Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[S:22]1[CH:26]=[CH:25][C:24]2[CH:27]=[C:28]([CH2:31][OH:32])[CH:29]=[CH:30][C:23]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[S:22]1[C:23]2[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:2]3[CH:7]=[CH:6][N:5]([C:8]4[CH:9]=[CH:10][C:11]5[N:15]=[C:14]([CH:16]6[CH2:18][CH2:17]6)[N:13]([CH3:19])[C:12]=5[CH:20]=4)[C:4](=[O:21])[CH:3]=3)=[CH:27][C:24]=2[CH:25]=[CH:26]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Reactant: OCc1ccc2sccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc5sccc5c4)cc3=O)cc21
Temperature: 100 °C
Yield: 10.5 %

Procedure:
A mixture of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), benzo[b]thiophen-5-ylmethanol (110 mg), cesium carbonate (326 mg) and DMF (3 ml) was heated at 100° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (15 mg) as a white solid.
Reaction SMILES: [CH:1]1([C:7]2([C:10]([NH:12][C:13]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][C:17](Cl)=[N:18]4)=[O:11])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(#N)C>[Cl:23][C:22]1[C:13]([NH:12][C:10]([C:7]2([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:8][CH2:9]2)=[O:11])=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH:16]=[CH:15]2
Reactant: O=C(Nc1c(Cl)ccc2nc(Cl)ccc12)C1(C2CCCCC2)CC1
Reactant: C1CNCCN1
Solvent: CC#N
Product: O=C(Nc1c(Cl)ccc2nc(N3CCNCC3)ccc12)C1(C2CCCCC2)CC1
Temperature: 110 °C
Yield: 33.8 %

Procedure:
To a 10 mL vial was added 1-cyclohexyl-N-(2,6-dichloro-5-quinolinyl)-cyclopropanecarboxamide (Example 26 (b)) (0.13 g), piperazine (0.091 g) and acetonitrile (3 mL). The vial was sealed and heated in a microwave at 110° C. for 40 minutes. The solvent was removed from the cooled reaction and the residue taken up in dichloromethane and purified (SiO2, ammonia:methanol:dichloromethane, 1:2:97 as eluant). The solvent was removed from the combined fractions and the product recrystallised from ethanol to afford the title compound (0.050 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:27][O:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:33]3[CH:32]=[CH:31][N:30]=[C:29]([O:28][CH3:27])[CH:34]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: COc1cc(B(O)O)ccn1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCOCC4)c23)ccn1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a degassed mixture of 2-chloro-5-iodo-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), (2-methoxypyridin-4-yl)boronic acid (2 equiv) and tripotassium phosphate trihydrate (3 equiv) in a 9:1 mixture of 1,4-dioxane and water (0.1 M) was added palladium 1,1-bis(diphenylphosphion)ferrocene dichloride (0.2 equiv). The reaction mixture was stirred at 80° C. for 1.5 h. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (15% ethyl acetate in petroleum ether) to afford the title compound (71% yield) as a white powder. MS (ESI) m/z 491.3 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:9]3[CH:14]=[C:13]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)[N:12]=[CH:11][C:10]=3[N:25]=2)=[N:4][O:5][N:6]=1.C(N(CC)C(C)C)(C)C.[NH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>ClCCl>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:9]3[CH:14]=[C:13]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH:41][CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[O:21])[N:12]=[CH:11][C:10]=3[N:25]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1-c1nc2cnc(Oc3cccc(C(=O)O)c3)cc2n1-c1ccccc1
Reactant: NCCN1CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nonc1-c1nc2cnc(Oc3cccc(C(=O)NCCN4CCOCC4)c3)cc2n1-c1ccccc1
Yield: 31 %

Procedure:
The product from Step 9 (0.020 g, 0.048 mmol) in dichloromethane (2 mL) and N,N-diisopropylethylamine (0.02 mL, 0.11 mmol) was treated with N-(2-aminoethyl)morpholine and the PyBoP reagent (2 equiv) and stirred at rt for 2 h. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC to give the compound (0.008 g, 31%). MS (ES+) m/e 527 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: COc1cccc(CBr)c1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cccc(OC)c2)c(=O)[nH]c1=O
Yield: 56 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3-methoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (213 mg, yield: 56.0%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][C:6]2[N:12]=[C:13]([N:24]3[CH2:30][CH:29]4[O:31][CH:26]([CH2:27][CH2:28]4)[CH2:25]3)[N:14]=[C:15](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4]1=[O:32])[CH3:2].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[CH:43][C:44]([NH2:47])=[N:45][CH:46]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:47][C:44]1[N:45]=[CH:46][C:41]([C:15]2[C:5]3[C:4](=[O:32])[N:3]([CH2:1][CH3:2])[CH2:9][C:8]([CH3:10])([CH3:11])[O:7][C:6]=3[N:12]=[C:13]([N:24]3[CH2:25][CH:26]4[O:31][CH:29]([CH2:28][CH2:27]4)[CH2:30]3)[N:14]=2)=[CH:42][CH:43]=1
Reactant: CCN1CC(C)(C)Oc2nc(N3CC4CCC(C3)O4)nc(OS(=O)(=O)C(F)(F)F)c2C1=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCN1CC(C)(C)Oc2nc(N3CC4CCC(C3)O4)nc(-c3ccc(N)nc3)c2C1=O
Temperature: 100 °C
Yield: 79.9 %

Procedure:
170 mg (353.83 μmol) of trifluoromethanesulfonic acid 6-ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl ester and 90.16 mg (389.21 μmol) of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-ylamine are dissolved in 3 ml of dioxane in a microwave tube. 150.21 mg (707.66 μmol) of tripotassium phosphate and 1 ml of water are added The solution is purged with argon. Finally, 24.84 mg (35.38 μmol) of bis(triphenylphosphine)palladium(II) chloride are added and the mixture is heated in a Biotage microwave machine for 15 minutes at 100° C. The reaction mixture is diluted in ethyl acetate and washed with water and then with saturated NaCl solution. The precipitate present in the organic phase is filtered off to give 120 mg of 4-(6-aminopyridin-3-yl)-6-ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-6H-9-oxa-1,3,6-triazabenzocyclohepten-5-one.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]([CH:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[NH:23][CH:24]=[CH:25][CH:26]=3)=[O:21])=[CH:15][C:14]=2[F:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[CH3:36][C:37]([O-])(C)C.[Na+].C(Br)C>C1COCC1>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[N:23]([CH2:36][CH3:37])[CH:24]=[CH:25][CH:26]=3)=[O:21])=[CH:15][C:14]=2[F:27])[CH2:11][CH2:12]1)=[O:5])[CH3:35]
Reactant: CCN(CC)C(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)c3ccc[nH]3)cc2F)CC1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCN(CC)C(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)c3cccn3CC)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To the solution of 1H-pyrrole-2-carboxylic acid {4-[4-(diethylcarbamoyl-phenyl-methyl)-piperidin-1-yl]-3-fluoro-phenyl}-amide (40 mg, 0.084 mmol) in THF (5 mL), NaOtBu (48 mg, 0.50 mmol) and ethyl bromide (54 mg, 0.50 mmol) was added. The mixture was stirred at 25° C. for 1 h and purified by PTLC to provide the title compound (27 mg, 42%). MS: 505.4. 1H NMR (CDCl3): 7.65 (s, 1H), 7.46 (dd, J=4.0, 2.4, 1H), 7.28-7.21 (m, 5H), 7.10-7.16 (m, 1H), 6.90-6.82 (m, 2H), 6.69-6.67 (m, 1H), 6.12 (dd, J=3.9, 2.6, 1H), 4.49 (dd, J=14.3, 6.8, 2H), 3.50-3.12 (m, 7H), 2.71-2.63 (m, 1H), 2.53-2.46 (m, 1H), 2.31-2.21 (m, 1H), 2.08-2.00 (m, 1H), 1.50-1.21 (m, 6H), 1.15-1.04 (m, 6H).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1.O>CS(C)=O>[OH:19][CH:16]1[CH2:17][CH2:18][N:13]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:15]1
Reactant: OC1CCNCC1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A solution of ethyl 4-fluorobenzoate (16.5 g, 98.1 mmol) and piperidin-4-ol (10.0 g, 98.8 mmol) in DMSO (20 mL) was heated at 120° C. under nitrogen for 48 hours. The mixture was cooled to room temperature, poured into water (400 mL), and the solids were filtered off, washed with water, followed by hexane, to afford ethyl 4-(4-hydroxypiperidin-1-yl)benzoate (20.0 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([O:22]C)[CH:20]=[CH:21][C:16]=4[O:15][CH:14]=3)=[C:9]([CH2:24][CH2:25][CH3:26])[CH:8]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][CH:14]=3)=[C:9]([CH2:24][CH2:25][CH3:26])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1coc2ccc(OC)cc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1coc2ccc(O)cc12
Temperature: 25 °C

Procedure:
To a solution of the product from Step 10 (0.34 g, 0.86 mmol) in dichloromethane (5.0 mL) cooled with an ice bath was added boron tribromide (1.0 M in dichloromethane, 1.7 mL, 1.7 mmol). The reaction mixture was gradually warmed to room temperature over 1 h, diluted with ethyl acetate and poured into a saturated solution of sodium bicarbonate. The organic layer was washed with brine, dried and filtered through a short path of silica gel to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([OH:25])=[O:24])[CH:13]=1.O[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1COCC1.C(Cl)Cl>[N:32]1([CH2:31][CH2:30][O:24][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:14]3[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=3)[CH:21]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(=O)O)c2)n1
Reactant: OCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(=O)OCCN3CCOCC3)c2)n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 43.9 %

Procedure:
4-Dimethylaminopyridine (4.4 mg, 0.036 mmol) is added to a stirred solution of 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid (100 mg, 0.24 mmol), N-(2-hydroxyethyl) morpholine (29.07 μL, 0.24 mmol) and 1,3-dicyclohexylcarbodiimide (0.31 mL, 1 M solution in DCM) in dry THF/DCM (6 mL, 1:1) and the reaction mixture is stirred for 5.5 hours at room temperature under nitrogen atmosphere. The mixture is filtered over a pad of Celite and the filtrate concentrated under reduced pressure. The residue is dissolved EtOAc (30 mL), washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by chromatography (SiO2 packed column) eluting with ethyl acetate/heptane to afford 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid 2-morpholin-4-yl-ethyl ester (56 mg, Example 75). LCMS: RT=2.07 minutes, MS: 534 (M+H); 1H NMR, (300 MHz, CDCl3): □8.62 (1H, s), 8.3 (1H, d, J=3.5 Hz), 8.1 (1H, d, J=3.5 Hz), 7.55 (1H, t, J=3.5 Hz), 7.42 (1H, s), 7.2 (2H, s), 6.48 (1H, s), 5.04 (1H, b), 4.5 (2H, t, J=2 Hz), 4.05 (3H, s), 3.72 (6H, t, J=2 Hz), 3.1 (2H, t, J=2 Hz), 2.8 (2H, t, 2 Hz), 2.6 (4H, t, 2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[N:3]=1.[CH2:15]([N:17]=[C:18]=[S:19])[CH3:16]>C(#N)C>[CH2:15]([NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[N:3]=1)[CH3:16]
Reactant: NC(=O)CCCSc1cccc(N)n1
Reactant: CCN=C=S
Solvent: CC#N
Product: CCNC(=S)Nc1cccc(SCCCC(N)=O)n1
Yield: 70.8 %

Procedure:
A mixture of 4-(2-aminopyrid-6-ylthio)butyramide (0.25 g.), ethylisothiocyanate (0.2 g.) and acetonitrile (5 ml.) was heated under reflux for 18 hours and then cooled, and the solid which crystallised was collected to give 4-[2-(3-ethylthioureido)pyrid-6-ylthio]butyramide (0.25 g.) which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:7](=[O:23])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][N:10]=2.C(N(CC)CC)C.O.Cl>C(Cl)Cl>[C:17]1([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][N:10]=3)[C:15](=[O:16])[C:6]3([CH2:5][CH2:4][CH2:3][CH2:2]3)[C:7]2=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1c(CCCCBr)c(O)c2cccnc2n1-c1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2cccnc2N(c2ccccc2)C(=O)C12CCCC2
Temperature: 25 °C

Procedure:
A suspension of 3-(4-bromobutyl)-4-hydroxy-1-Phenyl-1,8-naphthyridin-2(1H)one (5g.) in methylene chloride (350 ml.), in an atmosphere of nitrogen, was stirred at room temperature and to it was added triethylamine (4.1 ml.). The mixture was stirred at room temperature for 16 hrs. Water (300 ml.) was added and the aqueous layer was adjusted to pH 4.5 with hydrochloric acid. The organic layer was separated and the aqueous layer was back-extracted with methylene chloride. The combined organic layers were washed with water, dried (Na2SO4) , filtered and evaporated to yield a solid which was recrystallized from-isopropanol to yield 1'-phenylspiro[cyclopentane-1,3'-(1,8) naphthyridine]2',4'-(1'H)dione, m.p. 178°-179° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.Cl.CN(C)[CH2:18][CH2:19]CN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(O)C.FC(F)(F)C(O)=O>CN(C)C1C=CN=CC=1.ClCCl.CC#N.O>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([O:14][CH2:18][CH3:19])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Yield: 92.3 %

Procedure:
3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid, (1.63 g, 8.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.49 g, 7.8 mmol), 1-hydroxybenzotriazole hydrate (1.05 g, 7.8 mmol), and 4-dimethylaminopyridine (0.43 g, 3.5 mmol), were dissolved in 40 mL of anhydrous dichloromethane under argon. Triethylamine (4.0 mL, 29 mmol) was added to the room temperature mixture via syringe. Absolute ethanol (0.83 mL, 14.2 mmol) was then delivered to the solution, which was maintained at room temperature for 18 hours. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) chromatogram indicated that all of the starting material (Rt=3.7 min) was gone and that a single new product had formed (Rt=5.5 min). The solvent was removed by rotary evaporation and the residue was dissolved in 200 mL of ethyl acetate. The organic layer was washed with water (3×50 mL), 10% hydrochloric acid solution (3×50 mL), and 50% sodium bicarbonate solution (3×50 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give ethyl 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (1.6 g, 7.2 mmol, 86%) as a yellow solid. MS (ES) m/e 221 [M+H]+.
Reaction SMILES: Cl.[C:2]([CH2:21][CH2:22][S:23][CH2:24][CH2:25][NH:26]C=O)([C:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])[F:3].[OH-].[Na+]>C(O)C>[C:2]([CH2:21][CH2:22][S:23][CH2:24][CH2:25][NH2:26])([C:5]([C:8]([C:11]([C:14]([C:17]([F:18])([F:19])[F:20])([F:15])[F:16])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])[F:3]
Reactant: O=CNCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
Concentrated hydrogen chloride solution (37.5% by weight in water, ten-fold excess) was added to a solution of one equivalent of either C6F13C2H4SCH2CH2NHC(O)H in ethanol at 0° C. (32° F.). The reaction mixture was allowed to warm to ambient temperature while being stirred. After the initial foam formation ceased the reaction mixture was slowly heated and held at reflux temperature for 5 h. The progress of the reaction was monitored via gas chromatography. Upon complete conversion the pH of the solution was brought to 8-10 by carefully adding aqueous sodium hydroxide solution. The crude product separated as the bottom layer and was isolated as a dark brown slightly viscous liquid via a separatory funnel. It was washed with water and dried using molecular sieves (4 angstrom) to give the desired product C6F13C2H4SCH2CH2NH2.
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].C1(O)C=CC=CC=1.[H-].[Na+].F[C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]=1[C:21]#[N:22]>O1CCCC1.CS(C)=O>[O:1]([C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:20]=1[C:21]#[N:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-]c1ccccc1
Reactant: N#Cc1c(F)cccc1Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: N#Cc1c(Nc2ccccc2)cccc1Oc1ccccc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
Sodium phenoxide was generated by dissolving phenol (0.36 g, 3.83 mmol) in dry tetrahydrofuran (5 mL), and adding sodium hydride (0.087 g, 3.6 mmol). After gas evolution ceased, the solvent was evaporated and 2-fluoro-6-(phenylamino)benzonitrile (0.6 g, 2.83 mmol) dissolved in dimethyl sulfoxide (10 mL) was added. The mixture was heated to 110° C. while stirring under argon for 4 hours. The solvent was evaporated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water (5×), brine (1×) dried over anhydrous Na2SO4 filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 10–40% CH2Cl2 in hexane to give the title compound as a white amorphous solid. mp 146–147° C.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OC)OC.[H-].[Na+].[CH:20]([CH:22]1[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:25](=[O:36])[CH2:24][S:23]1)=O.Cl>COCCOC.O>[O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)/[CH:3]=[CH:20]/[CH:22]1[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:25](=[O:36])[CH2:24][S:23]1
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Reactant: O=CC1SCC(=O)N1CCCCCCC(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(O)CCCCCCN1C(=O)CSC1/C=C/C(=O)CCc1ccccc1
Temperature: 25 °C

Procedure:
Dimethyl 2-oxo-4-phenylbutylphosphonate (1 molar equivalent) is added dropwise over a 1/2 hour period to a stirred suspension of sodium hydride (2equivalents) in 1,2-dimethoxyethane maintained at or below 20° C. To the resulting reaction mixture is slowly added 7-(2-formyl-4-oxo-3-thiazolidinyl)heptanoic acid (1 molar equivalent) with good stirring and cooling (sufficient to maintain a reaction temperature at or below 20° C.). Upon completing this addition, the reaction is stirred at ambient temperature for 1 hour, then heated at reflux for 1/2 hour, cooled to room temperature, and diluted with water. The aqueous mixture is acidified with dilute hydrochloric acid and extracted with ether. The organic extract is dried over sodium sulfate, filtered, and evaporated in vacuo at 40° C. leaving the title compound as an oily residue which is purified chromatographically on silica gel.
Reaction SMILES: ClC(O[CH:5](Cl)[CH3:6])=O.C(N1CC=C([N:21]([CH3:38])[C:22](=[O:37])[C:23]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)([OH:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)CC1)C1C=CC=CC=1>C(Cl)Cl>[NH:21]1[CH2:6][CH:5]=[C:24]([CH2:38][NH:21][C:22](=[O:37])[C:23]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)([OH:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:23][CH2:22]1
Reactant: CN(C(=O)C(O)(c1ccccc1)C1CCCCC1)C1=CCN(Cc2ccccc2)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: O=C(NCC1=CCNCC1)C(O)(c1ccccc1)C1CCCCC1

Procedure:
A solution of 1-chloroethyl chloroformate (0.53 ml) in methylene chloride (5 ml) was added dropwise to a solution of N-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-methyl-2-cyclohexyl-2-hydroxy-2-phenylacetamide (1.50 g) in methylene chloride (25 ml) below 7° C. After being refluxed for 1 hour, the reaction mixture was evaporated in vacuo. To the residue was added methanol (20 ml) and the mixture was refluxed for 1.5 hours. The reaction mixture was evaporated in vacuo, and to the residue was added 1N aqueous solution of sodium hydroxide. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of 2-propanol and ethanol to give N-(1,2,3,6-tetrahydropyridin-4-yl)methyl-2-cyclohexyl-2-hydroxy-2-phenylacetamide (0.19 g).