Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br>C(Cl)Cl>[Br:18][C:10]1[C:9]([CH3:12])=[C:8]2[C:3]([CH2:4][CH2:5][CH2:6][C:7]2=[O:13])=[C:2]([CH3:1])[CH:11]=1
Reactant: Cc1ccc(C)c2c1CCCC2=O
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(Br)c(C)c2c1CCCC2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 15.0 g of 5,8-dimethyltetralone (purchased from Wiley Organics) in 250 mL of methylene chloride was added 28.7 g of aluminum chloride (purchased from Aldrich Chemical Co.). The mixture was cooled to 0° C. and then a solution of 15.2 g bromine in 90 mL of methylene chloride was added dropwise. After the mixture was stirred at room temperature for 2 h, it was cooled to 0° C. and then approximately 200 g of ice was added. The resulting mixture was filtered. The organic layer was separated and was washed with 1N aqueous sodium hydroxide, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting solid was crystallized from 1-chlorobutane to give 21.8 g of the title compound of Step A as a solid melting at 64°-68° C. 1H NMR (CDCl3): δ 2.11 (m, 2H), 2.25 (s, 3H), 2.64 (t, 2H), 2.66 (s, 3H), 2.77 (t, 2H), 7.53 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[C:4](=[O:19])[NH:3]1.[H-].[Na+].Cl[CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27](C(OC(C)(C)C)=O)[CH:26]=1>CN(C=O)C>[CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=2)[C:4](=[O:19])[N:3]1[CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Reactant: CC1(C)CCN(c2ccc(SC(F)(F)F)cc2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CCN(c2ccc(SC(F)(F)F)cc2)C(=O)N1Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the 4,4-dimethyl-1-{4-[(trifluoromethyl) sulfanyl]phenyl}tetrahydropyrimidin-2(1H)-one (10 mg, 0.03 mmol) in 2 mL DMF was added NaH (2.4 mg, 0.03 mmol). The mixture was allowed to stir at ambient temperature for 10 min. The reaction was treated with tert-butyl 3-(chloromethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (8.8 mg, 0.03 mmol) and allowed to stir at ambient temperature for 16 h. The reaction was partitioned between water and ether. The organics were washed with water and brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give 4,4-dimethyl-3-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-{4-[(trifluoromethyl)sulfanyl]phenyl}tetrahydropyrimidin-2(1H)-one. 1H NMR (399 MHz, CDCl3): δ 9.05 (s, 1 H); 8.30 (d, J=4.7 Hz, 1 H); 8.11 (d, J=7.9 Hz, 1 H); 7.63 (d, J=8.2 Hz, 2 H); 7.46-7.41 (m, 2 H); 7.36 (s, 1 H); 7.11-7.06 (m, 1 H); 4.80 (s, 2 H); 3.76-3.69 (m, 2H); 2.04-1.97 (m, 2 H); 1.36 (s, 6 H). LCMS [M+H]+=435.3.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([NH:19][CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[CH:15]=[CH:16][C:17]=1[CH3:18].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([N:19]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: CCOC(CNc1ccc(C)c(Br)c1)OCC
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(CN(c1ccc(C)c(Br)c1)S(=O)(=O)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Under a nitrogen stream, benzenesulfonyl chloride (3.12 mL g, 24.48 mmol) was added dropwise under ice cooling to a mixture of (3-bromo-4-methylphenyl)-(2,2-diethoxyethyl)-amine (4.91 g, 16.25 mmol), pyridine (10.1 mL, 124.88 mmol) and dichloromethane (41 mL), and the resultant mixture was then stirred at the same temperature for 1 hour. After stirring at room temperature for 2 hours, the reaction mixture was added to saturated aqueous sodium hydrogen carbonate. The resultant mixture was extracted with dichloromethane. The organic layer was washed with 5% aqueous hydrochloric acid and dried (anhydrous potassium carbonate). Solvent was then removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:4)), to thereby obtain the titled compound (5.94 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[CH:25][NH:24][N:23]=2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]([NH:21][C:22]3[CH:26]=[CH:25][NH:24][N:23]=3)[N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: COc1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methoxy-phenol and (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine to give [1-(4-methoxy-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 333(MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[N:8]=[C:9]2\[C:10](=[O:24])[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[C:17]\2=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:4][CH:3]=1.[S:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[C:18]1([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)/[C:9](=[N:8]/[C:5]3[CH:6]=[CH:7][C:2]([C:27]4[CH:28]=[CH:29][S:25][CH:26]=4)=[CH:3][CH:4]=3)/[C:10]2=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1/C(=N\c2ccc(Br)cc2)c2ccccc2N1c1ccccc1
Reactant: OB(O)c1ccsc1
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: C1CCOC1
Product: O=C1/C(=N\c2ccc(-c3ccsc3)cc2)c2ccccc2N1c1ccccc1
Yield: 35.6 %

Procedure:
A mixture of (3Z)-3-[(4-bromophenyl)imino]-1-phenyl-1,3-dihydro-2H-indol-2-one (50.0 mg, 0.133 mmol), thiophene-3-boronic acid (26.0 mg, 0.199 mmol), tetrakis(triphenylphosphine)palladium(0) (31.0 mg, 0.0268 mmol in THF (5 mL), and aqueous Na2CO3 (2M, 100 μL) was heated at 67° C. for 24 h. The crude product was concentrated in vacuo and the residue was extracted with CH2Cl2 (3×1 ml), and concentrated. The crude product was purified by preparative TLC using 10% methanol in CHCl3, giving the desired product (18 mg, 35%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].Cl.Cl.[NH:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]3[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:37][C:33]1[C:32]([F:38])=[C:31]([CH:36]=[CH:35][CH:34]=1)[NH:30][C:21]1[C:20]2[C:25](=[CH:26][C:27]([O:28][CH3:29])=[C:18]([O:17][CH:14]3[CH2:15][CH2:16][N:11]([S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[CH2:12][CH2:13]3)[CH:19]=2)[N:24]=[CH:23][N:22]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(S(=O)(=O)CCCCl)CC1
Reaction time: 16 h
Yield: 69.1 %

Procedure:
3-chloropropanesulfonylchloride (174 mg) was added to a solution of 6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline dihydrochloride (190 mg; starting material for Example 16) and diisopropylethylamine (140 mg) in methylene chloride (5 ml) at ambient temperature and the reaction mixture was stirred for 16 hours. The reaction mixture was adsorbed onto silica and the residue was purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 94/6). The fractions containing the expected product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-{1-[3-chloropropylsulfonyl]piperidin-4-yloxy}-7-methoxyquinazoline as a brown gum (0.15 g); Mass Spectrum: (M+H)+ 543.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([O:38][C:39](=[O:41])[CH3:40])[C@@:29]2([CH3:42])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:43][Si:44](OS(C(F)(F)F)(=O)=O)([CH3:46])[CH3:45].N1C(C)=CC=CC=1C>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([O:37][Si:44]([CH3:46])([CH3:45])[CH3:43])[C@@H:30]([O:38][C:39](=[O:41])[CH3:40])[C@@:29]2([CH3:42])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)O[C@@H]1[C@H](O)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(=O)O[C@@H]1[C@H](O[Si](C)(C)C)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)-12-acetoxyspirostan-11-ol was silylated with trimethylsilyltriflate and 2,6-lutidine in methylene chloride according to the procedure described in Tetrahedron Letters, 1981, 22, 3455.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)(=[O:17])=[O:16])[N:12]([C:25]2[C:26]([F:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[N:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:33][N:34](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:33]#[N:34])[CH:19]=2)(=[O:17])=[O:16])[N:12]([C:25]2[C:26]([F:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[N:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CN(Cc1cc(S(=O)(=O)c2cccc(Br)c2)n(-c2cccnc2F)n1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CN(Cc1cc(S(=O)(=O)c2cccc(C#N)c2)n(-c2cccnc2F)n1)C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of tert-butyl({5-[(3-bromophenyl)sulfonyl]-1-(2-fluoropyridin-3-yl)-1H-pyrazol-3-yl}methyl)methylcarbamate (315 mg) and zinc cyanide (107 mg) in dimethylformamide (3 mL) was sufficiently deaerated, tetrakis(triphenylphosphine)palladium(0) (138 mg) was added, and the mixture was further deaerated. After stirring under an argon atmosphere at 110° C. for 2 hr, the reaction mixture was allowed to cool to room temperature, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the title compound as a yellow oil (yield 247 mg, yield 87%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[S:19](Cl)(=[O:21])=[O:20]>C(N(CC)CC)C>[OH:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([NH:2][S:19]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)(=[O:21])=[O:20])=[CH:4][CH:5]=1
Reactant: Nc1ccc(O)c2ccccc12
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccc(O)c2ccccc12)c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.957 g 4-aminonaphth-1-ol hydrochloride salt was suspended in 80 ml dichloromethylene, to which at 0° C. was added 3.0 ml triethylamine. The suspension became a dark brown solution. To the solution was added 1.827 g thiophene-2-sulfonyl chloride. The mixture was stirred at r.t. overnight. The reaction mixture was diluted with dichloromethylene to 200 ml and washed with 1N HCl solution (30 ml×3), water (30 ml×3) and brine (30 ml). Dried over MgSO4, the organic phase was filtered and the filtrate was concentrated to dryness. The crude product was suspended in 50% methanol/H2O and filtered. The solid was washed with 50% methanol/H2O affording 2.7 g (90%) brown solid, m.p.: 146-148° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])=[O:16])([CH3:13])([CH3:12])[CH3:11]>CO.O>[C:10]([O:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[N:7]=[C:6]([NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:18]([NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH:19]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:22]=[CH:23][CH:24]=1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2ncc(F)c(Nc3cccc(NC(=O)OC(C)(C)C)c3)n2)c1
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (75 mg, 0.45 mmol) was dissolved in a mixture of MeOH (2 ml) and H2O (0.2 ml). 3-tert-butoxycarbonylaminoaniline (374 mg, 1.8 mmol) was added and the mixture was refluxed for 40 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis[3-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6+CD3OD): δ 7.96 (d, 1H, J=4.1 Hz), 7.83 (m, 1H), 7.60 (m, 1H), 7.34-7.42 (m, 2H), 7.15-7.19 (m, 2H), 7.06 (t, 1H, J=8.2 Hz), 6.93 (d, 1H, J=8.2 Hz), 1.43 (s, 9H), 1.40 (s, 9H); LCMS: purity: 93.2%; MS (m/e): 511.06 (M+, 100).
Reaction SMILES: BrC1C([C@H](OC(C)(C)C)C(OCC)=O)=C(C)C=[C:8]2C=1C=C[C:6](C)=[N+:7]2[O-].[C:26]([O:30][C@@H:31]([C:37]1[C:38]([C:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([CH2:48]O)[CH:41]=[CH:40]2)[C:32]([O:34][CH2:35][CH3:36])=[O:33])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C@@H:31]([C:37]1[C:38]([C:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([CH2:48][N:7]([CH3:8])[CH3:6])[CH:41]=[CH:40]2)[C:32]([O:34][CH2:35][CH3:36])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CO)ccc2c1C1=CCCCC1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1Br
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CN(C)C)ccc2c1C1=CCCCC1

Procedure:
(S)-Ethyl 2-tert-Butoxy-2-(5-cyclohexenyl-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)acetate was prepared following the procedure used to prepare compound (S)-ethyl 2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)acetate of Example 20 except that (S)-ethyl 2-tert-butoxy-2-(5-cyclohexenyl-2-(hydroxymethyl)-7-methylquinolin-6-yl)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(hydroxymethyl)-7-methylquinolin-6-yl)acetate. LCMS-ESI+ (m/z): 439.4 (M+H)+.
Reaction SMILES: [NH:1]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:2]([C:13]([NH:15][C@H:16]([C:24](OCC1C=CC=CC=1)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH3:41]>>[NH:1]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:2]([C:13]([NH:15][C@H:16]([C:24]([NH2:41])=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: N
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reaction time: 18 h

Procedure:
A mixture of Boc-D-Trp-Phe-OBzl (1.0 g) and 24% methanolic ammonia (20 ml) was allowed to stand at room temperature in a sealed tube for 18 hours. After evaporation, the residual crystals were collected and recrystallized from a mixture of water and ethanol to give Boc-D-Trp-Phe-NH2 (0.63 g).
Reaction SMILES: C1COCC1.Br.[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:9].O=[C:33]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[CH2:40][CH2:39][C:38]2[CH:37]=[C:36]([CH:47]=[CH:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[S:35][C:34]1=2.[ClH:54].O1CCOCC1>O1CCOCC1>[ClH:54].[CH3:7][N:8]([CH3:9])[CH2:10][CH2:11]/[CH:12]=[C:33]1\[C:34]2[S:35][C:36](/[CH:47]=[CH:48]/[C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:37][C:38]=2[CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]\1=2
Reactant: CCOC(=O)C=Cc1cc2c(s1)C(=O)c1ccccc1CC2
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cc2c(s1)/C(=C\CCN(C)C)c1ccccc1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
A 1.6 mol/L n-butyllithium-hexane solution (42 mL) was added to a THF (100 mL) solution of dimethylaminopropyltriphenylphosphonium hydrobromide (23.5 g) under ice-cooling, and the mixed solution was stirred at room temperature for 1 hour. A THF (100 mL) solution of the compound obtained in Example 1 (6.11 g) was added to this solution, and the mixture was further stirred overnight. The solvent was distilled off under a reduced pressure, an aqueous saturated ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol=9:1), the purified product obtained was dissolved in 1,4-dioxane (20 mL), a 4 mol/L hydrogen chloride-dioxane solution (1.1 mL) was thereto, and the mixture was stirred at room temperature for 1 hour. The solvents were distilled off under a reduced pressure, and the precipitated crystals were filtered off and dried, to give 0.51 g (6%) of the captioned compound as a mixture of E-form and Z-form.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH:13]=O)[CH:9]=2)[C:4](=[O:15])[O:3]1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:26]3[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]3)[CH:9]=2)[C:4](=[O:15])[O:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1Cc2cc(CC=O)ccc2C(=O)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC1Cc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)O1
Reaction time: 8 h

Procedure:
Freshly prepared (3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)acetaldehyde was dissolved in DCM. To the solution was added Boc-piperazine (671 mg, 3.6 mmol) followed by sodium triacetoxyborohydride (1.91 g, 9.0 mmol), the reaction mixture was allowed to stir overnight before being quenched with 10 mL of MeOH. The excess solvent was removed and the residue was re-redissolved in DCM; washed with water and brine, dried with magnesium sulfate, filtered, concentrated and purified via MPLC (50-100% EtOAc/Hex) to afford tert-butyl 4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazine-1-carboxylate.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+].[NH:27]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:28]([C:33](ON1C(=O)CCC1=O)=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31].Cl>O1CCOCC1.O>[NH:27]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:28]([C:33]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
The H-Asp(OtBu)-Leu-OH (3.02 g), sodium bicarbonate (1.68 g), and 30 mL of water were mixed to give a mixture of pH 8. Z-Leu-OSu (3.63 g) in dioxane (30 mL) was added to the mixture and was stirred at room temp for 2 h. The reaction mixture was acidified by addition of conc. HCl to pH 1.0, then was extracted with ethyl acetate (30 mL×3). The combined extracts were dried over Na2SO4, filtered, and concentrated. The crude product was dissolved in methanol and chromatographed on a column of Sephadex™ LH20 to yield Z-Leu-Asp(OtBu)-Leu-OH as a foamy solid (4.43 g).
Reaction SMILES: [Br:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[OH:13].FC(S(O[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=O)=O)(F)F.N1C(C)=CC=CC=1C>C(Cl)Cl>[Br:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[O:13][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CCOC(=O)N1CCC(Br)C(O)C1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)N1CCC(Br)C(O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-bromo-3-hydroxypiperidine-1-carboxylate (Preparation: Izamanishi, T. et al; 1982, Chem. Pharm. Bull., 30: 3617-3623) (10.17 g) was dissolved in anhydrous DCM (100 mL) under an argon atmosphere and cooled to 0° C. tert-Butyldimethylsilyl trifluoromethylsulfonate (10.2 mL) was added dropwise via syringe, followed by 2,6-lutidine (4.7 mL), also added dropwise via syringe. The reaction was stirred overnight, slowly warming to room temperature, then diluted with DCM (200 mL) and washed with saturated aqueous NaHCO3 (150 mL), saturated aqueous NH4Cl ((150 mL), brine (100 mL), dried over anhydrous MgSO4 and concentrated in vacuo, yielding the title compound as a crude product (15.1 g, 102%). MS (GC-EI)[(M-C4H7)+]: 310, 312 for C14H28BrNO3Si; NMR (CDCl3): 0.10 (s, 3H), 0.12 (s, 3H), 0.88 (s, 9H), 1.24 (t, 3H), 1.87 (m, 1H), 2.34 (m, 1H), 2.84-3.40 (m, 2H), 3.69 (m, 2H), 3.93 (m, 2H), 4.13 (q, 2H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1SC>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:21]2[N:20]([CH3:19])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CSc1nc2ccccc2n1C
Product: Cn1c(NCCCOc2cccc(CN3CCCCC3)c2)nc2ccccc21

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.41 g) and 1-methyl-2-methylthiobenzimidazole (1.57 g) were fused at 150° C. for 6 hours. The cooled residue was subjected to column chromatography on silica (chloroform:methanol 19:1) to give the title compound as an oil. This was treated with maleic acid to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-1-methylbenzimidazole dimaleate (0.87 g), m.p. 153°-154° C. (recrystallised from isopropanol).