Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH:7]2[O:34][CH:8]2[CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: CCCCCC(O)C=CC1CCC(O)C1CCCCCCC(=O)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCC(O)C1OC1C1CCC(O)C1CCCCCCC(=O)OC
Yield: 91.9 %

Procedure:
A solution of methyl 7-[2-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentyl]heptanoate (1.0 g.) [prepared as described in Example 5], metachlorperbenzoic acid (2.0 g.) and dichloromethane (30 ml.) was refluxed for days. The precipitated metachlorbenzoic acid was filtered from the cooled solution and washed with dichloromethane. The filtrate was washed successively with sodium sulphite solution, twice with 5% sodium bicarbonate solution and finally water, dried over sodium sulphate and evaporated to give methyl 7-[2-hydroxy-5-(3-hydroxy-1,2-epoxy-1-octyl)cyclopentyl]heptanoate (0.96 g.,92%), νmax 3450 cm-1, 1730 cm-1 and 1170 cm-1.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:19]([O:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])(=[O:21])[CH3:20]
Reactant: CC(CCO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)c1ccccc1
Yield: 98.8 %

Procedure:
Into a four-necked flask provided with a stirring means and a thermometer, 150 g (1 mol) of (+)-3-phenyl-l-butanol (XXVI-60), 500 ml of toluene and 200 ml of pyridine were charged, and 122.4 g (1.2 mol) of acetic acid anhydride and 1 g of 4-dimethylaminopyridine were further added thereto. The mixture was reacted for 4 hours while temperature being maintained at 40°-50° C. After completion of the reaction, the reaction mixture was poured into 500 ml of 4N hydrochloric acid, extracted and fractionated. The resulting organic layer was washed with 1N hydrochloric acid, water, 5% sodium bicarbonate aqueous solution ad water in the order. The thus-obtained organic layer was concentrated under a reduced pressure to obtain 190 g of (+)-1-acetoxy-3-phenylbutane (XXV-60) with yield of 99.0%.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1>N1C=CC=CC=1>[CH3:1][NH:2][C:3]([N:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][C:8]1=[O:12])=[O:4]
Reactant: O=c1cc(O)cc[nH]1
Reactant: CN=C=O
Solvent: c1ccncc1
Product: CNC(=O)n1ccc(O)cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A 0.64 ml quantity of methyl isocyanate was added to a suspension of 1.00 g of 4-hydroxy-2-pyridone in 20 ml of pyridine and the mixture was stirred at room temperature for one hour. Thereafter the general procedure of Example 36 was followed to produce the title compound in a yield of 30%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[CH:21]([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[CH3:23][N:22]1[C:15]2[N:16]([C:17](=[O:19])[N:18]=[C:13]([O:11][CH2:10][C:7]3[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=3)[C:4]#[N:5])[CH:14]=2)[CH2:20][CH:21]1[CH3:24]
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Reactant: N#Cc1cc(CO)ccc1F
Product: CC1Cn2c(cc(OCc3ccc(F)c(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-fluoro-5-(hydroxymethyl)benzonitrile and 7-chloro-1,2-dimethyl-2,3-dihydroimi-dazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=1.[F:25][C:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1)([F:28])[CH3:27].ClCCl.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.CCOC(C)=O>[F:25][C:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[S:6][C:5]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=1)([F:28])[CH3:27]
Reactant: COC(=O)/C=C/c1ccc(Oc2c(Br)sc3cc(O)ccc23)cc1
Reactant: CC(F)(F)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)(F)F)sc3cc(O)ccc23)cc1
Yield: 70.5 %

Procedure:
To a solution of (E)-methyl 3-(4-((2-bromo-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (95 mg, 0.234 mmol) in dimethoxyethane (3.0 mL) was added 2-(2-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (94 mg, 0.352 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (19.14 mg 0.023 mmol) and potassium carbonate (2.0M aqueous solution, 0.469 mL, 0.938 mmol). The resulting mixture was subjected to microwave irradiation at 100° C. for 20 min after which time the reaction was diluted with EtOAc and washed with sat. aq. NH4Cl solution (2×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo and the resulting crude material was purified by column chromatography (SiO2, 0-40% EtOAc/Heptane) to afford (E)-methyl 3-(4-((2-(2-(1,1-difluoroethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (77 mg, 0.165 mmol, 70% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.63-7.56 (m, 2H), 7.44-7.38 (m, 1H), 7.36 (d, J=8.8 Hz, 2H), 7.33 (d, J=4.1 Hz, 2H), 7.28-7.24 (m, 2H), 6.90-6.81 (m, 3H), 6.28 (d, J=16.1 Hz, 1H), 3.78 (s, 3H), 1.91 (t, J=18.4 Hz, 3H).
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[N+:15]([CH:18]([CH2:20][CH3:21])[CH3:19])([O-:17])=[O:16]>>[CH3:19][C:18]([N+:15]([O-:17])=[O:16])([CH2:20][CH3:21])[CH2:4][C:5]1[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([F:14])[CH:10]=2)[NH:7][CH:6]=1
Reactant: CN(C)Cc1c[nH]c2ccc(F)cc12
Reactant: CCC(C)[N+](=O)[O-]
Product: CCC(C)(Cc1c[nH]c2ccc(F)cc12)[N+](=O)[O-]

Procedure:
The procedure described in Example 3 applied to 5-fluorogramine and 2-nitrobutane yielded the intermediate product 3-(2'-methyl-2'-nitrobutyl)-5-fluoro-indole. Melting point 71°-72°C. (from benzine). Catalytic reduction thereof yielded 3-(2'-methyl-2'-aminobutyl)-5-fluoro-indole; melting point of the hydrochloride salt 248°-250°C. (from isopropanol).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH3:18])([CH3:7])[CH:4]([CH3:6])[CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH:2]([C:3]([NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH3:18])([CH3:7])[CH:4]([CH3:5])[CH3:6])=[O:1]
Reactant: COc1cccc(C(=O)NC(C)(CO)C(C)C)c1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1cccc(C(=O)NC(C)(C=O)C(C)C)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.2 %

Procedure:
To a stirred solution of N-(1-hydroxymethyl-1,2-dimethyl-propyl)-3-methoxy-2-methyl-benzamide (X, R1=2-Me-3-MeO—Ph, R2=i-Pr, R3=Me, 285 mg, 1.1 mmol) in CH2Cl2 (10 mL) at room temperature was added Dess-Martin periodinane solution (15% by weight, 2.4 mL, ca. 1.1 mmol). The mixture was stirred at room temperature for 4 h and poured into saturated aqueous NaHCO3 (50 mL). Solid Na2S2O3 (2.13 g, 8.6 mmol) was added and the mixture was stirred for 0.5 h. The mixture was extracted with ether (150 mL). The ether extract was washed with saturated aqueous NaHCO3 (50 mL), dried and evaporated under reduced pressure to afford N-(1-formyl-1,2-dimethyl-propyl)-3-methoxy-2-methyl-benzamide (293 mg) as an oil. 1H NMR (CDCl3) δ(ppm): 0.98 (d, J=6.6 Hz, 3H), 1.04 (d, J=6.6 Hz, 3H), 1.51 (s, 3H), 2.27 (s, 3H), 2.29 (m, 1H), 3.84 (s, 3H), 6.30 (br s, 1H), 6.91 (m, 1H), 6.96 (m, 1H), 7.18 (m, 1H), 9.60 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:11]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[CH2:31]([N:10]([CH2:9][CH:6]1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:45]([NH:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:46])[CH2:8][CH2:7]1)[S:11]([NH:14][C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1)(=[O:12])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1)Nc1ccccc1
Reaction time: 8 h

Procedure:
Amine (22) (25.2 mg, 46 μmole, 1.0 eq) was suspended in dichloromethane, then triethylamnine (16 μL, 114 μmole, 2.5 eq) and phenyl isocyanate (6 μL, 55 μmole, 1.2 eq) were added and the reaction stirred overnight. Silica gel chromatography provided the title compound. 1H NMR (500 MHz, DMSO-d6): δ 12.46 (s, 1H), 8.45 (s, 2H), 8.27 (s, 1H), 8.23 (s, 1H), 7.36 (d, 2H), 7.32 (d, 2H), 7.25 (t, 2H), 7.18 (m, 4H), 6.84 (t, 1H), 6.05 (t, 1H), 4.43 (s, 2H), 3.30 (water), 3.03 (s, 2H), 2.81 (t, 2H), 2.48 (DMSO), 1.60 (m, 4H), 1.30 (m, 1H), 1.21 (m, 1H), 0.64 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(F)cc2)cc1
Yield: 20.9 %

Procedure:
The title compound (60 mg, 21%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (275 mg, 0.818 mmol, prepared in example 1), 4-fluorobenzeneboronic acid (140 mg, 1.001 mmol), dichlorobis(triphenylphosphine)palladium(II) (23 mg, 0.033 mmol), 2 M sodium carbonate (295 mg in 1.4 mL water), and 1,2-dimethoxyethane (5.5 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 310 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [P:1]([O-:32])([O:28][CH2:29][CH2:30]Br)([O:3][CH2:4][CH:5]([O:26][CH3:27])[CH2:6][O:7][CH2:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:2].[S:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>C1(C)C=CC=CC=1>[P:1]([O-:32])([O:28][CH2:29][CH2:30][C:34]1[S:33][CH:37]=[CH:36][NH+:35]=1)([O:3][CH2:4][CH:5]([O:26][CH3:27])[CH2:6][O:7][CH2:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:2]
Reactant: c1cscn1
Reactant: CCCCCCCCCCCCCCCC(=O)COCC(COP(=O)([O-])OCCBr)OC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)COCC(COP(=O)([O-])OCCc1[nH+]ccs1)OC
Temperature: 60 °C
Reaction time: 96 h

Procedure:
In 3 ml of toluene was dissolved 0.9 g of the above 3-(2-oxoheptadecyloxy)-2-methoxypropyl 2-bromoethyl phosphate (5), and 1 ml of thiazole was added to the solution. The mixture was stirred at 60° C. for 4 days and then concentrated to dryness. The residue was purified by silica gel chromatography [eluent: (1) methanol and (2) chloroform-methanol-water (65:25:4)] to give 0.20 g of the desired compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:10]([CH3:12])[CH3:11])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][N:10]([CH3:12])[C:4]1[CH:3]=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: OB(O)c1ccccc1
Reactant: CN(C)c1cc(Br)ccc1C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1cc(-c2ccccc2)ccc1C=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a suspension of 4-bromo-2-dimethylaminobenzaldehyde (250 mg, 1.10 mmol), sodium carbonate (140 mg, 1.32 mmol), and phenylboronic acid (210 mg, 1.65 mmol) in 2.2 mL of N,N-dimethylformamide/water (2:1) was added palladium acetate (13 mg, 58 μmol) under nitrogen. After being stirred at 100° C. overnight, the reaction mixture was filtered. The filtrate was diluted with ethyl acetate, and the solution was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain the title compound as a yellow oil (226 mg, 91%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C([Si](C(C)C)(C(C)C)[O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C@@H:43]2[CH2:45][O:44]2)=[CH:37][C:36]=1[CH3:46])(C)C>>[CH2:22]([NH:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:45][C@H:43]([OH:44])[CH2:42][O:41][C:38]3[CH:39]=[CH:40][C:35]([OH:34])=[C:36]([CH3:46])[CH:37]=3)=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:14][CH2:15]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCN)cc2)CC1
Reactant: Cc1cc(OC[C@@H]2CO2)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Product: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O)c(C)c3)cc2)CC1
Yield: 16.8 %

Procedure:
4-{[4-(2-Aminoethyl)phenyl]sulfonyl}-N-octyl-1-piperidinecarboxamide (1.38 g, 3.258 mmol) was reacted with triisopropyl{2-methyl-4-[(2S)oxiranylmethoxy]phenoxy}silane (1.04 g, 3.095 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform:methanol) (0.395 g, 0.520 mmol).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])([O-:10])=[O:9]>>[CH:2]1([O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N+:8]([O-:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrC1CCCCC1
Reactant: O=[N+]([O-])c1ccccc1O
Product: O=[N+]([O-])c1ccccc1OC1CCCCC1

Procedure:
In a similar manner as in Example 1, bromocyclohexane was reacted with o-nitrophenol to yield 2-cyclohexoxynitrobenzene; which was reduced to the corresponding aniline; then reacted with N-methylolpyrrolidone to form the corresponding N-methylenepyrrolidonyl derivative; which was acylated with chloroacetyl chloride to form the desired product.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][C:13]1[CH2:14][C:15]2[C:20]([CH:21]=1)=[C:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=2.[Si:24]([CH3:28])([CH3:27])(Cl)[Cl:25].[Li]>CCOCC.C1COCC1>[Cl:25][Si:24]([CH:14]1[C:15]2[C:20](=[C:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=2)[CH:21]=[C:13]1[CH3:12])([CH3:28])[CH3:27]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2c(C)cc(C)cc2C1
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1=Cc2c(C)cc(C)cc2C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
A 2.5 M n-BuLi solution in hexane (37.2 mL, 0.093 mol) was added dropwise at 0° C. under nitrogen to a solution of 14.00 g of 2,4,6-trimethylindene (0.088 mol) in 100 mL of Et2O in a 500 mL 3-necked round flask. During the addition a white suspension was formed. The mixture was then allowed to warm up to r.t. and stirred for 30 min, with final formation of a white suspension. Then a solution of Me2SiCl2 (11.28 mL, 0.093 mol.) in 30 mL of THF was cooled to 0° C. and slowly added to the lithium salt suspension, also cooled to 0° C. The reaction mixture was allowed to warm up to r.t. and stirred for 2 h with final formation of a light yellow suspension. Then the solvents were removed in vacuo and the residue was extracted with 150 mL of toluene to remove LiCl. The light yellow filtrate was brought to dryness in vacuo to give 21.53 g of a yellow oil: its 1H-NMR analysis showed the presence of the target product together with traces of starting 2,4,6-trimethyl-indene (yield 97.5%).
Reaction SMILES: C([O-])(=O)C([O-])=O.[CH3:7][C:8]1[S:9][C:10]([CH3:20])=[CH:11][C:12]=1[C:13]([C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)=O.Cl[CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.[Mg]>>[S:17]1[CH:18]=[CH:19][C:15]([C:13]([C:12]2[CH:11]=[C:10]([CH3:20])[S:9][C:8]=2[CH3:7])=[C:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:16]1
Reactant: Cc1cc(C(=O)c2ccsc2)c(C)s1
Reactant: CN1CCC(Cl)CC1
Agent: O=C([O-])C(=O)[O-]
Agent: [Mg]
Product: Cc1cc(C(=C2CCN(C)CC2)c2ccsc2)c(C)s1

Procedure:
The starting carbinol was obtained in a manner analogous to Example 1 (a), from 12.2 grams (0.055) mole) of (2,5-dimethyl-3-thienyl)-3-thienyl ketone, 14.7 grams (0.11 mole) of 4-chloro-N-methyl-piperidine and 2.67 grams (0.11 gram atom, of magnesium.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(C(F)(F)F)cc1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-chloro-4-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH:31]=O)=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH2:31][N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(CN4CCOCC4)s3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.8 %

Procedure:
To a solution of 5-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazole-2-carbaldehyde (300 mg) in tetrahydrofuran (20 mL) were added morpholine (83 mg), sodium triacetoxyborohydride (270 mg) and triethylamine (177 μL) and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (141 mg, yield 41%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 543 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1.Br[CH2:31][CH2:32][O:33][CH2:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH2:31][CH2:32][O:33][CH2:34][CH3:35])[CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: CCOCCBr
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(S(C)(=O)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: CCOCCn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2C)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)pyridin-2(1H)-one (example 339, step 2) was reacted with 1-bromo-2-ethoxyethane in the presence of potassium carbonate and a catalytic amount of tetrabutylammonium iodide to give the title compound as a light brown solid, MS (ESI+): m/z=502.2 [M+H]+.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[C:25]1[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[N:29][CH:30]=1)=O.[Br:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Br:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][CH2:15][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[N:29][CH:30]=2)=[CH:44][CH:43]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(OC)cc2C=O)cn1
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(OC)cc2CNc2ccc(Br)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (446 mg, 2.1 mmol) was added to a DCE solution (7 mL) of ethyl 3-(5-(2-formyl-4-methoxyphenyl)picolinamido)propanoate, prepared as in Example 58 (500 mg, 1.4 mmol), 4-bromoaniline (362 mg, 2.1 mmol), and AcOH (0.08 mL, 1.4 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.