Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[C:6]([CH3:9])(O)C)[CH3:3].[CH:11](C=C1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(C)C(C[C@@H](O)CC1)=CC3)=O.C(C=C1CC[C@H]2[C@H]3[C@H](CC[C@]12C)C1CCC(=O)CC=1CC3)=O.CCC1C[C@@H]2[C@H](CC[C@@H]3[C@@H]4C(=CC(=O)CC4)CC[C@H]32)C1=CC=O>>[CH3:3][C:2](=[CH:4][C:5](=[O:10])[CH2:6][CH2:9][CH3:11])[CH3:1]
Reactant: CC(C)=CC(=O)C(C)(C)O
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=CC=O)CC[C@@H]12
Agent: CCC1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@H]2C1=CC=O
Agent: C[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=CC=O)CC(=O)CC4
Product: CCCC(=O)C=C(C)C

Procedure:
2,5-dimethyl-hex-2-en-5-ol-4-one; 17-(formylmethylene)-androst-5-en-3 β -ol; 17-(formylmethylene)-estr-5(10)-en-3-one; 13 β-ethyl-17-(formylmethylene)-gon-4-en-3-one; and
Reaction SMILES: [CH:1]12[CH:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]1[CH2:4][NH:3][CH2:2]2.Br[CH2:16][CH2:17][OH:18].C(Cl)(Cl)Cl.CO>C(#N)C>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:6]1[CH:1]2[CH:5]1[CH2:4][N:3]([CH2:16][CH2:17][OH:18])[CH2:2]2)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1C2CNCC21
Reactant: OCCBr
Solvent: CC#N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1C2CN(CCO)CC21
Temperature: 70 °C
Yield: 46 %

Procedure:
A mixture of tert-butyl 3-azabicyclo[3.1.0]hex-6-ylcarbamate (T. F. Braish et al. Synlett, 1996, page 1100 and T. Norris et al. J. Chem. Soc. Perkin I, 2000, page 1615-1622), 2-bromoethanol (669 mg, 3.36 mmol) and N,N-ethyldiisopropyl amine (0.087 mL) in acetonitrile (9 mL) was heated in the microwave at 70° C. for 30 minutes. Chromatography on silica gel with chloroform/methanol (20:1) gave 376 mg (46%) of the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N-:23]=[N+:24]=[N-:25].[Na+].CCO.N[C@@H]1CCCC[C@H]1N>[Cu]I.O>[N:23]([C:12]1[CH:13]=[C:14]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C:9]2=[CH:10][CH:11]=1)=[N+:24]=[N-:25]
Reactant: NC1=N[C@@]2(CCO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=Nc1ccc2c(c1)[C@@]1(CCOC(N)=N1)c1cc(Br)cnc1O2

Procedure:
A microwave vial was charged with (S)-3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (500 mg, 1.059 mmol, Intermediate 25), copper(I) iodide (20.17 mg, 0.106 mmol), (+)-sodium 1-ascorbate (10.49 mg, 0.053 mmol) and sodium azide (0.074 ml, 2.118 mmol). The vial was evacuated and backfilled with nitrogen. EtOH (2 ml), rac-trans-1,2-diaminocyclohexane (0.019 ml, 0.159 mmol) and water (0.9 ml) were added. The reaction mixture was heated overnight to 56° C. An additional portion of each reagent were added and the reaction was heated for additional 6 hours. The reaction mixture was partitioned between water and EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silical gel, 20-100% EtOAc/hexanes) to afford (S)-7-azido-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:25][NH:26][O:27][CH3:28].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:28][O:27][N:26]([CH3:25])[C:13]([C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=2)[CH:12]=1)=[O:15]
Reactant: COc1ccc(Cn2cc(C(=O)O)cn2)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C(=O)N(C)OC)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
According to Scheme 2 Step 1: A solution of 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (34.4 mmol, 8.00 g), oxalyl chloride (68.9 mmol, 5.92 mL) and a drop of DMF in DCM (80 mL) was stirred for 1 hour at room temperature. After evaporation, the crude product was dissolved in DCM (30 mL) and was added at 0° C. to a solution of N,O-dimethylhydroxylamine hydrochloride (103 mmol, 6.31 g) in DCM (100 mL) followed by Et3N (138 mmol, 19.2 mL). The reaction mixture was stirred for 1 hour at room temperature. The reaction was quenched with a saturated solution of Na2CO3 (300 mL) and the aqueous phase was extracted with DCM. The organic phase was dried over MgSO4, was filtered and was concentrated to yield N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide (33.8 mmol, 9.30 g, 98%) as a beige solid.
Reaction SMILES: Cl.COC(=O)C(NS(C1C=CC2C(=CC=CC=2)C=1)(=O)=O)CC1C=C2C(=CC=1)C(N)=NC=C2.Cl.Cl.[CH3:35][O:36][C:37](=[O:52])[CH:38]([NH2:51])[CH2:39][C:40]1[CH:49]=[C:48]2[C:43]([CH:44]=[CH:45][N:46]=[C:47]2[NH2:50])=[CH:42][CH:41]=1.[CH3:53][O:54][C:55]1[CH:64]=[C:63]2[C:58]([CH:59]=[CH:60][C:61]([S:65](Cl)(=[O:67])=[O:66])=[CH:62]2)=[CH:57][CH:56]=1>>[CH3:35][O:36][C:37](=[O:52])[CH:38]([NH:51][S:65]([C:61]1[CH:60]=[CH:59][C:58]2[C:63](=[CH:64][C:55]([O:54][CH3:53])=[CH:56][CH:57]=2)[CH:62]=1)(=[O:67])=[O:66])[CH2:39][C:40]1[CH:49]=[C:48]2[C:43]([CH:44]=[CH:45][N:46]=[C:47]2[NH2:50])=[CH:42][CH:41]=1
Reactant: COC(=O)C(N)Cc1ccc2ccnc(N)c2c1
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: COC(=O)C(Cc1ccc2c(N)nccc2c1)NS(=O)(=O)c1ccc2ccccc2c1
Agent: Cl
Product: COC(=O)C(Cc1ccc2ccnc(N)c2c1)NS(=O)(=O)c1ccc2ccc(OC)cc2c1

Procedure:
Using the procedure described for 11a, methyl ester 37i and compound 12a gave 3-(1-amino-7-isoquinolinyl)-2-[[(7-methoxy-2-naphthalenyl)sulfonyl)amino]propionic acid methyl ester. This ester was saponified and subsequently coupled with 4-methylpiperidine using the procedure described for 4 to give 37. 1H-NMR 200 MHz (CD3OD) δ: −0.20-0.77 (5H, m), 1.22-1.58 (3H, m), 1.73-3.20 (4H, m), 3.65-4.19 (2H, m), 3.93 (3H, s), 4.53-4.68 (1H, m), 7.00-7.06 (1H, m), 7.23-7.31 (2H, m), 7.43-7.51 (2H, m), 7.56-8.15 (6H, m).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([C:25]1[CH:34]=[CH:33][C:28]([C:29](OC)=[O:30])=[CH:27][CH:26]=1)([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:17])=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+].[N:40]#[C:41]Br>C(O)C.O1CCOCC1.O>[CH3:4][C:5]([C:25]1[CH:26]=[CH:27][C:28]([C:29]2[O:30][C:41]([NH2:40])=[N:3][N:2]=2)=[CH:33][CH:34]=1)([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]([CH3:17])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:24])=[CH:13][CH:14]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)c1ccc(C(C)(c2ccc(OC(C)(C)c3ccccn3)cc2)C(C)C)cc1
Reactant: NN
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)C(C)(c1ccc(OC(C)(C)c2ccccn2)cc1)c1ccc(-c2nnc(N)o2)cc1
Temperature: 25 °C

Procedure:
Hydrazine monohydrate (10 equiv.) is added to a stirred solution of 5g (1 equiv.) in ethanol and the resulting solution heated at reflux until 5g is consumed. After cooling to room temperature, the volatiles are removed in vacuo, and the residue is partitioned between EtOAc and water. The organic phase is separated, washed three times with water, brine, dried (MgSO4) and concentrated in vacuo. The crude residue is dissolved in dioxane to which aqueous sodium bicarbonate (1.1 equiv) in water is added dropwise via syringe. A solution of cyanogen bromide (1.1 equiv.) in dioxane is then added slowly, and the resulting mixture is aged at ambient temperature until the reaction is deemed complete. The reaction mixture is poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts are washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel affords the title compound 5h. If desired, 5h can be resolved into its enantiomeric components using preparative chiral HPLC techniques.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH:6](OCC)[O:7][CH2:8][CH3:9])=[O:5])[CH3:2].C=O.[C:27](O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][P:4]([CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH:6]1[CH2:27][CH2:9][CH2:8][O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(OCC)P(=O)(CCCNCc1ccc(Cl)cc1)OCC
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(CCCNCc1ccc(Cl)cc1)C1CCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g of 3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid ethyl ester are dissolved in 10 ml of methanol, 0.36 g (0.53 ml) of a 35% aqueous formaldehyde solution is added, and the mixture is stirred at room temperature for one hour. 0.4 g of glacial acetic acid and 0.40 g of sodium cyanoborohydride are added, and the mixture is stirred at room temperature for 2 hours, concentrated by evaporation under reduced pressure, taken up in dichloromethane and washed with 5% aqueous sodium hydrogen carbonate solution. The organic phase is separated off, dried over sodium sulfate and concentrated by evaporation under reduced pressure. The oily residue is purified by chromatography on silica gel, yielding 3-(p-chlorobenzylamino)propyl(tetrahydrofuran-2-yl)phosphinic acid ethyl ester in the form of a colourless oil.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6]([C:8]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=2[Cl:26])=[C:16]([F:27])[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[CH:9]=1)=[O:7])[CH:2]=[CH2:3].[O:28]1CCCC1.[OH2:33].C[N+]1([O-])CCOCC1.OS([O-])=O.[Na+]>C(OCC)(=O)C>[OH:33][CH:2]([CH2:3][OH:28])[CH2:1][O:4][NH:5][C:6]([C:8]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=2[Cl:26])=[C:16]([F:27])[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[CH:9]=1)=[O:7]
Reactant: C=CCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Reactant: C1CCOC1
Reactant: O
Agent: C[N+]1([O-])CCOCC1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCC(O)CO)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid allyloxy-amide 29tt (20 mg, 0.04 mmol) in 0.50 mL 4:1 tetrahydrofuran/water is added OSO4 (41 μL, 0.054 M solution in t-BuOH, 0.002 mmol) followed by NMO (7 mg, 0.06 mmol). The solution is stirred at room temperature for eight hours after which time HPLC analysis showed complete conversion to product. The solution is then stirred with saturated NaHSO3 and diluted with ethyl acetate. The organic phase is dried (Na2SO4). Purification by FCC (DCM −>20:1 DCM/MeOH) provided 16 mg desired product as an off-white solid. MS ESI (+) m/z 487, 489 (M+, Br pattern) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:21]=1[CH3:22])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([OH:18])[C:10]=1[O:19][CH3:20])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:31](OS(OCC)(=O)=O)[CH3:32].C(#N)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:21]=1[CH3:22])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH2:31][CH3:32])[C:10]=1[O:19][CH3:20])=[O:8]
Reactant: COc1cc(C)c(C(=O)c2c(OC)ccc(Cl)c2C)c(OC)c1O
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOc1c(OC)cc(C)c(C(=O)c2c(OC)ccc(Cl)c2C)c1OC

Procedure:
A mixture of 66B (1.15 g), potassium carbonate (1.0 g), diethylsulfate (0.54 g) and acetonitrile (20 ml) is heated to reflux for 3 hours. Upon cooling to room temperature water is added. The solid material is collected and the residue is re-crystallized from methanol yielding white crystals, 1.07 g (85.6% ), mp 131-132° C.
Reaction SMILES: [OH:1]O.[NH2:3][C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]=[CH:6][C:5]=1[C:15]#[N:16].N>C(O)C>[NH2:3][C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]=[CH:6][C:5]=1[C:15]([NH2:16])=[O:1]
Reactant: OO
Reactant: N#Cc1cnn(C2CCCCC2)c1N
Agent: N
Solvent: CCO
Product: NC(=O)c1cnn(C2CCCCC2)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18 ml of 30% strength hydrogen peroxide solution are added to a solution of 5-amino-1-cyclohexyl-1H-pyrazole-4-carbonitrile (1.86 g, 9.81 mmol) in a mixture of 73 mi of ethanol and 90 ml of concentrated aqueous ammonia solution at room temperature, and the mixture is stirred at room temperature for 1 h. The nonaqueous solvents are then stripped off in a rotary evaporator. The product precipitates as solids from the remaining mixture and is filtered off with suction, washed with a little water and dried under high vacuum.
Reaction SMILES: [OH-].[K+].C(O[CH:7]1[C:15]2[C:10](=[C:11]([CH3:21])[C:12]([CH2:17]COC)=[C:13]([CH3:16])[CH:14]=2)[C:9](=[O:22])[CH:8]1[CH3:23])(=O)C>O1CCCC1.[Zn]>[CH3:23][C:8]1[C:9](=[O:22])[C:10]2[C:15]([CH:7]=1)=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[C:11]=2[CH3:21]
Reactant: COCCc1c(C)cc2c(c1C)C(=O)C(C)C2OC(C)=O
Agent: [K+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1=Cc2cc(C)c(C)c(C)c2C1=O

Procedure:
The 2,5,6,7-tetramethyl-1-indenone was prepared by reducing 2,4,5,6-tetramethyl-1,3-indanione with zinc dust at 50° C. Product was purified by chromatography with 1% ethyl acetate in benzene to yield two isomers. The major isomer was treated with 10% potassium hydroxide, then purified by sublimation. The compound has the structure: ##STR6## Dehydropterosin O synthesis: 3-acetoxy-6(beta-methoxy) ethyl-2,5,7-trimethyl-1-indanone was dissolved in tetrahydrofuran and 10% potassium hydroxide and refluxed for two hours. The solution was then extracted three times with ether and the combined extracts chromatographed with 2% ethylacetate in benzene to yield the Dehydropterosin O compound. The compound has the structure: ##STR7## R=H Dehydropterosin B R=CH3Dehydropterosin O
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>C(Cl)Cl>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:22]2[CH2:23][CH2:24][CH:25]([NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH2:26][CH2:27]2)(=[O:20])=[O:21])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: C=CC(=O)Cl
Reactant: NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
Diisopropylethylamine (6.8 ml, 41.5 mmol) was added in one portion to a stirred solution of 1-(4-nitro-benzenesulfonyl)-piperidin-4-ylamine (2.36 g, 8.3 mmol) in DCM (10 ml) followed by the drop wise addition of acryloyl chloride (0.78 ml, 9.1 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the resulting precipitate was collected by filtration, washed with water and dried under vacuum to give the title compound (2.80 g, 98% yield) as a white solid. δH (500 MHz, DMSO) 8.39-8.51 (m, 2 H) 7.95-8.10 (m, 3 H) 6.11-6.21 (m, 1 H) 6.01-6.10 (m, 1 H) 5.56 (dd, J=10.09, 2.20 Hz, 1 H) 3.61-3.68 (m, 1 H) 3.52-3.60 (m, 2 H) 2.56-2.66 (m, 2 H) 1.83 (dd, J=13.20, 3.30 Hz, 2 H) 1.36-1.47 (m, 2 H). Tr=1.63 min, m/z (ES+) (M+H)+ 340.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:5]4[CH2:4][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:7]([CH3:8])[CH2:6]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@H](C)[C@@H](N)C1
Agent: Cl
Product: CCC(=O)N[C@H]1C[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from N-[(1R*,3S*,4S*)-3-amino-4-methylcyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f68) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH2:13][C@H:12]1[OH:26].CC(C)=O.C(O)(=O)C>CO>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C@@H:14]([OH:15])[CH2:13][C@H:12]1[OH:26]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1O

Procedure:
Refer to Chart E wherein E is --CH=CH--, R2 and R4 are methyl, V is ---(CH2)5 --, W is 1-pentyl, and ~ is either alpha or beta. A solution of sodium borohydride (0.6 g.) in 10 ml. of methanol at 0° C. is added to a solution of PGE1, methyl ester, 15-methyl ether (Example 5, 1.5 g.) in 60 ml. of methanol and the mixture is stirred at 0° C. for 30 minutes. Acetone (10 ml.) is added and the solution is made slightly acid with dilute acetic acid in methanol. The mixture is concentrated by evaporation under reduced pressure and the residue is taken up in dichloromethane. The resulting solution is washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed over silica gel wet-packed in 8% methanol in dichlormethane ad rinsed with 300 ml. of dichloromethane, eluting with 2-10% methanol-dichloromethane. Those fractions shown by TLC to contain PGF1α , methyl ester, 15-methyl ether free of starting material and impurities are combined and concentrated to yield the Formula -VI PGF1α -type title compound. Likewise, those fractions shown by TLC to contain PGF1β, methyl ester, 15-methyl ether are combined and concentrated to yield the Formula-VI PGF1β -type title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13](=O)[NH:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[NH:22][C:23]=1[CH3:24])=[O:5])[CH3:2].CN(C)C=O.O=P(Cl)(Cl)[Cl:38].C([O-])(=O)C.[K+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13]([Cl:38])=[N:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[NH:22][C:23]=1[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)Nc2c(c(=O)[nH]c(=O)n2-c2ccccc2)C1c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2c(c(Cl)nc(=O)n2-c2ccccc2)C1c1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
The compound from step 5 (11 g, 27.3 mmol) was taken in 100 ml dry chloroform and then charged with DMF (dimethylformamide) (2 ml, 27 mmol). POCl3 (14 ml) was dissolved in advance in 26 ml chloroform and was added under stirring in an argon atmosphere. The reaction mixture was then stirred at 70 C for 6 h. The reaction was monitored by LC-MS. The reaction mixture was cooled down to room temperature and poured into 25% ice cold solution of potassium acetate (150 ml) under vigorous stirring, organic phase was separated, aqueous phase was extracted with DCM (dichloromethane) (2×100 ml) and the combined organic solution was dried over magnesium sulfate and then the solvent was evaporated under vacuum yielding yellow solids (8.3 g, 19.7 mmol, 72%).
Reaction SMILES: [F:1][CH:2]([F:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.Br[CH2:31][CH2:32][CH3:33]>>[F:29][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:31][CH2:32][CH3:33])[CH:20]=2)[O:17][CH:18]=1
Reactant: CCCBr
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)cc1O
Product: CCCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)ccc1OC

Procedure:
Using the compound obtained in Example 272 and 1-bromopropane, white powdery 1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-propoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.[NH2:18][NH2:19]>C(O)C>[C:10]1([C:9]2[NH:19][N:18]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]n1
Yield: 67 %

Procedure:
To a solution of ethyl 2,4-dioxo-4-phenylbutanoate (16.0 g) in ethanol (150 mL) was added hydrazine monohydrate (4.0 mL), and the mixture was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether to give the title compound as a pale-brown solid (yield 12.0 g, 67%).
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[Br:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Reactant: Nc1cccc(Br)c1
Product: CC(C)(C)C(=O)Nc1nc(Nc2cccc(Br)c2)c2c(n1)[nH]c1ccccc12
Reaction time: 26 h
Yield: 80 %

Procedure:
Using the general procedure described above, the reaction of 6 (181 mg, 0.59 mmol) and 3-bromoaniline (771 mg, 4.48 mmol), was run for 26 hours, to provide 209 ing of 7 as a white solid in 80% yield. TLC Rf 0.28 (chloroform-methanol 20:1); mp 286.7-287.5° C.; 1H NMR (DMSO-d6) δ 1.27 (s, 9H, C(CH3)3), 7.19-7.49 (m, 4H, Ar—H), 8.18-8.46 (m, 4H, Ar—H), 8.79 (s, 1H, 4-NH, exch), 9.64 (s, 1H, 2-NH, exch), 11.89 (s, 1H, 9-NH, exch). Anal. Calculated (C21H20BrN5O): C, 57.54; H, 4.59; N, 15.97; Br, 18.22. Found: C, 57.34; H, 4.65; N, 15.80; Br, 17.96.
Reaction SMILES: [CH2:1]([C@H:8]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C@@H:9]([OH:36])[CH2:10][C@@H:11]([NH:25]C(OCC1C=CC=CC=1)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C.CO.O1CCOCC1.[OH-].[OH-].[Pd+2]>[NH2:25][C@@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:10][C@H:9]([OH:36])[C@@H:8]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccncc2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccc(-c2ccncc2)cc1
Reaction time: 18 h

Procedure:
The product from Example 150B (0.242 g, 0.41 mmol) was dissolved in a mixture of ethyl acetate (2.0 mL) and methanol (2.0 mL) and 20% Pd(OH)2 on carbon (0.10 g) and a solution of HCl in dioxane (0.10 mL, 4 N) were added, and the reaction was stirred under an atmosphere of hydrogen (balloon pressure) for 18 hours. The mixture was filtered through celite and the solvent was evaporated to give the title compound as the hydrochloride salt (0.273 g, which was used without further purification.