Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([CH2:33][CH2:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](O)=[O:38])=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:83][S:84]([NH2:87])(=[O:86])=[O:85]>C(Cl)Cl>[O:49]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:31])([CH3:32])[C:20]([CH2:33][CH2:34][C:35]([CH3:40])([CH3:41])[CH2:36][C:37]([NH:87][S:84]([CH3:83])(=[O:86])=[O:85])=[O:38])=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: CS(N)(=O)=O
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)NS(C)(=O)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
A solution of 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-3,3-dimethylpentanoic acid (30 mg, 0.043 mmol) in DCM (2 mL) was treated with HATU (28.6 mg, 0.075 mmol), N,N-diisopropylethylamine (0.026 mL, 0.150 mmol), and methanesulfonamide (5.3 mg, 0.055 mmol). The reaction mixture was stirred at rt for 16 h. The mixture was concentrated and the crude product was purified by prep HPLC (Method 13) to afford 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-3,3-dimethyl-N-(methylsulfonyl)pentanamide (9.1 mg, 23% yield). LC/MS m/e 776.5 (M+H)+, 2.34 min (ionization peak, no UV) (method 3). 1H NMR (500 MHz, DMSO-d6) δ 5.20 (d, J=5.1 Hz, 1H), 4.69 (s, 1H), 4.55 (br. s., 1H), 3.08 (br. s., 1H), 3.00-2.91 (m, 3H), 2.81 (d, J=2.6 Hz, 3H), 2.74 (s, 3H), 2.64-2.56 (m, 3H), 2.48 (d, J=5.5 Hz, 1H), 2.40-2.32 (m, 1H), 1.95-0.76 (m, 29H), 1.91 (s, 3H), 1.65 (s, 3H), 1.03 (s, 3H), 0.95 (s, 3H), 0.94 (s, 6H), 0.93 (s, 3H), 0.87 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[N:20][C:19](Cl)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:23]=[CH:24][N:25]=[CH:26][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[N:20][C:19]([C:30]5[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:23]=[CH:24][N:25]=[CH:26][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nn1
Reactant: OB(O)c1ccncc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: c1cc(-c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nn2)ccn1
Temperature: 100 °C
Yield: 28.4 %

Procedure:
To a solution of compound 140 (199 mg, 544 μmol) in dioxane (3 mL) were added pyridin-4-ylboronic acid (66.9 mg, 544 μmol), Pd2(dba)3 (24.9 mg, 27.2 μmol), tricyclohexylphosphine (15.3 mg, 54.4 μmol), and potassium phosphate (231 mg, 1.09 mmol) (in 1 mL of water). The reaction mixture was purged with N2 for 20 minutes and the reaction was heated at 100° C. degree for 18 hours. DCM was added to the reaction and the mixture was washed with water and brine. The organic layer was dried with sodium sulfate. The product was purified using Combiflash (DCM/methanol) followed by trituration with ethyl acetate to give compound 415 as a yellow solid (63 mg, 28%). 1H NMR (500 MHz, CD2Cl2) δ ppm 9.25 (1 H, s), 8.97-9.05 (2 H, m), 8.92 (1 H, s), 8.79 (2 H, d, J=6.1 Hz), 8.57 (1 H, d, J=5.1 Hz), 8.00-8.08 (3 H, m), 7.96 (1 H, dd, J=5.1, 1.2 Hz), 5.48 (1 H, quin, J=8.9 Hz), 2.48 (2 H, m), 2.20-2.28 (4 H, m), 1.95 (2 H, dddd, J=8.2, 4.5, 4.3, 4.2 Hz), 1.63 (2 H, br. s.); LCMS-ESI (POS), M/Z, M+1: Found 409.1, Calculated 409.2.
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[C:5]([C:9]1[CH:13]=[C:12](CO)[NH:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6].S(Cl)(Cl)=O>ClCCl>[C:5]([C:9]1[CH:13]=[C:12]([CH2:1][Cl:4])[NH:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1cc(CO)[nH]n1
Reactant: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(CCl)[nH]n1

Procedure:
To a chloroform (20 mL)-dichloromethane (10 mL) mixed solution of [3-(tert-butyl)-1H-pyrazol-5-yl]methanol (617 mg, 4.00 mmol), thionyl chloride (577 μL, 8.01 mmol) was added at room temperature and the resultant solution was stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product (931 mg) of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([C:9]2[O:10][C:11]3[C:16]([C:17](=[N:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[CH:5][CH:4]=1.[S-]CC.[Na+]>CN(C)C=O.O.ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[O:10][C:11]3[C:16]([C:17](=[N:19][S:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)(=[O:22])=[O:21])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)c2cc(=NS(=O)(=O)c3ccccc3)c3ccccc3o2)cc1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1cc(=NS(=O)(=O)c2ccccc2)c2ccccc2o1
Reaction time: 48 h

Procedure:
Combine 2-(4-methoxybenzoyl)-4-benzenesulfonylimino-4H-chromene (1 mmol) and sodium thioethoxide (2 mmol) in dimethylformamide (5 mL). Stir for 48 hours. Dilute the reaction mixture with water and dichloromethane. Separate the organic layer, dry over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([C:18]([OH:20])=[O:19])=[N:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1.[C:21]1(=[O:25])[CH2:24][CH2:23][CH2:22]1>C1COCC1>[CH:15]1([CH2:14][O:13][C:12]2[N:11]=[C:10]([C:18]([OH:20])=[O:19])[CH:9]=[CH:8][C:7]=2[C:21]2([OH:25])[CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(O)CCC2)c(OCC2CC2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, BuLi (0.58 mL, 0.89 mmol) was added dropwise to a solution of 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9 d, 0.2 g, 0.74 mmol) in THF (20 mL) at −78° C. The reaction mixture was stirred for 1 h at −78° C. then cyclobutanone (CAN 1191-95-3, 1.11 mL, 1.47 mmol) in THF (3 mL) was added to the above solution at −78° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was then quenched with NH4Cl and the pH was adjusted to 2 by addition of 1 N HCl. The mixture was extracted with ethyl acetate (3×10 mL); the organic layers were combined, washed with brine (2×10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was used for the next step without further purification; MS (EI): m/e=264.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=2)[CH:3]=1.[H-].[Na+].[CH3:26]I.O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH3:26])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=2)[CH:3]=1
Reactant: C[C@H](Nc1cc(-c2cnn(C)c2)cc(Cl)n1)c1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(F)cc1)N(C)c1cc(-c2cnn(C)c2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
92 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine was dissolved in 1.5 ml of tetrahydrofuran, and 17 mg of 60% sodium hydride was added thereto, and the mixture was stirred at room temperature for 10 minutes. 26 μl of methyl iodide was added thereto, and the reaction solution was subjected to microwave irradiation at 100° C. for 5 minutes. 8 mg of 60% sodium hydride and 26 μl of methyl iodide were added to the reaction solution, and the reaction solution was stirred at 130° C. for 10 minutes, and furthermore 17 mg of 60% sodium hydride and 26 μl of methyl iodide were added, and the mixture was stirred at 130° C. for 10 minutes. The reaction solution was added with water and subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 62 mg of the objective compound as pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][CH:5]2[C:15]([O:17][CH3:18])=[O:16].[CH3:19][N:20]1CCCC1=O>>[C:19]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][CH:5]2[C:15]([O:17][CH3:18])=[O:16])#[N:20]
Reactant: CN1CCCC1=O
Reactant: COC(=O)C1CC(C)(C)Oc2cc(F)c(Br)cc21
Product: COC(=O)C1CC(C)(C)Oc2cc(F)c(C#N)cc21
Temperature: 160 °C
Reaction time: 5 h
Yield: 62.3 %

Procedure:
methyl 6-bromo-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-carboxylate (232 mg, 0.732 mmol) was diluted with N-methylpyrrolidone (4 mL) followed by the addition of Cu(I)CN (328 mg, 3.66 mmol). The reaction was bubbled with Argon for 15 minutes and then heated at 160° C. The reaction was stirred for 5 hours and then allowed to cool. The reaction was loaded directly onto a Biotage 25 column eluting with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the title compound (120 mg, 62.3% yield).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH2:16]Br)[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5].[CH3:22][OH:23]>C(OCC)(=O)C>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH2:16][O:23][CH3:22])[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: O=C(Nc1cnc2[nH]c(CBr)cc2c1)c1ccccc1Br
Reactant: CO
Solvent: CCOC(C)=O
Product: COCc1cc2cc(NC(=O)c3ccccc3Br)cnc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A flask is charged with 200 mg (0.49 mmol) of 2-bromo-N-(2-(bromomethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (stage 1) and 5 mL of methanol. The solution is stirred at room temperature for 18 hours and then diluted in 100 mL of ethyl acetate, washed with 3×30 mL of water, dried over sodium sulphate and evaporated under reduced pressure. The raw product is then purified by silica gel chromatography (ethyl acetate/petroleum ether eluent). 30 mg of a yellow solid is obtained (17%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:11]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]([NH:14][N:15]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)C(C)C)(C)C.[C:39]1([N:45]=[C:46]=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C)C=O>[C:7]([O:6][C:4]([C@H:3]([C@@H:11]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]([NH:14][N:15]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:2][NH:1][C:46]([NH:45][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:47])=[O:5])([CH3:9])([CH3:10])[CH3:8]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CN)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CNC(=O)Nc1ccccc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 0.8 g of 2(R)-[2-amino-1(R)-(tert-butoxycarbonyl)ethyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide prepared as described in Example 33, part (i), 0.325 ml of N,N-diisopropylethylamine and 0.21 ml of phenyl isocyanate in 10 ml of dimethylformamide was stirred at 60° C. under nitrogen for 2.5 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1M hydrochloric acid. The ethyl acetate solution was separated and washed with sodium hydrogen carbonate solution and with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with diethyl ether and there was obtained 0.705 g of 2(R)-[1(R)-(tert-butoxycarbonyl)-2-(3-phenylureido)ethyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in the form of a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[C:14]=2[NH2:18])[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2].C(Cl)Cl.[F:24][C:25]1[CH:26]=[C:27]([CH2:35][C:36](O)=[O:37])[CH:28]=[CH:29][C:30]=1[C:31]([F:34])([F:33])[F:32].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[C:14]=2[NH:18][C:36](=[O:37])[CH2:35][C:27]2[CH:28]=[CH:29][C:30]([C:31]([F:32])([F:33])[F:34])=[C:25]([F:24])[CH:26]=2)[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(Cl)ccc2c1=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(Cl)ccc2c1=O
Temperature: 40 °C
Reaction time: 48 h

Procedure:
A vial was charged with (R)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (160 mg, 0.00054 mol), methylene chloride (10 mL, 0.2 mol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (145 mg, 0.000651 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (413 mg, 0.00108 mol), and N,N-diisopropylethylamine (0.189 mL, 0.00108 mol), and was stirred at 40° C. for 2 days. the solvent was removed under reduced pressureunder reduced pressure and the residue was purified by flash chromatography to afford the product as colorless oil.
Reaction SMILES: [CH3:1][C:2](N(C)C)=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][O:12][CH2:13][CH:14]1[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15]1.C(Cl)(=O)C>>[CH3:11][O:12][CH2:13][CH:14]1[CH2:15][O:16][C:17]2[CH:23]=[CH:22][C:21]([C:2]([CH3:1])=[O:3])=[CH:20][C:18]=2[O:19]1
Reactant: COCC1COc2ccccc2O1
Reactant: CC(=O)N(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)Cl
Product: COCC1COc2ccc(C(C)=O)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dimethyl acetamide (16.65 mol, 1.31 ml) was added slowly to anhydrous aluminum chloride (33.3 mmol, 4.44 g) at 0° C. in the presence of nitrogen and stirred for 30 min at a room temperature, and then, the titled compound prepared in Example 1 (3.77 mmol, 500 mg) was added slowly to the resulting mixture, followed by stirring for 15 min. Then, acetyl chloride (3.33 mmol, 0.28 ml) was added and stirred for 5 hours at a room temperature. Ice was added slowly to the mixture to destroy and remove the remaining aluminum chloride. The reaction mixture was neutralized with NaHCO3, extracted with ethylacetate, followed by removing the solvent. And then, the resultant was dried to prepare the titled compound (520 mg, 84%).
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:11]=[C:10]([C:12](OC)=[O:13])[O:9][N:8]=1)[CH:3]([F:5])[F:4].[BH4-].[Na+].Cl>CO>[F:16][C:2]([F:1])([O:6][C:7]1[CH:11]=[C:10]([CH2:12][OH:13])[O:9][N:8]=1)[CH:3]([F:4])[F:5]
Reactant: COC(=O)c1cc(OC(F)(F)C(F)F)no1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(OC(F)(F)C(F)F)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of methyl 3-(1,1,2,2-tetrafluoroethoxy)-5-isoxazole carboxylate (1.975 g, 8.124 mmol) in methanol (30 ml) was added sodium borohydride (0.40 g, 10.6 mmol) by small portions under ice-cooling, and the mixture was stirred overnight at room temperature. To the reaction solution was added dilute hydrochloric acid, the mixture was stirred at room temperature for 1 hr and washed three times with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate, and passed through silica gel. The solvent was evaporated under reduced pressure to give a crude product of [3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methanol as a yellow liquid (1.72 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[S:5])[NH2:4].[Cl:7][CH2:8][C:9](=O)[CH2:10]Cl>C(O)C>[Cl:7][CH2:8][C:9]1[N:4]=[C:3]([CH:2]([CH3:6])[CH3:1])[S:5][CH:10]=1
Reactant: CC(C)C(N)=S
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: CC(C)c1nc(CCl)cs1
Yield: 71.5 %

Procedure:
A mixture of 2-methylpropanethioamide (5.20 g), 1,3-dichloro-2-propanone (7.03 g) and ethanol (100 mL) was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-chloromethyl-2-isopropyl-1,3-thiazole as a colorless oil (6.33 g, yield 72%) from a fraction eluted with ethyl acetate-hexane (1:20, v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23](O)=[O:24])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][CH2:63][C:64]1[CH:75]=[CH:74][C:67]2[B:68]([OH:73])[O:69][C:70]([CH3:72])([CH3:71])[C:66]=2[CH:65]=1.Cl>C(#N)C>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([NH:62][CH2:63][C:64]5[CH:75]=[CH:74][C:67]6[B:68]([OH:73])[O:69][C:70]([CH3:72])([CH3:71])[C:66]=6[CH:65]=5)=[O:24])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC1(C)OB(O)c2ccc(CN)cc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)OB(O)c2ccc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)n4cccc34)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.72 mmol) in acetonitrile (5 ml) at 0° C. can be added Et3N (291.1 mg, 2.88 mmol), HATU (546.76 mg, 1.44 mmol) and 5-(aminomethyl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (194.2 mg, 0.86 mmol). The reaction mixture can be stirred overnight at rt. The mixture can be poured into 1N HCl solution and extracted with EA (20 ml×3). The combined organic layers can be washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue can be purified by prep-TLC and prep-HPLC to give the final title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.[CH2:21](Cl)[C:22]#[CH:23]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:20][CH2:23][C:22]#[CH:21])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Reactant: C#CCCl
Product: C#CCOc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC

Procedure:
The title compound was prepared from 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine and propargyl chloride by the procedure of Example 1A. Recrystallization from 95% ethanol gave off-white needles (73%); mp 160°-161°. Anal. Calcd for C16H18N4O3 : C, 61.13; H, 5.77; N, 17.82. Found: C, 60.96; H, 5.80; N, 17.75.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1.Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH2:10][CH2:11][CH3:12])[C:15](=[O:17])[NH:13][C:4]=2[CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCNc1ccc(Br)cc1N
Solvent: C1COCCO1
Product: CCCCn1c(=O)[nH]c2cc(Br)ccc21

Procedure:
A mixture of Example 166B (1.36 g, 5.59 mmol) and triphosgene (582 mg, 1.96 mmol) in dioxane was heated to reflux for 16 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:14][CH2:13]2)[N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH3:48])[C:26]2[O:30][C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[N:28][C:27]=2[CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:14][CH2:13]3)[N:3]=[C:2]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29]4[O:30][C:26]5[C:25]([CH3:48])=[CH:24][C:23]([CH3:22])=[CH:47][C:27]=5[N:28]=4)=[CH:37][CH:36]=3)[C:10]=12
Reactant: COCCN1CCC(n2nc(I)c3c(N)ncnc32)CC1
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COCCN1CCC(n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A mixture of 3-iodo-1-[1-(2-methoxyethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.2 g, 0.0005 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.28 g, 0.00078 mol), tetrakis(triphenylphosphine)palladium (0.029 g, 0.000025 mol) and sodium carbonate (0.13 g, 0.00125 mol) in ethylene glycol dimethyl ether (25 mL) and water (5 mL) was heated at 80° C. for 5 hours under an atmosphere of nitrogen. Additional N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.14 g, 0.00039 mol.) and tetrakis(triphenylphosphine)-palladium (0.015 g, 0.0000125 mol) were added, and the mixture was stirred at 80° C. for 16 hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 5%-20% methanol/dichloromethane as a mobile phase to give N2-(4-{4-amino-1-[1-(2-methoxyethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine (0.14 g, 0.00027 mol). 1H NMR (TFA-d, 400 MHz) δ 8.53 (s, 1H), 7.88 (m, 2H), 7.81 (m, 2H), 7.14 (s, 2H), 5.40 (br, 1H), 4.05 (m, 2H), 3.98 (m, 2H), 3.66 (m, 2H), 3.56 (s, 3H), 3.47 (m, 2H), 2.96 (m, 2H), 2.54 (br, 2H), 2.50 (s, 3H), 2.43 (s, 3H). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 9.6 min. MS: MH+ 513