Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([O:19][C:20]2[CH:21]=[C:22]([CH3:34])[C:23]3[CH:27]([CH2:28][C:29]([OH:31])=[O:30])[O:26][B:25]([OH:32])[C:24]=3[CH:33]=2)[CH:16]=[CH:15][N:14]=1)=O)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([O:19][C:20]2[CH:21]=[C:22]([CH3:34])[C:23]3[CH:27]([CH2:28][C:29]([OH:31])=[O:30])[O:26][B:25]([OH:32])[C:24]=3[CH:33]=2)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1cc(Oc2ccnc(NCCCNC(=O)OC(C)(C)C)n2)cc2c1C(CC(=O)O)OB2O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Oc2ccnc(NCCCN)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A solution of {6-[2-(3-tert-butoxycarbonylamino-propylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid (0.27 g, 0.57 mmol) in dioxane (7 mL) was treated with 4N HCl in dioxane (2 mL) at room temperature and stirred for 3 hours at room temperature. The precipitated solid was collected by vacuum filtration, dissolved in water and lyophilized to give {6-[2-(3-amino-propylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid hydrochloride salt as a yellow solid (0.12 g, 56%). 1H NMR (400 MHz, DMSO-d6) δ 8.57 (br s, 1H), 8.37-8.10 (br m, 1H), 7.94 (br m, 3H), 7.50-7.25 (br m, 1H), 7.20-7.05 (br m, 1H), 6.47 (br s, 1H), 5.54 (d, J=9.38 Hz, 1H), 3.36 (br m, 1H), 3.20-3.00 (m, 2H), 2.80 ((m, 1H), 2.67 (m, 1H), 2.33 (s, 3H), 2.20-2.07 (m, 1H), 1.95-1.60 (m, 2H). MS (ESI) m/z: 371 [M−1].
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][NH:5][C:6]1[C:18]2[C:17](=O)[C:16]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:10]=2[C:9]2[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:8]=2[N:7]=1.Cl.[OH:27][NH3+:28]>N1C=CC=CC=1.ClCCl.CO>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[C:18]2[C:17](=[N:28][OH:27])[C:16]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:10]=2[C:9]2[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:8]=2[N:7]=1
Reactant: [NH3+]O
Reactant: CN(C)CCNc1nc2cc(O)ccc2c2c1C(=O)c1cnccc1-2
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCNc1nc2cc(O)ccc2c2c1C(=NO)c1cnccc1-2
Temperature: 80 °C
Reaction time: 10 h

Procedure:
The compound of Example 41(18.0 mg) and hydroxylammonium hydrochloride (20.0 mg) (Tokyo Kasei Ltd.) were dissolved in pyridine (0.5 ml) (Wako Pure Chemical Industries Ltd.) and the solution was stirred at 80° C. for 10 hours. The reaction mixture was diluted with dichloromethane and filtered through a glass filter. The solid obtained was dissolved in methanol and passed through a Mega Bond Elut SCX (Varian). The column was washed with methanol and the product was eluted with ammonia water (25%, Wako Pure Chemical Industries Ltd.)—methanol=5:95. The solvent was evaporated to dryness. The desired product was obtained as an orange solid. ESI−MS: m/z 350 (MH+); 1H-NMR (MeOH-d4): δ2.45 (6H, s), 2.74 (2H, t, J=6.3 Hz), 3.63 (2H, t, J=6.3 Hz), 6.81 (1H, dd, J=6.6 Hz, 2.3 Hz), 6.93 (1H, d, J=2.3 Hz), 7.77 (1H, d, J=5.3 Hz), 7.83 (1H, d, J=9.2 Hz), 8.42 (1H, d, J=5.3 Hz), 9.16 (1H, s).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:15]([O:14][C:12]([N:10]1[CH2:11][CH:8]([C:7]2[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(c2cccnc2F)C1
Agent: [Fe+2]
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2cccnc2-c2ccccc2)C1
Yield: 72.5 %

Procedure:
To a solution of 3-(2-fluoro-pyridin-3-yl)-azetidine-1-carboxylic acid tert-butyl ester (25) (200 mg, 0.80 mmol), Ni(acac)2 (20 mg, 0.08 mmol), DPPF (32 mg, 0.08 mmol) in THF (10 mL) was added PhMgBr (1 M, 0.8 mL, 0.80 mmol). The resulting mixture was heated to reflux overnight under N2 atmosphere. TLC showed that the staring material was consumed completely. The solution was filtered and the filtrate was concentrated to give the residue, The crude compound was purified by column chromatography on silica gel to give the product 3compound (27) (180 mg, yield 78%) as solid. ESI-MS (M+1): 311 calc. for C19H22N2O2 310.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:77][N:78]1[CH2:83][CH2:82][S:81][CH2:80][CH2:79]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][CH2:59][CH2:60][CH2:61][S:62]([CH3:65])(=[O:64])=[O:63])=[CH:53][C:52]=2[N:66]([CH3:76])[S:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=1)(=[O:69])=[O:68])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH3:76][N:66]([C:52]1[CH:53]=[C:54]([O:58][CH2:59][CH2:60][CH2:61][S:62]([CH3:65])(=[O:63])=[O:64])[CH:55]=[C:56]2[C:51]=1[NH:50][C:49]([C:47]1[S:43][CH:44]([CH2:77][N:78]3[CH2:83][CH2:82][S:81][CH2:80][CH2:79]3)[CH2:45][N:46]=1)=[CH:57]2)[S:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=1)(=[O:68])=[O:69]
Reactant: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a solution of triphenylphosphine oxide (0.70 g) in dichloromethane (3 mL) was slowly added trifluoromethanesulfonic anhydride (0.41 mL) under ice-cooling, and the mixture was stirred for 30 min. A solution of N-[2-(benzylthio)-3-thiomorpholinopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxamide (0.75 g) and thioanisole (0.30 mL) in dichloromethane (10 mL) was added dropwise, and the mixture was stirred for 30 min under ice-cooling. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=50:50-90:10) to give the title compound (350 mg, yield: 54%) as a colorless amorphous solid. MS:625(MH+).
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.[F:8][C:9]1([F:24])[CH2:14][CH2:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[F:8][C:9]1([F:24])[CH2:14][CH2:13][C:12]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=2)=[CH:11][CH2:10]1
Reactant: CC1(C)OB(C2=CCC(F)(F)CC2)OC1(C)C
Reactant: Cn1nccc1I
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: Cn1nccc1C1=CCC(F)(F)CC1
Yield: 94.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using 5-iodo-1-methyl-1H-pyrazole (1.90 g, 9.14 mmol), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.00 g, 4.10 mmol), tetrakis(triphenylphosphine)palladium (0) (240 mg, 0.208 mmol), cesium carbonate (2.70 g, 8.29 mmol), 1,4-dioxane (10 mL) and water (5 mL), to yield the title compound (767 mg, 94%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH:16]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:16]([C:7](=[O:8])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:22]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CCOC(=O)CNCC(=O)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 21 h
Yield: 71.5 %

Procedure:
A solution of 5.0 g (21.7 mmol) of 3,5-dinitrobenzoyl chloride in 75 ml of methylene chloride was added dropwise with stirring to an ice bath cooled mixture of 4.7 ml (27 mmol) of diethyl iminodiacetate and 6.0 ml (43 mmol) of triethylamine in 25 ml of methylene chloride. The reaction mixture was stirred in the cooling bath for 30 minutes and then was left at room temperature for 21 hours. After washing with NaHCO3 solution, the organic layer was dried and concentrated to an oil which was chromatographed on 150 g of silica gel using 20-30% ethyl acetate-hexane. The combined pure fractions were recrystallized from methanol to give 5.95 g (72% yield, 79°-80°) of N-(3,5-dinitrobenzoyl)-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[CH:25]=O)=[CH:19][C:17]=2[CH:18]=1.[O:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][CH:25]=[C:31]3[O:27][C:28](=[O:33])[NH:29][C:30]3=[O:32])=[CH:19][C:17]=2[CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(/C=C/C=O)ccc2o1
Reactant: O=C1COC(=O)N1
Product: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(C=CC=C3OC(=O)NC3=O)ccc2o1
Yield: 44 %

Procedure:
In substantially the same manner as in Example 1, (E)-3-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-yl]acrolein was allowed to react with 2,4-oxazolidinedione to give 5-[3-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-yl]-2-propenylidene]-2,4-oxazolidinedione. The yield was 44%. Recrystallization from dichloromethane-methanol gave pale yellow needles, m-p.237°-239° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27](C3CCCCO3)[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:34])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:34][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCC[C@@H]3c3ccnn3C3CCCCO3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC[C@@H]1c1ccn[nH]1
Yield: 98.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S,2R)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide (265 mg, 0.407 mmol) prepared in Example 148f, triethylsilane (0.60 mL), trifluoroacetic acid (4.0 mL) and dichloromethane (6.0 mL), to yield the title compound (168 mg, 99%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1Br.[S-:15][C:16]#[N:17].[K+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[S:15][C:16]#[N:17]
Reactant: N#C[S-]
Reactant: O=[N+]([O-])c1cc(Br)c(Br)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CO
Product: N#CSc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To a stirred solution of 1,2-dibromo-3,5-dinitrobenzene (723 g, 2.22 mol) in MeOH (7.5 L) at rt was added potassium thiocyanate (431 g, 4.44 mol) and the resulting reaction mixture stirred under a nitrogen atmosphere for 16 h. The reaction mixture was then filtered and washed with methanol. The filtrate was concentrated at 30-33° C. under reduced pressure. The residue thus obtained was purified over silica gel (2-6% EtOAc-hexane) to obtain the desired product (549 g, 81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][CH:9]=[C:10]([I:11])[C:4]=2[C:3]=1[CH:12]=[O:13].[OH-].[Na+].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH:9]=[C:10]([I:11])[C:4]=2[C:3]=1[CH:12]=[O:13]
Reactant: O=Cc1c(F)cnc2[nH]cc(I)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(C=O)c(F)cnc32)cc1
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 5-fluoro-3-iodo-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde in DMF (12 mL) was added NaOH (0.716 g, 17.91 mmol). The deep red solution was stirred for 30 min after which 4-methylbenzene-1-sulfonyl chloride (3.13 g, 16.42 mmol) was added. The reaction mixture was stirred for 2 h, subsequently diluted with EtOAc, and washed with water and brine. The extracts were dried over MgSO4 and concentrated. Purification by silica column chromatography (DCM, 100%) afforded the title compound as light yellow solid (3.65 g, 55%). 1H NMR (400 MHz, DMSO-d6) δ 2.36 (s, 3 H) 7.45 (m, J=8.08 Hz, 2 H) 8.02 (m, J=8.34 Hz, 2H) 8.42 (s, 1 H) 8.59 (d, J=2.53 Hz, 1 H) 11.13 (s, 1 H). [M+H] calc'd for C15H10FIN2O3S, 445; found, 445.1.
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]2[C:7]([N:10]([CH3:19])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:8][O:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+]>Br>[N:13]1([CH2:12][CH2:11][N:10]([CH3:19])[C:7]2[C:6]3[CH:20]=[CH:21][C:3]([OH:2])=[CH:4][C:5]=3[O:9][N:8]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COc1ccc2c(N(C)CCN3CCOCC3)noc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(CCN1CCOCC1)c1noc2cc(O)ccc12
Temperature: 25 °C
Yield: 90 %

Procedure:
6-Methoxy-N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine (7.0 g) was dissolved in 48% hydrobromic acid (130 ml) and heated to reflux under nitrogen for 3 hours. The reaction was cooled to room temperature, neutralized with saturated sodium carbonate (Na2CO3) extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo. Flash chromatography (silica gel) eluting with 2:1 heptane/acetone provided the product (6.0 g), m.p. 91-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:13]([C:12]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[O:14])=[CH:23][CH:22]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
In a 500 mL round bottom flask crude 1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride (47 mmol) was dissolved in 200 mL CH2Cl2 to afford a dark solution. To this solution was added 8.2 g of 4-bromoaniline (47 mmol) and a few pellets of 4-(dimethylamino)pyridine. The resulting slurry was treated with 20 mL of N,N-diisopropylethylamine (115 mmol) to afford a dark solution. After stirring for 2 hours at room temperature the reaction was quenched by the addition of H2O and diluted with additional CH2Cl2. The organic layer was washed with 1N HCl, saturated NaHCO3 solution, dried (Na2SO4), filtered, and concentrated in vacuo to afford crude N-(4-bromophenyl)-1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide as a dark brown syrup. The crude product was purified by silica gel flash chromatography on a 300 g column using gradient elution from 0% to 30% EtOAc/hexane. Most of the product-containing fractions were impure. All product-containing fractions were combined and concentrated in vacuo to afford a sticky orange foam. This material was further purified by silica gel flash chromatography on a 160 g column using gradient elution from 0% to 20% EtOAc/hexane. Appropriate fractions were combined and concentrated in vacuo to afford N-(4-bromophenyl)-1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide as a pale orange foam that was broken up to a powder. The material is not completely pure. Yield: 2.61 g (12% yield); 1H NMR (400 MHz, CDCl3): δ 7.64 (br s, 1H), 7.56-7.55 (impurity), 7.54-7.53 (m, 1H), 7.52-7.51 (m, 1H), 7.50-7.49 (impurity), 7.48-7.44 (m, 3H), 7.43-7.41 (m, 1H), 7.38-7.36 (m, 1H), 7.36-7.34 (m, 1H), 7.11 (s, 1H); GC/MS (EI, 70 eV) 445, 443.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH2:38]([NH2:40])[CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:20]=[CH:21][C:22]([CH2:25][NH:40][CH2:38][CH3:39])=[CH:23][CH:24]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(C=O)cc3)ccc2-n2c(C)nnc21
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNCc1ccc(-c2ccc3c(c2)C(c2ccc(Cl)cc2)=N[C@@H](CC(=O)NCC)c2nnc(C)n2-3)cc1
Reaction time: 0.08 h

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-(4-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 6) (75 mg) was dissolved in DCM (5 ml). Ethylamine hydrochloride (18.42 mg) and acetic acid (8.62 μl) were added and the reaction mixture was stirred for 5 min. Sodium triacetoxyborohydride (160 mg) was added and the reaction mixture was stirred at room temperature, under nitrogen, over the weekend. Saturated sodium hydrogen carbonate solution (5 ml) was added and the reaction mixture was stirred for 10 min. The organic phase was separated and the saturated sodium hydrogen carbonate solution was extracted with DCM (10 ml). The DCM extracts were combined, dried and the solvent was evaporated. The residue was chromatographed (0-15% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator at 40° C. overnight to give (S)-2-(6-(4-chlorophenyl)-8-(4-((ethylamino)methyl)phenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (28.7 mg) as a white solid. LCMS (formate): MH+ 527/529, RT 0.67 min
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[C:12]2[O:21][C:22]1[CH:23]=[CH:24][C:25]2[NH:30][CH2:29][CH2:28][O:27][C:26]=2[CH:31]=1)C1C=CC=CC=1>C(O)C.[Pd]>[O:27]1[CH2:28][CH2:29][NH:30][C:25]2[CH:24]=[CH:23][C:22]([O:21][C:12]3[C:11]4[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([OH:8])[CH:10]=4)[N:15]=[CH:14][CH:13]=3)=[CH:31][C:26]1=2
Reactant: COc1cc2nccc(Oc3ccc4c(c3)OCCN4)c2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc4c(c3)OCCN4)c2cc1O
Reaction time: 18 h
Yield: 81 %

Procedure:
Palladium, 10 wt % on activated carbon (0.100 g, 0.940 mmol) was added to a solution of 7-(6-(benzyloxy)-7-methoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.156 g, 2.79 mmol) in ethanol (20.0 mL). The system was evacuated and purged with hydrogen (g) three times and then stirred under a H2 (g) atmosphere for 18 h. Additional palladium, 10 wt % on activated carbon (0.100 g, 0.940 mmol) was added to the reaction mixture. The system was evacuated and purged with hydrogen (g) three times and then stirred under a H2 (g) atmosphere for 20 h. The reaction mixture was filtered through a pad of Celite and concentrated to afford an orange brown solid. This material was purified via column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-100% (90:10:1, dichloromethane/methanol/ammonium hydroxide)-dichloromethane) to afford 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yloxy)-7-methoxyquinolin-6-ol (0.733 g, 81.0% yield) as a yellow solid. MS (MH+) 325.0; Calculated 324 for C18H16N2O4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[O:8][C:7]([CH2:12][N:13]1[CH:21]=[N:20][C:19]3[C:14]1=[N:15][CH:16]=[N:17][C:18]=3[N:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:6]2.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCOCC1>[CH2:37]([NH:44][C:9]([C:10]1[N:5]([NH:6][C:7](=[O:8])[CH2:12][N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:4]=[CH:3][C:2]=1[Cl:1])=[O:11])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2c1ncn2Cc1nn2ccc(Cl)c2c(=O)o1
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ncnc2c1ncn2CC(=O)Nn1ccc(Cl)c1C(=O)NCc1ccccc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution di-tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodicarbonate (100 mg, 0.2 mmol) in 2 mL of dry 1,4-dioxane under argon atmosphere 127 μL of benzylamine (1.16 mmol) were added and the mixture was stirred at 30° C. during 2 hours. At the end of this period, the reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by flash chromatography silica (dichloromethane/methanol). After purification were obtained 95 mg of tert-butyl 9-(2-(2-(benzylcarbamoyl)-3-chloro-1H-pyrrol-1-ylamino)-2-oxoethyl)-9H-purin-6-ylcarbamate (92% yield).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14]C(=O)O[C:10]2=O.B>O1CCCC1>[CH2:6]1[CH:2]2[C:3](=[O:5])[NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[CH2:10][N:1]2[CH2:8][CH2:7]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: B
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2CN2CCCC12

Procedure:
The above compound, melting point 174°-176°c., is obtained when 1,2,3,11a-tetrahydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepin-5,11(10H)-dione (prepared from proline and isatoic anhydride by the procedure of Example 1) is treated with 1M borane in tetrahydrofuran as described in the procedure of Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=O)=[CH:4][C:3]=1[Cl:18].C(OP([CH2:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])(OCC)=O)C.CC(C)([O-])C.[K+]>CN(C)C=O>[NH2:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])=[CH:4][C:3]=1[Cl:18]
Reactant: Nc1c(Cl)cc(C(=O)c2ccc(Cl)cc2)cc1Cl
Reactant: CCOP(=O)(CC(=O)N1CCOCC1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1Cl

Procedure:
This compound was prepared from 4-amino-3,4',5-trichlorobenzophenone, diethylphosphonoacetic acid morpholide and potassium tert.butoxide in dimethylformamide analogous to Example 4.