Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:20]([OH:22])=[O:21])[N:7]([CH2:17][CH2:18]Br)[CH:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:32]([SH:34])[CH3:33]>ClCCl>[C:1]([O:5][CH:6]([C:20]([OH:22])=[O:21])[N:7]([CH2:17][CH2:18][S:34][CH2:32][CH3:33])[CH:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCS
Reactant: CC(C)(C)OC(C(=O)O)N(CCBr)C(OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCSCCN(C(OC(C)(C)C)C(=O)O)C(OC(C)(C)C)C(=O)O

Procedure:
3.52 g (10 mmol) of N,N-bis-(tert-butoxycarboxy-methyl)-2-bromoethylamine is dissolved in 50 ml of absolute dichloromethane and mixed with 1.29 g (10 mmol) of diisopropylethylamine and 0.621 g (10 mmol) of ethylmercaptan. The reaction mixture is refluxed overnight. Then, the solution is extracted twice with semi-saturated, aqueous sodium bicarbonate solution. The organic phase is dried on sodium sulfate, and the solvent is evaporated in a vacuum. The residue is chromatographed on silica gel (eluant: dichloromethane/methanol 99:1).
Reaction SMILES: CC([S@@]([NH:7][C@@:8]1([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[O:11][CH2:10][CH2:9]1)=O)(C)C.[ClH:28].O1CCOCC1>CCO>[ClH:28].[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[C@:8]1([NH2:7])[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[O:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)[S@](=O)N[C@]1(c2ccc3ccccc3c2)CCOc2cccnc21
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: N[C@]1(c2ccc3ccccc3c2)CCOc2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-methyl-N—((S)-4-(naphthalen-2-yl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)propane-2-sulfinamide (45 mg, 0.118 mmol) in EtOH (0.4 mL) was added 4M HCl in 1,4-dioxane (0.059 mL, 0.237 mmol). The mixture was stirred at room temperature for 1 h. The mixture was concentrated and dried in vacuo to give the title compound, which was used in the next step without further purification. MS (ESI, positive ion) m/z: 277.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)(=[O:7])=[O:6].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])=O>>[CH3:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:2]([CH3:1])[C:3]=1[CH2:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])(=[O:7])=[O:6]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2

Procedure:
5-[(2,6-Dimethylbenzyl)sulfonyl]-1,3-dihydro-indol-2-one (315 mg, 1 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (170 mg, 1 mmol) to give the titled compound as an orange-brown solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11](O)=[O:12])[C:2]=1[C:14](O)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:12][CH2:11][C:3]1[C:2]([CH2:14][OH:15])=[CH:1][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: O=C(O)c1cc2ccccc2cc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2ccccc2cc1CO
Reaction time: 3 h
Yield: 84.8 %

Procedure:
A solution of 2,3-naphthalenedicarboxylic acid (4.6 g, 0.023 mole) in dry THF (135 mL, wanned to 50° C. to maintain solution) is added dropwise over 15 minutes to a 1.15 M lithium aluminum hydride solution in THF (45 mL, 0.052 mole). The solution is stirred 3 hours after which TLC indicated consumption of diacid and formation of a new major product. The reaction is quenched carefully with THF-water, then 2N hydrochloric acid (40 mL) is added, and the resulting mixture is extracted 3 times with ether. The combined ether extracts are washed with water (2 times), with saturated sodium bicarbonate solution (1 time), with water, and are dried (sodium sulfate), filtered, and concentrated to give a tan solid (3.67 g). The solid is recrystallized from ethyl acetate giving the title compound (2.91 g) as a light tan crystalline material, mp 161°-162° C. (lit. ref mp 160° C.).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>C(Cl)Cl.CCOCC>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[O:21])=[CH:15][CH:14]=1
Reactant: OCCc1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a stirred suspension of pyridinium chlorochromate (6.9 g, 21.4 mmol) in CH2Cl2 (100 ml) was added a solution of 2-(4-fluorophenyl)ethanol (3.0 g, 21.4 mmol) in CH2Cl2 (10 ml). The resulting suspension was stirred for 2 hours at room temperature and was then diluted with ether. The resulting suspension was filtered through a pad of Celite and washed with ether. The solvents were removed under reduced pressure to yield the crude title compound as a green oil (2.6 g, 86%), which was used as such for further reaction.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:28]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1)[CH3:29]>C(#N)C>[I:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:28]([C:30]4[CH:35]=[N:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[CH3:29])=[C:14]([O:19][CH3:20])[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(Cn2cnc3cc(I)cnc32)ccc1O
Reactant: COc1ccc(C(C)Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(C)Oc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 49.3 %

Procedure:
To a stirred mixture of 4-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-methoxyphenol (1.32 g, 3.46 mmol) and potassium carbonate (1.30 g, 9.41 mmol) in acetonitrile (25 mL) was added 5-(1-chloroethyl)-2-methoxypyridine (0.72 g, 4.20 mmol). The mixture was heated at 100° C. After 6.5 h, an additional quantity 5-(1-chloroethyl)-2-methoxypyridine (0.300 g, 1.75 mmol) was added, and heating was continued. After 22 h, the mixture was allowed to cool to room temperature and was partitioned between water and 1:5 ethyl acetate/diethyl ether. The phases were separated, and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (40 g SiO2 column, 0-10% 0.01 M ammonia in methanol/dichlormethane elute) afforded 0.88 g (49%) of 6-iodo-3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine as an impure solid.
Reaction SMILES: I[CH2:2][CH3:3].[F:4][C:5]1[CH:6]=[CH:7][C:8]([OH:30])=[C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]3[CH:17]=2)[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[CH2:28]([O:27][C:25]([C:24]1[CH:23]=[N:22][N:19]2[CH:20]=[CH:21][C:16]([N:12]3[CH2:13][CH2:14][CH2:15][C@@H:11]3[C:9]3[CH:10]=[C:5]([F:4])[CH:6]=[CH:7][C:8]=3[O:30][CH2:2][CH3:3])=[CH:17][C:18]=12)=[O:26])[CH3:29]
Reactant: CCI
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCC)cc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Iodoethane (0.17 g, 1.08 mmol) was added to a mixture of (R)-ethyl 5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (Int-76) (0.2 g, 0.54 mmol) and K2CO3 (0.23 g, 1.62 mmol) in CH3CN (10 mL) and continued stirring at 80° C. for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by column chromatography (using silica gel and 2% ethyl acetate in hexane as eluent) to afford the desired compound (Int-77). MS (ESI): m/z 398.1 (M+H).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[CH:4]=1.[CH2:18]([C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O.C1(C)C=CC=CC=1>[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([N:17]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:31]3)[C:5]=2[CH:4]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Yield: 67.9 %

Procedure:
Heat a suspension of 2-methyl-4H-3-thia4,9-diaza-benzo[f]-azulen-10-ylamine hydrochloride (466 mg, 1.75 mmol) and 2-(S)-phenethyl-piperazine (1.0 g, 5.3 mmol) in DMSO (2.5 mL) and toluene (10 mL) at reflux for 48 hours. Evaporate the toluene under vacuo and pour the resulting solution into water (10 mL). Purify the resulting brown solid by flash chromatography eluting with methylene chloride/methanol (95:5) to give 2-methyl-10-(3-(S)-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene as a yellow solid (478 mg, 65%): mp 75–84° C.; 1H NMR(CDCl3): δ1.76 (m, 2H), 2.31 (s, 3H), 2.60 (dd, 1H), 2.71 (m, 2H), 2.80 (m, 1H), 2.92 (m, 2H), 3.04 (m, 1H), 3.96 (m, 1H), 4.12 (m, 1H), 4.91 (s, 1H), 6.29 (s, 1H), 6.60 (d, 1H), 6.89 (t, 1H), 6.96 (t, 1H), 7.03 (d, 1H), 7.15–7.30 (m, 5H); MS (APCI) m/z (rel intensity) 403 (100).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9])#[N:2].N1C=CC=CC=1.[CH3:16][CH2:17][O:18]CC>C(OC(=O)C)(=O)C>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:17](=[O:18])[CH3:16])#[N:2]
Reactant: N#CCCCCCCO
Reactant: CCOCC
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCCCCCC#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6-Cyano-1-hexanol (7.1 g, 55.8 mmol) was dissolved in 30 mL of acetic anhydride under argon atmosphere. To this material was added 5.3 mL (65.4 mmol) of pyridine dropwise and the mixture was left to stir for 2 hours. The contents of the flask were then poured into a beaker containing 50 mL of ice water and the material was stirred for 15 minutes. The mixture was transferred to a 250 mL separatory funnel and ether (100 mL) was added. After shaking the ether phase was isolated and the aqueous phase washed twice more with ether (2×100 mL). The combined ether phase was washed with brine, dried (MgSO4) and filtered. Evaporation (rotary evaporator and vacuum pump) provided 6-cyano-1-acetoxyhexane (the compound of formula (C)) which was used immediately in the next step.
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O>C1(C)C=CC=CC=1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][C:20]3[CH:28]=[CH:27][C:23]([C:24](=[O:25])[NH2:26])=[CH:22][N:21]=3)[CH:15]=2)[CH2:10]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1Cc2ccc(Oc3ccc(C(N)=O)cn3)cc2C1
Temperature: 25 °C

Procedure:
Combine N-Boc-5-hydroxy-2-aminoindane (2.50 g, 10.0 mmol), 6-chloronicotinamide (1.49 g, 9.55 mmol K2CO3 (1.90 g, 14.3 mmol), DMA (25 ml) and toluene (20 ml) in a round bottom flask, equipped with Dean-Stark trap, condenser, and nitrogen inlet. Reflux the suspension for two hours before cooling to ambient temperature. Remove the solids via filtration, wash solids with EtOAc, and concentrate the filtrate/wash on a rotary evaporator. Dissolve the remaining oil in EtOAc, wash with water (2×) and brine, dry (MgSO4) and concentrate. Purify the material on silica gel (20% THF/DCM) to give [5-(5-carbamoyl-pyridin-2-yloxy)-indan-2-yl]carbamic acid tert-butyl ester (870 mg) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([O:22]CC)=O.[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1.Cl>>[CH:25]1([NH:30][C:20]([C:3]2[C:4](=[O:19])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[C:8]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=3)=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Agent: Cl
Product: O=C(NC1CCCC1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclopentylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.75 (1H, br), 8.24 (1H, s), 7.35 (1H, s), 7.32-7.20 (5H, m), 4.21 (1H, m, J=6.7 Hz), 4.04 (2H, s), 1.93-1.35 (8H, m); Anal. Calcd for C21H21N3O3.1.90 HCl: C, 58.29; H, 5.33; N, 9.71. Found: C, 58.31; H, 5.33; N, 9.85.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:16]([Cl:17])=[C:15]2[C:11]([CH2:12][C:13]([CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)([CH3:19])[C:14]2=[O:18])=[CH:10][C:9]=1[OH:26].[F:27][C:28]([F:34])([F:33])[S:29](Cl)(=[O:31])=[O:30]>CN(C)C=O>[F:27][C:28]([F:34])([F:33])[S:29]([O:26][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([Cl:17])[C:8]=1[Cl:7])[C:14](=[O:18])[C:13]([CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25]1)([CH3:19])[CH2:12]2)(=[O:31])=[O:30]
Reactant: CC1(CC2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(CC2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Anhydrous potassium carbonate (17.7 g., 0.128 mole) is added to a solution of 6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (13.35 g., 0.0426 mole) in dry dimethylformamide (60 ml.) The suspension is stirred for 1 hour at room temperature, cooled to 15° C. and then trifluoromethanesulfonyl chloride is added at 15°-18° C. After stirring for 1 hour at room temperature, the reaction mixture is poured into ice water (700 ml.). The oil that separates is extracted with ether (125 ml.). The combined organic extracts are washed with water, dried over magnesium sulfate and concentrated in vacuo to obtain the amber, oily product (18.8 g.), which is used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:25](O)(=[O:29])/[CH:26]=[CH:27]/[CH3:28].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:25]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:29])/[CH:26]=[CH:27]/[CH3:28]
Reactant: C/C=C/C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C/C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Yield: 97.9 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (2.6 mL), crotonic acid (1.6 g), WSC.HCl (3.6 g), and methylene chloride (110 mL), to give the captioned compound (4.4 g, 98%) as an oily product.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5](=[O:12])[C:4]=1[CH:13]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19].C(OC(C)C)(C)C>O1CCCC1>[CH3:2][C:3]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5](=[O:12])[C:4]=1[CH:13]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1cccs1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CC1=C(C)C(=O)C(C(CCCCC(=O)O)c2cccs2)=C(C)C1=O
Temperature: 70 °C
Reaction time: 17 h
Yield: 70.6 %

Procedure:
6N Hydrochloric acid (10 ml) was added to a solution of ethyl 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-(2-thienyl)hexanoate (1.7 g, 4.5 mmole) in tetrahydrofuran (10 ml), followed by stirring for 17 hours with heating at 70° C. After cooling, isopropyl ether was added to the mixture, and the organic layer was washed twice with water, dried and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with isopropyl ether-ethyl acetate (1:1), followed by recrystallization from isopropyl ether to give 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-(2-thienyl)hexanoic acid (1.1 g, 70%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([Cl:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.Cl>>[ClH:32].[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)(=[O:31])=[O:30])=[CH:27][CH:28]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Agent: Cl
Product: COc1ccc(S(=O)(=O)n2cc(C3=CCN(C)CC3)c3cc(C(F)(F)F)ccc32)cc1

Procedure:
(22.2 mg, 69%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and 4-methoxyphenylsulfonyl chloride (22.1 mg, 0.107 mmol). HRMS-FAB+ for C22H21N2O3SF3.HCl, calculated MH+ : 451.13031; found: 451.13007.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]([O:22]C)=O)[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH3:18])=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:19]=1.O.[NH4+:25]>>[F:1][C:2]1[CH:3]=[C:4]([C:20]([NH2:25])=[O:22])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH3:18])=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:19]=1
Reactant: [NH4+]
Reactant: CNCc1ccc(-c2nc3cc(F)cc(C(=O)OC)c3o2)cc1
Solvent: O
Product: CNCc1ccc(-c2nc3cc(F)cc(C(N)=O)c3o2)cc1
Yield: 22 %

Procedure:
Methyl 5-fluoro-2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (25 mg, 0.06 mmol) in ammonium water (2 mL) was stirred at 30° C. for 17 hr and the solvents were evaporated; the residue was purified by pre-HPLC to obtain 5-fluoro-2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide as a white solid (4 mg, yield 22%). 1H-NMR (400 MHz, MeOD-d4) δ 2.07 (s, 1H), 2.41 (s, 3H), 3.85 (s, 2H), 7.52-7.55 (m, 2H), 7.57-7.61 (m, 2H), 8.25-8.27 (d, J=7.6 Hz, 2H); LC-MS (ESI) m/z 300 [M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)=[O:4].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][NH2:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[Cl:13][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:25][CH2:24][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(CCl)Nc1cc(Cl)cc(Cl)c1
Product: COc1ccc(CNCC(=O)Nc2cc(Cl)cc(Cl)c2)cc1OC

Procedure:
In a manner similar to Preparation 12, react 2-chloro-N-(3,5-dichlorophenyl)acetamide with (3,4-dimethoxyphenyl)methanamine to obtain the title compound.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O)[CH2:2][CH:3]=[CH2:4].[CH2:13]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[CH2:13])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOC1CCCCC1=O
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=CCCOC1CCCCC1=C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of methyltriphenylphosphonium bromide (22.30 g, 62.4 mmol) in THF (125 mL) at rt was added sodium hexamethyldisilylazide (2M in THF, 31.2 mL, 62.4 mmol) dropwise. The mixture was heated to 60° C. for 1 hr. 2-(but-3-en-1-yloxy)cyclohexanone (7.0 g, 41.6 mmol.) was then added and the mixture was stirred at 60° C. for 3 hr. The reaction was cooled to rt, quenched with sat'd. aq.NH4Cl, and extracted with Et2O. The combined organics were dried filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 5.78-5.90 (m, 1H), 5.00-5.13 (m, 2H), 4.82 (s, 1H), 4.78 (s, 1H), 3.74 (dd, 1H, J=3.9 Hz, 6.3 Hz), 3.35-3.49 (m, 2H), 1.12-2.38 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H][H]>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(C=C2NC(=O)NC2=O)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COc1ccc(CC2NC(=O)NC2=O)cc1OCc1ccccc1
Yield: 47 %

Procedure:
A solution of 16.20 g (0.05 mole) of the benzylidene hydantoin from Example 4 in 100 mL of methanol and 25.0 g (0,055 mole) of 20% tetramethylammonium hydroxide-in-methanol is reduced with hydrogen and Raney nickel catalyst. After the theoretical uptake of hydrogen the mixture is filtered and acetic acid (ca 5 mL) and then water is added until just turbid. The first crop of solid is filtered. This is starting material. An additional 2 L of water is added to precipitate the product as crop 2; wt 7.60 g (47% yield). Recrystallization from methanol gives pure product; mp 155°-157° C.
Reaction SMILES: [CH3:1][C:2](=O)[C:3](=O)[CH2:4][CH2:5][CH3:6].[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH2:12].C(O)=O>CO>[CH3:1][C:2]([C:3]([CH2:4][CH2:5][CH3:6])=[N:12][C:11]1[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:10]=1[CH3:9])=[N:12][C:11]1[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:10]=1[CH3:9]
Reactant: CCCC(=O)C(C)=O
Reactant: Cc1cccc(C)c1N
Solvent: CO
Solvent: O=CO
Product: CCCC(=Nc1c(C)cccc1C)C(C)=Nc1c(C)cccc1C
Reaction time: 6 h

Procedure:
2,3-Hexanedione (4.0 mL, 33 mmol) was slowly added to the mixture of 2,6-dimethylaniline (10 g, 80 mmol) and 0.2 mL formic acid in 25 mL of methanol. The mixture was stirred for 6 hours. After this time period, the solvent and excess of aniline were removed under vacuum. The residual viscous oil was dissolved in n-pentane and cooled to give a yellow solid which was recrystallized from n-pentane. The product, 2-methyl-3-propyl-1,4-bis(2,6-dimethylphenyl)-1,4-diaza-1,3-butadiene was isolated as yellow crystals (1.9 g, 18%). 1H NMR (200 MHz, CDCl3, δ, ppm): 0.84 t (3H, J=7.28 Hz, (CH2)2CH3); 1.52 m (2H, CH2CH2CH3); 2.03 s (3H, N═CCH3); 2.05 s and 2.06 s (6H and 6H, 2,6- and 2′,6′-CH3); 2.50 m (2H, CH2CH2CH3); 6.89-7.15 m (6H, 2×C6H3). 13C NMR (50.3 MHz, CDCl3, δ, ppm): 14.59 (CH2CH2CH3); 16.38 (N═CCH3); 17.96 and 18.03 (0.2,6- and 2′, 6′-CCH3); 20.28 (CH2CH2CH3); 31.24 (CH2CH2CH3); 123.13 and 123.18 (4- and 4′-CH); 124.67 and 124.75 (2,6 and 2′,6′-C); 127.94 and 127.98 (3,5- and 3′,5′-CH); 147.99 (140 -C); 148.51 (1-C); 167.61 (N═CMe); 171.52 (N═CPr).