Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=O.C(OC(=O)C)(=O)C>>[F:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[C:4]1[O:9][C:8](=[O:10])[CH2:7][N:6]=1
Reactant: O=C(O)CNC(=O)c1cc(F)ccc1F
Solvent: CC(=O)OC(C)=O
Product: O=C1CN=C(c2cc(F)ccc2F)O1
Temperature: 100 °C

Procedure:
A 100 mL round-bottomed flask was charged with 2-(2,5-difluorobenzamido)acetic acid (1.7 g, 7.9 mmol) and acetic anhydride (7.46 mL, 79 mmol). The resulting suspension was heated to 100° C. for 20 minutes (during which time the solids had all dissolved) and cooled to room temperature. The mixture was concentrated in vacuo and azeotroped with toluene and dried under vacuum for a weekend. This yielded an orange-colored oil that was used without further purification. An analytical sample was obtained by trituration with tert-butyl methyl ether. 1H-NMR (CDCl3) δ 7.34 (m, 1H), 7.19-7.04 (m, 2H), 4.38 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O>>[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:2]1[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)[C:7]([C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Reactant: OB(O)c1ccccc1Cl
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(-c3ccccc3Cl)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 2-chlorophenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[C:9][C@:10]1([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@H:12]([O:23]C(=O)C)[C@@H:11]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C>CO>[CH2:1]([Si:3]([C:8]#[C:9][C@:10]1([CH2:35][O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@H:12]([OH:23])[C@@H:11]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CC[Si](C#C[C@]1(COCc2ccccc2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1)(CC)CC
Solvent: CO
Solvent: CCN(CC)CC
Product: CC[Si](C#C[C@]1(COCc2ccccc2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1OCc1ccccc1)(CC)CC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Compound 7 (2.00 g, 3.3 mmol) was dissolved in methanol (90.0 ml), and triethylamine (10.0 ml) was added to the solution, followed by stirring for 48 hours at room temperature. The reaction mixture was concentrated through distillation under reduced pressure, and the residue was purified by means of silica gel column chromatography (silica gel 200 ml, eluent; n-hexane:ethyl acetate=1:1), to thereby yield a white powdery compound (Compound 8; 1.72g, 3.06 mmol, 92.4%).
Reaction SMILES: NCCNCCNCCNCC.[N:13]12[CH2:26][CH2:25][N:19]([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2.C(=O)([O-])[O-].[K+].[K+].C(C=O)=O>C(#N)C>[N:13]12[CH:26]3[N:16]([CH2:17][CH2:18][N:19]4[CH:25]3[N:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]4)[CH2:15][CH2:14]2
Reactant: C1CN2CCNCCN(CCN1)CC2
Agent: CCNCCNCCNCCN
Agent: O=C([O-])[O-]
Agent: O=CC=O
Solvent: CC#N
Product: C1CN2CCN3CCN4CCN1C2C43

Procedure:
1.1.22 1,4,7,10-Tetraazabicyclo[5.5.2]tetradecane 1,4,7,10-tetraazadodecane (1.1.4) trihydrobromide in acetonitrile with potassium carbonate was reacted with glyoxal to form 1,4,7,10-tetraazatetracyclo-[5,5,2,04,13,010,14] tetradecane (1.1.23). Following separation the pure product was obtained by low pressure distillation. This was dissolved in acetonitrile and benzylbromide was added to form 1,7-dibenzylonium-1,4,7,10-tetraazatetracyclo[5,5,2,04,13,010,14] tetradecane (1.1.24). Following recrystallization from ethanol this was reacted with sodium borohydride. HCl was added, followed by water and NaOH, and the product extracted with chloroform. Following evaporation of solvent the solids were dissolved in methanol and HBr was added to obtain 1,7-dibenzyl-1,4,7,10-tetraazabicyclo [5.5.2] tetradecane (1.1.25) as the hydrobromide salt. This was dissolved in water and reduced using H2 and a Pd-C catalyst to remove the benzyl groups. Purification of the title compound was by crystallization of the hydrobromide salt. The base form was obtained by low pressure distillation following addition of base.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.Cl>C1C=CC=CC=1.C(Cl)(Cl)Cl.O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:10](=[O:12])[CH:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:13][S:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(CSc2cccc(OC)c2)C(=O)O)cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
2-(4-Methoxyphenyl)-3-(3-methoxyphenylthio)propionic acid obtained in Example 24 was dissolved in benzene (20 ml) and thionyl chloride (4.1 ml, 55.9 mmol) was added thereto. The reaction mixture was heated for 2 hours at 80° C. When the reaction is completed, the reaction solution was concentrated under reduced pressure to remove benzene and cooled to 5° C. Benzene (10 ml) was added to the reaction solution and then tin(IV) chloride (4.1 ml, 34.9 mmol) was slowly added dropwise thereto. The reaction mixture was stirred for 12 hours and then water (30 ml), concentrated hydrochloric acid (10 ml) and chloroform (30 ml) were added thereto. The reaction solution was heated under refluxing for one hour and extracted with chloroform. The organic layer was washed with water and sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=8:2) to obtain 1 g (yield in two reaction steps: 20%) of the title compound as a yellow solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH3:21])=[O:13])(OCC)=O)C.[CH3:22][C:23]1[C:24]2[N:25]([N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]=2[CH:32]=O)[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[CH3:22][C:23]1[C:24]2[N:25]([N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]=2[CH:32]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][CH3:21])=[O:13])[CH:26]=[CH:27][CH:28]=1
Reactant: CCOP(=O)(CC(=O)N1CCCCC1CC)OCC
Reactant: Cc1cccn2nc(-c3ccccc3)c(C=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2cccc(C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Sodium hydride (60%, 110mg) was added to a solution of 1-(2-diethoxyphosphorylacetyl)-2-ethylpiperidine (0.80 g) in tetrahydrofuran (5 ml) at 7° C. under nitrogen atmosphere. A solution of 4-methyl-2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.50 g) in tetrahydrofuran (5 ml) was added dropwise to the above solution at 10° C., and then stirred at room temperature for 1 hour. After evaporating the solvent, in vacuo saturated sodium chloride aqueous solution (20 ml) was added to the residue and extracted with ethyl acetate (20 ml×2). Combined extracts were washed with saturated sodium chloride aqueous solution (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 1-[3-(4-methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine (trans isomer) (788 mg) as an oil.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24](Br)[N:25]=3)[NH:20][CH:19]=2)=[O:17])([CH3:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37]>>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:32]4[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:25]=3)[NH:20][CH:19]=2)=[O:17])([CH3:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCC(OCc2ccccc2)CC1
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCC(OCc5ccccc5)CC4)c3n2)cc(OC)c1OC

Procedure:
(4-Benzyloxy-1-methyl-cyclohexyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (4-benzyloxy-1-methyl-cyclohexyl)-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanone and 3,4,5-trimethoxybenzeneboronic acid following general procedures as described in these Examples. M+H=516.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[CH:23][C:22]([C:40](=[NH:43])[NH:41][OH:42])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2].C(N(CC)CC)C.Cl[C:54](Cl)([O:56]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=3)=[CH:23][C:22]([C:40]3[NH:43][C:54](=[O:56])[O:42][N:41]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=N)NO)cc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(-c3noc(=O)[nH]3)cc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.4 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(N-hydroxy-carbamimidoyl)pyridin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (193 mg) and triethylamine (126 μl) are dissolved in dichloromethane (3 ml), and thereto is added triphosgene (268 mg) at 0° C. The mixture is stirred at room temperature for 30 minutes. To the reaction solution are added water and dichloromethane, and the organic layer is washed with saturated brine. Then the organic layer is dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=1:0→97:3) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)pyridin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (33 mg). MS (m/z): 667 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[I-:18].[Na+]>CC(C)=O>[I:18][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CI)CC1

Procedure:
treating tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate with sodium iodide in acetone to give the corresponding iodo compound, tert-butyl 4-(2-iodoacetyl)piperazine-1-carboxylate;
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:12]2[N:13]=[CH:14][S:15][C:11]=2[CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[C:12]2[N:13]=[CH:14][S:15][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2scnc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc2scnc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 156.3 %

Procedure:
Boron tribromide (3.09 ml, 1M solution in DCM, 3.09 mmol) was added dropwise at 0° C. to a stirred solution of 4-methoxy-benzothiazole (510 mg, 3.09 mmol) in dry DCM (30ml). The resulting solution was warmed to 40° C. and allowed to stir overnight. The resulting solution was concentrated in vacuo and diluted with water and HCl (2N). The aqueous phase was neutralised to pH˜7 with NaHCO3 and the solution extracted with EtOAc (3×100 ml) and the combined organic extracts dried (MgSO4) and the solvent removed in vacuo. The resulting oil was purified by flash chromatography eluting silica gel with hexane:EtOAc [4:1] to hexane:EtOAc [7:3] to give the title compound as a tan solid (730 mg, 80%); δH (300 MHz, CDCl3) 7.59 (1H, s, CH), 7.46 (1H, dd, Ar), 7.36 (1H, t, Ar), 7.02 (1H, dd, Ar).
Reaction SMILES: [Cl:1][CH:2]([Cl:14])[C:3]([F:13])([F:12])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.Cl.[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:18]=1[C:19]([N:21]=[C:22]=[O:23])=[O:20]>C1(C)C(C)=CC=CC=1>[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:18]=1[C:19]([NH:21][C:22]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][C:3]([F:12])([F:13])[CH:2]([Cl:1])[Cl:14])=[CH:10][CH:9]=1)=[O:23])=[O:20]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(OC(F)(F)C(Cl)Cl)cc1
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(OC(F)(F)C(Cl)Cl)cc1
Reaction time: 2 h
Yield: 463.9 %

Procedure:
In 200 milliliters of xylene, 11.5 grams (0.04 mole) of β,β-dichloro-α,α-difluoro-p-phenetidine.HCl and 3.6 grams (0.04 mole) of 2,6-dichlorobenzoyl isocyanate were refluxed with stirring for two hours. The xylene was thereafter removed by vacuum distillation. The residue which remained was mixed with 200 milliliters of hexane and a crystalline solid precipitated. This precipitated material was collected by suction filtration, washed with hexane and dried. The dried crude product was a light tan gummy solid melting at 160°-185° C. This crude product was purified by recrystallization from 60 milliliters of 83 percent aqueous acetic acid, leaving 85 grams of a white solid melting at 211°-213° C. (56 percent of theoretical). Nuclear magnetic resonance spectroscopy confirmed the structure as being ##STR13##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][CH2:18][CH:19]2[CH2:23][O:22]C(C)(C)[O:20]2)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=O.Cl.[NH2:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]([CH2:18][CH:19]([OH:20])[CH2:23][OH:22])[C:29](=[O:30])[CH2:28][N:27]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]=2[CH:16]=1
Reactant: CC1(C)OCC(CNc2ccc(Cl)cc2C(=O)c2ccccc2F)O1
Reactant: NCC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(O)CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of 5-chloro-2-{[(2,2-dimethyl-1,3-dioxolan-4-yl)-methyl]-amino}-2'-fluorobenzophenone are dissolved in 25 ml of absolute carbon tetrachloride, treated with 1.5 g of glycyl chloride hydrochloride and stirred for 1 hour at 25°C. Then the solvent is completely distilled off on a rotary evaporator and the residue is stirred with 25 ml of 3 N hydrochloric acid for 30 minutes. Subsequently the aqueous acidic solution is extracted with ether, made alkaline with 3 N sodium hydroxide or ammonia and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried over magnesium sulfate, filtered and evaporated. By chromatography on silica gel with ethyl acetate/methanol (9:1) there is isolated from the residue pure 7-chloro-1-(2,3-dihydroxypropyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one of melting point 116°-117°C. The compounds resulting as intermediates in the reaction 2-amino-4'-chloro-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)-methyl]-2' -(2-fluorobenzoyl)-acetanilide and 2-amino-4'-chloro-N-(2,3-dihydroxypropyl)-2'-(2-fluorobenzoyl)-acetanilide are not isolated.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1>C(#N)C>[OH:5][CH:3]([CH3:4])[CH2:2][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)CCl
Solvent: CC#N
Product: CC(O)Cn1ccnc1
Reaction time: 24 h

Procedure:
Chloroacetone (9.25 g.) in dry acetonitrile was added dropwise with stirring and ice cooling to a slurry of imidazole (13.6 g.) in acetonitrile (100 ml.). The mixture was stirred for 4 hours with ice cooling and then for 24 hours at room temperature. The solvent was removed and the product isolated by chromatography on silica gel, eluting with 10% methanol/dichloromethane. This material in 100 ml. of methanol was treated with excess sodium borohydride at 0° C. for 1 hour and acidified with methanolic hydrogen chloride. The solvent was removed, ethyl acetate added and the stirred mixture treated dropwise with saturated potassium carbonate solution until basic. The ethyl acetate was then decanted, dried, evaporated and the residue chromatographed on silica gel eluting with 10% methanol/dichloromethane to give pure 1-(2-hydroxypropyl)imidazole.
Reaction SMILES: I[C@H:2]([C@H:10]1[O:31][C@H:13]2[CH2:14][C@@H:15]([C:27]([O:29][CH3:30])=[O:28])[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:26])[C@H:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:12]2[CH2:11]1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].O1[C@H]2CC(C(O)=O)[C@@H](/C=C/[C@@H](O)[C@H](F)CCCC)[C@H]2C[C@H]1CCCCC(OC)=O>>[O:31]1[C@H:13]2[CH2:14][C@@H:15]([C:27]([O:29][CH3:30])=[O:28])[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:26])[C@H:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:12]2[CH2:11][C@H:10]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCC[C@@H](F)[C@H](O)/C=C/[C@H]1[C@H]2C[C@@H]([C@@H](I)CCCC(=O)OC)O[C@H]2C[C@H]1C(=O)OC
Agent: CCCC[C@@H](F)[C@H](O)/C=C/[C@@H]1C(C(=O)O)C[C@@H]2O[C@H](CCCCC(=O)OC)C[C@@H]21
Product: CCCC[C@@H](F)[C@H](O)/C=C/[C@H]1[C@H]2C[C@@H](CCCCC(=O)OC)O[C@H]2C[C@H]1C(=O)OC

Procedure:
By the procedure of Example 2, [5S,6S,8R,9S,11R,12S,15R,16R]-methyl 5-iodo-6,9-epoxy-11-carbomethoxy-16-fluoro-15-hydroxyprost-(13E)-enoate was converted to [6R,8R,9S,12S,15R,16R]-methyl 6,9-epoxy-11-carboxy-16-fluoro-15-hydroxyprost-(13E)-enoate.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(C2CCN(C(=O)c3cnc4c(C(=O)O)cnn4c3NCc3ccccc3)CC2)cc1
Product: Cc1ccc(C2CCN(C(=O)c3cnc4c(C(=O)NS(C)(=O)=O)cnn4c3NCc3ccccc3)CC2)cc1
Yield: 28.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(4-methylphenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.09 g, 0.19 mmol) obtained in step 2 and methanesulfonamide (0.090 g, 0.950 mmol), the title compound (0.03 g, 28%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Al](C)C.C([O:22][C:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:32]([C:34]2[S:35][C:36]([Cl:39])=[CH:37][CH:38]=2)=[O:33])[N:26]=1)=O)C.O>O1CCOCC1>[F:15][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:6]=[CH:7][C:2]=1[NH:1][C:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:32]([C:34]2[S:35][C:36]([Cl:39])=[CH:37][CH:38]=2)=[O:33])[N:26]=1)=[O:22]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: CCOC(=O)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-n2ccccc2=O)cc1F)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (259 mg; CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) at r.t. in dioxane (4 ml) under an argon atmosphere was added trimethylaluminium (0.63 ml; 2 M solution in heptane)-->foaming. The mixture was stirred at r.t. for 2 h. A solution of 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (100 mg) in dioxane (4 ml) was then added. The mixture was heated to 100° C. over night. The mixture was cooled to r.t. and H2O (0.8 ml) was added (-->bubbling). After 15 min stirring, MgSO4 was added and stirring was continued for another 15 min. The mixture was then filtered and the cake was washed with dichloromethane. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide as light yellow solid. 474.1 ([M+H]+)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:11]([C:30](=[O:32])[CH3:31])[CH2:12][C:13]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[C:14]=2[N:15]=1.C1COCC1.C(N(CC)CC)C>O>[Cl:20][C:18]1[N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)[C:14]2[N:15]=[C:10]([NH:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[N:11]([C:30](=[O:32])[CH3:31])[CH2:12][C:13]=2[N:19]=1
Reactant: CC(=O)N1Cc2nc(Cl)nc(Nc3ccc(F)c(Cl)c3)c2N=C1Cl
Reactant: CN1CCC(N)CC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2nc(Cl)nc(Nc3ccc(F)c(Cl)c3)c2N=C1NC1CCN(C)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
47.2 g (0.413 mol) of 1-methyl-4-aminopiperidine is added dropwise at ambient temperature to a mixture of 123.3 g (0.317 mol) of (3), 740 ml of THF and 61.7 ml (0.445 mol) of triethylamine. The mixture is stirred for 30 min at 50° C. It is left to cool to 40° C., 1480 ml of water are added and the mixture is then stirred for 90 minutes at 10° C. The product that crystallises out is filtered off, washed with 150 ml of water and dried in vacuo at 60° C. The product is dissolved in 1150 ml of ethyl acetate at boiling temperature. It is cooled to 10° C., filtered and the product that crystallises out is dried at 60° C. in vacuo.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:27]=[O:28])C.Cl>C1COCC1>[CH3:11][C:8]1([CH3:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH:27]=[O:28])[CH:10]=2)[CH2:6][O:7]1
Reactant: CN(C)C=O
Reactant: CC1(C)OCc2ccc(Br)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OCc2ccc(C=O)cc21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-1,1-dimethyl-1,3-dihydro-isobenzofuran (1.41 g, 6.3 mmol) in anhydrous THF (10 mL) was added under Argon at −78° C. 2.5 M nBuLi in hexane (2.7 mL, 6.6 mmol) and after stirring for 0.5 h at −78° C. DMF (0.98 mL, 12.5 mmol) was added. After stirring for 2 h at −78° C. the reaction mixture was added to 0.5 N cold aq. HCl and extracted with Et2O. Combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The title compound was obtained after chromatographic purification (Combi-Flash, 40 g silicagel, hexane-EtOAc 95:5 to 50:50) as a light yellow oil: TLC (hexane-EtOAc 1:1) Rf=0.50; HPLC RtA=1.43 min; 1H NMR (400 MHz, CDCl3): δ10.02 (s, 1H), 7.78 (d, 1H), 7.65 (s, 1H), 7.36 (d, 1H), 5.11 (s, 2H), 1.53 (s, 6H).