Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][O:11][C:10]2=[O:15])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([Sn](CCCC)(CCCC)CCCC)[S:25][C:18]=12>C1(C)C=CC=CC=1.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>[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:2]3[N:7]=[CH:6][C:5]([CH2:8][N:9]4[CH2:14][CH2:13][CH2:12][O:11][C:10]4=[O:15])=[CH:4][CH:3]=3)[S:25][C:18]=12
Reactant: O=C1OCCCN1Cc1ccc(Br)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1OCCCN1Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
To a solution of 197 (373 mg, 1.376 mmol) in toluene (10 mL) was added the 7-chloro-2-(tributylstannyl)thieno[3,2-b]pyridine 198 (631 mg, 1.376 mmol) and Pd(PPh3)4 (159 mg, 0.138 mmol). The reaction mixture was heated to reflux for 24 hours. The reaction mixture was then cooled to RT and concentrated. The residue was triturated with Et2O to afford the title compound 199 (363 mg, 73% yield) as beige solid. MS: 360 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26]1>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[N:25]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26]1
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(N3CCC(N)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and tert-butyl pyrrolidin-3-ylcarbamate. MS obsd. (ESI+) [(M+H)+] 407, 1H NMR (400 MHz, CD3OD) δ ppm 7.81 (s, 1 H), 7.71 (t, J=8.21 Hz, 2 H), 7.57-7.36 (m, 3 H), 7.27 (dd, J=8.59, 1.77 Hz, 1 H), 6.11 (s, 1 H), 5.21 (d, J=16.17 Hz, 1 H), 4.76 (d, J=15.92 Hz, 2 H), 4.50 (brs, 1 H), 3.88-3.71 (m, 2 H), 3.71-3.53 (m, 2 H), 3.53-3.36 (m, 3 H), 2.40 (s, 3 H), 2.26 (dq, J=12.63, 6.23 Hz, 1 H), 1.98-1.78 (m, 1 H).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([N:10]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[C:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[CH:11]2[C:20]3[CH:19]=[C:18]([C:21]([O:23]C)=[O:22])[CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>>[CH:1]1([CH2:6][CH2:7][C:8]([N:10]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:30][CH:31]=2)[CH:11]2[C:20]3[CH:19]=[C:18]([C:21]([OH:23])=[O:22])[CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2c(c1)C(N(Cc1ccc(C#Cc3ccc(F)cc3)cc1)C(=O)CCC1CCCC1)CCC2
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc2c(c1)C(N(Cc1ccc(C#Cc3ccc(F)cc3)cc1)C(=O)CCC1CCCC1)CCC2

Procedure:
The titled compound was prepared following the procedure F using methyl 8-((3-cyclopentylpropanoyl){4-[(4-fluorophenyl)ethynyl]benzyl}amino)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate in the presence of LiOH as a white powder (87%). 1H NMR (MeOD, 300 MHz) δ 1.07 (m, 2H), 1.59-2.26 (m, 12H), 2.28 (qt, J=7.6 Hz, 1H), 2.48 (m, 1H), 2.61 (m, 1H), 2.83 (m, 2H), 4.21 (d, J=18.5 Hz, 0.6H), 4.64 (d, J=18.3 Hz, 0.4H), 4.80 (m, 1H), 5.29 (m, 0.4H) 5.95 (m, 0.6H), 7.10 (m, 3H), 7.24 (d, J=8.5 Hz, 2H), 7.38 (d, J=7.9 Hz, 1H), 7.55 (m, 3H), 7.70 (d, J=6.8 Hz, 1H), 7.80 (d, J=6.7 Hz. 1H) M− (ESI): 522.0; M+ (ESI): 524.1
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:10]3([C:14](=[O:15])[NH:13][C:12](=O)[NH:11]3)[C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1>O1CCOCC1>[Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:10]3([C:14](=[O:15])[NH:13][C:12](=[S:26])[NH:11]3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C2(CCCc3sc(Br)cc32)N1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CCCc1sc(Br)cc12
Temperature: 110 °C
Yield: 97 %

Procedure:
2-Bromo-6,7-dihydro-5H-spiro[benzo[b]thiophene-4,4′-imidazolidine]-2′,5′-dione (0.5 g, 1.67 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) (0.371 g, 0.91 mmol) were suspended in 1,4-dioxane (5 mL). The mixture was heated by microwave irradiation at 110° C. for 2×30 min. The solution was concentrated in vacuo and the crude residue purified on silica gel using ethyl acetate in 40-60 petroleum ether (1:1) to afford the title compound as a colourless solid (0.28 g, 53%).
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[N:5]=1.[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>CN(C=O)C.O.C1COCC1>[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][S:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[N:5]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: Oc1cc(O)nc(S)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Oc1cc(O)nc(SCc2cccc(F)c2F)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium hydroxide (5.67 g) was added dropwise to a suspension of 2-mercaptopyrimidine-4,6-diol (14.56 g) in DMF (78 ml) and H2O (39 ml) and the mixture stirred for 30 min. A solution of 2,3-difluorobenzyl bromide (20.86 g) in THF (16 ml) was then added dropwise and the mixture stirred for 18 h. The reaction was then cooled to 0° C. and the precipitate was filtered and washed with H2O (4×100 ml) before drying in vacuo to afford the subtitle compound as a cream solid. Yield: 22.4 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([NH2:8])=[O:7])[C:4]=1[NH2:12].Br[C:14]1[S:15][CH:16]=[CH:17]N=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[N:12]=[C:14]1[S:15][CH:16]=[CH:17][N:8]1[C:6]2=[O:7]
Reactant: COc1cccc(C(N)=O)c1N
Reactant: Brc1nccs1
Product: COc1cccc2c(=O)n3ccsc3nc12
Yield: 87.1 %

Procedure:
16.6 g of 3-methoxyanthranilamide and 16.4 g of 2-bromothiazole were stirred for 7 hours at 150° C. After working up in the conventional manner there was obtained 20.2 g (87%) of the above compound; m.p. 230°-232° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[O:16][C:17]([F:23])([F:22])[O:18][C:19]=3[CH:20]=2)[C:12](=[O:24])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.C(OCC)(=O)C.CCCCCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[O:16][C:17]([F:23])([F:22])[O:18][C:19]=3[CH:20]=2)[C@H:12]([OH:24])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)c2cc3c(cc21)OC(F)(F)O3
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CSC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](O)c2cc3c(cc21)OC(F)(F)O3
Temperature: 0 °C

Procedure:
Add a solution of 2,2-Difluoro-9-oxo-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (2.2 mmol) in THF (20 mL), to a cooled (−78° C.) solution of Borane-methyl sulfide (2.6 mmol) and (R)-2-methyl-CBS-oxazaborolidine (3.3 mmol) in THF (20 mL). After warming slowly to 0° C. for 1 h, quench the reaction with methanol (2 mL). Remove solvent under vacuum and chromatograph using ethyl acetate/hexane (2-35%) to elute. This gives the title compound as a colorless solid.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH2:32][CH2:33][CH3:34].O>CS(C)=O.C(OCC)(=O)C>[CH2:32]([O:27][C:26]([C:24]1[N:25]=[C:21]([NH:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:22][CH:23]=1)=[O:28])[CH2:33][CH3:34]
Reactant: CCCI
Reactant: O=C(O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCOC(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 60 °C
Yield: 73.6 %

Procedure:
To a solution of 2-(trityl-amino)-thiazole-4-carboxylic acid (400 mg, 1.03 mmol) in DMSO (1 ml) was added KOH (215 mg, 1.55 mmol) followed by addition of 1-iodo-propane (263 mg, 1.55 mmol). The reaction was heated at 60° C. for 1 hour. It was taken into water and ethyl acetate. After separation, the organic layer was washed, dried and evaporated. The obtained crude product was purified via flash column (silica gel, 10% ethyl acetate in hexane) to yield 2-(trityl-amino)-thiazole-4-carboxylic acid propyl ester as a white solid (325 mg, 76%). LC/MS (m/z 429.14 (M+H)+); HPLC Rt: 4.182 min.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:74]=[CH:73][C:20]([C:21]([O:23][C:24]2[CH:72]=[CH:71][C:27]([C:28]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38](=[O:70])[C:39]4[CH:44]=[CH:43][C:42]([O:45][C:46](=[O:69])[C:47]5[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][S:65]C(=O)C)=[CH:49][CH:48]=5)=[CH:41][CH:40]=4)[CH:32]=3)=[O:29])=[CH:26][CH:25]=2)=[O:22])=[CH:19][CH:18]=1)(=O)C.Cl>C1COCC1.CO.O>[SH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][C:24]2[CH:72]=[CH:71][C:27]([C:28]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38](=[O:70])[C:39]4[CH:44]=[CH:43][C:42]([O:45][C:46](=[O:69])[C:47]5[CH:48]=[CH:49][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][SH:65])=[CH:51][CH:52]=5)=[CH:41][CH:40]=4)[CH:32]=3)=[O:29])=[CH:26][CH:25]=2)=[O:22])=[CH:73][CH:74]=1
Reactant: CC(=O)SCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)Oc3cccc(OC(=O)c4ccc(OC(=O)c5ccc(OCCCCCCCCCCCSC(C)=O)cc5)cc4)c3)cc2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Oc1ccc(C(=O)Oc2cccc(OC(=O)c3ccc(OC(=O)c4ccc(OCCCCCCCCCCCS)cc4)cc3)c2)cc1)c1ccc(OCCCCCCCCCCCS)cc1
Temperature: 25 °C

Procedure:
Compound BC4 (0.2 g, 0.2 mmol) was dissolved in 50:50 THF/MeOH (20 mL), and following addition of 3 mL conc. HCl to the flask, the mixture was heated to reflux for 6 hours. The mixture was let to cool to room temperature, diluted with water (10 mL), and extracted with CH2Cl2 (2×200 mL). The solvent was removed, and the residue purified by column chromatography (CH2Cl2: EtOH, 10:0.03). The product was then selectively precipitated from CH2Cl2 through dropwise addition of petroleum ether. Yield 0.11 g (60%). EA: Found: C, 69.37; H, 7.21. C56H66O10S2 requires C, 69.83; H, 6.91%. 1H NMR: δH (CDCl3; 300 MHz): 1.24-1.56 (30 H, m, CH2 / SH), 1.63 (4 H, m, S—CH2—CH2), 1.85 (4 H, m, O—CH2—CH2), 2.55 (4 H, q, 3J=7.4, SCH2), 4.07 (4 H, t, 3J=6.5 Hz, OCH2), 7.01 (4 H, d, 3J=8.9 Hz, Ar—H), 7.22 (3 H, m, Ar—H), 7.40 (4 H, d, 3J=8.7 Hz, Ar—H), 7.50 (1 H, t, 3J=8.2 Hz, Ar—H), 8.17 (4 H, d, 3J=8.9 Hz, Ar—H), 8.29 (4 H, d, 3J=8.7 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 25.1, 26.4, 28.8, 29.5, 29.7, 29.9, 29.9, 34.4, 53.8, 68.8, 114.8, 116.2, 119.7, 121.4, 122.5, 127.0, 130.3, 132.3, 132.8, 151.8, 155.9, 164.2, 164.5, 164.7. m/z (MALDI) 985.81 [M+Na]+, C56H66NaO10S2 requires 985.40.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[F:10][C:8]([F:9])([F:11])[C:5]1[CH:6]=[CH:7][C:2]([O:1][C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:3][CH:4]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Oc1ccc(C(F)(F)F)cn1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1ccc(C(F)(F)F)cn1)c1ccccc1
Yield: 66.4 %

Procedure:
A solution of 2-hydroxy-5-(trifluoromethyl)pyridine (0.49 g, 3.00 mmol), 1-methyl-3-(methyl -phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (15:85)) yielding the title compound (0.59 g, 66% yield) as a white solid.
Reaction SMILES: Br[CH2:2]C(=O)CC(C1C=CC=CC=1)C.[Br:14][CH2:15][C:16](=[O:28])[CH:17](C)[CH2:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:26]>>[Br:14][CH2:15][C:16](=[O:28])[CH2:17][CH:18]([C:19]1[C:20]([CH3:26])=[CH:21][CH:22]=[CH:23][C:24]=1[CH3:25])[CH3:2]
Reactant: CC(CC(=O)CBr)c1ccccc1
Reactant: Cc1cccc(C)c1CC(C)C(=O)CBr
Product: Cc1cccc(C)c1C(C)CC(=O)CBr

Procedure:
According to the same method the compounds 1-bromo-4-phenyl-2-pentanone and 1-bromo-4-(2,6-dimethylphenyl)-3-methyl-2-butanone were prepared.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[N+:19]([O-])=O)[CH3:3].Cl[Sn]Cl>CO.Cl>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH2:19])[CH3:1]
Reactant: CN(C)Cc1ccccc1Sc1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: CN(C)Cc1ccccc1Sc1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a yellow solution of compound 10 (200 mg, 0.65 mmol) in CH3OH (4 mL) and conc. HCl (2 mL), SnCl2 (0–3 g) was added. The mixture was stirred at room temperature overnight and the solvent was evaporated to dryness. Water (15 mL) was added to the residue and the mixture was extracted with ethyl acetate (10 mL×3). The organic layer was discarded and the aqueous layer was adjusted to pH 10 with 1 N NaOH. The cloudy solution was extracted with ethyl acetate (10 mL×3). The combined organic layer was dried over Na2SO4 and the solvent was evaporated in vacuo to dryness. The residue was purified by column chromatography (silica gel, CH2Cl2/CH3OH, 95/5) to yield compound 12 as a white solid (77 mg, 42.7%), Rf=0.3 (silica gel, CH2Cl2/CH3OH, 90/10), mp 56–58° C.; 1H NMR (CDCl3) δ 7.40–7.49 (m, 1H), 7.18–7.25 (m, 1H), 7.05–7.13 (m, 2H), 6.84–6.93) (m, 1H), 6.38–6.48 (m, 2H), 4.74 (s, b, 2H), 3.57 (s, 2H), 2.31 (s, 6H). Anal. Calcd for C15H17FN2S: C, 65.19; H, 6.20; N, 10.14. Found: C, 65.06; H, 6.23; N, 10.04.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:30])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32].[OH-].[Na+]>CS(C)=O.[Cl-].[Na+].O>[Cl:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][C@@H:13]([CH2:12][NH:32][CH3:31])[CH2:22][CH2:21]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CNC[C@H]1CCc2cccc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 60 °C
Yield: 71.8 %

Procedure:
To a solution of [(2R)-8-(2,6-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (239 mg, 0.54 mmol) in anhydrous dimethyl sulfoxide (1 mL) was added a solution of methylamine (2.0 M in tetrahydrofuran, 2.7 mL, 5.4 mmol) and the mixture heated to 60° C. in a sealed vial for 42 hours. The cooled reaction mixture was then poured into 1:1 v/v 2.0 M aqueous sodium hydroxide and saturated brine (50 mL) and the mixture extracted with ethyl acetate (50 mL). The separated organic phase was washed with 1:1 v/v 2.0 M aqueous sodium hydroxide and saturated brine (50 mL), and half saturated brine (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 0.5 to 5% ammonia saturated methanol solution in dichloromethane gave 125 mg (75%) of {[(2R)-8-(2,6-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}methylamine as a white solid. The product was dissolved in 2-propanol (1 mL) and diethyl ether (2.5 mL) and a solution of hydrogen chloride (1.0 M in diethyl ether, 0.39 mL, 0.39 mmol) was added followed by hexane (3 mL). The resulting white precipitate was filtered to afford 118 mg (64%) of {[(2R)-8-(2,6-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}methylamine hydrochloride as a white crystalline solid. HRMS: calcd for C17H17Cl2NO+H+, 322.07599; found (ESI, [M+H]+), 322.0757.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[NH2:43][C@@H:44]([CH2:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)[CH2:45][OH:46]>C(Cl)Cl>[CH:48]1([CH2:47][C@H:44]([NH:43][C:23]([C:22]2[CH:26]=[CH:27][C:19]([C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:6]4[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=4)[CH2:12][CH2:13]3)=[O:18])=[CH:20][CH:21]=2)=[O:25])[CH2:45][OH:46])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: N[C@H](CO)CC1CCCCC1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@H](CO)CC3CCCCC3)cc2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid (1.5 g) was dissolved in methylene chloride (60 ml) and then, triethylamine (0.7 ml) was added and cooled. Pivaloyl chloride (0.58 ml) was added slowly to the solution at 0~5° C. and the mixture was stirred at SoC for 2 hours. And then triethylamine (1.7 ml) and (S)-(+)-2-amino-3-cyclohexyl-1-propanol hydrochloride (0.87 g) were added in order, the solution was stirred at 0° C. for 3 hours and heated slowly to 20° C. and stirred for 1 hour. The reaction mixture was washed with water twice and the solvent was concentrated under reduced pressure. The concentrated residue was recrystallized using isopropanol and ether. The recrystallized product was filtered and dried to give 2.07 g (yield: 80%) of the desired compound. m.p.: 139~140° C.; 1H-NMR(CDCl3), ppm: δ 0.89~1.01(m, 2H), 1.22(m, 9H), 1.34(m, 1H), 1.45(m, 2H), 1.71(m, 4H), 1.81(m, 1H), 3.10(m, 4H), 3.51(m, 3H), 3.61(m, 1H), 3.76(m, 1H), 3.89(m, 2H), 4.13(m, 1H), 4.26(m, 1H), 6.59(m, 1H), 6.83(m, 1H), 6.95(m, 1H), 7.40(m, 2H), 7.67(m, 1H), 7.77(m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([S:13]([OH:16])(=O)=[O:14])=[CH:10]2)=[CH:5][CH:4]=1.[Na].S(Cl)([Cl:20])=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([S:13]([Cl:20])(=[O:16])=[O:14])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2ccc(S(=O)(=O)O)cc2c1
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Temperature: 80 °C

Procedure:
A mixture of 7-methoxynaphthalene-2-sulfonic acid, sodium salt (8.12 g, 31.1 mmol) in 80 mL of thionyl chloride is heated at 80° C. for 3 hours. A few drops of DMF is added with vigorous bubbling resulting and the mixture is heated for an additional 1.5 hours. The mixture is allowed to cool to room temperature and concentrated in vacuo. The residue is diluted in EtOAc and washed successively with water (2×), 1 N HCl solution and saturated NaCl. The organic layer is dried over anhydrous MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with 20% EtOAc/hexanes to afford the title compound (5.2 g, 20.2 mmol) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:13]=[CH:12]2)C1C=CC=CC=1>CO.[Pd]>[O:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[N:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(COc2ccc3nc(Oc4ccccc4)ccc3c2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc2nc(Oc3ccccc3)ccc2c1
Temperature: 25 °C
Yield: 61 %

Procedure:
To a solution of 6-(benzyloxy)-2-phenoxyquinoline 13 (0.862 g) in CH3OH (10 ml) is added 10% of palladium on C (10%). The reaction is stirred under H2 at room temperature for 1 night. After filtration on celite and concentration, the residue is purified by silica gel chromatography using AcOEt/petroleum ether 10/90 as eluent to give compound 2-phenoxy-6-quinolinol 14 as an oil.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.Cl.[CH3:23][N:24]1[CH2:30][C:29]2[CH:31]=[C:32](/[CH:35]=[CH:36]/[C:37](O)=O)C=N[C:28]=2[NH:27][C:26](=O)[CH2:25]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:27]([CH3:28])[CH2:26][C:25]2[N:24]([CH3:23])[C:30]3[C:36]([CH:37]=2)=[CH:35][CH:32]=[CH:31][CH:29]=3)=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CN1CCN(Cc2cc(/C=C/C(=O)O)cnc2N)CC1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CN1CCN(Cc2cc(/C=C/C(=O)N(C)Cc3cc4ccccc4n3C)cnc2N)CC1
Yield: 14 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[6-amino-5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (136 mg, 14%) was prepared as an off-white powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.7 (br s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 8.07 (br s, 2H), 7.55-7.01 (m, 6H), 6.41-6.17 (m, 1H), 5.07-4.85 (m, 2H), 3.73-3.62 (m, 7H), 3.11-2.98 (m, 8H), 2.73 (s, 3H); MS (ESI) m/e 433 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:33][C:30]3[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cc1ccc(N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Temperature: 140 °C
Yield: 35.6 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 mol), 6-methylpyridin-3-amine (56.9 mg, 526 mol), BINAP (10.9 mg, 17.5 mol), palladium (II) acetate (19.7 mg, 87.7 mol) and sodium tert-butoxide (84.3 mg, 877 mol) in DMF (1 mL) and toluene (500 μL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was cooled then diluted with water and extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 30-70% ethyl acetate in hexanes) gave N-tert-butyl-2-(6-methylpyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (57 mg, 125 mol, 36%) as a brown solid. MS (EI/CI) m/z: 455.2 [M+H].