Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:32])[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[Cl:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:32])[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[Cl:33])[CH:23]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(C=O)c2)cc1OC
Reactant: Nc1ccccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(CNc3ccccc3Cl)c2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.9 %

Procedure:
To a solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-formylbenzoate (332 mg, 0.697 mmol) and 2-chloroaniline (0.077 mL, 0.732 mmol) in anhydrous DCM (3.5 mL) was added acetic acid (0.042 mL, 0.732 mmol). The mixture was stirred at room temperature for 24 hours. NaBH(OAc)3 (369 mg, 1.74 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After addition of water (2.5 mL), the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a phase separator, and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography eluting with 1:1 DCM:EtOAc to afford the title compound as a white solid (274 mg, 67%).
Reaction SMILES: NN.[NH2:3][C:4]1[C:5]([N+:31]([O-:33])=[O:32])=[CH:6][C:7]2[C:13](=[O:14])[N:12]([C:15]3[CH:23]=[C:22]4[C:18]([CH:19]=[N:20][N:21]4S(C)(=O)=O)=[CH:17][CH:16]=3)[CH2:11][CH2:10][N:9]([CH2:28][CH3:29])[C:8]=2[CH:30]=1>C1COCC1.CO>[NH2:3][C:4]1[C:5]([N+:31]([O-:33])=[O:32])=[CH:6][C:7]2[C:13](=[O:14])[N:12]([C:15]3[CH:23]=[C:22]4[C:18]([CH:19]=[N:20][NH:21]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10][N:9]([CH2:28][CH3:29])[C:8]=2[CH:30]=1
Reactant: CCN1CCN(c2ccc3cnn(S(C)(=O)=O)c3c2)C(=O)c2cc([N+](=O)[O-])c(N)cc21
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: CCN1CCN(c2ccc3cn[nH]c3c2)C(=O)c2cc([N+](=O)[O-])c(N)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Hydrazine (0.6 mL) was added to a solution of 8-amino-1-ethyl-4-(1-methanesulfonyl-1H-indazol-6-yl)-7-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (1.1 g, 2.5 mmol) in 1:1 THF/MeOH (20 mL). The solution was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to afford 8-amino-1-ethyl-4-(1H-indazol-6-yl)-7-nitro-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-one (815 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:8](=[C:9]([CH3:15])[C:10]=1[CH2:11][C:12]([CH3:14])=[CH2:13])[N:7](C=O)[CH2:6][CH2:5]2.Cl.[OH-].[Na+]>CO>[CH3:13][C:12]1([CH3:14])[O:1][C:2]2=[C:3]([CH3:18])[C:4]3[CH2:5][CH2:6][NH:7][C:8]=3[C:9]([CH3:15])=[C:10]2[CH2:11]1
Reactant: C=C(C)Cc1c(C)c2c(c(C)c1O)CCN2C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c2c(c(C)c3c1NCC3)OC(C)(C)C2
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
2,3-Dihydro-5-hydroxy-4,7-dimethyl-6-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde (491 mg, 2.0 mmol) was dissolved in methanol (6 ml). To the solution was added concentrated hydrochloric acid (6 ml) and stirred for 3 hours with heating under reflux. The reaction mixture was cooled to 0° C., made weakly basic with 12N sodium hydroxide, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) and crystallized from hexane to obtain 330 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([O:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][NH:28][C:29]4=O)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:40])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([O:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][N:28]=[C:29]4[Cl:40])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2cnc3c(-c4cccnc4Oc4c(C)ccc5c(=O)[nH]ccc45)ncnc32)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cnc3c(-c4cccnc4Oc4c(C)ccc5c(Cl)nccc45)ncnc32)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-6-methylisoquinolin-1(2H)-one (0.76 g, 1.5 mmol) in phosphorous oxychloride (10 mL, 107 mmol) was stirred in a 100° C. oil bath for 1.0 h. The reaction mixture was allowed to cool to RT, diluted with toluene (100 mL) and concentrated in vacuo. The residue was partitioned between DCM (100 mL) and satd NaHCO3 (70 mL). The aqueous layer was extracted with DCM (50 mL). The combined organic layers were washed with satd NaHCO3 (50 mL), water (50 mL) brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 960 mg as a dark red solid. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with a gradient of 50% to 80% EtOAc in CH2Cl2, to provide 5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-1-chloro-6-methylisoquinoline as a clear viscous oil that solidified to a white solid upon standing. MS (ESI, pos. ion) m/z: 509.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[N:21]=[CH:20][C:19]4[C:14](=[CH:15][C:16]([O:22][CH:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[CH:17][CH:18]=4)[N:13]=3)=[CH:10][C:4]=2[NH:3]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:26]1[CH2:27][CH2:28][CH:23]([O:22][C:16]2[CH:15]=[C:14]3[C:19]([CH:20]=[N:21][C:12]([NH:11][C:9]4[CH:8]=[CH:7][C:5]5[NH:6][C:2](=[O:1])[NH:3][C:4]=5[CH:10]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Nc4ccc5[nH]c(=O)[nH]c5c4)nc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2ccc(Nc3ncc4ccc(OC5CCNCC5)cc4n3)cc2[nH]1
Yield: 30 %

Procedure:
A solution of crude tert-butyl 4-(2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-ylamino) quinazolin-7-yloxy)piperidine-1-carboxylate in 30% TFA/DCM was stirred at room temperature for 30 min. The solvent was evaporated and crude was purified by semi-prep HPLC to provide pure product in 30% yield ES/MS m/z 377.1 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH2:13][CH2:14][C:15]1[N:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-:24].[K+].[K+].OO>CS(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[CH2:13][CH2:14][C:15]1[N:20]=[C:19]([C:21]([NH2:22])=[O:24])[CH:18]=[CH:17][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(-c2ccccc2)nc1CCc1cccc(C#N)n1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1cc(-c2ccccc2)nc1CCc1cccc(C(N)=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)-picolinonitrile (10 mg, 0.035 mmol) in dimethyl sulfoxide (2 mL) at 0° C. was added potassium carbonate (24 mg, 0.175 mmol) and hydrogen peroxide (12 mg, 0.350 mmol). After stirring at room temperature for 1 h, the mixture was quenched with sat. NaHSO4 (aq.), and extracted with EtOAc (30 mL×2). The organic phase was dried and concentrated under reduced pressure. The residue was purified by prep-HPLC to give a white solid (3 mg). MS (ESI): m/z 307 [M+H]+.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([CH2:14]C(O)=O)#[N:13].O.Cl>N1C=CC=CC=1>[C:12]([CH:14]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:6]1)#[N:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N#CCC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N#CC=C1OC(=O)c2ccccc21
Reaction time: 6 h

Procedure:
A finely powdered mixture of phthalic anhydride (34 g.; 0.23 mole) and cyanoacetic acid (22 g.; 0.26 mole) was dissolved in dry pyridine (28 ml) and the mixture stirred for 6 hours at 60°-70° C. After cooling overnight the dark solid was treated with water (800 ml) and brought to pH 4-5 with hydrochloric acid. The resulting yellow solid was filtered off, washed well with water and recrystallised from glacial acetic acid, m.p. 178°-180° C (lit. m.p. 195° C).
Reaction SMILES: CC(=C[CH2:5][CH2:6][CH:7]([CH3:22])[CH2:8][C:9](=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[CH3:22][CH:7]1[CH2:6][CH2:5][CH:20]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:21])[CH2:8]1
Reactant: C=CCCCCCCCCCC(=O)CC(C)CCC=C(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: CC1CCC=CCCCCCCCCCC(=O)C1
Yield: 48.4 %

Procedure:
Grubbs' Catalyst, 2nd generation (benzylidene [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene] dichloro (tricyclohexylphosphine) ruthenium) (560 mg, 0.066 mmol, 2 mol %), was added to a solution of 2,6-dimethyl-nonadeca-2,18-dien-8-one (1 g, 3.3 mmol, prepared as above in EXAMPLE IV) in dichloromethane at room temperature. The reaction mixture was stirred at reflux for 12 hours. The reaction mixtures was subsequently concentrated and then chromatographed on silica with ethyl acetate in hexanes (2%) as the eluent providing 3-methyl-cyclohexadec-6-enone as a colorless oil (0.4 g). This oil was then filtered through a slurry of silica gel/activated charcoal.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[OH:8][C@@H:9]1[CH2:13][N:12]([CH2:14][C:15]2[CH:16]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:11](=[O:32])[CH2:10]1.O>ClCCl>[CH3:22][O:21][C:18]1[C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)=[CH:16][C:15]([CH2:14][N:12]2[C:11](=[O:32])[CH2:10][C@H:9]([O:8][C:6](=[O:7])[NH2:5])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(CN2C[C@@H](O)CC2=O)cc1-c1cccc([N+](=O)[O-])c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN2C[C@@H](OC(N)=O)CC2=O)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 20 mL vial with a stir bar was added chlorosulfonyl isocyanate (42 mg, 0.30 mmol), 1 mL dichloromethane, then P-248 (51.3 mg, 0.15 mmol) in 2 mL of dichloromethane. The reaction was stirred at room temperature for 18 hours after which 2 mL of water was added and the mixture was stirred at room temperature for 30 minutes. The layers were separated and the aqueous was extracted with dichloromethane. The combined organics were concentrated and then purified by preparative layer TLC using 50% acetone/dichloromethane to obtain P-253 (12.4 mg, 21%) as an off-white semi-solid. 1H NMR (400 MHz, DMSO-d6) 8.30 (s, 1H), 8.20 (dd, J=2.1, 8.6 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.33-7.26 (m, 2H), 7.16 (d, J=9.0 Hz, 1H), 6.59 (br. s., 2H), 5.04 (t, J=5.8 Hz, 1H), 4.49-4.30 (m, 2H), 3.80 (s, 3H), 3.46-3.38 (m, 1H), 3.21 (d, J=11.4 Hz, 1H), 2.78 (dd, J=6.9, 17.5 Hz, 1H), 2.23 (d, J=18.1 Hz, 1H) ppm. LC/MS=100.0%, 386.1 (APCI+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[N:10]([C:11]([S:17][CH3:18])=[N:12][CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1.O.[C:20](OC(=O)C)(=[O:22])[CH3:21]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]([C:20](=[O:22])[CH3:21])=[C:15]3[N:10]([C:11]([S:17][CH3:18])=[N:12][CH:13]=[CH:14]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CSc1nccc2cc(-c3ccc(F)cc3)nn12
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CSc1nccc2c(C(C)=O)c(-c3ccc(F)cc3)nn12
Temperature: 110 °C
Reaction time: 96 h
Yield: 70 %

Procedure:
To a slurry of 2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidine (1.5 g, 5.9 mmol) in acetic anhydride (10 mL) was added 4 drops of sulfuric acid. The reaction mixture was heated to 80° C. for 2 hours, to 110° C. for 2 hours, and to reflux for 2 hours. The solution was allowed to cool to room temperature and stirred for 4 days. The mixture was poured into water (350 mL) and extracted with ethyl acetate (2×75 mL). The organic phase was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 2:98 acetone:dichloromethane to yield 1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone (1.24 g, 70%). 1H NMR (DMSO): δ 8.12 (d, 1H), 7.98 (d, 1H), 7.65 (dd, 2H), 7.24 (m, 2H), 2.77 (s, 3H), 2.23 (s, 3H). MS m/z302 (M+1).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:26]=[CH:25][CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:10]=1[OH:22])=O)[CH3:2].COCCOC(/N=N/C(OCCOC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([S:3][C:4]1[C:5]([C:6]2[O:22][C:10]3[CH:11]=[CH:12][C:13]([C:15]([F:21])([F:20])[C:16]([F:18])([F:19])[F:17])=[CH:14][C:9]=3[N:8]=2)=[CH:23][CH:24]=[CH:25][N:26]=1)[CH3:2]
Reactant: CCSc1ncccc1C(=O)Nc1cc(C(F)(F)C(F)(F)F)ccc1O
Agent: COCCOC(=O)/N=N/C(=O)OCCOC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCSc1ncccc1-c1nc2cc(C(F)(F)C(F)(F)F)ccc2o1
Temperature: 50 °C
Reaction time: 4 h
Yield: 64.4 %

Procedure:
A mixture of 0.57 g of 2-ethylsulfanyl-N-[2-hydroxy-5-(pentafluoroethyl)phenyl]nicotinamide, 0.54 g of DMEAD, 0.57 g of triphenylphosphine and 6 ml of THF was stirred at 50° C. for 4 hours. A saturated aqueous ammonium chloride solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.35 g of 2-(2-ethylsulfanylpyridin-3-yl)-5-(pentafluoroethyl)benzoxazole (hereinafter, referred to as Compound of Present Invention 36).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]#[N:30])[N:24]=3)[CH:17]=2)=[CH:12][CH:11]=1)(C)(C)C>C(O)=O>[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]#[N:30])[N:24]=3)[CH:17]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2cccc(Oc3ccnc(C#N)n3)c2)cc1
Solvent: O=CO
Product: N#Cc1nccc(Oc2cccc(-c3ccc(CCN)cc3)c2)n1

Procedure:
A solution of {2-[3′-(2-cyano-pyrimidin-4-yloxy)-biphenyl-4-yl]-ethyl}carbamic acid tert-butyl ester (38 mg) in formic acid (0.35 ml) is stirred at rt for 1 h. This solution is evaporated under reduced pressure. The remaining oil is treated with diethyl ether to obtain crystals of 4-(4′-aminoethyl-biphenyl-3-yloxy)-pyrimidine-2-carbonitrile as salt with formic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@@H:12]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=[O:14].C([O-])(O)=O.[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@@H:12]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=[O:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Yield: 80.1 %

Procedure:
2-Chloro-4-fluorobenzonitrile (2.13 g, 13.8 mmol), (2S)-2-amino-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (2.6 g, 13.8 mmol) and NaHCO3 (3.5 g, 41.4 mmol) in DMSO (70 mL) and H2O (10 mL) were stirred at 95° C. for 15 h. After cooling, the reaction mixture was diluted with H2O (100 mL) and washed with Et2O (100 mL). The H2O layer was acidified to Congo Red midpoint and extracted with Et2O (2×). The combined organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated to give the titled product (3.59 g, 80%) as a foam. 1H-NMR (CDCl3) δ: 1.45 (9H, s), 2.89 (2H, m), 3.54 (1H, m), 4.42 (1H, m), 6.55 (1H, d, J=8.8 Hz), 6.70 (1H, s), 7.43 (1H, d, J=8.4 Hz). LC-MS (ES) m/e 325.4 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])/[CH:2]=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[P:11]([O-:16])([O:14][CH3:15])[O:12][CH3:13]>C[O-].[Na+]>[CH3:13][O:12][P:11]([CH:2]([C:1]([O:9][CH3:10])=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])(=[O:16])[O:14][CH3:15]
Reactant: COP([O-])OC
Reactant: COC(=O)/C=C\C(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CC(C(=O)OC)P(=O)(OC)OC
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
20 ml of 5% sodium methylate solution are added dropwise to 144 g (1 mol) of dimethyl maleate and 110 g of dimethyl phosphite until the exothermic reaction is completed. The reaction mixture is stirred for a further 30 minutes at 100° C. and then freed from low volatility constituents.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([OH:22])[C:14]2[N:15]3[CH:21]=[N:20][CH:19]=[C:16]3[S:17][CH:18]=2)[CH2:11][C@@H:10]([O:23][Si](C(C)(C)C)(C)C)[CH2:9]1)=[O:7])[CH:3]=[CH2:4].C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([OH:22])[C:14]2[N:15]3[CH:21]=[N:20][CH:19]=[C:16]3[S:17][CH:18]=2)[CH2:11][C@@H:10]([OH:23])[CH2:9]1)=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1csc2cncn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(O)c1csc2cncn12
Reaction time: 0.33 h
Yield: 113.9 %

Procedure:
Concentrated hydrochloric acid (0.34 ml) is added dropwise to a solution of 372 mg of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidine (stereoisomer B), described in Synthesis Example 4-a), in 8.5 ml of dry acetonitrile under ice cooling (internal temperature 3° C.). The mixture is stirred in this state for 20 min and diluted with 50 ml of ethyl acetate, and the diluted solution is adjusted to pH 9.2 by addition of a 5% aqueous sodium hydrogencarbonate solution, followed by shaking. The organic layer is separated. The aqueous layer is extracted twice with 50 ml of ethyl acetate while adjusting the pH value to 9.2 by addition of a 5% aqueous sodium hydrogencarbonate solution. The organic layer is combined with the above organic layer, and the combined organic layers are dried over magnesium sulfate, followed by filtration and the removal of the solvent by evaporation under reduced pressure to give 313 mg of crude (3R,5S)-1-allyloxycarbonyl-3-hydroxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidine (stereoisomer B) as a slight yellow viscous material.
Reaction SMILES: O[CH2:2][C:3]1([CH2:16][O:17]S(C)(=O)=O)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].O>O1CCCC1>[CH2:2]1[C:3]2([CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:7][CH2:8]2)[CH2:16][O:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)COC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
A solution of 1,1-dimethylethyl 4-hydroxymethyl-4-methanesulfonyloxymethyl-1-piperidinecarboxylate (Description 68, 3 g, 9.3 mmol) in tetrahydrofuran (200 mL) was added dropwise to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 2.2 g, 55.8 mmol) in tetrahydrofuran (50 mL) and the mixture was stirred at room temperature for 72 hours. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3×400 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (80:20 increasing to 50:50), to give the title compound (1.5 g, 71%). m/z (ES+) 228 (M+1).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].CO[CH:11]([CH3:15])[C:12](=O)[CH3:13]>C1(C)C=CC=CC=1>[CH3:15][C:11]1[O:2][C:1]2[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=2[C:12]=1[CH3:13]
Reactant: COC(C)C(C)=O
Reactant: Oc1cccc(O)c1
Solvent: Cc1ccccc1
Product: Cc1oc2cc(O)ccc2c1C
Temperature: 90 °C
Reaction time: 10 h
Yield: 60.7 %

Procedure:
A mixture of 1.9 g of resorcinol, 1.8 g of 3-methoxy-2-butanone, 0.2 g of Amberlyst-15 and 2 ml of toluene was stirred at 90° C. for 10 hours. After cooling, the catalyst was separated, and the filtrate was concentrated. The residue was purified by column chromatography to give 1.7 g of 2,3-dimethyl-6-hydroxybenzofuran as pale yellow crystals. The crystals were dissolved in 20 ml of acetic acid, and 0.2 g of 5% palladium-carbon was added. The mixture was stirred at room temperature for 12 hours in an atmosphere of hydrogen. The crude product was purified by column chromatography to give 1.5 g (yield 54%) of the desired product as a brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:12]=[CH:11]/[C:10]([O:14][CH3:15])=[O:13])[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: C=CC(=O)OC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cc(Cl)cc(Cl)c1
Temperature: 80 °C

Procedure:
To 1,3-dichloro-5-iodobenzene (300 mg, 1.099 mmol) and methyl acrylate (0.099 ml, 1.099 mmol) in DMF (10 ml) under nitrogen was added [Pd(t-BuP)]2 (56.1 mg, 0.110 mmol) and triethylamine (0.306 ml, 2.199 mmol). The reaction mixture was heated to 80° C. for 2 h. The reaction mixture was diluted with EtOAc and filtered through a silica cartridge (2 g). The organic solution was washed with water, saturated sodium bicarbonate solution, water and brine. The organic portion was dried using a phase separating column and the solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][C:6]=2[C:5]=1[C:12]([O:14]C)=O)=[C:2]=[S:3].[CH3:16][C:17]1[N:21]([CH2:22][CH2:23][CH2:24][NH2:25])[CH:20]=[N:19][CH:18]=1>>[CH3:16][C:17]1[N:21]([CH2:22][CH2:23][CH2:24][N:25]2[C:12](=[O:14])[C:5]3[C:6]4[CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:20]=[N:19][CH:18]=1
Reactant: Cc1cncn1CCCN
Reactant: COC(=O)c1c(N=C=S)sc2c1CCC2
Product: Cc1cncn1CCCn1c(=S)[nH]c2sc3c(c2c1=O)CCC3

Procedure:
The compound was synthesized starting from methyl 5,6-dihydro-2-isothiocyanato-4H-cyclopenta[b]thiophene-3-carboxylate (0.10 g, 0.42 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.058 g, 0.42 mmol) as described above.