Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH3:2][S:3]([CH2:5][CH2:6][CH2:7][NH2:8])=[O:4].C(N(CC)CC)C.[CH2:16]([N:34]=[C:35]=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CC(C)=O>[CH3:2][S:3]([CH2:5][CH2:6][CH2:7][NH:8][C:35]([NH:34][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:36])=[O:4]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: CS(=O)CCCN
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCCS(C)=O
Temperature: 25 °C

Procedure:
10.6 Grams of 3-(methylsulfinyl)propylamine hydrobromide, 5.6 g of triethylamine and 100 ml of acetone were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred at room temperature. To the resulting solution was slowly added dropwise 14.8 g of octadecyl isocyanate. After completion of the addition, the temperature of the solution was returned to room temperature, followed by refluxing with heating for 2 hours. The reaction mixture was cooled to room temperature, and the precipitated crystal was filtered off under reduced pressure and washed with distilled water. The crystal was recrystallized from 2-propanol to obtain 14.9 g of the desired product. m.p. 105° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=CC=[CH:12][C:13]=2[CH3:15])[C:8]([CH:16]=O)=[CH:7][C:6]=1[CH:18]([CH3:20])[CH3:19])(=[O:3])[CH3:2].[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22].O1CC[CH2:48][CH2:47]1>>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:47][CH:48]=[CH:12][C:13]=2[CH3:15])[C:8](/[CH:16]=[CH:26]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:7][C:6]=1[CH:18]([CH3:19])[CH3:20])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Oc1c(C(C)C)cc(C=O)c2cccc(C)c12
Reactant: C1CCOC1
Product: CCOC(=O)/C=C/c1cc(C(C)C)c(OC(C)=O)c2c(C)cccc12
Temperature: 25 °C

Procedure:
0.5 g of 4-acetoxy-3-isopropyl-5-methyl-1-naphthalenecarbaldehyde and 11 g of (carbethoxymethylene)triphenylphosphorane were dissolved in 50 ml of tetrahydrofuran and refluxed for 1 hour. The reaction mixture was cooled to room temperature and concetrated in vacuo. The resultant residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 0.5 g of the titled compound as pale yellow crystals.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][S:18][C:17]3=[O:22])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:23](=O)[CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:23](=[C:19]1[S:18][C:17](=[O:22])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][S:10]([C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)=[O:11])[C:20]1=[O:21])[CH2:24][CH2:25][CH3:26]
Reactant: O=C1CSC(=O)N1CCCCS(=O)c1cccc2nccn12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCS(=O)c2cccc3nccn23)C1=O

Procedure:
To a solution of 0.33 g (0.98 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylsulfinyl)butyl]thiazolidine-2,4-dione and 0.10 ml (1.1 mmol) of n-butyraldehyde in 5 ml of ethanol, 0.01 ml (0.1 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate) to yield 0.287 g (74.8%, yellow oily substance) of the desired product.
Reaction SMILES: [C:1]1([CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]Cl)[CH:2]=1.[CH3:11][O-:12].[Na+].[CH3:14][OH:15]>>[CH3:11][O:12][CH2:9][C:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:15][CH3:14])[CH:2]=1
Reactant: C[O-]
Reactant: CO
Reactant: ClCc1cccc(CCl)c1
Agent: [Na+]
Product: COCc1cccc(COC)c1
Temperature: 60 °C

Procedure:
To a solution of m-xylylene dichloride (25.0 g) in methanol (125 ml) was added a 28% methanol solution (82.6 g) containing sodium methoxide at room temperature, and the mixture was stirred with heating at 60° C. for 3 hr. The solvent was evaporated and water (150 ml) was added to the residue. The mixture was extracted twice with heptane (80 ml) and heptane was evaporated under reduced pressure to give m-xylylene glycol dimethyl ether (25.3 g). m-Xylylene glycol dimethyl ether (25.3 g) was dissolved in acetic acid (125 ml) and sodium acetate (68 g) was added, which was followed by dropwise addition of bromine (68 g) at room temperature. The mixture was stirred at room temperature for 3 hr and poured into 10% aqueous sodium sulfite solution (750 ml), which mixture was extracted twice with heptane (350 ml). The heptane layer was extracted twice with 10% aqueous sodium hydroxide solution (150 ml) and once with water (150 ml). The solvent was evaporated and the residue was purified by silica gel column chromatography using heptane-ethyl acetate (15:1) as an eluent to give the title compound (10.4 g, yield:29.7%) as a colorless transparent oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH2:13]([I:16])[CH:14]=[CH2:15]>C1(C)C=CC=CC=1>[I-:16].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N+:10]2[CH2:15][CH:14]=[CH2:13])=[CH:5][CH:4]=1
Reactant: C=CCI
Reactant: COc1ccc2cccnc2c1
Solvent: Cc1ccccc1
Product: C=CC[n+]1cccc2ccc(OC)cc21
Product: [I-]
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
7-(Methyloxy)quinoline (8.76 g; 55.09 mmol) and allyl iodide (19.72 ml; 110.18 mmol) were refluxed in toluene (120 ml) at 95° C. for 1 h, more allyl iodide (9.86 ml; 55.09 mmol) was added and the temperature of the reaction increased to 110° C. After a further 1 h the temperature of the reaction was increased to 120° C. and reaction continued for a further 0.5 h. The solvent was removed under vacuum and the resulting brown solid was washed with toluene and diethyl ether. The resultant solid were left to dry in a vacuum oven overnight to give the desired product (14.81 g; 82%)
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][C:8](=[O:21])[CH2:9][CH:10](O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH:10]2[O:22][C:6](=[O:5])[CH2:7][C:8](=[O:21])[CH2:9]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)CCc1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(=O)OC(CCc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
To a stirred solution of 7-(4-Fluoro-phenyl)-5-hydroxy-3-oxo-heptanoic acid tert-butyl ester (0.64 g, 2.06 mmol) in dry DCM was added TFA (0.24 g, 2.1 mmol) at 0° C. The resultant clear solution was stirred at rt for 16h. Removal of the volatile components under reduced pressure afforded the product 6-[2-(4-Fluoro-phenyl)-ethyl]-dihydro-pyran-2,4-dione as a white solid (0.32g, 66%). 1H NMR (300 MHz, CDCl3) δ1.8-2.2 (m, 2H), 2.25-2.55 (m, 2H), 2.65-2.95 (m, 2H), 3.55 (dd, ˜1H, J=10), 4.25-4.40(m, ˜0.5H), 4.6-4.7 (m, ˜0.5 H), 5.2 (s, ˜0.5 H), 6.90-7.05 (m, 2H), 7.1-7.2 (m, 2H), 10.8 (br, ˜0.5H). ESMS calcd (C13H13FO3): 236.1; found: 237.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:17][OH:18])=[O:16])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].CO.C1C[O:30]CC1>O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:17][OH:18])=[O:16])(=[O:30])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: C1CCOC1
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)C2CCCCC2)cc1
Solvent: O
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2-{[4-(2-butynyl oxy)phenyl]sulfinyl}-2-cyclohexyl-N-hydroxyacetamide (180 mg, 0.52 mmol) in MeOH/THF at room, wxone (5.0 g, excess) was added in water (20 ml). Reaction mixture was stirred at room temperature for 6 hrs and filtered. Methanol-THF layer was concentrated and extracted with chloroform. The organic layer was washed well with water, dried, filtered and concentrated. The product was purified by silica gel column chromatography by eluting it with 4:1 ethyl acetate; hexane and 2-{[4-(2-butynyl oxy)phenyl]sulfonyl}-2-cyclohexyl-N-hydroxyacetamide was isolated as a white solid. mp: 191° C.; Yield: 45 mg (24%); MS: 366.3 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 0.95-1.12 (band, 5H), 1.58 (m, 5H), 1.85 (t, J=2.22 Hz, 3H), 2.05 (m, 1H), 3.63 (d, J=9.1 Hz, 1H), 4.87 (d, J=2.34 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 7.76 (d, J=9 Hz, 2H), 9.01 (s, 1H), 10.7 (s, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[N:24]=[N+]=[N-])(=[O:3])[CH3:2].[H][H]>O=[Pt]=O.O1CCCC1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[NH2:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(N=[N+]=[N-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1OC(N)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4 g, that is, 11 mmol of the 2,3,4,6-tetra-O-acetylglucopyranosyl azide was added to 50 ml of dry tetrahydrofuran containing 200 mg of PtO2. The mixture was shaken under 40 psi of hydrogen for 2 hours, filtered, concentrated to dryness, to produce 2,3,4,6-tetra-O-acetylglucopyranosyl amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[CH:5]=[C:6]([CH:8]=1)[NH2:7].O=C(Cl)[O:13][C:14](Cl)(Cl)Cl.C(N(CC)CC)C.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[F:37]>O1CCCC1.O>[F:37][C:28]1[CH:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:27]=1[NH:26][C:14]([NH:7][C:6]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([C:9]#[N:10])[CH:5]=1)=[O:13]
Reactant: N#Cc1cc(N)cc(F)c1
Reactant: Nc1ccc(C(F)(F)F)cc1F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cc(F)cc(NC(=O)Nc2ccc(C(F)(F)F)cc2F)c1
Yield: 83.9 %

Procedure:
A solution of 6.15 g (45.18 mmol) of 5-fluoro-3-cyanoaniline in 90 ml of tetrahydrofuran is stirred at ambient temperature under an argon atmosphere. 4.3 ml (36.14 mmol) of diphosgene are added dropwise then 30 ml (135.54 mmol) of triethylamine. After refluxing in the reaction mixture for 3 hours, a solution of 7.10 g (39.64 mmol) of 4-amino-3-fluorotrifluoromethylbenzene in 10 ml of tetrahydrofuran is slowly added. The reflux is maintained for an additional 2 hours. The medium is then stirred into 100 ml of water, then extracted with 100 ml of ethyl acetate. The organic phase is washed with 100 ml of a saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness using a rotary evaporator. The solid residue obtained is recrystallized at high temperature in 90 ml of acetonitrile in order to give 10.35 g of 1-(2-fluoro-4-trifluoromethylphenyl)-3-(3-cyano-5-fluorophenyl)urea in the form of a cream solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8](Cl)[N:7]=1>C(O)CCC>[CH:1]1([NH:4][C:8]2[N:7]=[C:6]([Cl:5])[N:14]=[C:13]3[C:9]=2[NH:10][CH:11]=[N:12]3)[CH2:3][CH2:2]1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NC1CC1
Solvent: CCCCO
Product: Clc1nc(NC2CC2)c2[nH]cnc2n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Cyclopropylamine (6.65 g, 0.116M) and N,N-dfisopropylethylamine (20.8 ml, 0.116M) is added to a suspension of 2,6-dichloropurine (20 g,0.106M) in n-butanol (200 ml). The mixture is stirred at 60° C. for 20 hours. The mixture is cooled and the precipitate isolated by filtration, washed with n-butanol and dried under vacuum to give 6-cyclopropylamino-2-chloropurine; ES+ (M+1) 209.5; mp 249.7° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[NH:8][C:7](=[O:14])[CH2:6][NH:5]2.[N+:15]([O-])([OH:17])=[O:16].C1OC2C=C3C(NC(=O)C(=O)N3)=CC=2[O:20]1.C(C1C(CC)=CC=CC=1N)C>C(C(O)=O)(F)(F)F>[Cl:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[NH:8][C:7](=[O:14])[C:6](=[O:20])[NH:5]2
Reactant: CCc1cc2c(cc1Cl)NCC(=O)N2
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2cc3c(cc2[nH]c1=O)OCO3
Agent: CCc1cccc(N)c1CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2[nH]c(=O)c(=O)[nH]c2c([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 137 mg (0.65 mmol) of 36 in 4 mL of CF3CO2H kept in an ice bath was added dropwise 0.4 mL of fuming HNO3. The solution was stirred in the ice bath for 1 h and at room temperature overnight. It was evaporated and the residue was treated with 6 mL of water and stirred for 10 min. The mixture was filtered, washed with water, and dried to leave a yellow solid, 140 mg (80%); mp>330° C.; 1H NMR (DMSO-d6), 1.161 (t, 3, J=7.4), 2.712 (q, 2, J=7.6), 7.192 (s, 1), 12.209 (mb 2). MS, 269 (M+, 100), 254 (12), 226 (15), 160 (20). HRMS, Cacld for C10H8ClN3O4 269.0198; Found 269.0196.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[O:18][C:17]([B:19]([OH:21])[OH:20])=[CH:16][CH:15]=1)=O.N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:14]1[O:18][C:17]([B:19]([OH:21])[OH:20])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(B(O)O)o1
Yield: 20.4 %

Procedure:
A solution of 5-chlorooxindole (999 mg, 5.98 mmol), 5-formylfuran-2-boronic acid (832 mg, 5.98 mmol) and piperidine (0.59 mL, 5.98 mmol) in EtOH (5.0 mL) was stirred at rt 90 min. The resulting precipitate was collected by filtration to yield the desired compound (354 mg). LCMS (ES): m/z 290 [M+1]+.
Reaction SMILES: C([NH:4][C:5]1[CH:17]=[CH:16][C:8]2SC3C=CC=[CH:12][C:11]=3[C:7]=2[CH:6]=1)(=O)C.[OH-:18].[K+].Cl.[OH2:21]>C(O)C>[N:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:16][C:17]([OH:21])=[O:18])=[CH:11][CH:12]=1
Reactant: [OH-]
Reactant: O
Reactant: CC(=O)Nc1ccc2sc3ccccc3c2c1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C(O)CCc1ccncc1

Procedure:
To a solution of ethyl 3-pyridin-4-ylpropanoate (Method 2; 103.1 g, 576 mnaol) in water (400 ml) and ethanol (20 ml) at room temperature was added potassium hydroxide (60 g, 1600 mmol). After 18 hours hydrochloric acid (100 ml) was added to give a white solid. Yield 62.8 g (73%). NMR 8.38 (d, 2H), 7.21 (d, 2H), 2.70 (t, 2H), 2.52 (t, 2H); m/z 152.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[O:7][CH2:8][C:9](=[O:16])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([CH:26]=O)=[CH:18]1>C(O)C.N1CCCCC1>[NH:17]1[C:25]2=[N:24][CH:23]=[CH:22][CH:21]=[C:20]2[C:19]([CH:26]=[C:8]2[O:7][C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]2=[O:16])=[CH:18]1
Reactant: CCOC(=O)C1=C(NCCOC)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(NCCOC)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-[(2-methoxyethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g, 2.2 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.32 g, 2.2 mmol) in ethanol (3.0 mL), piperidine (5 drops) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid.
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH2:27])=[CH:22][C:21]=2[CH3:29])=[C:16]([CH3:30])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:32]>C(OCC)(=O)C.O1CCOCC1.C(O)(C)C>[ClH:32].[CH3:29][C:21]1[CH:22]=[C:23]([C:26]([NH2:27])=[O:28])[CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:7][CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:15][C:16]=1[CH3:30]
Reactant: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1-c1ccc(C(N)=O)cc1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(CNCCC(C)C)ccc1-c1ccc(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4′-Carbamoyl-2′,2-dimethyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-2e: 12 g, 28.3 mmol) was dissolved in ethyl acetate and treated with 20 mL of 4.0 M hydrogen chloride in dioxane. After stirring overnight at room temperature, the volatiles were removed under reduced pressure and the resulting crude material dissolved in methanol and then ethyl acetate was added to precipitate a white solid that was isolated via filtration. This solid was suspended in iso-propanol (1 g: 20 mL), heated at reflux for 20 minutes and stirred overnight at room temperature. The resulting slurry was collect via filtration, rinsing with chilled iso-propanol, and dried under vacuum to provide the title compound (E2-01).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[C:18]([CH3:26])[CH:17]=[C:16]4[CH3:27])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>>[F:32][C:33]([F:37])([F:36])[CH2:34][NH:35][C:23]([C:20]1[C:19]2[N:15]([C:16]([CH3:27])=[CH:17][C:18]=2[CH3:26])[C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:28]([F:29])([F:31])[F:30])[O:13][N:12]=2)=[CH:22][CH:21]=1)=[O:25]
Reactant: NCC(F)(F)F
Reactant: Cc1cc(C)n2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc(C(=O)O)c12
Product: Cc1cc(C)n2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc(C(=O)NCC(F)(F)F)c12

Procedure:
Using a procedure similar to that described in Example 1, except using 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-1,3-dimethylindolizine-8-carboxylic acid (90 mg) and 2,2,2-trifluoroethylamine (38 mg), the title compound was isolated as a solid (85 mg, 81%). Rf=0.35 (3:7 EA/heptane). MS (ES): M/Z [M+H]=552. 1H NMR (400 MHz, DMSO-d6): 2.18 (s, 3H), 2.19 (s, 3H), 4.11 (qd, J=9.7, 6.6 Hz, 2H), 4.48 (d, J=18.7 Hz, 1H), 4.56 (d, J=18.6 Hz, 1H), 6.57 (s, 1H), 6.62 (d, J=7.0 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 7.67 (d, J=1.7 Hz, 2H), 7.84 (t, J=1.9 Hz, 1H), 9.21 (t, J=6.3 Hz, 1H). 19F NMR (376 MHz, DMSO-d6): −78.8 (s, 3F) and −70.6 (t, J=9.9 Hz, 3F)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][C:8](=S)[NH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1.CCOCCO.[NH2:27][CH2:28][C:29]1([CH3:34])OCCO1.O>COCCO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][C:8]3[N:9]([C:29]([CH3:34])=[CH:28][N:27]=3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1
Reactant: CC1(CN)OCCO1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NNC(=S)C2
Solvent: COCCO
Solvent: CCOCCO
Solvent: O
Product: COc1ccc2c(c1)C(c1ccccc1)=Nn1c(C)cnc1C2
Reaction time: 10 h

Procedure:
500 mg of 8-methoxy-1-phenyl-4,5-dihydro-3H-2,3-benzodiazepine-4-thione is stirred in 1.5 ml of ethylene glycol monomethyl ether (Cellosolve® and 548 mg of 2-aminomethyl-2-methyl-1,3-dioxolane while argon is passing through it for 10 hours at 60° C. After filtration and washing with cold ethanol and diisopropyl ether, 550 mg of imino compound, which is dissolved in 10 ml of ethanol, mixed with 10 ml of concentrated hydrocholoric acid and refluxed for 3 hours, is obtained. It is added to water, set at pH 11 and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. After recrystallization from ethyl acetate/diisopropyl ether, 240 mg of 8-methoxy-3-methy-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine with a melting point of 140° C. is obtained.
Reaction SMILES: [CH2:1]([Si:5]([CH3:22])([C:12]1([CH2:18][CH:19]([CH3:21])[CH3:20])SCCCS1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[OH2:23]>CC#N.Cl[Hg]Cl>[CH2:1]([Si:5]([CH3:22])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12](=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC[Si](C)(c1ccccc1)C1(CC(C)C)SCCCS1
Reactant: O
Agent: Cl[Hg]Cl
Solvent: CC#N
Product: C=CCC[Si](C)(C(=O)CC(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 44 (6.19 g, 177 mmol) in CH3CN (200 mL) was added water (10 mL) and HgCl2 (24 g, 88 mmol). After stirring overnight at rt, the mixture was concentrated and partitioned between water (100 mL) and hexane (200 mL). The organic layer was isolated and the aqueous layer extracted twice with 50-mL portions of hexane. The combined organic extracts were washed with saturated aqueous NaCl and dried over Na2SO4. Concennation to dryness in vacuo at rt gave quantitatively crude ketone 45 as a yellow oil. This ketone was used in the next reaction without further purification: Rf=0.75 (1/19 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.54–7.51 (m, 2H), 7.41–7.35 (m, 3H), 5.91–5.78 (m, 1H), 4.99 (dd, J=17.0, 1.7 Hz, 1H), 4.90 (dd, J=10.0, 1.7 Hz, 1H), 2.44 (d, J=6.7 Hz, 2H), 2.16–2.06 (m, 3H), 1.16–1.07 (m, 2H), 0.78 (pd. J=6.7 Hz, 6H), 0.51 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH:34]=[O:35])[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(=O)([O-])[O-].C1(C)C=CC(S([CH2:50][N:51]=[C:52]=O)(=O)=O)=CC=1.O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[O:35][CH:52]=[N:51][CH:50]=3)[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Reactant: O=Cc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3-c3cnco3)CC2O)CCCCC1)c1cc2ccccc2o1
Yield: 100.9 %

Procedure:
The mixture of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-formylphenyl)piperidin-3-ol (3 g, 6 mmol) obtained in Step 1 of Example 61, photassium carbonate (2 g, 20 mmol) and p-toluenesulfonylmethyl isocyanate (TosMIC; 1.8 g, 9 mmol) was refluxed in 500 ml of methanol for about 2 hours. 150 ml of water was added to the concentrated reaction mixture, which was then extracted with dichloromethane. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 3.2 g of the titled compound.