Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][C:4]1([CH3:26])[CH2:21][N:8]2[C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N+:12]([O-])=[CH:11][C:10]=3[N:20]=[C:7]2[CH2:6][N:5]1[S:22]([CH3:25])(=[O:24])=[O:23].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH3:3][C:4]1([CH3:26])[CH2:21][N:8]2[C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[C:11]([NH2:2])[C:10]=3[N:20]=[C:7]2[CH2:6][N:5]1[S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: [NH4+]
Reactant: CC1(C)Cn2c(nc3c[n+]([O-])c4ccccc4c32)CN1S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)Cn2c(nc3c(N)nc4ccccc4c32)CN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ammonium hydroxide (5 mL) was added with vigorous stirring to a suspension of 10,10-dimethyl-9-(methylsulfonyl)-5-oxido-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline (0.91 g, 2.6 mmol) in dichloromethane (25 mL). p-Toluenesulfonyl chloride (0.50 g, 2.6 mmol) was added in one portion, and the reaction was stirred for four hours at ambient temperature. The organic layer was separated and washed with 1% aqueous sodium carbonate (50 mL) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting orange solid (0.77 g) was recrystallized from 1,2-dichloroethane to provide 10,10-dimethyl-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine as a white powder, mp 227-228° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:8][CH2:7][C:6]2[CH:9]=[C:10](/[CH:21]=[CH:22]/[C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=3)[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][C:5]=2[CH2:4][CH2:3]1.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH3:34][C:2]1([CH3:1])[CH2:8][CH2:7][C:6]2[CH:9]=[C:10](/[CH:21]=[CH:22]/[C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:32][CH:33]=3)[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][C:5]=2[CH2:4][CH2:3]1
Reactant: CCCCCCCCc1cc2c(cc1/C=C/c1ccc(C(=O)OCC)cc1)CCC(C)(C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCc1cc2c(cc1/C=C/c1ccc(C(=O)O)cc1)CCC(C)(C)CC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The ester was dissolved in 20 ml of ethanol/tetrahydrofuran (1:1) and treated with 5.8 ml of 3N NaOH. Thereafter, the mixture was stirred at room temperature for 3 days, poured on to ice, acidified with 2N HCl, extracted with ethyl acetate, washed with water, dried and evaporated. Recrystallization from ethyl acetate yielded 1.56 g of (E)-4-[2-(7,7-dimethyl-3-octyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)vinyl]benzoic acid as pale yellow crystals of melting point 179.5-180.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([N:14]2[CH2:18][CH:17]([S:19][CH:20]([CH:36]([CH:38]3[CH:41]([CH:42]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH3:43])[C:40](=[O:52])[NH:39]3)[CH3:37])C(=O)C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:16][CH:15]2[C:53]([N:55]([CH3:57])[CH3:56])=[O:54])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:58]([O:61][CH2:62][CH3:63])(=[O:60])[CH3:59]>ClCCl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:63]([CH2:62][O:61][C:58]([C:59]2[N:39]3[CH:38]([CH:36]([CH3:37])[C:20]=2[S:19][CH:17]2[CH2:16][CH:15]([C:53]([N:55]([CH3:57])[CH3:56])=[O:54])[N:14]([C:12]([O:11][CH2:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=4)=[O:13])[CH2:18]2)[CH:41]([CH:42]([O:44][Si:45]([C:48]([CH3:49])([CH3:51])[CH3:50])([CH3:46])[CH3:47])[CH3:43])[C:40]3=[O:52])=[O:60])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(C)=O
Reactant: CC(O[Si](C)(C)C(C)(C)C)C1C(=O)NC1C(C)C(SC1CC(C(=O)N(C)C)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CC(C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C(C)C12

Procedure:
Titanium tetrachloride (3.12 ml of a 1.0M solution in dichloromethane) is added to 1.5 ml of dry tetrahydrofuran under argon at .room temperature. To this mixture is added [2S-[2Alpha,4alpha[R*(or S*)-[1S*,1[2R*,3R*, -3(S*)]]]]]-2-[(dimethylamino)carbonyl]-4-[[1-[1-[3-[1-[[(1,1-di-methylethyl)dimethylsilyl]oxy]ethyl]-4-oxo-2-azetidinyl]ethyl]-3-[(4-nitrophenyl)methoxy]-2,3-dioxopropyl]thio]-1-pyrrolidinecarboxylic acid (4-nitrophenyl)methyl ester (0.392 g) in 2.5 ml of tetrahydrofuran. After 30 minutes the reaction mixture is treated with ice-cold saturated sodium bicarbonate solution and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic layer is washed with three portions of brine, dried over anhydrous sodium sulfate and by anhydrous magnesium sulfate. Filtration and concentration affords the crude carbapenem which is purified via silica gel chromatography (80% ethyl acetate hexanes). The title compound is obtained as a pale yellow oil (0.295 g) 77%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:9][CH:8]=2)=[N:3][CH:2]=1.NN>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=2)=[N:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1ccc(-c2ccncn2)cc1
Agent: NN
Solvent: CCO
Product: NCCCCOc1ccc(-c2ccncn2)cc1

Procedure:
A suspension of 4.6 g of 2-[4-[4-(pyrimidin-4-yl)phenoxy]butyl]-1H-isoindole-1,3(2H)-dione (Example 45) in 200 ml of boiling ethanol is treated with 0.8 ml of anhydrous hydrazine, and the mixture then refluxed for 9 hours. The hot suspension is filtered. The precipitate is washed with 125 ml of 1.5N HCl. The combined HCl and ethanolic filtrates are taken to dryness in vacuo to obtain the hydrochloride salt of the title compound. Mass spectrometry shows the residue to be the tide compound and the salt is utilized for synthesis without further purification, m.p. 208°-210° C. (dec.).
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][NH:4]1)[CH3:2].[CH3:12][N:13]=[C:14]=[S:15]>C(#N)C.C(O)C>[CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][N:4]1[C:14](=[S:15])[NH:13][CH3:12])[CH3:2]
Reactant: CN=C=S
Reactant: CCC1NCCc2[nH]cnc21
Solvent: CCO
Solvent: CC#N
Product: CCC1c2nc[nH]c2CCN1C(=S)NC
Yield: 69.7 %

Procedure:
A solution of 2.9 g of 4-ethyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (Farmaco, Ed. Sci. 1967, 22, 821) and 3 g of methyl isothiocyanate in 32 ml of acetonitrile and 8 ml of ethanol is refluxed for 8 h. The solution is evaporated in vacuo, and the residue crystallized from diethyl ether to give 3 g of 4-ethyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 230°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.CC1C=C(C)N2N=C(C=O)N=C2N=1.[CH:26]1([C:31]2([CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=3[O:49][CH3:50])[O:36][C:35](=[O:37])[CH:34]=[C:33]([OH:38])[CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:34]3[C:35](=[O:37])[O:36][C:31]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)([CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=4[O:49][CH3:50])[CH2:32][C:33]=3[OH:38])[N:10]=2)[CH:7]=1
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)c(OC)c1
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(Cl)cn4n3)C(=O)O2)c(OC)c1

Procedure:
The title compound was prepared analogously to Example B(97), where 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-Cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]6-cyclopentyl-dihydro-pyran-2,4-dione of that example. 1H NMR (400 MHz, DMSO-d6): δ 1.51-1.73 (m, 9H), 1.92-1.98 (m, 2H), 2.38-2.58 (m, 3H), 2.79 (d, J=16 Hz, 1H), 3.71 (s, 2H), 3.73 (s, 6H), 6.40-6.5 (m, 2H), 7.03 (d, J=8 Hz, 1H), 8.89 (d, J=2.6 Hz, 1H), 9.52 (d, J=2.6 Hz, 1H), 10.9 (s, 1H). Anal. Calcd. For C26H29ClN4O5.0.25H2O: C, 60.35; H, 5.75; N, 10.83. Found: C, 60.40; H, 5.65; N, 10.74. MS (ESI): 513 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:11]([N:18]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)[S:19]([C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCN(C)C1=O>[CH2:11]([N:18]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)[S:19]([C:22]1[CH:27]=[CH:26][C:25]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(F)cc2)cc1OC
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(N3CCC4(CC3)OCCO4)cc2)cc1OC
Temperature: 70 °C
Reaction time: 48 h

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (0.14 ml, 0.95 mM) was added to a solution of N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-fluoro-benzenesulfonamide(0.19 g, 0.47 mM) and potassium carbonate (0.66 g, 4.82 mM)in anhyrous 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidinone(5 ml). The reaction was stirred at 70° C. for two days. The reaction was quenched with water(50 ml). The precipitate was washed with water and dried under reduced pressure to afford 0.15 g of the desired product as a tan solid. H1 NMR(CDCl3) δ 1.81 (t, 4H, J=5.67 Hz), 3.50(t, 4H, J=5.97 Hz), 3.65(s, 3H), 3.81 (s, 3H), 4.01 (s, 4H), 4.66(s, 2H), 6.43(d, 1H, J=2.34 Hz), 6.53(m, 1H), 6.66(d, 1H, J=8.58 Hz), 6.90 (d, 1H, J=9.03 Hz), 7.19(m, 6H), 7.53(d, 2H, J=9.00 Hz). MS(ES) m/z 525.0; (MH+); HRMS for C28H32SN2O6: 525.2049.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C([O:13][C:14](=[O:35])[C:15]([S:18][C:19]1[S:20][CH:21]=[C:22]([CH2:24][CH2:25][NH:26][C:27]2[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=2)[N:23]=1)([CH3:17])[CH3:16])(C)(C)C.CC(C)CCCCO.[BrH:44].C(O)(=O)C>C(OCC)C>[BrH:44].[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:26]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:25][CH2:24][C:22]2[N:23]=[C:19]([S:18][C:15]([CH3:16])([CH3:17])[C:14]([OH:35])=[O:13])[S:20][CH:21]=2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: CC(C)CCCCI
Agent: Br
Agent: CC(C)CCCCO
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCc1cnc(N(CCCCC(C)C)CCc2csc(SC(C)(C)C(=O)O)n2)nc1

Procedure:
A compound obtained using 1-iodo-5-methylhexane, which is synthesized using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 5-methylhexanol as starting materials and in reference to non-patent reference [Tetrahedron, 38, 11461 (1998)], and by an operation similar to that of Example 326, was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]#[N:13])=[N:7]1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([N:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[CH:3]=2)[N:7]=[C:8]([C:12]#[N:13])[N:9]=1
Reactant: Cc1nc(C#N)nn1Cc1cccc(Br)c1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc(C#N)nn1Cc1cccc(N2CCN(C)CC2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carbonitrile (198 mg, 0.71 mmol), 1-methylpiperazine (159 μL, 1.4 mmol), Cs2CO3 (466 mg, 1.4 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (34 mg, 0.07 mmol) and tris(dibenzylideneacetone)dipalladium(0) (65.4 mg, 0.07 mmol) in toluene (3.5 mL) was degassed (freeze-pump-thaw, under N2). The reaction mixture was stirred at 100° C. overnight before being quenched with H2O (5 mL), taken up in EtOAc (15 mL), washed with H2O (3×10 mL), brine (2×10 mL), dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified on a Biotage pre-packed silica gel column with a gradient of 0% to 10% MeOH:DCM to afford 5-methyl-1-(3-(4-methylpiperazin-1-yl)benzyl)-1H-1,2,4-triazole-3-carbonitrile (120 mg, 57%) as a white solid. MS (ES+) C16H20N6 requires: 296 found: 297 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]1[CH2:14][O:13][S:10](=[O:12])(=[O:11])[CH2:9][CH2:8]1>C(O)(C)C>[N:1]1([CH2:14][CH2:7][CH2:8][CH2:9][S:10]([OH:13])(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=S1(=O)CCCCO1
Reactant: C1COCCN1
Solvent: CC(C)O
Product: O=S(=O)(O)CCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 18 %

Procedure:
Morpholine (3.56 g) was dissolved in isopropanol (25 ml) and treated with 1,4-butane sultone (5.58 g) at 10° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 days. The white precipitate that had formed was filtered and dried to give the title compound (1.64 g).
Reaction SMILES: C([C:5]1[C:6]([NH2:43])=[C:7]([CH:11]=[CH:12][C:13]=1[C@H:14]([NH:17][C:18]([N:20]1[C:26](=[O:27])[C@@H:25]([CH2:28][C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=2[O:36][CH3:37])[CH2:24][NH:23][C:22](=[N:38][NH:39][C:40](=O)[CH3:41])[CH2:21]1)=[O:19])[CH2:15][CH3:16])[C:8]([OH:10])=[O:9])(C)(C)C>O1CCOCC1>[NH2:43][C:6]1[CH:5]=[C:13]([C@H:14]([NH:17][C:18]([N:20]2[C:26](=[O:27])[C@@H:25]([CH2:28][C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[O:36][CH3:37])[CH2:24][N:23]3[C:40]([CH3:41])=[N:39][N:38]=[C:22]3[CH2:21]2)=[O:19])[CH2:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][C:7]([CH3:11])([CH3:8])[CH3:6])=[O:9]
Reactant: CC[C@@H](NC(=O)N1CC(=NNC(C)=O)NC[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1C(C)(C)C
Solvent: C1COCCO1
Product: CC[C@@H](NC(=O)N1Cc2nnc(C)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c(N)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
The compound 87a obtained at Step (1) (58.2 mg) was dissolved in 1,4-dioxane (1.5 ml), and the mixture was stirred at 100° C. for 30 minutes. The reaction solution was concentrated, then the residue was purified by flash column chromatography (silica gel, chloroform/ethyl acetate/methanol=7/7/2) to obtain tert-butyl 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3-methyl-7-oxo-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepin-8(9H)-yl]carbonyl}amino)propyl]benzoate (compound 87b) (33.4 mg).
Reaction SMILES: ClC1C=CC=C2C=1NC([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=C2.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]2[C:29]=1[NH:28][CH:27]=[CH:26]2>>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]2[C:29]=1[NH:28][C:27]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:26]2
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: COc1ccc(Br)c2[nH]ccc12
Product: COc1ccc(Br)c2[nH]c(B3OC(C)(C)C(C)(C)O3)cc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-bromo-4-methoxy-1H-indole.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.Cl[CH2:22][CH2:23][N:24]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:32]([N:24]([CH2:23][CH2:22][CH:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N#CCc1ccccc1
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC(CCN(Cc1ccccc1)Cc1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 90.7 %

Procedure:
Benzyl cyanide (0.97 mL, 8.4 mmole) was reacted with lithium bis(trimethylsilyl)amide (LHMDSA) (8.4 mL, 8.4 mmole) in 5 mL of THF at -78° C. for 1 hour. After an additional aliquot of LHMDSA (4.2 mL, 4.2 mmole) was added, N-(2-chloroethyl)dibenzylamine hydrochloride (1.0 g, 3.4 mmole) was then added. The reaction was allowed to stand at room temperature and was then warmed to 50° C. for 3.5 hours. The mixture was poured into ice/water, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford alpha-(N,N-dibenzylaminoethyl) benzyl cyanide (1.05 g), isolated in 94% yield (MS: (M+H)+ =341).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Br:34][C:35]1[S:36][C:37]([NH:43]C(OC(C)(C)C)=O)=[C:38]([C:40]([OH:42])=O)[N:39]=1.[NH2:51][C:52]1[CH:53]=[N:54][N:55]([CH3:73])[C:56]=1[N:57]1[CH2:63][CH2:62][CH:61]([F:64])[CH:60]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH2:59][CH2:58]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:43][C:37]1[S:36][C:35]([Br:34])=[N:39][C:38]=1[C:40]([NH:51][C:52]1[CH:53]=[N:54][N:55]([CH3:73])[C:56]=1[N:57]1[CH2:63][CH2:62][CH:61]([F:64])[CH:60]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:69])([CH3:70])[CH3:71])[CH2:59][CH2:58]1)=[O:42]
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)c2nc(Br)sc2N)c1N1CCC(F)C(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 111.8 %

Procedure:
A solution of PyBOP (3.06 g, 5.03 mmol) and 2-bromo-5-(tert-butoxycarbonyl-amino)thiazole-4-carboxylic acid (1.63 g, 5.04 mmol) in DCM (50 mL) was stirred at room temperature for 15 min. tert-Butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-ylcarbamate (1.37 g, 4.20 mmol) and DIPEA (1.17 mL, 6.71 mmol) were added and the mixture stirred at room temperature for 2 days. The reaction mixture was diluted with DCM (50 mL) and washed with water (3×50 mL). The organic layers was passed through a phase separation cartridge and concentrated under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 1-(4-(5-amino-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-ylcarbamate as a pink solid (2.50 g, 94%). 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 8.27 (s, 1H), 7.64 (s, 1H), 5.01 (s, 1H), 4.86-4.60 (m, 1H), 3.81-3.64 (m, 3H), 3.44-3.27 (m, 2H), 3.15-3.07 (m, 2H), 2.28-2.10 (m, 3H), 1.92-1.70 (m, 2H), 1.52 (s, 9H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]=[CH2:11])[CH:3](O)[CH2:4][C:5](O)=O.C([O-])(=O)C.[K+].[H-].[Na+].COP([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(OC)=O>C(OC(=O)C)(=O)C.O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:9][CH:10]2[CH:4]([CH:3]=1)[C:5](=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11]2
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: C=CCC(C)C(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1=CC2C(=CC(=O)OC(C)(C)C)CC2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methyl-3-hydroxyhept-6-enoic acid (2.21 g, 13.9 mmol) was dissolved in acetic anhydride (14 mL). To the solution, potassium acetate (3.29 g, 33.4 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was heated to 110 to 120° C. and stirred for 3.5 hours. To the reaction solution, ice water and toluene were then added, and this mixture was stirred at room temperature for 1 hour. The mixture was separated into aqueous and organic layers by the addition of saturated saline and toluene. Then, the organic layer was washed with a 1 N aqueous sodium hydroxide solution and saturated saline in this order, then dried over anhydrous magnesium sulfate, and then filtered. The filtrate was added to a reaction solution prepared by adding sodium hydride (>63% oil, 533.3 mg, 14.0 mmol) to a solution of tert-butyl dimethoxyphosphorylacetate (3.24 g, 14.5 mmol) in tetrahydrofuran (20 mL) under ice cooling, and the mixture was further stirred for 1.5 hours. The reaction solution was separated into aqueous and organic layers by the addition of a saturated aqueous solution of ammonium chloride and saturated saline. The aqueous layer was subjected to extraction with ethyl acetate. The organic layers were combined, then washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil substance (1.21 g, 40%, E/Z mixture).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:4]([F:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[C:27]([O:29]C)=[O:28]>>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[S:10][C:11]4[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=4[N:13]=3)=[C:4]([F:19])[CH:3]=2)[CH:24]=[CH:25][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: Fc1ccc2nc(Nc3ccc(Br)cc3F)sc2c1
Product: O=C(O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1F

Procedure:
As shown in Reaction Scheme 8, Intermediate VI-8 (3,3′-difluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-carboxylic acid) was prepared using a method similar to that employed in the preparation of Intermediate VI-1 using N-(4-bromo-2-fluorophenyl)-6-fluoro-1,3-benzothiazol-2-amine and commercially available [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid as starting materials.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.Cl[CH2:20][CH2:21][CH2:22]Cl>>[Cl:18][C:7]1[CH:6]=[CH:5][C:4]2[N:3]3[CH2:20][CH2:21][CH2:22][N:1]=[C:2]3[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([OH:11])[C:9]=2[CH:8]=1
Reactant: ClCCCCl
Reactant: NC1=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Product: OC1(c2ccccc2)C2=NCCCN2c2ccc(Cl)cc21

Procedure:
Reaction of 2-amino-5-chloro-3-phenyl-3H-indol-3-ol (2.58 g) with 1,3-dichloropropane (1.1 g) according to the procedure of Example 1 step (c) gives the title compound as its hydrochloride salt, m.p. 279°-282°C (decomp).