Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:11][C:12]1([CH3:21])[O:16][CH:15]([CH2:17][CH2:18]CO)[CH2:14][O:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][CH2:17][CH:15]2[CH2:14][O:13][C:12]([CH3:21])([CH3:11])[O:16]2)[CH:3]=1
Reactant: Brc1c[nH]c2cnccc12
Reactant: CC1(C)OCC(CCCO)O1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCC(CCn2cc(Br)c3ccncc32)O1
Yield: 199.9 %

Procedure:
A mixture of Example 695J (118 mg, 0.6 mmol), 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-propan-1-ol (131.6 mg, 0.9 mmol), polymer-supported PPh3 (400 mg, 1.2 mmol), and DBAD (0.268 mg, 1.2 mmol) in THF (3 mL) was stirred at room temperature for 8 hours. The reaction mixture was loaded onto the silica gel column and eluted with 100% EtOActo give 0.39 g of the desired product (67%). MS (DCI) m/e 326 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 8.94 (s, 1H), 8.23 (d, J=5.49 Hz, 1H), 7.88 (s, 1H), 7.41 (d, J=5.49 Hz, 1H), 4.37-4.40 (m, 2H), 3.91-3.97 (m, 2H), 3.47 (dd, J=7.63, 6.41 Hz, 1H), 2.07 (m, 1H), 1.98 (m, 1H), 1.34 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([C:29]([O:31]C)=[O:30])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[CH2:17][OH:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+]>CO>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([C:29]([OH:31])=[O:30])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[CH2:17][OH:18])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COC(=O)c1ccc2cc(-c3ccc(CO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2cc(-c3ccc(CO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Reaction time: 0.5 h

Procedure:
4.40 g (103 mmol) of the ester obtained in Example 11 in 50 ml of methanol are treated with 4 g of sodium hydroxide, with stirring, for 1 h 30 min. After the same treatment as in Example 8 and recrystallization from the ethanol/water mixture, 3 g (96%) of the expected product are isolated, which product melts at 267°-270° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([Br:19])C(=O)C1>ClCCl>[Br:19][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH3:11])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccc2c(Cl)ncnc21
Solvent: ClCCl
Product: Cn1cc(Br)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (12.15 g, 72.5 mmol) in Dichloromethane (DCM) (200 mL) was added NBS (13.55 g, 76 mmol) portionwise, and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated, and the solid was washed with water and dried to afford 5-bromo-4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (17 g) as an off-white solid.
Reaction SMILES: I[CH:2]1[CH:8]2[CH2:9][CH:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.N12CCCN=C1CCCCC2>C1C=CC=CC=1>[CH:5]12[CH2:9][CH:8]([O:7][C:6]1=[O:10])[CH:2]=[CH:3][CH2:4]2
Reactant: O=C1OC2CC1CCC2I
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1OC2C=CCC1C2
Yield: 66.1 %

Procedure:
To 4-iodo-6-oxabicyclo[3.2.1]octan-7-one (8.00 g, 31.7 mmol) in benzene (100 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (7.9 g, 32 mmol) under nitrogen, and the mixture was heated under reflux for 6 h. The white precipitate was filtered off from the cooled solution and washed with ether (100 ml). The combined filtrates were washed with water (50 ml), 1N HCl (50 ml), and brine (25 ml), and then dried over magnesium sulfate. The solvents were removed by rotary evaporation to afford the alkene as a light brown oil (2.6 g, 66%).
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[Si:6]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:39]=[CH:40][CH:41]=1)[CH:28]=[C:29]1[C:34](=[O:35])[O:33][C:32]([CH3:37])([CH3:36])[O:31][C:30]1=[O:38])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1C=CC=CC=1)[C:7]1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[Si:6]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:28]([CH:29]2[C:30](=[O:38])[O:31][C:32]([CH3:37])([CH3:36])[O:33][C:34]2=[O:35])[C:1]#[C:2][CH3:3])[CH:39]=[CH:40][CH:41]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:13])[CH3:7]
Reactant: CC1(C)OC(=O)C(=Cc2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C(=O)O1
Reactant: CC#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CC(c1cccc(CO[Si](C)(C)C(C)(C)C)c1)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, a solution (0.5 M, 12.0 mL) of 1-propynylmagnesium bromide in THF was added to a solution of 5-(3-(((tert-butyldiphenylsilyl)oxy)methyl)benzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.0 g) in THF (10 mL) at 0° C., and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound. This compound was used for the next step without further purification.
Reaction SMILES: COC1C=CC(N2C[C@H](C[N:15]3[CH2:20][CH2:19][CH:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)OC2=O)=CC=1>CS(C)=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(N2C[C@H](CN3CCC(Oc4ccc(F)cc4)CC3)OC2=O)cc1
Solvent: CS(C)=O
Product: Fc1ccc(OC2CCNCC2)cc1

Procedure:
3-p-methoxyphenyl-5(S)-[(4-p-fluorophenoxypiperidino)methyl]-2-oxazolidinone (hydrochloride), m.p. 246°-247°; [α]D =-28.9° (DMSO);
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[C:5](=[O:6])[O:4][CH2:3]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:9])[C@@H:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1
Reactant: CC1(C)COC(=O)C1=O
Solvent: Cc1ccccc1
Product: CC1(C)COC(=O)[C@@H]1O

Procedure:
The hydrogenation of 40.0 g of ketopantolactone, dissolved in 110 ml of toluene, with 100 ml of catalyst solution prepared according to Example 36 was carried out as described in Example 29. After a hydrogenation time of 2 hours the mixture was worked-up analogously to Example 2. pure (R)-pantolactone being obtained. [α]D20 =-47.9°. Optical purity 92.8%.
Reaction SMILES: C([O:9][CH:10]1[CH2:18][CH:13]2[O:14][C:15](=[O:17])[CH2:16][CH:12]2[CH:11]1/[CH:19]=[CH:20]/[C@@H:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[OH:22])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].Cl>CO>[CH:23]1([C@@H:21]([OH:22])/[CH:20]=[CH:19]/[C@@H:11]2[C@@H:12]3[C@@H:13]([O:14][C:15](=[O:17])[CH2:16]3)[CH2:18][C@H:10]2[OH:9])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CC2C(CC(OC(=O)c3ccccc3)C2/C=C/[C@H](O)C2CCCCC2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@H](O)C3CCCCC3)[C@H](O)C[C@@H]2O1
Yield: 103.3 %

Procedure:
To a solution of 42 (7.35 g, 19.1 mmol) in methanol (100 mL) was added K2CO3 (2.64 g, 19.1 mmol). After 2h, 200 mL of 2M HCl was added, the mixture was extracted with ethyl acetate (3×100 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated to afford crude diol 43 (5.53 g), which was used in the next step without purification.
Reaction SMILES: C(O[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:14]=2)[C:9]([OH:25])=[C:8]([C:26]([O:28][CH3:29])=[O:27])[N:7]=1)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C(OCC)(=O)C>[OH:25][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[C:6]([CH3:5])=[N:7][C:8]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1nc(COC(C)=O)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A glass lined Parr pressure reactor vessel equipped with a 4-blade impeller can be charged with 5c, Pd/C (about 0.4 to 0.5 molar equivalents), anhydrous Na2CO3 (about 0.5 molar equivalents), and ethyl acetate. The flask can then be vacuum-purged with nitrogen (3×) and vacuum-purged with hydrogen (3×). The flask can then be pressurized with hydrogen to set point 60 psi and stirred at 60° C. for 6-8 hrs until completion of reaction (5c <0.5%). The flask can then be cooled to 20-25° C., the pressure released to ambient, the head space purged with nitrogen three times and filtered through glass microfiber filter paper. The filtrate can be concentrated and precipitated from cold methanol and dried under vacuum at 50±5° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]#[N:13])[CH:9]=2)[NH:4][CH2:3]1.[CH:14]1([N:20]=[C:21]=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH2:3][C@@H:2]([NH:1][C:21]([NH:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:22])[CH2:11]2)#[N:13]
Reactant: O=C=NC1CCCCC1
Reactant: N#Cc1ccc2c(c1)C[C@H](N)CN2
Product: N#Cc1ccc2c(c1)C[C@H](NC(=O)NC1CCCCC1)CN2

Procedure:
The title compound was prepared from (S)-3-amino-1,2,3,4-tetrahydroquinoline-6-carbonitrile (52 mg, 0.3 mmol), prepared as described in Example 1F, and cyclohexyl isocyanate by procedures analogous to those described in Example 41A.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:17]=[C:18]3[C:26]4[C:25](Cl)=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:19]3=[O:28])=[CH:15][CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[CH:31]=[C:32]([NH2:37])[CH:33]=[CH:34][C:35]=1[F:36].Cl>>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:17]=[C:18]3[C:26]4[C:25]([NH:37][C:32]5[CH:33]=[CH:34][C:35]([F:36])=[C:30]([Cl:29])[CH:31]=5)=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:19]3=[O:28])=[CH:15][CH:16]=2)=[O:11])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C1Nc2ncnc(Cl)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Agent: Cl
Product: O=C1Nc2ncnc(Nc3ccc(F)c(Cl)c3)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Yield: 16 %

Procedure:
The title compound (16% yield) was prepared from 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide and 3-chloro-4-fluoro-phenylamine according to the procedure described for Example 12 without the conversion to HCl salt. MS 512.3 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(CC1CCCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
A solution of nickel(II) chloride hexahydrate (36.6 mg, 0.154 mmol) and (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylic acid methyl ester (302 mg, 0.77 mmol) in methanol (8 mL) was cooled to 0° C. and then treated with sodium borohydride (87 mg, 2.29 mmol) in four portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 15 h. The black solid was filtered using filter paper and washed with methanol. The combined solvents were concentrated in vacuo, and the residue was diluted with ethyl acetate (50 mL). The organic layer was washed successively with a 3N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (280 mg, 93%) as a viscous oil: EI-HRMS m/e calcd for C18H23F3O4S (M+) 392.1269, found 392.1276.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][O:27][C:28]1([C:34](O)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:34]([C:28]5([O:27][CH3:26])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:35])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: COC1(C(=O)O)CCCCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: COC1(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)CCCCC1

Procedure:
The title compound, white solid (22.2 mg, 57.7%), MS (ISP) m/z=471.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 1-Methoxycyclohexane-1-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([CH2:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[N:21]=2)[CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[NH:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[CH2:19][N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:38]([NH:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])=[CH:30][CH:29]=1)[CH:9]1[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11][CH2:10]1
Reactant: O=C=Nc1ccccc1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Solvent: ClCCl
Product: O=C(NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1)Nc1ccccc1
Yield: 72.3 %

Procedure:
To a cold (0° C.) solution of (4-aminomethyl-benzyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.136 g, 0.34 mmol) in CH2Cl2 (3.5 mL) was added phenyl isocyanate (41 μL, 0.38 mmol) and the resultant solution was stirred for 50 minutes. The cooling bath was removed and the mixture was concentrated under reduced pressure. Purification of the crude material by column chromatography on silica gel (25:1:1 CH2Cl2—CH3OH—NH4OH) provided the free base of the title compound (0.127 g, 72%) as a white solid.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:15]=3)[C:10]=2[CH3:22])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)[C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:15]=3)[C:10]=2[CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1c(C(=O)C2CCCCC2)sc2cc(C(F)(F)F)cnc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(c2sc3cc(C(F)(F)F)cnc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.1 %

Procedure:
To a mixture of cyclohexyl[3-methyl-6-(trifluoromethyl)thieno[3,2-b]pyridin-2-yl]methanone (805 mg) synthesized above, methyl 4-aminobenzoate (410 mg), triethylamine (2.75 mL) and methylene chloride (10 mL) was added titanium (IV) chloride (323 μL) at 0° C., and the mixture was stirred at room temperature for 1 day under argon atmosphere. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (10 mL) of the obtained oil in tetrahydrofuran were added acetic acid (282 μL) and sodium cyanoborohydride (309 mg), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% ethyl acetate/hexane) to give the title object compound (775 mg, 68%) as a pale-brown solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:28][C:29]([F:35])([F:34])[C:30]([NH:32][OH:33])=N>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[O:33][N:32]=[C:30]([C:29]([F:35])([F:34])[F:28])[N:27]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Reactant: N=C(NO)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(c4nc(C(F)(F)F)no4)CC2)C3)cc1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and 2,2,2-trifluoro-N-hydroxy-acetamidine following a procedure analogous to that described in Example 2. LC (method 5): tR=1.32 min; Mass spectrum (ESI+): m/z=495 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[Li+].[CH3:14][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:14])[N:7]=1
Reactant: CON(C)C(=O)c1cccnn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1cccnn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 123.1 %

Procedure:
To a solution of compound 2 (6.35 g, 21 mmol) in THF (20 mL) was added LiHMDS (1 M in THF, 22 mL, 22 mmol) via a syringe at −78° C. under a nitrogen atmosphere. After 1 h a solution of compound 2A (3.31 g, 20.66 mmol) in THF (32 mL) was added dropwise at −78° C. The mixture was stirred at −78° C. for 1.5 h then quenched by addition of a solution of sat. NH4Cl (50 mL), the resulting mixture was stirred overnight at room temperature, extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (2×50 mL), dried over sodium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether:THF=40:1) to give compound 3 (3.21 g, 42%) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=[O:6].[N:25]1(C(OC(C)(C)C)=O)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CS(C)=O.O>[N+:22]([C:3]1[C:2]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:12][CH:11]([CH2:17][CH:15]([CH2:14]3)[CH2:16]1)[CH2:10]2)=[O:6])([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc(Cl)c1[N+](=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc(N2CCNCC2)c1[N+](=O)[O-]
Temperature: 120 °C
Yield: 118.8 %

Procedure:
A mixture of 3-chloro-2-nitro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (2.80 g, Example 1a) and piperazine-1-carboxylic acid, tert-butyl ester (7.47 g) in dry dimethyl sulfoxide (10 ml) was heated at 120° C. under a nitrogen atmosphere for 24 h. The cooled reaction mixture was diluted with water and extracted thrice with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a solid. Purification by chromatography over silica gel, eluting with iso-hexane/ethyl acetate (2:1) gave the subtitle compound as a solid (3.8 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[CH3:32])[C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20]2[N:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][CH:21]=2)[CH:9]=1)=[O:7].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)[N:37]=1>CS(C)=O.N>[CH3:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[CH3:32])[C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20]2[N:25]=[C:24]([C:26]([NH2:37])=[O:27])[CH:23]=[CH:22][CH:21]=2)[CH:9]=1)=[O:7]
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Reactant: Cc1ccc(C(=O)c2cn(Cc3cccc(C(=O)O)n3)c3ccccc3c2=O)cc1C
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(C(N)=O)n3)c3ccccc3c2=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
27 mg (0.06 mmol) of 6-[3-(3,4-dimethyl-benzoyl)-4-oxo-4H-quinolin-1-ylmethyl]-pyridine-2-carboxylic acid hydrochloride was dissolved in a mixture of 2 mL DMSO and 0.2 mL 2 M methanolic ammonia followed by the addition of 100 mg (0.36 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The mixture was stirred for 1 h at r.t. followed by purification on reverse-phase HPLC and flash chromatography to give 17 mg of a white solid. LC-MSD, m/z for C25H21N3O3 [M+H]+=412.2; HPLC retention time: 1.7 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:17])([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:18].[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH2:21].Cl(O)(=O)(=O)=O>C(Cl)Cl>[C:20]([C:4]1[CH:5]=[C:6]([C:8]([CH3:17])([CH3:9])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:18])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:19])[CH3:21]
Reactant: C=C(C)c1ccccc1
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)c(C)c1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: COC(=O)CCCC(C)(C)c1cc(C)c(O)c(C(C)(C)c2ccccc2)c1

Procedure:
5.0 Parts of 2-methyl-4-(5-methoxycarbonyl-2-methyl-pent-2-yl)-phenol, 2.4 parts of α-methylstyrene, and 0.5 parts of 70% perchloric acid in 25 parts of methylene chloride were reacted and worked up as described in Example 61. Distillation gave methyl 5-(3-cumyl-4-hydroxy-5-methyl-phenyl)5-methyl-hexanoate, b0.7 210°-4° C. as an oil with the following percentage composition by weight.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1.[Br:12]N1C(=O)CCC1=O>CN(C=O)C.C(Cl)Cl>[Br:12][C:10]1[CH:9]=[CH:8][C:7]2[N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]=2[CH:11]=1
Reactant: CN1CCOc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCOc2cc(Br)ccc21
Temperature: 80 °C
Yield: 77.5 %

Procedure:
A mixture of the 104B (0.225 g, 1.51 mmol) and N-bromosuccinimide (0.269 g, 1.51 mmol) in DMF (10 mL) was heated at 80° C. overnight. The reaction mixture was dissolved in DCM and washed with water several times. The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 0.267 g (78%) of 104C. HPLC retention time=3.32 min. (Condition B) and LC/MS M+1=230.03 (d). 1H-NMR (500 MHz, CDCl3) δ 2.83 (s, 3H), 3.22 (t, 2H), 4.26 (t, 2H), 6.49 (d, 1H, J=8.8 Hz), 6.87 (s, 1H), and 6.90 (d, 1H, J=8.8 Hz).