of acetone, 1.52 g of 1,2,3,4-tetrahydroisoquinoline and 15 ml of acetone were used. The resulting crude product was then recrystallized from ethanol to obtain 1.58 g of 2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: IC.[Br:3][C:4]1[C:5]([Cl:23])=[C:6]([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:21])[CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:22])[CH:7]=[CH:8][CH:9]=1.[CH3:24]N(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O>[Br:3][C:4]1[C:5]([Cl:23])=[C:6]([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:21])[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:24])[C:11]2=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: O=c1[nH]c2c(F)cccc2c(=O)n1-c1cccc(Br)c1Cl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1c(=O)n(-c2cccc(Br)c2Cl)c(=O)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Iodomethane (0.102 mL, 1.62 mmol) was added slowly to a mixture of 3-(3-bromo-2-chlorophenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione (300 mg, 0.812 mmol), DMF (5 mL) and Cs2CO3 (529 mg, 1.62 mmol). The mixture was stirred at room temperature for 2 h, then was diluted with EtOAc, washed sequentially with water and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 0-30%), to provide 3-(3-bromo-2-chlorophenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione as a yellow solid (280 mg, 90% yield). Mass spectrum m/z 383, 385 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.09 (dq, J=7.8, 0.8 Hz, 1H), 7.79-7.71 (m, 1H), 7.49 (ddd, J=13.9, 8.1, 1.5 Hz, 1H), 7.32-7.29 (m, 2H), 7.29-7.22 (m, 2H), 3.88 (s, 1.5H), 3.86 (s, 1.5H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[C:12]([C:22]#[N:23])[CH:11]=3.C(O)C.[BH4-].[Na+]>O>[OH:7][CH:6]1[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]=2[C:2]1([CH3:24])[CH3:1])=[CH:14][C:13]([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[C:12]([C:22]#[N:23])[CH:11]=3
Reactant: CC1(C)C(=O)Oc2ccc3cc(C#N)c(Cn4cncn4)cc3c21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)c2c(ccc3cc(C#N)c(Cn4cncn4)cc23)OC1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1,2-dihydro-1,1-dimethyl-2-oxo-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1-b]furan-7-carbonitrile (0.07 g), ethanol (2 ml) and sodium borohydride (0.05 g) was stirred at room temperature for 18 h. Water (10 ml) was added, and the mixture was extracted with chloroform, and the extract was dried and evaporated to dryness under reduced pressure. The residue was recrystallised from ethyl acetate to give 1,2-dihydro-2-hydroxy-1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1-b]furan-7-carbonitrile, m.p. 219°-222°.
Reaction SMILES: 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.[F:34][C:35]1[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:36]=1[C:37]#[N:38].[S:44]1[CH:48]=[CH:47][C:46]([CH2:49]O)=[CH:45]1>O1CCCC1.ClCCl>[F:34][C:35]1[CH:42]=[C:41]([O:43][CH2:49][C:46]2[CH:47]=[CH:48][S:44][CH:45]=2)[CH:40]=[CH:39][C:36]=1[C:37]#[N:38]
Reactant: OCc1ccsc1
Reactant: N#Cc1ccc(O)cc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc(OCc2ccsc2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
A solution of triphenylphosphine (20 g) in tetrahydrofuran (300 mL) cooled at 0° C. is treated dropwise during 5 minutes with diisopropyl azodicarboxylate (15 mL) and stirred for 15 minutes at 0° C. It is then treated, dropwise, with a solution of 2-fluoro-4-hydroxybenzonitrile (7 g) and 3-thienylmethanol (7 g) in tetrahydrofuran (200 mL) during 2 hours, and stirring is continued at ambient temperature for 18 hours. The mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate (500 mL). This solution is washed with water (200 mL) and aqueous sodium hydroxide solution (1 N), dried over magnesium sulphate and concentrated in vacuo, to give an oil, which is passed through a pad of silica gel (thickness 5 cm) with the aid of dichloromethane. The resulting filtrate is concentrated in vacuo, to give an oil which crystallizes on standing. Recrystallization from isopropyl ether gives 2-fluoro-4-(3-thienyl-methoxy)benzonitrile (6 g), in the form of a white solid, m.p. 63-65° C.