Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3F)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20].[CH2:21]([N:24]([CH3:29])[CH2:25][C@H:26]([OH:28])[CH3:27])[CH:22]=[CH2:23]>CC(N(C)C)=O.[H-].[Na+]>[CH2:21]([N:24]([CH3:29])[CH2:25][C@@H:26]([CH3:27])[O:28][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([OH:20])=[C:2]([Cl:1])[CH:7]=1)=[N:10][CH:11]=[N:12]2)[CH:22]=[CH2:23]
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Reactant: C=CCN(C)C[C@@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=CCN(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Temperature: 110 °C
Yield: 68.3 %

Procedure:
2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (2 g) was added to a stirred solution of (2R)-1-[allyl(methyl)amino]propan-2-ol (2.24 g, prepared as described in Example 2-3) in DMA (100 ml) and sodium hydride (60% dispersion in oil, 692 mg), and the mixture heated to 110° C. for 16 hours. The mixture was concentrated in vacuo then a saturated solution of sodium bicarbonate (200 ml) was added and extracted with DCM (300 ml). The extract washed with brine, dried and concentrated in vacuo and the residue purified by chromatography using DCM—10% methanol/2N ammonia as eluent to give 4-[(5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}quinazolin-4-yl)amino]-2-chlorophenol as a yellow solid (1.88 g, 68%); NMR spectrum (DMSO-d6) 1.43 (d, 3H), 2.17 (s, 3H), 2.54 (dd, 1H), 2.97 (m, 3H), 4.94 (m, 1H), 5.00 (dd, 1H), 5.10 (dd, 1H), 5.63 (m, 1H), 6.98 (d, 1H), 7.18 (d, 1H), 7.29 (d, 1H), 7.42 (dd, 1H), 7.69 (t, 1H), 7.84 (d, 1H), 8.44 (s, 1H), 10.01 (bs, 1H), 10.26 (s, 1H); Mass spectrum MH+ 399.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C@H:12]([NH:14][CH2:15][C@H:16]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=2)[CH3:13])[CH:6]=1.[OH-].[Li+].Cl>O1CCCC1>[Si:27]([O:26][C@H:16]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=1)[CH2:15][NH:14][C@H:12]([CH3:13])[CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[CH:10]=[CH:9][CH:8]=1)([C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:29])[CH3:28]
Reactant: COC(=O)Cc1cccc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(CO)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
A solution of methyl(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate (Preparation 21) (7.04 g, 14.43 mmol) in tetrahydrofuran (40 ml) was treated with lithium hydroxide (28.9 ml of a 1M aqueous solution, 28.9 mmol) and the reaction left to stir at room temperature for 16 hours. Hydrochloric acid (28.9 ml of a 1M aqueous solution, 28.9 mmol) was added and then the tetrahydrofuran was removed in vacuo. The remaining aqueous layer was decanted and the residue washed with further water (10 ml). The residue was redisolved in methanol (30 ml) and the solvent removed in vacuo to give the title compound as a colorless foam (5.95 g) which was used without further purification. 1H NMR (400 MHz, CD3OD): δ=7.32 (1H, s), 7.25-7.18 (2H, m), 7.13 (1H, s), 7.12-7.10 (1H, d), 7.02-7.01 (1H, d), 6.79-6.77 (1H, d), 4.98-4.95 (1H, m), 4.65-4.64 (2H, d), 3.48 (2H, s), 3.48-3.43 (1H, m), 3.28-3.23 (1H, dd), 3.13-3.09 (1H, dd), 2.98-2.93 (1H, dd), 2.77-2.72 (1H, dd), 1.23-1.21 (3H, d), 0.86 (9H, s), 0.06 (3H, s), −0.13 (3H, s) ppm. LRMS (electrospray): m/z [M+H]+ 474, [M+Na]+ 496, [M−H]− 472. CHN analysis: found C, 64.15%; H, 8.25%; N, 2.84%. C26H39NO5Si+0.7H2O requires C 64.22%, H 8.37%, N 2.88%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH:21]2[CH2:23][CH2:22]2)=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][N:16](C)C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O.[NH2:24]N>CC(O)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH:21]2[CH2:23][CH2:22]2)=[C:6]([C:7]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][NH:16][N:24]=2)[CH:19]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)ccc1OC1CC1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c[nH]nc1-c1cc(Cl)ccc1OC1CC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Ethyl 2-(5-chloro-2-cyclopropoxybenzoyl)-3-(dimethyl-amino)acrylate (24 g, 71 mmol) was dissolved in 150 mL of HOAc. The reaction mixture was cooled to 0° C. then 85% hydrazine in water (25 mL) was added dropwise. The mixture was warmed to room temperature and stirred for 6 hours, then concentrated in vacuo. The residue was purified by EtOAc/Hexanes=1:2 to afford 24 g of the title compound as a syrup. 1H NMR (DMSO-d6, 400 MHz) δ: 13.41 (s, 1H), 8.26 (s, 0.5H), 7.88 (s, 0.5H), 7.49-7.24 (m, 3H), 4.07-3.99 (m, 2H), 3.82-3.74 (m, 1H), 1.17-1.10 (m, 3H), 0.73-0.46 (m, 4H).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1([CH:17]=[O:18])[CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:17]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[O:18])[CH2:16][CH2:15][CH2:14]1
Reactant: O=CC1CCC1
Reactant: CCOC(=O)c1ccc(I)cc1
Product: CCOC(=O)c1ccc(C(=O)C2CCC2)cc1

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate (16), using ethyl 4-iodobenzoate and cyclobutanecarbaldehyde. 1H NMR (400 MHz, CDCl3, δ): 7.93 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 4.58 (d, J=8.0 Hz, 1H), 4.29 (q, J=6.8 Hz, 2H), 2.50-2.58 (m, 1H), 1.70-2.02 (m, 6H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:11]2[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=3)=[N:9][C:8]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[OH-].[Li+]>>[O:31]=[S:2]1(=[O:1])[C:11]2[C:10]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=3)=[N:9][C:8]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)Cc1ccc(Nc2nc(-c3ccccc3)nc3c2S(=O)(=O)CCC3)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(Nc2nc(-c3ccccc3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 86.7 %

Procedure:
Following general procedure D, ethyl 2-(4-((5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (0.80 g, 1.83 mmol) was reacted with lithium hydroxide (0.380 g, 9.15 mmol) to afford the desired product (0.650 g, 86%) as a light yellow solid. MW=409.46. 1H NMR (DMSO-d6, 500 MHz) δ 12.34 (s, 1H), 8.76 (s, 1H), 8.29-8.25 (m, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.59-7.49 (m, 3H), 7.33 (d, J=8.5 Hz, 2H), 3.76-3.72 (m, 2H), 3.60 (s, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.43-2.35 (m, 2H); APCI MS m/z 410 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:24])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(OC)cc2)n1

Procedure:
Following the procedures in preparation 1, the desired compound was prepared using 10 g of ethyl 2-aminothiazol-4-ylglyoxylate, 9 g of p-methoxyphenyl isocyanate and 80 ml of dimethylformamide as yellow powders. The product has the following physical properties.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>>[CH3:1][O:2][NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1
Reactant: CON=Cc1ccc(C#N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(C#N)cc1
Yield: 75 %

Procedure:
Reduction of 4-cyanobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (75% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s, OCH3), 4.09 (2H, s, NCH2), 7.48 (2H, m, aromatics), 7.63 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 168° C. (dec.). Anal. calcd. for C9H10N2O—HCl: C, 54.41; H, 5.58; N, 14.10. Found: C, 54.44; H, 5.62; N, 13.94.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:13])=[N-]>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cccnc1Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccnc1Cl
Temperature: 25 °C

Procedure:
To a suspension of 2-chloronicotinic acid (15.75 g) in ethyl acetate (200 ml) was added excess diazomethane (ether solution) with stirring at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate with addition of charcoal. The title compound (15.5 g) was obtained by filtering the mixture and then evaporating under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:21])=[C:14]([C:19]#[N:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].Cl.[NH2:30][OH:31]>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:21])=[C:14]([C:19](=[N:30][OH:31])[NH2:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:22]=1
Reactant: NO
Reactant: N#Cc1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A mixture of 3-[(5-chloro-1,3-benzothiazol-2-yl)methoxy]-2,6-difluorobenzene-carbonitrile (250 mg, 0.74 mmol, 1 equiv.), Na2CO3 (181 mg, 1.70 mmol, 2.3 equiv.) and hydroxylamine hydrochloride (103 mg, 1.48 mmol, 2 equiv.) in absolute EtOH (5 ml) was stirred at 70° C. for 8 h. Excess Na2CO3 (181 mg, 1.70 mmol, 2.3 equiv.) and hydroxylamine hydrochloride (103 mg, 1.48 mmol, 2 equiv.) were added and the heating continued for 1 h. The reaction mixture cooled at room temperature, diluted with water (40 ml) and extracted with CH2Cl2 (3×60 ml). The combined organic extracts were dried (MgSO4) and evaporated to dryness under reduced pressure, to give 201 mg (73% yield) of the desired product. Mp 169-170° C., HPLC (Gemini C18, 50×4.6 mm): m/z 370 [M+H]+, Rt=3.82 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[N+:11]([C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:15](=[O:17])[NH:1][C:2]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
2-Amino-4-nitro-benzoic acid (1.00 g, 0.00549 mol) was dissolved in THF. Triphosgene (1.63 g, 0.00549 mol) was dissolved in THF and added. The reaction mixture was stirred at rt for 2 h, concentrated, triturated with H2O, filtered, and taken up in acetone to afford a pale yellow solid (1.14 g, 99.8%).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:24]#[N:25])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:10]=2)=[O:5])C.[C:26]([O:30][C:31](=[O:37])[C:32]([CH3:36])([CH3:35])[CH2:33][NH2:34])([CH3:29])([CH3:28])[CH3:27]>CCO>[C:26]([O:30][C:31](=[O:37])[C:32]([CH3:36])([CH3:35])[CH2:33][NH:34][C:4]([C:6]1[N:7]=[C:8]([C:24]#[N:25])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:10]=2)=[O:5])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)c1nc(C#N)c2cc(Oc3cccnc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccnc3)ccc2c1O
Yield: 80.1 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(pyridin-3-yloxy)-isoquinoline-3-carboxylic acid ethyl ester (19 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (25 mg) in EtOH (0.3 mL) was microwaved at 140° C. for 1 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (21 mg). LC MS ESI+: 463 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:27])([F:26])[F:25])/[CH:10]=[CH:11]/[C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[C:14]([CH3:23])[CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:27])([F:25])[F:26])/[CH:10]=[CH:11]/[C:12]2[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[C:14]([CH3:23])[CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)O
Temperature: 100 °C
Yield: 45 %

Procedure:
To a stirred solution of (E)-ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (1.7 g, 4.0 mmol) in 1,4-dioxane (10 mL) was added 11 N HCl (30 mL), and the reaction mixture was heated at 100° C. for 48 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with H2O and extracted with chloroform (CHCl3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure, and the crude compound was washed with n-hexane to afford the title compound as a white solid (0.7 g, 50%): mp 142-143° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.66 (s, 3H), 7.52-7.44 (m, 2H), 6.89 (dd, J=16.0, 8.0 Hz, 1H), 6.78-6.74 (d, J=16.0 Hz, 1H), 4.84 (m, 1H), 2.50 (s, 3H); ESIMS m/z 387.05 ([M−H]−); IR (thin film) 3448, 1701, 1109, 777 cm−1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([CH3:35])[CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:28]([CH3:35])[CH:27]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C)c1

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (1189 mg, 0.5 mmol) and 4-methoxy-2-methylphenylboronic acid (166 mg, 1.0 mmol) to afford after chromatographic purification the title compound (105 mg, 50%). 1H NMR (CDCl3, 300 MHz) δ 7.04 (d, 1H, J=8.5 Hz), 6.65-6.79 (m, 4H), 3.75-4.22 (m, 2H), 3.74 (s, 3H), 3.58-3.68 (m, 1H), 3.18-3.42 (m, 4H), 2.76-3.16 (m, 3H), 2.17 (s, 3H), 1.70-1.84 (m, 2H), 1.40 (s, 9H) ppm. MS-ApCI: 421 [M+H+].
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([B:35]4[O:39]C(C)(C)C(C)(C)[O:36]4)=[C:31]([CH2:44][O:45][CH2:46][O:47][CH3:48])[CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.Cl.I([O-])(=O)(=O)=O.[Na+]>CO.O1CCCC1>[CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([B:35]([OH:36])[OH:39])=[C:31]([CH2:44][O:45][CH2:46][O:47][CH3:48])[CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B4OC(C)(C)C(C)(C)O4)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B(O)O)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
The crude 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(3-((methoxymethoxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (215 mg, 0.317 mmol) was dissolved in methanol (1.0 mL) and tetrahydrofuran (4.0 mL). HCl (4.0 mL, 4.00 mmol) was added followed by addition of sodium periodate (542 mg, 2.54 mmol). The mixture was stirred at room temperature overnight. It was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×). The organic phase was washed with 10% aq. Na2S2O3, brine, dried over Na2SO4. Concentrated under reduced pressure, the residue was purified by reversed phase HPLC (10-100 MeCN/H2O with 0.05% TFA) to give product (54 mg, 29%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (q, J=4.36 Hz, 1H) 8.07 (s, 1H) 7.97 (dd, J=8.88, 5.37 Hz, 2H) 7.31-7.53 (m, 5H) 7.14-7.20 (m, 1H) 4.65 (s, 2H) 4.59 (s, 2H) 3.37 (s, 2H) 3.24 (s, 2H) 2.83 (d, J=4.68 Hz, 3H) 2.11-2.26 (m, 1H) 1.01 (br. s., 1H) 0.84 (br. s., 2H) 0.52 (br. s., 1H). LCMS (m/z, ES+)=597 (M+H+).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:42]([N:44]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[CH3:45])=[O:43])[CH2:10][C:11]1[CH:12]=[C:13]([CH2:17][CH:18]=[CH:19][C:20]2[N:21](C(OC(C)(C)C)=O)[C:22]3[C:27]([C:28]=2[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C>[Pd].C(O)C.CCOC(C)=O>[NH2:8][C@H:9]([C:42]([N:44]([C:46]1[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=1)[CH3:45])=[O:43])[CH2:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][C:20]2[NH:21][C:22]3[C:27]([C:28]=2[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)Cc1c(C=CCc2cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c3ccc(OC)cc3)c2)n(C(=O)OC(C)(C)C)c2ccccc12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)C(=O)[C@@H](N)Cc2cccc(CCCc3[nH]c4ccccc4c3CC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of (5)-tert-butyl 2-(3-(3-(2-(tert-butoxycarbonylamino)-3-((4-methoxyphenyl)(methyl)amino)-3-oxopropyl)phenyl)prop-1-enyl)-3-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (178 mg, 0.24 mmol) and palladium on carbon (134 mg, 10%) in 2.5 ml of ethanol and 2.5 ml of EtOAc, was degassed with nitrogen. The reaction was stirred at room temperature for 3 hours under an atmosphere of H2 at 1 atm. The suspension was purged with nitrogen and filtered through celite. The filtrate was concentrated and the crude product was used without further purification. MS (m/z) 728 [M+H]+. The crude product was redissolved in 1 ml of tetrahydrofuran and 1 ml of methanol and 2 ml of 2N (aq.) lithium hydroxide was added to the solution. The solution was heated at 60° C. for 2 hours. The solution was cooled in an ice bath and acidified with 1N (aq) HCl. The resulting mixture was extracted with EtOAc (2×25 ml). The organic layer was dried over Na2SO4, filtered and concentrated. TFA (2 ml) was added to the crude product. After 20 minutes, the solvent was removed and the residue was dried under high vacuum. The crude product was used without further purification. The crude product yield was (100 mg, 0.2 mmol). MS (m/z) 500 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2ncnc(Nc3cccc(C(F)(F)F)c3)c2c1
Product: CC(=O)Nc1ccc2ncnc(Nc3cccc(C(F)(F)F)c3)c2c1
Yield: 87 %

Procedure:
Using an analogous procedure to that described in Example 11, 6-amino-4-(3'-trifluoromethylanilino)quinazoline was reacted with acetic anhydride to give 6-acetamido-4-(3'-trifluoromethylanilino)quinazoline in 87% yield as a solid.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[O:8]1)=[O:6])[CH3:3].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: Oc1ccccc1
Reactant: CC(C)NC(=O)C1OC1c1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NC(=O)C(O)C(Oc1ccccc1)c1ccc(Cl)cc1

Procedure:
This compound was prepared from N-(1-methylethyl)-3-(4-chlorophenyl)-2-oxiranecarboxamide (7.2 g.), phenol (3.0 g.), sodium hydride (50% oil dispersion, 1.6 g.), 18-crown-6 (0.9 g.), and acetonitrile (250 ml.) as described in Example 12. The crude product was recrystallized from ethanol, giving 2.3 g. of the compound, m.p. 175°-177°. Another recrystallization from ethanol gave analytical sample, m.p. 176°-178°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:40][N:41]=[C:42]=[O:43]>C(Cl)Cl>[OH:30][C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:25][CH2:26][N:27]([C:42]([NH:41][CH3:40])=[O:43])[CH2:28][CH2:29]1
Reactant: CN=C=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N1CCC(O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
4-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) was dissolved in CH2Cl2 (1 mL). N,N-diisopropylethylamine (30 μL, 0.172 mmol) and methyl isocyanate (7 μL, 0.130 mmol) were added sequentially. The solution was stirred overnight at rt, then concentrated in vacuo on a Genevac. The resultant residue was dissolved in DMSO and purified via HPLC (30-64% CH3CN:H2O) to provide 4-hydroxy-N-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxamide (36 mg, 0.073 mmol). MS ESI: +m/z 493.1. 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 7.93 (s, 2H), 7.44 (s, 1H), 7.25 (d, J=5.1 Hz, 1H), 7.13 (s, 1H), 6.43 (d, J=4.8 Hz, 1H), 6.15 (s, 1H), 3.83-3.74 (m, 2H) (d, J=14.0 Hz, 2H), 3.07 (t, J=14.5 Hz, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 1.98-1.82 (m, 2H), 1.65 (d, J=13.9 Hz, 2H). rhSYK activity=+++
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([CH2:17][CH3:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14].CN1CCOCC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:17][CH3:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(CC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the product of Step G (75 mg, 0.21 mmol) and NMM (42 mg, 0.42 mmol) in DCM (3 mL) was added methanesulfonyl chloride (36 mg, 0.38 mmol). Then the mixture was stirred at room temperature for 3 h, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=3/1) to afford the title compound as colorless oil. LC/MS m/z=435.1[M+H]+.