Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=4)[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>>[NH2:28][C:25]1[C:24]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:23][C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[C:9]2[CH:10]=[CH:11][N:6]=[CH:7][CH:8]=2)=[CH:27][N:26]=1
Reactant: Nc1ccc(-c2ccc3nccc(-c4ccncc4)c3c2)cn1
Reactant: O=S(=O)(O)Cl
Product: Nc1ncc(-c2ccc3nccc(-c4ccncc4)c3c2)cc1S(=O)(=O)Cl
Temperature: 25 °C
Yield: 47 %

Procedure:
To cold (0° C.) chlorosulfonic acid (15 mL) under vigorous stirring was added 5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine (4.348 g, 14.57 mmol) portionwise. The reaction mixture was then heated at reflux for 16 hrs. Upon cooling to room temperature, LCMS indicated 47% of the title compound MS(ES)+m/e 396.9 [M+]+ and 37% of sulfonic acid by-product MS(ES)+ m/e 379.1 [M+]+. A 2 mL aliquot of this 0.456M solution of the title compound was used in the next reaction without further workup.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[C:25]1([C@@H:31]2[CH2:36][NH:35][CH2:34][CH2:33][NH:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:35]4[CH2:34][CH2:33][NH:32][C@H:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:36]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: c1ccc([C@@H]2CNCCN2)cc1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCN[C@H](c5ccccc5)C4)c(F)cc3cc2c1=O
Yield: 59.2 %

Procedure:
Working under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.21 g) and (R)-2-phenylpiperazine (0.7 g), and after recrystallization in ethanol (22 cc) containing dimethylformamide (30%), (R)-3-ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (1.02 g) is obtained in the form of a yellow solid, m.p. 216° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:3][CH2:2]1.Cl.CC(O)C>C(OCC)(=O)C>[NH:13]1[CH2:12][CH2:11][CH:10]([O:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCN2CCOCC2)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C1CC(OCCN2CCOCC2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Tert-butyl 4-(2-morpholinoethoxy)piperidine-1-carboxylate (78) (7.0 g, 22.26 mmol) was added to 6.0 HCl in propan-2-ol (30 mL, 180.00 mmol) and the reaction was stirred at 25° C. for 2 hours. The reaction mixture was evaporated to dryness and redissolved in methanol (75 mL) and water (7 mL), this was basified by stirring with solid sodium hydroxide for 1 hour. The reaction was filtered and evaporated to afford a gummy solid. This was stirred with ethyl acetate (75 mL) for 20 minutes, filtered and evaporated to afford a clear liquid. The crude product was purified by distillation at 1.2 mBar, collecting fractions that distilled at 120° C. to afford the desired material as a colourless oil (3.10 g, 65.0%); 1H NMR (400.132 MHz, CDCl3) δ 1.47-1.38 (2H, m), 1.93-1.89 (2H, m), 2.53-2.51 (4H, m), 2.63-2.56 (4H, m), 3.08 (2H, dt), 3.38-3.31 (1H, m), 3.61 (2H, t), 3.71 (4H, dd).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[CH3:6][C@H:7]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[C:25]([CH3:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2)[CH2:8][NH:9][CH3:10]>>[OH:3][CH2:2][C:1]([N:9]([CH3:10])[CH2:8][C@@H:7]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[C:25]([CH3:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2)[CH3:6])=[O:5]
Reactant: CNC[C@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Reactant: O=C(O)CO
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@@H](C)CN(C)C(=O)CO)c34)cc2C)cn1
Yield: 46 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and 5-[(1S)-1-methyl-2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine to give the title compound in 46% yield; NMR spectrum (CDCl3) 1.55 (d, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.96 (s, 3H), 3.59 (dd, 1H), 4.16-4.07 (m, 3H), 5.08 (m, 1H), 6.92 (d, 1H), 7.02 (d, 1H), 7.09 (d, 1H), 7.14 (d, 1H), 7.50 (m, 2H), 7.65 (m, 2H), 8.28 (s, 1H), 8.61 (s, 1H), 9.87 (s 1H); Mass spectrum: MH+ 488.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]#[N:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:34][O:35][CH:36](OC)OC>>[C:20]([C:3]1[C:4]([CH3:19])=[N:5][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[C:2]=1[N:1]=[CH:34][O:35][CH3:36])#[N:21]
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C#N
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC=Nc1c(C#N)c(C)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A mixture of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylpyrazole (5 g) and p-toluenesulphonic acid hydrate (0.1 g) in trimethylorthoformate (20 ml) was heated at reflux for 4.5 hours. After cooling, the reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in diethyl ether and left to crystallize at 0° C. The dark colored solid was recrystallized from a mixture of ethanol and water to give 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methyl-5-methoxymethyleneaminopyrazole (4.67 g), m.p. 75°-78° C. in the form of buff crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[N:14][N:4]2[N:3]=1.[CH3:15][NH:16][CH3:17]>CO>[CH3:15][N:16]([CH3:17])[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[N:14][N:4]2[N:3]=1
Reactant: Clc1nn2nnnc2c2c1CCCC2
Reactant: CNC
Solvent: CO
Product: CN(C)c1nn2nnnc2c2c1CCCC2

Procedure:
A mixture was prepared from 6 g of 6-chloro-7,8,9,10-tetrahydrotetrazolo[5,1-a]phthalazine, 150 ml of methanol and 125 ml of 40% aqueous dimethylamine. This mixture was heated at reflux for 3 hours and then cooled. The precipitate which formed was separated by filtration and partitioned between methylene chloride and water. The organic layer was separated, dried over sodium sulfate, and concentrated to leave a residual solid. This was recrystallized from ethanol to give 6-dimethylamino-7,8,9,10-tetrahydrotetrazolo[5,1-a]phthalazine melting at about 239°-240° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[CH:5][CH:4]=1)#[N:2].[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][S:9][C:7]1[N:6]=[CH:5][CH:4]=[C:3]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:2]=2)[N:8]=1
Reactant: CSc1nccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 53.8 %

Procedure:
6-Cyano-2-methylthiopyrimidine (1.37 g, 9.06 mmol) and methyl thiosalicylate (3.05 g, 18.1 mmol) were dissolved in toluene (30 ml), and triethylamine (3.80 ml, 27.2 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (1.40 g, 54%) as pale yellow crystals.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:11]([O:15][C:16]([N:18]1[C:22]2=[N:23][CH:24]=[C:25](O)[CH:26]=[C:21]2[CH:20]=[C:19]1[C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:11]([O:15][C:16]([N:18]1[C:22]2=[N:23][CH:24]=[C:25]([O:10][CH:7]3[CH2:8][CH2:9][N:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:5][CH2:6]3)[CH:26]=[C:21]2[CH:20]=[C:19]1[C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)n1c(C(=O)N2CCOCC2)cc2cc(O)cnc21
Reactant: OC1CCN(C2CC2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(C(=O)N2CCOCC2)cc2cc(OC3CCN(C4CC4)CC3)cnc21
Temperature: 0 °C
Reaction time: 20 h
Yield: 79.1 %

Procedure:
To the solution of 73 mg (0.5 mmol) N-cyclopropyl-4-piperidinol in 2 ml tetrahydrofuran, 0.15 g (0.43 mmol) 5-hydroxy-2-(morpholine-4-carbonyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester and 0.14 g (0.52 mmol) triphenylphosphine were added and the suspension cooled to 0° C. Then, 0.12 g (0.52 mmol) diisopropyl azodicarboxylate was added and the resulting solution stirred for 20 hours at room temperature. The solvent was evaporated and the residue flash-chromatographed on silica gel with ethyl acetate:methanol (9:1 v/v) as eluant to give 0.16 g (81%) the product as a colorless gum.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]#[CH:11])=[CH:4][N+:5]([O-:7])=[O:6].[NH:12]([C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])[N:20]=1)[C:13]([NH2:15])=[NH:14]>>[N+:5]([CH:4]=[C:3]([NH:8][CH2:9][C:10]#[CH:11])[NH:25][CH2:24][CH2:23][S:22][CH2:21][C:19]1[N:20]=[C:16]([NH:12][C:13]([NH2:15])=[NH:14])[S:17][CH:18]=1)([O-:7])=[O:6]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: C#CCNC(=C[N+](=O)[O-])SC
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1csc(NC(=N)N)n1

Procedure:
1-Methylthio-1-(2-propynylamino)-2-nitroethylene (prepared in Example 2, Step A, above) is reacted in an inert solvent with about an equimolar amount of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine to produce, after workup, the title product.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1>>[CH3:5][C:3]1[CH2:4][CH:7]2[C:6](=[O:12])[O:11][C:9](=[O:10])[CH:8]2[CH2:1][CH:2]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C=CC(=C)C
Product: CC1=CCC2C(=O)OC(=O)C2C1

Procedure:
reacting isoprene and maleic anhydride to form 4-methyl-1,2,3,6-tetrahydrophthalic anhydride;
Reaction SMILES: [CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21](O)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].Cl.[F:26][CH:27]1[CH2:30][NH:29][CH2:28]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([N:29]3[CH2:30][CH:27]([F:26])[CH2:28]3)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:2])[CH3:3]
Reactant: FC1CNC1
Reactant: CC(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)c1nc2cc(NC(=O)c3c(C(=O)N4CC(F)C4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 86.5 %

Procedure:
A mixture of 5-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 213 μmol), 3-fluoroazetidine hydrochloride (71.3 mg, 640 mmol), propylphosphonic anhydride (50% in ethyl acetate, 314 μl, 533 μmol) and diisopropylethylamine (223 μl, 1.28 mmol) in tetrahydrofuran (4 ml) was stirred for 2.5 days (weekend) at 25° C. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 4-(3-fluoro-azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (71 mg, 86.4%) as a white solid. mp: 226-227° C., MS: m/z=384.0 (M−H+)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].CO[C:13](OC)([N:15]([CH3:17])[CH3:16])[CH3:14]>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[C:13]([N:15]([CH3:17])[CH3:16])[CH3:14])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: COC(C)(OC)N(C)C
Product: CC(=CC(=O)c1ccc(Cl)cc1)N(C)C

Procedure:
A mixture of 25.0 g of 4-chloroacetophenone and 40 ml of N,N-dimethylacetamide dimethyl acetal was stirred and heated at reflux for 3 hours. The mixture was evaporated in vacuo to give a red solid. The solid was triturated with n-hexane and filtered. The solid was washed with n-hexane and dried to give 15.6 g of 1-(4-chlorophenyl)-3-(dimethylamino)-2-buten-1-one as red crystals, mp 103°-105° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:17][C:15]=2[N:16]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][C:15]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3sc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2nc3cc(C4CCNCC4)ccc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-carboxylate (130 mg, 0.27 mmol) dissolved in DCM (5 ml) and added TFA (0.5 ml). Reaction mixture stirred at rt for 3 h. DCM removed on rotavapour to obtain crude. Crude was triturated with ether to obtain 2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]thiazole 2,2,2-trifluoroacetate (150 mg). 2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]thiazole 2,2,2-trifluoroacetate (105 mg, 0.21 mmol) was dissolved in DCM (20 ml) and added TEA (0.23 ml, 1.66 mmol). This mixture stirred at rt for 30 mins and added isopropylchloro formate in toluene (51 mg, 0.42 mmol). After 30 mins reaction mixture quenched with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by combiflash using EtOAc and Petether (1:3) as eluent to afford the titled compound (60 mg) as a grey solid. M.P.: 174-177° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.71-8.65 (m, 1H), 8.00 (d, J 1.2, 1H), 7.93-7.81 (m, 3H), 7.35 (dd, J 1.6, 8.4, 1H), 4.96 (septet, J 6.2, 1H), 4.40-4.22 (m, 2H), 3.12 (s, 3H), 2.95-2.82 (m, 3H), 2.0-1.90 (m, 2H), 1.80-1.64 (m, 2H), 1.28 (d, J 6.3, 6 H).
Reaction SMILES: C([C:4]1[NH:5][C:6]([CH3:16])=[C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:8]=1[CH3:9])(O)=O.C([O-])(=O)C.[Na+]>O>[CH3:16][C:6]1[NH:5][CH:4]=[C:8]([CH3:9])[C:7]=1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCc1c(C)[nH]c(C(=O)O)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCc1c(C)c[nH]c1C
Temperature: 100 °C
Yield: 38.2 %

Procedure:
2-Carboxy-3,5-dimethyl-4-(2-methoxycarbonylethyl)pyrrole (1.3 g) was ground with 0.5 g of anhydrous sodium acetate and then heated at 100° C. for 3 days. The mixture was dissolved in water, extract with ethyl acetate and chromatographed on a column of silica gel in ethyl acetate:hexane 1:3 to give 0.4 g (38% yield) of 2,4-dimethyl-3-(2-methoxycarbonylethyl)pyrrole as a thick pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:6]=1)=[O:4].C(O)(=O)C(O)=O.[NH:23]1[C:26]2([CH2:29][O:28][CH2:27]2)[CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:23]2[C:26]3([CH2:29][O:28][CH2:27]3)[CH2:25][CH2:24]2)=[C:7]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:6]=1)=[O:4]
Reactant: C1CC2(COC2)N1
Reactant: COC(=O)c1ccc(Br)c(OCC2CC2)n1
Agent: O=C(O)C(=O)O
Product: COC(=O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 32 a), using 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (Example 9 d) and 6-oxa-1-azaspiro[3.3]heptane, oxalate salt (CAN 1359655-43-8) as starting materials. MS (EI): m/e=305.0 [M+H]+.
Reaction SMILES: Br[CH2:2][CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([OH:33])=[C:14]([CH:32]=1)[CH2:15][N:16]([C:19]1[N:24]=[N:23][C:22]([C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])=[CH:21][CH:20]=1)[CH2:17][CH3:18]>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:33][CH2:2][CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5])=[C:14]([CH:32]=1)[CH2:15][N:16]([C:19]1[N:24]=[N:23][C:22]([C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])=[CH:21][CH:20]=1)[CH2:17][CH3:18]
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Reactant: OC(CBr)C(F)(F)F
Product: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCC(O)C(F)(F)F)nn1

Procedure:
The title compound was prepared by reacting 3-bromo-1,1,1-trifluoropropan-2-ol and butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylate using a similar method to that of reference example 4.
Reaction SMILES: [CH2:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH:3]([OH:10])[CH2:2]1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[CH:16][C:17](F)=[N:18][CH:19]=1>CC(N(C)C)=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:10][C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:7]([OH:9])=[O:8])[CH2:1][CH2:2]2)=[N:18][CH:19]=1
Reactant: O=C(O)C1CCC(O)CC1
Reactant: Fc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)[C@H]1CC[C@@H](Oc2ccc(Br)cn2)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A solution of (1S,4S)-4-hydroxycyclohexanecarboxylic acid (2.14 g, 14.9 mmol) in DMA (10 mL) was added to a stirred suspension of NaH (1.32 g, 30.2 mmol) in DMA (15 mL) at 0° C. where it was stirred for 10 min. The suspension was taken off the cooling bath and 5-bromo-2-fluoropyridine (1.53 mL, 14.87 mmol, CAS 766-11-0) was added followed by DMA (10 mL). The reaction was heated at 100° C. for 2.5 h. The solvent was evaporated and DCM and 2M HCl were added, the phases separated and the aqueous phase was extracted with DCM (2×50 mL). The combined organics were dried over MgSO4, filtered and evaporated. The remaining crude was purified by flash chromatography using 5-75% EtOAc (1% HOAc) in heptane to afford the title compound (1.86 g, 42%) as solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=3)[S:12][C:3]=12.[CH3:21][NH:22][CH3:23].CN(C)C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.ClCCl.C(O)(=O)C>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:22]([CH3:23])[CH3:21])=[CH:15][CH:14]=3)[S:12][C:3]=12
Reactant: N#Cc1cnc2cc(-c3ccc(C=O)cc3)sc2c1Cl
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(-c2cc3ncc(C#N)c(Cl)c3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of 7-chloro-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (700 mg, 2.34 mmol) and 6.0 mL of 2.0 M dimethylamine in tetrahydrofuran in 30 mL of dichloromethane and 5 mL of dimethylformamide is cooled to 0–5° C. Sodium triacetoxyborohydride (2.5 g, 11.7 mmol) is added in portions and after 5 minutes 0.10 mL of acetic acid is added. The mixture is stirred at room temperature for 2 hours then quenched by the addition of ice water and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of dichloromethane to 10% methanol in dichloromethane to provide 496 mg (65%) of 7-chloro-2-{4-[(dimethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp 166–168° C.; 1H NMR (DMSO-d6) δ 2.21 (s, 6H), 3.52 (s, 2H), 7.48 (d, J=8 Hz, 2H), 7.95 (d, J=8 Hz, 2H), 8.28 (s, 1H), 9.11 (s, 1H); MS 328.1, 330.1 (M+H)+; HRMS found: 328.06622.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C.C1COCC1.C(OCC)C>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1ccccc1CCl
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(Cc2ccccc2F)CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A suspension of Mg (3.50 g, 144 mmol) in diethyl ether (75 mL) was treated with 2-fluorobenzyl chloride (19.0 g, 131 mmol), stirred until all the Mg dissolved, treated with N-benzyl 4-piperidone (27.2 g, 144 mmol) in RATIO THF/diethyl ether (40 mL), and stirred at room temperature until the reaction was complete by TLC analysis. The mixture was partitioned between ethyl acetate and saturated NH4Cl and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4), filtered, and concentrated to give a residue which was used without further purification. MS (ESI) m/e 300 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15]S(C(F)(F)F)(=O)=O)[CH:3]=1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([O:15][CH2:12][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][N:7]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Solvent: COCCOC
Product: N#Cc1c(OCCc2ccccn2)cc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester and sodium 2-(pyridin-2-yl)ethylate in DME. ES-MS m/e (%): 329 (M+Na+, 90), 307 (M+H+, 100).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24].C(=O)([O-])O.[Na+].C(OC(=O)C)C.CCCCCC>CC(C)=O.C(OCC)(=O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]1[C:10](=[O:24])[CH2:11][C@H:12]([OH:23])[C@@H:13]1[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCC[C@H](O)/C=C/[C@H]1C(=O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
14 4 mg of PGF2 α body (q) was dissolved in 0.8 ml of acetone in a 5 ml test tube and 12.4 μl of Jones reactant (2.4M) was added to the solution dropwise with a syringe at -30° C. in a stream of argon. The mixture was stirred at -30° C. for 30 minutes and then diluted with 1 ml of ethyl acetate. After 1 ml of a saturated aqueous solution of sodium hydrogencarbonate was added, the mixture was agitated vigorously. When the color of the aqueous layer shaded into green, 10 ml of ethyl acetate and 10 ml of a saturated aqueous solution of sodium hydrogen-carbonate were further added and the mixture was agitated vigorously. The organic layer and the aqueous layer were extracted with two 10 ml portions of ethyl acetate. The extract and the organic layer were dried together over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography over silica gel (1.4 g of silica gel manuf. by Merck; ethylacetate-hexane=1:3) to obtain 13.1 mg (91% yield) of PGD2 body (s).