Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:23](=[O:24])[N:6]2[C:7]([C:20]([O-:22])=[O:21])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[C:12]=3[CH3:19])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:26]([O:32][CH2:33]I)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:23](=[O:24])[N:6]2[C:7]([C:20]([O:22][CH2:33][O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:21])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[C:12]=3[CH3:19])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: Cc1c(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cncn12
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cncn12
Temperature: 10 °C
Reaction time: 4 h

Procedure:
To a solution of 29.4 mg of sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate in 0.8 ml of dry DMF was added 0.017 ml of iodomethyl pivalate under the atmosphere of argon at −30° C., and the mixture was stirred for 4 hours during which the temperature was raised up to 10° C. The reaction mixture was diluted with 10 ml of ethyl acetate, separated, and the aqueous layer was extracted twice with ethyl acetate, while the organic layer was washed with 10 ml of semi-saturated aqueous saline. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of 1 ml. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=20:1) and on Sephadex LH-20 (dichloromethane:methanol=1:1) in this sequence to give 7.9 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[N:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27][CH2:26][CH2:25][C:24]=2[CH:23]=[N:22][CH:21]=1>N1C=CC=CC=1>[N:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[N:27]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[CH2:26][CH2:25][C:24]=2[CH:23]=[N:22][CH:21]=1
Reactant: c1ccc2c(c1)NCCc1cncnc1-2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3cncnc3-c3ccccc32)cc1

Procedure:
As described for Example 1, 5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido[5,4-d] [1]benzazepine in pyridine to give the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][NH:13][CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:16][N:17]([CH3:24])[CH2:18]/[CH:19]=[CH:20]/[C:21](O)=[O:22].CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13]([C:21](=[O:22])/[CH:20]=[CH:19]/[CH2:18][N:17]([CH3:24])[CH3:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Clc1ncnc2sc3c(c12)CCNC3
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.6 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine (1000 mg, 4.0 mmol, 90% pure) in THF (20 mL) were added (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (730 mg, 4.4 mmol), EDCI (840 mg, 4.4 mmol), DMAP (97 mmol, 0.8 mmol) and diisopropylethylamine (120 mg, 8.0 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was then concentrated to dryness under reduced pressure. The residue was purified by ISCO using a 20% ethyl acetate in methanol to obtain 1100 mg (82%) of the desired product. LCMS RT=1.51 min, [M+1]+=337.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].I[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([NH:20][C:21]([CH:23]3[CH2:25][CH:24]3[CH3:26])=[O:22])[N:19]=2)[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([NH:20][C:21]([CH:23]3[CH2:25][CH:24]3[CH3:26])=[O:22])[N:19]=2)[N:16]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC1CC1C(=O)Nc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CC1C(=O)Nc1cn2nc(Oc3ccc(Cl)c(N)c3)ccc2n1
Yield: 73.4 %

Procedure:
Using 3-amino-4-chlorophenol (1.57 g, 11.0 mmol), N,N-dimethylformamide (25.0 mL), N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylcyclopropanecarboxamide (2.50 g, 7.31 mmol) and potassium carbonate (2.02 g, 14.6 mmol), and in the same manner as in Example 82, the title compound (1.92 g, 73%) was obtained as a brown powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][C@H:18]([CH3:22])[C:19](O)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Cl)([Cl:27])=O.CN(C=O)C>CCOCC>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][C@H:18]([CH3:22])[C:19]([Cl:27])=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@@H](Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.06 g (2.94 mmol) of (R)-2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid in 5 ml of dry ether under a nitrogen atmosphere and cooled to 0° is added 400 μl (5.50 mmol, 0.66 g) of thionyl chloride and 50 μl of DMF. After 5 hours at 0°, the reaction is stirred at RT overnight. The ether solution of acid chloride is then removed from the oily residue, and the ether and excess thionyl chloride are removed by rotoevaporation to give (R)-2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid chloride.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)O1.[NH2:28][C:29](=[O:43])[C@@H:30]([NH:32][C:33]1[N:38]=[C:37](Cl)[N:36]=[C:35]([C:40]([NH2:42])=[O:41])[CH:34]=1)[CH3:31].C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[NH2:28][C:29](=[O:43])[C@@H:30]([NH:32][C:33]1[N:38]=[C:37]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=3)=[CH:13][CH:14]=2)[N:36]=[C:35]([C:40]([NH2:42])=[O:41])[CH:34]=1)[CH3:31]
Reactant: CC1(C)OB(c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)OC1(C)C
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)n1)C(N)=O
Temperature: 10 °C
Yield: 31.3 %

Procedure:
A 50-mL vial with a screw-top septum was charged with 200 mg of 4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-1,3,2-dioxaborolane, 1 equivalent (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (129 mg, 0.53 mmol), 1.5 mL 2M aqueous Na2CO3, 0.07 equivalents PdCl2(PPh3)2 (28 mg, 0.04 mmol), and 8 mL dioxane. The vial was purged with nitrogen and heated to 10° C. for 6 h, at which time the reaction was complete. The mixture was diluted with 100 mL EtOAc and washed two times with 100 mL water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed by combiflash using a 40-gram silica column with a gradient EtOAc (100% max) in hexane to provide 76 mg (31% yield) of (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)pyrimidine-4-carboxamide as a white solid. m/z 461, 1H NMR (CD3OD): 8.56-8.49 (m, 2H), 7.35-7.27 (m, 2H), 7.17-7.11 (m, 3H), 7.09-7.02 (m, 2H), 4.64-4.49 (m, 1H), 4.56-1.49 (m, 3H).
Reaction SMILES: C([O:5][C:6](=[O:21])[CH:7]=[CH:8][C:9]1[CH:20]=[N:19][C:12]2[NH:13][CH2:14][C:15](=[O:18])[NH:16][CH2:17][C:11]=2[CH:10]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[O:18]=[C:15]1[CH2:14][NH:13][C:12]2[N:19]=[CH:20][C:9]([CH:8]=[CH:7][C:6]([OH:21])=[O:5])=[CH:10][C:11]=2[CH2:17][NH:16]1
Reactant: CC(C)(C)OC(=O)C=Cc1cnc2c(c1)CNC(=O)CN2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C=Cc1cnc2c(c1)CNC(=O)CN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
3-(3-Oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)-acrylic acid tert-butyl ester (96 mg, 0.31 mmol) was dissolved into 1:1 CH2Cl2/TFA (2 mL) and stirred at room temperature for 30 min. The solvents were removed in vacuo to afford the title compound as a brown solid (44 mg, 61%) and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6). 8.18 (t, J=5.7 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 7.37 (d, J=15.8 Hz, 1H), 7.35 (t, J=5.3 Hz, 1H), 6.24 (d, J=15.8 Hz, 1H), 4.28 (d, J=5.7 Hz, 2H), 3:98 (d, J=5.1 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:17][CH2:16][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:18]([C:20]1[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[N:24][CH:25]=1)=[CH2:19].[OH-].[K+]>CN1C(=O)CCC1>[OH:27][CH2:26][C:23]1[N:24]=[CH:25][C:20]([CH2:18][CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:17][CH2:16][C:5]2=3)=[CH:21][CH:22]=1
Reactant: CN1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Reactant: C=Cc1ccc(CO)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(C(=O)O)ccc3n2CCc2ccc(CO)nc2)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole-8-carboxylic acid, (5-vinylpyridin-2-yl)methanol and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=[C:9]2[C:12]#[N:13])=[CH:4][CH:3]=1.C1C(=O)N([Br:29])C(=O)C1>C1COCC1>[Br:29][C:11]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[C:9]([C:12]#[N:13])=[CH:8][C:7]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[CH:6]2
Reactant: COc1ccc(-c2cc(C#N)c3cc(O)ccc3c2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C#N)c3c(Br)c(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 7-hydroxy-3-(4-methoxyphenyl)-1-naphthonitrile (0.160 g, 0.58 mmol) with NBS (0.12 g, 0.70 mmol) in THF (10 mL) according to method C to yield 0.080 g (39%) of a yellow solid: mp 145-146° C.; 1H NMR (DMSO-d6): δ 3.83 (3H, s), 7.08 (2H, d, J=8.79 Hz), 7.42 (1H, d, J=8.79 Hz), 7.84 (2H, d, J=8.79 Hz), 8.04 (1H, d, J=8.79 Hz), 8.42 (1H, d, J=1.95 Hz), 8.53 (1H, d, J=1.95 Hz), 11.21 (1H, s); MS (ESI) m/z 354/356 (M+H+; MS (ESI) m/z 352/354 (M−H)−.
Reaction SMILES: CNN(NC)CC(O)=O.Cl.[C:11]([C:13]1([NH:19][C:20]([CH:22]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[N:12].C(C1(NC(C(N[C:69]([N:71]2[CH2:76]C[O:74][CH2:73][CH2:72]2)=O)CC(C)(C)C)=O)CC(C2C=CC=CC=2)NC(C2C=CC=CC=2)C1)#N>>[C:11]([C:13]1([NH:19][C:20]([CH:22]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:21])[CH2:14][CH2:15][N:16]([C:73](=[O:74])[CH2:72][N:71]([CH3:76])[CH3:69])[CH2:17][CH2:18]1)#[N:12]
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CC(c2ccccc2)NC(c2ccccc2)C1
Agent: CNN(CC(=O)O)NC
Agent: Cl
Product: CN(C)CC(=O)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CC1

Procedure:
The title compound was prepared from N.N-dimethylaminoglycine and morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride using the coupling method described in Example 1-part (d). The product was purified by reverse phase preparative HPLC to give the title compound as an off-white solid; MS, m/z 477=M+1.
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:18]([O:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]=1[Cl:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]c2ccccc2c(=O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2ccccc2c(OCc2ccccc2)c1Cl
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-chloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (1.1 g) in DMF (30 mL) were added benzyl bromide (0.57 mL) and potassium carbonate (720 mg) at room temperature, followed by stirring for 15 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=85/15) to obtain ethyl 4-(benzyloxy)-3-chloroquinoline-2-carboxylate (1.24 g).
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][CH2:11][CH:9]([OH:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: c1ccc(OCC2CO2)cc1
Agent: [Na+]
Solvent: CO
Product: COCC(O)COc1ccccc1

Procedure:
2-Phenoxymethyl-oxirane (0.15 g, 1.00 mMol) and sodium methoxide (0.054 g, 1.00 mMol) were dissolved in 10 ml of MeOH, then the reaction mixture was refluxed for 3 hours. The solvent MeOH was removed and the residue was extracted with ethyl acetate (3×20 ml), it was washed with brine, dried over MgSO4. The crude product was purified by column (25% EtOAc/Hexane) to yield 1-methoxy-3-phenoxy-propan-2-ol, whose structure is depicted below:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].FC(F)(F)S(O[C:15]1[C:16]2[CH2:36][N:35]([C:37](=[O:39])[CH3:38])[CH2:34][CH2:33][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[CH:24][CH:23]=2)[N:20]=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[OH:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:15]1[C:16]2[CH2:36][N:35]([C:37](=[O:39])[CH3:38])[CH2:34][CH2:33][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[CH:26][CH:27]=2)[N:20]=1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: OCC1CCCCN1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N3CCCCC3CO)c2C1
Yield: 56.4 %

Procedure:
1-(4-(2-(Hydroxymethyl)piperidin-1-yl)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (18.3 mg, 56.4%) was prepared from piperidin-2-ylmethanol and 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (example 88a) according to the general procedure for amine substitution of tosylate on pyrimidines.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([CH3:16])=O>>[CH2:19]([O:18][C:13](=[O:17])[C@H:14]([CH3:16])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1)[CH3:20]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)=O
Product: CCOC(=O)[C@H](C)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Following General Procedure AA above and using 4-chloro-3-(trifluoromethyl)aniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:31]([CH3:33])[CH3:32])[C:5]([C:7]1[NH:8][C:9]([CH2:22][C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])=[N:10][C:11](=[O:21])[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.ClCCl.CO>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])[N:8]2[CH2:2][CH2:3][N:4]([CH:31]([CH3:33])[CH3:32])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N(CCO)C(=O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCn2c(Cc3c(Cl)cccc3Cl)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
5-Benzyloxy-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (64) (0.11 g, 224 μmol, Eq: 1.00) was dissolved in dichloromethane (1.5 ml) and Ph3P (88.3 mg, 336 μmol, Eq: 1.5) was added. The clear colorless solution was stirred at room temperature for approx. 10 min and then diisopropyl azodicarboxylate (diisopropylazodicarboxylate) (71.6 mg, 68.9 μl, 336 μmol, Eq: 1.5) was added. Stirring was continued at room temperature for 1 h. The solvent was removed and the remaining oil was purified by SiO2 flash chromatography (12 g SiO2, dichloromethane/methanol 0-3% methanol). SiO2 flash chromatography was repeated (12 g SiO2, hexanes/ethyl acetate 7-50% ethyl acetate, then dichloromethane/methanol 0-3% methanol) to afford 9-benzyloxy-6-(2,6-dichlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (65) (0.045 g, 95.3 μmol, 42.5% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[C:3]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Br[C:27]1[CH:36]=[C:35]2[C:30]([CH2:31][CH:32]([CH3:51])[N:33]([C:37]3[CH:42]=[C:41]([N:43]4[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]4)[N:40]=[C:39]([NH2:50])[N:38]=3)[CH2:34]2)=[CH:29][CH:28]=1>>[NH2:50][C:39]1[N:38]=[C:37]([N:33]2[CH:32]([CH3:51])[CH2:31][C:30]3[C:35](=[CH:36][C:27]([C:5]4[CH:4]=[C:3]([C:16]([O:18][CH2:19][C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[O:17])[N:2]([CH3:1])[CH:6]=4)=[CH:28][CH:29]=3)[CH2:34]2)[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)[N:40]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3cc(C(=O)OCc4ccccc4)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 87A, Step 7 starting from benzyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (Example 87A, Step 6) and 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (Peak 2, Example 49, Step 7). LCMS (M+H)+: m/z=552.1.
Reaction SMILES: C(O[C:5](=[O:21])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C=C.CC1C2C(=CC=CC=2)C(C)=C2C=1C=CC1C2=CC=CC=1.[CH3:42][O:43][C:44]1[CH:65]=[CH:64][C:47]([C:48]([NH:50][C:51]([CH3:63])([CH3:62])[C:52]([N:54]2[CH2:58][CH2:57][CH2:56][CH:55]2C(O)=O)=[O:53])=[O:49])=[CH:46][CH:45]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.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>[CH2:14]([O:13][CH:8]1[CH:7]([NH:6][C:5]([CH:55]2[CH2:56][CH2:57][CH2:58][N:54]2[C:52](=[O:53])[C:51]([NH:50][C:48](=[O:49])[C:47]2[CH:46]=[CH:45][C:44]([O:43][CH3:42])=[CH:65][CH:64]=2)([CH3:63])[CH3:62])=[O:21])[CH2:11][C:10](=[O:12])[O:9]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)NC(C)(C)C(=O)N2CCCC2C(=O)O)cc1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1c2ccccc2c(C)c2c1ccc1ccccc12
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(C(=O)NC(C)(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
To a solution of (2-benzyloxy-5-oxo-tetrahydrofuran-3-yl)-carbamic acid allyl ester (40) (1.027 g, 3.5 mmol) in CH2Cl2 (20 ml) was added DMBA (543 mg, 3.48 mmol) and Pd(PPh3)4 (280 mg, 0.24 mmol) and the solution was stirred at room temperature under N2 for 20 minutes. A solution of 1-[2-(4-methoxy-benzoylamino)-2-methyl-propionyl]-pyrrolidine-2-carboxylic acid (818 mg, 2.45 mmol) in CH2Cl2 (5 ml) was added, followed by HOBT (0.534 g, 3.95 mmol) and EDC (738 mg, 3.84 mmol). The reaction was stirred at room temperature for 18 hours under N2. The solvent was evaporated, the crude material dissolved in EtOAc and washed with 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine and was dried over anhydrous Na2SO4, filtered and evaporated to give a yellow solid. Purification by flash column chromatography, eluting with ethyl acetate/hexanes (20/80 to 50/50%), gave the product as pale yellow solid (760 mg, 61% yield). 1H-NMR (500 MHz, CD3OD) δ 1.53 (d, 6H), 1.65-1.93 (m, 3H), 1.96-2.14 (m, 1H), 2.60 (dd, 0.1H), 2.77 (dd, 0.85H), 2.94 (dd, 0.85H), 3.04-3.11 (m, 0.2H), 3.42-3.52 (m, 1H), 3.57-3.67 (m, 1H), 3.84 (s, 3H), 4.38-4.76 (m, 3H), 4.84 (d, 1H), 5.64-5.70 (m, 1H), 6.96-7.03 (m, 2H), 7.23-7.43 (m, 5H), 7.78-7.97 (m, 2H). Analytical HPLC (C18 column) 13.32, 14.37 min. LC-MS (ES+) m/e=524.3 (M+H).
Reaction SMILES: [C:1]([C:3]([CH3:8])([CH3:7])[CH:4]=[N:5][OH:6])#[N:2].[Cl:9][CH2:10][C:11]([N:13]([CH3:17])[C:14](Cl)=[O:15])=[O:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:3]([CH3:8])([CH3:7])[CH:4]=[N:5][OH:6])#[N:2].[Cl:9][CH2:10][C:11]([N:13]([CH3:17])[C:14](=[O:6])[O-:15])=[O:12]
Reactant: CN(C(=O)Cl)C(=O)CCl
Agent: CC(C)(C#N)C=NO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C(=O)[O-])C(=O)CCl
Reaction time: 2 h
Yield: 137 %

Procedure:
To a mixture of 3.24 g (0.029 m) of 2-cyano-2-methylpropionaldoxime, 5.0 g (0.029 m) of N-chloroacetyl-N-methylcarbamoyl chloride in 50 ml of toluene was added 2.92 g (0.029 m) of triethylamine. After stirring for 2 hours, the solid was filtered. The filter cake was washed with water and hexane and air dried to afford 5.2 g of a white solid with a melting point of 115° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>CN(C=O)C>[N:21]1([C:2]2[N:7]=[C:6]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[N:5]=[C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:3]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cn(-c2nc(N3CCOCC3)nc(-n3ccnc3)n2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 32.5 %

Procedure:
The obtained 2,4-dichloro-6-morpholino-1,3,5-triazine (1.17 g, 4.98 mmol) was dissolved in DMF (30 ml), added with anhydrous potassium carbonate (2.91 g, 21.1 mmol) and imidazole (1.43 g, 21.0 mmol) and stirred at room temperature for 17 hours. The reaction mixture was evaporated under reduced pressure. The residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography, using dichloromethane and methanol (95:5) as eluant, to obtain 483 mg (yield: 32.6%) of the titled compound as colorless crystals.