Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](S[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[CH:11][CH:10]=[C:9]2[Cl:17])([CH3:4])([CH3:3])[CH3:2].[C:18](S[C:23]1[C:24]([F:34])=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[C:26]2[Cl:33])([CH3:21])([CH3:20])[CH3:19].O[O:36][S:37]([O-:39])=O.[K+]>CCOC(C)=O.O>[C:18]([S:37]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[CH:11][CH:10]=[C:9]2[Cl:17])(=[O:39])=[O:36])([CH3:21])([CH3:20])[CH3:19].[C:1]([S:37]([C:23]1[C:24]([F:34])=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[C:26]2[Cl:33])(=[O:39])=[O:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Sc1ccc2nccc(Cl)c2c1F
Reactant: O=S([O-])OO
Reactant: CC(C)(C)Sc1cc2c(Cl)ccnc2cc1F
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1F
Product: CC(C)(C)S(=O)(=O)c1ccc2nccc(Cl)c2c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(tert-butylthio)-4-chloro-7-fluoroquinoline and 6-(tert-butylthio)-4-chloro-5-fluoroquinoline (21.24 g, 79 mmol) and oxone (48.4 g, 79 mmol) in EtOAc (200 ml) and water (200 ml) was stirred at RT overnight. LCMS showed sulfoxide as well as sulfone. Added an additional 15 g of Oxone and stirred for 3 hours; the sulfoxide was still present. Added 15 g more of Oxone and stirred for 3 hours more. Sulfoxide was still present. Added 5 g more of Oxone and stirred overnight. Note each time more Oxone was added the amounts of EtOAc and water needed to be increased as well. The final amounts of solvent were ˜500 mL EtOAc and ˜500 mL water. The layers were separated and the aqueous layer was extracted once with ethyl acetate. The combined organics were filtered and concentrated. Split material into 2 batches for purification. Each batch was purified as follows: The crude sample was purified via Isco normal phase chromatography (330 g Gold column, 0%-20%, E/H). This purification yielded separation of the regioisomers. The two batches of purified products were recombined. Peak 1 was the 6-(tert-butylthio)-4-chloro-7-fluoroquinoline product (9.86 g) as a creamy white solid. 1H NMR (ACETONITRILE-d3) δ ppm 8.96 (d, 1H), 8.77 (d, J=7.3 Hz, 1H), 7.99 (d, J=11.4 Hz, 1H), 7.74 (d, J=4.8 Hz, 1H), 1.41 (d, J=1.0 Hz, 9H). MS: m/z: 302.0 [M+H]+. Peak 2 was the 6-(tert-butylsulfonyl)-4-chloro-5-fluoroquinoline product (1.71 g) as a white powder. 1H NMR (ACETONITRILE-d3) δ ppm 8.94 (d, 1H), 8.04-8.15 (m, 2H), 7.75 (d, J=4.8 Hz, 1H), 1.41 (d, J=1.3 Hz, 9H). MS: m/z: 302.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10]C)[C:7]([CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(C)c(C=O)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C=O)c(C)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
First step: To a stirring solution of 2,5-dimethyl-4-methoxybenzaldehyde (0.82 g, 5.0 mmol) at −20° C. in CH2Cl2 (10 mL) was added BBr3 (10 mL, 1M in CH2Cl2). The reaction mixture was stirred at room temperature for 16 hrs. It was added ice and diluted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:1) to afford 2,5-dimethyl-4-hydroxy-benzaldehyde as a yellow solid (0.43 g, 57%): 1H NMR (300 MHz, DMSO-d6): δ 10.41 (s, 1 H), 9.99 (s, 1 H), 7.56 (s, 1 H), 6.69 (s, 1 H), 2.51 (s, 3 H), 2.14 (s, 3 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=20% ethyl acetate in hexanes; Rf=0.48.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:31]1(=[O:35])[CH2:34][CH2:33][CH2:32]1.[Cl-].[NH4+]>O1CCCC1>[OH:35][C:31]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2(O)CCC2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
To a solution of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol) in tetrahydrofuran (3 ml) was added 1.6N solution of n-butyllithium in hexane (0.829 ml, 1.33 mmol) at −78° C., and the mixture was stirred at −78° C. for 15 min. At −78° C., a solution of cyclobutanone (0.0747 ml, 1.00 mmol) in tetrahydrofuran (1 ml) was added, and the mixture was stirred at −78° C. for 30 min. Saturated aqueous ammonium chloride solution (3 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (108 mg, 33.8%) as an oil.
Reaction SMILES: [NH:1]([C:15]([O:17]C(C)(C)C)=O)[C@H:2]([C:12]([OH:14])=O)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:22][C@H:23]([C:25]([O:27][CH3:28])=[O:26])[CH3:24].Cl.N(C(OC(C)(C)C)=O)[C@H](C(N[C@H](C(OC)=O)C)=O)COCC1C=CC=CC=1.FC(F)(F)C(O)=O.N[C@H](C(N[C@H](C(OC)=O)C)=O)COCC1C=CC=CC=1.FC(C(O)=O)(F)F.[NH:91]([C:103]([O:105][CH2:106][C:107]1[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=1)=[O:104])[C@H:92](C(O)=O)[CH2:93][C:94]1[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1>>[NH:91]([C:103]([O:105][CH2:106][C:107]1[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=1)=[O:104])[C@H:92]([C:15]([NH:1][C@H:2]([C:12]([NH:22][C@H:23]([C:25]([O:27][CH3:28])=[O:26])[CH3:24])=[O:14])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:17])[CH2:93][C:94]1[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@H](C)N
Agent: COC(=O)[C@H](C)NC(=O)[C@@H](N)COCc1ccccc1
Agent: COC(=O)[C@H](C)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](C)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 74 %

Procedure:
First, Boc-Ser(OCH2C6H5)-OH (4.93 g, 16.7 mmol) was coupled to H-Ala-OCH3.HCl (2.80 g, 20.0 mmol) by a mixed anhydride procedure to yield an oil, 6.1 g. Boc-Ser(OCH2C6H5)-Ala-OCH3 was then deblocked with trifluoroacetic acid, and the resulting product, H-Ser(OCH2C6H5)-Ala-OCH3 trifluoroacetate (6.15 g, 15.6 mmol), was coupled to Z-Phe-OH (3.89 g, 13.0 mmol) using a mixed anhydride procedure. This product was crystallized from ethyl acetate to yield 5.4 g of Z-Phe-Ser(OCH2C6H5)-Ala-OCH3 (m.p. 158°-159°).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])[CH:12]=1>CN(C)C=O>[ClH:17].[CH3:10][C:11]1[N:16]=[C:15]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])[CH:12]=1
Reactant: Cc1cc(N2CCc3ccccc3C2C)nc(Cl)n1
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(N2CCc3ccccc3C2C)nc(Nc2ccc(F)cc2C)n1
Product: Cl
Yield: 54.7 %

Procedure:
After 2-methyl-4-fluoroaniline(1.1 ml, 10.2 mmol) was added to a mixture solution of 6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.5 g, 5.5 mmol) and dimethylformamide(10 ml), 1.2 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]([OH:12])=O)[CH2:6]1)=[O:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1>ClCCl>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[C:10]([C@@H:7]1[CH2:8][CH2:9][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)=[O:12]
Reactant: C[Si](C)(C)c1nccs1
Reactant: COC(=O)[C@H]1CC[C@@H](C(=O)O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@@H](C(=O)c2nccs2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1R,3S)-3-(methoxycarbonyl)cyclopentanecarboxylic acid (130 mg, 0.76 mmol) in dichloromethane (3 mL) was added DMF (5.85 μL, 0.08 mmol). The solution was cooled to 0° C. oxalyl chloride (73.0 μL, 0.83 mmol) was added. The mixture was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature for one hour. The reaction was re-cooled to 0° C., 2-(trimethylsilyl)thiazole (178.0 mL, 1.13 mmol) was added and the mixture was stirred at room temperature for two hours. The mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford (1S,3R)-methyl 3-(thiazole-2-carbonyl)cyclopentanecarboxylate. MS ESI calc'd. for C11H14NO3S [M+H]+ 240. found 240. 1H NMR (500 MHz, DMSO-d6) δ 8.21 (d, J=3.0 Hz, 1H), 8.14 (d, J=3.0 Hz, 1H), 3.58 (s, 3H), 2.96-2.89 (m, 1H), 2.27-2.20 (m, 1H), 1.74-2.04 (m, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.N1(O)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C@H:51]1([NH2:58])[CH2:56][CH2:55][C@@H:54]([NH2:57])[CH2:53][CH2:52]1>CN(C=O)C.CCOC(C)=O>[NH2:57][C@@H:54]1[CH2:55][CH2:56][C@H:51]([NH:58][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=2)=[O:22])[CH2:52][CH2:53]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: N[C@H]1CC[C@@H](N)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@@H](N)CC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a 20 mL scintillation vial, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.10 g, 0.22 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (91 mg, 0.24 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (33 mg, 0.240 mmol), and N,N-diisopropylethylamine (38 μl, 0.22 mmol) were combined with DMF (4 ml) to give a light yellow solution. The reaction mixture was stirred at room temperature for 45 min. In a 20 mL round-bottomed flask, cis-cyclohexane-1,4-diamine (249 mg, 2.18 mmol) was dissolved in 0.4 mL DMF to give a colorless solution. The carboxylic acid reaction mixture was added dropwise to the amine solution. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc (−50 mL) and washed with sat NaHCO3 (3×25 mL) and H2O (3×25 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by chromatography over SiO2 with 0% to 10% MeOH in DCM with 0.1% NH4OH to afford 86 mg of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-4-amino-cyclohexyl)amide as a white solid. MS: [M+H]+=554.
Reaction SMILES: C(OC([N:11]1[CH2:17][C@H:16]2[C@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][C@@H:15]2[CH3:18])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[C:23]([O:22][C:20]([NH:19][C@:13]12[CH2:14][C@H:15]([CH3:18])[C@H:16]1[CH2:17][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: C[C@H]1C[C@]2(NC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1C[C@]2(NC(=O)OC(C)(C)C)CNC[C@H]12

Procedure:
(1R,5S,6S)-1-tert-Butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester (1.4 g, 3.9 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (10 mL). A small amount of 10% palladium-carbon (50% wet) was added, and the mixture was stirred in a hydrogen atmosphere for three hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 0.89 g (quantitative) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(Cl)(=O)[C:8](Cl)=[O:9].[Cl:13]C(Cl)C>Cl>[CH3:3][CH:2]([CH2:4][Cl:13])[C:1]([N:6]=[C:8]=[O:9])=[O:5]
Reactant: CC(Cl)Cl
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=C(C)C(N)=O
Agent: Cl
Product: CC(CCl)C(=O)N=C=O
Reaction time: 0.5 h

Procedure:
Into a suspension of methacrylamide (106 g; 1.25 mol) in dichloroethane (600 ml), dry hydrogen chloride gas was blown while cooling with ice for about 1 hour. Then, oxalyl chloride (243.9 g; 1.92 mol) was dropwise added thereto while continuing hydrogen chloride blowing and ice cooling. The resultant mixture was heated to reflux, and the refluxing was continued for 30 minutes. After being allowed to cool, the reaction mixture was distilled under reduced pressure to give alpha-methyl-beta-chloropropionyl isocyanate.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.Br[C:27]1C=CC2C3N=C(C(N)=O)SC=3CCOC=2C=1.FC(F)(F)C(NN)C>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:27])[C:20]([F:23])([F:21])[F:22])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: CC(NN)C(F)(F)F
Product: CC(n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2)C(F)(F)F

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with (2,2,2-Trifluoro-1-methyl-ethyl)-hydrazine to give 8-Bromo-2-[2-(2,2,2-trifluoro-1-methyl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. MS (ESI+) 445.0/447.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][CH2:34]2.CN1C=CN=C1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[C:36](=[O:40])[NH:35][CH2:34]4)=[O:23])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: Nc1ccc2c(c1)CNC2=O
Reactant: COc1ccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2cc(-c3cccc(C(=O)Nc4ccc5c(c4)CNC5=O)c3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
A mixture of 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (100 mg, 0.26 mmol), 5-aminoisoindolin-1-one (38 mg, 0.26 mmol), 1-methyl-1H-imidazole (84 mg, 1.02 mmol) and EDCI (196 mg, 1.02 mmol) in DMF (3 mL) was stirred for 16 h at room temperature. Ethyl acetate (5 mL) and water (5 mL) were added. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phases were combined and washed with brine (10 mL) then dried over Na2SO4. The residue was concentrated and triturated with MeOH (2 mL) to give 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(1-oxoisoindolin-5-yl)benzamide (26 mg, 20%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.68 (s, 1H), 9.97 (s, 1H), 8.61 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.24-8.08 (m, 4 h), 7.82-7.64 (m, 4 h), 7.41 (d, 1H, J=8.7 Hz), 7.11 (d, 1H, J=8.4 Hz), 4.39 (s, 2H), 4.02 (s, 3H), 3.76 (s, 3H). LC-MS: [M+H]+, 521.9, tR=1.434 min, HPLC: 96.12% at 214 nm, 96.79% at 254 nm, tR=3.673 min.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C@@H:9]([OH:26])[C@@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH2:27]([O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[S:42](Cl)(=[O:44])=[O:43])[CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32].N1C=CC=C[CH:47]=1>>[C:21]([O:20][C:19](=[O:25])[NH:18][C@H:10]([C@H:9]([OH:26])[CH2:8][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])[S:42]([C:35]1[CH:36]=[CH:37][C:38]([O:40][CH2:41][CH3:47])=[CH:39][C:34]=1[O:33][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])(=[O:44])=[O:43])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: C=CCCCCOc1cc(OC)ccc1S(=O)(=O)Cl
Reactant: C=CCCCCNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: c1ccncc1
Product: C=CCCCCOc1cc(OCC)ccc1S(=O)(=O)N(CCCCC=C)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirring solution of 10a (50 mg, 0.14 mmol) in pyridine (2 mL) was added 7a (64 mg, 0.20 mmol) and the resulting solution was allowed to stir for 2 h at 23° C. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography (3:1 hexanes:EtOAc) to yield 74 mg (84% yield) of 11a as a colorless oil. [α]D20 −1.4 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.25-1.34 (m, 12H), 1.47-1.50 (m, 2H), 1.57-1.60 (m, 2H), 1.82-1.90 (m, 2H), 1.97 (q, J=7.1 Hz, 2H), 2.11 (q, J=7.0 Hz, 2H), 2.92-2.95 (m, 2H), 3.10-3.17 (m, 1H), 3.30 (br s, 3H), 3.76 (br s, 2H), 3.84 (s, 3H), 3.90-3.92 (m, 1H) 4.03 (t, J=6.7 Hz, 2H), 4.65 (d, J=7.1 Hz, 1H), 4.89-5.04 (m, 4H), 5.66-5.82 (m, 2H), 6.46 (d, J=2 Hz), 6.49 (dd, J=8.8, 2.3 Hz, 1H), 7.17-7.29 (m, 5H), 7.83 (d, J=7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 24.9, 25.7, 27.9, 28.2, 28.3, 33.1, 33.2, 35.1, 49.9, 52.3, 54.5, 55.6, 69.1, 72.2, 79.4, 100.2, 104.1, 114.7, 115.0, 119.4, 126.2, 128.3, 129.5, 133.5, 137.8, 138.1, 138.2, 156.0, 157.6, 164.7; FT-IR (film, NaCl) νmax=3395, 2935, 1705, 1597, 1325 cm−1; ESI (+) LRMS m/z (ion): 653.13 (M+Na)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[C:13]2[N:14]([C:18]([Br:22])=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1)[CH3:6])=[O:4].CS[C:30](SC)=[N:31][C:32]#[N:33].[CH2:36]([NH2:38])[CH3:37]>CN(C)C=O.O>[Br:22][C:18]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:9]3[C:23]([Cl:26])=[CH:24][CH:25]=[C:7]([N:5]([C:3](=[O:4])[CH2:2][NH:1][C:30]([NH:38][CH2:36][CH3:37])=[N:31][C:32]#[N:33])[CH3:6])[C:8]=3[Cl:27])[C:13]2=[N:20][C:19]=1[CH3:21]
Reactant: CCN
Reactant: CSC(=NC#N)SC
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=NC#N)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 60 °C

Procedure:
A solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (300 mg) and dimethyl cyanodithioiminocarbonate (93 mg) in dimethylformamide (3 ml) was heated at 70° C. for 1 hour. After cooling the reacting mixture, to the mixture was added 70% solution of ethylamine in water (0.57 ml) and the mixture was heated at 60° C. for 2 hours. To this mixture was added water (3 ml) in an ice-water bath. The precipitates were collected by vacuum filtration and washed with ethyl acetate to give 3-bromo-8-[3-[N-[(2-cyano-3-ethylguanidino)acetyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (278 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25]>CO>[S:8]1[C:4]2[CH:3]=[C:2]([CH:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:11][N:12]([CH3:21])[CH2:13]3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25].[S:8]1[C:4]2[CH:3]=[C:2]([CH:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:11][N:12]([CH3:21])[CH2:13]3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Brc1ccc2ncsc2c1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: CN1Cc2ccccc2C(c2ccc3ncsc3c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Racemic 4-benzothiazol-6-yl-2-methyl-1,2,3,4-tetrahydroisoquinoline was prepared from 6-bromo-benzothiazole by a method similar to the one described in Example 129 (Steps B to C). The desired tetrahydroisoquinoline (20.5 mg) was dissolved in methanol and treated with a solution of maleic acid in methanol (1 mL) at 0° C. The solution was stirred at room temperature overnight, then concentrated, and the solid was washed with diethyl ether providing (+/−)-4-benzothiazol-6-yl-2-methyl-1,2,3,4-tetrahydroisoquinoline, maleate salt (30 mg, 98%, >99% AUC HPLC): 1H NMR (CD3OD, 500 MHz) δ 9.28 (d, J=3.9 Hz, 1H), 8.09-8.08 (m, 1H), 8.00-7.99 (m, 1H), 7.44-7.42 (m, 1H), 7.36-7.25 (m, 3H), 6.93-6.92 (m, 1H), 6.26-6.25 (s, 2H), 4.80-4.78 (m, 1H), 4.64-4.56 (m, 2H), 3.93-3.89 (m, 1H), 3.63-3.61 (m, 1H), 3.08 (s, 3H); ESI-MS m/z=281 [M+H]+.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13]2[C:27]3[CH2:28][CH2:29][N:30]([C:32](=[S:45])[NH:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[N+:42]([O-:44])=[O:43])[CH2:31][C:26]=3[S:25][C:14]=2[N:15]([CH:20]([CH2:22][CH2:23][CH3:24])[CH3:21])[C:16](=[O:19])[CH2:17][N:18]=1.C(O)C.C([BH3-])#N.[Na+]>O>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[NH:18][CH2:17][C:16](=[O:19])[N:15]([CH:20]([CH2:22][CH2:23][CH3:24])[CH3:21])[C:14]2[S:25][C:26]3[CH2:31][N:30]([C:32](=[S:45])[NH:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[N+:42]([O-:44])=[O:43])[CH2:29][CH2:28][C:27]=3[C:13]1=2
Reactant: CCCC(C)N1C(=O)CN=C(c2ccccc2Cl)c2c1sc1c2CCN(C(=S)Nc2ccc(OC)cc2[N+](=O)[O-])C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCCC(C)N1C(=O)CNC(c2ccccc2Cl)c2c1sc1c2CCN(C(=S)Nc2ccc(OC)cc2[N+](=O)[O-])C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Acetic acid (0.5 ml) is added to 0.16 g of 5-(2-chiorophenyl)-1,2,3,6,7,9-hexahydro-N-(4-methoxy-2-nitrophenyl)-2-oxo-1-(2-pentyl)-8H-pyrido[4′,3′:4,5]thieno[2,3-e]-1,4-diazepine-8-carbothioamide (0.26 mmol). Ethanol (3.5 ml) is added to this yellow suspension then acetic acid (1 ml) and finally sodium cyanoborohydride (0.033g, 0.52 mmol) are added dropwise. The reaction mixture is agitated for one hour then it is heated for one hour at 40° C. until solubilization. Then agitation is carried out for 2 hours at 22° C. The reaction medium is poured into ice-cooled water (30 ml), followed by agitation, filtering then washing abundantly with water. After drying under vacuum without heating, the desired product is obtained in the form of an orange powder (0.145 g, 83%)
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[H-].[Na+]>CN(C=O)C>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][C:3]1=[O:12]
Reactant: O=C1COc2ccccc2CN1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1COc2ccccc2CN1CCCCCBr
Reaction time: 1.5 h
Yield: 69.5 %

Procedure:
In 20 ml of DMF was dissolved 100 mg of 2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one and the solution then ice-cooled. Then, to the resulting solution were added 0.125 ml (1.5 equivalent) of 1,5-dibromopentane and 29.4 mg (1.2 equivalent) of a 60% sodium hydride oil dispersion and the mixture was stirred for 1.5 hour with ice-cooling. Thereafter, the reaction solution was reacted and/or treated and purified in the same manner as in Reference Example 1 to give 133 mg (yield: 69.5%) of the title compound.