Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5].Cl.C(N(C(C)C)CC)(C)C.[CH3:23][N:24]=[C:25]=[O:26]>ClCCl>[CH3:23][NH:24][C:25]([N:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:7]1)=[O:26]
Reactant: CN=C=O
Reactant: CCOC(=O)C1CNCCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C(=O)NC)CCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Commercially available ethyl 4-piperidone-3-carboxylate hydrochloride (203.2 mg; 0.98 mmol) was suspended in dichloromethane (7 ml), diisopropylethylamine (180 μl; 0.99 mmol) was added, followed by commercially available methyl isocyanate and (57 μl; 0.98 mmol). This mixture was stirred at ambient temperature for approximately 3 hours, and then diluted with fresh dichloromethane and washed with water. The dichloromethane solution was dried with anhydrous potassium carbonate and evaporated at ambient temperature under reduced pressure, giving ethyl 1-(N-methylaminocarbonyl)-4-oxo-3-piperidinecarboxylate (74.4 mg) as a white solid. MS m/z (positive ion) 479 (dimer+Na+; 40), 457 (dimer+; 25), 251 (M+Na+; 100), 229 (MH+; 90), 205 (25), 130 (25).
Reaction SMILES: [NH2:1][C:2](=[C:10]([C:15](=O)[CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])#[N:28]>[Ti](Cl)(Cl)(Cl)Cl.O>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:28]=[C:27]([N:29]([S:30]([CH3:33])(=[O:32])=[O:31])[CH3:34])[N:1]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Reactant: CN(C#N)S(C)(=O)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 80.3 %

Procedure:
10.0 g (37.7 mmol) of methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate were introduced into 50 ml of toluene together with 10.17 g (75.4 mmol) of N-cyano-N-methylmethanesulphonamide and the mixture was treated at room temperature with 3.61 g (18.9 mmol) of titanium tetrachloride. The reaction progressed exothermically. The red-orange-coloured suspension was heated to 110° C. and stirred for 4.5 h. It was then cooled to room temperature and treated with 30 ml of water. The organic phase was separated off and the aqueous phase was extracted with ethyl acetate (30 ml). The combined organic phases were washed with 30 ml of water and dried over magnesium sulphate. After filtering and concentrating the solution in a water-jet vacuum and drying in vacuo, 11.54 g of crude product were obtained in the form of a tacky oil.
Reaction SMILES: [C:1]([CH2:3][CH:4](OS(C)(=O)=O)[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)#[N:2].[NH:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([CH2:3][CH:4]([N:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1)[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(CC(CC#N)OS(C)(=O)=O)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(CC(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 100.8 %

Procedure:
To a solution of tert-butyl 4-{3-cyano-2-[(methylsulfonyl)oxy]propyl}-1,4-diazepane-1-carboxylate (4.00 g, 11.1 mmol) and 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (3.50 g, 11.1 mmol) in DMF (30 mL) was added potassium carbonate (4.6 g, 33 mmol). The resulting mixture was stirred at room temperature for 66 hours. The reaction solution was diluted with ethyl acetate (˜300 mL) then washed with water twice and brine. The organic solutions were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column (0% to 10% methanol/DCM) to give the desired product as clear oil (6.5 g, 100%). LCMS calculated for C29H45N8O3Si(M+H)+: m/z=581.3.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]=1[C:14]([OH:16])=[O:15])[CH:2]=[CH2:3]>C1(C)C=CC=CC=1.C(OC(=O)C)(=O)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:7]2[C:8]([O:16][C:14](=[O:15])[C:6]=12)=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(C(=O)O)c1C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C=CCOc1cccc2c1C(=O)OC2=O

Procedure:
A mixture of 45.8 g of 3-allyloxy-phthalic acid in 200 ml of toluene and 25.5 ml of acetic anhydride is heated to the reflux temperature for 3 hours and then evaporated under reduced pressure. The residue is crystallised from diethyl ether and gives 3-allyloxy-phthalic anhydride; melting point 115°-117°.
Reaction SMILES: [C:1](O)(=O)C.[CH3:5][C:6]1[C:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[C:9]2[NH:10][C:11]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:12][C:13](=[O:14])[N:8]2[N:7]=1.C[Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:1][N:7]1[N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)[N:10]=[C:9]2[C:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[C:6]1[CH3:5]
Reactant: CC(=O)O
Reactant: Cc1ccccc1Cc1c(C)nn2c(=O)cc(-c3ccncc3)[nH]c12
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccccc1Cc1c(C)n(C)n2c(=O)cc(-c3ccncc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a solution of 2-methyl-3-(2-methylbenzyl)-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one acetate (500 mg, 1.281 mmol) in dichloromethane/methanol (30 mL/15 mL) was added trimethylsilyldiazomethane (1.3 mL, 2.561 mmol). The mixture was stirred at room temperature for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by a silica gel chromatography to give the titled compound (223 mg, 51%); LC/MS: MS (ES+) m/e 345 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 2.27 (s, 3H), 2.42 (s, 3H), 4.04 (s, 2H), 4.24 (s, 3H), 6.51 (s, 1H), 7.10-7.20 (m, 4H), 7.88 (d, J=5.7 Hz, 2H), 8.70 (d, J=5.7 Hz, 2H).
Reaction SMILES: C(OC(=O)[NH:7][S:8]([N:11]1[CH2:16][CH2:15][C:14]([OH:40])([C:17]2[S:18][C:19]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[CH:25]=[C:24]([CH3:39])[CH:23]=3)=[CH:20][N:21]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:40][C:14]1([C:17]2[S:18][C:19]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[N:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[CH:31][N:30]=4)[CH:25]=[C:24]([CH3:39])[CH:23]=3)=[CH:20][N:21]=2)[CH2:15][CH2:16][N:11]([S:8]([NH2:7])(=[O:9])=[O:10])[CH2:12][CH2:13]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCN(S(=O)(=O)NC(=O)OC(C)(C)C)CC3)s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCN(S(N)(=O)=O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 82.2 %

Procedure:
To a solution of tert-butyl({4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-1-yl}sulfonyl)carbamate (45 mg, 0.073 mmol) in DCM (0.7 mL) was added TFA (0.120 mL, 1.5 mmol) and the reaction was stirred at room temperature for 80 min, then more TFA (0.120 mL, 1.5 mmol) was added. After 90 min most volatiles were removed by N2 flow and vacuum. The residue was diluted with saturated aqueous NaHCO3 and ethyl acetate. The combined organic layers were dried and evaporated to give 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-sulfonamide (31 mg, 0.06 mmol, 82% yield). MS ESI: [M+H]+ m/z 515.2. 1H NMR (600 MHz, CDCl3): δ 8.59 (d, J=4.8 Hz, 1H); 7.87 (s, 1H); 7.81 (s, 1H); 7.25 (s, 1H); 7.02 (s, 1H); 7.00 (d, J=4.8 Hz, 1H); 3.59 (d, J=12 Hz, 2H); 3.14 (m, 2H); 2.34 (s, 3H); 2.26 (m, 2H); 1.94 (d, J=12 Hz, 2H). rhSYK activity=+++
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]([N:18]1[CH2:17][CH2:16][N:15]([C:9]2[C:10]([C:12](=[O:14])[CH3:13])=[CH:11][C:2]([Cl:1])=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)[CH2:20][CH2:19]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccc2)CC1
Reaction time: 2 h
Yield: 129.5 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with benzoyl chloride (0.018 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated. The resulting residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromthane) to give the desired product (51 mg). LCMS calculated for C22H21ClN3O2 (M+H)+: m/z=394.1; Found: 394.0.
Reaction SMILES: [Cl:1][C:2]1[C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:21])[N:6]2[CH3:20].Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH2:30][CH3:31])[CH:28]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[Cl:1][C:2]1[C:10]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH2:30][CH3:31])[CH:28]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:21])[N:6]2[CH3:20]
Reactant: CN1C(=O)Cc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2Cl
Reactant: CCOc1cncc(Br)c1
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: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CCOc1cncc(-c2ccc3c(c2Cl)CC(=O)N3C)c1
Temperature: 115 °C

Procedure:
To 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (95 mg, 0.31 mmol) was added 3-bromo-5-ethoxy-pyridine (CAS#17117-17-8, 69 mg, 0.34 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.390 mL, 0.77 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (140 mg, 0.015 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 115° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 3%) to furnish 4-chloro-5-(5-ethoxy-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 303.0901 (M+H)1; 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (t, J=6.9 Hz, 3H), 3.26 (a, 3H), 3.61 (a, 2H), 4.15 (q, J=6.9 Hz, 2H), 6.84 (d, J=8.1 Hz, 1H), 7.28-7.33 (m, 2H), 8.26 (d, J=1.8 Hz, 1H), 8.32 (d, J=2.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].COC1C=C(C(O)[C:25]([O:27][CH3:28])=[O:26])C=CC=1OC>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]([OH:5])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COc1cc(F)c(C=O)cc1OC
Reactant: COC(=O)C(O)c1ccc(OC)c(OC)c1
Product: COC(=O)C(O)c1cc(OC)c(OC)cc1F
Yield: 44 %

Procedure:
139A (1.05 g, 44%) was prepared in 2 steps from 2-fluoro-4,5-dimethoxybenzaldehyde following procedures analogous to those used in the preparation of 137B. LC-MS: 267.11 (M+Na)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:30])[C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[C:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[CH:8][CH:7]=1.[S:31]1[CH:35]=[C:34]([CH:36]=O)[N:33]=[CH:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]([CH3:30])[C:5](=[O:29])[C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[C:23]2[CH2:28][CH2:27][N:26]([CH2:36][C:34]3[N:33]=[CH:32][S:31][CH:35]=3)[CH2:25][CH2:24]2)=[CH:10][CH:11]=1
Reactant: CN(CCO)C(=O)c1ccc(C(=C2CCNCC2)c2cccc3cccnc23)cc1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CN(CCO)C(=O)c1ccc(C(=C2CCN(Cc3cscn3)CC2)c2cccc3cccnc23)cc1
Reaction time: 20 h
Yield: 48.6 %

Procedure:
Compound 1C (3.3 g, 8.3 mmol) and 4-thiazolecarboxaldehyde (1.4 g, 12.4 mmol) in dichloroethane (16 mL) were stirred for 30 min. under nitrogen. Sodium triacetoxyborohydride (5.3 g, 24 9 mmol) was added and the reaction was stirred for 20 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated. Column chromatography (120 g silica gel, eluting with 4% 7N NH3/MeOH in CH2Cl2) gave 2.01 g 1D as a white solid (49%). 1H NMR (500.333 MHz, CDCl3) δ 8.90 (dd, J=4.1, 1.7 Hz, 1H), 8.76 (d, J=1.9 Hz, 1H), 8.11 (dd, J=8.0, 1.5 Hz, 1H), 7.72 (dd, J=7.3, 2.3 Hz, 1H), 7.51-7.46 (m, 2H), 7.37-7.33 (m, 3H), 7.31-7.29 (m, 2H), 7.18 (s, 1H), 3.85 (s, br, 2H), 3.76 (s, 2H), 3.67 (br s, 2H), 3.26 (br s, 1H), 3.02 (s, 3H), 2.78-2.71 (m, 1H), 2.67-2.52 (m, 4H), 2.46-2.37 (m, 1H), 2.14-2.04 (m, 2H). TOF MS E+ 499.21.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.[Br-:24].[Li+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[Br:24][CH2:6][CH2:7][N:8]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)N(CCOS(C)(=O)=O)N=Cc1ccccc1
Reactant: [Br-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Li+]
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)N(CCBr)N=Cc1ccccc1
Reaction time: 3 h

Procedure:
3.4 g. of the ethyl ester product from part (b) are dissolved in 100 ml. of acetone. 1.3 g. (50% excess) of lithium bromide and 0.1 g. of 18-Crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) are added and the mixture is stirred for three hours at 50°. After the reaction has been completed as determined by TLC, the solvent is distilled off and the reaction mixture is taken up in 50 ml. of methylene chloride and shaken with 50 ml. of water. The organic phase is dried and concentrated to yield the crude product as an oil which, after scratching, crystallizes in several hours. Recrystallization from isopropanol yields purified [1-(2-bromoethyl)-2-(phenylmethylene)hydrazino]oxoacetic acid, ethyl ester; m.p. 56°-57°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11].[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>O.CC(C)=O>[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:11][CH2:10][CH:9]([O:12][CH3:13])[O:8][CH3:7])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(CN)OC
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(CNC(=O)c1ccc(Br)cc1)OC
Temperature: 25 °C

Procedure:
Potassium carbonate (8.0 g) was added to a solution of 2,2-dimethoxyethylamine in water (90 ml) and acetone (40 ml) at rt. The reaction mixture was cooled in an ice-water bath and 4-bromobenzoyl chloride (16.4 g) dissolved in acetone (70 ml) was added drop-wise over 90 min. The stirred reaction mixture was allowed to warm to rt. After a further 2 h the reaction mixture was extracted into EtOAc (3×75 ml), the combined organics were washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and evaporated to give the amide as an off white solid (18.5 g). LCMS electrospray (+ve) 289 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9](Br)[CH:10]=1)=[O:4].[C:18]1(B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21][CH2:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9]([C:18]2[CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:10]=1)=[O:4]
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Br)c1
Product: COC(=O)c1cnc(OCC(F)(F)F)c(C2=CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 12a using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid methyl ester (CAN 1211589-51-3) and 2-(1-cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9) as starting materials; MS (EI) 302.0 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([O:34][CH3:35])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][C@@H:37]1[CH2:41][OH:42]>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:36]4[CH2:40][CH2:39][CH2:38][C@@H:37]4[CH2:41][OH:42])[C:17]=23)=[CH:20][C:21]=1[O:34][CH3:35]
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Reactant: OC[C@H]1CCCN1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCC[C@@H]4CO)c23)ccc1OCc1cccc(F)c1
Yield: 37 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and (R)-2-pyrrolidinemethanol to give the title compound in 37% yield; NMR Spectrum: 1.50 (m, 1H), 1.64 (m, 2H), 1.80 (m, 1H), 2.32 (q, 1H), 2.59 (m, 1H), 2.78 (dt, 1H), 3.15 (t, 1H), 3.27 (m, 3H), 3.80 (s, 3H), 4.37 (hidden by water, 2H), 4.40 (t, 1H), 4.46 (s, 1H), 5.11 (s, 2H), 7.02 (d, 1H), 7.16 (t, 2H), 7.28 (td, 2H), 7.38 (d, 1H), 7.44 (q, 1H), 8.27 (d, 2H), 8.29 (s, 1H); Mass Spectrum: 509 (MH+).
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH3:2].Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([OH:25])[C:23]=1[OH:24])[C:17]([O:19][CH3:20])=[O:18]>CCCCCC>[OH:25][C:22]1[C:23]2[O:24][C:1]([CH3:2])=[N:13][C:14]=2[CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[CH:21]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: COC(=O)c1cc(N)c(O)c(O)c1
Agent: Cl
Solvent: CCCCCC
Product: COC(=O)c1cc(O)c2oc(C)nc2c1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To stirred triethyl orthoacetate (35.0 mL, 190 mmol) was added methyl 3-amino-4,5-dihydroxybenzoate hydrochloride (6.00 g, 27.3 mmol). The stirred suspension was refluxed for 20 min and cooled to room temperature. The reaction mixture was poured into hexane (200 mL). The formed precipitate was separated by filtration and vacuum-dried to afford the desired benzoxazole (4.98 g, 24.04 mmol, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.74 (br. s, 1H), 7.66 (d, J=1.4 Hz, 1H), 7.43 (d, J=1.4 Hz, 1H), 3.85 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]([N:34]([CH3:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)=[O:33])[CH3:30]>>[CH3:30][N:29]([CH2:31][C:32]([N:34]([C:35]1[CH:36]=[CH:37][C:38]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:40]=1)[CH3:42])=[O:33])[CH3:28]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)CC(=O)N(C)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-dimethylaminomethylcarbonyl-N-methyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C28H28N4O4
Reaction SMILES: N[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.N([O-])=[O:18].[Na+].[OH-].[Na+]>OS(O)(=O)=O>[OH:18][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=N[O-]
Reactant: CCOC(=O)c1c(N)ncc2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1c(O)ncc2ccccc12
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a suspension of ethyl 3-aminoisoquinoline-4-carboxylate (583 mg, 2.70 mmol) in 6.8 mL of H2SO4 5 N cooled to 0° C. was added sodium nitrite (223 mg, 3.24 mmol, dissolved in 1 mL of water). The reaction mixture was stirred at 0° C. for 2.5 h and then NaOH(aq) 1N was added until pH=7. The aqueous phase was extracted twice with DCM and the combined organic phases were dried over MgSO4, filtered and evaporated to give the title compound of Step A which was used without further purification in the next step (583 mg, 99%). MS (ESI) mass calcd. for C12H11NO3, 217.1. m/z found 218.1 [M+H]+.
Reaction SMILES: CO.[C:3]([O:7][C:8]([N:10]([CH2:38][C:39]1[CH:48]=[CH:47][C:42]2[O:43][CH2:44][CH2:45][O:46][C:41]=2[CH:40]=1)[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]([O:31]CCCC)=[O:30])[CH:27]=3)[C:22]([CH3:36])=[CH:21][C:20]2=[O:37])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O.[OH-].[Li+]>O>[C:3]([O:7][C:8]([N:10]([CH2:38][C:39]1[CH:48]=[CH:47][C:42]2[O:43][CH2:44][CH2:45][O:46][C:41]=2[CH:40]=1)[CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]([OH:31])=[O:30])[CH:27]=3)[C:22]([CH3:36])=[CH:21][C:20]2=[O:37])[CH2:15][CH2:16]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCCCOC(=O)c1ccc2c(C)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(C(=O)O)ccc12
Reaction time: 0.5 h
Yield: 101.3 %

Procedure:
To 11 mL of a methanol solution containing 0.65 g of butyl 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylate, 55 mg of lithium hydroxide monohydrate was added and stirred for 30 min. Then, 55 mg of lithium hydroxide monohydrate and 1.1 mL of water were added and stirred for 2 hours. The methanol was removed under reduced pressure, water and chloroform were added, and adjusted to pH 5.0 with acetic acid. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.60 g of 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylic acid as a white foam.