Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@:10]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][C@H:12]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C.[Pd]>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@@:10]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][C@H:12]2[S:24]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]
Reactant: [H][H]
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: N[C@@H]1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Yield: 48.8 %

Procedure:
(1R*,2R*,5S*,6R*)-2-benzylamino-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane (Description 4; 8.34 g, 16 mmol) was dissolved in methanol (150 mL) and acetic acid (150 mL), then treated with 10% palladium on activated charcoal (2 g). The suspension was then hydrogenated at 50 psi hydrogen for 16 hours, then filtered. The filtrate was concentrated in vacuo, and the oil remaining suspended in saturated aqueous sodium hydrogen carbonate solution (250 mL). This was extracted with ethyl acetate (2×250 mL) and the extracts were dried (MgSO4), then concentrated. Purification by silica chromatography yielded the title compound as a gum (3.37 g, 7.8 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:17])=[O:16]
Reactant: OCCOCCc1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCOCCc1ccc(F)cc1
Yield: 87 %

Procedure:
The 2-[2-(4-fluorophenyl)ethoxy]ethanol obtained according to the preceding paragraph was sulfonylated with methanesulfonyl chloride in a manner analogous to that described in Example 1(c) to give 8.2 g (87%) of 2-[2-(4-fluorophenyl)ethoxy]ethyl methanesulfonate in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:14]=[O:15])=[CH:4]1)[CH3:2].[O-:16][Mn](=O)(=O)=O.[K+].CCOCC>CC(C)=O.O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([OH:16])=[O:15])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C=O)c2ccc(OC)cc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CCn1cc(C(=O)O)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.4 %

Procedure:
1-Ethyl-6-methoxy-1H-indole-3-carbaldehyde (600 mg, 2.95 mmol) is dissolved in acetone (85 mL). A solution of KMnO4 (450 mg, 2.85 mmol) in H2O (28 mL) is added. This is stirred at room temperature for 5 hours. Another solution of KMnO4 (450 mg, 2.85 mmol) in H2O (25 mL) is then added. After stirring for another hour at room temperature, the reaction is complete. The reaction mixture is quenched with 10% H2O2 (1.5 mL), and is then filtered through celite. The filtrate is stripped down under vacuum to roughly 1/3 of the volume. The residue is acidified with 6N HCl, and is extracted into ethyl acetate. Purification by silica gel column (hexanes/acetone/acetic acid, 70/30/1) yields crude product. Trituration with ether yields pure 1-ethyl-6-methoxy-1H-indole-3-carboxylic acid (365 mg, 56%) as a yellow solid.
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:28]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: O
Product: COc1cccc(S(=O)(=O)NC2CCN(CCc3c[nH]c4ccccc34)CC2)c1

Procedure:
Using an analogous procedure to Example 1 3-[2-(4-amino-1-piperidyl)ethyl]indole monohydrate may be reacted with m-methoxybenzenesulphonyl chloride to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]([F:26])([F:25])[F:24])=[N:4][N:5]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20])=[CH:12][CH:11]=2)[C:6]=1[CH:7]1[CH2:9][CH2:8]1.CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>>[Cl:1][C:2]1[C:3]([C:23]([F:24])([F:26])[F:25])=[N:4][N:5]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[C:18](=[CH:29][N:30]([CH3:32])[CH3:31])[C:19](=[O:21])[CH3:20])=[CH:14][CH:15]=2)[C:6]=1[CH:7]1[CH2:8][CH2:9]1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)Nc1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)cc1
Product: CC(=O)C(=CN(C)C)C(=O)Nc1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
N-{4-[4-chloro-5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3-oxobutanamide (1.6 g, 3.98 mmol) and N,N-Dimethylformamide dimethylacetal (2.6 g, 21.9 mmol) were mixed and stirred at rt for overnight. Workup (AcOEt/H2O) followed by purification on 60-120 mesh silicagel using AcOEt and Peteher (1:1) as eluent afforded N-{4-[4-chloro-5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-2-[(dimethylamino)methylene]-3-oxobutanamide (1.3 g).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH:8]([S:11]([CH2:14][S:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]2)(=[O:17])=[O:16])(=[O:13])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1.O.Cl>ClCCl>[CH2:1]([CH:5]1[CH2:6][CH2:7][CH:8]([S:11]([C:14]([S:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[N+:37]=[N-:38])(=[O:13])=[O:12])[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCCCC1CCC(S(=O)(=O)CS(=O)(=O)C2CCC(CCCC)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCC1CCC(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCC(CCCC)CC2)CC1
Reaction time: 0.25 h
Yield: 20.6 %

Procedure:
In 91 g of dichloromethane were dissolved 10.5 g (0.025 mol) of the bis(4-n-butylcyclohexylsulfonyl)methane prepared above and 7.5 g (0.038 mol) of p-toluenesulfonylazide. The solution was cooled on an ice bath, to which 3.7 ml (0.0025 mol) of diazabicyclo[5.4.0]-7-undecene (DBU) was added dropwise at a temperature below 5° C. The solution was ripened at the temperature for 15 minutes, after which 38 g of water and 10 g of 12N conc. hydrochloric acid were added. The organic layer was separated and washed with 50 g of water. The solvent was distilled off in vacuum, leaving an oily matter. It was purified by silica gel column chromatography (using dichloromethane as a developing solvent), obtaining 2.3 g of the desired bis(4-n-butylcyclohexylsulfonyl)diazomethane. The yield was 20%.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=O.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[N:27][C:26]([NH2:29])=[N:25][CH:24]=2)=[CH:19][C:18]=1[F:30]>C(O)(C)(C)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][C:26]3[N:27]([C:2]([CH2:5][C:6]4[CH:7]=[C:8]5[C:13](=[CH:14][CH:15]=4)[N:12]=[CH:11][CH:10]=[N:9]5)=[CH:3][N:29]=3)[N:28]=2)=[CH:19][C:18]=1[F:30]
Reactant: O=CC(Cl)Cc1ccc2nccnc2c1
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Solvent: CC(C)(C)O
Product: Fc1cc(-c2cnc3ncc(Cc4ccc5nccnc5c4)n3n2)ccc1Br
Temperature: 110 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A mixture of 2-chloro-3-quinoxalin-6-ylpropanal (110 mg, 0.52 mmol), and 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (140 mg, 0.52 mmol) in tert-butyl alcohol (4 mL) was stirred at 110° C. overnight. After cooling to RT, it was concentrated and purified by chromatography on silica gel with EtOAc in Hexane (0-40%) to afford the desired product (140 mg, 62%). LCMS: (M+H)=435.2.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2ccc(=O)n3c2N1C[C@H]3CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1CN2C(=O)CCc3ccc(=O)n1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (1S)-1-(hydroxymethyl)-1,2,5,6-tetrahydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (1.909 g, 8.67 mmol) in DCM (100 ml) at 0° C. under argon was treated with Et3N (1.450 ml, 10.40 mmol) and then methanesulfonyl chloride (0.743 ml, 9.54 mmol) and then allowed to warm to rt and stirred at rt for 1 h. The reaction mixture was then treated with saturated aqueous NaHCO3 (100 ml) and the mixture was extracted with DCM (2×100 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude intermediate [(2S)-4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-2-yl]methyl methanesulfonate. This was dissolved in dry CH3CN (100 ml) and then treated with pyridine (1.402 ml, 17.34 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (3.47 g, 17.34 mmol) and heated at 70° C. for 20 h. After 20 h more 1,1-dimethylethyl 4-piperidinylcarbamate (3.47 g, 17.34 mmol) and pyridine (1.402 ml, 17.34 mmol) were added and the temperature was increased to reflux (heating block 95° C.) and reaction was stirred at this temperature for a further 4 h. The reaction mixture was then evaporated, treated with saturated aqueous NaHCO3 (200 ml) was then added and the mixture was extracted with DCM (3×200 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude product as a brown solid.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[F:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=2[S:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1cc(F)ccc1S(=O)(=O)N1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(=O)(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
(Step 2) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.36 g) in methanol (10 ml) was added a solution of 1-[5-fluoro-2-(morpholin-4-ylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 1 (0.58 g) and triethylamine (0.65 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, the mixture was partitioned with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.17 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:7][C:5]=2[N:6]=1.C([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:22][CH:21]=1)(=O)C.CC1C=CC=C(C)C=1NC(=O)CN1CCNCC1>>[OH:14][CH:13]([CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)[CH2:15][N:32]1[CH2:31][CH2:30][N:29]([CH2:28][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([OH:19])=[CH:21][CH:22]=2)=[O:35])[CH2:34][CH2:33]1
Reactant: CC(=O)Oc1ccc(NC(=O)CN2CCNCC2)cc1
Reactant: Cc1nc2cc(OCC3CO3)ccc2s1
Agent: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Product: Cc1nc2cc(OCC(O)CN3CCN(CC(=O)Nc4ccc(O)cc4)CC3)ccc2s1

Procedure:
Compound 54 was prepared in the manner of compound 7 substituting compound 33 for compound 6 and compound 57 for compound 5 in part D of compound 7: Mass Spectrum (MH+)=457.5.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(=O)(O)[O-].[NH4+].[N:35]1C=CC=CC=1>C(#N)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12](=[O:14])[NH2:35])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 150.8 %

Procedure:
To a mixture of 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (2.00 g, 9.94 mmol), Boc anhydride (2.82 g, 12.9 mmol), ammonium bicarbonate (0.982 g, 12.4 mmol) in 30 mL of acetonitrile at room temperature was added pyridine (0.482 mL, 5.96 mmol). The cloudy, colorless reaction mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was partitioned between 100 mL of ethyl acetate and 30 mL of 1 M HCl. The organic phase was washed with 30 mL of saturated. NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 1.80 g (90%) of (1-carbamoyl-cyclopropyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[N:6]=[CH:5][C:4]([C:3]([N:25]2[CH2:30][CH2:29][S:28][CH2:27][CH2:26]2)=[O:24])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Reactant: C1CSCCN1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 89 %

Procedure:
As described for example 272, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (97.6 mg, 0.3 mmol) was converted, using thiomorpholine instead of 4-aminotetrahydropyran, to the title compound (106 mg, 89%) which was obtained as a white solid. MS: m/e=397.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29]O[CH2:27][CH2:26][C:11]=3[N:12]([C:14]([NH:16][C@@H:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18](NC)=[O:19])=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].N[C@H:31](CO)C(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29][CH2:31][CH2:27][CH2:26][C:11]=3[N:12]([C:14]([NH:16][C@@H:17]([C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:18][OH:19])=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)[C@H](N)CO
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(C)(C)C
Product: CC(C)(C)[C@@H](CO)NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCCC2

Procedure:
Compound 51 was prepared according to the procedure described for the synthesis of compound 28 by replacing intermediate 16 with intermediate 18, and replacing tert-leucine methylamide with tert-leucinol. 1H NMR (CDCl3) δ 7.54-7.60 (m, 1H), 7.41-7.47 (m, 2H), 7.17-7.23 (m, 1H), 6.95 (dd, J=7.3, 3.4 Hz, 1H), 3.80-3.86 (m, 1H), 3.65-3.70 (m, 1H), 3.04 (m, 2H), 2.64 (m, 2H), 1.74-1.84 (m, 4H), 1.04 (s, 9H). LCMS (+ESI) m/z=378.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8](SC)=[N:7][C:6]=2[N:5]([CH2:14][CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)[C:4](=[O:25])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH:37]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([NH:43][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[N:7][C:6]=2[N:5]([CH2:14][CH2:15][CH2:16][OH:17])[C:4](=[O:25])[CH:3]=1
Reactant: CSc1ncc2c(N)cc(=O)n(CCCO[Si](C)(C)C(C)(C)C)c2n1
Reactant: NC1CCCCC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Nc1cc(=O)n(CCCO)c2nc(NC3CCCCC3)ncc12
Reaction time: 0.67 h
Yield: 23.9 %

Procedure:
To a solution of 5-amino-8-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (150 mg, 0.395 mmol) in DCM (9 mL) was added 3-chloroperoxybenzoic acid (77% max., 106 mg, 0.474 mmol) at RT under argon atmosphere and the resulting mixture was stirred for 40 min. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in anhydrous dimethyl sulfoxide (ca. 9 mL). Cyclohexylamine (0.226 mL, 1.975 mmol) was then added at RT and the resulting mixture was stirred at 80° C. for 1.5 h. The reaction mixture was then quenched with water (70 mL) and an aqueous saturated solution of ammonium chloride (30 mL). The resulting mixture was extracted with EtOAc; the organic extracts were washed twice with water (50 mL), dried over MgSO4, filtered and evaporated under reduced pressure. To the residue, dissolved in THF, was added a solution of tetrabutylammonium fluoride (1 M in THF, 0.59 mL) at RT and the resulting mixture was stirred overnight. The solid formed was collected by filtration, washed with hexane and purified by preparative TLC (DCM/MeOH, 90/10) to give 30 mg of 5-amino-2-cyclohexylamino-8-(3-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow powder. MS=318 [M+H]+; MP=131.0-132.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([NH2:21])[CH2:19][CH3:20].Cl>O>[N+:9]([C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH:21][CH2:18][CH2:19][CH3:20])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCNc1ccc(O)cc1[N+](=O)[O-]
Reaction time: 5 h

Procedure:
34.7 g (0.2 mole) of 4-chloro-3-nitrophenol, 21 g of sodium carbonate, 0.1 g of copper-I chloride and 20 g of n-propylamine are heated in a bath from room temperature up to a bath temperature of 120° C. After 5 hours, the reaction mixture is taken up in water, acidified (pH 2) with hydrochloric acid and extracted 3 times with ethyl acetate in order to remove unreacted starting material. After neutralisation, the aqueous phase is again extracted 3 times with ethyl acetate. After drying and concentration, these extracts give the desired product in the form of a red oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1cccc(Br)c1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(NCc1cccc(Br)c1)c1ccccc1
Yield: 98 %

Procedure:
In a manner similar to that of Example 1(d), 15 by reacting 7 g (32 mmol) of 3-bromobenzylamine with 4 ml (35 mmol) of benzoyl chloride, 9.1 g (100%) of expected product are obtained.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([NH:49][C:50]([CH3:53])([CH3:52])[CH3:51])[N:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:50]([NH:49][C:44]1[N:43]=[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[CH:47]=[CH:46][C:45]=1[F:48])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)Nc1nc(N)ccc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)c(NC(C)(C)C)n2)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
To 2 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.56 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 0.42 g of 2-amino-6-(t-butylamino)-5-fluoropyridine. The solution was concentrated under reduced pressure to obtain yellow solid residue. To this residue were added 0.6 g of anhydrous potassium carbonate and 1.5 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 20 minutes and allowed to cool. The solution was separated by adding 40 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, supplemented with 2 ml of ethanol, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 0.48 g of the title compound as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Si:15]([O:22][C:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl>[Si:15]([O:22][C:23]1([CH2:29][CH2:30][CH2:31][NH:32][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)[Si](C)(C)OC1(CCCN)CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1(CCCNc2c([N+](=O)[O-])cnc3ccccc23)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
4-Chloro-3-nitroquinoline (0.700 g, 3.37 mmol) was added in two portions to a solution of 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propan-1-amine (0.960 g, 3.54 mmol) and triethylamine (0.610 mL, 4.38 mmol) in dichloromethane (15 mL) at 0° C. After 30 min, the reaction was allowed to warm to rt and stir overnight. The mixture was diluted with dichloromethane (40 mL) and was washed with saturated aqueous sodium bicarbonate (30 mL). The aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford a yellow solid. The crude product was purified using HPFC (silica gel, gradient elution with 0-2% ethyl acetate/hexanes) to yield N-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]-3-nitroquinolin-4-amine as a bright yellow solid (1.40 g, 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:7]#[N:8])([O-])=O.C.CN(C)N>CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: CN(C)N
Solvent: CO
Product: N#Cc1cc(N)cc(C(F)(F)F)c1

Procedure:
3-Nitro-5-trifluoromethylbenzonitrile (1 g, 4.63 mmol) was dissolved in methanol (8 mL) and added activated charcoal (0.1 g), FeCl3.6H2O (17 mg, 0.06 mmol) and N,N-dimethylhydrazine (3.7 mL, 48.6 mmol). The mixture was refluxed overnight. The mixture was filtered and the volatiles removed in vacuo. The residue was purified by chromatography on silica using a mixture of heptane and ethyl acetate (4:1) as eluent affording 3-amino-5-trifluoromethylbenzonitrile.