Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[Br:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:17][CH2:16][CH2:15][Br:14])[CH:6]=1)=[O:4]
Reactant: BrCCCBr
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(CCCBr)c2ccccc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
In a flask was dissolved indole-3-carboxylic acid methyl ester (2.0 g, 11.4 mmole) and 1,3-dibromopropane (11.5 g, 57 mmol) in 15 mL of DMF. To this solution was added cesium carbonate (5.5 g, 17 mmol). The flask was sealed and the content was stirred at 40° C. overnight. The solution was then partitioned between ether and water. The ethereal phase was washed twice with water and once with brine and was finally evaporated. The residue was purified on silica (heptane-ethyl acetate 4:1), to give 2.2 g (75%) of the sub-title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=4)[NH:12][N:11]=3)[CH:8]=[CH:9][C:2]1=2.[OH:21]O.[OH-].[Na+].Cl>O.C(O)C>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH2:20])=[O:21])[CH:17]=4)[NH:12][N:11]=3)[CH:8]=[CH:9][C:2]1=2
Reactant: OO
Reactant: N#Cc1ccc2[nH]nc(-c3ccc4c(c3)CCO4)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc2[nH]nc(-c3ccc4c(c3)CCO4)c2c1
Temperature: 45 °C
Yield: 53 %

Procedure:
A mixture of 3-(2,3-dihydrobenzo[b]furan-5-yl)-1H-indazole-5-carbonitrile (0.50 g, 1.9 mmol), 95% ethanol (6 mL), aqueous 30% hydrogen peroxide (3 mL), and 6.0 N aqueous sodium hydroxide (1 mL) was heated at 45° C. for 3 h. The reaction mixture was diluted with water (40 mL) and acidified to pH 6 with 3 N hydrochloric acid. The solid was filtered and dried in a vacuum oven to give product (0.080 g, 53% yield): 1H NMR (DMSO-d6) δ 13.22 (s, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 7.90 (d, 2H), 7.76 (d, 1H), 7.55 (d, 1H), 7.32 (s, 1H), 6.91 (d, 1H), 4.59 (t, 2H), 3.28 (t, 2H); ES-MS (m/z) 280 [M+1]+.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=2)[C:15]2[C:23]3[C:28]([CH2:29][C:14]1=2)=[CH:27][CH:26]=[CH:25][CH:24]=3.N1C2C(C=CC3C=2C=C2C=3C=CC=C2)=CC=1.[Cl:46][Si:47](Cl)([CH3:49])[CH3:48]>C1COCC1>[Cl:46][Si:47]([CH3:49])([CH3:48])[CH:29]1[C:14]2[N:13]([CH3:12])[C:21]3[C:16]([C:15]=2[C:23]2[C:28]1=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=3
Reactant: C[Si](C)(Cl)Cl
Reactant: Cc1ccc2c(c1)c1c(n2C)Cc2ccccc2-1
Agent: C1=Nc2c3c(ccc2=C1)=c1ccccc1=C3
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc2c(c1)c1c(n2C)C([Si](C)(C)Cl)c2ccccc2-1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
9.5 mL of a 2.5 M solution of n-BuLi in hexane (23.75 mmol) were added dropwise to a solution of 5.1 g of N-methyl-2-methyl-5,6-dihydroindeno[2,1-b]indole, obtained as reported above, (purity 98.2%, Mw=233.32, 21.46 mmol; indenoindole: n-BuLi=1:1.1) in 70 mL of THF, previously cooled to −78° C. At the end of the addition, the brown solution was allowed to warm up to room temperature and stirred for 6 hours. Then it was cooled again to −78° C. and added dropwise to a solution of dichlorodimethylsilane (Mw=129.06, d=1.064, 2.6 mL, 21.43 mmol; indenoindole: Me2SiCl2=1:1) in 20 mL of THF, previously cooled to −78° C. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred overnight. The solvents were evaporated under reduced pressure to give a brown sticky solid, which at the 1H-NMR analysis resulted to be the target product, with few by-products. The product was used in the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:64]([SH:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=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].O1CCOCC1>[CH2:64]([S:71][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Br:1])=[CH:3][N:4]=[CH:5]2)=[CH:10][CH:9]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: SCc1ccccc1
Reactant: Brc1ccc2c(Br)cncc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cncc2cc(SCc3ccccc3)ccc12
Temperature: 60 °C

Procedure:
To a vial charged with 4,7-dibromoisoquinoline (Pharmabridge, Inc., Doylestown, Pa.) (0.783 g, 2.73 mmol) was added dioxane (10.91 ml), DIEA (0.953 ml, 5.46 mmol), Xantphos (0.316 g, 0.546 mmol), Pd2(dba)3 (0.250 g, 0.273 mmol) and benzyl mercaptan (0.323 ml, 2.73 mmol). The vessel was sealed and heated to 60° C. for 4 hrs affording conversion to desired product as the primary species. The mixture was dried under reduced pressure and the crude material purified with a 40 HP silicycle column (SiliCycle, Inc. Quebec City, Canada) ramping EtOAc in heptane (0 to 25%, then isocratic at 25%, with 10% DCM isocratic throughout) providing product 7-(benzylthio)-4-bromoisoquinoline (0.573 g, 1.735 mmol, 63.6% yield), obtained as an orange solid. m/z (ESI) 330.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][CH3:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:33]([C:30]2[CH:29]=[CH:28][C:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)=[CH:32][CH:31]=2)[CH3:34])=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=2)[CH:5]=1
Reactant: CNc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COC(=O)c1ccc(-c2cc(Cl)ccc2CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(Cl)ccc2CN(C)c2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 50 °C

Procedure:
Methyl 5-(2-(bromomethyl)-5-chlorophenyl)picolinate (200 mg, 0.59 mmol), 4′-chloro-N-methyl-[1,1′-biphenyl]-4-amine (141 mg, 0.65 mmol), and K2CO3 (122 mg, 0.88 mmol) were diluted with acetone (3 mL) and heated to 50° C. After 18 h the resulting mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](O)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:32]4[N:31]([CH3:30])[CH:35]=[CH:34][CH:33]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cccc1C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cccn2C)c1

Procedure:
Prepared as described in Example 105 using (1R,28)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 39 mg, 100 mmol) and 1-methyl-2-pyrrolecarboxylic acid (25 mg, 200 μmol). Yield 35 mg (70%).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OC([N:21]1[CH:25]=[C:24]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([C:36]3[CH2:40][C:39]([C:45]4[CH:50]=[C:49]([Cl:51])[CH:48]=[C:47]([Cl:52])[CH:46]=4)([C:41]([F:44])([F:43])[F:42])[O:38][N:37]=3)=[CH:28][CH:27]=2)[CH:23]=[N:22]1)=O)(C)(C)C.[OH-].[Na+]>ClCCl>[Cl:51][C:49]1[CH:50]=[C:45]([C:39]2([C:41]([F:43])([F:42])[F:44])[O:38][N:37]=[C:36]([C:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]([C:24]4[CH:23]=[N:22][NH:21][CH:25]=4)=[CH:27][CH:28]=3)[CH2:40]2)[CH:46]=[C:47]([Cl:52])[CH:48]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3ccccc23)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(-c3cn[nH]c3)c3ccccc23)=NO1

Procedure:
Trifluoroacetic acid anhydride (0.18 ml) is added to a solution of 4-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalen-1-yl}-pyrazole-1-carboxylic acid tert-butyl ester (135 mg) in dichloromethane (1 ml). After 1 hour at room temperature an aqueous solution of sodium hydroxide (30%) is added. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-(3,5-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-naphthalen-1-yl]-5-trifluoromethyl-4,5-dihydro-isoxazole as a colorless solid: m.p. 117-120° C. (compound 1.17, table 1).
Reaction SMILES: [NH:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:15][N:16]=[C:17]=[S:18]>C(O)C>[NH:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:17]([NH:16][CH3:15])=[S:18])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CN=C=S
Reactant: N=C(N)Nc1nc(CCCCN)c[nH]1
Solvent: CCO
Product: CNC(=S)NCCCCc1c[nH]c(NC(=N)N)n1
Reaction time: 8 h

Procedure:
A mixture of 2-guanidino-4-(4-aminobutyl)imidazole (0.15 g.) and methylisothiocyanate (0.1 g.) in ethanol (10 ml.) was stirred overnight and then evaporated to dryness. The residue was purified by chromatography on a silica gel column using chloroform/methanol/ammonia (s.g. 0.880) 80:20:0.3 v/v/v. The appropriate fractions on evaporation gave a gum which crystallized on triturating in petroleum ether (b.p. 40°-60° C.) to give 2-guanidino-4-[4-(3-methylthioureido)butyl]imidazole, m.p. 179°-184° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:18]([F:21])=[CH:19][CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32].Cl>O1CCCC1.N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[C:15]2[C:7]([C:5]([C:4]3[C:3]([F:22])=[C:2]([NH:1][S:31]([C:25]4[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=4[F:23])(=[O:33])=[O:32])[CH:20]=[CH:19][C:18]=3[F:21])=[O:6])=[CH:8][NH:9][C:10]2=[N:11][CH:12]=1)#[N:17]
Reactant: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.1 %

Procedure:
To 3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (28, 100 mg, 0.335 mmol) in 2.7 mL of tetrahydrofuran, 0.24 mL of pyridine was added. 2,5-Difluoro-benzenesulfonyl chloride (29, 107 mg, 0.503 mmol) was added and the solution was stirred at room temperature for 48 hours. The reaction mixture was poured into 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound (P-0004, 105 mg). MS(ESI)[M+H+]+=475.0.
Reaction SMILES: CC1[CH:15]=[C:14]2[C:5]([S:6](=[O:23])(=[O:22])[C:7]3[CH:8]=[C:9]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:29]([OH:32])(=[O:31])[CH3:30]>O.[O-2].[O-2].[O-2].[Cr+6]>[C:29]([C:30]1[CH:3]=[CH:4][C:5]2[S:6](=[O:23])(=[O:22])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:8]=3)[C:13](=[O:16])[C:14]=2[CH:15]=1)([OH:32])=[O:31]
Reactant: Cc1ccc2c(c1)C(=O)c1ccc(-c3nnn[nH]3)cc1S2(=O)=O
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(=O)c1ccc(-c3nnn[nH]3)cc1S2(=O)=O
Reaction time: 16 h

Procedure:
7-Methyl-3-(5-tetrazolyl)thioxanthone-10,10-dioxide (0.78g) was suspended in acetic acid (50 ml) and chromium trioxide (0.98g) in water (2.0 ml) added dropwise, followed by concentrated sulphuric acid (0.5 ml) added dropwise. The mixture was heated on the steam bath for 1 hr., then boiled under reflux for 4 hr. Further chromium trioxide (0.98 g) was added and the mixture boiled for a further 16 hr. The green solution was diluted with water, and the precipitated solid filtered off and washed with water. The solid was boiled with acetic acid (200 ml), filtering at the boil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][OH:12].[H-].[Na+].O>O1CCCC1>[CH3:11][O:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a stirred solution of 10 g of 2-chloro-5-nitropyridine and 2 g of dry methanol in 40 ml of dry tetrahydrofuran, 2.8 g of sodium hydride (about 60%, in oil) is added under cooling in an ice-water bath. The mixture is stirred at room temperature for 1 hour, and 30 ml of water is added. The mixture is extracted with three 40-ml portions of ethyl acetate, and the combined extracts are dried over magnesium sulfate. The solvent is distilled off to give 8.0 g of crude 2-methoxy-5-nitropyridine.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([NH:10][C:11]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][N:14]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].IC.[NH4+].[Cl-]>C1COCC1>[C:6]([NH:10][C:11]([C:13]1[C:18]([CH3:1])=[C:17]([Cl:19])[CH:16]=[CH:15][N:14]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)NC(=O)c1cc(Cl)ccn1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(Cl)ccnc1C(=O)NC(C)(C)C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 29 mL, 72 mmol) is added dropwise to N-tert-butyl-4-chloropyridine-2-carboxamide (7.00 g, 32.9 mmol) in THF (70 mL) at −78° C. After 1 h at −78° C. iodomethane (6.8 mL, 109 mmol) is added and stirring is continued for 1 h. Saturated NH4Cl (10 mL) is added and the organic layer is separated, dried and evaporated under reduce pressure to give a residue that is purified by flash chromatography (eluent 0-20% EtOAc/cyclohexane) to furnish N-tert-butyl-4-chloro-3-methyl-pyridine-2-carboxamide (5.7 g, 76%).
Reaction SMILES: [NH2:1][CH:2]=[CH:3][CH3:4].[C:5]1([CH2:11][CH:12]2[O:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH2:2]([NH:1][CH2:13][CH:12]([OH:14])[CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=[CH2:4]
Reactant: c1ccc(CC2CO2)cc1
Reactant: CC=CN
Solvent: CO
Product: C=CCNCC(O)Cc1ccccc1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
A solution of 1-aminopropylene (10.6 grams, 0.186 mol) in methanol was added to a methanolic solution of 3-phenylpropyleneoxide (5.07 grams, 0.037 mol) and the mixture heated to reflux for 30 minutes. The mixture was allowed to warm to room temperature and concentrated in vacuo to yield 7.2 grams (99%) of N-allyl-3-phenyl-2-hydroxypropylamine. 1H NMR (CDCl3, dTMS) 7.24-7.18 (5H, m, Ar-H), 5.84 (1H, ddt, 3JHH =17.1 Hz, 3JHH =10.2 Hz, 3JHH =6 Hz, CH2CH), 5.2-5.0 (2H, m, CH=CH2), 3.86 (1H, m, CHOH), 3.19 (2H, m, NCH2CH=CH2), 2.76-2.66 (3H, m, NCH2CH(OH)CHHPh), 2.50 (1H, dd, 2JHH =12 Hz, 3JHH =9 Hz). 13C NMR (CDCl3) 138.4, 136.5, 129.3, 128.4, 126.3, 116.0, 70.6, 54.0, 51.9, 41.7.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH:20][C:21](=[O:23])[CH3:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2c1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1ncc2[nH]c3ccc(NC(C)=O)cc3c2c1C
Temperature: 0 °C

Procedure:
0.6 g of 6-amino-4-methyl-β-carbolin-3-carboxylic acid ethyl ester is dissolved in 6 ml of pyridine and 1.5 ml of acetic anhydride and the whole is stirred for 16 hours at room temperature. The mixture is then stirred into 30 ml of ice water and intensely extracted with ethyl acetate. The extracts are washed until neutral with semisaturated common salt solution, dried using sodium sulphate and filtered. The solvent is distilled off in vacuo. The residue (0.78 g) is recrystallized from acetone-diisopropyl ether. 0.49 g of 6-acetamido-4-methyl-β-carbolin-3-carboxylic acid ethyl ester of melting point 273°-278° C. is obtained.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:23]([NH2:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24].[CH3:33][O:34][CH2:35][O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[CH3:46])[C:40](O)=[O:41]>CN(C=O)C>[CH3:33][O:34][CH2:35][O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[CH3:46])[C:40]([NH:32][C:23]([CH3:25])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24])=[O:41]
Reactant: COCOc1cc(C(=O)O)ccc1C
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C
Yield: 79.6 %

Procedure:
In a similar manner to Step 1 of Example 137, 3-methoxymethoxy-4-methylbenzoic acid (2.69 g) was dissolved in DMF (53 mL), and the solution was treated with EDCI (5.04 g, 26.3 mmol), HOBT monohydrate (2.01 g, 13.1 mmol) and cumylamine (3.80 mL, 26.4 mmol), followed by purification by slurry using hexane to obtain 3-methoxymethoxy-4-methyl-N-(1-methyl-1-phenylethyl)benzamide (3.42 g, yield 83%, 2 steps).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:31])[CH:25]=2)=[CH:20][CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:72]1([NH2:79])[C:73]([NH2:78])=[CH:74][CH:75]=[CH:76][CH:77]=1>CN(C)C=O>[NH2:78][C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][C:72]=1[NH:79][C:14](=[O:15])[CH:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:28](=[O:29])(=[O:30])[NH:27][C:26](=[O:31])[CH:25]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC(Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of (2S)-2-((2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoylamino)-3-[4-(1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]-propanoic acid (15.0 mg, 0.0276 mmol) in N,N-dimethylformamide (3 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (10.5 mg, 0.027 mmol) and N,N-diisopropylethylamine (24 μL, 0.14 mmol) and premixed for 5 minutes. To the solution was added 1,2-benzenediamine (4.2 mg, 0.04 mmol) and stirred at room temperature overnight. Preformed ester was yellow in color and upon addition of the diamine continued to darken over several minutes. Product was purified by preparative LCMS to afford the desired product (7.3 mg, 42%). LCMS found for C32H36N5O7S (M+H)+: m/z=634.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17](=O)[CH2:18]Br>CN1C(=O)CCC1.C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]([C:17]2[N:10]=[C:8]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[O:9][CH:18]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2nc(-c3cccc(Cl)c3)co2)cc1
Temperature: 135 °C
Reaction time: 2.5 h
Yield: 43.4 %

Procedure:
under an N2 atmosphere, 4-nitrobenzamide (5.3 g, 32 mmol) and 3-chlorophenacyl bromide (4.9 g, 21 mmol) were combined in NMP (3.0 mL) and heated to 135° C. After 2.5 hours at 135° C., the reaction was diluted with 20 mL of toluene and allowed to cool to room temperature. The solid was removed by filtration and the filtrate was concentrated in vacuo. The resulting solid from concentration of the filtrate was triturated with ethyl acetate. The solid was collected by filtration and afforded 4-(3-chlorophenyl)-2-(4-nitrophenyl)oxazole (2.74 g, 43% yield). ESI m/z=301.0 (M+H+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:26]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:39][NH2:40].O>ClCCl>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:39][NH2:40])=[O:22])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:26]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)O)c1)C2=O
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic acid (1.36 g, 3.68 mmol) obtained in Step 1 was dissolved in dichloromethane (18 mL), and the mixture was stirred at room temperature for 1 hour after adding 1,1′-carbonyldiimidazole (657 mg, 4.05 mmol). Thereafter, hydrazine.monohydrate (0.53 mL, 11.0 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. Then, water was added to the mixture, stirred, and the precipitated solid was filtered off. After concentrating the filtrate under reduced pressure, the residue was recrystallized from dichloromethane and water to give (S)-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (1.21 g, 86%).