Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([Cl:17])[CH:16]=[C:11]2[C:10]([CH2:18][C:19]2[C:20]([F:41])=[N:21][C:22]([N:25](C(OC(C)(C)C)=O)[CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[C:31]([F:33])[CH:32]=3)=[CH:23][CH:24]=2)=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:17][C:15]1[CH:16]=[C:11]2[C:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[C:31]([F:33])[CH:32]=4)=[N:21][C:20]=3[F:41])=[CH:9][NH:8][C:12]2=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cncc(F)c1)c1ccc(Cc2cn(C(=O)OC(C)(C)C)c3ncc(Cl)cc23)c(F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cncc(CNc2ccc(Cc3c[nH]c4ncc(Cl)cc34)c(F)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To 3-{6-[tert-butoxycarbonyl-(5-fluoro-pyridin-3-ylmethyl)-amino]-2-fluoro-pyridin-3-ylmethyl}-5-chloro-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (144, 0.280 g, 0.478 mmol) in 10.0 mL of dichloromethane, trifluoroacetic acid (1.00 mL, 13.0 mmol) was added and the reaction stirred at room temperature overnight. This was pooled with a separate reaction run similarly and concentrated under vacuum. The resulting material was combined with aqueous potassium carbonate and ethyl acetate and mixed. The aqueous layer was separated and the organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and the solvent removed under vacuum to provide the desired compound (P-2001, 99 mg). MS (ESI) [M+H+]+=386.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\NC1C=NC(N2CCC(N3CCCC3)CC2)=CC=1.BrC1C=C2C(=CC=1)[C:40](=[O:44])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:44][CH3:40]
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc(N2CCC(N3CCCC3)CC2)nc1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (24), 0.53 g (86% yield) of brown solid is obtained from 0.335 g (1.24 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline 1,3(2H,4H)-dione, and 0.30 g (1.24 mmol) of 6-(4-pyrrolidin-1-ylpiperidin-1-yl)pyridin-3-yl]amine; mp: 214-215° C.; MS (ESI) m/z 498.1 (M+H)+1
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([O:13][C:14](=[O:35])[NH:15][N:16]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:23]2[C:18]([N:19]([CH3:34])[C:20](=[O:33])[N:21]([CH3:32])[C:22]2=[O:31])=[CH:17]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(#N)C.O>[CH2:6]([O:13][C:14](=[O:35])[N:15]([N:16]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:23]2[C:18]([N:19]([CH3:34])[C:20](=[O:33])[N:21]([CH3:32])[C:22]2=[O:31])=[CH:17]1)[CH2:2][CH2:3][CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCBr
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(NC(=O)OCc3ccccc3)cc2n(C)c1=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: Cn1c(=O)c2c(-c3ccccc3)n(N(CCCO)C(=O)OCc3ccccc3)cc2n(C)c1=O
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
3-Bromopropan-1-ol (0.645 ml, 7.14 mmol) was added to a suspension of (1,3-Dimethyl-2,4-dioxo-5-phenyl-1,2,3,4-tetrahydro-pyrrolo[3,4-d]pyrimidin-6-yl)-carbamic acid benzyl ester (step 1) (2.22 g, 5.49 mmol), K2CO3 (2.276 g, 16.47 mmol) and benzyltrimethylammonium chloride (0.102 g, 0.549 mmol) in acetonitrile (50 ml). The mixture was heated to 60° C. and stirred for 40 mins. The reaction mixture was cooled to RT and diluted with water. The mixture was extracted with EtOAc (2×) and the combined organic phases washed with brine, dried over sodium sulphate and evaporated under reduced pressure. Purification by chromatography on silica, eluting with EtOAc/hexane and then MeOH/EtOAc afforded the title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:27])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1>C(O)C(C)C>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH2:17][CH:18]([CH3:13])[CH3:9])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Solvent: CC(C)CO
Product: CC(C)COc1cc(OC2CCN(C)CC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1

Procedure:
Using an analogous procedure to that described in Example 51, 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline was reacted with isobutanol to give the title compound; NMR Spectrum: (CDCl3) 1.05 (d, 6H), 1.95–2.05 (m, 2H), 2.08–2.28 (m, 3H), 2.3 (s, 3H), 2.3–2.4 (m, 2H), 2.7 (br s, 2H), 3.82 (d, 2H), 4.6 (m, 1H), 6.03 (s, 2H), 6.5 (s, 1H), 6.7 (d, 1H), 6.8 (s, 1H), 6.95 (d, 1H), 8.5 (s, 1H), 9.25 (s, 1H); Mass Spectrum: M+H+ 485 and 487.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([NH2:15])=[O:14])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:2]3[N:3]=[C:4]([NH:11][C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([NH2:15])=[O:14])[C:5]4[S:10][CH2:9][CH2:8][C:6]=4[N:7]=3)[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CC(C)[C@@H](Nc1nc(Cl)nc2c1SCC2)C(N)=O
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@@H](Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2)C(N)=O
Temperature: 160 °C
Yield: 88.2 %

Procedure:
400 mg (R)-2-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ylamino)-3-methyl-butyramide, 750 mg 1-(4-chloro-phenyl)-piperazine and 1.2 ml diisopropylethylamine are placed in 9 ml dioxane, then heated in the microwave for 1 hour and 45 minutes at 160° C. Then water is added. The precipitate formed is suction filtered and dried. 550 mg of the product are obtained as a powder. Analytical HPLC (method B): RT=3.03 min.
Reaction SMILES: [NH:1](/[C:8](/[NH:21][CH:22]([CH3:24])[CH3:23])=[CH:9]\[C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C.O>[Cl:19][C:15]1[N:14]=[C:13]2[C:12]([C:10](=[O:11])[CH:9]=[C:8]([NH:21][CH:22]([CH3:24])[CH3:23])[N:1]2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][C:16]=1[F:18]
Reactant: CC(C)N/C(=C/C(=O)c1cc(F)c(Cl)nc1Cl)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Nc1cc(=O)c2cc(F)c(Cl)nc2n1-c1ccccc1
Temperature: 85 °C
Yield: 58.1 %

Procedure:
(2Z)-3-Anilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen-1-one (40.0 mg, 0.109 mmol) was dissolved in 4 mL of DMF. NaH (8.70 mg, 0.217 mmol, 60% dispersion in oil) was added and the reaction was heated to 85° C. under argon for 2 h. The reaction mixture was cooled to room temperature and diluted with water and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 100% EtOAc to 95:5 EtOAc:MeOH provided 7-chloro-6-fluoro-2-(isopropylamino)-1-phenyl-1,8-naphthyridin-4(1H)-one (21 mg, 64%) as a white solid: LCMS RT: 2.57 min, MH+: 332.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]Br>CO.CC(O)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:17])[CH:12]=[C:11]([F:15])[C:10]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1c(F)cccc1OCc1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CO
Product: Nc1c(F)cc(Br)cc1OCc1ccccc1
Reaction time: 4 h

Procedure:
To a solution of 2-benzyloxy-6-fluorophenylamine (7.29 g, 33.6 mmol) in MeOH/HOAc (3:1 v/v, 30 mL) at 0° C. is added bromine (2.2 mL, 47 mmol) in MeOH/HOAc (3:1 v/v, 4 mL) drop wise. After it is stirred for 4 h, the reaction is completed by LC/MS. The reaction mixture is concentrated, and the residue is stirred with EtOAc and 1N NaOH to dissolve solid. Additional base is added to make the aqueous alkaline, and then EtOAc layer is separated. The organic phase is washed with brine, dried and filtered. The concentrated residue is purified to give the title compound: 1H NMR (CDCl3) 7.39 (m, 5H), 6.86 (dd, 1H, J=9.8, 2.0 Hz), 6.81 (m, 1H), 5.05 (s, 2H), 3.77 (br s, 2H); MS (M+H)+=296, 298.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10](=[O:27])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23](OC)=[O:24])=[O:20])[CH:14]=1.[Cl-].[NH4+:29].N>>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10](=[O:27])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]([NH2:29])=[O:24])=[O:20])[CH:14]=1
Reactant: [NH4+]
Reactant: COC(=O)CNC(=O)c1cccc(C=CC(=O)c2c(O)cc(C)[nH]c2=O)c1
Agent: N
Agent: [Cl-]
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(C(=O)NCC(N)=O)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture of 0.37 g of 4-hydroxy-3-[3-[3-[(methoxycarbonylmethyl)aminocarbonyl]phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone, 18 mg of ammonium chloride and 4 ml of aqueous concentrated ammonia was stirred at room temperature for 1 hour. Two ml of aqueous concentrated ammonia was added, and this was further stirred for 30 minutes, and concentrated under reduced pressure. The residue was washed with tetrahydrofuran, and the resulting crude crystals were recrystallized from dimethylformamide to obtain 0.11 g of 4-hydroxy-3-[3-[3-[(aminocarbonylmethyl)aminocarbonyl]phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (91a)] as a yellow crystal.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:40][C@@H:41]([CH2:43][CH3:44])[CH3:42])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[C@H:41]([NH:40][C:19]1[N:18]=[C:17]2[CH2:16][NH:15][CH2:24][CH2:23][C:22]2=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][CH:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[CH2:27][CH2:26]1)([CH2:43][CH3:44])[CH3:42].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC[C@@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC[C@@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (R)-6-benzyl-N-(sec-butyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (174.6 mg, 0.281 mmol) in THF (2.81 mL) was treated with Pd(OH)2 (20 wt %, 59.2 mg, 0.084 mmol). Hydrogen gas (balloon) was bubbled through the reaction mixture for 5 min. The vent needle was removed and the reaction was allowed to stir at room temperature under hydrogen atmosphere for 1 h. The reaction mixture was opened to air and filtered through a pad of Celite™, eluting with EtOAcMeOH. The filtrate was collected and concentrated under reduced pressure to give (R)—N-(sec-butyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine as a TFA salt (136.4 mg) as a yellow oil, which was carried forward without additional purification. ESI-MS m/z [M+H]+ 418.5.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH2:23][OH:24])[CH:9]=1)([CH3:4])[CH3:3].C(Cl)Cl.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.CC1(C)N([O])C(C)(C)CCC1>CCOC(C)=O>[CH3:4][C:2]([Si:5]([CH3:25])([CH3:26])[O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:23]=[O:24])[C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:12][CH:13]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2CO)c1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A 200 mL round bottom flask was charged with 83.18B (1.21 g, 3.21 mmol), DCM (9 mL), iodobenzene diacetate (available from Aldrich) (1.24 g, 3.86 mmol), and TEMPO (available from Aldrich) (0.0502 g, 0.321 mmol). The solution was stirred for 2 hours at room temperature and diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3, saturated aqueous Na2S2O3, and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 83.18C (1.05 g, 87% yield) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:15][C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1cccc2c1CCCC2
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc2c1CCCC2

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 1-amino-5,6,7,8-tetrahydronaphthalene by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][CH2:7][CH2:8][CH:9]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].Br[CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:7][CH2:8][CH:9]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:25][CH3:26])[CH3:2]
Reactant: CCOC(=O)CNCCC=C(c1ccccc1)c1ccccc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)CN(CC)CCC=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
A mixture of 0.158 g (0.5 mmol) of N-[(4,4-diphenyl)but-3-enyl]glycine ethyl ester (Compound A26), 0.234 g (2.1 mmol) bromoethane, 0.281 g (2 mmol) potassium carbonate and 0.068 g (0.4 mmol) potassium iodide was stirred under argon for 20 hours at room temperature. The reaction mixture was filtered, the solvent evaporated, and the residue chromatographed on a silica gel column with 20% ethyl acetate in hexanes to yield 0.112 g (66%) N-[(4,4-diphenyl)but-3-enyl]-N-ethylglycine ethyl ester (Compound A16) as an oil. NMR spectra showed: 1H NMR (CDCl3, 300 MHz) 7.60-7.00 (m, 10 H), 6.09 (t, 1 H), 4.13 (q, 2 H), 3.27 (s, 2 H), 2.72 (t, 2 H), 2.61 (q, 2 H), 2.28 (dt, 2 H), 1.23 (t, 3 H), 1.01 (t, 3 H); 13C NMR (CDCl3, 75 MHz) 171.77, 142.96, 142.86, 140.33, 130.09, 128.49, 128.35, 127.48, 127.27, 127.19, 60.58, 54.90, 53.98, 48.20, 28.19, 14.57, 12.70.
Reaction SMILES: C([O:8][C:9]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:12]=2[N:11]2[C:28](=[O:31])[N:29]=[N:30][C:10]=12)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[C:15](=[O:16])[N:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:12]=2[N:11]2[C:28](=[O:31])[N:29]=[N:30][C:10]=12
Reactant: O=c1nnc2c(OCc3ccccc3)c(=O)n(-c3ccccc3)c3cc(Cl)ccc3n1-2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=c1nnc2c(O)c(=O)n(-c3ccccc3)c3cc(Cl)ccc3n1-2

Procedure:
44.6 g of 4-(benzyloxy)-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione in 400 ml of ethanol containing 2.0 g of 10% palladium-on-charcoal is hydrogenated at an initial hydrogen pressure of 40 p.s.i. After 0.1 mole of hydrogen has been absorbed, the reaction is stopped, filtered and the solvent evaporated. The residue is triturated with ether and the title compound filtered off and dried.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[NH2:8].[CH3:22][C:23]([OH:27])([C:25]#[CH:26])[CH3:24]>>[NH2:8][C:7]1[C:6]([NH2:9])=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[CH:3][C:2]=1[CH2:26][CH2:25][C:23]([CH3:24])([OH:27])[CH3:22]
Reactant: Nc1c(I)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C#CC(C)(C)O
Product: CC(C)(O)CCc1cc(-c2ccccc2C(F)(F)F)cc(N)c1N

Procedure:
The title compound was prepared from 3-iodo-5-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (as prepared in Example 9, step A) and 2-methyl-but-3-yn-2-ol according to the procedures described in Example 10, steps A and B.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]1[CH2:15][CH:14]([OH:16])[CH:13]=[CH:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:11][CH:12]1[CH2:13][C:14](=[O:16])[CH2:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1C=CCC(CNCc2ccccc2)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C1CC2CC(C1)N(Cc1ccccc1)C2
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 5-(benzylaminomethyl)cyclohex-2-enol (3.80 g, 17.5 mmol) in dry dichloromethane (150 ml) was added activated manganese dioxide (18.0 g, 210 mmol) in one portion. The mixture was stirred vigorously under nitrogen for 2 h. The yellow solution was filtered through Celite and the solids were washed with dichloromethane (2×50 ml). The combined filtrates were concentrated by rotary evaporation to give an orange oil, which solidified on brief standing. The solid was recrystallized from hot hexane/ether to afford the ketone as an off-white solid (2.6 g, 68%).
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(O)(=O)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.[Na+].C([O-])(=O)C.[K+]>C(Cl)(Cl)(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:1][C:2]2[S:6][CH:5]=[N:4][CH:3]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1cncs1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: O=S(=O)(Cc1cncs1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A carbon tetrachloride (15 ml) suspension of 5-methylthiazole (380 mg, 3.83 mmol), N-chlorosuccinic imide (511 mg, 3.83 mmol), 2,2′-azobis(2-methylpropionitrile) (62 mg, 0.380 mmol) and acetic acid (0.22 ml, 3.83 mmol) was heated under reflux for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then, concentrated under reduced pressure. The resulting residue was dissolved in butanol (10 ml). To the resulting solution were added sodium 4-chlorophenylsulfinate (761 mg, 3.83 mmol) and potassium acetate (376 mg, 3.83 mmol), followed by stirring at 70° C. for 23 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed successively with water and brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column. The fraction obtained from the hexane:ethyl acetate (=1:1) eluate was concentrated under reduced pressure, whereby the title compound (76 mg, 7.2%) was obtained as a pale yellow solid.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][OH:29]>CCCCCC.C(OCC)(=O)C>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][O:29][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCc1cccc(F)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Fc1cccc(COc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)c1

Procedure:
2-Methylthio-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (from Reference Example 3) was reacted with 3-fluorobenzyl alcohol according to the procedures described in Example 1 to afford 2-(3-fluorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine as the higher Rf product.(95/5 hexane/ethyl acetate TLC. HPLC/MS: 460 (M+); Rt=4.66 min; 1H-NMR 500 MHz (CDCl3): δ 5.53 (s, 2H), 7.04 (d over m, J=9 Hz, 3H), 7.2-7.3 (m, 6H), 7.36-7.4 (m, 2H), 8.61 (s, 1H).
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[Cl-].[Zn+2:7].[Cl-]>O>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zn+2:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zn+2:7].[Zn+2:7]
Reactant: O=P(O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
7,000 g of water and 553 g of 85% phosphoric acid were mixed, and 545 g of zinc chloride was dissolved therein to obtain an aqueous zinc phosphate solution having a phosphorus/zinc molar ratio of 1.20.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[NH:10][C:9]2=O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O.C(N(CC)C(C)C)(C)C>>[Cl:26][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[N:10]=1
Reactant: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(Cl)nc2c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
Into a round bottom flask was added methyl 3-(4-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (0.28 g, 0.76 mmol) dissolved in phosphoryl chloride (3.2 mL, 34.5 mmol) and N,N-diisopropylethylamine (0.29 mL, 1.7 mmol). The reaction mixture was heated to 120° C. and stirred for 5 h. The mixture was then cooled to rt and concentrated. The residue was poured over ice and the resulting solid was filtered and washed with water to afford methyl 2-chloro-3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.26 g, 98%). LC-MS: (FA) ES+ 350.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C1(N)CCCCC1>C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[C:14]([N+:11]([O-:13])=[O:12])[CH3:15]
Reactant: O=Cc1cc(F)ccc1F
Reactant: CC[N+](=O)[O-]
Solvent: NC1CCCCC1
Solvent: CC(=O)O
Product: CC(=Cc1cc(F)ccc1F)[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A mixture of 2,5-difluorobenzaldehyde (25.0 g, 0.176 mol), nitroethane (26.41 g, 0.352 mol) and cyclohexylamine (17.45 g, 0.176 mol) in 150 mL of acetic acid was stirred at 80° C. overnight. After cooling to rt the solvent was evaporated, the residue was purified by column chromatography (silica-gel, CH2Cl2/acetone=19/1 v/v) to give a yellow solid product, 28.5 g, 81.3% yield. MS: 197.6 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 7.94 (s, 1H), 7.46-7.43 (m, 1H), 7.41-7.35 (m, 2H), 2.31 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)OCC(OCC)=O.ClC1C=CC=CC=1O[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O(CC(OCC)=O)C1C=CC=CC=1>>[C:2]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=[CH:4][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)COc1ccccc1Cl
Reactant: CCOC(=O)COc1cccc(Cl)c1
Agent: CCOC(=O)COc1ccccc1
Product: CCOC(=O)Cc1ccccc1

Procedure:
Following Example 15 but using ethyl 3-chlorophenoxyacetate, ethyl 2-chlorophenoxyacetate or ethyl phenoxyacetate, respectively, in place of ethyl phenylacetate, the final compounds obtained were the PGE2 analogs of Example 15 wherein R (of structure IV) is 3-chlorophenoxymethyl, 2-chlorophenoxymethyl or phenoxymethyl.