Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][N:10]=[C:9]1[CH:13]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH3:25])[CH2:14][CH:15]=[CH2:16])=O)(C)(C)C.[OH-].[Na+].CCOC(C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:25][C:19]1[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH:13]([C:9]1[NH:10][CH2:11][CH2:12][N:8]=1)[CH2:14][CH:15]=[CH2:16]
Reactant: C=CCC(Oc1cccc(C)c1C)C1=NCCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCC(Oc1cccc(C)c1C)C1=NCCN1

Procedure:
2-[1-(2,3-dimethyl-phenoxy)-but-3-enyl]-4,5-dihydro-imidazole-1-carboxylic acid tert-butyl ester (120 mg) was dissolved in a solution of 10% trifluoroacetic acid in dichloromethane (5 ml). After 24 hours the mixture was shaken between NaOH (2M) and EtOAc and the organic phase dried with Na2SO4 and evaporated to yield 2-[1-(2,3-Dimethyl-phenoxy)-but-3-enyl]-4,5-dihydro-1H-imidazole as crystals m.p. 72-74° C.
Reaction SMILES: O=C1[C@@H]2C[C@@H](CN2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)S1.O[C@@H]([C@H]1C(=O)N2[C@@H]1[C@@H](C)C(S[C@H]1C[C@@H](C(=O)[NH:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([S:61](=[O:64])(=[O:63])[NH2:62])=[CH:57][CH:56]=3)NC1)=[C:29]2[C:33]([O:35]CC1C=CC([N+]([O-])=O)=CC=1)=[O:34])C.C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[CH3:29][C:33]([OH:35])=[O:34].[CH:60]1[C:55]([CH2:54][NH2:53])=[CH:56][CH:57]=[C:58]([S:61]([NH2:62])(=[O:63])=[O:64])[CH:59]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CN[C@H](C(=O)NCc4ccc(S(N)(=O)=O)cc4)C3)[C@H](C)[C@H]12
Agent: O=C1S[C@H]2C[C@@H]1N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)O
Product: NCc1ccc(S(N)(=O)=O)cc1
Temperature: -15 °C
Yield: 267.4 %

Procedure:
Intermediate 1 and (4R,5S,6S)-4nitrobenzyl 6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-3-(((3S,5S)-5-((4-sulfamoylbenzyl)carbamoyl)pyrrolidin-3-yl)thio)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (raw material 3) (2980 g, 5.01 mol) were dissolved in dimethylformamide, and the solution was cooled to −15° C. Triethylamine was added dropwise under nitrogen protection. After the reaction is over, ethyl acetate was added. The mixture was sequentially washed with water, dilute hydrochloric acid and saturated sodium bicarbonate, and the organic layer was dried over anhydrous sodium sulfate. The ethyl acetate layer was concentrated and the precipitate was filtered, and dried to obtain 3300 g of a solid (i.e. intermediate 2) with a yield of 79.46% and a purity of 94.75%.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.Cl[C:13]1[CH:14]=[C:15](OB(O)O)[CH:16]=[CH:17][CH:18]=1.[C:23](=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:23][C:13]1[CH:14]=[C:15]([C:2]2[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1nc(Br)sc1C
Reactant: OB(O)Oc1cccc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(-c2cccc(C)c2)sc1C
Yield: 69.7 %

Procedure:
0.3 g of methyl 2-bromo-5-methyl-1,3-thiazole-4-carboxylate and 0.2 g of 3-chlorophenylboric acid were dissolved in toluene, and 0.15 g of tetrakistriphenyl phosphine and 0.7 g of potassium carbonate were added. The reaction solution was heated under reflux for 4 hours in a nitrogen atmosphere. The reaction solution was cooled, filtered through Celite and evapoarated. The residue was purified by silica gel column chromatography, to give 0.2 g of methyl 2-(3-methylphenyl)-5-methyl-1,3-thiazole-4-carboxylate.
Reaction SMILES: C[Al](C)C.[NH4+:5].[Cl-].C.C[O:9][C:10]([C@@H:12]1[C@H:16]([CH3:17])[CH2:15][CH2:14][N:13]1[C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])=O>C1(C)C=CC=CC=1>[CH3:17][C@@H:16]1[CH2:15][CH2:14][N:13]([C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C@@H:12]1[C:10]([NH2:5])=[O:9]
Reactant: [NH4+]
Reactant: COC(=O)[C@@H]1[C@H](C)CCN1[C@@H](C)c1ccccc1
Agent: C
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C[C@@H]1CCN([C@@H](C)c2ccccc2)[C@@H]1C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trimethylaluminum in toluene (2 M, 6.46 mmol) was added dropwise to a mixture of NH4Cl (6.47 mmol) in toluene (3.2 mL) at 0° C. with the formation of methane gas. The reaction mixture was allowed to warm to rt, stirred for a further 15 min and then slowly treated with (2S,3R)-3-methyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid methyl ester (prepared as described in Tet. Lett. 1997, 38, 85-88) (6.47 mmol). After stirring for 56 h, the mixture was cooled to 0° C., quenched with 1M HCl and then washed with CH2Cl2 (3×). The aqueous phase was basified with a saturated solution of NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a colorless oil. ESI-MS: [M+H]+ 233; HPLC: tR 2.35 min (method A).
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:43])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=2)=[CH:17][CH:16]=1)[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O.[Cl:52]CCl>>[ClH:52].[CH3:42][O:41][C:26]1[CH:25]=[C:24]([CH2:23][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH:8]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[CH2:7][C:6]([OH:44])=[O:5])=[CH:16][CH:17]=2)=[O:43])[CH:29]=[CH:28][C:27]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]
Reactant: COc1cc(CC(=O)Nc2ccc(C(CC(=O)OC(C)(C)C)N3CCOCC3)cc2)ccc1NC(=O)Nc1ccccc1C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)Nc2ccc(C(CC(=O)O)N3CCOCC3)cc2)ccc1NC(=O)Nc1ccccc1C
Product: Cl
Reaction time: 1 h

Procedure:
A mixture of 3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-3-(morpholin-4-yl)-propanoic acid tert-butyl ester [100 mg, Reference Example 11(a)] anhydrous trifluoroacetic acid (3 ml) and dichloromethane (5 ml) allowed to stand at ambient temperature for 1 hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 1.0M hydrochloric acid. The aqueous layer was evaporated and the residue was triturated with a mixture of methanol and diethyl ether to yield the title compound (46 mg) as a white solid, m.p. 164-171° C. (amorphous). MS: MH+ 547.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[NH:13][CH:14]=[CH:15][N:16]=2)=[O:9])[CH:5]=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[N:13]([CH3:24])[CH:14]=[CH:15][N:16]=2)=[O:9])[CH:5]=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: Nc1nc(C(=O)NCc2ncc[nH]2)cc(-c2ccco2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccnc1CNC(=O)c1cc(-c2ccco2)nc(N)n1
Reaction time: 0.33 h
Yield: 56.9 %

Procedure:
A solution of 2-amino-6-(2-furyl)-N-(1H-imidazol-2-ylmethyl)pyrimidine-4-carboxamide (300 mg, 1.06 mmol) in DMF (15 mL) at room temperature was treated with NaH (44 mg, 1.11 mmol), stirred for 20 min, treated with MeI (99 μl, 1.58 mmol) and stirred at room temperature for 16 h. The mixture was poured into water (30 mL), extracted with EtOAc (3×10 mL) and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; EtOAc] to give the title compound (180 mg, 57%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH2:12][NH:13]C(OC(C)(C)C)=O)[C:6]=2[CH:21]=1.C[O-].[Na+].[Cl:25][CH:26]([F:28])[F:27]>CN(C)C=O>[ClH:25].[NH2:13][CH2:12][CH2:11][O:10][C:7]1[C:6]2[CH:21]=[C:2]([O:1][CH:26]([F:28])[F:27])[CH:3]=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(O)cc12
Reactant: FC(F)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: NCCOc1noc2ccc(OC(F)F)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
To a solution of 5-hydroxy-3-(2-(N-t-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole (100 mg) in dimethylformamide (4 ml) was added sodium methoxide (90 mg) and the mixture was stirred at room temperature for 10 minutes, then followed by introduction of chlorodifluoromethane gas for 20 minutes. The reaction mixture was poured into ice water (30 ml), extracted with ethyl acetate (twice each with 30 ml) and the combined extracted were dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (9/1) as an eluent, to give the title compound (19 mg, 16%) as a colorless powder.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:8][C:9]=1[CH2:10][C:11]#N)[CH2:2][CH2:3][CH3:4].[OH-:23].[Na+].Cl.[OH2:26]>C(O)(C)C>[CH2:1]([C:5]1[N:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:8][C:9]=1[CH2:10][C:11]([OH:26])=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: [OH-]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC#N
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC(=O)O
Temperature: 100 °C

Procedure:
1.1 g [4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-acetonitrile were dissolved in a mixture of 1 ml water and 6 ml isopropanol. 1.36 g Sodium hydroxide were added and the mixture heated to 100° C. After three hours the cooled reaction mixture was neutralized with concentrated hydrochloric acid and extracted three times with portions of 50 ml ethyl acetate. The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo to provide 1.15 g crude [4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-acetic acid as brown oil. This material was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH:12]1[CH2:16][C@@H:15]([C:17]([OH:19])=O)[C@H:14]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:13]1)(=[O:11])=[O:10].[NH2:29][CH2:30][C:31]#[N:32]>>[C:30]([CH2:31][NH:32][C:17]([C@@H:15]1[CH2:16][CH:12]([S:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])[CH2:13][C@H:14]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:19])#[N:29]
Reactant: O=C(O)[C@@H]1CC(S(=O)(=O)c2ccc(F)cc2Cl)C[C@H]1COc1ccc(F)cc1
Reactant: N#CCN
Product: N#CCNC(=O)[C@@H]1CC(S(=O)(=O)c2ccc(F)cc2Cl)C[C@H]1COc1ccc(F)cc1

Procedure:
The title compound was prepared in analogy to example 68 step 11 using (1R,2R)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-(4-fluoro-phenoxymethyl)-cyclopentanecarboxylic acid (epimeric mixture, example 143 and 144 step 6) and aminoacetonitrile. Light yellow foam gum (44%). MS (EI): 469.3 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]#[C:5][CH2:6][NH2:7])[CH2:3][CH2:2]1.S=[C:9]1[CH2:13][S:12][C:11](=[O:14])[NH:10]1>C(O)C>[CH:1]1([C:4]#[C:5][CH2:6][NH:7][C:9]2[CH2:13][S:12][C:11](=[O:14])[N:10]=2)[CH2:3][CH2:2]1
Reactant: NCC#CC1CC1
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(NCC#CC2CC2)CS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of 3-cyclopropylprop-2-yn-1-amine (4.61 g) in ethanol (50 mL) was added 4-thioxo-1,3-thiazolidin-2-one (3.24 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (4.20 g).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[H-].[Na+].[O:11]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:17]=2)=[N:12]1>C1COCC1>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:21]([C:19]1[S:20][C:16]([C:13]2[CH:14]=[CH:15][O:11][N:12]=2)=[CH:17][CH:18]=1)(=[O:22])=[O:23]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccon2)s1
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccon3)s2)c1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-amino-4-bromo-3-methylisoxazole (177 mg, 1.0 mmol) in dry THF (2 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.2 mmol) in dry THF (1 ml) at 0°-5° C. After stirring at 0°-5° C. for 5 min, the reaction was warmed to room temperature for 10 min to complete the reaction. The reaction mixture was re-cooled to 0° C., and 5-(3-isoxazolyl)thiophene-2-sulphonyl chloride (273 mg, 1.1 mmol), which had been dissolved in dry THF (2 ml), was added slowly. Stirring was continued for 1 h; during this period the reaction mixture slowly attained ambient temperature. THF was removed under reduced pressure. The residue was dissolved in water (10 ml), the pH was adjusted to 2-3 by adding concentrated HCl, and was extracted with methylene chloride (3×10 ml). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-isoxazolyl)thiophene-2-sulfonamide. The pure material was obtained by recrystallization using hexanes/ethyl acetate (160 mg, 41% yield), m.p. 120°-123° C.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][NH:18][N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].Br[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CCBr
Reactant: Fc1ccc(Br)c(OC2CCN(c3noc(-c4cc[nH]n4)n3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1

Procedure:
The title compound was prepared in a similar manner as described in Example 7 (step 4) from 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]piperidine, sodium hydride and ethyl 3-bromopropionate and obtained as the more polar major isomer.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=[O:39])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:39]=[C:27]1[CH2:28][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:9]=2[NH:22]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccn2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccccn4)cc3NC(=O)C2)c1
Yield: 85.5 %

Procedure:
Prepared from (2-amino-4-pyridin-2-ylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G19) (124 mg, 0.4 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (147 mg, 0.48 mmol) according to the general procedure K. The obtained material (199 mg) was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (124 mg).
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](C)=[O:5].[Cl:11][C:12]1[C:22]([Cl:23])=[C:21]([C:24](=O)[CH:25]=[C:26]([CH3:28])[CH3:27])[CH:20]=[CH:19][C:13]=1[O:14][CH2:15][C:16]([OH:18])=[O:17].[CH2:30](O)C>>[Cl:11][C:12]1[C:22]([Cl:23])=[C:21]([C:24]2[CH2:25][C:26]([CH3:28])([CH3:30])[CH2:27][C:4](=[O:5])[CH:3]=2)[CH:20]=[CH:19][C:13]=1[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCO
Reactant: CC(C)=CC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: [Na]
Product: CC1(C)CC(=O)C=C(c2ccc(OCC(=O)O)c(Cl)c2Cl)C1

Procedure:
To a stirred solution of sodium (1.449 g, 0.063 mole) in ethanol (150 ml) and ethyl acetoacetate (8.20 g, 0.063 mole) was added (2,3-dichloro-4-(3-methyl-1-oxo-2-butenyl)phenoxy]acetic acid (9.09 g, 0.03 mole). The reaction mixture was heated at reflux for 31/2 hours then the solvent was distilled at reduced pressure. The residue was acidified with hydrochloric acid, extracted with ether and sodium bicarbonate, acidified with hydrochloric acid, extracted with ether and methylene chloride, washed with water, dried over magnesium sulfate, and evaporated at reduced pressure to give 4.5 g of [2,3-dichloro-4-(5,5-dimethyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid which melted at 178°-180° C. after purification by chromatography on silica and recrystallization from 42 ml of acetonitrile.
Reaction SMILES: C(OC(=O)CN1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O)C1C=CC=CC=1.[O:32]=[C:33]1[N:39]([CH2:40][C:41]([NH:43][C@H:44]2[CH2:48][C:47](=[O:49])[O:46][CH:45]2[O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:42])[C:38]2[CH:58]=[CH:59][CH:60]=[CH:61][C:37]=2[N:36]([C:62](=[O:66])[CH2:63]OC)[CH2:35][C@@H:34]1[NH:67][C:68](=[O:78])[C:69]1[CH:74]=[C:73](Cl)[C:72](O)=[C:71](Cl)[CH:70]=1>>[O:32]=[C:33]1[N:39]([CH2:40][C:41]([NH:43][C@H:44]2[CH2:48][C:47](=[O:49])[O:46][CH:45]2[O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:42])[C:38]2[CH:58]=[CH:59][CH:60]=[CH:61][C:37]=2[N:36]([C:62](=[O:66])[CH3:63])[CH2:35][C@@H:34]1[NH:67][C:68](=[O:78])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: COCC(=O)N1C[C@H](NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N(CC(=O)N[C@H]2CC(=O)OC2OCc2ccccc2)c2ccccc21
Agent: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Product: CC(=O)N1C[C@H](NC(=O)c2ccccc2)C(=O)N(CC(=O)N[C@H]2CC(=O)OC2OCc2ccccc2)c2ccccc21

Procedure:
was synthesized from 600b via methods used to prepare 688a from 600b afford 30 mg of 693, 1H NMR (CD3OD) δ1.7(s, 3H), 1.8(s, 3H), 2.51(d, 1H, 2.6(m, 1H), 2.8(m, 1H), 3.0(m, 1H), 3.75(br. d, 2H), 4.0-4.1(dd, 2H), 4.5-5.0(m, 6H), 5.45(s, 1H), 5.55(s, 1H), 7.15-7.85(m, 14H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[O:26][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1ccccc1
Reactant: BrCC1CCCC1
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CCCC3)n(Cc3ccccc3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 2-(1-benzyl-5,6-difluoro-1H-benzoimidazol-2-yl)-5-chloro-phenol (Example 48, intermediate a) and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Colorless powder (33%). MS (Turbo Spray): m/z=453.0 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.N[NH:24][C:25]([NH2:27])=[S:26].[C:28]([OH:34])([C:30](F)(F)F)=O>>[NH2:10][C:9]1[CH:6]=[CH:5][CH:4]=[CH:3][C:30]=1[C:28](=[O:34])[CH2:12][CH2:13][NH:14][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:12]([C:13]3[S:26][C:25]([NH2:27])=[N:24][N:14]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1cnc(-c2ccc(CBr)cc2)c(-c2ccccc2)c1
Reactant: NNC(N)=S
Product: Nc1nnc(-c2cnc(-c3ccc(CNCCC(=O)c4ccccc4N)cc3)c(-c3ccccc3)c2)s1
Temperature: 60 °C

Procedure:
A mixture of the nitrile (0.014 g, 0.032 g) and thiosemicarbazide (0.004 g, 0.049 mmol) in TFA was heated to 60° C. for 15 hr. The mixture was then cooled and concentrated. The residue was taken up in DMF and purified by reverse phase HPLC (5% CH3CN:95% H2O:0.01% TFA to 95% CH3CN: 5% H2O: 0.01% TFA). NMR (500 MHz, d6 DMSO) δ 12.98 (bs, 1H), 8.77 (bs, 2H), 8.08 (d, 1H, J=2.19 Hz), 7.95 (d, 2H, J=7.1 Hz), 7.70 (d, 1H, J=6.84 Hz), 7.67-7.60 (m, 3H), 7.50 (t, 2H, J=7.81 Hz) 7.38-7.25 (m, 7H), 6.79 (d, 1H, J=7.6 Hz), 6.57 (t, 1H, J=8.05 Hz), 4.22 (t, 2H, J=5.61 Hz), 3.39 (t, 2H, J=6.8 Hz), 3.28-3.15 (m, 2H) LRMS m/z (M+H) Calcd: 507.0, found: 507.0
Reaction SMILES: [C:1]([C@H:4]1[CH2:7][C@@H:6]([CH2:8][CH:9]=[O:10])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2]>C1(C)C=CC=CC=1>[OH:10][CH2:9][CH2:8][C@@H:6]1[CH2:7][C@H:4]([C:1](=[O:3])[CH3:2])[C:5]1([CH3:12])[CH3:11]
Reactant: CC(=O)[C@H]1C[C@@H](CC=O)C1(C)C
Solvent: Cc1ccccc1
Product: CC(=O)[C@H]1C[C@@H](CCO)C1(C)C
Temperature: 90 °C

Procedure:
2-((1S,3S)-3-acetyl-2,2-dimethylcyclobutyl)acetaldehyde (8.4 g, 0.05 mol.), toluene (50 g, 600 wt. %) and (ethylenediamine)[1,2-bis(diphenylphosphino)ethane]ruthenium (bispivalate) (4.8 mg, 0.00625 mmol, 0.0125 mol.%) were loaded altogether in a 125 ml autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged under stirring with nitrogen (3 times 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 50 bars hydrogen. It was then heated to 90° C. and hydrogen pressure was maintained to 50 bars during all the reaction to afford desired product with 98% selectivity. Upon reaction completion (checked by both hydrogen consumption and GC), autoclave was then cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars) and reaction mixture was then transferred to a round-bottomed flask and solvent was removed under vacuum. After flash chromatography, 1-((1S,3S)-3-(2-hydroxyethyl)-2,2-dimethylcyclobutyl)ethanone was obtained in 94% yield.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:28])[NH:17][C@H:18]([C:25](F)=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16]([NH:17][C@@H:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]([OH:2])=[O:26])=[O:28])([CH3:14])([CH3:13])[CH3:12].[C:11]([O:15][C:16](=[O:28])[NH:17][C@H:18]([C:25](=[O:26])[NH:7][CH2:8][CH2:9][SH:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: NCCS
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)F)c1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCCS)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (78.4 mg, 0.93 mmol) in 4.6 mL water was added 2-aminoethanethiol hydrochloride (57.0 mg, 0.50 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25k (115.3 mg, 0.46 mmol) in 4.6 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 130.8 mg (84% from 24k) of 26k as an off-white paste.