Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][C:8]([CH3:19])([C:14]([O:16]CC)=[O:15])[C:9]([O:11]CC)=[O:10]>O.CO>[CH3:3][CH:4]([CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][C:8]([CH3:19])([C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(C)(CCCC(C)CC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)CCCC(C)(C(=O)O)C(=O)O

Procedure:
First, 8.18 g (0.22 mol) of sodium hydroxide was dissolved in a mixture solution of 28 ml of water and 14 ml of methanol, thus forming a solution. Next, g of the crude product (II), not refined, was added to the resultant solution and reacted with the solution at 20° C. for three to five hours, thereby obtaining 18.4 g of 4-methylhexylmethylmalonic acid (III). This reaction is represented as follows: ##STR4##
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[O:11]=[C:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]1[S:34][C:33]2[N:35]3[C:26](=[CH:27][N:28]=[C:29]3[CH:30]=[CH:31][CH:32]=2)[CH:25]=1)=[O:23].C(N(CC)CC)C.[I-].[Na+].N12CCCNC1CCCC=C2>C(#N)C>[C:2]1([CH2:1][N:16]2[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]3[S:34][C:33]4[N:35]5[C:26](=[CH:27][N:28]=[C:29]5[CH:30]=[CH:31][CH:32]=4)[CH:25]=3)=[O:23])[C:12](=[O:11])[CH2:17]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: O=C(NCCCN1CCNCC1=O)C1=Cc2cnc3cccc(n23)S1
Agent: C1=CN2CCCNC2CCC1
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCCN1CCN(Cc2ccccc2)CC1=O)C1=Cc2cnc3cccc(n23)S1

Procedure:
Benzylchloride (187 mg, 1.48 mmol) was added to a stirred solution of N-[3-(2-oxopiperazin-1-yl)propan-1-yl]-5-thia-1,8b-diazaacenaphtylene-4-carboxamide dihydrochloride (518 mg, 1.20 mmol), triethylamine (605 mg, 5.98 mmol), sodium iodide (216 mg, 1.44 mmol) and 1,8-diazabicyclo[5.4.0]undecene (366 mg, 2.41 mmol) in acetonitrile (20 ml) at room temperature. After refluxing under nitrogen for 2 days, the reaction mixture was concentrated in vacuo. The residue was dissolved in water and extracted with chloroform. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (20 g) with Ethyl acetate-Methanol (8:1) to give N-[3-(4-phenylmethyl-2-oxopiperazine-1-yl)propane-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide as a purple amorphous powdeer (303 mg, 56%).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH2:5])[CH2:2]1.[Cl:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:8]=1>CO.C(#N)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:5][CH:3]2[CH2:4][O:1][CH2:2]2)[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:18])[F:19])[N:8]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: NC1COC1
Solvent: CC#N
Solvent: CO
Product: FC(F)(F)COCc1cc(NC2COC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
A solution of oxetan-3-amine (77 mg, 1.06 mmol) in MeOH (2 mL) was added dropwise to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (92 mg, 0.35 mmol) in acetonitrile (2 mL). The mixture stirred at rt overnight. The mixture was separated by preparative chromatography to give the title compound (58 mg, 55%).
Reaction SMILES: Cl.[C-:2]1([C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]>C1(C)C=CC=CC=1>[C-:2]1([CH2:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20])[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: O=C(CCCCCCCCCCCBr)[c-]1cccc1
Agent: [Fe+2]
Agent: Cl
Agent: c1cc[cH-]c1
Solvent: Cc1ccccc1
Product: BrCCCCCCCCCCCC[c-]1cccc1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
Following a general procedure for preparing 24 (Creager et al. (1994) J. Electroanal. Chem., 370: 203–211), to a freshly prepared zinc/mercury amalgam (6.7 g granulated Zn, 0.4 g HgCL2) in a 100 mL flask was added 10 M HCl (40 mL) with stirring. A solution of 22 (3.0 g, 6.7 mmol) in toluene (40 mL) was added in one portion. The resulting two-phase mixture was heated to reflux and stirred vigorously. After 16 h under reflux, during which two 5 mL portions of 10 M HCl were added, the reaction flask was cooled to rt. The phases were separated, and the organic layer was washed with water (3×100 mL) and dried (MgSO4). The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica, petroleum ether/diethyl ether, 10:1) to afford a brown oil (2.6 g, 90%) that solidified upon standing in the freezer: mp 40–42° C.; 1H NMR δ 1.29 (s, 16H), 1.47 (m, 2H), 1.86 (m, 2H), 2.32 (m, 2H), 3.42 (m, 2H), 4.05 (s, 2H), 4.06 (s, 2H), 4.10 (s, 5H); 13C NMR δ 28.2, 28.8, 29.5, 29.6, 31.1, 32.9, 34.0, 67.0, 68.1, 68.5, 89.6; FAB-MS obsd 432.1114, calcd exact mass 432.1115 (C22H33BrFe).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[CH3:13][CH:14]([CH3:22])[CH2:15][CH2:16][CH2:17][C:18](OC)=[O:19].CC(C)CCCC(O)=O.S(=O)(=O)(O)O>C1COCC1.CO>[CH3:13][CH:14]([CH3:22])[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)CCCC(C)C
Reactant: COP(C)(=O)OC
Agent: CC(C)CCCC(=O)O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: COP(=O)(CC(=O)CCCC(C)C)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of dimethyl methylphosphonate (2.17 ml, 20 mmol) in anhydrous THF (20 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 13.7 mL, 22 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl 5-methylhexanoate (1.44 g, 10 mmol), prepared from 5-methylhexanoic acid (from Avocado) and methanol at the presence of the catalytic amount of the concentrated sulfuric acid (the procedure described in Intermediate 17.1), was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (EtOAc:Hexanes=1:1) to give the product (1.80 g) with colorless oil in 76% yield. 1HNMR (CD3OD, ppm) δ 0.866 (d, J=6.5 Hz, 6H), 1.16 (m, 2H), 1.56 (m, 3H), 2.58 (t, J=7.3 Hz, 2H), 3.10 (d, J=22.7 Hz, 2H), 3.70 (s, 3H), 3.79 (s, 3H)
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31]N>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1ccccn1
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccn3)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and pyridin-2-yl-hydrazine according to example 43 gave the desired product. MS: M=393.9 (M+H)+
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])C.[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[OH:12][CH:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:25]([CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][C:18]([F:17])([F:28])[F:29])=[CH:21][CH:22]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Product: O=C1N(Cc2ccc(OC(F)(F)F)cc2)CCC12CCC(O)CC2

Procedure:
The title compound was prepared in analogy to example 108, step 3 from 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (obtained in example 2, step 3) by treatment with 4-trifluoromethoxybenzylamine as a mixture of cis and trans diastereomers. Light yellow viscous oil. MS (m/e): 344.147 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH:13]([CH3:15])[CH3:14])[C:11](=[O:16])[O:10][C:9]2=O)=[CH:4][CH:3]=1.[CH2:18]([C:25]1[CH:29]=[CH:28][NH:27][C:26]=1CO)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:12]([CH:13]([CH3:15])[CH3:14])[C:11]([O:10][CH2:9][C:26]2[NH:27][CH:28]=[CH:29][C:25]=2[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[CH:4][CH:3]=1
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(Cl)cc1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)C(Nc1ccc(Cl)cc1)C(=O)OCc1[nH]ccc1Cc1ccccc1
Reaction time: 20 h

Procedure:
To a solution of 3-(4-chlorophenyl)-4-isopropyloxazolidine-2,5-dione (336 mg, 1.32 mmol) and 4-dimethylaminopyridine in 5 ml of dry tetrahydrofuran is added a solution of 3-benzylpyrrolylmethyl alcohol (1.26 mmol) in 3 ml of dry tetrahydrofuran. The reaction mixture is stirred for about 20 hours, under dry air, and then diluted with ether followed by washing with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. After drying over calcium sulfate, solvent is evaporated. The crude product is chromatographed on a rotary chromatograph eluting with 15% ether/hexane to give 3-benzylpyrrolylmethyl 2-(4-chlorophenylamino)-3-methylbutanoate.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].CC1(C)[O:21][C@H:20]([CH2:22][O:23][C:24]2[C:33]([CH3:34])=[CH:32][C:27]([C:28]([NH:30]O)=[NH:29])=[CH:26][C:25]=2[Cl:35])[CH2:19][O:18]1>>[Cl:35][C:25]1[CH:26]=[C:27]([C:28]2[N:30]=[C:12]([C:10]3[S:11][C:7]([CH2:6][N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[C:8]([CH3:15])[CH:9]=3)[O:14][N:29]=2)[CH:32]=[C:33]([CH3:34])[C:24]=1[O:23][CH2:22][C@@H:20]([OH:21])[CH2:19][OH:18]
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1OC[C@@H]1COC(C)(C)O1
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(OC[C@@H](O)CO)c(Cl)c3)no2)cc1C
Yield: 40.4 %

Procedure:
The title compound (22 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3-chloro-5-methyl-benzamidine (37 mg, 117 μmol) in analogy to Example 197; LC-MS: tR=0.54 min; [M+1]+=466.05.
Reaction SMILES: [N:1]#[C:2][NH2:3].[CH3:4][S:5][CH:6]([C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)[CH3:7].Cl[O-].[Ca+2].Cl[O-].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[C:2]([N:3]=[S:5]([CH:6]([C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)[CH3:7])[CH3:4])#[N:1]
Reactant: N#CN
Reactant: CSC(C)c1ccc(C(F)(F)F)nc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: CC#N
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)=NC#N
Temperature: -5 °C
Reaction time: 1.08 h

Procedure:
Acetonitrile (50 mL), cyanamide (1.14 grams, 27.1 mmoles) and 3-[1-(methylthio)ethyl]-6-(trifluoromethyl)pyridine (5.00 grams, 22.6 mmoles, 99+% assay) were combined in a 100 mL, 3-necked round bottom flask equipped with a thermowell/K-thermocouple, stopper, nitrogen oil bubbler and magnetic stir bar. The stirred solution was cooled to about −5° C. with an acetone/ice bath. To this solution was added 55.96 grams of an aqueous 6.0 wt % calcium hypochlorite solution (3.36 grams of calcium hypochlorite, 23.5 mmoles, 65% available chlorine) dropwise over 44 minutes. Some undissolved solids were present in the calcium hypochlorite solution and were added as well. The temperature was kept below 0° C. during the addition. The pale yellow reaction mixture was allowed to stir at about 0° C. for 65 minutes. To the yellow reaction mixture was added 0.53 g (2.8 mmoles) of sodium metabisulfite, in portions as a solid to destroy any remaining oxidant. A white flocculant was present in the reaction mixture. It was removed by vacuum filtration of the entire reaction mixture through a medium sintered glass filter funnel. The filtrate was transferred to a separatory funnel and the phases were allowed to settle. The phases were separated and the aqueous phase re-extracted with acetonitrile (10 mL) and (15 mL). Sodium chloride (10.01 grams) was added to the aqueous phase during the second extraction to facilitate a phase break. The organics were combined and this acetonitrile/sulfilimine solution was used directly in the following oxidation. LC analysis indicated a 1.00:1.08 area ratio of the two sulfilimine isomers and showed sulfilimine at 80 area % and sulfoxide (two isomers) at 13 area %.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][CH:19]([C:23]([NH2:25])=[O:24])[CH2:20][CH2:21][CH3:22])=[O:17])[CH2:12][C:13](=[O:15])[OH:14])=[O:9])[CH2:4][CH2:5][S:6][CH3:7].ClC1C=C(Cl)C(Cl)=CC=1[O:35][C:36](=O)[C@H:37]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[NH:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40].Cl.N[C@H](C(N[C@H](C(N[C@@H](C(N)=O)C)=O)CC(=O)O)=O)CCSC.C(OC(N[C@H](C(N[C@H](C(N[C@H](C(N[C@@H](C(N)=O)C)=O)CC(=O)O)=O)CCSC)=O)CC1C2C(=CC=CC=2)NC=1)=O)(C)(C)C>>[CH2:42]([O:41][C:39]([NH:38][C@H:37]([C:36]([NH:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][CH:19]([C:23]([NH2:25])=[O:24])[CH2:20][CH2:21][CH3:22])=[O:17])[CH2:12][C:13](=[O:14])[OH:15])=[O:9])[CH2:4][CH2:5][S:6][CH3:7])=[O:35])[CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)=[O:40])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CCCC(NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)CCSC)C(N)=O
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Oc1cc(Cl)c(Cl)cc1Cl)OCc1ccccc1
Agent: CSCC[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Agent: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Agent: Cl
Product: CCCC(NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(N)=O

Procedure:
When equivalent quantities of L-methionyl-L-aspartyl-DL-norvaline amide hydrochloride and N-benzyloxycarbonyl-L-tryptophan 2,4,5-trichlorophenyl ester are substituted for the L-methionyl-L-aspartyl-D-alanine amide hydrochloride and the N-t-butoxycarbonyl-L-tryptophan 2,4,5-trichlorophenyl ester of Example 6, and the procedure detailed therein substantially repeated, there is obtained N-benzyloxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-DL-norvaline amide. This compound is represented by the following formula.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:48])[CH2:5][NH:6][C:7]([C:9]1[C:14]([O:15]CC2C=CC=CC=2)=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[C:39]([C:45]([CH3:47])=[CH2:46])[CH:38]=4)=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[N:10]=1)=[O:8])[CH3:2]>CO>[CH2:1]([O:3][C:4](=[O:48])[CH2:5][NH:6][C:7]([C:9]1[C:14]([OH:15])=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[C:39]([CH:45]([CH3:47])[CH3:46])[CH:38]=4)=[CH:35][CH:36]=3)[CH2:29][CH2:30]2)[N:10]=1)=[O:8])[CH3:2]
Reactant: C=C(C)c1cc(-c2ccc(N3CCC(Cc4nc(C)c(OCc5ccccc5)c(C(=O)NCC(=O)OCC)n4)CC3)cc2)ccc1CO
Solvent: CO
Product: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(CO)c(C(C)C)c4)cc3)CC2)nc(C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
Ethyl({[5-(benzyloxy)-2-{(1-[4′-(hydroxymethyl)-3′-isopropenylbiphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.094 g, 0.14 mmol) was dissolved in methanol (3 mL), and a palladium-activated carbon ethylenediamine complex (0.090 g) was added, followed by stirring at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered with celite, the filtrate was concentrated under reduced pressure, and subsequently the resulting residue was purified by chromatography on a silica gel column (Biotage Ltd., elution solvent: dichloromethane/ethyl acetate) to afford the title compound (0.049 g, 0.088 mmol) as a yellowish white amorphous solid (yield 60%).
Reaction SMILES: C1(C)C=CC=CC=1.C1O[C:11]2([CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH2:13][CH2:12]2)[O:10]C1.C(O)=O>O>[F:23][C:21]1[CH:22]=[C:17]([CH:14]2[CH2:13][CH2:12][C:11](=[O:10])[CH2:16][CH2:15]2)[CH:18]=[C:19]([F:24])[CH:20]=1
Reactant: Fc1cc(F)cc(C2CCC3(CC2)OCCO3)c1
Solvent: O=CO
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCC(c2cc(F)cc(F)c2)CC1
Yield: 103.1 %

Procedure:
To 50 ml of toluene was added 31 g (0.12 mol) of 4-(3,5-difluorophenyl)cyclohexanone monoethylene ketal obtained above and 76 g (1.7 mol) of formic acid, and the mixture was refluxed for 4 hours. The reaction solution was successively with water, a saturated aqueous sodium carbonate and water, dried over magnesium sulfate, and then the solvent was distilled off to afford 26 g of 4-(3,5-difluorophenyl)cyclohexanone.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH:12]=[CH:13][CH2:14][OH:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1>CC(C)=O.O=[Mn]=O>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: OCC=Cc1ccc(-n2cccn2)nc1
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: O=CC=Cc1ccc(-n2cccn2)nc1
Yield: 42.6 %

Procedure:
A mixture of the compound from step C (185 mg, 0.92 mmol) and MnO2 (1.60 g, 18.40 mmol) in acetone (15 mL) was heated to reflux for 1 h. The cooled reaction mixture was filtered through Celite and the filtrate was concentrated. Purification by chromatography (SiO2, 2:1 hexane/ethyl acetate) yielded 78 mg (43%) of the title compound. MS 200 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][C:32]([CH3:37])([CH3:36])[CH2:31]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][C:32]([CH3:36])([CH3:37])[CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: CC1(C)CC(CCCCBr)CCO1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCOC(C)(C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 224 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(4-bromobutyl)-2,2-dimethyltetrahydro-2H-pyran but conducting the alkylation over 1.5 hours at 60° C.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[Cl:1][CH:2]=[CH:3][CH2:4][C:5]12[O:19][CH:6]1[CH:7]=[CH:8][CH:9]=[CH:10]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClC=CCc1ccccc1
Solvent: ClC(Cl)Cl
Product: ClC=CCC12C=CC=CC1O2
Reaction time: 72 h
Yield: 39.3 %

Procedure:
16.6 g of o-chloroallylbenzene was dissolved in 100 ml of chloroform and to the mixture was added dropwise, while maintaining the temperature at 0° - 5° C, 25 g of m-chloroperbenzoic acid dissolved in 600 ml of chloroform. The resulting mixture was allowed to stand at the same temperature for 72 hours. After the separated m-chlorobenzoic acid was filtered off, the filtrate was washed with 10% sodium hydroxide solution, then with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was distilled under reduced pressure to give 7.2 g (yield 38.8%) of o-chloroallylbenzene oxide having a boiling point of 93° C/3 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(F)cc3)c3c(F)cc(F)cc23)CC1

Procedure:
(7.6 mg, 46.4%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmoles) and 4-fluorophenylsulfonyl chloride (11.7 mg, 0.06 mmol) with 1M NaN(TMS)2 (60 μL, 0.06 mmoles) in THF (0.5 mL) at RT.
Reaction SMILES: N(OC(C)(C)C)=[O:2].N[C:9]1[C:14]([O:15][CH3:16])=[C:13]([Cl:17])[CH:12]=[C:11]([F:18])[C:10]=1[N:19]1[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]1=[O:31].Cl>S([O-])([O-])(=O)=O.[Cu+2].[Cu-]=O.O.[N+]([O-])([O-])=O.[Cu+2].O.O.O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(#N)C>[Cl:17][C:13]1[CH:12]=[C:11]([F:18])[C:10]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[C:9]([OH:2])[C:14]=1[O:15][CH3:16]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Reactant: CC(C)(C)ON=O
Agent: O=[Cu-]
Agent: [Cu+2]
Agent: Cl
Solvent: O
Solvent: CC#N
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1O
Reaction time: 16 h

Procedure:
An acetonitrile (10 ml) solution of copper (II) sulfate (0.52 g, 3.26 mmol), copper (I) oxide (0.47 g, 3.26 mmol) and copper (II) nitrate hemipentahydrate (0.76 g, 3.26 mmol) was stirred at −30° C., and added with tert-butyl nitrite (0.41 g, 3.97 mmol) and then an acetonitrile (3 ml) solution of 3-(2-amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.94 g, 2.56 mmol). After stirred for 16 hr (−30° C. to room temperature), the mixture was poured into cold 5% hydrochloric acid (30 ml) and then extracted with ethyl acetate (20 ml×3). The organic phase was washed with brine and dried over Na2SO4. Preparative TLC was used for purification (silica gel plates, 2000 microns, ether). Yield: 0.16 g, 0.44 mmol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[C:18]1([C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN1C(=O)CCC1>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([N:29]2[CH2:30][CH2:31][N:26]([C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:25])[CH2:27][CH2:28]2)=[CH:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:17])=[O:16]
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
A solution of N-(5-bromo-2-nitrophenyl)benzenamine (200 mg, 0.68 mmol) and phenyl(piperazin-1-yl)methanone (257 mg, 1.36 mmol) in NMP (1.5 mL) was heated to 110° C. for 16 h. The solution was cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish (4-(4-nitro-3-(phenylamino)phenyl)piperazin-1-yl)(phenyl)methanone (187 mg, 0.46 mmol), 68% yield. 1H NMR (500 MHz, CDCl3) d (ppm) 3.10-3.61 (m, 8H), 6.34 (dd, J=2.6, 9.7 Hz, 1H), 6.41 (d, J=2.6 Hz, 1H), 7.24-7.48 (m, 10H), 8.19 (d, J=9.7 Hz, 1H), 9.86 (s, 1H). 13C NMR (125 MHz, CDCl3): d (ppm) 171.0, 155.7, 145.8, 139.3, 135.5, 130.6, 130.2, 129.4, 129.1, 127.6, 126.1, 125.0, 106.2, 96.9, 46.7, 29.9.