Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(O)=O.[Na+].C([O-])(=O)C.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([C:23]3[CH:24]=[C:25]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][N+:47]([CH3:50])([CH3:49])[CH3:48])=[O:42])[C:26](=[O:40])[N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)[C:28]=3[CH3:29])=[CH:21][CH:20]=[N:19]2)=[CH:14][CH:13]=1)#[N:11].[C:51]1([S:57]([OH:60])(=[O:59])=[O:58])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(OCC)C>CO>[C:51]1([S:57]([O-:60])(=[O:59])=[O:58])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.[C:10]([C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:22]([C:23]3[CH:24]=[C:25]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][N+:47]([CH3:49])([CH3:48])[CH3:50])=[O:42])[C:26](=[O:40])[N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)[C:28]=3[CH3:29])=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:17]=1)#[N:11]
Reactant: O=S(=O)(O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCC[N+](C)(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CO
Product: O=S(=O)([O-])c1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A column of DOWEX 1×8 (50-100 mesh, Cl−) (approximately 10 g) was activated by passing through a aqueous saturated NaHCO3-solution (approximately 70 mL), followed by washing with H2O (100 mL) (until the pH of the eluent was neutral) and MeOH (40 mL). 3-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamido)-N,N,N-trimethylpropan-1-aminium acetate (300 mg, 0.48 mmol, Example 8) was dissolved in MeOH (2 mL) and the solution was allowed to pass slowly through the column followed by about 20 mL of MeOH. Benzenesulfonic acid (76 mg, 0.48 mmol) was added to the filtrate and the solution was evaporated, the residue was co-evaporated with EtOH and then dissolved in EtOH (0.5 mL) and THF (3.5 mL). The mixture was heated at 50° C. for 0.5 hr and was then stirred at room temperature over the weekend. No precipitate had formed over this time. Diethylether (3 mL) was added and the mixture was stirred at room temperature. After 1 hr a solid had started to precipitate and the slurry was stirred overnight. The precipitate was filtered off, washed with heptane and dried to afford the title compound as an off-white solid (300 mg, 86%); 1H NMR (400 MHz, dmso) δ 1.81 (3H, s), 1.90 (2H, m), 3.01 (9H, s), 3.27 (4H, m), 6.72 (1H, d), 7.30 (3H, m), 7.59 (2H, m), 7.67 (2H, d), 7.71 (1H, d), 7.85 (2H, m), 7.94 (4H, m), 8.04 (1H, s), 9.41 (1H, t). APCI-MSm/z: 563 [M+]
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:91]=[CH:90][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][CH2:73][CH2:74][C@H:75]([NH:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[C:76](OCC#N)=[O:77])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]>C(#N)C>[N:60]([C:63]1[CH:91]=[CH:90][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][CH2:73][CH2:74][C@@H:75]([NH:82][C:83]([O:85][C:86]([CH3:87])([CH3:89])[CH3:88])=[O:84])[C:76]([O:40][C@H:39]2[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36][C@H:35]2[CH2:34][O:33][P:30]([O:29][C@H:28]2[CH2:27][C@H:26]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:25][C@@H:24]2[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:77])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.8 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (143 mg, 0.224 mmol) and (S)-cyanomethyl 5-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk58) (400 mg, 0.896 mmol) in acetonitrile (1 mL) was added to buffer A (33 mL), and the mixture was stirred at room temperature for 1.5 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk59) (54.7 mg, 24%).
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]([CH3:5])[CH3:4].[CH3:7][C:8](=[CH:11][CH2:12][CH3:13])[CH:9]=[O:10]>CCOCC>[CH3:7][C:8]([CH:9]([OH:10])[CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:11][CH2:12][CH3:13]
Reactant: CC(C)CBr
Reactant: CCC=C(C)C=O
Agent: [Mg]
Solvent: CCOCC
Product: CCC=C(C)C(O)CC(C)C

Procedure:
The Grignard reagent obtained by reacting 11.8 g (0.49 g-atoms) of magnesium in 50 ml of ether with 67.13 g (0.49 mol) of isobutyl bromide in 250 ml of ether is reacted with 40.0 g (0.41 mol) of 2-methyl-2-pentenal in 100 ml of ether. The fractional distillation of the crude product (94 g) over a 20 cm Widmer column gives 44.4 g (69.4%) of olfactorily good 4,7-dimethyl-3-octen-5-ol of boiling point 47°-48° C./0.04 Torr.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[O:32]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:33])[N:23]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccccc2OC)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccccc1-c1csc(N2C(=O)c3ccccc3C2=O)c1C(=O)O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-(2-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 17, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][C:9]1[O:13][C:12]2[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1)=[O:5])C.[OH-].[Na+].C(O)C.Cl>O>[C:4]([CH2:6][CH2:7][CH2:8][C:9]1[O:13][C:12]2[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCc1cc2cccc([N+](=O)[O-])c2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCc1cc2cccc([N+](=O)[O-])c2o1
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
A solution of 2-(3-ethoxycarbonylpropyl)-7-nitrobenzo[b]furan (1.0 g) in a mixture of aqueous 1N-sodium hydroxide (7.2 ml) and ethanol (5 ml) was stirred at 50° C. for 1 hour. The reaction mixture was diluted with water and acidified with 4N-hydrochloric acid. The separated solid was collected, washed with water and dried to give 2-(3-carboxypropyl)-7-nitrobenzo[b]furan (752 mg).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].[CH3:15][C:16]1[N:20]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)[N:19]=[CH:18][C:17]=1[C:31]([NH:33][C:34]1[CH:35]=[N:36][C:37]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[C:38]([CH3:40])[CH:39]=1)=[O:32].ClCCl>O>[CH3:8][N:9]([CH3:14])[S:10]([N:44]1[CH2:43][CH2:42][CH:41]([C:37]2[N:36]=[CH:35][C:34]([NH:33][C:31]([C:17]3[CH:18]=[N:19][N:20]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)[C:16]=3[CH3:15])=[O:32])=[CH:39][C:38]=2[CH3:40])[CH2:46][CH2:45]1)(=[O:12])=[O:11]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCNCC1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(S(=O)(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
Triethylamine (73 μl) and dimethylsulfamoyl chloride (56 μl) were added to a mixture of 5-methyl-N-[5-methyl-6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (222 mg) described in Reference Example 171 and dichloromethane (10 ml), stirred at room temperature for 6.5 hours, triethylamine (146 μl) and dimethylsulfamoyl chloride (56 μl) were added and stirred at room temperature for 7.5 hours. Water was added to the reaction solution, extracted with chloroform, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The precipitated solid was washed with ethyl acetate and ethanol to give the titled compound (122 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]([N:48]3[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]3)=[N:46][CH:47]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:42]4[CH:43]=[CH:44][C:45]([N:48]5[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]5)=[N:46][CH:47]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Yield: 69 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (150 mg, 0.286 mmol) was coupled with tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (intermediate 69C) (167 mg, 0.429 mmol) in sodium carbonate (76 mg, 0.715 mmol), Pd(PPh3)2Cl2 (10 mg, 0.014 mmol), DME/water (5/1 mL). This afforded 140 mg (69.0% yield) after purification by column chromatography (60-120 silica gel) using 2% methanol in DCM as eluent. MS: m/z=708.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=O.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Si]([N:36]=[N+:37]=[N-:38])(C)(C)C.C([O-])(O)=O.[Na+]>CC#N.O.CCOC(C)=O>[CH:14]1([C:12]2[N:11]([C:3]3[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=3[F:1])[N:38]=[N:37][N:36]=2)[CH2:16][CH2:15]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1F)C1CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(F)c(-n2nnnc2C2CC2)c1
Reaction time: 0.03 h
Yield: 44.9 %

Procedure:
A stirred solution of N-(2-fluoro-5-nitrophenyl)cyclopropanecarboxamide (210 mg, 1.0 mmol) in MeCN (6 mL) under nitrogen was cooled to −10 to −20° C. (ice/MeOH bath) and a precipitate developed. Tf2O (0.34 mL, 2.0 mmol) was added dropwise over 3-5 min (a solution developed). The mixture was stirred in the cold bath for a further 2 min then TMS-N3 (0.53 mL, 4.0 mmol) was added dropwise over 2 min (bath temp ca. −10° C.). After complete addition, the mixture was stirred for 90 min (bath temperature ca. 15° C.). The mixture was worked-up by addition of EtOAc (30 mL) and saturated NaHCO3 (15 mL). After stifling for 2 min, the mixture was placed in a separating funnel and H2O (30 mL) added. The aqueous and organic layers were partitioned and the aqueous layer extracted with EtOAc (2×20 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent removed under vacuum to leave a crude residue. The residue was dry-loaded on to silica gel then purified by column chromatography on silica gel using EtOAc/heptane (2:8 to 4:6) as eluent to give the desired product (112 mg, 45% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[N:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][N:21]([CH2:31][C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)[C:20](=[O:24])[N:19]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:25]([F:26])([F:28])[F:27]
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Reactant: Cn1cc(CCl)cn1
Agent: Cl
Product: Cn1cc(Cn2ccc(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting with 4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-2(1H)-pyrimidinone and 4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride. LC-MS (ESI): m/z 505 [M+H]+; 4.28 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]#[N:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:15])[CH3:16])[C:11]([C:17]#[N:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-cyano-5-dimethylamino-phenyl)-carbamic acid tert-butyl ester (Example J23) (276 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl)-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (320 mg, 64%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:25]1[CH:26]=[N:27][N:28]([CH:30]2[CH2:33][CH:32]([C:34]([O:36][CH3:37])=[O:35])[CH2:31]2)[CH:29]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:26]=[N:27][N:28]([CH:30]3[CH2:33][CH:32]([C:34]([O:36][CH3:37])=[O:35])[CH2:31]3)[CH:29]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][CH:21]=[CH:22][N:23]=2)[CH:3]=1
Reactant: COC(=O)C1CC(n2cc(Br)cn2)C1
Reactant: Cc1cc(Nc2ncccn2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C1CC(n2cc(-c3cc(C)cc(Nc4ncccn4)c3)cn2)C1
Temperature: 90 °C

Procedure:
A mixture of N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine (220 mg, 0.707 mmol), methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 1) (183 mg, 0.707 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), X-phos (34 mg, 0.071 mmol), and cesium carbonate (691 mg, 2.12 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was degassed via a subsurface argon sparge for 5 minutes. The mixture was then heated to 90° C. under an argon atmosphere for 2 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (100 mL) and water (25 mL). The organic layer was separated and washed with water (25 mL) and then brine (25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (0-100% ethyl acetate/hexanes) to afford methyl 3-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 1) MS ESI calc'd. for C20H22N5O2 [M+H]+ 364. found 364. 1H NMR (500 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.46 (d, J=4.5 Hz, 2H), 8.16 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.40 (s, 1H), 6.98 (s, 1H), 6.81 (t, J=5.0 Hz, 1H), 5.05-5.00 (m, 1H), 3.67 (s, 3H), 3.24-3.17 (m, 1H), 2.81-2.74 (m, 2H), 2.67-2.60 (m, 2H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:6]2.[H-].[Na+].CN(C)C=O.[CH3:26][O:27][CH2:28]Cl>O1CCCC1.C(OCC)(=O)C>[CH3:26][O:27][CH2:28][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=2[N+:11]([O-:13])=[O:12])[CH:4]=[C:5]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COCCl
Reactant: CCOC(=O)c1cc2c(C)ccc([N+](=O)[O-])c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C)ccc([N+](=O)[O-])c2n1COC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of ethyl 4-methyl-7-nitro-1H-indole-2-carboxylate (7.0 g), 60% sodium hydride (1.35 g) and N,N-dimethylformamide (40 ml) was stirred at room temperature for 30 min. This solution was ice-cooled, and a solution of chloromethyl methyl ether (2.6 ml) in tetrahydrofuran (15 ml) was added dropwise. The mixture was stirred at 4° C. for 4 hr, and the reaction solution was diluted with ethyl acetate, washed with saturated brine, aqueous citric acid solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:95-1:5) to give the title compound (5.6 g, yield 68%) as pale-yellow needle crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[CH:21]([CH3:22])[CH2:20][CH:19]([C:23]([NH:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:35][NH2:36]>CCO>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:21]([CH3:22])[CH2:20][C@H:19]([C:23]([NH:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:36][N:35]=1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CC(C(=O)NCc3ccccc3)CC2C)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)C[C@H]2C)n1
Temperature: 100 °C

Procedure:
To a suspension of racemic (3S,5R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide (360 mg total, 0.81 mmol) in EtOH (50 mL) at room temperature was added hydrazine monohydrate (2 mL) in one portion. The suspension was heated in an oil bath to 100° C. for 20 hours. LCMS showed there was still 40% starting material remaining. To the mixture was added 2 mL of hydrazine monohydrate, followed by heating to 100° C. for another 24 h. LCMS showed conversion complete. The mixture was cooled to room temperature, and filtered through celite. The filtrate was concentrated in vacuo, and the resulting residue was taken up in 8 mL of water to form a suspension, which was briefly sonicated. The mixture was filtered. The solids collected were combined with another run starting with 190 mg of racemic (3S,5R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide. The combined crude products were purified by silica gel column chromatography using gradient elution of 1% A in CHCl3 to 75% A in CHCl3. A was a mixture of 800/80/3200 CH3OH/NH4OH/CHCl3. Trituration of the purified material in a mixture of CHCl3 (2 mL) and hexane (8 mL), followed by drying under vacuum at 65° C. for 14 hours afforded the title compound (228 mg) as a beige powder. LC-MS (ES) m/z=457 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.42 (d, J=6.1 Hz, 3H), 2.00-2.06 (m, 1H), 2.52-2.58 (m, 1H), 2.99 (s, 3H), 3.00-3.10 (m, 1H), 3.68-3.73 (m, 1H), 3.95-4.10 (bs, 1H), 4.21-4.33 (bs, 1H), 4.39-4.47 (m, 2H), 6.23 (s, 1H), 7.25-7.37 (m, 5H), 7.52 (dd, J=8.5, 1.1 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.85 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[C@@H:13](Br)[C@H:12]([OH:15])[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[O:5]1>CS(C)=O>[CH3:3][C:4]1([CH3:16])[CH:13]2[O:15][CH:12]2[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[O:5]1
Reactant: CC1(C)Oc2ccncc2[C@@H](O)[C@@H]1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)Oc2ccncc2C2OC21

Procedure:
0.4 g of a 60% strength oil dispersion of NaH are added to a solution of 2.82 g of trans-2,2-dimethyl-3-bromo-6-azachroman-4-ol in 15 ml of DMSO, with stirring. The mixture is stirred for 1 hour, 2,2-dimethyl-3,4-epoxy-6-azachroman being intermediately formed. 1.43 g of 1H-2-pyridone and a further 0.5 g of NaH dispersion are added and the mixture is stirred at 20° for 16 hours. Working up analogously to Example 1 gives "A", melting point 208°-210°.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:8][C:9]([OH:11])=O)=[C:5]([CH3:7])[N:6]=1.[CH2:12]([C@@H:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:20][N:21]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:22][CH2:23][N:24]1[C:9](=[O:11])[CH2:8][C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[CH3:7])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: Cc1nc(C)c(CC(=O)O)s1
Product: COc1ccc(N2CCN(C(=O)Cc3sc(C)nc3C)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using (2,4-dimethyl-thiazol-5-yl)-acetic acid and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as starting materials to afford product as an oil. LC/MS (Method B) 2.46 min, [M+1]+ 505. Potency class B.