Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:13]2=[O:30])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[C:31]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]3([C:11]4[C:2](=[CH:3][C:4]5[O:8][N:7]=[C:6]([CH3:9])[C:5]=5[CH:10]=4)[O:1][CH2:31]3)[C:13]2=[O:30])=[CH:27][CH:26]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: COc1ccc(CN2C(=O)C(c3cc4c(C)noc4cc3O)c3ccccc32)cc1
Product: COc1ccc(CN2C(=O)C3(COc4cc5onc(C)c5cc43)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(4-methoxybenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 138-139° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J=9.0 Hz, 2H), 7.35 (d, J=9.0 Hz, 2H), 7.21-7.18 (m, 1H), 7.11-7.09 (m, 1 H), 6.96 (d, J=9.0 Hz, 1H), 6.94-6.88 (m, 2H), 6.79 (d, J=9.0 Hz, 1H), 5.16-4.79 (m, 4H), 3.78 (s, 3H), 2.45 (s, 3H); MS (ES+) m/z 412.9 (M+1).
Reaction SMILES: [O:1]=[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[NH:14][C:15](=O)[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=2)[CH2:4][CH2:3]1.[CH2:24]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[O:1]=[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[N:14]=[C:15]([NH:39][CH:36]3[CH2:37][CH2:38][N:34]([C:32]([O:31][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:33])[CH2:35]3)[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2s1
Reactant: NC1CCN(C(=O)OCc2ccccc2)C1
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(NC3CCN(C(=O)OCc4ccccc4)C3)c2s1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 3 by using 2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthieno[3,2-d]pyrimidin-4(3H)-one and benzyl-3-amino-1-pyrrolidinecarboxylate. MS obsd. (ESI+) [(M+H)+] 548.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1.CN(C=O)C.[C:23]1([C:29](=O)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]/[C:29](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)O/C(=C/c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
Oxalyl dichloride (236 μl, 2.78 mmol) was added dropwise to a solution of 1-methylpiperidine-4-carboxylic acid hydrochloride (500 mg, 2.78 mmol) in DCM (30 ml) and few drops of DMF (catalytic amount). The reaction was stirred at room temperature for 2 hours. The volatiles were removed under vacuum, and the crude was taken up with pyridine (40 ml). 1,2-Diphenylethanone (546 mg, 2.78 mmol) was added, and the resulting suspension was heated under microwave irradiation at 140° C. for 1 hour. Pyridine was removed under vacuum, and the crude was purified by flash chromatography (DCM/MeOH=95/5) to obtain (E)-1,2-diphenylvinyl 1-methylpiperidine-4-carboxylate (62 mg).
Reaction SMILES: [F:1][C:2]([F:19])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(N(CC)CC)C.[CH:27]([S:35](Cl)(=[O:37])=[O:36])=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:29]1([CH:28]=[CH:27][S:35]([N:16]2[CH2:17][CH2:18][N:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][C:2]([F:1])([F:19])[CH:3]([F:4])[F:5])=[CH:8][CH:9]=3)[CH2:14][CH2:15]2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: FC(F)C(F)(F)Oc1ccc(N2CCNCC2)cc1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C=Cc1ccccc1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine (1.39 g, 0.005 mol) was dissolved in DCM (250 ml) and triethylamine (2.1 ml, 0.015 mol) was added. This was cooled to 0° C. and styrene sulphonyl chloride (CAS Number 52147-97-4, 1.11 g, 0.0055 mol) was added. Allowed to reach ambient temperature and stirred overnight. Washed with H2O and separated off the organic phase. Dried over MgSO4, filtered and evaporated to dryness to an oil which was purified by flash column chromatography (Merck 9385 silica), eluting with 80% iso-hexane/ethyl acetate to yield 1-[(-2-phenylvinyl)sulphonyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine as a yellow solid. Yield 650 mg (25%)
Reaction SMILES: [C:1]([N:4]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][CH:24]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:36])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[K+]>O1CCCC1.CO>[C:1]([N:4]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][CH:24]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:36])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCN(CC)C(CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)C(CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1)C(=O)O
Temperature: 50 °C
Yield: 55 %

Procedure:
Methyl 4-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydro-quinolin-1(2H)-yl]carbonyl}phenoxy)-2-(diethylamino)butanoate was hydrolyzed to the acid by dissolving in 6 ml tetrahydrofuran/methanol (1/1) and potassium hydroxide (0.04 g in 2 ml water) was added. The mixture was heated to 50° C. for 18 hours. The mixture was cooled to room temperature and concentrated. Then neutralized with 1M HCl and extracted with dichloromethane. The dichloromethane solution was dried and concentrated. The residue was purified by silica gel chromatography (87% CH2Cl2/13% methanol) to afford 4-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2-(diethylamino)butanoic acid (0.04 g, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([Cl:10])=[O:9])=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Cl>CCOCC.O1CCOCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:9])=[CH:4][CH:3]=1.[ClH:10].[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)Cl
Reactant: CN1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN1CCN(C(=O)C(C)(C)Oc2ccc(Br)cc2)CC1

Procedure:
1-(2-(4-Bromophenoxy)-2-methylpropanoyl)-4-methylpiperazine was prepared in accordance to the procedure described in Example 29(a) from 2-(4-bromophenoxy)-2-methylpropanoyl chloride and 1-methylpiperazine (5.3 mL, 17.5 mmol). This compound (2.37 g, 6.95 mmol) was dissolved in Et2O and HCl in dioxane (4M, 2.26 mL) was added dropwise with stirring. The precipitate was filtered off and dried to yield the sub-title compound (2.5 g, 95%).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[NH2:17][CH2:18][CH2:19][SH:20]>>[CH3:10][O:9][C:8]1[C:3]([CH2:2][S:20][CH2:19][CH2:18][NH2:17])=[N:4][CH:5]=[CH:6][C:7]=1[O:11][CH3:12]
Reactant: NCCS
Reactant: COc1ccnc(CO)c1OC
Solvent: O=S(Cl)Cl
Product: COc1ccnc(CSCCN)c1OC

Procedure:
3-Fluoro-2-methyl-4-nitropyridine N-oxide is treated with an excess of sodium methoxide and the product is heated in acetic anhydride and deacetylated to give 2-hydroxymethyl-3,4-dimethoxypyridine. 2-Hydroxymethyl-3,4-dimethoxypryidine is treated with thionyl chloride and the product is treated with cysteamine to give 2-(3,4-dimethoxy-2-pyridylmethylthio)ethylamine.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[C:16]1[C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([C:30](=[O:37])[NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:24]=3[O:23][C:22]3[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12]2)=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>O>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][NH:31][C:30]([C:25]1[C:24]2[O:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[C:11]3[CH2:10][CH:9]4[NH:8][CH:13]([CH2:14][CH2:15]4)[CH2:12]3)[C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:37].[C:40]([OH:42])([C:39]([F:44])([F:43])[F:38])=[O:41]
Reactant: CN(C)CCNC(=O)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C)CCNC(=O)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2

Procedure:
Compound 2m was treated with a 95:5 mixture of trifluoroacetic acid:water at rt, and the mixture was lyophilized, yielding the title compound 15 as a TFA salt.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28]>>[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)=[O:23])[CH2:32][CH2:31]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(C(=O)N3CCN(S(C)(=O)=O)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 1-methanesulfonylpiperazine.
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)=[O:5].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)C>C1(C)C(C)=CC=CC=1>[CH2:25]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:2]2[N:17]=[CH:16][CH:15]=[CH:14][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)=[O:5])[CH2:20][CH2:21]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Nc1cccc(Cl)c1)c1cccnc1Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(Cl)c1)c1cccnc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
A solution of 2-chloro-(N-3-chlorophenyl)nicotinamide (280 mg, 1.05 mmol, 1.05 eq) prepared in Preparation Example 5, 4-amino-1-benzylpiperidine (1.0 mmol), and anhydrous potassium carbonate (1.3 mmol) in ortho-xylene was stirred for 24 hrs under reflux. The reaction mixture was cooled to a room temperature, added with ethylacetate, and extracted twice with 1N HCl. The aqueous layer thus formed was washed with 30 ml of ethylacetate, adjusted to a pH of about 9-10 by adding 2 N sodium hydroxide, and extracted two or three times with 20 ml of methylene chloride. The organic layer was dried over a desiccant, and concentrated in a reduced pressure. A desired fraction obtained by purification through silica gel chromatography was concentrated in a reduced pressure and dried in a vacuum to afford the title compound. Yield: 66.5% 1H NMR (DMSO-d6) δ8.15˜8.30 (m, 2H), 8.03 (d, 1H), 7.90 (s, 1H), 7.66 (d, 1H), 7.60 (d, 1H), 7.30˜7.60 (m, 6H), 7.19 (d, 1H), 6.70 (m, 1H), 4.10 (bs, 1H), 3.95 (s, 1H), 2.85˜3.15 (m, 2H), 2.70˜2.85 (m, 2H), 1.90˜2.15 (m, 2H), 1.60˜1.85 (m, 2H) ppm.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:11](=[O:12])[C:5](=[CH:4][NH:23][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:16])[N:22]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cccc(N)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1cccc(C)n1)C(=O)OCC
Yield: 106.4 %

Procedure:
Add diethyl ethoxymethylenemalonate (10.0 ml, 55.0 mmol) to a solution of 6-methyl-pyridin-2-ylamine (5.41 g, 50.0 mmol) in toluene (100 ml). Heat the mixture under reflux overnight. Evaporate the solvent in vacuo to provide 2-[(6-methyl-pyridin-2-ylamino)-methylene]-malonic acid diethyl ester (14.8 g) as a white solid. MS (ES+): 279 (M+H).
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](OC)(OC)OC>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:10][O:9][C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(OC)OC
Reactant: O=C1CCCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC1=CCCCCCC1
Yield: 75.2 %

Procedure:
In the presence of 0.2 g of para-toluenesulfonic acid, 16.5 g (0.13 mol) of cyclooctanone and 16.5 g (0.15 mol) of trimethyl orthoformate were stirred at room temperature for four hours. The resultant mixture was heated at 100° C. for 14 hours. The vacuum distillation of the mixture gave 13.7 g (75% in yield) of 1-methoxycyclooctene having a boiling point of 83° to 88° C./27 mmHg.
Reaction SMILES: [CH2:1]([P:3](Cl)([CH2:5][O:6][S:7]([C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])(=[O:9])=[O:8])=[O:4])[CH3:2].[CH:19]([OH:23])([CH2:21][CH3:22])[CH3:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([P:3]([CH2:5][O:6][S:7]([C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])(=[O:9])=[O:8])(=[O:4])[O:23][CH:19]([CH2:21][CH3:22])[CH3:20])[CH3:2]
Reactant: CCP(=O)(Cl)COS(=O)(=O)c1c(C)cccc1Cl
Reactant: CCC(C)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)OP(=O)(CC)COS(=O)(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of 5.83 g of P-ethyl[[(2-chloro-6-methylphenyl)sulfonyloxy]-methyl]phosphinoyl chloride (Example 51) and 0.2 g of 4-dimethylaminopyridine (DMAP) in 15 ml of methylene chloride at 10° C. was added dropwise over 10 minutes a solution of 1.52 g of sec-butanol and 2.32 g of triethylamine in 8 ml of methylene chloride. After 1 hour, the cooling bath was removed and the reaction was warmed to room temperature and stirred an additional two hours. The reaction mixture was diluted with ethyl acetate, 20 ml, ether, 50 ml, and water, 60 ml, and the organic phase was separated, washed with an additional 50 ml of water, dried with magnesium sulfate, filtered and concentrated. The resulting oil was dissolved in 4 ml of methylene chloride and flash chromatographed on Merck silica gel using blends of ethyl acetate and hexanes. Similar fractions were combined to yield 3.2 g of desired product as a tan oil.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[SH:26]>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][S:26][C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Sc1cccs1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CSc2cccs2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and thiophene-2-thiol. m/e+ 351 for C20H19N2S2 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.53 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.29 (dd, J=1.1, 5.1 Hz, 1H), 7.20 (d, J=8.0 Hz, 2H), 7.04 (dd, J=1.4, 9.1 Hz, 1H), 6.95 (dd, J=1.1, 3.6 Hz, 1H), 6.87 (dd, J=3.6, 5.5 Hz, 1H), 4.40 (s, 2H), 2.37 (s, 3H), 2.33 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3, δ) 145.528, 144.436, 137.718, 135.777, 132.167, 131.485, 131.098, 129.437, 128.391, 128.057, 127.944, 122.074, 121.711, 117.032, 114.621, 33.849, 21.527, 18.699 ppm.
Reaction SMILES: [CH3:1]C1C=C(O)C=CC=1O.CC1C(C)=C(C=CC=1O)O.[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([CH:27]=1)[OH:26]>[O-2].[O-2].[Mn+4].CO>[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([OH:26])[C:27]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: Cc1cc(O)ccc1O
Agent: [Mn+4]
Agent: Cc1c(O)ccc(O)c1C
Agent: [O-2]
Solvent: CO
Product: Cc1c(C)c(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into an autoclave (inner volume: 9 ml, made of SUS 316, equipped with a manometer) were charged 0.111 g of methylhydroquinone, 3.463 g of methanol and 4.6 mg of manganese dioxide (manufactured by High Purity Chemicals Co.). The reaction was started by elevating the temperature up to 350° C. with sand bath. The pressure during the reaction was 16 MPa. After 2 hours, the autoclave was quickly cooled and the reaction solution was taken out from the autoclave when the temperature was cooled back to the room temperature. The measurement according to the process described above revealed that the conversion of methylhydroquinone was 45% by mole, the selectivity of dimethylhydroquinone was 64% by mole, the selectivity of trimethylhydroquinone was 17% by mole and no tetramethylhydroquinone was produced. As byproducts, methyl ethers of dimethylquinone and trimethylquinone, represented by the formulae shown above, were formed with a selectivity of 6% and 2%, respectively.
Reaction SMILES: C([C@H]1CC[C@H](OC2C=C3C(=CC=2)N=C(CN2CC(C(O)=O)C2)C=C3C(F)(F)F)CC1)(C)(C)C.C[O:35][C:36]([CH:38]1[CH2:41][N:40]([CH2:42][C:43]2[CH:52]=[C:51]([CH:53]3[CH2:55][CH2:54]3)[C:50]3[C:45](=[CH:46][CH:47]=[C:48]([O:56][C@H:57]4[CH2:62][CH2:61][C@H:60]([C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:59][CH2:58]4)[CH:49]=3)[N:44]=2)[CH2:39]1)=[O:37]>>[C:63]([C@H:60]1[CH2:59][CH2:58][C@H:57]([O:56][C:48]2[CH:49]=[C:50]3[C:45](=[CH:46][CH:47]=2)[N:44]=[C:43]([CH2:42][N:40]2[CH2:39][CH:38]([C:36]([OH:37])=[O:35])[CH2:41]2)[CH:52]=[C:51]3[CH:53]2[CH2:54][CH2:55]2)[CH2:62][CH2:61]1)([CH3:66])([CH3:64])[CH3:65]
Reactant: COC(=O)C1CN(Cc2cc(C3CC3)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C(F)(F)F)c3c2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C4CC4)c3c2)CC1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid using 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid methyl ester as starting material. ESI-MS(M+H+): 437.3; 1H NMR (400 MHz, METHANOL-d4) Shift 7.97 (d, J=9.04 Hz, 1H), 7.70 (d, J=2.76 Hz, 1H), 7.41 (dd, J=2.64, 9.16 Hz, 1H), 7.08 (s, 1H), 4.71 (s, 2H), 4.36-4.59 (m, 5H), 3.70-3.86 (m, 1H), 2.38-2.51 (m, 1H), 2.30 (d, J=10.54 Hz, 2H), 1.85-1.99 (m, 2H), 1.37-1.53 (m, 2H), 1.19-1.34 (m, 4H), 1.05-1.19 (m, 1H), 0.92 (s, 9H), 0.81-0.89 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.Br[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(Br)nc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Yield: 52.1 %

Procedure:
A solution of 399 (1 g, 2.40 mmol) and 6-bromonicotinaldehyde (450 mg, 2.40 mmol) in 1,4-dioxane (10 mL) was treated sequentially with bis-trimethyl tin (500 μA, 787 mg, 2.40 mmol) and Pd(PPh3)4 (270 mg, 0.24 mmol). The reaction mixture was then heated to reflux under nitrogen overnight, cooled, and concentrated. The crude product was purified by flash chromatography using the gradient 5%-10% MeOH in DCM and subsequent trituration by MeOH, providing pure 400 (494 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.11 (s, 1H), 9.10 (m, 1H), 8.65 (d, 1H, J=5.2 Hz), 8.62 (s, 1H), 8.51 (d, 1H, J=8.8 Hz), 8.48 (dd, 1H, J=2.8 Hz, J=10.4 Hz), 8.38 (dd, 1H, J=2.1 Hz, J=8.2 Hz), 8.20 (m, 1H), 7.73 (t, 1H, J=9.0 Hz), 7.01 (d, 1H, J=5.5 Hz). MS (m/z): (M+1) 395.9.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:61][CH:62]=[CH:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: N=C(OCC=Cc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (50 mg in 1.5 ml 33% methylene chloride in cyclohexane), cinnamyl trichloroacetimidate (26 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 15 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (10 mg).