Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: C1CCNC1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN3CCCC3)n1-2

Procedure:
A stirred mixture of 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (1.37 g., 0.004 mole), potassium iodide (0.67 g., 0.004 mole), pyrrolidine (0.853 g., 0.012 mole) and tetrahydrofuran (100 ml.) is kept at ambient temperature (25° C.) for 18 hours and then concentrated in vacuo. The residue is mixed with water and extracted with methylene chloride. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is crystallized to give 8-chloro-1-(pyrrolidinomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:24](O)=[O:25])[CH2:5][CH2:4]1)=[O:2].S(Cl)(Cl)=O.[CH3:31][N:32]([CH:34]=O)[CH3:33]>>[CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:24]([NH:3][C:9]2[CH:10]=[CH:11][C:12]([CH2:34][N:32]([CH3:31])[CH:33]3[CH2:22][CH2:21][O:20][CH2:17][CH2:16]3)=[CH:13][CH:8]=2)=[O:25])[CH2:5][CH2:4]1)=[O:2]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
In DMF (10.0 ml) was suspended 1-formyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (433 mg). To the suspension was added thionyl chloride (0.22 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and to the mixture was added THF (15.0 ml). On the other hand, to 4-[[N-methyl-N-tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (434 mg) was added THF (10.0 ml) and then added triethylamine (1.29 ml). The previously prepared acid chloride suspension was added dropwise at 0° C. The mixture was stirred at room temperature for 4 hours. To the mixture was added water, and the mixture was washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (554 mg, 81%) as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14][C@H:13]1[CH2:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C.O1CCOCC1>[NH2:18][C@@H:15]1[CH2:16][CH2:17][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:13]([CH2:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH2:14]1
Reactant: CC(C)S(=O)(=O)C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)C[C@@H]1C[C@H](N)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 114.6 %

Procedure:
A solution of tert-butyl(1R,3R,4S)-4-benzyloxycarbonylamino-3-(isopropylsulfonylmethyl)cyclohexylcarbamate (111 mg) in ethyl acetate (4 mL) was treated with a solution of HCl in dioxane (4.0 M, 4 mL). The mixture was stirred at rt for 50 min, then was concentrated to provide the hydrochloride salt of benzyl (1S,2R,4R)-4-amino-2-(isopropylsulfonylmethyl)cyclohexylcarbamate (100 mg) as a white glassy solid. MS found: (M+H)+=369.2.
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:26][O:27][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C@H:20]1[CH2:24][CH2:23][CH2:22][O:21]1)[C:11]3=[O:25].CC(=[N:31][OH:32])C.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[NH2:9][C:8]1[C:7]2[CH:6]=[C:5]3[C:10]4([C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[N:12]([CH2:19][C@H:20]5[CH2:24][CH2:23][CH2:22][O:21]5)[C:11]4=[O:25])[CH2:26][O:27][C:4]3=[CH:3][C:2]=2[O:32][N:31]=1
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Reactant: CC(C)=NO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1noc2cc3c(cc12)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 20.4 %

Procedure:
To a stirred solution of 6-fluoro-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.59 g, 1.6 mol) and acetone oxime (0.35 g, 4.8 mmol) in N,N-dimethylformamide (20 mL) was added cesium carbonate (1.56 g, 4.8 mmol). The reaction mixture was stirred at ambient temperature for 19 h, then heated at 60° C. for 7 h and allowed to cool to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in a mixture of ethanol (30 mL), water (10 mL), and concentrated hydrochloric acid (2 mL) and stirred at reflux for 4 h. The mixture was allowed to cool to ambient temperature and neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with (ethyl acetate/hexanes (1/3)+0.1% v/v 7 N methanolic ammonia) to afford 3-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.37 g, 60%): mp 116-119° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.35-7.32 (m, 1H), 7.13-7.02 (m, 3H), 6.09 (s, 1H), 6.84-6.81 (m, 1H), 4.91 (ABq, 2H), 4.31-4.25 (m, 1H), 4.13-4.09 (m, 2H), 3.86-3.66 (m, 4H), 2.12-1.87 (m, 4H); (ES+) m/z 377.9 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH2:30][CH2:29]2)(=[O:25])=[O:24]>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:31]3[C:32]4[C:28](=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:34][CH:33]=4)[CH2:29][CH2:30]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N3CCc4cc(S(C)(=O)=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 5-(methylsulfonyl)indoline (intermediate-26) (0.160 g, 48.0%).
Reaction SMILES: [CH3:1][N:2]([CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:27][CH:26]=2)[CH2:16][CH2:15][CH2:14]1)[CH2:3][CH2:4][CH2:5][O:6]C1CCCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C(O)C>[CH3:1][N:2]([CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:41])[C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:29][CH:30]=2)[CH2:16][CH2:15][CH2:14]1)[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CCCOC3CCCCO3)c3ccccc32)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CCCO)c3ccccc32)cc1
Temperature: 60 °C
Yield: 55.7 %

Procedure:
To a solution of 5-{N-methyl-N-[3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propyl]amino}-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) in ethanol (10 ml) is added pyridinium p-toluenesulfonate (0.03 g) and the mixture is heated at 60° C. overnight. After the mixture is refluxed for more 2 hours, water and pyridinium p-toluenesulfonate (0.03 g) are added thereto. The mixture is refluxed for 4 hours. The reaction solution is concentrated and to the resulting residue is added dichloromethane. The mixture is basified with aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1) to give 5-[N-methyl-N-(3-hydroxypropyl)amino]-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.26 g) as colorless amorphous.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)[CH:3]([OH:6])[CH2:4][OH:5].C(N(CC)CC)C.C1C(=O)N([O:37][C:38]([CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])=O)C(=O)C1>CN(C=O)C>[CH2:45]([O:44][C:42](=[O:43])[NH:41][CH2:40][C:38](=[O:37])[NH:1][CH:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)[CH:3]([OH:6])[CH2:4][OH:5])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: NC(Cc1cc(F)cc(OCc2ccccc2)c1)C(O)CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)OCc1ccccc1)NC(Cc1cc(F)cc(OCc2ccccc2)c1)C(O)CO
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a solution of 3-amino-4-(3-benzyloxy-5-fluoro-phenyl)-butane-1,2-diol (5.60 g, 18.34 mmol, 1.00 eq.), triethylamine (5.11 mL, 36.68 mmol, 2.00 eq.) and anhydrous DMF (100 mL) at 0° C. is added Z-glycine N-succinimidyl ester (6.18 g, 20.17 mmol, 1.10 eq.) with stirring under N2. After 2 hours, the reaction is quenched with 1N HCl, extracted with ethyl acetate, and washed with 10% NaHCO3 and then brine. The organic layer is then dried with MgSO4, filtered through Celite, and concentrated in vacuo, yielding the crude product as a light amber oil. Purification via flash chromatography in 5% MeOH/CHCl3 (rf. 0.33, KMnO4 stain), affords the final product as a white solid (5.40 g., 59% yield overall). Calculate mass for C27H29FN2O6: 496.20. Mass found for C27H29FN2O6: (OAMS) ES+: 497.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH2:13]Cl.[CH3:21][NH2:22]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@H:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH2:13][NH:22][CH3:21]
Reactant: CN
Reactant: ClCCC(c1ccccc1)n1ccc2c(Cl)cccc21
Product: CNCC[C@@H](c1ccccc1)n1ccc2c(Cl)cccc21

Procedure:
4-chloro-1-(3-chloro-1-phenyl-propyl)-1H-indole (0.228 g) was reacted with methylamine following the procedure of step 3 of Example 11 to afford 0.135 g of (S)-[3-(4Chloro-indol-1-yl)-3-phenyl-propyl]-methyl-amine, (M+H=300).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:9](=[CH:10][N:11]=[C:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:13]=3)[N:8]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[N:7]=2)=[N:2]1.[C:27]([N:34]1[CH2:39][CH2:38][CH:37](Br)[CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[CH:13]=[C:14]3[C:6]([C:3]4[CH:4]=[CH:5][N:1]([CH:37]5[CH2:38][CH2:39][N:34]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:35][CH2:36]5)[N:2]=4)=[N:7][N:8]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:9]3=[CH:10][N:11]=2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: c1cncc(-c2cc3c(-c4cc[nH]n4)nn(C4CCCCO4)c3cn2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Temperature: 100 °C

Procedure:
A mixture of 3-(1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (44.0 mg, 0.13 mmol), 1-N—BOC-4-bromopiperidine (100.8 mg, 0.38 mmol), and Cesium Carbonate (124.3 mg, 0.38 mmol) in N,N-Dimethylformamide (5 mL) was heated at 100° C. for 7 days. The mixture was concentrated to afford tert-butyl 4-(3-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, which was used without purification.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C([BH3-])#N.[Na+]>>[F:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][NH:3][O:2][CH3:1])=[CH:12][CH:11]=1
Reactant: CON=CCCc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCCCc1ccc(F)cc1
Yield: 75 %

Procedure:
Reduction of 3-(4-fluorophenyl)-propionaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 1-B gave the title hydroxylamine as a clear oil after chromatography on silica gel and distillation in vacuo (75% yield): bp 70-75° C./0.7 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CHCl3) δ (ppm): 1.85 (2H, m, CH2), 2.68 (2H, t, J=7.9 Hz, CH2), 2.95 (2H, t, J=7.1 Hz, CH2), 3.56 (3H, s, OCH3), 5.58 (1H, broad, NH), 6.99 (2H, m, aromatics), 7.17 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 97-100° C. Anal. calcd for C10H14FNO—HCl: C, 54.67; H, 6.88; N, 6.38. Found: C, 54.72; H, 6.71; N, 6.42.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3](=O)[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Cl.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1>C(O)(=O)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:5]([C:6]3[CH:7]=[C:8]([C:12]4[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:4][C:3]([C:2]([F:25])([F:1])[C:21]([F:24])([F:23])[F:22])=[N:35]2)=[CH:30][CH:29]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CSc1ccc(-c2cccc(C=CC(=O)C(F)(F)C(F)(F)F)c2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(Cl)cc3)c2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
4,4,5,5,5-Pentafluoro-1-(4′-methylsulfanyl-biphenyl-3-yl)-pent-1-en-3-one (200.0 mg, 0.54 mmol) prepared in Step 3 of Preparation 4 and 4-chlorophenylhydrazine hydrochloride (106.0 mg, 0.59 mmol) were added to acetic acid (3.0 mL). The reaction mixture was stirred at 120° C. for 8 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 163.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]([C:28]3[O:29][C:30](=[O:43])[C:31]4[C:36]([C:37]=3[C:38]3[S:42][CH:41]=[N:40][CH:39]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][Si](C(C)(C)C)(C)C)[CH:12]=3)[C:3]=12>Cl.CCO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]([C:28]3[O:29][C:30](=[O:43])[C:31]4[C:36]([C:37]=3[C:38]3[S:42][CH:41]=[N:40][CH:39]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:27])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([F:17])[CH:16]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1cncs1)n1nc(-c2cc(F)cc(O[Si](C)(C)C(C)(C)C)c2)c2c(N)ncnc21
Agent: Cl
Solvent: CCO
Product: CC(c1oc(=O)c2ccccc2c1-c1cncs1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
3-(1-(4-amino-3-(3-((tert-butyldimethylsilyl)oxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(thiazol-5-yl)-1H-isochromen-1-one single enantiomer (intermediate R2, first eluted enantiomer under the conditions described above, 0.084 g, 0.13 mmol) was dissolved in a solution of 1M HCl in EtOH (0.416 ml) and the mixture was stirred at RT overnight. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography on silica gel cartridge (DCM to DCM:MeOH=95:5) to afford title compound as a pale blue solid (0.043 g, 0.086 mmol, 66%). This compound proved to be the first eluted enantiomer under Chiral HPLC conditions of Method A7: Rt=16.0 min, ee>99%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].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>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-c2ccc(Cl)cc2)nc1
Temperature: 100 °C
Yield: 103.8 %

Procedure:
A flask was charged with 2-bromo-5-nitropyridine (4 g, 19.71 mmol), 4-chlorophenylboronic acid (4.54 g, 27.6 mmol), Pd(PPh3)4 (1.139 g, 0.985 mmol), potassium carbonate (8.16 g, 59.1 mmol), dioxane (40 ml) and water (20 ml) at room temperature. The flask was sealed, flushed with nitrogen for three times and heated at 100° C. for 3 hours. The reaction mixture was diluted with EtOAc (100 ml) and filtered. The filtrate was concentrated. The residue was washed with water by filtration. The afforded solid was dissolved in EtOAc (200 ml) and washed with saturated aqueous sodium bicarbonate solution and brine, dried over Na2SO4, concentrated, and dried under vacuum to afford crude 2-(4-chlorophenyl)-5-nitropyridine (4.8 g, 75% purity, 78% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 7.27-7.36 (m, 4H) 7.51-7.61 (m, 3H).
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([C:7]1[CH:8]=[C:9]([F:49])[C:10]([NH:21][CH:22]2[CH2:27][CH2:26][N:25](C(OCC3C=CC=CC=3)=O)[CH2:24][CH:23]2[N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])=[N:11][C:12]=1[NH:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=1)#[N:6]>[Pd].C(OCC)(=O)C.CO>[O:48]=[C:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:46](=[O:47])[N:38]1[CH:23]1[CH:22]([NH:21][C:10]2[C:9]([F:49])=[CH:8][C:7]([C:5]#[N:6])=[C:12]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=3)[N:11]=2)[CH2:27][CH2:26][NH:25][CH2:24]1
Reactant: Cc1cncc(Nc2nc(NC3CCN(C(=O)OCc4ccccc4)CC3N3C(=O)c4ccccc4C3=O)c(F)cc2C#N)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cncc(Nc2nc(NC3CCNCC3N3C(=O)c4ccccc4C3=O)c(F)cc2C#N)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
Ammonium formate (6 mg) and 10% Pd/C (6 mg) were added to an ethyl acetate/MeOH (1 ml/1 ml) solution containing benzyl 4-((5-cyano-3-fluoro-6-((5-methylpyridin-3-yl)amino)pyridin-2-yl)amino)-3-(1,3-dioxoisoindolin-2-yl)piperidin-1-carboxylate (37 mg) obtained in the 1st step in a nitrogen atmosphere, followed by heating and stirring at 70° C. for 1 hour. Next, ammonium formate (30 mg) and 10% Pd/C (30 mg) were added to the solution, followed by heating and stirring at 70° C. for 1 hour. The reaction solution was cooled to room temperature and insoluble matter was removed by filtration through Celite. Filter cake was washed with ethyl acetate. The resulting filtrate was mixed with wash liquid. The obtained organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. A white solid of 6-((3-(1,3-dioxoisoindolin-2-yl)piperidin-4-yl)amino)-5-fluoro-2-((5-methylpyridin-3-yl)amino)nicotinonitrile (15 mg) was thus obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][N:14]1[CH:18]=[C:17]([CH:19]=O)[C:16]([CH3:21])=[N:15]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][N:14]1[CH:18]=[C:17]([CH:19]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[C:16]([CH3:21])=[N:15]1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: Cc1nn(C)cc1C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1nn(C)cc1C=C1N=C(c2cccs2)OC1=O
Temperature: 90 °C
Yield: 29.3 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 1,3-dimethyl-1H-pyrazol-4-carboxaldehyde (41 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 24 mg of the above-captioned compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[N:17]=[C:18](Cl)[S:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[N:17]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2csc(Cl)n2)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2csc(-c3ccccc3)n2)c1

Procedure:
The chloro thiazole (114) (80 mg, 0.24 mmol) was coupled to phenylboronic acid (32 mg, 0.26 mmol) using Method E, except that the reaction mixture was heated for a total of 4 h. The crude residue was purified by column chromatography eluting with 25% EtOAc in heptane to give the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25]4([C:28]([OH:30])=O)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[NH3:39]>>[OH:1][C:2]([CH3:37])([CH3:38])[CH2:3][C@@:4]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25]4([C:28]([NH2:39])=[O:30])[CH2:26][CH2:27]4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(-c2ccc(C3(C(=O)O)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: N
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 50 %

Procedure:
The title compound was prepared from 1-[6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazin-3-yl]-cyclopropanecarboxylic acid and ammonia (32% in water) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 50% of theory; LC (method 1): tR=1.72 min; Mass spectrum (ESI+): m/z=515 [M+H]+.