Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(NC(C)C)(C)C.[CH:15]#[C:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O.C(OCC)(=O)C.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.[Cu]I>[C:15]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)#[C:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCCC
Reactant: Ic1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CCCC#Cc1ccccn1
Temperature: 85 °C
Yield: 88.3 %

Procedure:
To a degassed solution of 2-iodopyridine (0.519 mL, 4.88 mmol), bis(triphenylphosphine)palladium(II) chloride (0.205 g, 0.293 mmol), copper(I) iodide (0.046 g, 0.244 mmol), and diisopropylamine (2.78 mL, 19.5 mmol) in N,N-dimethylformamide (20 mL) was added 1-pentyne (0.721 mL, 7.32 mmol). The reaction was heated to 85° C. for 3 hrs. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), washed with a 10% aqueous solution of lithium chloride (2×100 mL), washed with a 2M aqueous solution of ammonium hydroxide (100 mL), washed with brine (100 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (3/2) afforded 2-(pent-1-ynyl)pyridine (636 mg, 4.31 mmol). The compound had an HPLC retention time=0.982 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH—90% Water—0.2% H3PO4; Solvent B=90% MeOH—10% water—0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=146.3. 1H NMR (400 MHz, CDCl3) δ ppm 1.06 (t, 3H), 1.67 (dt, J=7.23 Hz, 2H), 2.43 (t, J=7.15 Hz, 2H), 7.18 (ddd, J=7.65, 4.89, 1.00 Hz, 1H), 7.38 (d, J=7.78 Hz, 1H), 7.62 (td, J=7.72, 1.88 Hz, 1H), and 8.55 (d, J=4.27 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22]CC(OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.N[C:48]1[CH:60]=[CH:59][C:51]([C:52]([O:54]C(C)(C)C)=[O:53])=[CH:50][CH:49]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C:48]2[CH:60]=[CH:59][C:51]([C:52]([OH:54])=[O:53])=[CH:50][CH:49]=2)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccc(C(=O)O)cc1

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, tert-butyl 4-aminobenzoate was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: C([NH:8][CH:9]1[CH2:12][C:11]2([CH2:15][C:14]([CH2:25][O:26]CC3C=CC=CC=3)([CH2:16][O:17]CC3C=CC=CC=3)[CH2:13]2)[CH2:10]1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)C>[NH2:8][CH:9]1[CH2:12][C:11]2([CH2:13][C:14]([CH2:16][OH:17])([CH2:25][OH:26])[CH2:15]2)[CH2:10]1
Reactant: c1ccc(CNC2CC3(C2)CC(COCc2ccccc2)(COCc2ccccc2)C3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NC1CC2(C1)CC(CO)(CO)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 104.8 %

Procedure:
20% Palladium hydroxide (254 mg) was added to an ethanol (30 ml) solution of the compound (1.27 g, 2.88 mmol) obtained in Step 4 above and the resulting mixture was stirred at room temperature for 3 days under hydrogen atmosphere. The catalyst was removed by filtration through celite and then the filtrate was concentrated under reduced pressure to give 517 mg (99%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:11]N(CCCCCCC)CC)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].C(Cl)(=O)C.[C:26]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=1)(=[O:28])[CH3:27]>O1CCCC1>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:27][C:26]([C:29]1[CH:30]=[CH:31][C:32]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])=[CH:33][CH:34]=1)=[O:28])[CH3:2]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: CCCCCCCN(CC)CN(CC)CCCCCCC
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCCN(CC)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The Bis(ethylheptylamino)methane (0.95 g, 3.2 mmol) of Preparation 15 in 8 ml of tetrahydrofuran (THF), under nitrogen, is cooled in an ice bath and treated dropwise over 2 min with 0.23 ml (0.25 g, 3.2 mmol) of acetyl chloride; the mixture is stirred 15 min in the cold and 45 min at ambient temperature. The mixture is cooled in an ice bath and a solution of N-(4-acetylphenyl)methanesulfonamide, as described in Preparation 1, (dried by azeotrope from carbon tetrachloride then benzene) (0.68 g, 3.2 mmol) in 10 ml of THF is added dropwise over 5 min. It is stirred in the cold for 1 hr then at room temperature for 72 hrs. The solvent is removed in vacuo (bath <30° C.) and the residue partitioned between cold diluted HCl and ether. The layers are separated and the aqueous layer is extracted with additional ether (4×50 ml). The pooled ether extract is washed with cold diluted HCl. The aqueous layers are combined and brought to pH 8.5 with saturated NaHCO3. This is extracted with ethyl acetate (3×75 ml). The pooled ethyl acetate extract is washed with brine, dried (Na2SO4), acidified with excess ethereal HCl and concentrated to give a mixture which includes the title compound that can be used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.N1C=CC=CC=1>[Cu](I)I.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:18]1([C:17]#[C:16][C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#Cc2ccccc2)cc(C(=O)OC)c1
Yield: 75 %

Procedure:
In a 1 L four-neck flask equipped with a thermometer, a Dimroth condenser, a nitrogen introduction tube and an agitator, 99.7 g (0.365 mol) of the second intermediate (dimethyl 5-bromoisophthalate), 1.1 g (0.00419 mol) of triphenylphosphine, 0.275 g (0.00144 mol) of copper iodide and 41.0 g (0.401 mol) of phenylacethylene were charged and nitrogen was passed into the flask. Then, 375 mL of dehydrated triethylamine and 200 mL of dehydrated pyridine were added therein and the mixture was agitated and dissolved. After passing the nitrogen for one hour, 0.3 g (0.000427 mol) of dichlorobis(triphenyl phosphine)palladium was quickly added and the mixture was heated and refluxed in an oil bath for one hour. Then, triethylamine and pyridine were removed under reduced pressure to obtain a brown viscous solution. The solution was added to 500 mL of water and filtered to separate a solid. The solid was washed with 500 mL of water, 500 mL of 5 mol/L hydrochloric acid and 500 mL of water each two times and dried under reduced pressure at 50° C. Thus, 80.6 g of dimethyl 5-phenylethynylisophthalate was obtained (the yield was 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][CH2:39][CH2:40][Cl:41]>O>[Cl:41][CH2:40][CH2:39][CH2:38][O:25][C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[CH:17][N:16]([C:10]3[S:11][C:12]([C:13]([NH2:15])=[O:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[C:20]=2[CH:21]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCCl)cc32)nc1-c1cccc(Cl)c1
Yield: 79.4 %

Procedure:
A mixture of 0.370 g (1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 3 mL of dimethylformamide, 1.6 g (5 mmole) of cesium carbonate and 0.297 mL (3 mmole) of 1-bromo-3-chloro-propane was heated at 100 degrees for 1 hour. The cooled mixture was diluted with 20 mL of water and the resulting precipitate collected by filtration. The solid was triturated with diethyl ether to give 0.355 g of 2-[6-(3-chloro-propoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.34a) as a brown solid.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)(=[NH:4])[NH2:3].[NH2:13][N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]=[C:15]1[NH2:25]>>[ClH:1].[ClH:1].[C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[N:13][N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]=[C:15]1[NH2:25])(=[NH:4])[NH2:3]
Reactant: N=C(N)c1cccc(C=O)c1
Reactant: Nc1nc(-c2ccccc2)cn1N
Agent: Cl
Product: N=C(N)c1cccc(C=Nn2cc(-c3ccccc3)nc2N)c1

Procedure:
Analogously to Example 31, 3-amidinobenzaldehyde hydrochloride is reacted with 1,2-di-amino-4-phenyl-imidazole, yielding the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=3)[CH:16]=1)[CH2:11]2.[CH2:29]([CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][C:35]([F:40])=[CH:36][CH:37]=2)[NH:32]1)[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:29]([CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][C:35]([F:40])=[CH:36][CH:37]=2)[N:32]1[C:26]([C:22]1[CH:21]=[C:20]([NH:19][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH2:11][C:3]2([C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:10][C:2]2=[O:1])[CH2:18]3)[CH:25]=[CH:24][N:23]=1)=[O:27])[CH3:30]
Reactant: CCC1Cc2ccc(F)cc2N1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1Cc2ccc(F)cc2N1C(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ccn1

Procedure:
186 mg (0.50 mmol) 4-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)picolinic acid, 220 mg (0.60 mmol) 2-ethyl-6-fluoro-2,3-dihydro-1H-indole, 0.26 mL (1.5 mmol) DIPEA and 0.18 g (0.55 mmol) TBTU in 5.0 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and the organic solvent was evaporated down. The aqueous residue was made alkaline with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1.O>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:21]2[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(COc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenol (190 mg, 0.97 mmol) in DMSO (5.0 mL) was added potassium carbonate (276 mg, 2.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes, before addition of ethyl 4-(bromomethyl)benzoate (235 mg, 0.97 mmol). The resulting mixture was heated to 70° C. with stirring for 3 hours before cooling back to room temperature. Water (50 mL) and EtOAc (50 mL) were added and the layers partitioned. The aqueous fractions were washed with EtOAc (2×50 mL) and the combined organic layers dried over magnesium sulfate, filtered and concentrated in vacuo to yield a white solid as the title compound (350 mg, 100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][CH:10]=[C:9]([CH2:13][CH2:14][NH2:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>C1COCC1>[CH3:2][O:3][C:4]1[C:12]2[O:11][CH:10]=[C:9]([CH2:13][CH2:14][NH:15][C:24](=[O:25])[O:26][CH2:27][CH3:28])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc2c(CCN)coc12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCc1coc2c(OC)cccc12
Reaction time: 18 h
Yield: 82 %

Procedure:
To the suspension of 2-(7-methoxy-1-benzofuran-3-yl)ethanamine hydrochloride (from step 2) (0.432 g, 1.9 mmol) in dry THF, triethylamine (0.769 g, 7.6 mmol) was added followed by ethyl chloroformate (0.265 g, 2.4 mmol) and stirred for 18 hrs. Water was added to it and extracted with ethyl acetate. Organic layer was concentrated and purified on Silica gel column to yield Ethyl 2-(7-methoxy-1-benzofuran-3-yl)ethylcarbamate (82%).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][N:7]([CH3:11])[C:8]([NH2:10])=[NH:9].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[C:29](Cl)(Cl)[C:30](Cl)=[O:31].Cl>O1CCCC1.C(Cl)(Cl)Cl>[ClH:21].[CH3:6][N:7]([CH3:11])[C:8]([NH:10][C:30](=[O:31])[CH2:29][C:23]1[C:22]([Cl:21])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:28])=[NH:9]
Reactant: O=C(Cl)C(Cl)(Cl)c1c(Cl)cccc1Cl
Reactant: CN(C)C(=N)N
Agent: Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN(C)C(=N)NC(=O)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
10.89 g of 1,1-dimethylguanidine sulfate, 6.4 g of a 50% sodium hydroxide solution and 30 ml tetrahydrofuran are stirred for 2 hrs at RT. 5 g of anhydrous sodium sulfate are added, followed by the dropwise addition of a solution of 2,6-dichlorodichorophenylacetyl chloride (8.94 g) in 16 ml of tetrahydrofuran. The resulting mixture is stirred overnight at RT. The reaction mixture is evaporated to dryness and the residue stirred with 50 ml H2O at RT for 1 hr. The mixture is filtered and the solid washed with H2O and dried in vacuo. The resulting solid is extracted with 50 ml of boiling acetonitrile, filtered while hot, and the filtrate evaporated in vacuo. The resulting white solid is extracted with hot chloroform, filtered and the filtrate evaporated to dryness. The residue is recrystallized from benzene/chloroform. The solvent is removed and the residue dried in vacuo. The resulting material is taken up in ca 100 ml of chloroform, washed with 100 ml H2O and the chloroform layer separated, dried with magnesium sulfate and evaporated to dryness to afford a yellow oil. The yellow oil is taken up in chloroform and the resulting solution brought to pH 2 with methanolic hydrochloric acid. The solution is evaporated to dryness and the residual yellow solid crystallized to afford 4.38 g of tan crystalline solid, M.P. 225.5°-227° C.
Reaction SMILES: C(OC(C1N(CC2C3C=C(F)C=CC=3SC=2)C2C(C=1CNC)=CC(F)=CC=2)=O)C.Cl.C([O:33][C:34]([C:36]1[N:37]([CH2:53][C:54]2[C:55]3[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:56]=3[S:57][CH:58]=2)[C:38]2[C:43]([C:44]=1[CH2:45][N:46]([C:48]([O:50][CH3:51])=[O:49])[CH3:47])=[CH:42][C:41]([F:52])=[CH:40][CH:39]=2)=[O:35])C>>[F:52][C:41]1[CH:42]=[C:43]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH2:53][C:54]1[C:55]3[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:56]=3[S:57][CH:58]=1)[C:36]([C:34]([OH:35])=[O:33])=[C:44]2[CH2:45][N:46]([C:48]([O:50][CH3:51])=[O:49])[CH3:47]
Reactant: CCOC(=O)c1c(CN(C)C(=O)OC)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12
Agent: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12
Agent: Cl
Product: COC(=O)N(C)Cc1c(C(=O)O)n(Cc2csc3ccc(F)cc23)c2ccc(F)cc12

Procedure:
5-Fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-methylaminomethyl-1H-indole-2-carboxylic acid ethyl ester; salt with hydrogen chloride was converted to 5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-[(methoxycarbonyl-methyl-amino)-methyl]-1H-indole-2-carboxylic acid ethyl ester as described in Example 77.1. which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give 5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-[(methoxycarbonyl-methyl-amino)-methyl]-1H-indole-2-carboxylic acid as a white solid. MS: 443.4 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[C:9]([Cl:16])=[CH:8][C:4]=1[C:5]([OH:7])=O.ClC(OCC)=O.[CH2:23]([N:25]1[CH2:32][CH:31]2[CH:27]([CH2:28][CH2:29][CH2:30]2)[CH:26]1[CH2:33][NH2:34])[CH3:24]>O1CCCC1.C(N(CC)CC)C>[CH2:23]([N:25]1[CH2:32][CH:31]2[CH:27]([CH2:28][CH2:29][CH2:30]2)[CH:26]1[CH2:33][NH:34][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:16])[C:10]([NH:12][C:13](=[O:15])[CH3:14])=[CH:11][C:3]=1[O:2][CH3:1])[CH3:24]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Reactant: CCN1CC2CCCC2C1CN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CC2CCCC2C1CNC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 6 parts of 2-methoxy-4-acetylamino-5-chloro benzoic acid in 50 parts of anhydrous tetrahydrofuran, were added 2.5 parts of triethylamine. The solution thus obtained was poured portionwise in a mixture of 2.7 parts of ethyl chloroformate in 80 parts of tetrahydrofuran maintained at 0° C. After stirring for 10 minutes, 4.1. parts of N-ethyl-2-aminomethyl-3-azabicyclo (3,3,0) octane were added. After being maintained at room temperature for 10 minutes, the temperature was progressively increased and, finally, the reaction mixture was refluxed for 60 minutes. After cooling, the mixture was filtered and the filtrate was evaporated in vacuo. After recrystallization in 50 parts of ethyl acetate, there were obtained 5.5 parts of N-ethyl-2-(2-methoxy-4-acetylamino-5-chloro benzamido methyl)-3-azabicyclo (3,3,0) octane, M.P. 156°-157° C (ethyl acetate).
Reaction SMILES: S1(OS(=O)(=O)OOOO1)(=O)=O.[K].[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[O:21][CH3:22].C(OCC)(=[O:25])C.CCCCCC>O.C(#N)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:22][O:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[C:14]=1[CH:13]=[O:25]
Reactant: CCOC(C)=O
Reactant: COc1cccc(C)c1C
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: O=S1(=O)OOOOS(=O)(=O)O1
Solvent: CCCCCC
Solvent: O
Solvent: CC#N
Product: COc1cccc(C)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.2 %

Procedure:
Potassium peroxy disulphate (89.31 g, 0.33 mol) and copper (II) sulphate pentahydrate (27.22 g, 0.11 mol) was added to a solution of 2,3-dimethylanisole (15 g, 0.11 mol) in acetonitrile water mixture (750 ml, 1:1). The reaction mixture was stirred for 15 min at reflux until no starting material remained as judged by TLC (Thin Layer Chromatography). On cooling the reaction mixture to room temperature, the product was extracted into dichloromethane (2×225 ml). The organic layer was washed with water (2×100 ml) and brine solution (100 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Column chromatography using 4/96 ethyl acetate/hexane yielded 2-Methoxy-6-methylbenzaldehyde (7.32 g, 44.2%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:40]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]([O:47][CH3:48])=[O:46])=[CH:35][CH:34]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Product: COC(=O)c1ccccc1-c1ccc(CN2C(=O)C(NC(=O)CC(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-butanamide (Example 51, Step A) and methyl 4'-bromomethyl-1,1'-biphenyl-2-carboxylate (prepared by the method of D. J. Carini, et al, EPO publication 324,377) by the procedure described in Example 1, Step K. 1H NMR (300 MHz,CDCl3): 1.37 (s,3H), 1.39 (s,3H), 1.75 (m,1H), 2.3-2.6 (m,5H), 3.52 (s,3H), 4.50 (m,1H), 4.80 (d,14 Hz,1H), 5.06 (s,2H), 5.34 (d,14 Hz,1H), 5.65 (s,1H), 6.72 (d,7 Hz,1H), 7.1-7.4 (m,15H), 7.48 (dt;2,8 Hz;1H), 7.78 (dd;2,8 Hz;1H). FAB-MS: calculated for C38H39N3O6 633; found 634 (M+H,60%).
Reaction SMILES: [OH-:1].[Li+].CC1(C)C2CC[C@@]31[C@H](C2)N([C:14](=[O:24])[C@H:15]([CH3:23])[C@H:16]([O:21][CH3:22])[CH2:17][CH2:18][CH:19]=[CH2:20])S(=O)(=O)C3>O.O1CCCC1>[CH3:22][O:21][C@H:16]([CH2:17][CH2:18][CH:19]=[CH2:20])[C@@H:15]([CH3:23])[C:14]([OH:24])=[O:1]
Reactant: C=CCC[C@@H](OC)[C@@H](C)C(=O)N1[C@H]2CC3CC[C@@]2(CS1(=O)=O)C3(C)C
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC[C@@H](OC)[C@@H](C)C(=O)O
Temperature: 60 °C

Procedure:
A solution of 2M lithium hydroxide in water (5 ml) was added to a stirred solution of 10c (223 mg, 0.60 mmol.) in tetrahydrofuran (15 ml). The stirred mixture was heated to 60° C. for 15 hours. The reaction mixture was partially evaporated before adding 2M hydrochloric acid (20 ml). The solution was extracted with ethyl acetate (3×15 ml). The extract was dried over sodium sulfate filtered and evaporated to give a yellow gum (209 mg). The gum was purified on a silica column eluting with 25% ethyl acetate, 75% hexane to yield 10d as a yellow gum (68 mg, 66%). 1H NMR δ (300 MHz NMR, CDCl3) 1.15-1.19 (d, 3H), 1.57-1.67 (m, 2H), 2.11-2.23 (m, 2H), 2.74-2.85 (m, 1H), 3.39-3.42 (s, 3H), 3.45-3.53 (m, 1H), 4.97-5.10 (m, 2H), 5.76-5.91 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:47][C:44]([F:45])([F:46])[C:42]1[CH:41]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:48])[F:49])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:25]=1[O:34][C:35]1[N:36]=[CH:37][CH:38]=[CH:39][N:40]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2ncccn2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2ncccn2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(pyrimidin-2-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (115 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(pyrimidin-2-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (96 mg). MS (m/z): 676 [M+H]+