Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([O:14][CH3:13])[CH:16]=1)[CH2:7][CH2:6]2
Reactant: COc1cccc(CCl)c1
Reactant: Oc1ccc2c(c1)CCNC2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(CN2CCc3cc(O)ccc3C2)c1
Reaction time: 5 h

Procedure:
4.3 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide, 3.1 g of 3-methoxybenzyl chloride and 2.8 g of finely powdered potassium carbonate are first stirred at room temperature for 2 hours and then at 80° C. for 5 hours. After cooling, the solvent is removed in vacuo, the residue is taken up with water/methylene chloride, and the organic phase is again shaken with water and dried over magnesium sulfate. After evaporation in a rotary evaporator, a yellow oil remains, and this crystallizes after trituration with ethyl acetate.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[I-].[CH3:15][S+](C)(C)=O.O>CS(C)=O>[O:1]1[C:5]2[C:6]([CH:10]3[CH2:15][O:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: C[S+](C)(C)=O
Reactant: O=Cc1cccc2ccoc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1cc(C2CO2)c2occc2c1

Procedure:
A solution of benzofuran-7-carboxaldehyde (4.4 g) in dry dimethylsulphoxide was added dropwise to a stirred solution of sodium hydride (60% dispersion in oil, 2.5 g) and trimethylsulphoxonium iodide (7.6 g) in dimethylsulphoxide (50 ml) at room temperature. After 1 hour iced water was added and extracted with diethylether. The extracts were washed with water, dried, filtered and evaporated to a yellow oil. Chromatography on silica eluting with 10:1:90 ether:triethylamine:hexane gave 7-benzofuranyl oxirane as an oil.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[F:12][C:13]([F:19])([F:18])[CH2:14][C:15](O)=[O:16].[C:20]([O:24][C:25](=[O:43])[N:26]([C@:28]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=1)([CH2:32][CH:33]=[CH2:34])[CH2:29][NH:30][CH3:31])[CH3:27])([CH3:23])([CH3:22])[CH3:21].O>O1CCCC1>[C:20]([O:24][C:25](=[O:43])[N:26]([C@:28]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=1)([CH2:32][CH:33]=[CH2:34])[CH2:29][N:30]([CH3:31])[C:15](=[O:16])[CH2:14][C:13]([F:19])([F:18])[F:12])[CH3:27])([CH3:21])([CH3:22])[CH3:23]
Reactant: O=C(O)CC(F)(F)F
Reactant: C=CC[C@@](CNC)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@](CN(C)C(=O)CC(F)(F)F)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
1-Hydroxybenzotriazole monohydrate (11.5 g) was dissolved in anhydrous tetrahydrofuran (0.8 L). At room temperature, 3,3,3-trifluoropropionic acid (120.3 g) was added thereto. Under cooling with ice, 1-[3-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (180.0 g) was added to the mixture, and the resultant mixture was stirred for 10 minutes at the same temperature. A solution of tert-butyl[2-(S)-(3,4-dichlorophenyl)-1-methylamino(4-penten-2-yl)]methylcarbamate (318.8 g) in anhydrous tetrahydrofuran (0.9 L) was added thereto, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, extracted with ethyl acetate, sequentially washed with water, aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=6:1 to 5:1 to 2:1 to 1:1), to thereby give the title compound (275.7 g, 69.7%, 5 steps).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C.O>[Si:22]([C@@:3]1([OH:4])[C@@H:5]([CH2:6][O:7][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn([C@H]2C[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of thymidine (5.00 g, 20.64 mmol) and imidiazole (9.0 g, 132.1 mmol) in anhydrous DMF (11 mL), a solution of TBSCl (9.96 g, 66.05 mmol) in DMF (11 mL) was added dropwise, and the mixture was stirred at room temperature overnight under a N2 atmosphere. After the mixture was diluted with water (100 mL), the formed precipitate was filtered and dissolved in ethyl ether (125 mL). The ether solution was washed twice with water (25 mL each) and once with brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure to a waxy solid, which was re-crystallized from hexane/ethyl either (10:1) to yield 3′,5′-O-bis-tert-butyldimethylsilyl-thymidine dT.04 (10.64 g, 90%).
Reaction SMILES: Cl[C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CS(C)=O.O>[NH2:13][C:12]1[C:2]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cnc(NC2CCCCC2)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Ethyl 6-chloro-5-nitronicotinate (1.00 g, 4.33 mmol) prepared according to A. H. Berrie et al. (J. Chem. Soc. 1951, 2590) was dissolved in DMSO (2 mL) and cyclohexylamine (0.54 g, 5.4 mmol) was added. The mixture was stirred for 1 h at room temperature, diluted with water and the yellow precipitate collected by filtration. The product was washed with water and dried (0.95 g, 74% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[C:16]([O:20][C:21]([O:23]C(OC(C)(C)C)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][O:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:8][C:7]=1[C:12]([F:14])([F:15])[F:13])=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1sc(N)nc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(NOC(=O)OC(C)(C)C)nc1C(F)(F)F
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
A suspension of ethyl-2-amino-4-trifluoromethyl-thiazole-5-carboxylate (5.05 g, 21.02 mmol), di-t-butyldicarbonate (4.82 g, 22.07 mmol) and 4-dimethylaminopyridine (260 mg, 2.1 mmol) in dichloromethane (209 mL) was stirred under nitrogen for 1.5 h. The solvent was evaporated in vacuo. The residue was chromatographed on a silica gel column. Elution with 5% EtOAc in hexanes, followed by 15% EtOAc in hexanes afforded the title compound (6.57 g, 92%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[O-:29][CH2:30][CH3:31].[Na+]>C(O)C.CO>[CH2:30]([O:29][CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1)[CH3:31]
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCOCc1nc(-c2c(-c3ccccc3)noc2C)cn1-c1ccc([N+](=O)[O-])cc1
Yield: 92 %

Procedure:
As described for Example 150, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (50 mg, 0.13 mmol), using sodium ethoxide in ethanol instead of sodium methoxide in methanol, was converted to the title compound (47 mg, 92%) which was obtained as a yellow solid. MS: m/e=405.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][C:13](=[O:18])[NH:14]3)[CH2:9]2)=[CH:6][C:5]([C:19]#[N:20])=[CH:4][C:3]=1[NH:21]C1N=C(N(CC)CC2C=CC(OC)=CC=2)C2=NC=C(C#N)N2N=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.[Cl:60]CCCl>>[NH2:21][C:3]1[C:2]([Cl:1])=[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]([NH:14][C:13](=[O:18])[CH2:12][Cl:60])[C@H:10]([OH:11])[CH2:9]2)[CH:6]=[C:5]([C:19]#[N:20])[CH:4]=1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@H]4NC(=O)CO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Reactant: ClCCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N)c(Cl)c(N2CC[C@@H](NC(=O)CCl)[C@H](O)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was taken up in DCE (0.8 mL), anisole (0.043 mL, 0.391 mmol) and TFA (0.5 mL, 6.49 mmol). The mixture stirred 2 h at 25° C. and solvent was removed. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 25-65% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (+/−)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)-2-chloroacetamide (2.2 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][N:8]1[C:13]2=[CH:14][NH:15][C:16]([C:17]3[S:18][CH:19]=[C:20]([CH3:22])[N:21]=3)=[C:12]2[C:11](=[O:23])[N:10]([CH3:24])[C:9]1=[O:25].Br[CH2:27][CH:28]([S:41][C:42]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40]>CC(N(C)C)=O>[O:39]=[C:38]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:40])[N:30]1[CH2:29][CH:28]([S:41][C:42]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:27][N:15]1[C:16]([C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[C:12]2[C:13]([N:8]([CH3:7])[C:9](=[O:25])[N:10]([CH3:24])[C:11]2=[O:23])=[CH:14]1
Reactant: Cc1csc(-c2[nH]cc3c2c(=O)n(C)c(=O)n3C)n1
Reactant: O=C1c2ccccc2C(=O)N1CC(CBr)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CC(CN2C(=O)c3ccccc3C2=O)SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
Cesium carbonate (1.537 g, 4.72 mmol) was added to a solution of 1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Intermediate Nd) (0.652 g, 2.359 mmol) and 2-(3-bromo-2-(tritylthio)propyl) isoindoline-1,3-dione (2.011 g, 2.59 mmol) in dimethylacetamide (10 ml) and the mixture was stirred at 55° C. for 16 hours. The mixture was cooled to room temperature, partitioned between water (150 ml) and ethyl acetate (150 ml). The organic layer was separated, washed with brine (150 ml), dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-75% EtOAc/hexane afforded the title compound.
Reaction SMILES: [CH2:1]=O.[S:3](=[O:6])([OH:5])[O-:4].[Na+:7].[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>O>[C:8]([NH:12][CH2:1][S:3]([O-:5])(=[O:4])=[O:6])([CH3:11])([CH3:10])[CH3:9].[Na+:7]
Reactant: CC(C)(C)N
Reactant: C=O
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)NCS(=O)(=O)[O-]
Temperature: 72.5 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
37% Formaldehyde solution (18 g, 0.22 mol) was added to a suspension of sodium bisulfite (22 g, 0.2 mol) in water (25 mL). To this mixture was added tert-butylamine (28 mL, 19.4 g, 0.26 mol) at such a rate that the temperature of the reaction mixture was not exceeding 30° C. When the addition was complete, a distillation apparatus was set and the mixture was stirred at 70-75° C. for 10 minutes (excess of tert-butylamine was distilled off) and cooled to 10-15° C. The formed precipitate was filtered, washed with methanol and dried at 20-25° C. to give sodium tert-butylaminomethylsulfonate (30 g, 80%), as white plates, decomposition without melting above 180-190° C. (smell of amine),
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:7]([S:8]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1nc(C)cnc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
4-Dimethylaminopyridine (0.1 g) was added to a solution of 2-chloropyridine-3-sulphonyl chloride (1.06 g), 2-amino-3-methoxy-5-methylpyrazine (0.695 g) and pyridine (0.424 ml) in dichloromethane (5 ml) and the mixture was stirred at ambient temperature for 18 hours. The solution was then transferred to a silica gel Mega Bond Elut column. Elution with 0-40% ethyl acetate/hexane gave 2-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.47 g) as an oil; 1H NMR (d6-DMSO): 2.3 (s, 3H), 3.9 (s, 3H), 7.5 (s, 1H), 7.65 (dd, 1H), 8.45 (dd, 1H), 8.7 (dd, 1H); mass spectrum (+ve CI): 315 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:10]=1)[C:5]([OH:7])=O.C([O:21][C:22](=[O:38])[CH2:23][CH2:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28]([C:32](=[NH:35])[NH:33]O)=[CH:27][C:26]=1[CH2:36][CH3:37])(C)(C)C>>[CH2:36]([C:26]1[CH:27]=[C:28]([C:32]2[N:33]=[C:5]([C:4]3[CH:8]=[C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[N:10]=[C:2]([CH3:1])[CH:3]=3)[O:7][N:35]=2)[CH:29]=[C:30]([CH3:31])[C:25]=1[CH2:24][CH2:23][C:22]([OH:38])=[O:21])[CH3:37]
Reactant: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Reactant: Cc1cc(C(=O)O)cc(N2CCOCC2)n1
Product: CCc1cc(-c2noc(-c3cc(C)nc(N4CCOCC4)c3)n2)cc(C)c1CCC(=O)O

Procedure:
The title compound is prepared in analogy to Example 8 from 2-methyl-6-morpholin-4-yl-isonicotinic acid and 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid tert-butyl ester; LC-MS: tR=0.98 min; [M+1]+=437.25.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=O)=[C:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[NH:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].N1CCCCC1>CCO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=[C:32]5[NH:26][C:27](=[O:28])[NH:29][C:30]5=[O:31])=[C:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: O=C1CNC(=O)N1
Reactant: CN1CCN(c2cccc(Nc3ccn4ncc(C=O)c4n3)c2)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN1CCN(c2cccc(Nc3ccn4ncc(C=C5NC(=O)NC5=O)c4n3)c2)CC1
Temperature: 70 °C

Procedure:
To 5-(3-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (74 mg, 0.221 mmol) in EtOH was added hydantoin (22 mg, 0.221 mmol) and piperidine (22 μL, 0.221 mmol). The mixture was heated at 70° C. The solid formed was filtered off and the filtrate was prepared by HPLC to yield 5-((5-(3-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=419)
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C([O-])=O.[C:34]([C@H:37]1[CH2:41][CH2:40][NH2+:39][CH2:38]1)([OH:36])=[O:35].CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:39]3[CH2:40][CH2:41][C@H:37]([C:34]([OH:36])=[O:35])[CH2:38]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=C(O)[C@H]1CC[NH2+]C1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC[C@H](C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Reaction time: 2 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (1.2 g, 2.9 mmol) was added to a solution of (3S)-3-carboxypyrrolidinium trifluoroacetate (0.50 g, 2.3 mmol) and DIPEA (3 mL, 17 mmol) in DCE (20 mL) at 80° C. The reaction mixture was stirred for 2 hrs. and the solvent was concentrated. The product was purified by MPLC on silica gel using 30% acetone in DCM containing 1% of AcOH to provide the title compound as white solid. Yield: 600 mg (42%); MS (ESI) (M+H)+=484.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N+:9]([O-])[C:10]3[C:15]([C:16]=2[N+:17]([O-:19])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.[C:21]1([N:27]=C=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[NH:27]([C:8]1[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[C:16]([N+:17]([O-:19])=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=[N+]([O-])c1c(N2CCOCC2)c[n+]([O-])c2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(N2CCOCC2)c(Nc2ccccc2)nc2ccccc12

Procedure:
The 3-morpholino-4-nitroquinoline-N-oxide (3 g, 0.011 mol) was suspended in dimethylformamide (40 ml) and following addition of phenyl isocyanate (3.4 g, 0.029 mol), the mixture was added on an oil bath at 80°-90° C. for ca. 3 hours. The reaction mixture was totally charged into water and subjected to extraction with chloroform. The chloroform layer was washed with water and dried with anhydrous sodium sulfate. After the chloroform was distilled off under vacuum, the residue was subjected to recrystallization with ethanol. The resulting crystal was recovered by filtration under vacuum to obtain 2-anilino-3-morpholino-4-nitroquinoline in an amount of 2.95 g (yield, 77%).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH3:19][C:20]1[C:25]([CH2:26]Br)=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[CH2:26][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: Cc1ccccc1CBr
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2C)CCCC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.4 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (870 mg, 3.58 mM), a-bromo-o-xylene (662 mg, 3.58 mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.21 g (98%) of the 9-[(2-methylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a dark oil. 1H NMR (DMSO-d6) δ7.5-7.2 (m, 4H), 7.15 (t, 1H, J=8 Hz), 7.0 (t, 1H, J=8 Hz), 6.15 (d, 1H, J=8 Hz), 5.55 (s, 2H), 3.85 (s, 3H), 2.6 (m, 2H), 2.4 (m, 2H), 2.4 (s, 3H), and 2.1 (m, 2H). IR (CHCl3, cm−1) 3010, 2952, 1724, 1671, 1653, 1604, 1460, 1444, 1290, 1174, and 1122. MS (ES) m/e 348.5.
Reaction SMILES: CO[C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[N:8][C:9](SC)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH3:19].[CH3:29][O-:30].[Na+]>>[CH2:26]([CH:23]([N:22]1[C:7]2[N:8]=[C:9]([O:30][CH3:29])[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[CH3:19])[C:6]=2[CH:5]=[CH:4][C:3]1=[O:28])[CH2:24][CH3:25])[CH3:27]
Reactant: CCC(CC)Nc1nc(SC)nc(-c2ccc(F)cc2C)c1/C=C/C(=O)OC
Reactant: C[O-]
Agent: [Na+]
Product: CCC(CC)n1c(=O)ccc2c(-c3ccc(F)cc3C)nc(OC)nc21

Procedure:
Prepared as described above in Example 98 starting from (E)-3-[4-(1-ethyl-propylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid methyl ester and sodium methoxide to afford the title compound 8-(1-ethyl-propyl)-4-(4-fluoro-2-methyl-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 0.89 (m, 6H), 2.02 (m, 2H), 2.22 (s, 3H), 2.33 (m, 2H), 3.39 (m, 2H), 4.09 (s, 3H), 5.35 (m, 0.5H), 5.62 (m, 0.5H), 6.41 (br d, 1H, J=9.6 Hz), 7.03 (m, 2H), 7.28 (m, 2H). LC MS (m/e)=356 (MH+). Rt=2.50 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13](Cl)(=[O:15])[CH3:14].[N+](C1C=CC=CC=1)([O-])=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:14][C:13]([OH:15])=[O:18])[CH:7]=[CH:6]2
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CC(=O)Cl
Reactant: COc1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2cc(CC(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 1.6 g. of 2-methoxynaphthalene, 1.6 g. of acetyl chloride, and 20 ml. of nitrobenzene, there are added 4.0 g. of aluminum chloride. The resulting mixture is stirred for 48 hours at 25°C; then it is washed with water until free of chloride ion. The mixture is dried over sodium sulfate and evaporated under reduced pressure. The residue, 2-acetyl-6-methoxynaphthalene, is refluxed in 2 ml. of morpholine containing one-half gram of sulfur for 2 hours; the reaction mixture is then filtered and evaporated. The resulting reaction derivative is extracted with diethyl ether; the extracts are combined and evaporated. The residue is refluxed in 10 ml. of concentrated hydrochloric acid for 2 hours, cooled to 25°C, and neutralized with aqueous sodium hydroxide. The mixture is then extracted with ether and the extracts are combined, washed with water to neutrality, dried and evaporated to yield 2-(6-methoxy-2-naphthyl)acetic acid.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[O:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:14][CH2:13][CH2:12][C:11]([OH:15])=[O:10]
Reactant: O=C1CCCO1
Reactant: Oc1ccccc1Cl
Agent: [Na]
Solvent: CCO
Product: O=C(O)CCCOc1ccccc1Cl
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
To a solution of sodium (405 mg, 1.08 mmol) in ethanol (11.1 mL) was added 2-chlorophenol and the reaction mixture was stirred for 5 minutes before adding dihydro-furan-2-one (1.4 g, 16.1 mmol). The reaction mixture was stirred for 5 hours at 100° C. after which time the ethanol was slowly evaporated by continuous heating to 150° C. for another 12 hours. After such time the residue was dissolved in water (7 mL) and aqueous hydrochloric acid (1N) was added until precipitation occurred. The precipitate was isolated by filtration, washed with water and dried in vacuo to yield the title compound as yellow solid (2.79 g, 80.4%).