Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.[Cl:22][C:23]1[S:27][C:26]([NH:28][C:29](=O)[O:30]C2C=CC([N+]([O-])=O)=CC=2)=[N:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:29](=[O:30])[NH:28][C:26]3[S:27][C:23]([Cl:22])=[CH:24][N:25]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)s1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(Br)cc32)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.5 %

Procedure:
2-Amino-5-chlorothiazole hydrochloride (1.00 g, 5.80 mmol) was dissolved in methylene chloride (50 mL), and the obtained solution was then washed with a saturated aqueous solution of sodium hydrogen carbonate. The resulting solution was dried over anhydrous sodium sulfate and was then filtered. After that, pyridine (0.47 mL, 5.80 mmol) and 4-nitrophenyl chloroformate (1.18 g, 5.80 mmol) were added to the filtrate, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, a solid was collected by filtration, was then washed with methylene chloride, and was then dried to obtain 4-nitrophenyl (5-chlorothiazol-2-yl)carbamate (980 mg, 56%) in the form of a white solid. t-Butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (65.1 mg, 0.184 mmol) synthesized by a method described in the known method (International Publication WO2009/089454) or a method similar thereto was dissolved in N,N′-dimethylformamide (2 mL). Thereafter, 4-nitrophenyl (5-chlorothiazol-2-yl)carbamate (55.2 mg, 0.184 mmol) and triethylamine (13 μL, 0.092 mmol) were added to the above obtained solution, and the obtained mixture was then stirred at 50° C. for 3 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the captioned compound (60.0 mg, 64%) in the form of a white solid.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([N:17]1[CH2:31][CH2:30][CH2:29][C@H:18]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])=[O:4])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([N:17]1[CH2:31][CH2:30][CH2:29][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of EtSO2—D—Phe—Pro—OBn (28.5 g, 64 mmol) in ethyl acetate (500 mL) was added 10% Pd/C (5 g). The vessel was evacuated and placed under an atmosphere of hydrogen. After stirring for 16 h, the solution was filtered over diatomaceous earth, and the filter pad was then washed twice with methanol and filtered. The combined filtrates were concentrated in vacuo to give 22 g (97%) of off-white solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][NH:8][CH2:7]1)(=[O:3])[CH3:2].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[C:1]([NH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCC1CNCCO1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Reaction time: 17 h
Yield: 78.9 %

Procedure:
A mixture of 2-acetylaminomethylmorpholine (7.0 g), 4-fluorobenzyl chloride (12 g), potassium carbonate (56 g), potassium iodide (1 g), and methyl ethyl ketone (100 ml) is refluxed with stirring for 17 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is diluted with water and extracted with chloroform. The organic layer is separated, washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is recrystallized from toluene to give the title compound (9.3 g), mp 120°-122° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[F:15][C:13]1[CH:12]=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:10]=[C:9]([OH:8])[CH:14]=1
Reactant: COC(=O)C=Cc1cc(F)cc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cc(O)cc(F)c1
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a solution of methyl 3-(3-(benzyloxy)-5-fluorophenyl)acrylate (2.60 g) in methanol (15 mL) was added 10% palladium-activated carbon (2.20 g), and the mixture was stirred for 1 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (710 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)[CH2:2][C:3]#[CH:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23](I)=[N:24][CH:25]=2)=[CH:16][CH:15]=1>C(N(CC)CC)C.CN(C=O)C.CCOC(C)=O.CO.[Cu]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>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:4]#[C:3][CH2:2][CH2:1][C:5]3[CH:6]=[CH:7][C:8]([CH2:11][OH:12])=[CH:9][CH:10]=3)=[N:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: C#CCCc1ccc(CO)cc1
Reactant: Clc1ccc(-c2ccc(I)nc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: OCc1ccc(CCC#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere 76 mg (0.4 mmol) CuI and 281 mg (0.4 mmol) Pd(PPh3)2Cl2 are added to a solution of 1.27 g (7.92 mmol) (4-but-3-ynyl-phenyl)-methanol and 2.5 g (7.92 mmol) 5-(4-chloro-phenyl)-2-iodo-pyridine in 40 mL triethylamine and 20 mL DMF and the reaction mixture is stirred for 2 h at 65° C. The solvent is eliminated in vacuo, the residue is dissolved in a little EtOAc and MeOH and purified by chromatography on silica gel (gradient: cyc/EtOAc 3:1 to cyc/EtOAc 1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:15](OCC)=[O:16].C(Cl)(=O)C>O1CCOCC1>[CH:11]([C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:15](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc(N)c(C(=O)O)c1
Reactant: CCOC(=O)Cl
Solvent: C1COCCO1
Solvent: CC(=O)Cl
Product: CC(C)c1ccc2[nH]c(=O)oc(=O)c2c1
Reaction time: 3 h

Procedure:
A mixture of 2-amino-5-isopropylbenzoic acid (30. g, 16.7 mmol) and ethyl chloroformate (1.75 mL, 18.4 mmol) in dioxane (20 mL) was heated under reflux for 2 h. After cooling, acetyl chloride (1.4 mL) was added and heating under reflux continued for another 3 h. After cooling, the mixture was evaporated and the resulting solid digested with tert-butyl methyl ether: heptane (1:1, 20 mL) by heating under reflux for 1 h. The soild was then filtered off and washed with tert-butyl methyl ether: heptane (1:1, 10 mL). Yield 3.1 g (89%). m/z 204 (M—H−).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([CH:8]([CH2:21][CH3:22])[C@H:9]([NH:12][C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:10]#[N:11])[CH3:7].[NH4+].[OH-:24]>>[CH2:21]([CH:8]([CH2:6][CH3:7])[C@@H:9]([C:10]([NH2:11])=[O:24])[NH:12][C@H:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])[CH3:22]
Reactant: CCC(CC)[C@@H](C#N)N[C@@H](C)c1ccccc1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CCC(CC)[C@H](N[C@@H](C)c1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To 25 mL of sulfuric acid at 0° C. was added (S)-3-ethyl-2-{[(S)-1-phenylethyl]amino}pentanenitrile (2.7 g, 11.6 mmol) portionwise. The mixture was warmed to 25° C. After 2 days, the reaction mixture was poured over about 100 g of crushed ice. Concentrated NH4OH was added to neutralize the acid. This mixture was extracted with EtOAc (3×100 mL), dried over Na2SO4, filtered and concentrated to give 3-ethyl-N2-[(S)-1-phenylethyl]-L-norvalinamide (2.6 g, 90%), which was used in the next step without purification. Mass Spectrum (+ESI): 249 (M+H)+. Anal. Calc'd for C15H24N2O: C, 72.54; H, 9.74; N, 11.28. Found: C, 72.24; H, 10.04; N, 11.01
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:34])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:35][CH2:36][C@H:37]([OH:39])[CH3:38].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]([NH:35][CH2:36][C@H:37]([OH:39])[CH3:38])=[O:30])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:34])[CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: C[C@@H](O)CN
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylic acid (580 mg, 1.24 mmol) synthesized in Example (66g) was dissolved in dichloromethane (15 mL), and (R)-(−)-1-amino-2-propanol (196 μL, 2.48 mmol), WSCI•HCl (366 mg, 1.91 mmol) and 4-dimethylaminopyridine (228 mg, 1.87 mmol) were added, followed by stirring at room temperature for 18 hours under nitrogen atmosphere. To the reaction solution, 0.25N hydrochloric acid (100 mL) was added, and extraction was carried out with ethyl acetate (100 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=3%-9%) to afford the desired compound (486 mg, yield 75%) as a white solid.
Reaction SMILES: [N:1]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:2]=1[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H][H]>C(O)C.[Pt]=O>[NH:1]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH:2]1[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)Cc1ccc2ccccc2n1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: COC(=O)CC1CCc2ccccc2N1
Yield: 111.1 %

Procedure:
In 120 ml of ethanol, 6 g of methyl quinaldinate was reduced by hydrogen in the presence of 400 mg of platinum oxide to give 6.8 g of methyl 1,2,3,4-tetrahydroquinaldinate as an oil. 3.0 g of the resulting methylester was further reduced in a dry ether by 1 g of lithium aluminum hydride to give 2.6 g of 1,2,3,4-tetrahydro-2-quinolinemethanol. A mixture of 1.6 g of the resulting alcohol, 0.93 ml of dimethylsulfonic acid, 2.16 g of calcium carbonate and 8 ml of water was stirred at room temperature for 6 hours. To the reaction mixture was added ether and insolubles were removed by filtration. The organic portion was separated, washed with water and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the organic portion was purified by silica gel column chromatography (eluent: chloroform) to give 1.4 g of 1-methyl-1,2,3,4-tetrahydro-2-quinolinemethanol as a pale yellow oil.
Reaction SMILES: Br[CH:2]1[CH2:19][CH:18]([OH:20])[CH2:17][C:16]2[CH:15]=[C:14]3[C:5]([C:6](=[O:28])[C:7]4[CH:8]=[CH:9][CH:10]([CH2:26][CH3:27])[C:11]5([O:25][CH2:24][CH2:23][O:22]5)[C:12]=4[C:13]3=[O:21])=[C:4]([OH:29])[C:3]1=2.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34]>>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][CH:2]1[CH2:19][CH:18]([OH:20])[CH2:17][C:16]2[CH:15]=[C:14]3[C:5]([C:6](=[O:28])[C:7]4[CH:8]=[CH:9][CH:10]([CH2:26][CH3:27])[C:11]5([O:25][CH2:24][CH2:23][O:22]5)[C:12]=4[C:13]3=[O:21])=[C:4]([OH:29])[C:3]1=2
Reactant: CN(C)CCN
Reactant: CCC1C=CC2=C(C(=O)c3cc4c(c(O)c3C2=O)C(Br)CC(O)C4)C12OCCO2
Product: CCC1C=CC2=C(C(=O)c3cc4c(c(O)c3C2=O)C(NCCN(C)C)CC(O)C4)C12OCCO2

Procedure:
7-Bromo-9-(1,1-ethylenedioxy)ethyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (571 mg) prepared in the foregoing step and N,N-dimethylethylenediamine (10 ml) were subjected to reaction in a nitrogen stream while cooling with ice for 1 hour. Excess of the N,N-dimethylethylenediamine was eliminated by distillation under reduced pressure. The residue was dissolved in dichloromethane (2 ml) and ether (4 ml) was added thereto, whereby 7-(2-dimethylaminoethyl)amino-9-(1,1-ethylenedioxy)ethyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione was obtained as yellow crystals (124 mg). M.P., 192°-196° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:7]([C:8]([Cl:12])=[C:9]([Cl:11])[CH:10]=1)=[N:6][N:5]([CH2:13][C:14](=O)[CH3:15])[CH:4]=2.[Si](OC(C)[CH2:26][N:27]1C=C2C(C(Cl)=C(Cl)C=C2Cl)=N1)(C(C)(C)C)(C)C.[Si:40]([O:47][CH:48]([CH3:64])[CH2:49][NH:50][CH2:51][C:52]1[C:57]([Cl:58])=[CH:56][C:55]([Cl:59])=[C:54]([Cl:60])[C:53]=1[N+:61]([O-:63])=[O:62])([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41].[N+](C1C(Cl)=C(Cl)C=C(Cl)C=1C=O)([O-])=O>>[NH2:50][C:14]([CH3:15])([CH2:13][N:5]1[CH:4]=[C:3]2[C:7]([C:8]([Cl:12])=[C:9]([Cl:11])[CH:10]=[C:2]2[Cl:1])=[N:6]1)[C:26]#[N:27].[Cl:58][C:57]1[C:52]2[C:53]([C:54]([Cl:60])=[C:55]([Cl:59])[CH:56]=1)=[N:61][N:50]([CH2:49][C:48](=[O:47])[CH3:64])[CH:51]=2.[Si:40]([O:47][CH:48]([CH3:64])[CH2:49][NH:50][CH2:51][C:52]1[C:57]([Cl:58])=[CH:56][C:55]([Cl:59])=[C:54]([Cl:60])[C:53]=1[N+:61]([O-:63])=[O:62])([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: CC(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Agent: CC(CNCc1c(Cl)cc(Cl)c(Cl)c1[N+](=O)[O-])O[Si](C)(C)C(C)(C)C
Agent: O=Cc1c(Cl)cc(Cl)c(Cl)c1[N+](=O)[O-]
Product: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Yield: 60 %

Procedure:
2-Amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.16 g, 60%) was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(4,6,7-trichloro-2H-indazol-2-yl)propan-2-one (0.25 g). 1-(4,6,7-Trichloro-2H-indazol-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 116 part c and d except starting from 2-[2-(tert-butyldimethylsilanyloxy)propyl]-4,6,7-trichloro-2H-indazole (1.4 g, 69%) that was prepared using a procedure similar to that described in Example 143 part a except starting from [2-(tert-butyldimethylsilanyloxy)propyl]-(2-nitro-3,4,6-trichlorobenzyl)amine (2.2 g). [2-(tert-Butyldimethylsilanyloxy)propyl]-(2-nitro-3,4,6-trichlorobenzyl)amine (2.2 g, 44%) was prepared using a procedure similar to that described in Example 116 part a except starting from 2-nitro-3,4,6-trichlorobenzaldehyde (3 g) that was prepared as follows:
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C@H:11]([N:29]([C:37](=[O:39])[CH3:38])[C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:12][C@H:13]([CH3:28])[N:14]2[C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.ClC1C=CC(N(C(=O)CC)[C@H]2C3C(=CC=C(OCC(O)=O)C=3)N(C(=O)C3C=CC(F)=CC=3)[C@@H](C)C2)=CC=1>>[C:37]([N:29]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@H:11]1[C:10]2[C:15](=[CH:16][C:7]([O:6][CH2:5][C:4]([OH:40])=[O:3])=[CH:8][CH:9]=2)[N:14]([C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C@@H:13]([CH3:28])[CH2:12]1)(=[O:39])[CH3:38]
Reactant: CCOC(=O)COc1ccc2c(c1)N(C(=O)c1ccc(N(C)C)cc1)[C@@H](C)C[C@H]2N(C(C)=O)c1ccc(Cl)cc1
Agent: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(=O)O)cc21
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)C)cc2)c2cc(OCC(=O)O)ccc21

Procedure:
(±)-Cis-[4-[acetyl-(4-chloro-phenyl)-amino]-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-7-yloxy]-acetic acid was prepared from (±)-cis-[4-[acetyl-(4-chloro-phenyl)-amino]-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-7-yloxy]-acetic acid ethyl ester following the saponification procedure described above for the synthesis of (±)-cis-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH2:17][N:18]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:19]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[C:27]1([S:24]([N:18]2[CH2:17][CH2:16][C:15]3[C:20](=[CH:21][CH:22]=[CH:23][C:14]=3[N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:19]2)(=[O:26])=[O:25])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCN(S(=O)(=O)c2ccccc2)C3)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)N1CCc2c(cccc2N2CCNCC2)C1

Procedure:
4-(2-Benzenesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.76 mg) from Step 5 was dissolved in 3 mL of trifluoroacetic acid (TFA) and heated briefly via steam bath. Excess TFA was removed in vacuo, and the residue was recrystallized from absolute ethanol to yield 83 mg of 2-Benzenesulfonyl-5-piperazin-1-yl-1,2,3,4-tetrahydroisoquinoline trifluoroacetic acid salt as a white solid, MP=214–216° C., MS M+H=358.
Reaction SMILES: [NH2:1][C:2]1([CH2:7][NH:8][CH:9]2[CH:16]3[CH2:17][C:12]4([OH:20])[CH2:13][C:14]([OH:19])([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[OH:19][C:14]12[CH2:15][CH:16]3[CH2:17][C:12]([OH:20])([CH2:11][CH:10]([CH:9]3[N:8]3[CH2:7][C:2]4([CH2:6][CH2:5][CH2:4][CH2:3]4)[NH:1][C:31]3=[O:33])[CH2:18]1)[CH2:13]2
Reactant: NC1(CNC2C3CC4(O)CC2CC(O)(C3)C4)CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1NC2(CCCC2)CN1C1C2CC3(O)CC1CC(O)(C2)C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.6 %

Procedure:
To a mixture of 6-[(1-amino-cyclopentylmethyl)-amino]-adamantane-1,3-diol (250 mg, obtained in examples 122, step B) and N,N-diisopropylethylamine (0.62 ml) in CH2Cl2 (3.0 ml), a solution of triphosgene (90 mg) in THF (1 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hr. The mixture was poured into saturated NaHCO3 solution, and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was triturated with CH2Cl2 to obtain the title compound (100 mg, 37%) as a white solid. MS (ESI): 307.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)CCC>CN(C=O)C.[Cl-].[Na+].O.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:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:4]1[CH:3]=[CH:2][CH:7]=[C:6]([C:34]2[CH:39]=[N:38][CH:37]=[CH:36][N:35]=2)[CH:5]=1)[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccnc(C(F)(F)F)c2)c2cccc(F)c21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC1=NC(c2cccc(-c3cnccn3)c2)(c2ccnc(C(F)(F)F)c2)c2cccc(F)c21
Temperature: 180 °C
Yield: 13.8 %

Procedure:
1-(3-Bromophenyl)-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine (131 mg, 0.29 mmol), 2-(tributylstannyl)pyrazine (0.096 mL, 0.31 mmol) and Pd(Ph3P)4 (33.6 mg, 0.03 mmol) were dissolved in DMF (2 mL) and the reaction mixture was heated in a microwave reactor at 180° C. for 15 min. Brine was added and the mixture was extracted with EtOAc (3×). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. Purification by preperative HPLC afforded the title compound 18 mg (14% yield).
Reaction SMILES: [C:1]([Cl:5])(Cl)([Cl:3])[Cl:2].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1.Cl>>[Cl:10][C:11]1[CH:12]=[C:13]([F:18])[C:14]([F:17])=[CH:15][C:16]=1[C:1]([Cl:5])([Cl:3])[Cl:2]
Reactant: Fc1ccc(Cl)cc1F
Reactant: ClC(Cl)(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Fc1cc(Cl)c(C(Cl)(Cl)Cl)cc1F
Temperature: 25 °C
Yield: 65.4 %

Procedure:
Into a 200 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, 97 ml (1 mol) of carbon tetrachloride and 26.7 g (0.2 mol) of aluminum chloride were charged, and 14.9 g (0.1 mol) of 1-chloro-3,4-difluorobenzene was gradually dropwise added over a period of 1.5 hours under reflux so that hydrochloride gas was slowly generated. The generated hydrochloride gas was absorbed by an aqueous sodium hydroxide solution. After completion of the dropwise addition, the mixture was reacted for 10 minutes. After cooling to room temperature, the reaction mixture was poured into 300 ml of ice water. The organic layer was separated and washed with 100 ml of water, then with 100 ml of 5% of sodium hydrogen carbonate aqueous solution and further with 100 ml of water. After distilling off carbon tetrachloride, the residue was distilled under reduced pressure to obtain 17.4 g (yield: 65.4%) of 2-chloro-4,5-difluorobenzotrichloride. Boiling point: 104°-106° C./8 mmHg, nD20 1.540; purity: 98.2%
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[CH3:28][S:29]([N:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:19])[F:20])=[CH:8][CH:9]=2)[CH2:14][CH2:15]1)(=[O:31])=[O:30]
Reactant: FC(F)(F)CCCOc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc(OCCCC(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of the 1-[4-(4,4,4-trifluorobutoxy)phenyl]piperazine product from Part B (5 g, 17 mmol) in methylene chloride (50 mL) was added triethyl amine (4 mL). The mixture was cooled to 0° C. Methane sulfonyl chloride (2.4 g, 21 mmol) in a solution of methylene chloride (10 mL) was then added dropwise. After 2 hr, the reaction was complete. The solvent was removed under reduced pressure to produce a solid residue. To this solid was added water (100 mL). The resulting mixture was filtered and washed with water, and then dried under high vacuum to produce 6 g (95% yield) of the desired compound in the form of a tan solid. Proton NMR and MS were consistent with the desired structure.