Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.C(N(CC)CC)C.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](Cl)=[O:24]>C(O)C.[Pd]>[NH:6]1[CH:5]=[C:4]([NH:1][C:23](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[CH:8]=[N:7]1
Reactant: O=C(Cl)c1ccccn1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1cn[nH]c1)c1ccccn1
Reaction time: 3 h

Procedure:
A solution of 4-nitro-1H-pyrazole (2.5 g, 22 mmol) in ethanol (80 mL) was added to a Parr vessel under an argon atmosphere. Carefully into the vessel, 10% Pd/C (0.2 g) was added. The vessel was sealed and H2 was added to a pressure of 40 psi. The vessel was shaken for 3 hours and then the catalyst removed by filtration. The catalyst was washed with ethanol and the combined filtrates where evaporated to dryness under reduced pressure. The residue was dissolved in THF (350 mL), treated with triethyl amine (6.9 mL, 49 mmol) and cooled on an ice bath under an argon atmosphere. Picolinoyl chloride hydrochloride (3.94 g, 22.3 mmol) was added in one portion. When the reaction was complete, the solvent was removed under reduced pressure and the residue dissolved in dichloromethane. The solution was extracted with water, NaHCO3 sat, dried, and the solvent removed under reduced pressure. The crude residue was re-crystallized from ethyl acetate to afford N-(1H-pyrazol-4-yl)picolinamide. (2.19 g, 52%). 1H NMR (DMSO-d6) δ 10.88 (s, 1 H), 8.7 (s, 1 H), 8.12 (m, 2 H), 8.04 (m, 1 H,), 7.96 (s, 1 H), 7.65 (m, 1 H). MS: m/z=189[M+1]+.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([C:13](O)=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=N[CH:33]=[CH:32]2)=O)C=1.C([CH:38](C([O-])=O)[C:39]([O-:41])=[O:40])C.[Mg+2].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][CH:9]1[CH2:10][C:11]([C:13](=[O:14])[CH2:38][C:39]([O:41][CH2:32][CH3:33])=[O:40])([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC(OCc2ccccc2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(C(=O)[O-])C(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Temperature: 0 °C
Yield: 85.8 %

Procedure:
A 37.24 g (115.7 mmol) portion of 1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutane-3-carboxylic acid was dissolved in 300 ml of tetrahydrofuran to which, while cooling in an ice bath with stirring, was added 20.63 g (127.2 mmol) of N,N-carbonyldiimidazole. After 10 minutes of stirring, the ice bath was detached and the reaction mixture was stirred at room temperature for 3 hours. To the reaction solution which was cooled in an ice bath with stirring was added dropwise 200 ml of tetrahydrofuran solution containing 36.45 g (127.2 mmol) of magnesium ethylmalonate. After 1 hour of stirring, the ice bath was detached, and the reaction mixture was stirred at room temperature for 10 hours. While cooling in an ice bath with stirring, the reaction mixture was mixed with 10% citric acid aqueous solution and then with ethyl acetate to effect separation of layers, and the resulting organic layer was washed with saturated sodium bicarbonate aqueous solution. The organic layer was further washed with saturated brine. After extraction of the aqueous layer with ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by a silica gel column chromatography to give 38.84 g (85.8%) of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22](O)[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]2)[C@@H:13]([Cl:28])[CH2:12]3)[CH2:9][C@H:8]1[CH3:29])(=[O:3])[CH3:2].CS(Cl)(=O)=O.O>N1C(C)=CC(C)=CC=1C.CN(C=O)C>[C:1]([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]2)[C@@H:13]([Cl:28])[CH2:12]3)[CH2:9][C@H:8]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
A solution of 14.0 g of 21-acetoxy-6α-chloro-11β-hydroxy-16α-methyl-1,4-pregnadiene-3,20-dione in 29 ml of collidine and 90 ml of DMF is combined with 11 ml of methanesulfonic acid chloride containing 3% sulfur dioxide and agitated at room temperature. After 15 minutes, 15 ml of water is added under ice cooling. The thus-obtained precipitate is filtered off, washed with water, and dried in the open air. The crude product is chromatographed on silica gel. With 33-61% ethyl acetate-hexane, 12.1 g of 21-acetoxy-6α-chloro-16α-methyl-1,4,9(11)-pregnatriene-3,20-dione is obtained. A sample, recrystallized from ethyl acetate-hexane, melts at 181° C. [α]D25 =+22° (chloroform).
Reaction SMILES: [C:1]([N:11]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@@H:24]([CH2:26][N:27]=[N+]=[N-])[O:23][C:22]3=[O:30])=[CH:17][C:16]=2[F:31])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(P([C:45]2[CH:50]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH2:51]>C1COCC1>[F:31][C:16]1[CH:17]=[C:18]([N:21]2[CH2:25][C@H:24]([CH2:26][NH:27][C:50](=[O:51])[CH3:45])[O:23][C:22]2=[O:30])[CH:19]=[CH:20][C:15]=1[CH:13]1[CH2:14][N:11]([C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:12]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 3 h

Procedure:
To a stirred solution of (S)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-azidomethyl-2oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 7, 1.63 g, 3.84 mmol) in dry THF (20 mL) was added triphenylphosphine (1.11 g, 4.23 mmol). After 3 hr, water (0.69 mL, 38.4 mmol) was added and the reaction stirred for 2 days at which time the solvents were evaporated. The residue was chromatographed over silica gel (150 g, 40-60 μm) eluting with 5-10% methanol-chloroform. The title compound was isolated as a viscous colorless oil. FAB-HRMS: theory 400.1672 (M+1); meas. 400.1676.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8](=[O:32])[N:9]([CH2:30][CH3:31])[CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:47])[CH2:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[C:41](Br)[CH:40]=1>>[CH3:35][O:36][C:37](=[O:47])[CH2:38][C:39]1[CH:40]=[C:41]([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:19])([F:18])[F:20])=[CH:16][C:11]=2[CH2:10][N:9]([CH2:30][CH3:31])[C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][CH:33]=2)=[O:32])[CH:42]=[C:43]([Cl:45])[CH:44]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NCc1ccc(Cl)cc1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)NCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 3-(4-chloro-benzyl)-1-ethyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCCC1CCCCO1
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 220 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH2:1]([NH:5][C:6](=O)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[CH2:2][CH2:3][CH3:4].C([O:22][C:23]([C:25]1[C:26]2[CH2:34][CH:33]([CH3:35])[CH2:32][CH2:31][C:27]=2[S:28][C:29]=1[NH2:30])=O)C>>[CH2:1]([N:5]1[C:23](=[O:22])[C:25]2[C:26]3[CH2:34][CH:33]([CH3:35])[CH2:32][CH2:31][C:27]=3[S:28][C:29]=2[N:30]=[C:6]1[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1cc(OC)c(OC)c(OC)c1
Reactant: CCOC(=O)c1c(N)sc2c1CC(C)CC2
Product: CCCCn1c(-c2cc(OC)c(OC)c(OC)c2)nc2sc3c(c2c1=O)CC(C)CC3

Procedure:
Compound No. 691 was prepared according to the method described for the compound No. 683 using N-butyl-3,4,5-trimethoxy-benzamide and 2-amino-5-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester as starting materials.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)O1.Cl[C:30]1[CH:35]=[N:34][N:33]2[C:36]([C:39]3[CH:40]=[C:41]([NH:45][C:46]([NH:48][CH2:49][C:50]([F:53])([F:52])[F:51])=[O:47])[CH:42]=[CH:43][CH:44]=3)=[CH:37][N:38]=[C:32]2[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[F:53][C:50]([F:51])([F:52])[CH2:49][NH:48][C:46]([NH:45][C:41]1[CH:40]=[C:39]([C:36]2[N:33]3[N:34]=[CH:35][C:30]([C:9]4[CH:10]=[CH:11][C:12]([N:15]5[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:19][CH2:20]5)=[N:13][CH:14]=4)=[CH:31][C:32]3=[N:38][CH:37]=2)[CH:44]=[CH:43][CH:42]=1)=[O:47]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)cnn23)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate (46.3 mg, 0.119 mmol, Aldrich, Cat. No. 654337), N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (40.0 mg, 0.108 mmol, Example 30, Step 3), tetrakis(triphenylphosphine)palladium(0) (6.25 mg, 0.00541 mmol) and sodium carbonate (34.4 mg, 0.324 mmol) in dioxane (1 mL) and water (0.3 mL) was degassed and recharged with nitrogen three times, and heated and stirred at 110° C. for 3 h. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was the desired product which was directly used in next step without further purification. LCMS (M+H)+: m/z=597.2.
Reaction SMILES: [C:1](=[O:18])(ON1C(=O)CCC1=O)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[N+:20]([C:23]1[CH:24]=[C:25]([C@@H:29]([NH2:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[N+:20]([C:23]1[CH:24]=[C:25]([C@@H:29]([NH:31][C:1](=[O:18])[O:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C[C@H](N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 118.4 %

Procedure:
Benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.36 g, 5.5 mmol) was added to a solution of (S)-1-(3-nitrophenyl)ethanamine HCl (1 g, 4.95 mmol) in CH2Cl2 (70 mL) and DIEA (2.2 mL, 12.4 mmol) and the reaction mixture was stirred for 1 h. The mixture was diluted with CH2Cl2 (100 mL), washed with NaHCO3, brine, dried over Na2SO4 and concentrated in vacuo to yield 59A (1.76 g, 99%) as a white solid. MS (ESI) m/z 323.02 (M+Na)+.
Reaction SMILES: [F:1][C@:2]1([CH3:19])[C@H:6]([OH:7])[C@@:5]([F:10])([CH2:8][OH:9])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].C1C(=O)N([Br:27])C(=O)C1>CN(C=O)C>[Br:27][C:15]1[C:14](=[O:17])[NH:13][C:12](=[O:18])[N:11]([C@H:3]2[C@@:2]([F:1])([CH3:19])[C@H:6]([OH:7])[C@@:5]([F:10])([CH2:8][OH:9])[O:4]2)[CH:16]=1
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: C[C@]1(F)[C@H](n2cc(Br)c(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Temperature: 80 °C
Yield: 104.5 %

Procedure:
In a 2 mL microwave vial, chiral 1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (70 mg, 0.252 mmol), and NBS (67.2 mg, 0.377 mmol), were dissolved in DMF (0.7 ml). The mixture was capped and heated under microwave irradiation at 80° C. for 10 min. LC/MS analysis indicated the starting material was completely consumed and the formation of the desired production as the only major product. The solvent was evaporated, and the residue was purified by a 2×4 g silica gel cartridge, eluted with 0-70% EtOAc in hexanes to provide the title compound as a white solid (94 mg, 90%)
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:54][NH:55][O:56][CH3:57].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:15]([N:55]([CH3:54])[O:56][CH3:57])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CNOC
Reactant: CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)OC
Reaction time: 0.05 h

Procedure:
To 400 μL CH2Cl2 was added 47.4 mg (200 μmole) of EtOCO-Phe, 34.8 mL (200 μmole) DIEA, and 88.4 mg (200 μmole) BOP. After 3 min, 19.4 mg (200 μmole) N,O-dimethyl-hydroxylamine.HCl and 34.8 mL (200 μmole) DIEA were added. The reaction was monitored by TLC, and after 45 min it was diluted with CH2Cl2, washed 2× with dilute HCl and 2× with saturated NaHCO3. The organic layer was dried with Na2SO4, filtered, and the filtrate evaporated by rotary evaporation to give the title compound. NMR (300 MHz, CDCl3): δ 7.20 (m, Ph, 5H), 4.82 (br m, Phe-α, 1H), 4.00 (q, CH3 CH2OCO, 2H), 3.62 (s, N(CH3)OCH3, 3H), 3.11 (s, N(CH3)OCH3, 3H), 3.00 (dd, Phe-b, 1H), 2.85 (dd, Phe-b, 1H), 1.17 (t, CH3CH2OCO, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:35][CH3:36])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:25][C:26]4[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=4[C:28]([NH2:30])=[O:29])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:38]N.[OH-].[K+]>CCOC(C)=O>[CH3:1][N:2]([CH3:37])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:35][CH3:36])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:25][C:26]4[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=4[C:28]([NH:30][CH3:38])=[O:29])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CN
Reactant: COc1cc2c(cc1Nc1nc(Nc3ccccc3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Temperature: 25 °C

Procedure:
The remaining reaction mixture from the preparation of 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide was diluted with a solution of methylamine (2M in THF 15 mL, 30 mmol). The resulting mixture maintained at rt for 2 days and was diluted with EtOAc (200 mL), washed with a saturated NaHCO3 solution (200 mL) and a saturated NaCl solution (125 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2, followed by trituration using a mixture of CH2Cl2 and Et2O. The crude product was dissolved in dioxane (13 mL) and was treated with a 1M aqueous KOH solution (1.121 mL, 1.121 mmol). The resulting mixture was heated at 90° C. for 6 h and was allowed to cool to rt and diluted with EtOAc (100 mL), washed with a saturated NaHCO3 solution (50 mL) and a saturated NaCl solution (50 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-methylbenzamide as a beige solid (70 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 6H), 2.83 (d, J=4.40 Hz, 3H), 3.04-3.28 (m, 4H), 3.78 (s, 3H), 4.18 (t, J=8.33 Hz, 2H), 6.23-6.38 (m, 1H), 6.87-7.07 (m, 3H), 7.60 Hz, 1H), 7.60 (s, 1H), 7.72 (d, 7.33 Hz, 1H), 8.64 (s, 1H), 8.67-8.81 (m, 1H), 8.90 (d, J=8.24 Hz, 1H), 11.26 (s, 1H), 11.73 (s, 1H); ESIMS (M+H)+=515.33.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:37](=[O:44])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH2:38].CC(C)([O-])C.[K+]>C1COCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:8]2[C:5]3[CH:6]=[N:7][C:2]([NH:38][C:37](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:3][C:4]=3[N:10]([C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc2c(cn1)c(-c1ccc(F)cc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
6-Chloro-3-(4-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.48 g, 3.02 mmol), tert-butyl carbamate (1.062 g, 9.06 mmol), and chloro(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (0.249 g, 0.362 mmol) was dissolved in THF (30 mL) then potassium tert-butoxide (6.65 mL, 6.65 mmol, 1 M in THF) was added. The reaction mixture was purged under argon for five minutes then heated to 80° C. and stirred overnight. The reaction mixture was diluted with DCM and washed with NaOH (1 N) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo while loading onto silica gel. The residue was purified by flash chromatography (2-20% EtOAc/isohexane) to give tert-butyl (3-(4-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)carbamate (403 mg, 0.706 mmol, 23%). MS ESI calc'd. For C36H31FN4O2 [M+1]+ 571, found 571.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](O)=[O:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C@H:24]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)[C@@H:25]([NH2:27])[CH3:26])=[CH:20][CH:21]=3)[CH:16]=[N:15]2)=[CH:10][CH:9]=1>C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C@H:24]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)[C@@H:25]([NH:27][C:3](=[O:4])[C@H:2]([OH:1])[CH3:6])[CH3:26])=[CH:20][CH:21]=3)[CH:16]=[N:15]2)=[CH:12][CH:13]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: C[C@@H](O)C(=O)O
Solvent: C1CCOC1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)[C@@H](C)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,1-carbonyldiimidazole (31 mg, 190 μmol) in THF (1 ml) was added (2R)-2-hydroxypropanoic acid (18 mg, 20 μmol) to give a colorless solution. The reaction mixture was stirred for 1 h at r.t. Then a solution of (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 39 mg, 100 μmol) in THF (0.5 ml) was added, and the stirring was continued at r.t. overnight. The solvent was removed in vacuo, the residue dissolved in acetonitrile/water mixture, and the crude product purified by preparative HPLC. Yield 16 mg (35%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:22]([O-])([N+]([O-])=O)=[O:23]>>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: COCC(C)N(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: COCC(C)N(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 27.8 %

Procedure:
3.3 g of 1-(2-chloroethyl)-3-(1-methyl-2-methoxy-ethyl)-3-(L-arabinopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 10-(2). 1.0 g of 1-(2-chloroethyl)-1-nitroso-3-(1-methyl-2-methoxy-ethyl)-3-(L-arabinopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([NH:11]CC2C=CC(OC)=CC=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:11][C:5]1[N:4]=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: COc1ccc(CNc2ncc(F)cc2C(N)=O)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(F)cnc1N
Yield: 81.2 %

Procedure:
5-Fluoro-2-(4-methoxy-benzylamino)-nicotinamide (220 mg, 0.80 mmol) in CH2Cl2 (2 ml) and anisole (1 ml) was treated with TFA (2.57 ml, 34.6 mmol) at 60° C. for 3 hours. The reaction mixture was brought to dryness and the residue purified by column chromatography (silica gel, EtOAc/heptane, 1/4) to yield 2-amino-5-fluoro-nicotinamide (100 mg, 0.65 mmol; 81%) as yellow solid. MS (m/e): 156.1 [M+H+].