Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1.C(O)C>O>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13](=[O:14])[CH2:12][C:11]([CH3:10])=[O:15]
Reactant: C=C1CC(=O)O1
Reactant: Cc1ccc(N)c(C)c1
Solvent: CCO
Solvent: O
Product: CC(=O)CC(=O)Nc1ccc(C)cc1C
Temperature: 85 °C
Yield: 95 %

Procedure:
2.48 kg/h (20.5 mol/h) of 2,4-dimethylaniline, 1.83 kg/h (21.3 mol/h) of diketene (purity 98%) and 8 kg/h of a mixture of 2.4 kg/h of ethanol and 5.6 kg/h of water are metered separately but simultaneously into a reactor which has been preheated to about 80° C. The reactor consists of a double-shell glass vessel of about 0.6 l capacity and is equipped with a stirrer, thermometer, reflux condenser and, at the bottom, with a run-off. Immediately the metering has started, the heat evolved by the reaction causes the reactor contents to reflux at about 85° C. The heating of the reactor is discontinued and the reaction is continued by limiting the reactor contents to about 0.3 1 by continuous pumping out. The reactor discharge is cooled to about 15° C. with stirring, and the light-colored crystals which are formed are separated from about 7 kg/h of the pale yellow mother liquor by filtration. The moist product, which is obtained at about 5 kg/h, is washed with about 4 kg/h of cold aqueous 30% strength ethanol and dried, leaving 4 kg/h (19.5 mol/h) of 2',4'-dimethylacetoacetanilide (melting point about 89° C.) corresponding to a yield of 95% based on amine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CS(O[CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:33]([O:32][C:31]([NH:30][CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1)=[O:37])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(C)cc1
Yield: 58.9 %

Procedure:
In a similar manner to that described in Reference example 25, a reaction was carried out using ethyl 3-(4-hydroxyphenyl)-2-(4-methylphenoxy)propionate (300 mg), which is the-product of Reference example 35(c), t-butyl 2-methanesulfonyloxy-ethylcarbamate (598 mg) and potassium carbonate (691 mg) and the reaction mixture was treated to afford the title compound (261 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[N:11]=[CH:12][CH:13]=[N:14]2)[CH3:6])[CH3:2].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:39][C@@H:40]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=3)[C:41](O)=[O:42])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:35][CH:33]2[C:34]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])[CH2:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[N:11]=[CH:12][CH:13]=[N:14]3)=[O:42])=[CH:50][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2nccnc12
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2nccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 48.3 %

Procedure:
According to the procedure described in the synthesis method of Compound III-5, (S)-1,1-diethoxy-N-(quinoxalin-5-ylmethyl)propan-2-amine (Compound IX-12) (1.93 g, 6.65 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (3.36 g, 7.31 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: chloroform:methanol=100:0 to 98:2) to obtain the title compound (2.35 g, 48%).
Reaction SMILES: [CH:1]1([C:6]2[C:16]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:30]>C(OCC)(=O)C>[ClH:30].[CH:1]1([C:6]2[C:16]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2CCCC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(c(C3CCCC3)c1)OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of tert-butyl 9-cyclopentyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (130 mg, 0.410 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (81.3 mg, 78.2%) as a solid.
Reaction SMILES: [C:1]([C@@H:3]([NH:22][C:23]([C:25]1([NH:31]C(=O)OC(C)(C)C)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[NH2:31][C:25]1([C:23]([NH:22][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)=[O:24])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: CCS(=O)(=O)c1ccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)cc2)cc1
Solvent: O=CO
Product: CCS(=O)(=O)c1ccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(N)CCOCC3)cc2)cc1
Temperature: 50 °C
Yield: 52.9 %

Procedure:
To (S)-tert-butyl 4-(1-cyano-2-(4′-(ethylsulfonyl)biphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (v(ii)), 920 mg) was added formic acid (3 mL) and the mixture heated to 50° C. for 30 min. The mixture was evaporated to dryness, dissolved in methanol (9 mL) and purified on reverse phase HPLC eluting with 25 to 95% methanol in 0.1% TFA on a Waters SunFire column. The material was converted to free base by evaporating the relevant fractions, dissolving in dichloromethane (20 mL) and shaking with saturated sodium bicarbonate solution (20 mL). The dichloromethane was dried and evaporated to afford the titled compound as a solid (397 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:5]2[OH:26].[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CCOC(C)=O.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].O1CCOCC1>[CH3:36][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[O:16])=[C:5]2[OH:26]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Reactant: Cc1ccccc1B(O)O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1-c1ccc2c(c1)C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C2(C)C
Temperature: 110 °C
Yield: 55.8 %

Procedure:
To 1,1-dimethylethyl N-((6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (250 mg, 658 μmol, Example 40A-D) and o-tolylboronic acid (134 mg, 987 μmol), were added 1,4-dioxane (3291 μL), and K2CO3 in water (987 μL, 1975 mmol). The reaction was flushed with nitrogen for 10 minutes. Next, Pd2(dba)3 (60.3 mg, 65.8 μmol) and X-Phos (62.8 mg, 132 μmol) were added, and the reaction was heated at 110° C. for 4 hours. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (160 mg) as a yellow oil. MS (m/z)=380(M+H-tBu)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH:7]=[CH:6]2)=[O:2].[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:2][CH:1]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH:7]=[CH:6]2
Reactant: CN(C)C(=O)n1ccc2cc(C=O)ccc21
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CN(C)C(=O)n1ccc2cc(C(O)c3ccccc3)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a stirred solution of 5-formyl-N,N-dimethyl-1H-indole-1-carboxamide (0.63 g, 2.9 mmol) in anhydrous THF (5 mL) was added phenyl magnesium bromide solution (3 M in diethyl ether, 1.1 mL, 3.3 mmol) at −78° C. under argon. The reaction mixture was stirred at −78° C. for 1 hr, at rt for 1 hr and quenched by the slow addition of saturated aq ammonium chloride aqueous solution (10 mL) Water (10 mL) was added, the reaction mixture was extracted with ethyl acetate (20 mL) dried (Na2SO4), filtered through a pad of silica gel, and concentrated to give 5-(hydroxy(phenyl)methyl)-N,N-dimethyl-1H-indole-1-carboxamide (0.9 g, 3 mmol, 100% yield) as a syrup, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:18].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:18]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: Cc1noc(NS(=O)(=O)c2cc(Cl)ccc2Cl)c1Br
Yield: 53 %

Procedure:
2,5-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide 2,5-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,5-dichlorobenzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a yellow powder, m.p. 148-150° C., yield 53%.
Reaction SMILES: C1(C[NH:8][CH:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]2)C=CC=CC=1.S1C=CC=C1.[H][H]>CO.[Pd]>[NH2:8][CH:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: CCOC(=O)N1CCCC(NCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CCOC(=O)N1CCCC(N)CC1
Yield: 100 %

Procedure:
69.1 Parts of ethyl hexahydro-4-[(phenylmethyl)amino]-1H-azepine-1-carboxylate were hydrogenated in the presence of a solution of thiophene in methanol 4% and methanol at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 46.9 parts (100%) of ethyl 4-aminohexahydro-1H-azepine-1-carboxylate as a residue (interm. 3).
Reaction SMILES: [N+]([O-])([O-])=O.[K+].S[CH2:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:11][C:10]=1[CH3:20].[S:21]([Cl:25])(Cl)(=[O:23])=[O:22]>CC#N.ClCCl>[CH3:16][N:15]([CH3:17])[C:13]([C:12]1[CH:18]=[CH:19][C:9]([CH2:8][CH2:7][S:21]([Cl:25])(=[O:23])=[O:22])=[C:10]([CH3:20])[CH:11]=1)=[O:14]
Reactant: Cc1cc(C(=O)N(C)C)ccc1CCS
Reactant: O=S(=O)(Cl)Cl
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)C)ccc1CCS(=O)(=O)Cl
Temperature: -40 °C
Reaction time: 2.5 h
Yield: 73.7 %

Procedure:
Potassium nitrate (583 mg, 5.77 mmol) was added to a solution of 4-(2-mercapto-ethyl)-3,N,N-trimethyl-benzamide (514 mg, 2.30 mmol) in MeCN (23 ml) at room temperature. The mixture was cooled to −40° C., and sulfuryl chloride (1.68 M solution in dichloromethane, 3.46 ml, 5.81 mmol) was then added dropwise over 15 minutes. After stirring at −40° C. to −20° C. for 2.5 hours, the reaction mixture was diluted with dichloromethane (80 ml) and quenched with a saturated aqueous sodium bicarbonate solution (20 ml). The organic layer and the aqueous layer were separated, and the organic layer was then washed with a saturated aqueous sodium chloride solution (30 ml), dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→1/2) to give 2-(4-dimethylcarbamoyl-2-methyl-phenyl)-ethanesulfonyl chloride as a colorless solid (491 mg, 74%).
Reaction SMILES: [C:1]([CH2:4][N:5]1[N:9]=[C:8]([CH3:10])O[C:6]1=[O:11])(=O)[CH3:2].[NH3:12]>C(#N)C>[CH3:2][C:1]1[NH:12][C:6](=[O:11])[N:5]([N:9]=[CH:8][C:10]2[CH:6]=[N:5][CH:4]=[CH:1][CH:2]=2)[CH:4]=1
Reactant: N
Reactant: CC(=O)Cn1nc(C)oc1=O
Solvent: CC#N
Product: Cc1cn(N=Cc2cccnc2)c(=O)[nH]1
Reaction time: 1 h

Procedure:
A solution of 156 g of 3-acetylmethyl-2,3-dihydro-5-methyl-2-oxo-1,3,4-oxadiazole in 600 ml of acetonitrile is treated with 170 g of aqueous ammonia solution (30%), and the mixture is stirred for one hour at 80° in an autoclave. A pressure of approximately 8 bar is in this case established. The resulting suspension is evaporated, the residue is dissolved in 500 ml of methanol, and 40 g of gaseous HCl are passed into the solution at 50°. The reaction mixture is stirred for 30 minutes at 50°, and 107 g of 3-formylpyridine are then added dropwise at the same temperature. The reaction mixture is stirred for a further 30 minutes at 50°, then cooled to 0°, and filtered with suction. The filter cake, consisting of 2,3-dihydro-2-oxo-1-pyrid-3-ylmethyleneamino-4-tert-butyl-1H-imidazole hydrochloride (compound no. 4.1.1 in table 4), is dissolved in water at room temperature. The pH of the solution is brought to approximately 7 using aqueous sodium hydroxide solution (30%), during which process a precipitation of crystals is observed at a pH of approximately 3. The crystals are filtered off with suction and dried in vacuo, yielding the title compound melting at 200°-202°.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:13]=[C:12]([O:14]C(=O)C)[C:11]([O:18][CH3:19])=[CH:10][C:4]=1[CH2:5][NH:6][C:7](=[O:9])[CH3:8]>O1CCOCC1>[Br:2][C:3]1[CH:13]=[C:12]([OH:14])[C:11]([O:18][CH3:19])=[CH:10][C:4]=1[CH2:5][NH:6][C:7](=[O:9])[CH3:8]
Reactant: COc1cc(CNC(C)=O)c(Br)cc1OC(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(CNC(C)=O)c(Br)cc1O

Procedure:
10% Aq. hydrochloric acid (2.5 ml) was added to a solution of 2-bromo-4-acetoxy-5-methoxy-N-acetyl-benzylamine 2 (0.45 g, 1.66 mmol) in dioxane (15 ml) and the mixture was refluxed for 2 hours, then cooled and the solvent was concentrated under vacuum and the residue was basified with 10% aq. NaOH. The resulting solid was collected by filtration, washed with cold water and dried to furnish the title compound as white solid in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[Cl:41])[C:5]([N:7](C(=O)C1C=CC(Cl)=C(Cl)C=1)[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](OCC)=[O:24])=[CH:17][CH:16]=2)=[N:12][CH:13]=1)=[O:6].[OH-].[Na+].Cl.[CH2:45]([N:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1)[C:46]1[CH:54]=[CH:53][C:52]2[O:51][CH2:50][O:49][C:48]=2[CH:47]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C1COCC1.C(O)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[Cl:41])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([N:58]3[CH2:59][CH2:60][N:55]([CH2:45][C:46]4[CH:54]=[CH:53][C:52]5[O:51][CH2:50][O:49][C:48]=5[CH:47]=4)[CH2:56][CH2:57]3)=[O:24])=[CH:17][CH:16]=2)=[N:12][CH:13]=1)=[O:6]
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: CCOC(=O)CCc1ccc(Cc2ccc(N(C(=O)c3ccc(Cl)c(Cl)c3)C(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1)c1ccc(Cl)c(Cl)c1

Procedure:
To a solution of ethyl 3-(4-{5-[bis(3,4-dichlorobenzoyl)amino]-2-pyridylmethyl}phenyl)propionate (177 mg, 0.281 mmol) in THF (5 mL) and ethanol (5 mL) were added 5 M aqueous sodium hydroxide (0.0929 mL, 0.463 mmol) and water (1 mL), and the resulting solution was refluxed for 1 hour. To this reaction solution was added 5 M hydrochloric acid (0.12 mL), and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was dissolved in DMF (3 mL), and to the resulting solution were then added 1-piperonylpiperazine (102 mg, 0.463 mmol), triethylamine (0.137 mL, 0.983 mmol) and diethyl cyanophosphonate (0.0703 mL, 463 mmol), and stirred for 1.5 hours at room temperature. Water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=70:1→40:1→20:1), to thereby yield 44.1 mg of a free form. This free form was dissolved in ethanol (5 mL) and 5 M hydrochloric acid (0.03 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from water-containing isopropanol, to thereby yield 19.6 mg of the title compound.
Reaction SMILES: [N:1]1([C:6](=[CH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[BH4-].[Na+]>CO>[N:1]1([C:6](=[CH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[CH:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[OH:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)C(=O)C=C(C(=O)c1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(=O)C=C(C(O)c1ccc(Cl)cc1)n1cncn1

Procedure:
The product (6.4 g, 0.02 mol) of Stage 2 was dissolved in methanol(100 ml) and to this solution was added sodium borohydride (0.2 g, 0.005 mol) at 0°. After stirring at room temperature for 15 hours the methanol was removed in vacuo. The residue was washed with water and neutralised with dilute hydrochloric acid. Recrystallisation of the solid from petroleum ether/ethanol gave the title compound as white needles, m.p. 156°-160°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15](I)=[CH:16][N:17]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[CH:11][CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([N:43]3[CH2:48][CH2:47][CH:46]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:45][CH2:44]3)[CH:40]=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:37]3[CH:38]=[C:39]([N:43]4[CH2:44][CH2:45][CH:46]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])[CH2:47][CH2:48]4)[CH:40]=[N:41][CH:42]=3)=[CH:16][N:17]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4c(F)cccc4F)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)c3)c3nc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
A solution of 5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (92 mg, 0.180 mmol), crude tert-butyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidin-4-ylcarbamate (127 mg, 0.316 mmol) and Pd(PPh3)4 (20.83 mg, 0.018 mmol, Strem) in toluene (1 mL) and Ethanol (1.000 mL) was treated with Na2CO3, 2.0 M (0.180 mL, 0.361 mmol). The reaction vessel was capped, degassed and backfilled with argon; and the reaction was heated to 100° C. After 20 h, the solution was cooled to 23° C., diluted with EtOAc (100 mL) and washed with brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 30-90% EtOAc/hexane), affording tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (85 mg, 71%). MS (ESI, pos. ion) m/z: 660.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([O:14][Si](C(C)(C)C)(C)C)[CH2:10][CH:9]=2)=[N:6][CH:7]=1.C(=[NH:36])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].Cl>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C.O>[NH2:36][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C1=CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: Cc1cc(N)cnc1C1=CCC(O)CC1
Yield: 84.4 %

Procedure:
A suspension of 5-bromo-2-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohex-1-en-1-yl)-3-methylpyridine (5.59 g) of Reference Example 110(1), benzophenonimine (2.77 g), palladium acetate (41 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (114 mg) and sodium tert-butoxide (2.1 g) in toluene (30 ml) was stirred under reflux for two hours. After completion of the reaction, the reaction solution was left stand, concentrated hydrochloric acid (20 ml) and water (60 ml) were added and stirred at room temperature for two hours. Then, diethyl ether was added and extracted with 1N hydrochloric acid aqueous solution. The resulting aqueous layer was cooled with ice, adjusted to pH>10 by the addition of 4N aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the titled compound (2.52 g) as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:15][CH2:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[Li+]>CO.O>[C:18]([O:17][CH2:16][CH2:15][N:9]1[C:10]([C:11]([F:13])([F:14])[F:12])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1cnn(CCOC(C)(C)C)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OCCn1ncc(C(=O)O)c1C(F)(F)F
Yield: 75.8 %

Procedure:
To a solution of 1-(2-tert-butoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (620 mg, 2.0 mmol) in methanol (2 mL) and water (2 mL) was added lithium hydroxide (67 mg, 2.8 mmol). The reaction mixture was stirred at reflux for 4 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was then acidified carefully with 6.0 N aqueous HCl. The resulting mixture was extracted with methylene chloride (2×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide 1-(2-tert-butoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid as a red oil (425 mg, 75%), which was used without further purification.