Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:20]=[CH:21][CH2:22][CH3:23]>CCOCC>[CH:21]([C:13]1[CH:14]=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=[C:10]([CH:1]([CH2:2][CH3:3])[CH3:8])[C:11]=1[NH2:12])([CH2:22][CH3:23])[CH3:20]
Reactant: C=CCC
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: [Al+3]
Agent: [Al]
Agent: [Cl-]
Solvent: CCOCC
Product: CCC(C)c1cc(Cc2ccccc2)cc(C(C)CC)c1N

Procedure:
81 g of 4-benzylaniline, 1.2 g of aluminium powder, 3.6 g of anhydrous aluminium chloride and 100 g of but-1-ene are heated for 24 hours at +260° C. in an autoclave. After cooling, the reaction mass is poured into ice-cold dilute sodium hydroxide solution and taken up in ether. The ether phase is separated off, dried over sodium sulfate and subjected to fractional distillation; b.p. 130°-134° C./0.03 torr. Chromatographic purification on silica gel using hexane/ethyl acetate as eluant affords the title compound of formula ##STR12## in the form of a colourless oil; refractive index nD24 : 1.5579.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])[CH3:3].[CH3:18][C:19]([O:22][C:23]([NH:25]/[C:26](/N1N=CC=C1)=[N:27]/[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:31]([O:30][C:28]([N:27]=[C:26]([NH:25][C:23]([O:22][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:24])[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:15]([OH:17])=[O:16])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(CCCCN)C(=O)O
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 111 %

Procedure:
A solution of N-α-Boc-L-lysine 18 (5.00 g, 20.3 mmol) in CH2Cl2 (100 mL) was charged with N,N′-bis-Boc-1-guanylpyrazole (5.10 g, 16.6 mmol) and triethylamine (5.54 mL, 40.6 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was washed with 10% aqueous citric acid (2×80 mL) and the solvent was removed under reduced pressure. The residue was dissolved in 1 N NaOH (200 mL), the pH of solution was adjusted to 5-6 with 1 N HCl, and the mixture was extracted with CH2Cl2 (300 ml). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (2×200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford compound 10 (9.00 g, 91%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 4.10-4.02 (m, 1H), 3.36 (t, J=6.8 Hz, 2H), 1.90-1.78 (m, 1H), 1.73-1.56 (m, 3H), 1.52 (s, 9H), 1.45-1.31 (m, 2H), 1.47 (s, 9H), 1.43 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]([F:53])=[CH:4][C:5]2[C:10]3[C:11]4[C:50](=[O:51])[NH:49][C:48](=[O:52])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:43][C@H:42]([CH2:44][OH:45])[CH2:41][C@H:32]([O:33][CH2:34][C:35]7[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=7)[C@H:23]6[O:24][CH2:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:46])=[C:16]([F:47])[CH:15]=5.C(N(CC)CC)C.CS(Cl)(=O)=O.[Na+].[I-:67]>ClCCl.CN(C1C=CN=CC=1)C.CC(C)=O>[F:1][C:2]1[C:3]([F:53])=[CH:4][C:5]2[C:10]3[C:11]4[C:50](=[O:51])[NH:49][C:48](=[O:52])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:43][C@H:42]([CH:44]([I:67])[OH:45])[CH2:41][C@H:32]([O:33][CH2:34][C:35]7[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=7)[C@H:23]6[O:24][CH2:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:46])=[C:16]([F:47])[CH:15]=5
Reactant: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@H](CO)C[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: [I-]
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@H](C(O)I)C[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 39 %

Procedure:
A mixture of 2, 3, 9, 10-tetrafluoro-12-(2, 3-di-O-benzyl-4-deoxy-β-D-glucopyranosyl)-6, 7, 12, 13-tetrahydro(5H)indolo[2, 3-a]pyrrolo[3, 4-c]carbazole-5, 7-dione (2.00 g, 2.76 mmol) and freshly activated and pulverized 4A molecular sieves (0.60 g) in 100 mL of dichloromethane was cooled at 5C. under Ar and triethylamine (0.77 mL, 5.52 mmol), DMAP (0.20 g, 1.64 mmol) and methanesulfonyl chloride (0.32 mL, 4.14 mmol) were added sequentially. The mixture was stirred at the same temperature for 2 h and then it was filtered and the filter-cake was washed with ethyl acetate. The flitrate was diluted with ethyl acetate (200 mL) and ether (50 mL) and then it was washed (H2O×2, brine), dried (MgSO4) and evaporated to give a yellow glass. This material was taken up in 100 mL of acetone, NaI ( ) was added and the mixture was heated to reflux under Ar for 18 h. The cooled mixture was then evaporated to dryness and the residue was taken up in 10 mL of ethyl acetate, washed (H2O×2, brine) dried (MgSO4) and evaporated. The resulting solid was chromatographed (SiO2/2-32% ethyl acetate-hexane) to give the title compound (0.90 g, 39%) as an amorphous yellow solid: 1H NMR (CDCl3, 400 MHz) δ10.17 (s, 1H), 9.10 (dd, J=10.6, 8.4 Hz, 1H), 9.02 (dd, J=10.6, 8.5 Hz, 1H), 7.55 (m, 2H), 7.35 (m, 6H), 6.92 (t, J=7.4 Hz, 1H), 6.76 (t, J=7.6 Hz, 2H), 6.20 (d, J=7.6 Hz, 2H), 5.75 (d, J=9.2 Hz, 1H), 4.77 and 4.71 (ab q, J=11.5 Hz, 2H), 4.13 (m, 2H), 3.99 (t, J=8.7 Hz, 1H), 3.80 (m, 2H 3.63 (d, J=9.0 Hz, 1H), 3.48 (d, J=10.8 Hz, 1H), 2.42 (m, 1H), 2.32 (m, 1H). MS (ESI−) m/e 832 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][C@H:14]([C:25]([O:27]C)=[O:26])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:15][C@H:14]([C:25]([OH:27])=[O:26])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)OCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.8 %

Procedure:
To a solution of 1-tert-butyl 3-methyl (3R,5S)-5-{[(benzyloxy)carbonyl]amino}piperidine-1,3-dicarboxylate (115 g) in methanol (700 ml) was added 1 M aqueous sodium hydroxide solution (350 ml) under ice-cooling and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure to about 1/3 volume, and the residual aqueous solution was washed with ethyl acetate-hexane (1:1, 600 ml). The aqueous layer was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (98.5 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[Br:25])[NH2:21].C([O-])(O)=O.[Na+]>CCO>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[Br:25]
Reactant: Nc1ccc(Br)c(Br)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Br)c(Br)c1
Yield: 31.9 %

Procedure:
A mixture of 6.20 g (26.6 mmol) of 4-chloro-6-nitroquinoline-3-carbonitrile and 8.00 g (31.9 mmol) of 3,4-dibromoaniline in 160 mL of EtOH was refluxed under N2 for 5 hr. Satd NaHCO3 was added and volatile material was removed. The residue was slurried with hexane, collected, washed with hexane and H2O and dried. The insoluble material was repeatedly extracted with boiling EtOAc and the solution was then filtered through silica gel. The solvent was removed to give 3.80 g of 4-(3,4-dibromophenylamino)-6-nitroquinoline-3-carbonitrile as a green solid: mass spectrum (electrospray, m/e): M+H 448.9.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([OH:18])=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:25]=1)=[O:18]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
Diisopropylethylamine (2.3 mL) was added to a DMF solution (15 mL) of picolinic acid (814 mg), methyl 4-aminobenzenecarboxylate (1.0 g) and HATU (2.8 g), and stirred overnight at room temperature. Water was added to the reaction solution, and the resulting precipitate was taken out through filtration. The obtained residue was purified through silica gel column chromatography (chloroform/methanol=500/10 to 500/15) to obtain the entitled compound (1.4 g).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@H:9]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH3:29])[CH:23]=1)=[O:7].[CH:39]([O-:41])=[O:40].[NH4+].C[OH:44].O>[C].[Pd].O1CCCC1>[C:6]([OH:44])(=[O:7])/[CH:5]=[CH:30]/[C:39]([OH:41])=[O:40].[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH3:29])[CH:23]=1)=[O:7]
Reactant: O=C[O-]
Reactant: CO
Reactant: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: [Pd]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Product: O=C(O)/C=C/C(=O)O
Temperature: 50 °C
Reaction time: 5.5 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-benzylpiperazine (2.94 g), ammonium formate (1.74 g) and 10% palladium-carbon (0.58 g) in a mixed solvent of methanol (11.8 ml), water (5.9 ml) and tetrahydrofurane (10 ml) was stirred for 5.5 hours at 50° C. under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through Celite® pad. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in methanol and treated with fumaric acid (468 mg) to give colorless powder of fumaric acid salt (1:1) of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.24 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH:21]=[CH2:22]>C(#N)C>[CH2:22]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[CH2:21][CH:20]=[CH2:19]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCCOc1ccc([N+](=O)[O-])c(F)c1

Procedure:
To an acetonitrile (25 mL) solution of 3-fluoro-4-nitrophenol (1.57 g; 10.0 mmol) and potassium carbonate (2.09 g; 15.1 mmol), 4-bromo-1-butene (2.21 g; 16.0 mmol) was added, and the mixture was refluxed and then reacted overnight. After completion of the reaction, the solution was filtrated by Celite, and then the filtrate was concentrated under a reduced pressure. The residue was purified by column chromatography (solvent, hexane:methylene chloride=6:4) using methylene chloride, and then the effluent was concentrated to obtain 4-(3-butenyloxy)-2-fluoronitrobenzene (1g) (1.71 g, 81% of yield, a light yellow oil) represented by the following formula.
Reaction SMILES: [F:1][C:2]([F:13])([C:9]([F:12])([F:11])[F:10])[CH2:3][CH2:4][S:5][CH2:6][C:7]#[N:8].OO.S([O-])([O-])=[O:17].[Na+].[Na+].[OH2:22]>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:13][C:2]([F:1])([C:9]([F:10])([F:11])[F:12])[CH2:3][CH2:4][S:5]([CH2:6][C:7]#[N:8])(=[O:17])=[O:22]
Reactant: N#CCSCCC(F)(F)C(F)(F)F
Reactant: O
Reactant: O=S([O-])[O-]
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: N#CCS(=O)(=O)CCC(F)(F)C(F)(F)F
Temperature: 65 °C

Procedure:
To a suspension of 17.81 g of (3,3,4,4,4-pentafluorobutylthio)acetonitrile and 0.28 g of sodium tungstate dihydrate in 30 ml of water was added 8.94 ml of 31% aqueous hydrogen peroxide while the suspension was stirred. The temperature of the mixture was raised to 65° C., and 8.94 ml of 31% aqueous hydrogen peroxide was added thereto. The mixture was stirred at 70° C. for 1 hour. In the middle of the reaction, the formation of a deduced sulfoxide compound was confirmed by thin layer chromatography (TLC) analysis. The reaction mixture was cooled to room temperature, and 30 ml of an aqueous sodium sulfite solution was added thereto, followed by extraction with 150 ml of ethyl acetate three times. Organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from chloroform:hexane=1:2 to obtain 17.84 g of (3,3,4,4,4-pentafluorobutylsulfonyl)acetonitrile represented by the formula:
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]2[C:4](=[C:5]([C:21]#[N:22])[N:6]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:7]=2)[CH:3]=1.C1COCC1.O.[Cl-].[NH4+]>CO.[Fe]>[NH2:11][C:10]1[C:2]([Br:1])=[CH:3][C:4]2[C:8]([CH:9]=1)=[N:7][N:6]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[C:5]=2[C:21]#[N:22]
Reactant: N#Cc1c2cc(Br)c([N+](=O)[O-])cc2nn1-c1ccc(F)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1c2cc(Br)c(N)cc2nn1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 0.7 %

Procedure:
To a suspension of 5-bromo-2-(4-fluorophenyl)-6-nitro-2H-indazole-3-carbonitrile (500 mg, 139 mmol) in a mixture of methanol (50 mL), THF (5 mL) and water (2.5 mL) was added ammonium chloride (370 mg, 6.91 mmol) followed by iron powder (386 mg, 6.91 mmol). The mixture was heated to 80° C. and stirred vigorously for 90 min. The resulting suspension was filtered through celite and washed with EtOAc. The filtrate was concentrated, and the residue was suspended in water and extracted with EtOAc. The organic layer was contracted to give 6-amino-5-bromo-2-(4-fluorophenyl)-2H-indazole-3-carbonitrile (310 mg, 68%) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 7.99 (s, 1H), 7.80˜7.82 (m, 2H), 7.23˜7.57 (m, 2H), 7.03 (s, 1H), 4.40 (s, 2H). MS (M+H)+: 331/333.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)=[CH:4][C:3]=1[C:21]([NH:23][C:24]1[CH:29]=[C:28]([C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])[CH:27]=[CH:26][C:25]=1[CH3:36])=[O:22].[CH2:37](OC(OCC)OCC)C>>[CH:33]1([NH:32][C:30]([C:28]2[CH:27]=[CH:26][C:25]([CH3:36])=[C:24]([N:23]3[C:21](=[O:22])[C:3]4[C:2](=[CH:20][CH:19]=[C:5]([O:6][C@@H:7]5[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8]5)[CH:4]=4)[N:1]=[CH:37]3)[CH:29]=2)=[O:31])[CH2:34][CH2:35]1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)ccc1N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O[C@@H]3CCN(C(=O)OC(C)(C)C)C3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (C) in the portion of Example 18 which is concerned with the preparation of starting material, tert-butyl (3R)-3-{4-amino-3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}pyrrolidine-1-carboxylate was reacted with triethylorthoformate to give tert-butyl (3R)-3-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]pyrrolidine-1-carboxylate; NMR Spectrum: (DMSOd6) 0.54 (m, 2R), 0.68 (m, 2H), 1.39 (s, 9H), 2.15 (m, 5H), 2.85 (m, 1H), 3.50 (m, 4H), 5.19 (m, 1H), 7.54 (m, 3H), 7.72 (d, 1H), 7.83 (s, 1H), 7.89 (d, 1H), 8.19 (s, 1H), 8.41 (s, 1H); Mass Spectrum: M+Na+ 527.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[C:10]([O:12]C)[C:9]([Cl:14])=[CH:8][C:7]=1[CH2:15][C:16]([OH:18])=[O:17].[CH3:19]O>ClCCl>[Cl:5][C:6]1[CH:11]=[C:10]([OH:12])[C:9]([Cl:14])=[CH:8][C:7]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COc1cc(Cl)c(CC(=O)O)cc1Cl
Reactant: CO
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1cc(Cl)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Boron tribromide (1.581 mL, 16.72 mmol) was added dropwise to 2-(2,5-dichloro-4-methoxyphenyl)acetic acid (Intermediate 4-4; 655 mg, 2.79 mmol) in dichloromethane (20 mL) at ambient temperature under nitrogen. The resulting solution was stirred at ambient temperature for 60 minutes. The reaction mixture was cautiously added to methanol (100 mL) (—care reaction is vigorous and exothermic—mixture became reasonably warm during the addition) and the mixture was stirred for a further 2 hours at ambient temperature. The reaction mixture was evaporated to dryness and redissolved in DCM (100 mL), and washed sequentially with 2M HCl (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(2,5-dichloro-4-hydroxyphenyl)acetate (258 mg, 39.4%) as a pale yellow solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])(=O)=O)=CC=1.[CH3:19][C@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][N:25]1[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][C@H:20]1[CH3:19])[CH3:17]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CCOCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOCCCCN1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of 3 g of 4-ethoxybutyl p-toluenesulfonate, 2.65 g of tert-butyl (3R)-3-methylpiperazine-1-carboxylate, 3.07 mL of triethylamine, and 30 mL of acetonitrile was stirred at 90° C. for 3 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 3.1 g of tert-butyl (3R)-4-(4-ethoxybutyl)-3-methylpiperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C@@H:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18]([NH:25][C@H:26]([C:31](O)=[O:32])[C@H:27]([CH2:29][CH3:30])[CH3:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:18]([NH:25][C@@H:26]([C@@H:27]([CH3:28])[CH2:29][CH3:30])[C:31]([NH:17][C@H:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:32])([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C1(c2ccc(Cl)cc2)CCC1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C1(c2ccc(Cl)cc2)CCC1

Procedure:
By similar method as example 2, resolved (S)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (II-S) (250 mg) was condensed with Boc-L-isoleucine (210 mg) to give the title compound (2S,3S)-2-(Boc-amino)-N-{(S)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-3-methylvaleramide.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[S:23]1C=[N:26][N:25]=[C:24]1N>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[S:23][CH:24]=[N:25][N:26]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1nncs1
Product: Cc1nc(NCc2ccccn2)nc(Nc2nncs2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 1,3,4-thiadiazol-2-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.10 (s, 3H), 2.25 (s, 3H), 4.68 (d, J=2.0 Hz, 2H), 7.18-7.51 (m, 3H), 7.70 (t, J=7.8 Hz, 1H), 8.50 (s, 1H), 9.01 (s, 1H), 10.93 (bs, 1H); MS (ESI) m/z 314.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[CH:7]([CH3:18])[CH2:6]1.FC(F)(F)C(O)=O>CCCCCC.C(O)(C)C>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C@@H:7]([CH3:18])[CH2:6]1
Reactant: Cc1cccc(C)c1CN1CC(C)c2ccc(CC(=O)O)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: CCCCCC
Product: Cc1cccc(C)c1CN1C[C@H](C)c2ccc(CC(=O)O)cc21
Yield: 57.7 %

Procedure:
The compound [78] obtained in Example 78 (26 mg) was optically resolved by chiral column chromatography (CHIRALCEL (registered trademark) OD CHIRALCEL OD) manufactured by Daicel Corporation, 2 cm ×25 cm; 0.1% trifluoroacetic acid, hexane/isopropyl alcohol=85/15; flow rate 20 mL/min). (3R*)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]acetic acid [79A] (15 mg) as a pale brown solid was obtained from the preceding fraction (retention time: 5.3 minutes), and (3S*)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]lacetic acid [79B] of the same (16 mg) as a pale brown solid was obtained from the posterior fraction (retention time: 10.8 minutes). (Both of them were un-identified, and thus one of them was referred to as 3R*, and the other one as 3S* for convenience.)
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17](O)=O)=[N:15][CH:16]=1)[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[N:15][CH:16]=1)[CH3:10]
Reactant: CCc1ccc(C(=O)O)nc1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(-c2nc3ccccc3[nH]2)nc1

Procedure:
11.3 g. of o-phenylenediamine, 15.1 g. of 5-ethylpicolinic acid and 80 g. of polyphosphoric acid were heated at 180°-190° C. under a nitrogen gas current for 3 hours with stirring. The reaction mixture was diluted with 1,000 ml. of water and then neutralized with sodium carbonate. The resulting crystals were filtered off, dried and recrystallized from ethyl acetate to give 17.1 g. of colorless needles of the product (78% of theory). M.P. 172.5°-173° C.