Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[F:30][C:31]1[CH:32]=[CH:33][C:34]2[N:38]=[C:37]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[N:36]([CH3:45])[C:35]=2[CH:46]=1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:42]3[CH2:43][CH2:44][N:39]([C:37]4[N:36]([CH3:45])[C:35]5[CH:46]=[C:31]([F:30])[CH:32]=[CH:33][C:34]=5[N:38]=4)[CH2:40][CH2:41]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cn1c(N2CCNCC2)nc2ccc(F)cc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCc4ccc(F)cc4)c4ccccc4-c4ccccc43)CC2)nc2ccc(F)cc21

Procedure:
Prepared analogously to Example 1e from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 6-fluoro-1-methyl-2-piperazin-1-yl-1H-benzimidazole.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[C:7]([OH:13])(=O)[CH2:8][C:9]([OH:11])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:13])[CH2:8][C:9](=[O:11])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: CNC(=O)NC
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)CC(=O)N(C)C1=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
276 g (3.14 mol) of 1,3-dimethylurea and 376 g (3.62 mol) of malonic acid were dissolved in 600 ml of glacial acetic acid at 60° to 70° C. To the solution was added 1250 ml of acetic anhydride and the temperature was gradually raised to 90° C. After stirring for 6 hours, the reaction mixture was allowed to stand at room temperature overnight and then the glacial acetic acid and acetic anhydride were distilled off under reduced pressure. The residue was poured into 500 ml of ethanol while it was still hot, the crystals thus-deposited were collected by filtration and refluxed by heating in a mixture of 380 ml of concentrated hydrochloric acid and 400 ml of water for 2 hours. The mixture was allowed to stand under cooling with ice for 6 hours, the crystals thus-deposited were collected by filtration and washed with a small amount of ethanol to obtain 360 g of 1,3-dimethylbarbituric acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[N:6][N:5]2[C:12]=1[S:13]([N:16]=CN(CC(C)C)CC(C)C)(=[O:15])=[O:14].O.N>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[N:6][N:5]2[C:12]=1[S:13]([NH2:16])(=[O:14])=[O:15]
Reactant: C#Cc1ccc2nc(Cl)c(S(=O)(=O)N=CN(CC(C)C)CC(C)C)n2n1
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: C#Cc1ccc2nc(Cl)c(S(N)(=O)=O)n2n1
Temperature: 25 °C

Procedure:
N′-(2-Chloro-6-ethynylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine (792 mg, 2.00 mmol) was suspended in dioxane (10.0 mL), and 28% ammonia water (4.00 g, 65.8 mmol) was added dropwise to the suspension under stirring at room temperature. The mixture was stirred at room temperature for 3 days, then concentrated to remove ammonia, and adjusted to pH 1 with conc. hydrochloric acid. The reaction solution was diluted with water and extracted with ethyl acetate, and the extract was dehydrated over anhydrous magnesium sulfate and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound as pale yellow crystals. The yield was 71 mg (13.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=O.[OH-].[K+].C(O)C>O>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])/[CH:10]=[CH:11]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CC(=O)c1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1cccc(F)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A mixture of 3-fluorobenzaldehyde (7.63 mL, 72.4 mmol), 3-fluoroacetophenone (10 g, 72.4 mmol), potassium hydroxide (5.18 g, 92.6 mmol), ethanol (23 mL) and water (47 mL) was stirred overnight at room temperature. After the reaction solution was diluted with water, the solid was collected by filtration and washed with ethanol and diethyl ether, to give the title compound (16.4 g, 93%).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=1)[C:7]2=[O:12].N([O-])=O.[Na+].CS(C)=O.[IH:32].C([O-])(O)=O.[Na+]>>[O:18]1[C:17]2[CH:22]=[CH:23][C:14]([CH2:13][N:6]3[CH:5]=[CH:4][C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[I:32])[C:7]3=[O:12])=[CH:15][C:16]=2[O:21][CH2:20][CH2:19]1
Reactant: Nc1cccc2c(=O)n(Cc3ccc4c(c3)OCCO4)ccc12
Reactant: I
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1c2cccc(I)c2ccn1Cc1ccc2c(c1)OCCO2
Reaction time: 1 h

Procedure:
5-Amino-2-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-2H-isoquinolin-1-one (260 mg, 0.00084 mol) was added to a solution of sodium nitrite (200 mg, 0.003 mol) in dimethyl sulfoxide (4 mL, 0.06 mol) at 35° C. Aqueous hydrogen iodide (0.5 mL, 0.004 mol) in dimethyl sulfoxide (4 mL, 0.06 mol) was added, and the reaction mixture was stirred for 1 hour. The cooled reaction mixture was neutralized with sat. aq. NaHCO3 and extracted with methylene chloride (3×50 mL). The combined methylene chloride extracts were washed with brine, dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified via flash column chromatography (12 g of silica gel, 0-50% EtOAc/Hexane) gave a light yellow solid. MS m/z (M+H) 420.0.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([OH:17])[CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1)C.[OH-].[Na+].O>CCO>[OH:17][CH:5]([CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1)[C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(O)C1Sc2ccccc2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(O)C1Sc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of hydroxy-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid ethyl ester (1.12mmol) in 5 mL of EtOH is added NaOH (1N) (2.24 mmol) and the mixture is stirred at room temperature for 1 hour. Water (20 ml) is added into the mixture followed by extraction (EtOAc, 3×10 mL). The aqueous layer is then treated with HCl (1N) (2.5 mL) and extracted with EtOAc (3×30 mL). The combined extracts are washed with brine and dried over MgSO4. After filtering off the drying agent, the solution is concentrated to provide the crude product hydroxy-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid as a off white solid. Yield: 76%. MS: (ES+): 240 [M+1].
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10]([C:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)[S:15][CH:16]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:26][S:27]([O:23][CH:20]1[CH2:21][CH2:22][N:17]([C:14]2[S:15][CH:16]=[C:12]([C:10]([O:9][CH2:8][C:7]3[CH:24]=[CH:25][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:11])[N:13]=2)[CH2:18][CH2:19]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)c1csc(N2CCC(O)CC2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)CC1
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
To a solution of 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-4-hydroxypiperidine (0.75 g, 2.06 mmol) (obtained as described in Reference Example 14(4)) in anhydrous methylene chloride (38 ml) were added methanesulfonyl chloride (0.18 ml, 2.33 mmol) and triethylamine (0.35 ml, 2.51 mmol) in an ice bath. The mixture was brought to room temperature in 10 minutes, and then stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1) as the eluant to afford 4-methanesulfonyloxy-1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)piperidine (0.87 g, yield 96%) as a colorless solid.
Reaction SMILES: [Na].C(O[CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:25])[CH:11]2[NH:15][C:16](=[O:24])[CH2:17][C:18]2[S:19][CH2:20][CH2:21][S:22][CH:23]=2)[C:8]=1[C:26]([OH:28])=[O:27])(=O)C.C(=O)(O)[O-].[Na+].[CH3:34][C:35]1[S:36][C:37](=[S:40])[NH:38][N:39]=1>O.C(OC(C)C)(C)C>[C:26]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][S:40][C:37]1[S:36][C:35]([CH3:34])=[N:39][N:38]=1)[CH:11]([NH:15][C:16](=[O:24])[CH2:17][C:18]1[S:19][CH2:20][CH2:21][S:22][CH:23]=1)[C:10]2=[O:25])([OH:28])=[O:27]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC3=CSCCS3)C2SC1
Reactant: Cc1n[nH]c(=S)s1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)OC(C)C
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC4=CSCCS4)C3SC2)s1
Temperature: 60 °C
Reaction time: 16 h
Yield: 51.4 %

Procedure:
The sodium salt of 3 -acetoxymethyl-2-carboxy-7-[(5,6-dihydro-1,4-dithiin-2-yl )acetamido]-8-oxo-5-thia-1-aza-bicyclo [4,2,0]oct-2-ene (10 g.) is dissolved in distilled water (200 cc.). Sodium bicarbonate (2.25 g.) followed by 2-methyl-5-thioxo-1,3,4-thiadiazoline (3.54 g.) are added to the solution and the mixture is heated with stirring at 60° C. for 16 hours. After cooling, the reaction mixture is washed with ethyl acetate (200 cc.). The pH of the mixture is brought to 6.5 by addition of 4N hydrochloric acid and then the mixture is washed again with ethyl acetate (200 cc.). The mixture is acidified to pH 2 by addition of 4N hydrochloric acid in the presence of ethyl acetate (200 cc.). After decanting the organic phase, the aqueous phase is extracted twice with ethyl acetate (total 200 cc.). The organic extracts are combined, washed three times with water (total 500 cc.), dried over sodium sulphate, treated with decolourizing charcoal, filtered and then concentrated to dryness under reduced pressure (20 mm.Hg). The solid residue obtained is taken up in diisopropyl ether (200 cc.), filtered off and then dried under reduced pressure (2 mm.Hg). 2-Carboxy-7-[(5,6-dihydro-1,4-dithiin-2-yl )acetamido]-3-[(5-methyl-1,3,4-thiadiazol-2-yl )thiomethyl]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (6 g.), melting at 170° C., is thus obtained.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Br:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][C:29]2[S:30][C:31]([CH3:35])=[C:32]([CH3:34])[CH:33]=2)=[CH:26][CH:25]=1>CN(C)C=O>[Br:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][C:29]2[S:30][C:31]([CH3:35])=[C:32]([CH3:34])[C:33]=2[C:9]([C:8]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=2)=[O:11])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Reactant: Cc1cc(Cc2ccc(Br)cc2)sc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2c(Cc3ccc(Br)cc3)sc(C)c2C)cc1C1CCCC1
Yield: 52.7 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (3.50 g, 15.9 mmol, RN-59216-82-9), oxalyl chloride (1.52 mL, 17.5 mmol), N,N-dimethylformamide (2 drops) tin(IV) chloride (2.04 mL, 17.5 mmol) and 2-(4-bromobenzyl)4,5-dimethylthiophene (4.46 g, 15.9 mmol). Purification on silica gel eluting 5% EtOAc/pet. ether gave 4.05 g (53%) of the title compound as yellow oil. (DMSO-d6) δ 1.43-1.47 (m, 2H), 1.61-1.75 (m, 4H), 1.81 (s, 3H), 1.91-1.99 (m, 2H), 2.28 (s, 3H), 3.24 (quintet, 1H), 3.84 (s, 2H), 3.88 (s, 3H), 7.02 (d, 2H), 7.06 (d, 1H), 7.40 (d, 2H), 7.52 (dd, 1H), 7.57 (d, 1H).
Reaction SMILES: [CH2:1]([S:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:7])=O)[CH3:2].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[CH2:1]([S:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)=[O:7])[CH3:2]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CCSC(C(=O)O)(c1ccccc1)c1ccccc1
Product: CCSC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)(c1ccccc1)c1ccccc1

Procedure:
Example 16 was prepared from (ethylsulfanyl)(diphenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 658.6 (M+H)+.
Reaction SMILES: [Br-:1].[K+].BrBr.[C:5]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])(=[O:7])[CH3:6]>O>[C:5]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([Br:1])[C:10]=1[CH:11]=[O:12])(=[O:7])[CH3:6]
Reactant: COc1cccc(C=O)c1OC(C)=O
Reactant: [Br-]
Agent: BrBr
Agent: [K+]
Solvent: O
Product: COc1ccc(Br)c(C=O)c1OC(C)=O
Reaction time: 8 h
Yield: 78.9 %

Procedure:
To a solution of potassium bromide (40 g) in H2O (250 mL) was added bromine (6.8 mL). To the dark red solution was added aldehyde 10 (20.2 g). The turbid orange solution was stirred overnight, filtered, rinsed with ethyl acetate, recrystallized from ethyl acetate/hexane to afford yellow crystals (22.4 g, 79%): m.p. 121.6-123.4° C., lit18 m.p. 119-120° C.; EIMS m/z 274 (M+, 81Br), 272 (M+, 79Br), 232, 230, 186, 184, 43; 1H NMR δ 10.26 (1H, s, CHO), 7.51 (1H, d, J=9.0 Hz, H4), 7.05 (1H, d, J=9.0 Hz H2, H4), 3.85 (3H, s, OCH3), 2.38 (3H, s, COCH3); 13C—NMR (75.5 MHZ) δ 190.38, 168.71, 151.78, 140.37, 131.41, 126.49, 117.69, 116.35, 56.40, 20.44. Anal. Calcd. For C10H9O4Br: C, 43.98; H, 3.32. Found: C, 44.46; H, 3.55.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Br:13]Br>C(Cl)Cl.CCOCC>[Br:13][CH:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Br:1])[C:7]1=[O:12]
Reactant: BrBr
Reactant: O=C1CCCc2c(Br)cccc21
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1c2cccc(Br)c2CCC1Br
Yield: 79.4 %

Procedure:
A clear yellow solution of 5-bromo-3,4-dihydro-1(2H)-naphthalenone (12.09 g, 53.7 mmol) in freshly opened Et2O (220 mL) under an N2 atmosphere was chilled to −5° C. HCl was bubbled in subsurface for 1 min, causing no visible change. The dropwise addition of a solution of Br2 (8.58 g, 53.7 mmol) in CH2Cl2 (20 mL) and Et2O (2 mL) to the vigorously stirring solution of 5-bromo-3,4-dihydro-1(2H)-naphthalenone over 2 h (each drop was allowed to fully decolorize before adding the next) produced a product mixture that assayed by HPLC. Peak area showed 79.4% title compound, 9.5% unreacted 5-bromo-3,4-dihydro-1(2H)-naphthalenone, 0.6% unidentified, and 9.4% 2,2,5-tribromo-1-tetralone. The addition of H2O produced a top light brown organic phase, and a clear, colorless bottom aqueous phase which was separated. After drying with MgSO4, the organic layer was concentrated under vacuum at room temperature to give the crude intermediate title compound as a light brown oil (16.08 g, 98.5%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:17]([OH:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>[O-2].[O-2].[O-2].[Cr+6].O>[CH3:15][NH:14][C:12]([C:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][O:9][C:10]=1[CH2:16][C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:24])=[O:13]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccccc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: CNC(=O)c1c(-c2ccccc2)noc1CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 50 g. (0.155 mole) of 3-phenyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide and 800 ml. acetic acid at room temperature is treated dropwise rapidly with 18.4 g. (0.185 mole) of chromium trioxide in 185 ml. water. The resulting solution is stirred for 2 hours at room temperature and a portion of the acetic acid is removed in vacuo. The remainder is poured onto ice water and extracted with methylene chloride. The methylene chloride layer is washed with 2 N sodium hydroxide, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with hot ether, cooled to 0° C. and filtered to give N-methyl-5-phenacyl-3-phenyl-4-isoxazole carboxamide, m.p. 125° to 128° C.
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1)(=O)=O.[I-:19].[Na+]>CC(C)=O.O>[I:19][C@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](I)C1
Yield: 42.7 %

Procedure:
A solution of tert-butyl N-[(1S,3R)-3-(methanesulfonyloxy)cyclopentyl]carbamate (2.1 g, 7.52 mmol, 1.00 equiv) and sodium iodide (7 g, 46.70 mmol, 6.21 equiv) in acetone (40 mL) was stirred at 50° C. for 30 min. The reaction mixture was diluted with 100 mL of water then extracted with 2×30 mL of ethyl acetate. The combined organic layers was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/5) to give 1.0 g (43%) of tert-butyl N-[(1S,3S)-3-iodocyclopentyl]carbamate as a white solid.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][OH:15].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][O:15][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1
Reactant: OCc1ccco1
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccco2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
To 4 ml of N,N-dimethylformamide, 0.334 g of 5-chloro-3-methylthio-1,2,4-thiadiazole and 0.196 g of 2-furanmethanol were dissolved, and added 0.084 g of sodium hydride (60% in oil) at about 0° C., followed by stirring at about 0° C. for 0.5 hours and at room temperature for 4 hours. Then, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with tert-butylmethylether. The organic layer was concentrated, and the residue obtaind was subjected to silica gel column chromatography to obtain 0.25 g of 5-(2-furyl)methoxy-3-methylthio-1,2,4-thiadiazole.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:28]2[CH2:30][O:29]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:28]([OH:29])[CH2:30][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: COc1ccc(C2CO2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1OC
Reaction time: 0.08 h
Yield: 25.8 %

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.2 g, 6.0 mmol) in 6 mL DMF, was added sodium hydride (720 mg, 12 mmol) under nitrogen at 0° C. and stirred for 5 min. 2-(3,4-Dimethoxy-phenyl)-oxirane (2.16 g, 18 mmol) was diluted in DMF (2 mL) and added dropwise to the reaction mixture under nitrogen atmosphere. The reaction mixture was stirred at RT for 5 h. After consumption of starting material (TLC and LCMS), the reaction mixture was poured in ice-cold water and extracted with EtOAc (3×50 mL). The combined organic layer was washed with water (5×30 mL) and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel 100-200 mesh, eluent: 6% MeOH in DCM) to obtain 590 mg of 1-(3,4-dimethoxy-phenyl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 7.19 (m, 2H), 6.98 (d, 1H), 6.83 (m, 2H), 6.78 (s, 1H), 4.98 (t, 1H), 4.1 (m, 2H), 4.83 (s, 3H), 4.8 (s, 3H), 3.6 (dd, 2H), 2.68-2.88 (m, 3H), 2.53 (m, 1H), 2.5 (s, 3H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers 66a and 66b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([F:33])=[C:15]([C:17]34[CH2:24][CH:23]3[CH2:22][CH2:21][S:20][C:19]([NH:25]C(=O)OC(C)(C)C)=[N:18]4)[CH:16]=2)=[O:9])=[N:6][CH:7]=1>ClCCl.FC(F)(F)C(O)=O>[NH2:25][C:19]1[S:20][CH2:21][CH2:22][CH:23]2[C:17]([C:15]3[CH:16]=[C:11]([NH:10][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)=[O:9])[CH:12]=[CH:13][C:14]=3[F:33])([CH2:24]2)[N:18]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)CC2CCS1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1=NC2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)CC2CCS1
Temperature: 23 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
tert-Butyl (1SR,7SR)-1-(5-(5-chloropicolinamido)-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (intermediate rac-A9a) (29 mg; 0.06 mmol) was dissolved in dichloromethane (3 ml) and at 23° C. trifluoroacetic acid (TFA) (0.8 ml) was added. The yellow solution was stirred for 2 hours at 23° C. The reaction mixture was extracted with sat NaHCO3 solution and dichloromethane. The organic layer was washed with water and brine, the aqueous layers were reextracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and evaporated to give a light yellow oil which was chromatographed on 10 g SiO2—NH2 with dichloromethane+dichloromethane/methanol 19:1 to give the 5-chloro-pyridine-2-carboxylic acid [3-((1SR,7SR)-3-amino-4-thia-2-aza-bicyclo[5.1.0]oct-2-en-1-yl)-4-fluoro-phenyl]-amide (13.34 mg; 58%) as an off white solid. MS (ISP): m/z=391.0 [(M+H)+] and 393.1 [(M+2+H)+].
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C@H:4](/[CH:8]=[CH:9]/[C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]1[CH2:19][C:20]#[C:21][CH2:22][O:23][CH2:24][C:25]#[N:26].[H][H]>[Pd].CO>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][CH2:9][C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]1[CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]#[N:26]
Reactant: [H][H]
Reactant: N#CCOCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N#CCOCCCCN1C(=O)CCC[C@@H]1CCC(=O)Cc1ccccc1
Reaction time: 19 h
Yield: 56.1 %

Procedure:
Palladium on carbon (10 wt. %, 7 mg) was added to a solution of {4-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-but-2-ynyloxy}-acetonitrile (35 mg, 0.10 mmol) in MeOH (3.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 20 mg (56%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]2[NH:12][N:11]=[N:10][N:2]=2)=[CH:4][CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Oc1ccc(-c2nnn[nH]2)cc1
Yield: 83 %

Procedure:
Into the same device as used in Example 1 were placed 1.19 g (0.010 mole) of paracyanophenol, 1.95 g (0.030 mole) of sodium azide, 4.13 g (0.030 mole) of triethylamine hydrochloride and 12 ml of toluene. The mixture was reacted for 8 hours in the same manner as in Example 1, giving 1.34 g (0.0083 mole) of 5-(4-hydroxyphenyl)-1H-tetrazole (yield 82.7% based on paracyanophenol).