Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].[CH2:2](Cl)[C:3]([CH3:6])([CH3:5])[CH3:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](F)[C:10]=1[C:16]1[O:17][CH2:18][C:19](C)(C)[N:20]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:4][C:3]([CH3:6])([CH3:5])[CH2:2][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[C:10]=1[C:16]([NH:20][CH2:19][CH3:18])=[O:17]
Reactant: CC(C)(C)CCl
Reactant: CC1(C)COC(c2c(F)cccc2F)=N1
Agent: O=C([O-])O
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)c1c(F)cccc1CC(C)(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
A solution of p,p'-di-t-butyl biphenyl (5.559 g, 0.021 mol) and THF (100 mL) was stirred at 0° C. under an atmosphere of argon. Lithium wire (0.021 mol, 0.15 g) was added in small pieces and the mixture was allowed to stir at 0° C. for 24 h. The mixture was cooled to -78° C. and neopentyl chloride (2.0 g, 0.01875 mol) was added dropwise. The mixture was stirred at -78° C. for 1 h, and the compound of Example g (3.17 g, 0.015 mol) was added all at once. The mixture was continuously stirred or 4 h and 50 mL sat aq NaHCO3 was added. This mixture as extracted with three 50 mL portions of ethyl acetate. The combined extracts were washed twice with water, dried (MgSO4), and concentrated. The crude concentrate was purified by HPLC eluting with 1:4 ethyl acetate/hexanes. The oxazoline was as a clear oil in 27% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:18])[C:9]2[C:17]3[CH:16]=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[C:6]([F:19])[CH:5]=[CH:4][C:3]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[F:1][C:2]1[C:7]([C:8]([C:9]2[C:17]3[CH:16]=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[O:18])=[C:6]([F:19])[CH:5]=[CH:4][C:3]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncncc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncncc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To propane-1-sulfonic acid 2,4-difluoro-3-[hydroxy-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl-amide (P-0001, 0.150 g, 0.392 mmol), 3 mL of tetrahydrofuran was added, followed by Dess-Martin periodinane (0.166 g, 0.392 mmol). The reaction was allowed to stir at room temperature for 1 hour, then the reaction was extracted with ethyl acetate and 5:1 saturated sodium bicarbonate:saturated sodium thiosulfate. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with a gradient of 1 to 5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to give the desired compound (P-0002, 110 mg). MS(ESI)[M+H+]+=381.2. LC/MS indicated 97.0% purity.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:11]/[S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C@H:8]([NH:11][S:12]([C:14]([CH3:15])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC/C(=N\S(=O)C(C)(C)C)c1ccnc(Br)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](NS(=O)C(C)(C)C)c1ccnc(Br)c1
Reaction time: 2.5 h

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid [1-(2-bromo-pyridin-4-yl)-prop-(E)-ylidene]-amide (6.0 g, 19 mmol) in THF (280 mL) was added a 1 M solution of L-Selectride in THF (37.8 ml, 37.8 mmol) dropwise. After 2.5 hours, the reaction mixture was quenched with saturated aqueous NH4Cl (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×400 mL). The combined organic layers were washed with brine, and concentrated. The residue was purifed by silica gel chromatography eluting with a gradient of 0-100% EtOAc in hexanes to afford an oily solid, which after further drying provided 2-methyl-propane-2-sulfinic acid [(R)-1-(2-bromo-pyridin-4-yl)-propyl]-amide as a crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:26]1([CH:29]=[CH:30]B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:30]=[CH:29][CH:26]2[CH2:28][CH2:27]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(C=CC2CC2)OC1(C)C
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=CC2CC2)Cc2ccccc2C1
Yield: 47.9 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (600 mg, 1.34 mmol) and 2-(2-cyclopropyl-vinyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.11 mL, 5.36 mmol) in EtOH (10 mL) and dioxane (10 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0), (4.84% Pd, 285 mg, 0.13 mmol) and 2M aqueous solution of K2SO4 (2.68 mL, 5.36 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (137) as white solid (250 mg, 49%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]=[N+]=[N-])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+]>CO>[CH2:23]([NH:1][CH2:2][CH2:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(Oc2ccc(CCN)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
Take up the mixture of 4-[4-(2-aminoethyl)phenoxy]benzenesulfonyl azide (0.210 g, 0.661 mmol) in methanol (9.9 mL). Add benzaldehyde (0.20 mL, 1.98 mmol) and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH4 (0.075 g, 1.98 mmol) and stir for 1.5 hours. Filter the reaction mixture and purify by flash 40 chromatography, eluting with 3% (2.0 M NH3 in methanol), 30% hexanes and 67% ethyl acetate to give the title compound (0.0696 g, 25.8%): TOF MS ES+ 383.1 (M+H)+, HRMS calcd for C21H23N2O3S 383.1429 (M+H)+, found 383.1436, time 0.33 min; TLC [silica gel 60 F254, 10% (2.0 M NH3 in methanol) in dichloromethane] Rf=0.31.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:5][C:6]([CH3:13])=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1.S(=O)(=O)(O)O>>[CH3:13][C:6]1[NH:5][C:4]([CH:3]=[O:2])=[N:8][C:7]=1[C:9]([F:12])([F:10])[F:11]
Reactant: COC(OC)c1nc(C(F)(F)F)c(C)[nH]1
Agent: O=S(=O)(O)O
Product: Cc1[nH]c(C=O)nc1C(F)(F)F
Yield: 7.9 %

Procedure:
The same operation as in Example (33b) was performed using 2-(dimethoxymethyl)-5-methyl-4-(trifluoromethyl)-1H-imidazole obtained in Example (36b) (about 2.17 mmol) and 2 N sulfuric acid (15 mL), to obtain 30.5 mg of the title compound as a white solid (7.9%).
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1.Cl.[CH:27](O)(C)C>>[OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[C:19]([O:21][CH:22]([CH3:27])[CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Ethyl 4',5,7-trihydroxy-2-isoflavonecarboxylate (100 mg) was added to 10 ml of isopropanol saturated with HCl gas, and the mixture was heated at 70° C. with stirring for five hours. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform), and the solid thus obtained was recrystallized from a chloroform/methanol mixed solvent, giving 60 mg of isopropyl 4',5,7-trihydroxy-2-isoflavonecarboxylate.
Reaction SMILES: C(C1[C:11]2[C:6](=[N:7][C:8](CC)=[CH:9][C:10]=2CC)N(C2C3C(=CC=CC=3)CC2)C=1/C=C/C(NC1CCOC(C)(C)C1)=O)#N.[C:38]([C:40]1[C:48]2[C:43](=[N:44][C:45]([CH2:51][CH3:52])=[CH:46][C:47]=2[CH2:49][CH3:50])[N:42]([CH:53]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH2:55][CH2:54]2)[C:41]=1/[CH:62]=[CH:63]/[C:64]([NH:66]C1C=NC=CC=1)=[O:65])#[N:39].C(C1C2C(=NC(CC)=CC=2CC)N(C2C3C(=CC=CC=3)CC2)C=1/C=C/C(O)=O)#N.NC1C=CN=CC=1>>[C:38]([C:40]1[C:48]2[C:43](=[N:44][C:45]([CH2:51][CH3:52])=[CH:46][C:47]=2[CH2:49][CH3:50])[N:42]([CH:53]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH2:55][CH2:54]2)[C:41]=1/[CH:62]=[CH:63]/[C:64]([NH:66][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][CH:11]=1)=[O:65])#[N:39]
Reactant: CCc1cc(CC)c2c(C#N)c(/C=C/C(=O)Nc3cccnc3)n(C3CCc4ccccc43)c2n1
Reactant: CCc1cc(CC)c2c(C#N)c(/C=C/C(=O)NC3CCOC(C)(C)C3)n(C3CCc4ccccc43)c2n1
Agent: CCc1cc(CC)c2c(C#N)c(/C=C/C(=O)O)n(C3CCc4ccccc43)c2n1
Agent: Nc1ccncc1
Product: CCc1cc(CC)c2c(C#N)c(/C=C/C(=O)Nc3ccncc3)n(C3CCc4ccccc43)c2n1

Procedure:
In the same manner described in (4) of Example 2, (E)-3-[3-cyano-1-(2,3-dihydro-1H-inden-1-yl)-4,6-diethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-N-(3-pyridinyl)-2-propenamide was synthesized from (E)-3-[3-cyano-1-(2,3-dihydro-1H-inden-1-yl)-4,6-diethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-propenoic acid and 4-aminopyridine.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:44])[NH:10][C:11]1[C:12](=[O:43])[N:13]2[C:17](=[C:18]([C:20](=[O:22])[CH3:21])[CH:19]=1)[CH2:16][CH2:15][C@H:14]2[C:23](=[O:42])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:34]C(OC(C)(C)C)=O)=[NH:33])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:44])[NH:10][C:11]1[C:12](=[O:43])[N:13]2[C:17](=[C:18]([C:20](=[O:22])[CH3:21])[CH:19]=1)[CH2:16][CH2:15][C@H:14]2[C:23](=[O:42])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[NH:33])[NH2:34])=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc(NC(=O)OCc2ccccc2)c(=O)n2c1CC[C@H]2C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cc(NC(=O)OCc2ccccc2)c(=O)n2c1CC[C@H]2C(=O)NCc1ccc(C(=N)N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
The compound (22 mg, 0.116 mmol) obtained from Step E was dissolved in CH2Cl2 and treated with TFA (180 μL, 2.32 mmol). Let stir 2 h at room temperature. Concentrated under vacuum, lyopholized to give a white solid (18 mg). 1HNMR (300 MHz, CD3OD) δ 2.49 (s, 3H) 3.2–3.4 (m, 2H) 4.6–4.9 (m, 2H) 5.2 (m, 1H), 5.25 (s, 2H) 7.3–7.5 (m, 9H), 7.6 (m, 2H) 7.8 (m, 2H). MS m/e 502.4 [M+H].
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>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]>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:3]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3c2ncn3C(C)C)cc1
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: COc1ccc(CNc2nc(-c3ccc(OC)cc3OC)nc3c2ncn3C(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
Boronic Acid coupling reactions: A 10 mL flame-dried Schlenk flask equipped with a magnetic stir bar was charged with 2-chloro-6-(4-methoxybenzylamino)-9-isopropylpurine (0.193 g, 0.5 mmol, 1.0 equiv), 2,4-dimethoxyphenylboronic acid (0.136 g, 0.75 mmol, 1.5 equiv), Pd2(dba)3 (0.0069 g, 0.0075 mmol, 0.015 equiv.), ligand 1 (0.0051 g, 0.015 mmol, 0.03 equiv.) and Cs2CO3 (0.326 g, 1.0 mmol, 2.0 equiv.). The Schlenk flask was evacuated and backfilled with argon and charged with anhydrous 1,4-dioxane (2.0 mL). The reaction was stirred under argon at 80° C. and monitored by TLC. When the reaction was complete after 8 hours, the solvent was removed in vacuo and the reaction crude was purified by flash column chromatography (3% methanol in dichloromethane) to afford desired 2-(2,4-dimethoxyphenyl)-6-(4-methoxybenzylamino)-9-isopropylpurine (207 mg, 96%). 1H NMR (400 MHz, CDCl3) δ 1.59 (d, 6H, J=6.8 Hz), 3.79 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 4.87–4.96 (m, 3H), 6.14 (br, 1H), 6.57–6.60 (m, 2H), 6.85 (d, 2H, J=8.6 Hz), 7.34 (d, 2H, J=8.6 Hz), 7.73 (s, 1H), 7.78 (d, 1H, J=8.2 Hz); HRMS (MALDI-FTMS) [MH+] C24H28N5O3 434.2187, found: 434.2168.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[Cl:10].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>N1C=CC=CC=1>[Cl:10][C:4]1[CH:5]=[C:6]([OH:9])[CH:7]=[CH:8][C:3]=1[NH:2][C:12](=[O:13])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(O)cc1Cl
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(O)cc1Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-3-chlorophenol hydrochloride (3.00 g) in pyridine (20.0 mL) were added benzyl chloroformate (2.62 mL) under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (2-chloro-4-hydroxyphenyl)carbamate (1.59 g).
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[O-2].[Ca+2:39]>C(OCC)(=O)C>[Ca+2:39].[CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([O-:30])=[O:29])=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([O-:30])=[O:29])=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline (0.5 g, 0.9 mmole) was dissolved in ethyl acetate (15 ml) which had been previously saturated with water, and calcium oxide (50, 0.9 mmol) was added thereto. The mixture was stirred for 2 hours at room temperature. Excess of calcium oxide was removed by filtration, and from the filtrate the solvent was distilled off under reduced pressure. The thus obtained residue was dissovled in ethyl acetate, and n-hexane was added thereto while stirring to obtain dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline calcium salt (0.40 g).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:12]([C:14]2[N:15]=[CH:16][C:17]([O:20][C:21]3[CH:22]=[C:23]([C:35]([NH:37][C:38]4[CH:42]=[CH:41][N:40](C(OC(C)(C)C)=O)[N:39]=4)=[O:36])[CH:24]=[C:25]([O:27][C@@H:28]([CH3:34])[CH2:29][O:30][CH:31]([F:33])[F:32])[CH:26]=3)=[N:18][CH:19]=2)=[O:13])[CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[N:8]1([C:12]([C:14]2[N:15]=[CH:16][C:17]([O:20][C:21]3[CH:22]=[C:23]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:34])[CH2:29][O:30][CH:31]([F:33])[F:32])[CH:26]=3)[C:35]([NH:37][C:38]3[CH:42]=[CH:41][NH:40][N:39]=3)=[O:36])=[N:18][CH:19]=2)=[O:13])[CH2:9][CH2:10][CH2:11]1
Reactant: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of 1,1-dimethylethyl 3-({[3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)phenyl]carbonyl}amino)-1H-pyrazole-1-carboxylate (115 mg, 0.17 mmol) in DCM (16 mL) and stirred at RT for 2 hours. The solvent was removed in vacuo, DCM (20 mL) added and the mixture washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL), brine (20 mL), dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a white foam (93 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=[O:11])[C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:32][CH2:33]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCCO)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCC=O)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
2-((2-chloro-5-cyano-4-(3-hydroxypropyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (82 mg, 0.155 mmol, Example 566C) was taken up in DCM (1 mL) and cooled to 0° C. Dess-Martin periodinane (85 mg, 0.202 mmol) was added, and the reaction was stirred at room temperature for 1.5 h. An additional 0.2 eq. of Dess-Martin (13 mg) was added and the reaction stirred for 1 h. The reaction mixture was quenched with 2M K3PO4 solution and extracted 2× with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-60% EtOAc/Hex; 40 g column). 2-((2-chloro-5-cyano-4-(3-oxopropyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (40 mg) was obtained as a yellow glass.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[CH:9]2.[CH3:18][N:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])[C:20](=[O:23])[CH:21]=[CH2:22]>C(O)C>[CH3:18][N:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])[C:20](=[O:23])[CH2:21][CH2:22][NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[CH:9]2
Reactant: Cn1c(=O)ccc2cc(OCCCN)ccc21
Reactant: C=CC(=O)N(C)c1ccccc1C
Solvent: CCO
Product: Cc1ccccc1N(C)C(=O)CCNCCCOc1ccc2c(ccc(=O)n2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
6-(3-Amino-propoxy)-1-methyl-1H-quinolin-2-one (194 mg) was added to an ethanol solution (5 ml) of N-methyl-N-o-tolyl-acrylamide (146 mg). The mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was condensed under reduced pressure to give the title compound (172.6 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:19])[CH3:18])=[CH:4][C:3]=1[CH3:9]
Reactant: CC(=O)Cl
Reactant: Cc1cc(N)ccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Br)c(C)c1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A stirred solution of 4-bromo-3-methylaniline (3.0 g, 0.016 mole) and triethylamine (4.5 ml, 0.032 mole) in dichloromethane (30 ml) at 0° C. was treated with acetyl chloride (1.2 ml, 0.017 mole) and allowed to warm to room temperature over 1 h. The mixture was washed with water, then 5M HCl acid and dried (Na2SO4), then concentrated in vacuo to afford the title compound as a pale yellow solid (3.07 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:62]1[CH:63]=[C:64]([OH:68])[CH:65]=[CH:66][CH:67]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[OH:68][C:64]1[CH:63]=[C:62]([NH:1][C:2]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][C:3]=2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:67]=[CH:66][CH:65]=1
Reactant: Oc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1cccc(O)c1
Temperature: 25 °C

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-phenylbenzoate 0.20 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 17 mg, tris(dibenzylideneacetone)dipalladium(0) 7 mg, palladium acetate 2 mg and cesium carbonate 0.48 g was added 3-iodophenol 0.41 g, and it was heated and refluxed for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B (spherical type), eluent; hexane:ethyl acetate=6:1] to give tert-butyl 2-((3-hydroxyphenyl)amino)-4-phenylbenzoate.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:23](OC)=[O:24])=[C:11]3[C:16]=2[O:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:12]3)=[C:5]([CH3:27])[O:4][N:3]=1.[AlH4-].[Li+]>O1CCCC1>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:12][C:11]=3[C:10]([CH2:23][OH:24])=[CH:9][CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2c(C)noc2C)c2c1NC(c1ccccc1)CO2
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc(CO)c2c1OCC(c1ccccc1)N2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
A solution of methyl 8-(3,5-dimethylisoxazol-4-yl)-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate (0.150 g, 0.412 mmol) in tetrahydrofuran (4.50 mL) at 0° C. was treated with 1.0 M lithium tetrahydroaluminate in THF (0.823 mL, 0.823 mmol) dropwise. After complete addition the mixture was stirred at 0° C. for 15 min. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL), warmed to R.T., and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give a colorless residue. Purification by flash column chromatography (100% hexanes to 70% EtOAc [containing 5% methanol]/30% hexanes) gave the desired product (0.13 g, 94%) as a white foam. LCMS calculated for C20H21N2O3 (M+H)+: m/z=337.2. found: 337.2.