Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][OH:23].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][O:23][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: CN(C)CCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 48 h
Yield: 71.8 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 3-dimethylamino-1-propanol (69 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 67 mg (0.28 mmol, 71%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 241 (M+1)+, calc. 241 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]([O:11]C)=[O:10])[CH2:6][CH2:5][CH2:4][O:3]1.O.CO.[OH-].[Na+]>C1COCC1>[O:1]=[C:2]1[N:7]([CH2:8][C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][O:3]1
Reactant: COC(=O)CN1CCCOC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CN1CCCOC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of 0.068 g (0.39 mmol) of methyl (2-oxo-1,3-oxazinan-3-yl)acetate from step B above in 6 mL of THF and 2 mL of water and 2 mL of methanol was added 0.60 mL (1.2 mmol) of an aqueous 2.0 M sodium hydroxide solution. The resulting mixture was stirred at ambient temperature for 3 h and then evaporated in vacuo to remove the methanol and THF. The aqueous phase was acidified with a 2 N hydrochloric acid solution until a pH of 2 was achieved and then extracted with a 30% isopropyl alcohol in chloroform mixture (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound as an off-white solid (0.06 g, 99%). 1H NMR (CD3OD, 500 MHz) δ: 4.32 (t, J=5.4 Hz, 2H), 4.03 (s, 2H), 3.41 (t, J=6.2 Hz, 2H), 2.10-2.05 (m, 2H). LC-MS: m/z (ES) 160 (MH)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:23]C(OCC)=O)[C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:29])[C:6]([C:30]([O:32]CC)=[O:31])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+].[ClH:37]>C(O)C>[ClH:37].[NH2:23][C:9]1[C:10]([F:22])=[C:11]([N:15]2[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]2)[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:29])[C:6]([C:30]([OH:32])=[O:31])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)Nc1c(F)c(N2CCNC(C)C2)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCN1

Procedure:
A mixture of ethyl 1-cyclopropyl-5-ethoxycarbonylamino-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate, 20% aqueous sodium hydroxide, and ethanol was refluxed for 12 hours. The reaction mixture was treated with activated carbon and adjusted at pH 1-2 with 10% hydrochloric acid. After cooling, the resulting crystals were collected by filtration and recrystallization from water-ethanol to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride, m.p. >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16](I)[C:15]([CH3:19])=[N:14]1.[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([CH:20]=[CH2:21])[C:15]([CH3:19])=[N:14]1
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C
Temperature: 70 °C

Procedure:
To a stirred solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)4-iodo-3-methylpyrazole (2.06 g) in dimethylformamide (25 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.1 g) and vinyltri-n-butyltin (2 ml). The mixture was heated at 70° C. for 2 hours. The reaction mixture was eyaporated and then partitioned between water and ether. The aqueous layer was separated and extracted twice with ether. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatigraphy on silica gel eluted with hexane: ether (9:1). Combination and evaporation of appropriate fractions gave a yellow solid which was further purified by reverse phase high performance chromatography on C18 silica eluted with acetonitrile: methanol: water (40:10:50). Combination and evaporation of appropriate fractions gave the title compound as a white solid, m.p.68.1-68.7° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][NH2:13]>C(OCC)C>[CH3:12][NH:13][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CN
Solvent: CCOCC
Product: CNc1nc(SC)ncc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Through a 5° C. solution of 14.5 g (78.1 mmol) of 4-chloro-2-(methylthio)-5-pyrimidinecarbonitrile in 800 mL of diethyl ether is bubbled methylamine gas for a period of 15 minutes. The reaction mixture is allowed to warm to room temperature, set overnight, and filtered. The solids are washed with diethyl ether, then efficiently with 50 mL of water, and dried to give 12.0 g (81%) of the title compound: mp 189-190° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[C:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.I[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:14][CH2:16][CH3:17])[C:6]([CH3:12])([CH3:13])[CH2:7][CH2:8][CH2:9]2
Reactant: CC1(C)CCCc2cc(Br)c(O)cc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc2c(cc1Br)CCCC2(C)C

Procedure:
A mixture of 3-bromo-8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-ol (Compound A-2, 5.77 g, 22.62 mmol); iodoethane (7.2 mL, 90.5 mmol), and potassium carbonate (4.68 g, 34 mmol) in acetone (50 mL) was stirred at 70° C. overnight. The solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, 2.5% ethyl acetate in hexane) to afford the title compound as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].Cl[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>CN(C)C=O>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][N:4]1[C:5](=[O:6])[CH2:7][NH:1][C:2]1=[O:3]
Reactant: O=C1CNC(=O)N1
Reactant: ClCc1ccccn1
Solvent: CN(C)C=O
Product: O=C1CNC(=O)N1Cc1ccccn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
5.0 g of hydantoin, 8.2 g of 2-chloromethylpyridine and 6.9 g of potassium carbonate anhydride were dissolved into 100 ml of N,N-dimethylformamide and these were stirred under room temperature for 1 hour and at 80° C. for 30 minutes. The N,N-dimethylformamide was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluate solvant; chloroform:methanol =9:1). Thus 4.8 g of the captioned compound was thus obtained.
Reaction SMILES: [C:1]([C:9]1[N:10]2[C:14](=[CH:15][CH:16]=1)[C:13](C(OCC)=O)([C:17]([O:19]CC)=[O:18])[CH2:12][CH2:11]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)C.[OH-].[Na+]>[C:1]([C:9]1[N:10]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17]([OH:19])=[O:18])[CH2:12][CH2:11]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccc2n1CCC2C(=O)O
Temperature: 70 °C
Reaction time: 24 h
Yield: 2.3 %

Procedure:
A mixture of diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate (600 mg, I.69 mmol) in diethyl ether and 20% aqueous sodium hydroxide (10 mL) was refluxed with vigorous stirring for 24 hours. The aqueous layer was washed with ether (20 mL), and acidified with concentrated hydrochloric acid. The aqueous layer was washed with ethyl acetate (3×20 mL). The ethyl acetate extracts were combined and warmed at 70° C. for 4 hours. The ethyl acetate solution was concentrated under reduced pressure to yield 400 mg (93%) of 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid as a pure solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Nc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2nc3ccccc3o2)cc1
Yield: 65.1 %

Procedure:
2-aminophenol 7.86 g (72 mmole), 4-bromobenzaldehyde 16 g (87 mmole), and 2.8 g of PTSA (14 mmole) was stirred in 150 ml of Toluene, the reaction mixture was then heated to reflux for 16 hours, after cooling, the reaction mixture was extracted with water, and then the organic layer was evaporated to dry, the residue was then recrystallized with acetone to get 12.85 g of product (yield=65.12%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([CH3:10])=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)[CH:7]=[CH:6][N:5]=1.Cl[C:22]1[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=1>C1COCC1>[C:18]([N:15]1[CH2:14][CH2:13][N:12]([CH2:11][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([NH:3][C:22]3[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=3)[C:9]=2[CH3:10])[CH2:17][CH2:16]1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCN(Cc2ccnc(N)c2C)CC1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2ccnc(Nc3ncc(C#N)s3)c2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (60% dispersion, 14 mg, 0.35 mmol) was stirred in 1 mL anhydrous THF. 1-[4-(2-Amino-3-methyl-pyridin-4-ylmethyl)-piperazin-1-yl]-ethanone (0.039 g, 0.157 mmol) was added followed, after 10 min by the addition of 2-chloro-thiazole-5-carbonitrile (0.027 g, 0.19 mmol). The reaction was stirred at RT for 30 min then was heated to reflux. After 2 h an additional 0.010 g NaH (0.25 mmol) was added. After 1 h the reaction was cooled to RT and quenched with water. The pH was adjusted to 7 with 1M HCl and the mixture was extracted 3× with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC to provide the pure titled compound. TFA salt: 1H NMR (CD3OD) δ8.37 (d, 1H, J=5.1 Hz), 8.08 (s, 1H), 7.19 (d, 1H, J=5.1 Hz), 4.45 (s, 2H), 3.81 (bs, 4H), 3.35 (s, 4H), 2.47 (s, 3H), 2.15 (s, 3H). MS [M+H]+=357.3.
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].[NH:19]([C:21]1[N:22]=[N:23][C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:25]([CH3:27])[N:26]=1)[NH2:20]>C(Cl)Cl>[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]([NH:20][NH:19][C:21]1[N:22]=[N:23][C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:25]([CH3:27])[N:26]=1)=[O:18])=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: Cc1nc(NNC(=O)CNC(=O)OC(C)(C)C)nnc1-c1ccccc1
Yield: 75.8 %

Procedure:
The reaction of ethyl chloroformate (2.441 g) with N-t-butoxycarbonylglycine (3.938 g) in methylene chloride under ice cooling gave a solution comprising the mixed acid anhydride, which was reacted with 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.015 g) in a similar manner to that of Example 17-(1) to give 3-[2-(N-t-butoxycarbonylglycyl)hydrazino]-5-methyl-6-phenyl-1,2,4-triazine (4.068 g). The purification was conducted with column chromatography on silica gel (80 g) using a mixture of methylene chloride and methanol (30:1) as an eluent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]([OH:19])=O)=[C:6]2[C:10]=1[O:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:7]2.Cl.Cl.[NH2:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[CH:23]([NH:22][C:17]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:10]3[O:9][C:8]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[N:7][C:6]=13)=[O:19])[CH2:24]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1ccc(Br)c2oc(-c3ccccc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CN2CCC1CC2)c1ccc(Br)c2oc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.9 %

Procedure:
A mixture of 7-bromo-2-phenylbenzo[d]oxazole-4-carboxylic acid (200 mg, 0.62 mmol), (±)-3-aminoquinuclidine dihydrochloride (148 mg, 0.74 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (237 mg, 1.24 mmol) and 1-hydroxybenzotriazole (167 mg, 1.24 mmol) in DMF (2.5 mL) was stirred 5 min at room temperature, then triethylamine (0.34 mL, 2.48 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) followed by semi-preparative HPLC to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-7-bromo-2-phenylbenzoxazole-4-carboxamide (34 mg, 13%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.41 (d, J=7.0 Hz, 1H), 8.29-8.26 (m, 2H), 8.09 (d, J=8.5 Hz, 1H), 7.66-7.57 (m, 4H), 4.31-4.27 (m, 1H), 3.51 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.15-2.85 (m, 4H), 2.81 (dd, J=14.0, 4.0 Hz, 1H), 2.17-2.14 (m, 1H), 2.07-2.02 (m, 1H), 1.79-1.61 (m, 3H); MS (ESI+) m/z 426 (M+H); HPLC>99% (AUC), tR=13.09 min.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:11])[C:22]2[CH:23]=[C:18]([F:17])[CH:19]=[CH:20][C:21]=2[F:24])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Fc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCC(C(=O)c2cc(F)ccc2F)CC1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
To a stirred suspension of 100 g of 1-acetyl-4-piperidine carboxylic acid chloride in 500 ml of 1,4-difluorobenzene was added in aliquots, 211 g of anhydrous aluminum chloride. The mixture was stirred at reflux under nitrogen for 3 hrs and allowed to cool to room temperature. The mixture was poured into ice and extracted twice with ethyl acetate. The extracts were washed with saturated sodium bicarbonate solution and dried over anhydrous potassium carbonate. Filtration followed by evaporation of the solvent provided an oil which crystallized on standing. The solid was washed with cyclohexane and dried to provide 73.3 g (52.1%) of 1-acetyl-4-(2,5-difluorobenzoyl)piperidine: mp 82°-87° C. Recrystallization from a mixture of isopropyl alcohol, diisopropyl ether and hexane provided product with mp 93°-95° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=O)[C:5]=1[OH:12])[CH:2]=[CH2:3].CCN(CC)CC.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[CH2:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]2[C:5]=1[O:12][C:20](=[O:22])[CH:21]=[CH:7]2)[CH:2]=[CH2:3]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCc1cccc(C=O)c1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCc1cccc2ccc(=O)oc12
Temperature: 160 °C
Yield: 40 %

Procedure:
To a solution of 3-allylsalicylaldehyde (1.62 g, 10.0 mmol) in acetic anhydride (2 mL) in a 5 mL Emrys process vial was added Et3N (2.0 ml). The reaction was heated at 160° C. for 45 min in an Emrys Optimizer Microwave reactor then was cooled to RT. The reaction was diluted with 50 mL of ethyl acetate, the organic layer was washed with aqueous ammonium chloride, aqueous sodium chloride, dried (Na2SO4), and concentrated. Purification of the residue by flash chromatography on silica gel (gradient elution: 5% to 30% Ethyl acetate/Hexanes) yielded the title compound (750 mg, 40%) as a colorless oil: MS (ES) m/e 186.9 (M+H)+.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][CH:21](C(=O)C)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].ClC1C=CC=[C:34]([C:38]([O:40]O)=[O:39])C=1>ClCCl>[C:38]([O:40][CH:21]1[CH2:20][CH:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:22]1)(=[O:39])[CH3:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)C1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Yield: 45.2 %

Procedure:
To a stirred solution of 1-(3-[tert-butyl(diphenyl)silyl]oxycyclobutyl)ethanone (0.65 g, 0.0018 mol) in dichloromethane (10 mL) at 0° C. was added sodium bicarbonate (0.39 g, 0.0046 mol) and m-chloroperbenzoic acid (1.0 g, 0.0046 mol) with stirring. The reaction was stirred at rt over night. LCMS showed incomplete reaction, another 2.5 eq. of mCPBA and NaHCO3 were added and the reaction was stirred for another day. The reaction was quenched with 20% aq. Na2S2O3 solution (50 mL) and stirred for a further 30 min at rt, then extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, concentrated and purified on silica gel with Combiflash (silica gel, 0-10% EtOAc/Hex) to give the desired product (0.3 g, 40%) as colorless oil. LCMS calculated for C22H29O3Si(M+H)+: 369.2. Found: 369.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][CH:22]([F:32])[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH:22]([F:21])[F:32])[CH:25]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1cccc(OC(F)F)c1
Product: O=C(NCc1cccc(OC(F)F)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 3-difluoromethoxy-benzylamine (46.6 mg, 0.39 mmol). The title compound was obtained as a solid (100 mg, 42% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.43 (1H, m), 8.98 (2H, s), 8.47 (1H, s), 7.39 (1H, m), 7.11 (1H, m), 7.06 (2H, m), 4.42 (2H, m), 3.32 (1H, m). MS m/z: 504.06, 506.07 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17]C)=O)[CH:10]=[N:9]1.[CH:19](OC)=O.[NH2:23][C:24]([NH2:26])=[S:25]>C1COCC1.CO>[CH3:7][N:8]1[CH:12]=[C:11]([CH2:13][C:14]2[C:15](=[O:17])[NH:23][C:24](=[S:25])[NH:26][CH:19]=2)[CH:10]=[N:9]1
Reactant: NC(N)=S
Reactant: COC=O
Reactant: COC(=O)CCc1cnn(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To a stirred ice-cooled solution of potassium tert-butoxide (8.41 g, 74.9 mmol) in dry THF (150 mL) under argon was added dropwise a solution of methyl 3-(1-methyl-1H-pyrazol-4-yl)propanoate (4.2 g, 24.97 mmol) and methyl formate (4.50 g, 74.9 mmol) in THF (150 mL). The mixture was then allowed to warm to room temperature and stirring continued overnight. After removing the solvent, thiourea (1.901 g, 24.97 mmol) and methanol (100 mL) was added. The mixture was heated at 50° C. overnight. After removing the solvent, water (10 mL) was added. and acidified to pH 3 with HCl. The mixture was stirred in ice bath for 1 h. Filtration then drying in vacuo at 50° C. overnight then afforded the title compound (2.8 g, 12.60 mmol, 50.4% yield). LCMS: rt=0.99 min, [M+H+]=223
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:26]=[C:25]([I:27])[CH:24]=[CH:23][C:21]=1[NH2:22].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:22][C:21]1[CH:23]=[CH:24][C:25]([I:27])=[CH:26][C:20]=1[F:19])[CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)Nc1ccc(I)cc1F
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (1.1 g, 4.06 mmol) and 2-fluoro-4-iodoaniline (800 mg, 3.38 mmol) in pyridine (15 mL) at −10° C. was slowly added phosphorus oxychloride (0.35 mL, 3.72 mmol) under an atmosphere of dry nitrogen. The mixture was stirred for 2 hours at −10° C. After removal of the solvent and the excess reagent by rotary evaporator, ice water was added. The mixture was extracted with dichloromethane and the organic layer washed with 1 M aqueous citric acid, brine, saturated aqueous sodium carbonate, brine and dried over sodium sulfate. The solvents were removed to give [(S)-1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-thiophen-2-yl-ethyl]-carbamic acid tert-butyl ester as a yellow viscous oil for use in the next step (1.52 g, 92%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:29][CH2:28][CH2:27][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:26])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11])=[O:7])(C)(C)C.C(N(CC)CC)C.[O:37]([CH2:44]C(Cl)=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>Cl.O1CCOCC1.C(Cl)Cl>[OH:26][CH:17]([C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:10](=[O:11])[C@@H:9]1[CH2:27][CH2:28][CH2:29][N:8]1[C:6](=[O:7])[CH2:44][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Reactant: O=C(Cl)COc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(COc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
(2S)-1-[N-(tert-Butoxycarbonyl)-L-prolyl]-2-(1-hydroxy-2-phenoxyethyl)pyrrolidine (996 mg) was dissolved in 4N hydrochloric acid/1,4-dioxane (12 ml), and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated to dryness, and the residue obtained was dissolved in methylene chloride (10 ml). After triethylamine (0.68 ml) was added thereto under ice-cooling, phenoxyacetyl chloride (0.34 ml) was dropwise added. After stirring the mixture under ice-cooling for 0.5 hour, and then at room temperature for 1.5 hours, the reaction mixture was poured into ice-water, and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, and saturated brine successively, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 1.05 g of the title compound.