Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=O.[F:21][CH2:22][C:23]1([C:27]#[N:28])[CH2:26][NH:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:21][CH2:22][C:23]1([C:27]#[N:28])[CH2:26][N:25]([C:4](=[O:6])[C@H:3]([N:7]2[C:16](=[O:17])[C:15]3=[CH:18][NH:19][C:13]4[C:14]3=[C:9]([CH:10]=[CH:11][N:12]=4)[CH2:8]2)[CH:2]([CH3:20])[CH3:1])[CH2:24]1
Reactant: N#CC1(CF)CNC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2ccnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)N1CC(C#N)(CF)C1)N1Cc2ccnc3[nH]cc(c23)C1=O
Yield: 31.9 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (80 mg, 0.293 mmol) under nitrogen. DMF (0.5 mL), 3-(fluoromethyl)azetidine-3-carbonitrile (93 mg, 0.439 mmol), HOBt (67.2 mg, 0.439 mmol), EDC (84 mg, 0.439 mmol) and N,N-dimethylpyridin-4-amine (53.6 mg, 0.439 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (34.5 mg, 25.3%). 1H NMR (400 MHz, DMSO-d6) δ 0.78 (dd, J=6.57, 3.79 Hz, 3 H) 0.97 (dd, J=12.88, 6.32 Hz, 3 H) 2.30-2.41 (m, 1 H) 3.99 (dd, J=9.98, 4.42 Hz, 1 H) 4.22 (d, J=9.35 Hz, 2 H) 4.36 (s, 1 H) 4.62-4.71 (m, 1 H) 4.76-4.88 (m, 2 H) 4.87-5.03 (m, 1 H) 5.02-5.09 (m, 1 H) 7.09 (t, J=4.80 Hz, 1 H) 7.88 (dd, J=5.56, 2.27 Hz, 1 H) 8.27 (t, J=5.31 Hz, 1 H) 12.25 (d, J=8.84 Hz, 1 H). [M+H] calc'd for C19H20FN5O2, 370; found, 370.5.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])(C)(C)C.[C:31]([C:33]1[CH:41]=[CH:40][C:36](C(O)=O)=[CH:35][CH:34]=1)#[N:32].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>Cl.O1CCOCC1.C(Cl)Cl>[C:31]([C:33]1[CH:41]=[CH:40][C:36]([C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[O:7])=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOc1cccc(C#N)c1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)N[C@@H](CCOc2cccc(C#N)c2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.12 g (2.73 mmol) of benzyl (2S)-2-t-butoxycarbonylamino-4-(3-cyanophenoxy)butanoate was dissolved in 10 ml of 4 N solution of hydrogen chloride in dioxane, and they were stirred at room temperature for 2 hours. The solvent was evaporated, and the obtained oily residue was dissolved in 14 ml of dichloromethane. 390 mg (2.73 mmol) of 4-cyanobenzoic acid, 405 mg (3.00 mmol) of HOBt, 0.83 ml (6.00 mmol) of triethylamine and 575 mg (3.00 mmol) of WSC.HCl were successively added to the solution under cooling with ice, and they were stirred at room temperature overnight. After the treatment with methylene chloride as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:26][CH:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28](Cl)=[O:29]>C1COCC1>[Cl:26][CH:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1)C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 15 (0.10 g, 0.39 mmol) in THF (10 mL), was added triethylamine (0.059 g, 0.58 mmol) and 2-chloro-2-phenylacetyl chloride (0.110 g, 0.58 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5 methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[OH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:5]([C:11]#[N:12])=[C:6]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Reactant: OCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 2-(2-hydroxyethyl)pyridine and DBU in DME. ES-MS m/e (%): 319 (M+H+, 100).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]([C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[OH:9]
Reactant: COc1cc(C(=O)c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1OC
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1cc(O)c(O)c([N+](=O)[O-])c1)c1nc2ccccc2[nH]1
Temperature: 0 °C

Procedure:
1.0 g of 2-benzimidazolyl (3,4-dimethoxy-5-nitrophenyl) ketone and 8.0 g of pyridine hydrochloride are held at 200° for 60 minutes. The dark solution is poured while still warm into ice-water and extracted three times with 100 ml of ethyl acetate each time. The organic phase is washed with water, dried over sodium sulfate and evaporated. After recrystallization from ethyl acetate/hexane, there is obtained 2-benzimidazolyl (3,4-dihydroxy-5-nitrophenyl) ketone in the form of yellow crystals of m.p. 249°-250°
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH2:11])=[O:5].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH:29]=O.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.CO.[Cl-].[Na+].O.O>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:29][C:28]1[CH:31]=[CH:32][C:33]([F:34])=[C:26]([F:25])[CH:27]=1)=[O:5]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
The crude (1R,2S)-2-amino-cyclopentanecarboxylic acid methyl ester hydrochloride (prepared as described in Example 11a, 0.54 mmol) was dissolved in tetrahydrofuran (6 mL). Magnesium sulfate (185 mg), triethylamine (80 μL, 0.57 mmol) and 3,4-difluoro-benzaldehyde (122 μL, 1.11 mmol) were added at 25° C. and the resulted mixture was stirred at 25° C. for 16 h. The solid was filtered off and the filtrate was concentrated in vacuo to give an oil. This oil was dissolved in methanol (10 mL) and sodium borohydride (42 mg, 1.11 mmol) was then added portionwise. The mixture was stirred at 25° C. for 1 h. Saturated aqueous sodium bicarbonate solution (2 mL), water (2 mL) and saturated aqueous brine solution (1 mL) were added. The mixture was extracted with ethyl acetate (3×10 mL) and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1R,2S)-2-(3,4-difluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (126.1 mg, 0.469 mmol, 86.7% over two steps). This crude product was directly used in next step without further purification. LC-MS (ESI) calcd for C14H17F2NO2 269.1, found 270.1 [M+H+].
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH:18]([OH:20])[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[OH:20][CH:18]1[CH2:19][CH:14]([CH2:13][NH:12][C:10]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][N:8]=3)[CH:3]=[C:2]([C:37]3[CH:36]=[CH:35][C:34]([N:31]4[CH2:30][CH2:29][O:28][CH2:33][CH2:32]4)=[CH:39][CH:38]=3)[N:11]=2)[CH2:15][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(O)CC(CNc2nc(Cl)cc3nccnc23)C1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Product: CC(C)(C)OC(=O)N1CC(O)CC(CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1

Procedure:
The title compound was prepared according to the procedures of Compound 1 (B) using tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)-5-hydroxypiperidine-1-carboxylate and 4-morpholinophenylboronic acid. MS (m/z): 521 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:36]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:35])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:34])[C:20]=2[C:21]2[CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][CH:26]=2)[N:13]=1.Cl>CO.O1CCOCC1>[NH2:36][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:34])[C:20]=1[C:21]1[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=1)=[O:35]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1=CCNCC1

Procedure:
tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (0.10 g, 0.16 mmol) was dissolved in MeOH (3 mL) and HCl in 1,4-dioxane (4.0
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=O.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.O1CCCC1.CO.C(O)(=O)C.ClCCl.C(N(CC)CC)C>[CH3:1][CH:2]([CH3:16])[CH2:3][CH:4]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=1)[C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1c(C(=O)CC(C)C)oc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(CC(C)C)c2oc3ccccc3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a mixture of 3-methyl-1-(3-methyl-1-benzofuran-2-yl)butan-1-one (200 mg) synthesized above, methyl 4-aminobenzoate (140 mg), triethylamine (1.03 mL) and dichloromethane (5 mL) was added titanium (IV) chloride (122 μL) at 0° C., and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown solid. To a mixture of the obtained solid, acetic acid (1 mL), methanol (5 mL) and tetrahydrofuran (5 mL) was added sodium cyanoborohydride (175 mg) by small portions, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (254 mg, 78%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C([Li])CCC.Br[CH2:10][C:11]([C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:12]>C1COCC1>[CH2:1]([S:3][CH2:10][C:11]([C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:12])[CH3:2]
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Reactant: CCS
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCSCC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
Ethyl mercaptan (5.76 ml., 4.83 g., 0.078 mol) in 250 ml. THF was cooled to -70°. n-Butyllithium (50 ml. of 1.55M in hexane, 0.078 mol) was added over 10 minutes at that temperature. The mixture was then allowed to warm to 10°, recooled to -70°, and 1-adamantyl bromomethyl ketone (20 g., 0.078 mol) in 125 ml. THF added over. The mixture was stirred 15 minutes at -70° C., stripped to one fifth volume, diluted to 600 ml. with ether, washed 2×200 ml. saturated NH4Cl, 3×150 ml. H2O and 1×200 ml. brine, dried over MgSO4 and stripped to yield title product as an oil, 18.5 g. 1H-nmr (300 MHz) 1.2 (t, 3H), 1.6-2.1 (m, 15H), 2.5 (q, 2H), 3.35 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([I:24])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=C)[CH3:8])=[O:6].ClC1C=C(C=C(Cl)C=1)C(N(C[C@H](C1C=CC(F)=CC=1)CC=C)C)=[O:30]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([I:24])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=[O:30])[CH3:8])=[O:6]
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Cl)cc(Cl)c1)c1ccc(F)cc1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Br)cc(I)c1)c1ccc(F)cc1
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(Br)cc(I)c1

Procedure:
The compound was synthesized in an analogous way to that of Method 21b but using 3-bromo-N-[(2S)-2-(4-fluorophenyl)pent-4en-1-yl]-5-iodo-N-methylbenzamide rather than 3,5-dichloro-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methylbenzamide (yield, 100%). 1H NMR (500 MHz, CDCl3): 2.6-3.2 (cm, 4H), 3.4-3.9 (cm, 2H), 4.0-4.2, (cm, 2H), 6.8-8.2 (cm, 7H), 9.8 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)[NH:3]1.[C:24]1([C:30]([NH2:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C:30]([NH:38][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:23])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(N)(c1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: CC(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)(c1ccccc1)c1ccccc1
Yield: 55 %

Procedure:
The title compound was prepared in a yield of 55% in a similar manner to that described in Example 2 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 1,1-diphenylethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24].[OH-].[Na+].[NH2:29]O.Cl>CO.O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]2[O:22][NH:29][C:17](=[O:18])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: NO
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2ccc(F)cc2Cl)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)N1CCC(c2cc(=O)[nH]o2)CC1c1ccc(F)cc1Cl
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
Methyl 2-(2-chloro-4-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.655 g, 4.29 mmol) was dissolved in MeOH (22 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.180 g, 4.50 mmol) dissolved in water (2.200 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.276 mL, 4.50 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was then transferred with a pipette into a prewarmed (80° C.) solution of 6 M hydrogen chloride (22.16 mL, 132.98 mmol) and the mixture was stirred at 80° C. for 15 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min (3 runs). Methyl 2-(2-chloro-4-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.995 g, 65.4%) was yielded as a white solid. MS m/z 355 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].CO[CH:15](O)[C:16]([F:19])([F:18])[F:17].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH:15]([C:16]([F:19])([F:18])[F:17])[O:12][C:9]([CH3:10])([CH3:11])[C:3]=2[CH:4]=1
Reactant: CC(C)(O)c1cc(Br)ccc1N
Reactant: COC(O)C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CC1(C)OC(C(F)(F)F)Nc2ccc(Br)cc21
Temperature: 80 °C

Procedure:
A mixture of 2-(2-amino-5-bromo-phenyl)-propan-2-ol (5 g, 21.7 mmol), trifluoroacetaldehyde methyl hemiacetal (5 mL), and magnesium sulfate (10 g) in toluene (75 mL) was heated at 80° C. under nitrogen. After disappearance of the starting material, the reaction was filtered through a pad of silica gel and the filtrate dried over sodium sulfate and concentrated to give 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine as an amorphous solid: 1H-NMR (DMSO-d6) δ 7.31 (d, 1H, J=1.99 Hz), 7.19 (dd, 1H, J=8.73, 2.38 Hz), 6.88 (s, 1H), 6.74 (d, 1H, J=8.33 Hz), 5.32 (m, 1H), 1.52 (s, 6H).
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]([F:14])([F:13])[S:10]([O-:12])=[O:11])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Na+:15].[OH:16]O>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[C:1]([O:7][CH2:8][C:9]([F:14])([F:13])[S:10]([O-:16])(=[O:12])=[O:11])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Na+:15]
Reactant: OO
Reactant: CCCCC(=O)OCC(F)(F)S(=O)[O-]
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCC(=O)OCC(F)(F)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
A 100 mL reactor was charged with 6.6 g (purity 28%, 7.3 millimoles) of sodium 2-valeryloxy-1,1-difluoroethanesulfinate, 60 mL of water, 0.0047 g (0.014 millimoles/0.0019 equivalents) of sodium tungstate dihydrate, and 1.9 g (16.4 millimoles/2.25 equivalents) of 30% hydrogen peroxide solution, followed by stirring at room temperature for 1.5 hours. The reaction liquid was heated under reduced pressure, followed by distilling volatile component to dryness, thereby obtaining 6.6 g of the target sodium 2-valeryloxy-1,1-difluoroethanesulfonate. Upon this, purity was 26%, and yield was 88%.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)=[O:32])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClCCl.CO>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)=[O:32])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(C(=O)Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c3cc(OC(F)F)ccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN1CCN(C(=O)Cn2nc(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)c3cc(OC(F)F)ccc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66559.5 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (41.7 mg, 62.2 μmol) in dichloromethane (3 mL) under Ar trifluoroacetic acid (208 mg, 0.140 mL, 1.83 mmol) was added at 25° C. After 18 h, the reaction was concentrated in vacuo to give a yellow residue. The residue was dissolved in a mix of dichloromethane/methanol/NH3OH (3:2:0.25, 5.25 mL) and stirred at 25° C. After 2.5 h, the material was concentrated and dried in vacuo (200 mTorr, 40° C.) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (22.4 mg, 41.4 mmol, 67%) as a yellow solid. MS (M)'=541; 1H NMR (DMSO-d6) δ: 12.84 (d, J=2.8 Hz, 1H), 9.02 (s, 1H), 8.41 (d, J=3.0 Hz, 1H), 8.23 (d, J=2.3 Hz, 1H), 7.89 (s, 1H), 7.75 (d, J=9.3 Hz, 1H), 7.41 (dd, J=2.3, 9.0 Hz, 1H), 7.21 (t, J=74.5 Hz, 1H), 5.71 (br. s, 2H), 3.82 (br. s, 2H), 3.50 (br. s, 2H), 2.74 (br. s, 2H), 2.67 (br. s, 2H), 2.33 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[C:20]=1[C:29]([O:31]C)=[O:30])(=[O:17])=[O:16])[CH3:2].[Li+].[I-]>N1C=CC=CC=1>[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[C:20]=1[C:29]([OH:31])=[O:30])(=[O:17])=[O:16])[CH3:34]
Reactant: CCN(CC)CCC/C=C/c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCN(CC)CCC/C=C/c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2

Procedure:
A solution of Example 596A (420 mg, 0.9 mmol), and LiI (482 mg, 4 equiv.) in 9 mL of pyridine was reacted in two vials in a microwave at 150° C. for 35 minutes. After concentration, the crude product was purified by preparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size) using a gradient of 10% to 95% acetonitrile/10 mM aqueous NH4OAc over 12 minutes (15 minute run time) at a flow rate of 70 mL/min. in 36 mg (8%) yield. MS (ESI(+)) m/e 471 (M+H)+; MS (ESI(−)) m/e 469 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ 1.21 (t, J=6.72 Hz, 6H) 1.55 (m, 4H) 2.01 (s, 2H) 2.28 (q, J=6.11 Hz, 2H) 2.55 (s, 2H) 2.86 (s, 2H) 3.05 (m, 6H) 6.30 (m, 1H) 6.81 (m, 1H) 7.11 (d, J=8.31 Hz, 1H) 7.17 (d, J=15.89 Hz, 1H) 7.35 (m, 1H) 7.51 (t, J=6.97 Hz, 1H) 7.57 (m, 1H) 7.93 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][OH:3].[H-].[Na+].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH2:20]Cl)=[N:18][N:19]=[C:15]3[CH2:14][N:13]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:11]=2[CH:28]=1>CN(C)C=O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH2:20][N:2]([CH3:1])[OH:3])=[N:18][N:19]=[C:15]3[CH2:14][N:13]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:11]=2[CH:28]=1
Reactant: CNO
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(O)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 16, a solution of N-methylhydroxylamine in dimethylformamide is treated with sodium hydride suspended in mineral oil, and the mixture is treated with 8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-bromo-1-[(methylhydroxyamino)methyl]-6-(2-pyridyl)4H-s-triazolo[4,3-a][1,4]benzodiazepine.