Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]([C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)O.C1C=CC(OP(OC2C=CC=CC=2)([N:28]=[N+:29]=[N-:30])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:28]([CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[N:11][CH:10]=1)[CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)=[N+:29]=[N-:30]
Reactant: OC(CC1OCCO1)c1ccc(C(F)(F)F)nc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC(CC1OCCO1)c1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(1,3-dioxolan-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanol (18.54 g, 0.070 mol) and diphenylphosphonic azide (36 mL, 0.17 mol) in toluene (40 mL) was cooled to 0° C. and neat 1,8-diazabicyclo[5.4.0]undec-7-ene (25 mL, 0.17 mol) was added. The reaction mixture was stirred at 0° C. for 2 hr and then at 20° C. overnight. The mixture was washed with water and 5% HCl. The aqueous phase was extracted with CH2Cl2. The combined orangic layers were concentrated in vacuo and the residue was purified by silica gel column (0-100% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 40 (1.33 g, 10.0 mmol) in acetonitrile (50 mL) were sequentially added potassium carbonate (5.53 g, 40.0 mmol) and ethyl bromoacetate (1.67 g, 10.0 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between EtOAc (200 mL) and water (150 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 90 (2.1 g, 99%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:15]=1[NH2:16].CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[C:14]([F:13])=[CH:20][C:19]([F:21])=[CH:18][C:17]=2[F:22])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: Nc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSc1nc(Cl)c(C=O)c(Nc2c(F)cc(F)cc2F)n1
Temperature: 50 °C
Yield: 87 %

Procedure:
A solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde [Santilli, et al., J. Heterocycl. Chem. 1971, 8, 445-45] (1.0 g, 4.48 mmol) in CHCl3 (20 mL) was added 2,4,6-trifluoroaniline (0.735 mg, 5 mmol) followed by Et3N (0.94 mL, 6.72 mmol, 1.5 eq). The reaction mixture turned yellow and was heated to 50° C. for 8 h, 1 M aq Na2CO3 (50 mL) was added and the layers were separated. The organic layer was washed with 50 mL satd aq NaCl solution, dried through anhydrous MgSO4 and evaporated. The crude product was purified by flash chromatography to afford 1.3 g (87%) of pure 4-chloro-6-(2,4,6-trifluorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. LC MS (m/e)=334.0 (MH+).
Reaction SMILES: [Mg].C1C[O:5][CH2:4]C1.Br[C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl>CN(C=O)C>[CH2:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH:4]=[O:5])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCc1ccsc1Br
Reactant: C1CCOC1
Agent: Cl
Agent: [Mg]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccsc1C=O
Yield: 50 %

Procedure:
Magnesium turnings (0.528 g, 22 mmol) dissolved and 60 mL of dry THF was placed in a 100 mL round bottom flask. 2-Bromo-3-tetradecylthiophene (7.2 g, 20 mmol) was added dropwise to above solution. The mixture was refluxed until almost all the magnesium turnings disappeared. After the mixture was transferred to a clean flask, dry DMF (4 mL) was added dropwise. The mixture was refluxed overnight and cooled in an ice bath. A 5% HCl solution (20 mL) was added to the reaction mixture. The organic portion was extracted by dichloromethane, washed by a 10% KOH solution (50 mL×3), and dried by MgSO4. After removal of the solvent, the crude product was purified by column chromatography on silica gel (using 5% ethyl acetate in hexane as an eluant) to give 3-teradecylthiophene-2-carboxaldehyde as a colorless oil (yield=50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Cl-].[CH3:16][CH:17]1[CH2:21][CH2:20][C:19](=[O:22])[N:18]1[NH3+:23]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:23][N:18]2[C:19](=[O:22])[CH2:20][CH2:21][CH:17]2[CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: CC1CCC(=O)N1[NH3+]
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Agent: [Cl-]
Solvent: c1ccncc1
Product: COC(=O)CC(=NN1C(=O)CCC1C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.1 %

Procedure:
A mixture of 7.50 g (38.2 mmol) of methyl 3-(4-fluorophenyl)-3-oxopropanoate and 11.5 g (76.5 mmol) of 2-methyl-5-oxopyrrolidin-1-aminium chloride in 50 ml of pyridine is stirred at room temperature for 72 h. The reaction mixture is concentrated under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 10.4 g (93%) of the desired product as a mixture of isomers; log P(HCOOH): 2.13 and 2.45; 1H-NMR (ppm): δ (DMSO-d6)=1.16-1.19 (m, 3H), 1.58-1.62 (m, 2H), 2.20-2.22 (m, 1H), 2.36-2.41 (m, 1H), 3.54 (s, 2.25H), 3.64 (s, 0.75H), 3.80 (d, 1H), 3.90 (d, 1H), 3.80 (q, 1H), 7.24 (t, 0.6H), 7.29 (t, 1.4H), 7.44-7.47 (m, 0.6H), 7.89-7.92 (m, 1.4H); LC-MS: m/z=293 [M+H]+.
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].COCCO[AlH2-]OCCOC.[Na+]>ClCCl.C1(C)C=CC=CC=1>[CH3:3][NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)Nc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 0 °C
Yield: 89.2 %

Procedure:
A solution of 0.5 g (1.4 mMol) [6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-carbamic acid methyl ester in 3.0 ml dichloromethane was added over 10 minutes to a solution of 1.98 ml (6.9 mMol) Red-Al® (70% in toluene) and 2.5 ml toluene (exothermic, cool with a water bath to avoid temperature to go >50° C.). The reaction mixture was stirred 2 hours at 50° C. in CH2Cl2, extracted with ethyl acetate and cooled to 0° C. 4 ml Aqueous NaOH 1N were carefully (exothermic) added over 15 minutes, followed by 20 ml ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with deionized water and brine, dried (Na2SO4) and concentrated under reduced pressure to yield 0.37 g (89%) methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine as an orange resin. MS (ISP): 297 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[O:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=2)[CH:21]=1.C(N(CC)CC)C>C1COCC1>[NH2:33][C:17]1[N:18]=[CH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:29][CH2:28]3)[CH:26]=2)=[CH:21][C:16]=1[C:8]1[O:7][C:15]2[C:10]([N:9]=1)=[N:11][CH:12]=[CH:13][CH:14]=2
Reactant: COCC(=O)Cl
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ncccc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ncccc5o4)c3)cn2)CC1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
2-methoxyacetyl chloride (0.023 ml) was added in one portion to a stirred solution of 3-oxazolo[4,5-b]pyridin-2-yl-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (90 mg) and triethylamine (0.069 ml) in THF (40 ml). The resulting mixture was stirred at 23° C. for 2 hours and concentrated to dryness. The product was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness and the resulting solid was triturated overnight with acetonitrile, filtered and dried under vacuum at 50° C. overnight to afford 1-[4-[4-(6-amino-5-oxazolo[4,5-b]pyridin-2-yl-3-pyridyl)pyrazol-1-yl]-1-piperidyl]-2-methoxy-ethanone (80 mg) as a solid. Mass spectrum: M+H+ 434; RT 2.23 min
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([OH:5])=[O:4].[CH2:16]([OH:23])[C:17]([NH2:22])([CH2:20][OH:21])[CH2:18][OH:19]>C(O)C.[Pd]>[NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH2:16]([OH:23])[C:17]([NH2:22])([CH2:20][OH:21])[CH2:18][OH:19]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: NC(CO)(CO)CO
Solvent: CCO
Product: NCC(=O)O

Procedure:
The title compound was prepared by hydrogenation of a solution of Z-Gly-Tris in ethanol at 40 pa. pressure in a Parr hydrogenator in the presence of palladium on carbon (10%). The removal of the Z group was monitored by HPLC. The catalyst was removed by filtration and washed with ethanol. Evaporation of the solvent gave the title compound in 95% yield. The preparation of Z-Gly-Tris is described in Whittaker, R. G., Hayes, P. J., and Bender, V. J. (1993). Peptide Research 6; 125 and Australian Patent No. 649242.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9](O)=[O:10])=[CH:3][CH:2]=1.[CH3:26][C:27]1([CH3:35])[O:34][C:32](=[O:33])[CH2:31][C:29](=[O:30])[O:28]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:16]([O:15][C:13](=[O:14])[NH:12][C@H:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][CH:5]=1)[C:9]([CH:31]1[C:32](=[O:33])[O:34][C:27]([CH3:35])([CH3:26])[O:28][C:29]1=[O:30])=[O:10])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: -5 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of (R)-3-biphenyl-4-yl-2-t-butoxycarbonylamino-propionic acid (50 g, 146 mmol), Meldrum's acid (23.3 g, 161 mmol) and DMAP (27.8 g, 227 mmol) in anhydrous DCM (500 mL) was added a solution of DCC (33.3 g, 161 mmol) in anhydrous DCM (200 mL) over 1 hour at −5° C. under nitrogen. The mixture was stirred at −5° C. for 8 hours, then refrigerated overnight, during which tiny crystals of dicyclohexylurea precipitated. After filtration, the mixture was washed with 5% KHSO4 (4×200 mL) and saturated aqueous NaCl (1×200 mL), then dried under refrigeration with MgSO4 overnight. The solution was evaporated to yield the title compound (68 g, light yellow solid), which was used without further purification. LC-MS: 490 [M+Na], 957 [2M+Na].
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([NH:23][CH3:24])=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+]>O1CCCC1.O>[Cl:1][C:2]1[N:11]=[C:10]([N:23]([C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[CH3:24])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: CNc1ccc(OC)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N(C)c2nc(Cl)nc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.2 %

Procedure:
A mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.386 mmol), 4-methoxy-N-methylaniline (55 mg, 0.401 mmol) and sodium acetate (60 mg, 0.732 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL) was stirred at room temperature for 48 h. The reaction mixture was evaporated to dryness and the residue was crystallized using ethanol/water and isolated as white solid (60 mg, 60%). 1H NMR (CDCl3): 8.19 (s, 1H), 7.32-7.26 (m, 2H), 7.09-7.07 (m, 2H), 6.16 (s, 1H), 4.03 (s, 3H), 3.87 (s, 3H), 3.75 (s, 3H), 3.32 (s, 3H).
Reaction SMILES: Cl[CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(N(CC)CC)C.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1COCC1>[CH:13]1[C:14]2[CH:2]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: ClC1c2ccccc2-c2ccccc21
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc2c(c1)-c1ccccc1C2N1CCNCC1
Yield: 81.1 %

Procedure:
A solution of 9-chlorofluorene (8.4 g), triethylamine (0.85 mL) and piperazine (27 g) in THF (200 mL) was refluxed under argon for 6 hours. It was then filtered and the solvent was removed under vacuum. The crude product was washed with water, chromatographed on silica gel and eluted with 5% MeOH saturated with NH3 in CH2Cl2 to afford the title compound (8.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:18]([CH2:17][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1)=[O:41]
Reactant: COc1ccc(-c2cccc(C#N)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: COc1ccc(-c2cccc(C#N)c2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 22 (386 mg, 0.86 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (238 mg, 1.03 mmol) using Method D to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]=[CH2:16])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:23]([CH2:24][C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:32])[CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CO>[CH2:14]([N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:12][N:11]([CH2:18][C:19]2[N:23]([CH2:24][C:25]3[C:26]([Cl:32])=[CH:27][CH:28]=[CH:29][C:30]=3[Cl:31])[CH:22]=[N:21][CH:20]=2)[C:10]1=[O:13])[CH:15]=[CH2:16]
Reactant: C=CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Reactant: ClCc1cncn1Cc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(Cc2cncn2Cc2c(Cl)cccc2Cl)c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
41 mg (0.17 mmol) of the compound from Example 12A were dissolved in 2 ml of DMF, and 48 mg (0.17 mmol) of the compound from Example 40A and 85 mg (0.26 mmol) of cesium carbonate were added. The mixture was stirred at 80° C. for 16 h. After cooling to RT, the reaction mixture was diluted with 1 ml of methanol and directly purified chromatographically [Method 19]. This gave 4 mg (5% of theory) of the target compound.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][SH:7].Cl[C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17]>CN1CCCC1=O>[CH3:16][C:11]1[C:10]([CH3:17])=[C:9]([S:7][CH2:6][CH2:5][CH2:4][OH:3])[CH:14]=[CH:13][N+:12]=1[O-:15]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: OCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1c(SCCCO)cc[n+]([O-])c1C
Reaction time: 0.25 h

Procedure:
6 g (60% pure) of NaOH are added in portions to 50 ml of dry N-methylpyrrolidone (NMP), the mixture is stirred for 15 min, 9.5 g (0.11 mol) of 3-hydroxypropyl mercaptan are metered in over a period of 20 min. and the mixture is stirred again for 30 min. until the evolution of gas has ended. A solution of 14.4 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine N-oxide in 100 ml of NMP is then added dropwise in the course of 20 min. and the reaction mixture is stirred at room temperature for 1 hour, subsequently at 70° C. for 1 hour and thereafter at 100° C. for a further hour.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH:8]=[C:9]([O:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[Cl:23])(=[O:15])=[O:14])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:24])[O:3]1.[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:26][N:5]1[C:6]2[CH:11]=[CH:10][C:9]([O:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[Cl:23])(=[O:15])=[O:14])=[CH:8][C:7]=2[C:2]([CH3:25])([CH3:1])[O:3][C:4]1=[O:24]
Reactant: CC1(C)OC(=O)Nc2ccc(OS(=O)(=O)c3cccc(Cl)c3Cl)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)OC(C)(C)c2cc(OS(=O)(=O)c3cccc(Cl)c3Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a stirred solution of (4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,3-dichlorobenzenesulfonate (0.50 g, 1.24 mmol) in dimethylformamide (DMF) (6 mL) with potassium carbonate (0.51 g, 3.72 mmol) was added methyl iodide (0.1 mL, 1.60 mmol). After stirring overnight at room temperature, the solution was then quenched with ammonium chloride solution (sat.) and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. Trituration with ether gave (1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,3-dichlorobenzenesulfonate as a white solid (0.30 g, 59%). 1H NMR (DMSO-d6): δ 8.14 (dd, J=8.1, 1.5 Hz, 1H), 7.92 (dd, J=8.1, 1.5 Hz, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.12 (s, 2H), 7.00 (m, 1H), 3.25 (s, 3H), 1.49 (s, 6H). MS (ESI) m/z 416/418/420 ([M+H]+); Anal. calcd for C17H15Cl2NO5S: C, 49.05; H, 3.63; N, 3.36. Found: C, 49.01; H, 3.44; N, 3.15.
Reaction SMILES: [P:1]([Cl:14])(Cl)(=[O:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[CH2:15]([OH:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CCCCCCCCCC.CN1C=CN=C1>ClCCl.CCCCCC>[P:1]([Cl:14])(=[O:12])([O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[O:31][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: O=[N+]([O-])c1ccc(OP(=O)(Cl)Cl)cc1
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCOP(=O)(Cl)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
p-Nitrophenyl phosphorodichloridate (75 g, 0.29 mol) in anhydrous dichloromethane (300 mL) was added to a 1 L, three necked, round-bottomed flask with stir bar that had been purged with N2. A solution of hexadecanol (71.03 g, 0.29 mol) and N-methylimidazole (23.35 mL, 0.29 mol) in anhydrous dichloromethane (250 mL) was added dropwise over a period of 2 hours. The reaction mixture was stirred for an additional 1 hour before pouring into a 1 L separatory funnel. N-methylimidazole hydrochloride salts separated at the bottom as an oil and were removed from the funnel. Dichloromethane was removed from the mixture at less than 30° C. under vacuum to give an amber oil which was taken up in hexane (400 mL) and placed in a freezer overnight. The reaction mixture was then thawed and the soluble portion was filtered to remove the crystals of p-nitrophenyl phosphorodichloridate. The solvent was removed from the filtrate via rotary evaporation at less than 35° C. to give n-hexyl p-nitrophenyl phosphorochloridate.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>O1CCCC1>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(N)c1
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: Nc1cccc(NC(=O)/C=C\C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 9.96 g (92 mmol) of 1,3-phenylenediamine and 250 ml of tetrahydrofuran. A solution prepared by dissolving 9.03 g (92 mmol) of maleic anhydride in 27 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of about 1 hour, then, the mixture was stirred at room temperature overnight. After completion of the reaction, the deposited crystal was separated by filtration, and the filtrate was condensed to dryness, to obtain 16.68 g of coarse (2Z)-4-[(3-aminophenyl)amino]-4-oxo-2-butenoic acid. To 16.68 g of coarse (2Z)-4-[(3-aminophenyl)amino]-4-oxo-2-butenoic acid was added 450 ml of tetrahydrofuran, and the mixture was refluxed with heating for 1 hour, then, the deposited crystal was isolated by hot filtration, and dried to obtain 7.58 g of coarse ((Z)-3-(3-aminophenylcarbamoyl)acrylic acid. Further, to this crystal was added 30 ml of methanol, and the mixture was stirred at room temperature for 1 hour, then, the deposited crystal was isolated by filtration, and dried to obtain 6.94 g of (2Z)-4-[(3-aminophenyl)amino]-4-oxo-2-butenoic acid as a yellow-white solid. Yield: 36.5%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH:12]2OCC[O:27][CH:11]12.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]1=[O:27]
Reactant: CCCCCC(O)C=C[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CO
Product: CCCCCC(O)C=C[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OC
Reaction time: 8 h

Procedure:
A mixture of 9-ethylenedioxy-15-hydroxyprost-13-enoic acid methyl ester (35 mg), methanol (3 ml) water (0.5 ml) and p-toluenesulfonic acid (10 mg) is allowed to stand at room temperature overnight, taken up in ether, washed to neutrality with water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield 15-hydroxy-9-oxoprost-13-enoic acid methyl ester γmaxFilm 3450, 1745 cm-1, identical to the compound of the same name described in British Pat. No. 1,218,998, cited above.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[C:11]([C:8]1([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[CH2:10][CH2:9]1)=[O:13]
Reactant: CNC
Reactant: O=C(O)C1(c2cccc(Br)n2)CC1
Product: CN(C)C(=O)C1(c2cccc(Br)n2)CC1
Yield: 70 %

Procedure:
The title compound was prepared from 1-(6-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 70% of theory; LC (method 3): tR=2.97 min; Mass spectrum (ESI+): m/z=255/257 (Br) [M+H]+.
Reaction SMILES: [CH:1]([C:4]1([CH3:26])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[S:16][CH:17]=[C:18]([N+:19]([O-:21])=[O:20])[C:13]3=[CH:12][C:11]=2[C:22]([O:24]C)=[O:23])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([C:4]1([CH3:26])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[S:16][CH:17]=[C:18]([N+:19]([O-:21])=[O:20])[C:13]3=[CH:12][C:11]=2[C:22]([OH:24])=[O:23])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2c([N+](=O)[O-])csc2nc1C1=NC(C)(C(C)C)C(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C1(C)N=C(c2nc3scc([N+](=O)[O-])c3cc2C(=O)O)NC1=O

Procedure:
The ester (1.0 g, 0.00266 mol) from Example 21 is stirred in 100 mL methanol and 10 mL 10% sodium hydroxide solution for 24 hours. Water (25 mL) is added and the methanol removed in vacuo. Acidification of the aqueous layer gives a brown precipitate which upon filtration and crystallization from methanol-water has mp 260° C.