Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)CC)C.[O:27]=[S:28]1(=[O:37])[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1>C1COCC1.O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:34]([N:31]3[CH2:32][CH2:33][S:28](=[O:37])(=[O:27])[CH2:29][CH2:30]3)=[O:35])[CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)N1CCS(=O)(=O)CC1
Reactant: CC(C)(C)c1cc(NC(=O)C2CCCNC2)no1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)C2CCCN(C(=O)N3CCS(=O)(=O)CC3)C2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperidine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (100 mg; 0.347 mmol) in anhydrous THF (1 mL) is added triethylamine (0.098 mL; 0.7 mmol) and 1,1-dioxo-1λ6-thiomorpholine-4-carbonyl chloride (71.15 mg; 0.36 mmol). The reaction mixture is left stirring at room temperature overnight. The reaction mixture is diluted with water and extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:26]=[CH:25][C:10]([O:11][CH2:12][CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.O.NN>CO>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][NH2:14])=[CH:25][CH:26]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1ccc(Cn2cccn2)cc1
Agent: NN
Solvent: O
Solvent: CO
Product: NCCOc1ccc(Cn2cccn2)cc1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A mixture of N-{2-[4-(1-pyrazolyl)methylphenoxy]ethyl}phthalimide (2.79 g), hydrazine hydrate (0.47 g) and methanol was heated at reflux under stirring for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove most of the methanol, to which methylene chloride (200 ml) was added. The organic layer was washed with 2N sodium hydroxide, dried with anhydrous sodium sulfate, and concentrated under reduced pressure, which afforded 1.69 g of 2-[4-(1-pyrazolyl)methylphenoxy]ethylamine as a colorless oil. Yield, 97%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.[CH2:22]([NH:29][CH2:30][CH3:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:22]([N:29]([CH2:30][CH3:31])[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCNCc1ccccc1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCN(Cc1ccccc1)c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 12.5 %

Procedure:
A mixture of methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate (0.30 g, 0.86 mmol), benzyl(ethyl)amine (0.20 mL, 1.29 mmol), cesium carbonate (0.39 g, 1.20 mmol), tris(dibenzylidenacetone)dipalladium (0) (0.031 g, 0.034 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.032 g, 0.052 mmol) and toluene (6 mL) was stirred under a nitrogen atmosphere at 80° C. for 16 hrs. The reaction mixture was cooled, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Then the residue was dissolved in a mixed solution of methanol (4 mL) and tetrahydrofuran (6 mL), 1N aqueous sodium hydroxide solution (1.8 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was adjusted to pH 7 with 1N hydrochloric acid, and separated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/2) to give the title compound (42 mg, yield 13%) as yellow crystals. MS (APCI−): 388 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([SiH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[CH3:13]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Si:21]([CH3:22])([CH3:23])[CH2:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:17][CH:16]=1)[CH3:13]
Reactant: CCOc1ccc([SiH](C)C)cc1
Reactant: C=CCc1ccc(F)c(Cl)c1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCOc1ccc([Si](C)(C)CCCc2ccc(F)c(Cl)c2)cc1
Temperature: 130 °C
Yield: 81.5 %

Procedure:
Three drops of a 30% strength solution of hexachloroplatinic acid in isopropanol were added with the aid of a pipette to a mixture of 234 g (1.37 mol) of 3-(3-chloro-4-fluorophenyl)propene and 261 g (1.45 mol) of (4-ethoxyphenyl)dimethylsilane. After a short time, an exothermic reaction took place and the mixture warmed to about 130° C. After cooling, the product was distilled in vacuo. 392 g (82%) of (4-ethoxyphenyl)-(dimethyl)-(3-(3-chloro-4-fluorophenyl)propyl)silane were obtained as a colorless oil of b.p.0.1 =165°-170° C., the purity of which was determined to be 97.4% by gas chromatography.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.Cl[CH2:26][C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[C:27]([CH2:26][N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)#[N:28]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(CC#N)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 150 mg), chloroacetonitrile (31 μL) and anhydrous potassium carbonate (124 mg) in dry acetonitrile (4 mL) under N2 was stirred at ambient temperature for 20 hours, diluted with methylene chloride (20 mL), washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is recrystallized from methylene chloride/diethyl ether to give the title compound, mp 165-167° C.
Reaction SMILES: Cl[C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][C:6]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>C(O)(C)C>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:2]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3[C:4](=[CH:5][C:6]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:8]=3)[N:3]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc2c(=O)n(C)c(Cl)nc2c1
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(=O)n(C)c(NCc3ccc(Cl)cc3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a suspension of methyl 2-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate (70.0 mg, 0.28 mmol) in isopropyl alcohol (3 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.58 mmol) and p-chlorobenzylamine (84.2 μL, 0.69 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 5% MeOH/DCM) to afford methyl 2-[(4-chlorobenzyl)amino]-3-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate (92 mg, 93%). LC-MS: (FA) ES+ 358.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1)=O)C.[NH3:16].CO>>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[N:11]=[C:6]([C:4]([NH2:16])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1nc(OC)cc(OC)n1
Reactant: N
Solvent: CO
Product: COc1cc(OC)nc(C(N)=O)n1
Yield: 100 %

Procedure:
Ethyl-4,6-dimethoxy-pyrimidin-2-carboxylate (25 g, 1 eq.) in NH3/MeOH (7 M, 15 mL) was irradiated in a microwave reactor at 100° C. for 15 min. The solution was concentrated in vacuo to yield compound 286 as a beige solid in 100% yield. MS (ESI, EI+): m/z=184 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:30]#[C:31][Si](C)(C)C)[CH:27]=[CH:26][C:25]=3[O:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:30]#[CH:31])[CH:27]=[CH:26][C:25]=3[O:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40])[C:5]2=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1ccc(OCC(O)CO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(OCC(O)CO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a stirred solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2,3-dihydroxy-propoxy)-5-(2-trimethylsilanyl-ethynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione (7.8 mg, 0.013 mmol) in MeOH (3 ml) was added 2N NaOH (1 mL) dropwise. The reaction mixture was stirred at room temperature for 30 min and then extracted with ethyl acetate several times. The combined organic extract was dried over MgSO4 and concentrated to give the title compound as a white solid (6.2 mg). MS (H+), 551
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]2[C:17]([CH:28]=1)=[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[O:19][N:20]=2.[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([C:18]2[O:19][N:20]=[C:16]3[CH:15]=[CH:14][C:13]([CH:34]([C:33]4[CH:36]=[CH:37][C:30]([CH3:29])=[CH:31][CH:32]=4)[OH:35])=[CH:28][C:17]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Reactant: Cc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C(O)c2ccc3noc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
nBuLi 1.6 M in hexane (0.112 mol) was added dropwise at −70° C. under N2 flow to a mixture of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.097 mol) in THF (300 ml). The mixture was stirred at −70° C. for 15 min. A mixture of 4-methyl-benzaldehyde (0.112 mol) in THF (100 ml) was added dropwise. The mixture was stirred at −70° C. for 30 min, then hydrolized and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue was purified by column chromatography over silica gel (20-45 μm) (eluent: DCM(EtOAc 96/4). The pure fractions were collected and the solvent was evaporated, yielding 13 g (38.3%) of 3-(3-chlorophenyl)-α-(4-methylphenyl)-2,1-benzisoxazole-5-methanol (intermediate 18).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH2:21][CH3:22])[CH:15]=1>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>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:15][C:16]=1[CH2:21][CH3:22]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCc1cc(Br)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCc1cc(-c2cccc([N+](=O)[O-])c2)ccc1N
Yield: 26.6 %

Procedure:
This compound was prepared by General Method 14 (EXAMPLE 191) from 3-nitrobenzeneboronic acid (0.47 g, 2.8 mmol), 4-bromo-2-ethylaniline (432 mg, 2.16 mmol), and (PPh3)4Pd (75 mg, 0.065 mmol) to afford 139 mg (20%) of 4-amino-3-ethyl-3'-nitrobiphenyl. Data for 4-amino-3-ethyl-3'-nitrobiphenyl: 1H NMR (400 MHz, acetone-d6) 8.38 (t, J=2.1, 1H), 8.08 (m, 1H), 8.00 (m, 1H), 7.66 (t, J=8.0, 1H), 7.45 (d, J=2.3, 1H), 7.39 (dd, J=8.3,2.3, 1H), 6.83 (d, J=8.3, 1H), 4.68 (br s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[NH:17]1[CH2:20][CH:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[O:28])[CH2:23][CH2:22]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>O.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:17]2[CH2:18][CH:19]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[O:28])[CH2:25][CH2:26]3)[CH2:20]2)=[O:14])=[CH:15][CH:16]=1
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Reactant: O=C(O)c1ccc(Oc2ccccn2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Oc2ccccn2)cc1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 44c (60 mg, 0.28 mmol), 5e (105 mg, 0.36 mmol), HATU (159 mg, 0.42 mmol), Et3N (1 mL), and DMF (3 mL) was stirred at room temperature overnight, and then poured into water (10 mL). The mixture was extracted with EtOAc. The extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, 7% MeOH/CH2Cl2) to give 98 mg of Cpd 913. MS m/z (M+H+) 450.0.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:12])[CH3:11])=[CH:6][CH:5]=1.C[O:16][C:17](=O)[C:18]1[C:23]([I:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:25][C:21]1[CH:20]=[C:19]2[C:18](=[C:23]([I:24])[CH:22]=1)[C:17](=[O:16])[N:12]([CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)[CH3:11])[CH2:26]2
Reactant: COC(=O)c1c(I)cc(F)cc1CBr
Reactant: CC(N)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(c1ccc(OC(F)(F)F)cc1)N1Cc2cc(F)cc(I)c2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
A mixture of 1-(4-trifluoromethoxy-phenyl)-ethylamine (0.246 mL, 1.2 mmol), 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester (0.372 g, 1.0 mmol), and K2CO3 (0.276 g, 2 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-Fluoro-7-iodo-2-[1-(4-trifluoromethoxy-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.192 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.68 (d, 3H), 3.88-4.26 (dd, 2H), 5.78 (q, 1H), 7.06 (d, 1H), 7.20 (d, 2H), 7.41 (d, 2H), 7.67 (d, 1H). GC-MS: m/z 465 (M)+, 450 (M−15)+.
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=3)[N:7]=[CH:6][C:5]=2[C:16]#[N:17])[CH2:3][CH2:2]1.COC1C=CC(/C=[C:33]2/[C:34]([NH:36][C:37]([S:39]/2)=[NH:38])=[O:35])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:38][C:37]1[S:39]/[C:33](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([C:16]#[N:17])=[C:4]3[CH:1]2[CH2:3][CH2:2]2)/[C:34](=[O:35])[N:36]=1
Reactant: N#Cc1cnc2ccc(C=O)cc2c1C1CC1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(/C=C3\SC(N)=NC3=O)cc2c1C1CC1

Procedure:
Similar procedure as described in example 38 was used, starting from 4-cyclopropyl-6-formyl-quinoline-3-carbonitrile (example 57c), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-cyclopropyl-quinoline-3-carbonitrile. LC-MS m/e 321 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=2)=[N:13][CH:14]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[N:30]=1.C(N(CC)CC)C.O>CS(C)=O>[F:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[CH:22]=[C:23]2[CH2:24][CH2:25][N:26]([C:36]([NH:35][C:31]3[N:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[O:37])[CH2:27][CH2:28]2)=[N:13][CH:14]=1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: Fc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(F)cn3)c2)CC1
Temperature: 25 °C
Yield: 42 %

Procedure:
A solution of 5-fluoro-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine trifluoroacetate (0.466 g), phenyl pyridazin-3-ylcarbamate (0.274 g, 1.40 equiv), and triethylamine (0.634 mL, 5.00 equiv) in dimethyl sulfoxide (2.0 mL, 0.30 M) was heated to 65° C. for 2 h. The reaction was cooled to room temperature. Water was added and then the solution was extracted with ethyl acetate (3 times). The organic extracts were combined and washed with water, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a 12 g silica gel column using 20-50% ethyl acetate/dichloromethane over 60 minutes as the eluent to give the title compound as a yellow foam. 0.155 g, 42% yield. 1H NMR (400 MHz, CDCl3) δ ppm 2.46 (2H, t, J=5.5 Hz), 2.59 (2H, t, J=5.5 Hz), 3.61 (2H, t, J=5.8 Hz), 3.71 (2H, t, J=5.8 Hz), 6.39 (1H, s), 6.84-6.99 (3H, m), 7.02 (1H, d, J=7.8 Hz), 7.34 (1H, t, J=7.8 Hz), 7.39-7.54 (2H, m), 8.02 (1H, d, J=3.1 Hz), 8.47 (1H, d, J=8.6 Hz), 8.74 (1H, d, J=3.5 Hz).
Reaction SMILES: [C:1]1([C:7]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.C(O[I:20](C1C=CC=CC=1)OC(=O)C)(=O)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[I:20][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:7]1([C:11]([OH:13])=[O:12])[CH2:8][CH2:9][CH2:10]1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: II
Solvent: CN(C)C=O
Product: O=C(O)C1(c2ccccc2I)CCC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of 1-phenyl-1-cyclobutanecarboxylic acid (2.00 g, 11.4 mmol) in DMF (10 mL) containing palladium (II) acetate (0.109 g, 0.567 mmol), iodine (2.16 g, 8.51 mmol) and (diacetoxyiodo)benzene (2.47 g, 8.51 mmol) was stirred at 60° C. for 18 hours in the absence of light. Additional iodine (2.16 g, 8.51 mmol) and (diacetoxyiodo)benzene (2.47 g, 8.51 mmol) were added and stirring was continued at 60° C. for 8 hours. A final addition of iodine (2.16 g, 8.51 mmol) and (diacetoxyiodo)benzene (2.47 g, 8.51 mmol) was performed and stirring was continued at 60° C. for 16 hours. The reaction mixture was partitioned between EtOAc and water and the aqueous phase was extracted several times with EtOAc. The combined organic fractions were washed with 10% sodium metabisulfate (3×30 mL), 10% citric acid (2×30 mL), water, brine, and then dried (MgSO4), filtered and the solvent evaporated. The crude product was dry loaded onto silica gel and the product was separated using silica column chromatography (Biotage Isolera, 40 g SiO2 Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A52 as a cream solid (425 mg, 12%). LCMS-A: rt 5.711 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[S:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=1.[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>CN(C)C=O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:20][C:17](=[O:19])[CH3:18])[N:14]=1
Reactant: CC(=O)[O-]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nc(CCl)cs1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1csc(-c2ncc([N+](=O)[O-])n2C)n1
Temperature: 0 °C

Procedure:
2-(1-Methyl-5-nitroimidazol-2-yl)-4-chloromethylthiazole (0.7 mole) and anhydrous sodium acetate (2.5 mole) were mixed with dimethylformamide and heated for 31/2 hours. The reaction mixture was poured on to 21/2 liters of ice/water slurry and stirred. The product was collected, washed in water, dried dissolved in boiling benzene and filtered. The filtrate was evaporated to dryness to give 2-(1-methyl-5-nitroimidazol-2-yl)-4-acetoxymethylthiazole.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])([O:3][CH:4]([CH3:6])[CH3:5])=[O:2].[H][H]>C(O)C.[C].[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:7][C:1]([O:3][CH:4]([CH3:6])[CH3:5])=[O:2])[CH:16]=1
Reactant: [H][H]
Reactant: CC(C)OC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(C)OC(=O)Nc1cc(N)ccc1C(=O)O

Procedure:
A solution was prepared by dissolving 13.08 g of 2-carboisopropoxyamino-4-nitrobenzoic acid in 200 ml of ethyl alcohol and was mixed with 3 g of a 10% palladium-carbon catalyst. The resultant reaction mixture was stirred at room temperature in a hydrogen gas atmosphere for 2 hours. Then, the reaction mixture was filtered through a Celite filter and the catalyst on the Celite filter was washed with ethyl alcohol. The entire amount of the filtrate was collected, concentrated and dried under a reduced pressure, and the resultant crude product was recrystallized from an ethyl alcohol-water mixed solvent. The resultant 4-amino-2-carboisopropoxyaminobenzoic acid was obtained in a yield of 11.3 g and exhibited a melting point of 197° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][CH2:10][C@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([CH3:25])[CH:18]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN1C(=O)N(C)CC1>[CH2:1]([N:8]1[C@H:9]([CH3:15])[CH2:10][N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([CH3:25])[CH:18]=2)[C@@H:12]([CH3:14])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)ccc1C#N
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Product: Cc1cc(N2C[C@@H](C)N(Cc3ccccc3)C[C@@H]2C)ccc1C#N
Temperature: 210 °C
Reaction time: 48 h
Yield: 25.2 %

Procedure:
To a solution of 3.81 g of (2R,5S)-1-benzyl-2,5-dimethylpiperazine in 20 ml of DMI were added 3.80 g of 4-fluoro-2-methylbenzonitrile and 7.27 g of diisopropylethylamine, followed by 2 days of stirring in a sealed tube at 210° C. After the addition of ethyl acetate to the reaction solution, the mixture was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the resulting residue was purified by silica gel column chromatography to obtain 1.50 g of the title compound as a solid from an eluate eluted with hexane-ethyl acetate (85:15, v/v).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[N+:20]([O-])=O)=[CH2:2]>[Pd].CO>[NH2:20][C:4]1[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])[CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: C=Cc1ccc(-c2ccc(C(=O)OC)cc2C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(-c2ccc(C(=O)OC)cc2C)cc1N

Procedure:
Methyl 4′-ethenyl-2-methyl-3′-nitrobiphenyl-4-carboxylate (1.6206 g, 5.45 mmol), palladium on carbon (0.290 g, 0.273 mmol) and MeOH (50 mL) were stirred under a balloon atmosphere of H2 at room temperature overnight. The reaction crude was filtered and concentrated in vacuo to afford a light yellow oil. The resulting oil was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel 100 g cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 40%). Related fractions were pooled and evaporated to afford a light yellow oil as the titled compound. LCMS calc.=269.14. found=270.30 (M+H)+.