Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]/[CH:4]([OH:12])[CH2:5][C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][CH3:9].[C:13]1([C:19](Br)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1]/[CH:2]=[CH:3]/[CH:4]([O:12][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:5][C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][CH3:9]
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC(C)(C)CC(O)/C=C/Br
Product: CCCC(C)(C)CC(/C=C/Br)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 3.53 g. (15 moles) of 1-bromo-5,5-dimethyl-trans-1-octen-3-ol (Example 1177) with 4.85 g. (15 moles) of triphenylmethyl bromide in 35 ml. of pyridine and purification on Florisil ®, all as described in Example 728 gives the title compound.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)=[O:18])[CH3:15].C([BH3-])#N.[Na+].O>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([N:28]3[CH2:27][CH2:26][N:25]([C:22]4[CH:21]=[CH:20][C:19]([C:17]([O:16][CH2:14][CH3:15])=[O:18])=[CH:24][CH:23]=4)[CH2:30][CH2:29]3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C1CCC(C2CCCCC2)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(N2CCN([C@H]3CC[C@@H](C4CCCCC4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-cyclohexylcyclohexanone (1.54 g), 1-(4-ethoxycarbonylphenyl)piperazine (2 g) and titanium(IV) isopropoxide (3.18 ml) was stirred at room temperature. After 1 hour, the IR spectrum of the mixture showed no ketone band, and the viscous solution was diluted with absolute ethanol (8.5 ml). Sodium cyanoborohydride (0.343 g) was added, and the solution was stirred for 3 hours. Water (3 ml) was added with stirring, and the resulting in organic precipitate was filtered and washed with ethanol. The filtrate was extracted with ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with (hexane/ethyl acetate)=(3/1). The fractions containing the less polar compound were collected and evaporated under reduced pressure to give ethyl 4-[4-(cis-4-cyclohexylcyclohexyl)piperazin-1-yl]benzoate (692 mg) as byproduct. The fractions containing the more polar compound were collected and evaporated under reduced pressure to give ethyl 4-[4-(trans-4-cyclohexylcyclohexyl)piperazin-1-yl]benzoate (587 mg).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[N:19]3[C:20]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4C4C(C3=O)=CC=CC=4)[C:6]=2[CH:22]=1.CC([O-])(C)C.[Na+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:4]1[C:5]2[NH:19][C:20]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:22]=[CH:2][CH:3]=1
Reactant: Nc1ccc2c(c1)c1cccc3c4ccccc4c(=O)n2c31
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)[nH]c1ccccc12

Procedure:
6.5 g (23 mmol) of 5-amino-7b-azabenzo[e]acephenanthrylen-8-one, 7.1 g (23 mmol) of 2,2′-dibromodiphenyl, 16 g (72 mmol) of NaOtBu, 1.4 g (1.58 mmol) of Pd2 dba3 and 6.3 ml (6.3 mmol) of t-Bu3P are heated at 110° C. for 36 h in 150 ml of toluene under a protective-gas atmosphere. After cooling, the precipitated solid is filtered off with suction, washed with water and ethanol and dried. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum. The yield after sublimation is 7 g (16 mmol, 71%) with a purity of 99.9%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=1[O:30][CH3:31])(=[O:21])=[O:20])[CH3:2].Cl.Cl[CH2:35][C:36]1[N:37]=[C:38]([CH3:41])[S:39][CH:40]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[C:28]([C:26]1[CH:25]=[CH:24][C:23]([O:30][CH3:31])=[C:22]([S:19]([N:18]([CH2:35][C:36]2[N:37]=[C:38]([CH3:41])[S:39][CH:40]=2)[CH2:17][CH2:16][C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:15])[CH3:14])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:32])(=[O:20])=[O:21])[CH:27]=1)#[N:29]
Reactant: Cc1nc(CCl)cs1
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc(C(C)C)ccc1CCN(Cc1csc(C)n1)S(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.5 %

Procedure:
A suspension of 300 mg of ethyl[2-(2-(5-cyano-2-methoxy-benzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate, 132 mg of 4-chloromethyl-2-methyl-1,3-thiazole hydrochloride and 189 mg of potassium carbonate in 2.0 mL of N,N-dimethylformamide was stirred at room temperature for 18 hours, then at 50° C. for 3 hours. To the reaction mixture were added 60 mg of 4-chloromethyl-2-methyl-1,3-thiazole hydrochloride and 45 mg of potassium carbonate, and the mixture was stirred at the same temperature for 2.7 hours. To the reaction mixture were added 60 mg of 4-chloromethyl-2-methyl-1,3-thiazole hydrochloride and 45 mg of potassium carbonate, and the mixture was stirred at the same temperature for 3 hours. Furthermore, to the reaction mixture was added 2 mL of N,N-dimethylformamide, and the mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture were added water and saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, aqueous sodium chloride solution, and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 311 mg of ethyl [2-[2-[(5-cyano-2-methoxybenzenesulfonyl)-(2-methyl-1,3-thiazol-4-ylmethyl)amino)ethyl]-5-isopropylphenoxy]acetate.
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]C(=O)C)[C:6]=1[C:15]([O:17]C)=[O:16].[OH-].[Na+].Cl>C(O)C>[OH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([SH:4])[C:6]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1c(OC(C)=O)cccc1SC(=O)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(O)cccc1S

Procedure:
A mixture of S-3-acetoxy-2-carbomethoxyphenyl dimethylthiocarbamate (0.70 g, 2.7 mmol) and 20% aqueous sodium hydroxide (60 ml) in ethanol (20 ml) was stirred at reflux temperature for 18 hours. The cooled mixture was acidified by the addition of concentrated hydrochloric acid. The resulting mixture was extracted with diethyl ether, and the combined organic extracts were washed with water, saturated aqueous sodium chloride solution, dried (sodium sulfate), and evaporated to give 2-hydroxy-6-mercaptobenzoic acid as a light brown solid; yield 0.29 g (63%).
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CCCCN[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:28][C@H:29]([C:45]([N:47]1[CH2:55][CH2:54][CH2:53][C@H:48]1[C:49]([O:51][CH3:52])=[O:50])=[O:46])[CH2:30][CH2:31]CCNC(OCC1C=CC=CC=1)=O.[F:56][C:57]([C:60]([OH:62])=[O:61])([F:59])[F:58]>N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CCC(=O)OCC1C=CC=CC=1>[NH2:28][C@H:29]([C:45]([N:47]1[CH2:55][CH2:54][CH2:53][C@H:48]1[C:49]([O:51][CH3:52])=[O:50])=[O:46])[CH2:30][CH2:31][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1.[F:56][C:57]([C:60]([OH:62])=[O:61])([F:59])[F:58]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCC(=O)OCc1ccccc1

Procedure:
Instead of Boc-Lys(Z)-OH in (b), Boc-Glu(Bzl)-OH was used as a starting compound to obtain H-Glu(Bzl)-Pro-OMe trifluoroacetate (oil).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:17]=3)[NH:12][C:6]=2[CH:5]=1.I[CH3:26]>CN(C=O)C.O.CCOC(C)=O>[Br:3][C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:17]=3)[N:12]([CH3:26])[C:6]=2[CH:5]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(-c2cnn(C(=O)OC(C)(C)C)c2)cc2cnc(Br)cc21
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Sodium hydride (60% in mineral oil, 7.1 mg, 0.178 mmol) was added to a solution of tert-butyl 4-(6-bromo-1H-pyrrolo[3,2-c]pyridin-2-yl)-1H-pyrazole-1-carboxylate (27) (43 mg, 0.118 mmol) in DMF (515 μL) at 0° C. The reaction mixture was then stirred for 30 min at 0° C. before the addition of iodomethane (18 μL, 0.237 mmol). After stirring for 30 min, it was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The crude was purified via Biotage (DCM/EtOAc 99/1 to 90/10; 12+M column) to afford the title compound as a white solid (35 mg, 78%). 1H NMR (500 MHz, CDCl3) 1.71 (s, 9H), 3.78 (s, 1H), 6.68 (d, J=0.6 Hz, 1H), 7.46 (m, 1H), 7.94 (d, J=0.6 Hz, 1H), 8.32 (d, J=0.6 Hz, 1H), 8.64 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.Cl.[OH-].[Na+].COC1C=C(C=CC=1)N>CO>[Br:1][C:2]1[C:3]([NH2:10])=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: COc1cccc(N)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Br)c(N)c1
Yield: 93.1 %

Procedure:
4-Bromo-3-nitroanisole (19.8 g, 85.1 mmol) was dissolved in methanol (150 ml). Conc. HCl (40 ml) was added to the resultant solution, and the mixture was stirred while cooling. During stirring, reduced iron (14.3 g) was added to the mixture by small portions, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was condensed under reduced pressure. 2N-Caustic soda solution (100 ml) was added to the condensate, and the insoluble matter was filtered off. The filtrate was extracted with chloroform. The organic phase was dried and condensed under reduced pressure to obtain 16.0 g of the title compound, 3-methoxyaniline, as a brown oil (93.0%).
Reaction SMILES: CS([C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[C:18]4=[N:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=[C:17]4[N:16]=[CH:15]3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.CS(C1SC2C=C(CN3C4=NC=C(C(OC)=O)C=C4N=C3)C=CC=2N=1)(=O)=O.[NH2:54][C@@H:55]1[CH2:60][CH2:59][CH2:58][CH2:57][C@H:56]1[OH:61].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[OH:61][C@@H:56]1[CH2:57][CH2:58][CH2:59][CH2:60][C@H:55]1[NH:54][C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[C:18]4=[N:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=[C:17]4[N:16]=[CH:15]3)[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(S(C)=O)sc2c1
Agent: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(S(C)(=O)=O)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 100 °C
Reaction time: 19 h

Procedure:
A 2:1 mixture of methyl 3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate and methyl 3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (360 mg) from Step 4 of this Example was dissolved in anhydrous DMA (10 mL), and (1R,2R)-(−)-2-aminocyclohexanol (322 mg, 2.79 mmol) and DIEA (360 mg, 2.79 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 100° C. for 19 h. LCMS indicated the reaction was not complete. To the reaction mixture was added additional (1R,2R)-(−)-2-aminocyclohexanol (100 mg, 0.870 mmol) and the reaction vessel was sealed and the mixture was heated at 100° C. for a further 15 h. After the reaction mixture was cooled to rt, one half of the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford methyl 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (19 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.96 (d, J=7.3 Hz, 1H), 8.76 (m, 1H), 8.54 (m, 1H), 7.99 (br s, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.16-7.33 (m, 2H), 5.51 (br s, 2H), 4.76 (br s, 1H), 3.89 (s, 3H), 3.30-3.50 (m, 2H), 2.02 (m, 1H), 1.86 (m, 1H), 1.50-1.70 (m, 2H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 438 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]2[CH2:10][CH2:11][C@:12]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][C@@H:23]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19])([CH3:14])[O:13][C:4]=2[C:3]=1[CH3:31].[NH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]2[CH2:10][CH2:11][C@:12]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][C@@H:23]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19])([CH3:14])[O:13][C:4]=2[C:3]=1[CH3:31].[NH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([O-:8])=[O:38])=[CH:35][CH:34]=1
Reactant: Nc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Solvent: c1ccncc1
Product: Nc1ccc(C(=O)[O-])cc1

Procedure:
The reaction of alpha-tocopherol with 4-aminobenzoic acid chloride was carried out in the same manner with Example I, except that 10 mol % of 4-(dimethylamino)pyridine was added together with pyridine. This reaction was confirmed to proceed in a similar pattern to that of Example I as measured by thin layer chromatography. The remaining processes of Example I were repeated to produce alpha-tocopherol 4-aminobenzoate (0.61 g, yield 68%).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)C1C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH3:15][C:12]1([CH3:16])[O:11][C@@H:10]([CH2:9][OH:8])[CH2:14][O:13]1
Reactant: CC1(C)OC[C@H](COCc2ccccc2)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](CO)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
10% Palladium-carbon (2.3 g) was added to thus obtained (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (14.398 g, 64.74 mmol) in ethyl acetate(250 ml) and the mixture was stirred for 3 hours at 25° C. under an atmosphere of hydrogen. After the reaction was over, palladium-carbon was filtered off and the solvent was condensed in vacuo. The crude product was distilled to give 7.61 g of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (yield 89%, b.p. 70° C. at 6 mmHg, optical purity 97.4% e.e., specific rotation [α]D20 +10.78°(c=1,MeOH))).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:10])([OH:3])=[O:2].[C:33](N1C=CN=C1)(N1C=CN=C1)=O.CO.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[CH2:21]([O:20][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:11]=1[C:9](=[O:10])[C:8]1[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[C:6]([CH2:5][CH2:4][C:1]([O:3][CH3:33])=[O:2])[CH:7]=1)[C:15]([OH:17])=[O:16])[CH:22]([CH3:23])[CH3:24]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)COc1ccc(C(=O)c2ccc(C(=O)O)cc2OCC(C)C)cc1CCC(=O)O
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(C(=O)c2ccc(C(=O)O)cc2OCC(C)C)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
In 2 ml of methylene chloride is dissolved 0.15 g of 4-[3-(2-carboxyethyl)-4-isobutoxybenzoyl]-3-isobutoxybenzoic acid, to which is added 0.12 g of 1,1′-carbonyldiimidazole. After stirring the mixture at ambient temperature for one hour, 15 μl of methanol is added, and the mixture thus obtained is stirred at the same temperature as above for one hour. Ethyl acetate and water are added to the reaction mixture, pH is adjusted to 2 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 0.05 g of 3-isobutoxy-4-[4-isobutoxy-3-(3-methoxy-3-oxopropyl)benzoyl]benzoic acid as a white solid product.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(C)(C)C.[ClH:34]>O1CCOCC1.C(OCC)C>[ClH:32].[ClH:34].[NH2:7][CH2:8][CH2:9][N:10]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1)[C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)c1ccc(-c2ccncc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCN(Cc1ccc(Cl)cc1)C(=O)c1ccc(-c2ccncc2)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
The {2-[(4-chlorobenzyl)-(4-pyridin-4-yl-benzoyl)-amino]-ethyl}-carbamic acid tert-butyl ester (184 mg, 0.395 mmol) was dissolved in 2.0 mL of 1,4-dioxane and treated with 2.0 mL of 4M HCl in 1,4-dioxane. The reaction was allowed to stir for one hour to completion and diluted with diethyl ether. The product was isolated by vacuum filtration to afford the N-(2-amino-ethyl)-N-(4-chlorobenzyl)-4-pyridin-4-yl-benzamide bis-hydrochloride salt as a fine pale-yellow powder (166 mg, 96%). 1H NMR (DMSO-d6, 400 MHz) δ 8.91 (d, J=6.0 Hz, 2H), 8.26 (d, J=6.0 Hz, 2H), 8.13 (brs, 3H), 8.05 (d, J=8.0 Hz, 2H), 7.76 (d, J=7.6 Hz, 2H), 7.45 (brs, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.26 (d, J=7.6 Hz, 2H), 4.57 (brs, 2H), 3.61 (m, 2H), 3.08 (m, 2H). LCMS (APCI+) m/z 366 [M+H]+; Rt=2.13 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O.[H][H]>[Pt](=O)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:13])([F:14])[CH:10]([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[NH2:15]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)cc1F
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Nc1ccc(OC(F)(F)C(F)F)cc1F
Reaction time: 2 h
Yield: 85 %

Procedure:
0.20 Gram of 2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)nitrobenzene, 0.03 g of platinum dioxide and 5 ml of ethyl acetate were added to a reactor, and the atmosphere in the reactor was replaced by a hydrogen stream with stirring. Stirring was then continued at room temperature for 2 hours while introducing a hydrogen gas. Thereater, the reaction solution was filtered off, and the filtrate was concentrated to obtain 0.15 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)aniline.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11][C:5]2=[N:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:9]2[C:10]([CH3:13])([CH3:12])[CH2:11][C:5]3=[N:4][N:3]=[C:2]([CH3:1])[N:6]3[C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]2=3)=[CH:21][CH:20]=1
Reactant: Cc1nnc2n1-c1ccccc1NC(C)(C)C2
Reactant: Clc1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(C)(C)C2
Temperature: 90 °C

Procedure:
A disposable tube was charged with 1,5,5-trimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (150 mg, 0.657 mmol), 1-chloro-4-iodobenzene (204 mg, 0.854 mmol), RuPhos precat. (23.94 mg, 0.033 mmol), sodium 2-methylpropan-2-olate (126 mg, 1.314 mmol), and a stirbar before being evacuated and purged with nitrogen three times. Toluene (3 mL, 0.5 M) was added, and the mixture was stirred at 90° C. 48 h. The mixture was cooled, diluted with ethyl acetate, filtered, and purified by reverse phase HPLC to yield the title compound as an off-white amorphous solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[C:13]([N+:25]([O-])=O)[CH:12]=2)[CH3:9])=[CH:4][CH:3]=1.[NH4+].[Cl-]>CO.[Fe]>[NH2:25][C:13]1[CH:12]=[C:11]([O:10][CH:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH3:9])[CH:16]=[CH:15][C:14]=1[S:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1
Reactant: CC(Oc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(Oc1ccc(Sc2ccc(O)cc2)c(N)c1)c1ccccc1
Yield: 104.1 %

Procedure:
The product from Example 22C (560 mg, 1.25 mmol) was reacted with Fe (279 mg, 5.0 mmol) and NH4Cl (76 mg, 1.40 mmol) in 5 mL MeOH/5 mL THF/2.5 mL water following the procedure from Example 10E giving the title compound as a solid (439 mg, 84%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCCOc1ccc(C)nc1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCCOc1ccc(CBr)nc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 36.9 %

Procedure:
To a solution of 2.16 gm (9.0 mmol) of acetic acid 2-(6-methyl-2-nitro-pyridin-3-yloxy)-ethyl ester 94, 1.76 gm (9.9 mmol) of N-bromosuccinimide in 125 mL of CCl4 was added 0.074 gm (44.9 μmol) of AIBN and the reaction was heated to reflux for 1 h. After 1 h a 500 watt sun lamp was used to irradiate the refluxing solution for an additional 4 h. The mixture was poured into 300 mL of CCl4 and washed with water twice (150 mL), saturated brine and the organic layer was dried (anhydrous Na2SO4) and the solvents removed at reduced pressure. Column chromatography of the residue using 50%-30%-10% CH2Cl2-hexanes yielded 1.06 gm (37%) of a light yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.06 (s, 3H), 4.31 (t, 2H, J=4.1 Hz), 4.41 (t, 2H, J=4.1 Hz), 4.48 (s, 2H), 7.49 (d, 2H, J=8.5 Hz), 7.65 (d, 2H J=8.5 Hz).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[S:12][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)=[O:7].Cl.[CH3:23]O>>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[S:12][C:11]([CH2:13][C:14]([O:16][CH3:23])=[O:15])=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C(O)Cc1ccc(C(=O)c2cccc(C(F)(F)F)c2)s1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(C(=O)c2cccc(C(F)(F)F)c2)s1
Reaction time: 12 h

Procedure:
1.60 gm of 5-(m-trifluoromethylbenzoyl)-thiophene-2-acetic acid were dissolved in 30 cc of methanol and the solution was saturated with gaseous hydrochloric acid and refluxed for 1 hour. The solvent was then distilled off under reduced pressure and the residue was taken up in a minimum of isopropyl ether. An equal volume of petroleum ether was added to the solution. Crystallization was induced by scratching and the solution was iced for 12 hours. The crystals were separated, washed with petroleum ether and dried to obtain 1.35 gm of methyl 5-(m-trifluoromethyl benzoyl)-thiophene-2-acetate.