Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:18]2[CH:17]=[C:16]3[C:8]([C:9]4[CH:10]=[C:11]5[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19]([CH3:26])([CH3:25])[C:12]5=[CH:13][C:14]=4[CH2:15]3)=[CH:7][C:6]=2[C:5]([CH3:28])([CH3:27])[CH2:4][CH2:3]1.C([Li])CCC.[C:35]([C:39]1[CH:40]=[CH:41][C:42](=[C:44]([CH3:46])[CH3:45])[CH:43]=1)([CH3:38])([CH3:37])[CH3:36].O>C1COCC1.CCCCCC>[C:35]([C:39]1[CH:40]=[CH:41][CH:42]([C:44]([CH:20]2[CH2:21][C:22]([CH3:24])([CH3:23])[C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][C:12]=3[C:19]2([CH3:26])[CH3:25])[CH2:15][C:16]2[CH:17]=[C:18]3[C:2]([CH3:29])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:28])([CH3:27])[C:6]3=[CH:7][C:8]4=2)([CH3:46])[CH3:45])[CH:43]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CCC2(C)C
Reactant: CC(C)=C1C=CC(C(C)(C)C)=C1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C1=CC(C(C)(C)C2CC(C)(C)c3cc4c(cc3C2(C)C)Cc2cc3c(cc2-4)C(C)(C)CCC3(C)C)C=C1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
To a solution of 1.55 g (4.0 mmol) of 1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorene in 50 ml of THF, 2.6 ml (−4.2 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. To the resulting red solution, a solution of 0.97 g (6.0 mmol) of 3-tert-butyl-6,6-dimethylfulvene in 25 ml of THF was further dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. Then, 60 ml of water was added. The organic phase extracted with ether and separated was dried over magnesium sulfate and then filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a solid. The solid was purified by column chromatography (silica gel, developing solvent: hexane) to obtain 0.95 g of a light yellow solid (yield: 43%). The analyzed values are given below.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:4][C:3]=1[CH3:23].[NH2:24][C:25]([NH2:27])=[O:26]>Cl.O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:19]=[CH:20][CH:21]=3)[NH:24][C:25](=[O:26])[N:27]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc(C(=O)/C=C/c2cccc(OCC(=O)O)c2)ccc1O
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3cccc(OCC(=O)O)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Yield: 54.4 %

Procedure:
(E)-2-(3-(3-(4-Hydroxy-3-methylphenyl)-3-oxoprop-1-enyl)phenoxy)acetic acid (15.0 g, 48.0 mmol) and urea (14.4 g, 0.24 mol) was suspended in 200 mL of 4N HCl solution in dioxane, and the reaction mixture was heated to reflux overnight, then cooled to room temperature. The resulted mixture was concentrated in vacuo to remove dioxane. The residues were suspended in 150 mL of 2-propanol and heated in a 90° C. oil bath for 10 minutes, then cooled down to room temperature by itself. The suspension was filtered, washed with 50 mL of 2-propanol and dried in the air. 9.2 g (54%) of yellow powder was obtained. 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 8.00 (s, 1H), 7.90 (m, 1H), 7.75 (m, 1H), 7.65 (s, 1H), 7.40-7.55 (m, 2H), 7.16 (m, 1H), 6.95 (m, 1H), 4.80 (s, 2H), 2.20 (s, 3H). MS (EI): 353 (MH+).
Reaction SMILES: CN1CCCC1=[O:7].[Cl:8][C:9]1[C:10]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:11]2[C:29]3[CH2:30][CH2:31][S:32][CH2:33][C:28]=3[S:27][C:12]2=[N:13][C:14]=1[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Cl:8][C:9]1[C:10]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)=[C:11]2[C:29]3[CH2:30][CH2:31][S:32](=[O:7])[CH2:33][C:28]=3[S:27][C:12]2=[N:13][C:14]=1[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: COc1ccc(-c2c(Cl)c(CN3C(=O)c4ccccc4C3=O)nc3sc4c(c23)CCSC4)cc1
Reactant: CN1CCCC1=O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)c4ccccc4C3=O)nc3sc4c(c23)CCS(=O)C4)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To N-methylpyrrolidone (140.56 L) was added 2-{[3-chloro-4-(4-methoxyphenyl)-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1H-isoindole-1,3(2H)-dione (14.056 kg) and the mixture was dissolved by heating at about 40° C. Then, vanadium (IV) oxyacetylacetone (49.09 g) was added thereto and the 30% hydrogen peroxide was added dropwise, while maintaining at 20 to 23° C. The mixture was stirred at the same temperature for 1 hour and then cooled to 3° C., followed by adding dropwise 0.5 N sodium thiosulfate (5 L) and then water (281.14 L). The mixture was stirred for 1 hour under ice-cooling. The crystals deposited was filtered off, dried and dissolved in N-methylpyrrolidone (135.65 L). Active carbon (678 g) was added and the mixture was stirred at room temperature for 30 minutes. The active carbon was filtered off and washed with N-methylpyrrolidone (13.565 L). The filtrate and washings were combined and to the mixture was added dropwise isopropyl ether (298.43 L). The crystals deposited were filtered off, washed with isopropyl ether (67.83 L ×2) to obtain the titled compound (9.56 kg, 64.3%). 1H-NMR (CDCl3) δ: 2.01-2.19 (1H, m), 2.54-2.73 (2H, m), 3.00-3.07 (1H, m), 3.89 (3H, s), 3.95 (1H, d, J=16.9 Hz), 4.05 (1H, d, J=16.9 Hz), 5.20 (2H, s), 6.99-7.03 (2H, m), 7.16-7.20 (2H, m), 7.76-7.80 (2H, m), 7.91-7.95 (2H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20]([NH:22]C(OC(C)(C)C)=O)=[N:19]C=3C)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1.[C:31](O)([C:33]([F:36])([F:35])[F:34])=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20]([NH2:22])=[N:19][C:31]=3[C:33]([F:36])([F:35])[F:34])=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:2]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)NCC1(c2cccnc2)CCCCC1
Solvent: ClCCl
Product: Nc1nc(C(F)(F)F)c(C(=O)NCC2(c3cccnc3)CCCCC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-tert-butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid (1-pyridin-3-yl-cyclohexylmethyl)-amide (2.45 g) and TFA (10 mL) in methylene chloride (10 mL) is stirred at RT for 2 h and concentrated in vacuo. Water is added to the residue and the mixture is basified with Na2CO3 solution and extracted with EtOAc. The extract is washed with brine, dried and concentrated in vacuo to afford the title compound.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](N(C)C)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:2]1(/[CH:1]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: C(=C/c1ccccc1)\c1ccccc1
Product: C=Cc1ccccc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 9 %
Yield: 55 %

Procedure:
1.44 ml (12.5 mmols) of benzoyl chloride, 1.88 ml (12.5 mmols) of N-benzyldimethylamine and 0.0281 g (0.125 mmol) of palladium acetate are added to 25 ml of toluene in a pressure apparatus constructed of glass. The apparatus is flushed with ethylene in order to remove the air. Ethylene is then injected at 10 bar and the mixture is stirred for 4 hours at 120° C. 55% of styrene and 9% of trans-stilbene are formed.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][NH2:21])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.CS[C:25]1[NH:26][CH2:27][CH2:28][N:29]=1>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][NH:21][C:25]2[NH:29][CH2:28][CH2:27][N:26]=2)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSC1=NCCN1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: I
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2CNC1=NCCN1
Temperature: 150 °C
Yield: 49.8 %

Procedure:
C-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine (100 mg, 0.31 mmol) and 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydroiodide (76 mg, 0.31 mmol) were added to 2 mL CH2Cl2, and the reaction mixture was heated to gentle reflux until all of the solvent was evaporated. The reaction mixture was heated to 150° C. for 30 minutes and then cooled. The crude mixture was basified by dropwise addition of aqueous NaOH solution, and then purified by preparative liquid chromatography (CH2Cl2/MeOH 90:10) on a short silica gel column. Removal of the solvent afforded 57 mg (47%) of (6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine. MS: 370 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N:3]=1.[NH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1.C(O)(=O)/C=C/C(O)=O>C(O)CCC.C(O)(C)C.O>[CH2:7]([N:6]1[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N:3]=[C:2]1[NH:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[CH3:8]
Reactant: CCn1c(Cl)nc2ccccc21
Reactant: CN1CCC(N)C1
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Solvent: CCCCO
Solvent: CC(C)O
Product: CCn1c(NC2CCN(C)C2)nc2ccccc21
Yield: 63 %

Procedure:
A solution of 38.6 g (0.21 mol) of 2-chloro-1-ethylbenzimidazole and 24 g (0.24 mol) of 3-amino-1-methylpyrrolidine in 150 mL of n-butanol was heated to reflux for 72 h and concentrated on the rotary evaporator (70° C./30 mm). The residue was partitioned between CHCl3 and dilute NaOH. The CHCl3 solution was dried (Na2SO4) and concentrated. For purification the material obtained was converted to the difumarate salt. The residue (68 g) was treated with a boiling solution of 64 g of fumaric acid in 600 mL of isopropyl alcohol and 100 mL of H2O. The resulting salt weighted 48 g (63% yield). A sample was recrystallized from ethanol-H2O, mp 204°-212° C. (dec).
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][S:18]([N:15]2[CH2:14][CH2:13][C:9]3([N:8]=[C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[NH:11][C:10]3=[O:12])[CH2:17][CH2:16]2)(=[O:20])=[O:19])[CH:28]=[CH:27][CH:26]=1
Reactant: O=C1NC(C2CCCCC2)=NC12CCN(S(=O)(=O)CCc1cccc([N+](=O)[O-])c1)CC2
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CCS(=O)(=O)N2CCC3(CC2)N=C(C2CCCCC2)NC3=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.6 %

Procedure:
10% Pd—C (1 g) was added to a solution of Compound 18d (1 g, 2.23 mmol) in ethanol (10 ml), and the mixture was stirred at room temperature for two days in an H2 atmosphere. The reaction mixture was filtered, and the filtrate was then concentrated under reduced pressure to give 8-[2-(3-amino-phenyl)-ethanesulfonyl]-2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (920 mg, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)[CH:8](O)[C:7]=2[CH:27]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)=[CH:8][C:7]=2[CH:27]=1
Reactant: COc1ccc2c(c1)C(O)C(c1nccn1C)C(CCc1ccccc1)O2
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C=C(c1nccn1C)C(CCc1ccccc1)O2

Procedure:
By proceeding analogously similar 2-substituted 3-(1-methyl-1H-imidazol-2-yl) 2H-1-benzopyran-6-ols can be prepared. The above 6-methoxy-2-(2-phenylethyl)-3-(1-methyl-1H-imidazol-2-yl) 2H-1-benzopyran is prepared by refluxing for 2 hours a mixture of 6-methoxy-2-(2-phenylethyl)-3-(1-methyl-1H-imidazol-2-yl) 2,3-dihydro-4H-1-benzopyran-4-ol (2 g) (prepared following the procedure described in J. Het. Chem. (1984) 21, 311), phosphorous pentoxide (2 g) and Amberlite® 1R 122 (20 mg) in anhydrous benzene (200 ml).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].Cl>ClCCl>[C:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 63.9 %

Procedure:
A solution of 4-hydroxybenzoic acid (6.91 g) and pyridine (12.1 ml) in dichloromethane (100 ml) was cooled to an ice-water temperature, and hereto was added dropwise pivaloyl chloride (13.26 g). The mixture was stirred at same temperature for 1.5 hours, and thereto was added a 10% aqueous hydrochloric acid solution (50 ml). The organic layer was washed with H2O (100 ml) and brine, and dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 ml)-H2O (15 ml), and the mixture was stirred at 50° C. for 17.5 hours. After being cooled to an ice-water temperature, the mixture was basified with a saturated aqueous sodium hydrogen carbonate solution (about 100 ml). After being stirred at room temperature for 4 hours, the mixture was acidified with a 36% aqueous hydrochloric acid solution at an ice-water temperature. The resultant mixture was extracted with ethyl acetate (100 ml), and the organic layer was dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1-9:1) and triturated with diisopropyl ether to give 4-pivaloyloxybenzoic acid (7.10 g) as a colorless solid. ESI-Mass m/Z 221 (M−H). 1H-NMR (DMSO-d6) δ 1.31 (s, 9H), 7.23 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.7 Hz, 2H), 10.03 (brs, 1H).
Reaction SMILES: Cl[CH:2]([N:12]=[C:13]=[O:14])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:11].[F:15][C:16]([F:31])([F:30])[C:17]1[CH:18]=[C:19]([NH:23][C:24]2[CH2:28][CH2:27][C:26](=[O:29])[CH:25]=2)[CH:20]=[CH:21][CH:22]=1>ClCCl>[O:14]=[C:13]1[N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:30])[F:31])[CH:18]=2)[C:24]2[CH2:28][CH2:27][C:26](=[O:29])[C:25]=2[CH:2]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=2[F:11])[NH:12]1
Reactant: N#Cc1ccc(C(Cl)N=C=O)c(F)c1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC1
Solvent: ClCCl
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)c(F)c1

Procedure:
A solution of 4-(chloro(isocyanato)methyl)-3-fluorobenzonitrile (Step 1, 3.05 g, 14.5 mmol) in dichloromethane (10 mL) is added to a solution of 3-(3-(trifluoromethyl)-phenylamino)cyclopent-2-enone (3.50 g, 14.5 mmol) in dichloromethane (10 mL), and the mixture is heated at reflux over night. All volatiles are removed under reduced pressure, and the residue is purified by reversed phase HPLC (Agilent ZORBAX™ SB-C18, gradient of acetonitrile in water, 0.1% formic acid). Yield: 474 mg; ESI mass spectrum [M+H]+=416; Retention time HPLC: 0.94 min (Z017_504). LB5FAI00917
Reaction SMILES: [N:1]([C:4]12[CH2:9][CH:8]1[CH2:7][N:6]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=C=O.Cl>O1CCOCC1>[C:20]1([CH:5]2[N:6]([S:10]([C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)(=[O:11])=[O:12])[CH2:7][CH:8]3[C:4]2([NH2:1])[CH2:9]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC3(N=C=O)C2c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N2CC3CC3(N)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
To a solution of racemic 1-isocyanato-2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane Intermediate 5) in 1,4-dioxane (150 mL) was added 12% HCl aqueous (75 mL) dropwise and the reaction was allowed to stir for 16 hours at room temperature. The organic solvent was removed at reduced pressure and the flask containing the reaction residue was placed in a 0° C. bath. Methylene chloride and 2N NaOH were added until the pH of the aqueous layer was from about 9 to about 11. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated to a crude weight of 3.9 g. This was adsorbed onto silica and flash chromatographed on silica with a gradient of 40% EtOAc/Hexanes to EtOAc as eluant. 2-Phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hex-1-ylamine was obtained (2.0 g, 59% yield). The material was dissolved in hot chloroform and crystallized by adding a small amount of ether to the cooling solution.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][N:7]([C:9]([O:11][CH3:12])=[O:10])[C@H:6]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[O:14])[C@@H:5]([C:27](OC)=[O:28])[CH2:4]1.[OH:31][NH2:32].Cl.NO.C[O-].[Na+].Cl>CO>[OH:31][NH:32][C:27]([C@H:5]1[CH2:4][C@H:3]([O:2][CH3:1])[CH2:8][N:7]([C:9]([O:11][CH3:12])=[O:10])[C@@H:6]1[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:20]1)=[O:14])=[O:28]
Reactant: COC(=O)[C@H]1C[C@H](OC)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1C[C@@H](OC)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of dimethyl (2S,3S,5S)-5-methoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (0.027 g, 0.000064 mol) in methanol (0.30 mL, 0.0074 mol) was added 1.640 M of N-hydroxyamine in methanol (0.7850 mL), freshly made from the corresponding hydroxylamine HCl salt and sodium methoxide. The mixture was stirred at rt for 1 h, then acidified with 1N HCl. The crude mixture was applied directly on RP-HPLC to afford the product as a TFA salt (23 mg, 68%). MS (ESI): (M+H)+=421.2.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[NH:6][N:7]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[N:6]([CH2:17][CH2:16][C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: OCCc1cccs1
Reactant: Cn1c(=O)[nH]nc(Br)c1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(Br)nn(CCc2cccs2)c1=O
Temperature: 70 °C
Yield: 78.3 %

Procedure:
0.4 g (1.94 mmol) of intermediate 2a are placed in the presence of 0.24 mL (2.14 mmol) of 2-thiophen-2-yl-ethanol, 0.61 g (2.33 mmol) of triphenylphosphine in 4 mL of THF. At 0° C., 0.54 mL (2.33 mmol) of DEAD in solution in toluene are added dropwise. The reaction medium is heated for 7 h at 70° C. After concentration, the obtained residue is taken up with ethyl acetate and washed with water. After drying on MgSO4, the organic phase is dry concentrated. The obtained residue is purified by flash chromatography on silica (CH2Cl2/MeOH, gradient 100/0 to 97/3 over 30 min). 0.48 g of crystals corresponding to the compound 4k are obtained (yield: 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].ClC1C=CC(C(NC2C=CC=C(C3OCCO3)C=2)=O)=CC=1.N1CCC(C(OC)=O)C1.C([O:45][C:46]([CH:48]1[CH2:53][CH2:52][N:51]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([NH:61]C(=O)C3C=CC(Cl)=CC=3)[CH:56]=2)[CH2:50]C1)=[O:47])C>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:61][C:57]1[CH:56]=[C:55]([CH:60]=[CH:59][CH:58]=1)[CH2:54][N:51]1[CH2:52][CH2:53][CH:48]([C:46]([OH:45])=[O:47])[CH2:50]1)=[O:11]
Reactant: O=C(Cl)Cc1ccc(F)cc1Cl
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Agent: COC(=O)C1CCNC1
Agent: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(Cl)cc1
Product: O=C(Cc1ccc(F)cc1Cl)Nc1cccc(CN2CCC(C(=O)O)C2)c1

Procedure:
The title compound is prepared according to the reaction sequence 2.001a-2.001d described above using 2-(2-chloro-4-fluorophenyl)acetyl chloride instead of 4-chlorobenzoyl chloride as in 2.001a and methyl pyrrolidine-3-carboxylate instead of ethyl isonipecotate as in 2.001c: LC-MS A: tR=0.63 min; [M+H]+=391.01.
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][N:7]=1)=O.C(O)(=O)[CH2:9][C:10]([OH:12])=[O:11]>N1C=CC=CC=1.N1CCCCC1.O>[S:4]1[CH:5]=[CH:6][N:7]=[C:3]1[CH:1]=[CH:9][C:10]([OH:12])=[O:11]
Reactant: O=Cc1nccs1
Reactant: O=C(O)CC(=O)O
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1nccs1
Temperature: 100 °C
Yield: 12.4 %

Procedure:
Mix 2-formyl thiazole (10.0 g, 88.4 mmol) and malonic acid (9.2 g, 88.4 mmol). Dissolve in pyridine (7.2 mL, 88.5 g) and add 3 drops of piperidine. Heat the mixture at 100° C. under nitrogen for 3 hours, cool, dilute with water, and filter the solids to afford 1.7 g of the title compound as a white solid. Concentrate the filtrate, acidify with 1N HCl, extract with ethyl acetate (2×100 mL), wash with brine (100 mL), dry (sodium sulfate), filter and concentrate to afford an additional 4.8 g of 3-thiazol-2-yl-acrylic acid MS: m/e=156 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[OH:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][OH:34]>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:31]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:29][OH:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCNCCO
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)N(CCO)CCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 300 g. of sodium 4-acetylbenzenesulfonate is added in portions to a well-stirred, cooled solution of 500 ml. of bis(2-hydroxyethyl)amine in 750 ml. of water. The mixture is stirred at room temperature for 16 hours, cooled to 0-5° C. and the precipitate of 4-acetyl-N,N-bis(2-hydroxyethyl)benzenesulfonamide is collected by filtration and crystallized from water; m.p. 87.5°-89.5° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:1][C@H:2]2[CH2:19][CH2:18][C@@:17]3([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]4[C@@H:16]3[CH2:15][CH2:14][C@@:12]3([CH3:13])[C@H:8]4[CH2:9][CH2:10][C:11]3=[O:21])[CH2:3]2)=[O:37])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: C[C@]12CC[C@H](O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O[C@H]2CC[C@@]3(C)C(C2)C(=O)C[C@@H]2[C@@H]3CC[C@]3(C)C(=O)CC[C@@H]23)CC1
Yield: 62 %

Procedure:
Prepared in 62% yield from 3β-hydroxyandrostane-6,17-dione and 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid by the procedure described in Prepn. 43. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.65 (1H, m), 3.60-1.20 (29H, m), 1.35 (9H, s), 0.78 (3H, s), 0.69 (3H, s).