Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29](F)=[CH:28][CH:27]=1>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:22]2[CH2:23][CH2:24][N:19]([C:12]3[N:11]=[C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=3)[CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COc1cccc(Nc2cc(N(C)C)nc(N3CCNCC3)n2)c1
Solvent: ClCCl
Product: COc1cccc(Nc2cc(N(C)C)nc(N3CCN(c4ccc(Br)cc4)CC3)n2)c1
Temperature: 100 °C
Yield: 41.4 %

Procedure:
A mixture of N4-(3-methoxyphenyl)-N6,N6-dimethyl-2-(1-piperazinyl)-4,6-pyrimidinediamine (36 mg, 0.1 mmol), 1-bromo-4-fluorobenzene (20 mg, 0.13 mmol) was heated at 100° C. for 1 h. The crude product was dissolved in CH2Cl2 (0.5 mL) and purified by preparative TLC using 5% methanol in EtOAc, giving the desired product (20 mg, 40%).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([C:17]([C:19]3[C:20]([C:40]([F:43])([F:42])[F:41])=[CH:21][C:22]4[O:27][C:26]([CH3:29])([CH3:28])[C:25](=[O:30])[N:24]([CH2:31][CH2:32][NH:33][C:34](=[O:38])[CH:35]([F:37])[F:36])[C:23]=4[CH:39]=3)=[O:18])[CH:14]([CH3:16])[CH3:15])[CH2:9][N:8]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:3][CH2:2]1.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58][C:59](O)=[O:60])=[CH:54][CH:53]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58][C:59]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][CH2:6][C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([C:17]([C:19]3[C:20]([C:40]([F:41])([F:42])[F:43])=[CH:21][C:22]4[O:27][C:26]([CH3:28])([CH3:29])[C:25](=[O:30])[N:24]([CH2:31][CH2:32][NH:33][C:34](=[O:38])[CH:35]([F:37])[F:36])[C:23]=4[CH:39]=3)=[O:18])[CH:14]([CH3:16])[CH3:15])[CH2:9][N:8]2[C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])=[O:60])=[CH:54][CH:53]=1
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)C(F)F)[C@@H]1CC[C@H](CCNC2CC2)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)C(F)F)[C@@H]1CC[C@H](CCN(C(=O)Cc2ccc(Cl)cc2)C2CC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of tert-butyl (2R,5R)-2-[2-(cyclopropylamino)ethyl]-5-[{[4-{2-[(difluoroacetyl)-amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(isopropyl)amino]piperidine-1-carboxylate (86 mg) in N,N-dimethylformamide (1 ml) were added 4-chlorophenylacetic acid (22 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34 mg), 1-hydroxybenzotriazole monohydrate (24 mg) and triethylamine (50 μl), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution. Then, the mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/acetone=2/1) to give the title compound (90 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[CH2:10][N:11]2[C:15]3[C:16](=[O:34])[N:17]([CH3:33])[C:18]([CH:27]([OH:32])[C:28]([O:30]C)=[O:29])=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[C:14]=3[CH:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.[Li+].[OH-]>C(OC(C)(C)C)(=O)C.O1CCCC1>[C:14]([O:32][CH:27]([C:18]1[N:17]([CH3:33])[C:16](=[O:34])[C:15]2[N:11]([CH2:10][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:35])[CH:12]=[CH:13][C:14]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[C:28]([OH:30])=[O:29])([CH3:19])([CH3:15])[CH3:13]
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2ccn(CC(=O)Nc3ccc(F)cc3)c2c(=O)n1C
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3CC(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An ice cold mixture of methyl 2-(1-(2-((4-fluorophenyl)amino)-2-oxoethyl)-6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetate (20.5 mg, 0.043 mmol) in t-Butyl acetate (5.0 mL) was treated with perchloric acid (0.2 mL, 0.102 mmol) and then stirred at ambient temperature for 2 hours. The mixture was quenched with 3M NaOH and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate filtered and concentrated. The residue was dissolved in Methanol (1.000 mL) and Tetrahydrofuran (THF) (1.000 mL), treated with 1N LiOH (0.4 mL, 0.400 mmol) and then heated to 70° C. for 80 minutes. The mixture was concentrated and then purified by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) to give the desired product as a light brown residue. 1H NMR (400 MHz, CHLOROFORM-d) ppm 10.54 (s, 1H), 7.62-7.44 (m, 3H), 7.36-7.14 (m, 4H), 7.07-6.91 (m, 2H), 6.09 (d, J=2.9 Hz, 1H), 5.50 (s, 1H), 5.22-5.16 (m, 1H), 5.15-5.08 (m, 1H), 3.76 (s, 3H), 2.44 (s, 3H), 1.00 (s, 9H); LC/MS (m/z) ES+=520 (M+1).
Reaction SMILES: [C:1]([O:5]/[N:6]=[C:7](\[C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1)/[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OO.S([O-])(O)(=O)=[O:29].[K+]>C(O)C>[C:1]([O:5]/[N:6]=[C:7](\[C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1)/[C:8]1[CH:13]=[C:12]([C:14](=[O:29])[NH2:15])[CH:11]=[CH:10][C:9]=1[OH:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O/N=C(/c1cc(C#N)ccc1O)c1ncccc1O
Reactant: O=S(=O)([O-])O
Agent: OO
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)O/N=C(/c1cc(C(N)=O)ccc1O)c1ncccc1O
Reaction time: 2 h

Procedure:
To a solution of (Z)-2-(5-cyano-2-hydroxybenzoyl)-3-hydroxypyridine O-t-butyloxime (0.98 g) in ethanol (20 ml) were added at 0° C. 6N NaOH (0.15 ml) and 30% aqueous solution of hydrogen peroxide (1.5 ml). The mixture was stirred for 2 hours at temperatures ranging from 50° to 60° C. The reaction mixture was cooled by aeration, which was then neutralized with a saturated aqueous solution of potassium hydrogensulfate, then the solvent was concentrated. The concentrate was subjected to extraction with chloroform and dried (anhydrous magnesium sulfate), followed by distilling off the solvent. The residue was recrystallized from chloroform to give (Z)-2-(5-carbamoyl-2-hydroxybenzoyl)-3-hydroxypyridine O-t-butyloxime (0.42 g) (Compound 71).
Reaction SMILES: C(OC(C1C=C2C(=CC=1)NC(=O)C2)=O)C(C)C.CN(C=C1C2C(=CC(CO[Si](C(C)(C)C)(C)C)=CC=2)NC1=O)C.[CH2:41]([O:45][C:46]([C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52](=[O:57])[C:51]2=[CH:58][N:59]([CH3:61])C)=[O:47])[CH:42]([CH3:44])[CH3:43].Cl.NC1[CH:69]=[CH:68][C:67]([S:70]([NH2:73])(=[O:72])=[O:71])=[CH:66][CH:65]=1>>[CH2:41]([O:45][C:46]([C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52](=[O:57])[C:51]2=[CH:58][NH:59][C:61]1[CH:69]=[CH:68][C:67]([S:70](=[O:72])(=[O:71])[NH2:73])=[CH:66][CH:65]=1)=[O:47])[CH:42]([CH3:43])[CH3:44]
Reactant: CC(C)COC(=O)c1ccc2c(c1)C(=CN(C)C)C(=O)N2
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CC(C)COC(=O)c1ccc2c(c1)CC(=O)N2
Agent: CN(C)C=C1C(=O)Nc2cc(CO[Si](C)(C)C(C)(C)C)ccc21
Agent: Cl
Product: CC(C)COC(=O)c1ccc2c(c1)C(=CNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 66 %

Procedure:
3-Methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid isobutyl ester was prepared in 59% yield from isobutyl 4-aminobenzoate according to Procedure D: 1H NMR (DMSO-d6): δ0.93 (d, J=6.6 Hz, 6H), 1.93 (s, 3H), 1.98 (septet, J=6.6 Hz, 1H), 4.02 (m, 2H), 4.62 (s, 1H), 6.92 (d, J=8.2 Hz, 1H), 7.79 (s, J=1H), 7.86 (d, J=8.2 Hz, 1H), 10.91 (s,1H); ESI−MS m/z 302 (M+23)−. Zinc reduction of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid isobutyl ester according to Procedure δ provided 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid isobutyl ester in 99% yield: 1H NMR (DMSO-d6): δ0.93 (d, J=6.6 Hz, 6H), 1.97 (septet, J=6.6 Hz, 1H), 3.53 (s, 2H), 3.99 (d, J=6.6 Hz, 2H), 6.88 (d, J=8.2 Hz, 1H), 7.75 (s, J=1H), 7.82 (d, J=8.2 Hz, 1H), 10.72 (s, 1H); ESI−MS m/z 256 (M+23)+. Conversion of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid isobutyl ester to 3-[(dimethylamino)methylene]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid isobutyl ester (mixture of E and Z isomers) was accomplished in 75% yield according to Procedure G: 1H NMR (DMSO-d6): δ0.94 Z (d, J=8.8 Hz, 6H), 0.94 E (d, J=8.8 Hz, 6H), 1.94-2.01 Z and E (m, 2H), 3.30 Z (s, 6H), 3.32 E (s, 6H), 3.97-3.99 Z and E (m, 4H), 6.75 Z (d, J=8.2 Hz, 1H), 6.83 E (d, J=8.2 Hz, 1H), 7.47 E (s, 1H), 7.53 Z (d, J=.8.2 Hz, 1H), 7.59 E (d, J=8.2 Hz 1H), 7.73 Z (s, 1H), 7.88 Z (s, 1H), 7.98 E (s, 1H), 10.34 Z (bs, 1H), 10.44 E (bs, 1H); ESI−MS m/z 289 (M+1)+. The title compound was prepared in 66% yield from 3-[(dimethylamino)methylene]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid isobutyl ester and 4-aminobenzenesulfonamide hydrochloride according to Procedure J: 1H NMR (DMSO-d6): δ0.96 (d, J=6.6 Hz, 6H), 2.01 (septet, J=6.6 Hz, 1H), 4.04 (d, J=6.6 Hz, 2H), 6.93 (d, J=8.2 Hz, 1H), 7.26 (s, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.71 (dd, J=1.6, 8.2 Hz, 1H), 7.76 (d, J=8.7 Hz, 2H), 8.27 (s, 1H), 8.86 (d, J=12.5 Hz, 1H), 10.83 (d, J=12.5 Hz, 1H), 10.95 (s, 1H); APCI−MS m/z 414 (M−H)−. Anal. Calcd for C20H21N3O5S: C, 57.82, H, 5.09; N, 10.11; S, 7.72. Found C, 57.91, H, 5.16; N, 10.02; S, 7.65.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([Li])CCC.CN(OC)[C:23](=[O:25])[CH3:24]>C1COCC1>[F:15][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[CH:3][C:2]=1[C:23](=[O:25])[CH3:24]
Reactant: CON(C)C(C)=O
Reactant: Fc1ccc(CN2CCOCC2)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cc(CN2CCOCC2)ccc1F
Temperature: -75 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A solution of 4-(3-bromo-4-fluorobenzyl)morpholine (35.5 g) of Preparation No. 53 in THF (400 mL) is cooled to −75° C., and n-butyllithium is added via addition funnel maintaining the temperature below −65° C. A solution of N-methyl-N-methoxyacetamide (16.0 g, prepared as described in Tetrahedron Lett. 1983, 24, 1857) in THF (50 mL) is added via addition funnel, again maintaining temperature below −65° C. The reaction is stirred at −75° C. for 1 hour and then is allowed to warm to room temperature overnight. The reaction mixture is quenched with 1 N HCl (150 mL) and diluted with ethyl acetate (400 mL). The layers are separated, and the aqueous layer is basified with sat. sodium bicarbonate solution. The aqueous layer is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with sat. sodium bicarbonate (2×100 mL) and brine (50 mL). The aqueous layers are back-extracted with ethyl acetate (100 mL). The combined organic layers are dried (Na2SO4) and concentrated in vacuo to a yellow oil. The oil is purified by fractional distillation at 135-140° C./0.3 torr to afford 19.7 g (64%) of the title compound as a clear, colorless oil.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([Cl:18])[CH:12]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[C:26]#[CH:27]>O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([N:5]1[C:9](=[O:10])[N:8]([CH2:27][C:26]#[CH:25])[C:7]([C:11]2[CH:12]=[C:13]([Cl:18])[N:14]=[C:15]([Cl:17])[CH:16]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(-c2cc(Cl)nc(Cl)c2)[nH]c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C#CCn1c(-c2cc(Cl)nc(Cl)c2)nn(C(C)(C)C)c1=O
Reaction time: 2.5 h

Procedure:
To 2.06 g (7.2 mmol) of crude 2-(t-butyl)-5-(2,6-dichloro-4-pyridyl)-1,2,4-triazolin-3-one were added 30 mL of ethyl acetate, 1 drop of water, and 1.00 g (7.30 mmol) of powdered K2CO3. The mixture was heated to reflux and after 15 min 1.10 g (7.4 mmol) of an 80% by weight solution of propargyl bromide in toluene was added. Refluxing was continued for 2.5 hours. The mixture was cooled, diluted with 175 mL of ethyl acetate, washed with 25 mL of water, and dried over MgSO4. Reomoval of the solvent left 2.18 g of crude product as a reddish solid. The crude product was combined with 0.69 g of material from another run and purified by flash chromatography first on a silica gel column and then on a neutral alumina column eluted portionwise in both cases with ether hexane mixtures containing successively greater percentages of ether to afford 0.97 g of 2-(t-butyl)-5-(2,6-dichloro-4-pyridyl)-4-propargyl-1,2,4-triazolin-3-one (Compound 1) as a white solid, m.p. 107°-109° C. 1H-NMR (CDCl3)∂1.6 (9H,s), 2.45 (1H,t), 4.6 (2H,d), 7.75 (2H,s).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CS(O[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)=O.C(O)CCCCCCCCC.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CCO>[CH2:17]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CCCCCCCCCCOS(C)(=O)=O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCCCCCCCCCO
Product: CCCCCCCCCCN1CCN(C(=O)OCC)CC1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
Ethyl 1-piperazinecarboxylate (77.3 g, 0.28 mole), 1-decanol methanesulfonate (77.3 g, 0.28 mole) from the condensation of 1-decanol with methane sulfonyl chloride, K2CO3 (39.0 g, 0.28 mole), and 500 mL of EtOH were combined and refluxed for 2 days under N2. After cooling to room temperature, the reaction was partitioned between water and Et2O. The organic layer was separated, washed 3 times with water, dried over Na2SO4 and stripped of all solvent under reduced pressure to yield the crude product oil. Chromatographic purification of the crude oil gave 53.4 g of ethyl 4-decyl-1-piperazinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:10]([CH2:11][CH:12]([NH:14]C(=O)OC(C)(C)C)[CH3:13])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[NH2:26].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.Cl>CN1CCCC1=O.O1CCCC1.O.C(N(CC)CC)C>[ClH:1].[ClH:22].[NH2:14][CH:12]([CH3:13])[CH2:11][N:10]1[C:3]2[C:2]([NH:26][C:25]3[CH:27]=[CH:28][C:29]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=4)=[C:23]([Cl:22])[CH:24]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: CC(Cn1ccc2ncnc(Cl)c21)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(N)Cn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.2 %

Procedure:
A solution of tert-butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1-methylethyl]carbamate (350 mg) and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (423 mg) in 1-methyl-2-pyrrolidone (3.5 mL) was stirred at 120° C. for 4 hrs. After cooling to room temperature, triethylamine (0.24 mL) and di-tert-butyl dicarbonate (0.13 mL) were added, and the mixture was stirred for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=19:1→3:2→ethyl acetate) to give a brown solid. To a solution of the obtained solid in tetrahydrofuran (20 mL) was added 2N hydrochloric acid (10 mL) at room temperature, and the mixture was stirred at 60° C. for 20 hrs. After concentration under reduced pressure, ethanol was added and the mixture was further concentrated. To the residue was added diisopropyl ether, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give the title compound (225 mg) as pale-yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[C:11](Br)=[C:10]([CH3:13])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([S:17]([N:20]1[C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[NH2:32])(=[O:19])=[O:18])([CH3:16])[CH3:15]>>[CH:14]([S:17]([N:20]1[C:24]2[CH:25]=[C:26]([C:11]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:8][O:9][C:10]=3[CH3:13])[CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[NH2:32])(=[O:18])=[O:19])([CH3:16])[CH3:15]
Reactant: Cc1onc(-c2ccccc2)c1Br
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(B(O)O)cc21
Product: Cc1onc(-c2ccccc2)c1-c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1

Procedure:
Beginning with 3-phenyl-4-bromo-5-methylisoxazole and 1-isopropylsulfonyl-2-aminobenzimidazole-6-boronic acid, the title compound may be prepared essentially as described in EXAMPLE 59.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][CH2:8][N:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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:22][C:19]1[CH:20]=[CH:21][C:16]([N:7]2[CH2:8][CH2:9][C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:23][C:6]2=3)=[CH:17][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3ccccc3)cc1N(c1ccc(Cl)cc1)CC2
Yield: 32.3 %

Procedure:
A solution of 8-bromo-6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (30 mg, 0.08 mmol), phenylboronic acid (20 mg, 0.16 mmol), Tetrakis(triphenylphosphine)palladium(0) (10 mg) and Cs2CO3 (60 mg, 0.16 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. under microwave for 20 min. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=12:1) to afford 6-(4-chlorophenyl)-1-methyl-8-phenyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (10 mg, yield 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11](=[O:22])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].[CH3:23][NH2:24].O>CN(C)C=O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]1[CH2:12][C:11](=[O:22])[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:24]1[CH3:23]
Reactant: CN
Reactant: COc1ccccc1C=CC(=O)C=Cc1ccccc1OC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1C1CC(=O)CC(c2ccccc2OC)N1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.6 %

Procedure:
1,5-Bis(2-methoxyphenyl)-1, 4-pentadien-3-one (20c, 0.26 g, 0.9 mmol) was dissolved in dimethyl formamide (5 ml). Methylamine (51, 0.40 ml, 4.6 mmol, 40% in water) was added and the mixture stirred for 24 hr at room temperature. The mixture was poured into water (50 ml) and stirred for 24 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The solid was recrystallized twice from ethanol to give 0.16 g (55%) of a white solid: mp 146-148° C.; 1H NMR δ 1.89 (s, 3H), 2.50 (d, 2H, J=13.7 Hz), 2.65 (t, 2H, J=11.9 Hz), 3.82 (s, 6H), 4.11 (d, 2H, J=11.5 Hz), 6.87 (d, 2H, J=8.3 Hz), 7.03 (t, 2H, J=7.2 Hz), 7.23 (t, 2H, J=5.8 Hz), 7.72 (d, 2H, J=7.6 Hz); 13C NMR: δ 40.3, 49.2, 55.4, 61.2, 110.7, 121.0, 127.6, 127.8, 131.5, 156.3, 208.1; Exact mass calcd for C20H23NO3: 325.1678, observed (M+H) 326.1754.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:38]=[CH:37][C:32]3[O:33][CH2:34][CH2:35][O:36][C:31]=3[CH:30]=2)[CH:22]=1)(=O)C.C[O-].[Na+]>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@H:6]2[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([O:19][CH3:20])[O:7]2)=[CH:22][C:23]=1[CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1
Reactant: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a suspension of compound 140 (40 mg, 0.07 mmol) in CH3OH (5.0 mL) was added NaOMe (100 μL, 25% solution in CH3OH) at room temperature. After 1 h, the resulting mixture was concentrated in vacuo. The crude was purified by preparative HPLC (reverse phase) to provide the title compound (18 mg, 62%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16](C)[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C(C(NC)=O)=C([F:61])C(C2C=NN(CCCO)C=2)=CC=1>>[F:61][C:18]1[C:14]([C:15](=[O:20])[NH:16][CH3:17])=[C:13]([NH:21][C:22]2[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]3[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=3[O:48][CH3:49])[N:23]=2)[CH:12]=[CH:11][C:10]=1[C:8]1[CH:7]=[N:6][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:9]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(F)c3C(=O)NC)n2)c(OC)c1)OCC
Yield: 30 %

Procedure:
Prepared analogously to Compound 1B replacing compound 1C with 6-amino-2-fluoro-3-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylbenzamide (281 mg, 961 μmol) to afford 204 mg of the title compound (30%). 1H NMR (400 MHz, CD3OD) δ=8.32 (s, 1H), 8.15 (d, J=1.8 Hz, 1H), 7.94-8.01 (m, 2H), 7.89 (d, J=8.1 Hz, 1H), 7.73 (t, J=8.6 Hz, 1H), 6.98 (t, J=2.0 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 4.32 (t, J=7.0 Hz, 2H), 3.97-4.07 (m, 4H), 3.89 (s, 3H), 3.55-3.60 (m, 2H), 3.24 (s, 1H), 3.19 (s, 1H), 2.91 (s, 3H), 2.10 (quin, J=6.5 Hz, 2H), 1.23 (t, J=7.1 Hz, 6H). MS (ESI): m/z=710.21 [M+H]+. UPLC: tR=1.39 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C@H:19]([CH3:20])[C:18](=O)[NH:17][C@H:16]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:15][C@@H:16]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:17][CH2:18][C@H:19]1[CH3:20])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H]1C(=O)N[C@H](Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CN[C@H](Cc2ccccc2)CN1Cc1ccccc1
Temperature: 0 °C

Procedure:
Lithium aluminum hydride (1 M in THF, 4.2 ml, 4.2 mmol) was added dropwise over 15 min to a solution of (3R,6R)-1,3-dibenzyl-6-methylpiperazine-2,5-dione (0.30 g, 0.98 mmol) in THF (6.0 ml) stirring at 0° C. After stirring at 65° C. for 19 h, the reaction was allowed to cool to room temperature and was slowly quenched with water (0.40 ml). Sodium hydroxide (1 N, 0.8 ml) and then water (0.60 ml) were added and the gelatinous solid was filtered rinsing with THF. The filtrate was evaporated in vacuo and the residue was transferred to a separatory funnel with EtOAc. Washing the organic layer with brine and drying with MgSO4 afforded product (0.28 g) after evaporation of the solvent. This was used in the next step without further purification.