Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]1([C@H:26]([NH2:28])[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:11][C:4]1[CH:5]=[C:6]([C:8]([NH:28][C@@H:26]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH3:27])=[O:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: COC(=O)c1c(Cl)cc(C(=O)[O-])cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)cc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl
Yield: 96 %

Procedure:
A solution of 2,6-dichlorobenzene-1,4-dicarboxylic acid, 1-methyl ester (Example 4; 3.00 g, 12.0 mmol), (R)-(+)-1-(1-naphthyl)ethylamine (2.00 g, 11.7 mmol), HBTU (5.68 g, 15.0 mmol), HOBT (2.04 g, 15.1 mmol), and diisopropylethylamine (6.20 g, 48.0 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature over the weekend. The solvent was evaporated and ethyl acetate (150 mL) was added. The solution was washed with 1 M HCl (100 mL) and the aqueous layer was back-extracted with ethyl, acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and brine (200 mL each), then dried (MgSO4), filtered, evaporated and chromatographed (30% ethyl acetate/hexanes) to give 2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoic acid, methyl ester (4.52 g, 96%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([S:36]([CH2:39][CH2:40]Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:11][N:10]([CH2:40][CH2:39][S:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:42])([F:28])[F:43])[CH:31]=3)(=[O:37])=[O:38])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(CCCl)c1cccc(C(F)(F)F)c1
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC#N
Product: O=S(=O)(CCN1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)c1cccc(C(F)(F)F)c1
Yield: 19.2 %

Procedure:
To a stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (1.7 gram, 6.60 mmol) and collidine (2 ml) in acetonitrile (25 ml) was slowly added a solution of 2-((3-(trifluoromethyl)phenyl)sulfonyl)ethyl chloride (1.5 gram, 5.50 mmol) in acetonitrile (20 ml) and the resulting solution was heated at reflux temperature for 16 hours. After concentration in vacuo the residue was dissolved in ethylacetate and washed with aqueous sodium hydrogencarbonate solution. The resulting ethylacetate layer was successively washed with 1 N hydrochloric acid solution and aqueous sodium hydrogencarbonate solution. Subsequent flash chromatographic purification (petroleum ether/diethyl ether=1/2 (v/v)) gave an oil which was crystallised from diisopropyl ether to afford 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1-[2-((3-(trifluoromethyl)phenyl)sulfonyl)ethyl]-1H-pyrazole (0.52 gram, 19% yield). Melting point: 118-119° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=O)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].Cl.[NH2:19][OH:20].O.O.O.C([O-])(=O)C.[Na+]>C(#N)C.O>[CH2:1]([N:4]([CH2:15][CH:16]=[N:19][OH:20])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: NO
Reactant: C=CCN(CC=O)C(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C=CCN(CC=NO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A solution of benzyl N-allyl-N-(2-oxoethyl)carbamate (25 g, 107 mmol) in acetonitrile (150 mL) is treated with hydroxylamine hydrochloride (9.68 g, 139 mmol) and a solution of sodium acetate trihydrate (16 g, 117.9 mmol) in water (75 mL). The mixture is stirred at room temperature overnight. The acetonitrile is evaporated and the aqueous solution is extracted with ethyl acetate. The organic layer is separated, dried over magnesium sulfate, and concentrated under vacuum to give the title compound (24 g, 90%). ES/MS (m/e): 249 (M+H).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:12]([CH2:14][CH2:15][NH:16][CH2:17][C@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH:6]=[CH:7][C:8]3=[O:35])=[CH:4][CH:3]=1.[Si:36]([O:43][CH2:44][CH:45]=O)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[C:39]([Si:36]([CH3:38])([CH3:37])[O:43][CH2:44][CH2:45][N:16]([CH2:17][CH:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19]1)[CH2:15][CH2:14][CH:12]1[C:11]2=[C:10]3[C:5](=[CH:4][CH:3]=[C:2]2[F:1])[CH:6]=[CH:7][C:8](=[O:35])[N:9]3[CH2:13]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: O=C1CSc2ccc(N3C[C@@H](CNCCC4Cn5c(=O)ccc6ccc(F)c4c65)OC3=O)cc2N1
Product: CC(C)(C)[Si](C)(C)OCCN(CCC1Cn2c(=O)ccc3ccc(F)c1c32)CC1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 76 %

Procedure:
Starting from the compound of Example 10 and tert-butyldimethylsilyloxy-acetaldehyde and using procedure E, the title compound was obtained as a colourless solid (100 mg; 76% yield).
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8](=[O:10])[C:7]([N+:11]([O-])=O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1>[Pd].C(OCC)(=O)C>[NH2:11][C:7]1[C:8](=[O:10])[NH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(C2CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1ccc(N)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
A mixture of 6-cyclopropyl-3-nitro-2-(1H)-pyridinone (2 g, 13.3 mmol) and 10% palladium on carbon (600 mg) in ethyl acetate (100 ml) was stirred at room temperature under an atmosphere of hydrogen overnight. The catalyst was removed by filtration through a bed of Celite and the filtrate concentrated to yield 1.63 g of product as a white microcrystalline solid. 1H NMR (CDCl3) δ 0.94 (t, J=7.3 Hz, 3 H), 1.67 (m, 2 H), 2.49 (t, J=7.5 Hz, 2 H), 4.00 (br s), 5.88 (d, J=7.1 Hz, 1 H), 6.59 (d, J=7.1 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:6]([CH3:11])=[N:7][NH:8][C:9]=1[CH3:10].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:9]([CH3:10])=[N:8][N:7]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[C:6]=1[CH3:11]
Reactant: COC(=O)Cc1c(C)n[nH]c1C
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (3.90 g, 23 mmol, Enamine EN300-15247) and 4-nitrobenzyl bromide (4.60 g, 20.7 mmol) in acetonitrile was added K2CO3 (2.76 g, 19.9 mmol) and the mixture was stirred for one hour at room temperature. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic phase was dried over MgSO4 and evaporated under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:16][O:15][C:14]3=[O:23])[S:11][CH:12]=2)=[CH:4][CH:3]=1.O.[CH3:25][N:26](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[O:23]=[C:14]1[N:13]([C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:25]#[N:26])=[CH:3][CH:4]=3)[N:9]=2)[CH:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:16][O:15]1
Reactant: CN(C)C=O
Reactant: O=C1OCC(CC(F)(F)F)N1c1nc(-c2ccc(Br)cc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(-c2csc(N3C(=O)OCC3CC(F)(F)F)n2)cc1
Temperature: 120 °C
Yield: 79 %

Procedure:
3-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-4-(2,2,2-trifluoroethyl)-1,3-oxazolidin-2-one (0.53 g, 1.3 mmol), prepared in step 3 of Example 67, and zinc cyanide (91 mg, 0.78 mmol) were dissolved in 15 mL of DMF. The mixture was purged with nitrogen for 15 min, tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol) was added, and the mixture was heated at 120° C. for 3 h. The mixture was cooled and diluted with ethyl acetate and poured into 200 mL of water. The mixture was extracted with ethyl acetate, the organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (25% hexane in methylene chloride) afforded racemic 4-{2-[2-oxo-4-(2,2,2-trifluoroethyl)-1,3-oxazolidin-3-yl]-1,3-thiazol-4-yl}benzonitrile (364 mg, 79%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[C:13]=1[C:20]([O:22][CH3:23])=[O:21].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(CNC(=O)OCc2ccccc2)c1C(=O)OC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Triethylamine (1.87 g, 18.5 mmol) was added to a stirred suspension of methyl-3-(aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 8 mmol) in dichloromethane (30 ml). The mixture was cooled in an ice bath to 4° C. Benzyl chloroformate (1.66 g, 10 mmol) was added slowly keeping the temperature between 4–7° C. After the addition was complete, the cooled mixture was stirred an additional 30 minutes and then warmed to room temperature for 4 hours. The mixture was washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed and the residue was purified by chromatography (dichloromethane/ethyl acetate 95 to 5) to give 2.1 g (76%) of the product as a solid; 1H NMR (CDCl3) δ 7.87 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.36–7.26 (m, 5H), 5.41 (b, 1H), 5.09 (s, 2H), 4.36 (d, J=6.3 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:24])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)C(=O)Nc1ccc(I)cn1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=S)Nc1ccc(I)cn1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
N-(5-Iodo-pyridin-2-yl)-2,2-dimethyl-propionamide (example 39, step 1) (5.8 g, 19.1 mmol) was dissolved in 30 ml of toluene and Lawesson's reagent (7.7 g, 19.1 mmol, 1 equiv.) was added at room temperature. The reaction mixture was stirred for 48 hours at 110° C. The crude product was purified by flash chromatography by directly loading the cooled toluene reaction mixture onto a 300 g silica gel column and eluting with heptane:ethyl acetate 100:0→80:20. The desired N-(5-iodo-pyridin-2-yl)-2,2-dimethyl-thiopropionamide was obtained as a yellow oil (5.1 g, 75% yield), MS: m/e=321.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:35]([N:39]=[C:40]=[O:41])([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C>[C:35]([NH:39][C:40](=[O:41])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)=[O:20])[CH2:17]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: Nc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Reactant: CC(C)(C)N=C=O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)Nc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
N-({1-[4-(4-Amino-phenyl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 15, 100 mg, 0.21 mmol) in DMF (2 mL) was treated with t-butyl-isocyanate (Aldrich, 25 mg, 0.25 mmol) at room temperature for 48 hours. The reaction mixture was directly purified on a silica gel column using a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[C:11]([Cl:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:11]([Cl:24])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCc2ccccc2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of tert-butyl 3-[4-(benzyloxy)-2-chlorophenyl]propanoate (22.5 g) in dichloromethane (67.6 mL) was added trifluoroacetic acid (24.8 mL), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3-[4-(benzyloxy)-2-chlorophenyl]propanoic acid (13.5 g).
Reaction SMILES: [CH2:1]([O:5][C@H:6]1[N:9]([CH:10](O)[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3].S(Cl)([Cl:41])=O.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:5][C@H:6]1[N:9]([CH:10]([Cl:41])[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(O)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(Cl)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
To a solution of diphenylmethyl α-[4(R)-acetonyloxy-3(R)-phenylacetamido-2-oxo-azetidin-1-yl]glycolate (2.136 g) in anhydrous methylene chloride (20 ml) are added thionyl chloride (0.90 ml) and pyridine (0.33 ml) with stirring at 0° C. After stirring for 1 hour at 0° C., the mixture is poured into ice water, and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give the crude product of a mixture of epimers at position α.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1)=[O:7])(=O)[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1.C(OCC)(=O)C>[O:15]1[C:11]2[CH:10]=[CH:9][C:8]([C:6]3[O:7][C:1]([CH3:2])=[N:4][N:5]=3)=[CH:16][C:12]=2[CH:13]=[CH:14]1
Reactant: CC(=O)NNC(=O)c1ccc2occc2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1nnc(-c2ccc3occc3c2)o1
Yield: 220.8 %

Procedure:
A solution of N′-acetyl-1-benzofuran-5-carbohydrazide (20.7 g, 36.2 mmol) and p-toluenesulfonyl chloride (36.2 g, 190 mmol) in pyridine (200 mL) was stirred under an argon atmosphere at 80° C. for 16 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed water, 2 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from tetrahydrofuran to give the title compound (16.0 g, yield 84%) as colorless crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13]CC)=[O:12])[C:2]=1[C:16]([O:18]CC)=[O:17].[OH-].[Na+]>C(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=[O:12])[C:2]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1cc2ccccc2nc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2ccccc2nc1C(=O)O

Procedure:
To a solution of diethyl 2,3-quinolinedicarboxylate (0.162 mol) in ethanol (150 mL) is added a solution of sodium hydroxide (0.50 mol) in water (400 mL). The mixture is heated at reflux for five hours, and the ethanol then removed by distillation at atmospheric pressure. The solution is cooled in an ice bath, diluted with water (100 mL), and acidified with concentrated hydrochloric acid, added in small increments. The precipitate is filtered, washed with water, and air dried to afford the desired 2,3-quinolinedicarboxylic acid as the trihydrate; mp 271°-277° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C-:12]#[N:13].[K+]>O.CCO>[C:12]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:13]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(C(=O)O)cc1
Yield: 78.6 %

Procedure:
A suspension of 4-bromomethylbenzoic acid (25.26 g, 0.12 mol) and KCN (20 g, 0.31 mol) in 5:7 H2O/EtOH (60 mL) was heated to 75°-80° C. for four hours. The cooled reaction was partially concentrated, H2O added, and extracted 1× with EtOAc. After acidification of the aqueous layer, the resulting precipitate was filtered and washed well with H2O to yield 13.6 g; 4 EtOAc extractions of the filtrate yielded an additional 2.7 g. Recrystallization of the combined solids from H2O/EtOH using activated charcoal and filtering through Celite afforded 15.20 g of 4-cyanomethylbenzoic acid.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1>ClCCl.O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][C:14]=1[Br:1]
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N)c(Br)c1
Reaction time: 18 h
Yield: 88 %

Procedure:
A solution of bromine (7.0 mL, 137.3 mmol) in dichloromethane is added dropwise to a cold (−10° C.) solution of ethyl 4-aminobenzoate (22.0 g, 133.3 mmol) in dichloromethane. The reaction mixture is allowed to come to room temperature, stirred for 18 h and diluted with water. The organic phase is separated, washed twice with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (SiO2, 8/1 hexanes/EtOAc as eluent) to afford the title compound as a white solid, 28.6 g (88% yield), identified by HNMR and mass spectral analyses. MS m/e 242 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.01 Hz, 3 H), 4.22 (q, J=7.16 Hz, 2 H), 6.18 (brs, 2 H), 6.81 (d, J=7.91 Hz, 1H), 7.65 (dd, J=8.54, 1.98 Hz 1 H), 7.89 (d, J=1.83 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH:52]2[CH2:66][N:56]3[C:57](=[O:65])[NH:58][C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][C:64]=4[C:55]3=[N:54][CH2:53]2)=[CH:48][CH:47]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([CH:52]3[CH2:66][N:56]4[C:57](=[O:65])[NH:58][C:59]5[CH:60]=[CH:61][CH:62]=[CH:63][C:64]=5[C:55]4=[N:54][CH2:53]3)=[CH:48][CH:47]=2)=[O:11])[CH2:6][CH2:7]1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
A mixture of (4-Methyl-piperazin-1-yl)-acetic acid (3.2 mg, 0.020 mmol), N,N-diisopropylethylamine (0.017 mL, 0.10 mmol), and HBTU (9.1 mg, 0.024 mmol) in 0.6 mL DMF was stirred at rt for 10 minutes, then 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (7.6 mg, 0.026 mmol) added and the reaction continued at rt. At 1.75 hours the reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated to an oily solid. The residue was chromatographed eluting with 10% MeOH/CHCl3 containing Et3N. The obtained oily solid was then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and evaporated to give the title compound as a white solid (4.8 mg, 73%). 1H NMR (CDCl3) δ: 9.14 (s, 1H), 8.99 (br. s, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.38-7.44 (m, 1H), 7.22-7.27 (m, 2H), 7.12 (t, J=7.6 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 4.53 (dt, J=13.1, 3.6 Hz, 1H), 3.95 (dt, J=16.2, 3.6 Hz, 1H), 3.53-3.69 (m, 2H), 3.15 (s, 2H), 3.00-3.12 (m, 1H), 2.67 (br. s, 4H), 2.52 (br. s, 4H), 2.33 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].CCOCC>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:18][CH2:19][CH2:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[O:22])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)COc1ccc(SCCCC(=O)c2ccc(Cl)cc2)c2c1CCC2

Procedure:
Compound 1D (300 mg, 1.26 mmol), 4-chloro-1-(4-chloro-phenyl)-butan-1-one (327 mg, 1.51 mmol), and cesium carbonate (616 mg, 1.89 mmol) in 10 ml anhydrous acetonitrile were stirred at ambient temperature for 72 hours. The reaction was then run through 0.5 g SiO2 eluting with Et2O. The eluant was collected and concentrated to give the title compound, pure enough for subsequent use. MS m/z 419 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10](O)([CH2:13][CH3:14])[CH2:11][CH3:12])=[CH:8][C:7]([CH3:16])=[N:6][N:5]2[C:17]=1[C:18]1[S:19][C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)=[CH:21][C:22]=1[CH3:23].COCCN(S(F)(F)[F:41])CCOC>C(Cl)Cl>[CH2:11]([C:10]([C:9]1[C:4]2[N:5]([C:17]([C:18]3[S:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[CH:21][C:22]=3[CH3:23])=[C:2]([CH3:1])[N:3]=2)[N:6]=[C:7]([CH3:16])[CH:8]=1)([F:41])[CH2:13][CH3:14])[CH3:12]
Reactant: CCC(O)(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C)c(C)nc12
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CCC(F)(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
To a −78° C. solution of 3-{2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazin-8-yl}-pentan-3-ol (0.23 g, 0.55 mmol) and CH2Cl2 (3 mL) is added a solution of [bis(2-methoxyethyl)amino]sulfur triflouride (0.14 g, 0.60 mmol) and CH2Cl2 (2 mL). The solution is warmed to ambient temperature and stirred overnight. The solution is washed with sat. NaHCO3 (5 mL) and concentrated. The reside is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.13 g, 0.31 mmol, 57%). 1H NMR (CDCl3) δ 0.80 (t, J=7.5 Hz, 6H), 2.14 (s, 3H), 2.16-2.31 (m, 2H), 2.46 (s, 3H), 2.54 (s, 3H), 2.56 (s, 3H), 2.59-2.70 (m, 2H), 6.98 (s, 1H), 7.00 (d, J=7.6 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.52 (s, 1H), 7.56 (dd, J=7.8, 7.6 Hz, 1H). LC/MS (m/z): calcd. for C24H27FN4S (M+H)+: 423.2; found: 423.4.