Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:19]N1C(=O)CCC1=O>C1COCC1>[Br:19][C:16]1[CH:17]=[C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[N:8]=2)[C:13]([NH2:18])=[N:14][CH:15]=1
Reactant: COc1cccc2nc(-c3cccnc3N)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COc1cccc2nc(-c3cc(Br)cnc3N)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.4 %

Procedure:
A mixture of 3-(7-methoxy-1,3-benzoxazol-2-yl)pyridin-2-amine (85 mg) and 1-bromopyrrolidine-2,5-dione (69.0 mg) in THF (2 ml) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated to dryness and the resulting solid was triturated with water to give a solid which was collected by filtration and dried under vacuum to give 5-bromo-3-(7-methoxy-1,3-benzoxazol-2-yl)pyridin-2-amine (120 mg) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:38]2[C:33]([CH:34]=[N:35][C:36](OS(C(F)(F)F)(=O)=O)=[N:37]2)=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([C@H:10]2[CH2:11][CH2:12][C@H:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:4]=1[NH:5][C:36]1[N:35]=[CH:34][C:33]2=[CH:32][CH:31]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[N:38]2[N:37]=1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: COc1cc([C@H]2CC[C@H](N3CCOCC3)CC2)ccc1N
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc([C@H]2CC[C@H](N3CCOCC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 120 °C

Procedure:
Into an 8-dram vial, 2-methoxy-4-[trans-4-(morpholin-4-yl)cyclohexyl]aniline (0.125 g, 0.430 mmol), Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (98 mg, 0.26 mmol), N,N-Diisopropylethylamine (0.0749 mL, 0.430 mmol), and 1-Methoxy-2-propanol (0.70 mL, 7.2 mmol) were added. The reaction mixture was heated at 120° C. for 6 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-{2-methoxy-4-[trans-4-(morpholin-4-yl)cyclohexyl]phenyl}-7-(2-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine as a yellow solid (65 mg, 48%). LCMS (E/I+) 514.23 (M+H). NMR 1H (DMSO-d6)-9.71 (bs, 1H), 8.97 (s, 1H), 8.03 (d, 1H, J=8.03 Hz), 7.81 (d, 1H, J=7.74 Hz), 7.60 (s, 1H), 7.46 (t, 1H, J=7.74 Hz), 7.22 (d, 1H, J=8.32 Hz), 7.10 (t, 1H, J=7.74 Hz), 6.98 (d, 1H, J=4.64 Hz), 6.94 (d, 1H, J=4.64 Hz), 6.89 9 s, 1H), 6.69 (d, 1H, J=8.33 Hz), 4.02 (d, 2H, J=12.02 Hz), 3.87 (s, 3H), 3.79 (s, 3H), 3.70 (t, 2H, J=11.78 Hz), 3.46 (d, 2H, J=12.02v), 3.28 (bs, 1H), 3.15 (q, 2H, J=11.54 Hz), 1.97-2.10 (m, 4H), 1.47-1.64 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>ClCCl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC1=NN(c2ccc(Cl)c(Cl)c2)CC1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Nc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-amine (0.62 g, 2.7 mmol) in dichlorometane (45 ml), MnO2 (1.04 g, 10.8 mmol) was added and the mixture stirred at room temperature during 4 hrs. The final mixture was filtered throught decalite and the filtered solution evaporated to dryness in vacuo. The red crude solid was crystallized in ethyl ether/petroleum ether yielding 0.46 g of 1-(3,4-dichlorophenyl)-1H-pyrazol-3-amine.
Reaction SMILES: [CH3:1]I.[OH:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2>ClCCl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:1][O:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2
Reactant: CI
Reactant: O=C1Cc2c(CCO)cccc2N1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: COCCc1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl iodide (1.41 g, 10 mmol) was added to a stirred mixture of silver trifluoromethanesulfonate (2.56 g, 10 mmol) and 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (0.88 g, 5 mmol) in dichloromethane (20 mL) at 0° C. The precipitate formed after 5-10 minutes changed color from yellow to gray then dark purple. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and filtered through celite. The filtrate was concentrated and chromatographed on silica gel to give 4-(2-methoxy-ethyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]([F:16])([F:15])[C:10](OCC)=[O:11].CN(C1C=CC=CN=1)C>O1CCCC1>[F:8][C:9]([F:16])([F:15])[C:10]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:11]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: O=C(N=c1cccc[nH]1)C(F)(F)F
Reaction time: 22 h
Yield: 13.7 %

Procedure:
2-aminopyridine in an amount of 0.94 g (10 mmol) was dissolved in 20 mL of tetrahydrofuran (THF), following which 2.84 g (20 mmol) of ethyl trifluoroacetate and 1.22 g (10 mmol) of dimethylaminopyridine were added, and refluxing was carried out for 22 hours. THF was removed by distillation, following which purification was carried out with a silica gel column (developing solvent: 4:1 solution of hexane and ethyl acetate), giving 0.26 g of 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide (yield, 13.7%).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[CH:14][C:13]2=[O:26])[C:3]([OH:27])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(Cl)cc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(Cl)cc2Cl)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,4-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (340 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (106 mg, 0.003 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(2,4-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (300 mg, 78%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][CH2:11][O-:12].[Na+].CCO>CCO>[Cl:1][C:2]1[N:7]=[C:6]([O:12][CH2:11][CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Cl)ncc1F
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of the product from step (a) (10.0 g, 59.9 mmol) in abs. EtOH (40 mL) at 0° C. under nitrogen atmosphere was added 1M NaOEt/EtOH (61 mL, 61 mmol) and the mixture was stirred for 1 hour. Solvent was evaporated in vacuo and the residue partitioned between H2O and Et2O. The aqueous phase was extracted with Et2O and the combined organic phase was washed with brine, dried (Na2SO4) and evaporated (water aspirator pump, 35° C.) to provide the desired product (8.74 g, 83%) as a yellowish solid: mp 30-32° C. (lit. 31-32° C.); 1H NMR (CDCl3): δ1.46 (t, J=7.0 Hz, 3H), 4.53 (quartet, J=7 Hz, 2H), 8.17 (d, J=2.1 Hz, 1H); MS m/z 179 (M+3, 17%), 177 (M+1, 50%), 149 (100%). Anal. Calcd. for C6H6ClFN2O: C, 40.81; H, 3.42; N, 15.86. Found, C, 40.90; H, 3.45; N, 15.81.
Reaction SMILES: C([N:8]1[CH2:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][C:9]21[CH2:12][O:11][CH2:10]2)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>CCO.[OH-].[OH-].[Pd+2]>[CH2:10]1[C:9]2([CH2:13][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][NH:8]2)[CH2:12][O:11]1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)C2(COC2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CNC2(COC2)C1
Yield: 105.3 %

Procedure:
A solution of ethyl 5-benzyl-2-oxa-5-azaspiro[3.4]octane-7-carboxylate (550 mg, 2.00 mmol) in 30 mL of EtOH was stirred with 10% Pd(OH)2/C(105 mg) in the presence of TFA (20 μL) at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was dissolved in 20 mL of DCM and washed with saturated Na2CO3 (20 mL). The organic layer was dried over Na2SO4 and then concentrated in vacuo to afford ethyl 2-oxa-5-azaspiro[3.4]octane-7-carboxylate (390 mg, yield: 100%) as viscous oil.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1>C(#N)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:17][CH:18]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CSCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
To a solution of ethyl 2-mercaptoacetate (Aldrich, 1.0 mL, 9.1 mmol) in acetonitrile (10.0 mL) were added K2CO3 (2.76 g, 20.0 mmol) and 1-(bromomethyl)-4-fluorobenzene (2.27 g, 12.0 mmol). The mixture was stirred at room temperature for 12 h. After filtration and concentration, the residue was purified by flash column chromatography on SiO2 to give ethyl 2-(4-fluorobenzylthio)acetate (1.89 g, 91% yield). MS (ESI+): m/z 251.08 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:23]=2)[N:18]=[CH:17]1.Cl.C[C:38]1([NH2:41])[CH2:40][CH2:39]1>N1C=CC=CC=1>[CH:38]1([NH:41][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([CH3:6])=[C:8]([N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N:27]5[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:35])[CH2:29][CH2:28]5)[CH:23]=4)[N:18]=[CH:17]3)[CH:9]=2)[CH2:40][CH2:39]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C(C)C)CC3)cc2c1=O
Reactant: CC1(N)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCN(C(C)C)CC3)cc2c1=O
Temperature: 120 °C
Yield: 39.5 %

Procedure:
Phosphorus oxychloride (0.11 ml) was added to a mixture of 4-methyl-3-[6-(4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.30 g), 1-methylcyclopropylamine hydrochloride (0.13 g) and pyridine (5 ml) and the resultant was heated to 120° C. for 5 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The mixture was evaporated. The residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was dried (magnesium sulphate) and evaporated and the residue purified by column chromatography on a silica column using initially methylene chloride and then a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.13 g); NMR Spectrum: (CDCl3) 0.76 (m, 4H), 1.09 (d, 6H), 2.20 (s, 3H), 2.20 (s, 3H), 2.72 (in, 5H), 3.35 (m, 4H), 6.61 (s, 1H), 7.43 (m, 2H), 7.66 (m, 3H), 7.78 (m, 2H); Mass Spectrum: M+H+ 460.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:21])[CH:10]=2)=[C:5]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)[C:4]1=[O:32].Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35].N12CCCC1=NCCC2>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:31][N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:5]2[C:4](=[O:32])[N:3]([CH2:2][O:1][C:34](=[O:35])[O:36][CH2:37][CH:38]=[CH2:39])[C:7](=[O:8])[C:6]=2[C:9]2[C:17]3[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:21])[CH:10]=2)=[CH:23]1
Reactant: C=CCOC(=O)Cl
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(CO)C2=O)c2ccccc21
Agent: C1CN=C2CCCN2C1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C=CCOC(=O)OCN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cn(C)c3cc([N+](=O)[O-])ccc23)C1=O
Temperature: 20 °C
Reaction time: 14 h

Procedure:
A solution of 200 mg (0.47 mmole) of 1-hydroxymethyl-3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione, prepared as in the example 1a, was dissolved in 90 ml of THF and treated with 300 mg (2.5 mmol) of 4-dimethylaminopyridine (DMAP). To this solution at 5° C. was added 90 mg (0.75 mmole) of allyl chloroformate. While still cool, 300 mg (2.4 mmol) of 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) (Aldrich) was added dropwise. This was stirred for 14 hours at 20° C. The solvent was evaporated and the mixture was purified by chromatography using silica gel and eluting with a mixture of EtOAc/Hexane to afford carbonic acid allyl ester 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl ester as a red solid (m.p. 191-194° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[C:6]([CH3:9])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(CC(=O)O)cc(Cl)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(C)c(O)c(Cl)c1
Temperature: 70 °C
Yield: 91 %

Procedure:
A solution of (3-chloro-4-hydroxy-5-methyl-phenyl)-acetic acid (5b) (1.4 g, 6.98 mmol) in methanol (60 mL) was treated with concentrated sulfuric acid (0.5 mL) at room temperature under argon. The reaction mixture was heated to 70° C. for 24 h. At this time, the reaction mixture was concentrated under vacuum. The resulting oil was diluted with ethyl acetate (100 mL). The organics were washed with water (2×50 mL), dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography using silica gel eluted with 10% ethyl acetate in petroleum ether to afford 3-chloro-4-hydroxy-5-methyl-phenyl)-acetic acid methyl ester (6b) (1.36 g, 91%) as a white solid; EI(+)-HRMS m/z calcd for C10H11ClO3 (M+) 214.0397, found 214.0400. Molecular Weight=214.6504; Exact Mass=214.0397
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10](O)[CH:11]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:19])=O.N12CCCN=C1CCCCC2.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10]([Cl:19])[CH:11]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(O)nc2[nH]nc(C)c12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)c1cc(Cl)nc2[nH]nc(C)c12
Temperature: 110 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
6-Hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (30.0 g), phosphorous oxychloride (12.6 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (22.3 mL) were dissolved in toluene (550 mL) at 0° C. (ice bath), then stirred at 110° C. for 5 h, then cooled to r.t. The mixture was poured into a vigorously stirred solution of potassium acetate (39.9 g) in water (1 l). The aqueous solution was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was used for the next step without further purification. 28.6 g (88%) of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[CH3:29])[N:3]=1.[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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]>[CH2:30]([C:32]1[N:33]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[N:3]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(CN1CCC(C(C)(C)O)CC1)n2C
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOC[C@@H]2C)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Temperature: 150 °C
Yield: 37.9 %

Procedure:
A mixture of 2-{1-[2-chloro-9-methyl-6-((S)-3-methylmorpholin-4-yl)-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol (200 mg, 0.47 mmol), 2-ethylbenzimidazole (73 mg, 0.50 mmol), tris(dibenzylideneacetone)dipalladium (12 mg, 2.5 mol %), XPhos (20 mg, 10 mol %) and Cs2CO3 (218 mg, 0.67 mmol) in DMF (6 mL) was purged with argon then heated at 150° C. for 1 h in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-5%) then (Si-PCC, MeOH:DCM, 0-3%) affording 775 (95 mg, 38%). LCMS (method I): RT 2.65 min, [M+H]+ 533.3. 1H NMR (CDCl3, 400 MHz): δ 8.03-8.02 (1 H, m), 7.75-7.74 (1 H, m), 7.27-7.24 (2 H, m), 5.40 (2 H, brd s), 4.09-4.03 (1 H, m), 3.88 (3 H, s), 3.83 (2 H, s), 3.75-3.55 (4 H, m), 3.36 (2 H, q, J=7.48 Hz), 2.98-2.95 (2 H, m), 2.11 (2 H, t, J=10.92 Hz), 1.81-1.71 (2 H, m), 1.45-1.44 (6 H, m), 1.34-1.31 (4 H, m), 1.19 (6 H, s)
Reaction SMILES: O[CH:2]([C:37]1[CH:38]=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=1)[C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3CCCC[O:19]3)[C:9](=[O:24])[N:8]([CH3:25])[C:7]=2[N:6]=[CH:5][C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1>C(O)=O.[Zn]>[CH:18]([O:17][CH2:16][CH2:15][CH2:14][N:10]1[C:11](=[O:13])[C:12]2[C:3]([CH2:2][C:37]3[CH:38]=[N:39][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:41][CH:42]=3)=[C:4]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=3)[CH:5]=[N:6][C:7]=2[N:8]([CH3:25])[C:9]1=[O:24])=[O:19]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(C(F)(F)F)nc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Agent: [Zn]
Solvent: O=CO
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(C(F)(F)F)nc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Temperature: 50 °C
Yield: 52.7 %

Procedure:
To a solution of 5-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethyl)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 32, step 2, 75 mg, 0.114 mmol) in HCOOH (3 mL) was added Zn dust (37.5 mg, 0.573 mmol). The reaction was heated at 50° C. for 2 h, cooled to RT and filtered. The filtrate was concentrated and dried to give 3-(1-methyl-2,4-dioxo-6-(3-(trifluoromethyl)phenoxy)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (35 mg, 52.4% yield) as a solid. LCMS: MH+ 583 and TR=1.979 min.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH:37]2[CH2:39][CH2:38]2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH:37]1([NH:36][S:33]([C:29]2[CH:28]=[C:27]([NH:26][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])[CH2:39][CH2:38]1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NC2CC2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 550.1 [(M−H)−]; mp 252° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.S(Cl)(Cl)=O.[NH2:25][C:26]1[CH:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[CH:28][C:27]=1O.C(N(CC)CC)C.CS(O)(=O)=O.C(=O)([O-])O.[Na+]>O.O1CCCC1>[CH3:35][O:34][C:32]([C:30]1[CH:29]=[CH:28][C:27]2[O:20][C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)=[N:25][C:26]=2[CH:31]=1)=[O:33]
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2oc(-c3ccc4c(c3)nc(C)n4C3CCOCC3)nc2c1
Yield: 15.4 %

Procedure:
To 2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (182 mg, 0.612 mmol) was added thionyl chloride (2 mL), and this was stirred at reflux for 3 hours. After the reaction was complete, concentration at reduced pressure gave a residue that was added to 2-amino-4-methoxycarbonylphenol (117 mg, 0.612 mmol), triethylamine (309 mg, 3.06 mmol) and tetrahydrofuran (5 mL), and this was stirred at room temperature for 14 hours. After the reaction was complete, this was concentrated, and to a dioxane (5 mL) solution of the residue obtained was added methanesulfonic acid (353 mg, 1.46 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water and saturated aqueous sodium hydrogen carbonate solution were added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (37 mg, 15% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[O:18][C:17](=[O:19])[C:16]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:15]=1>CN1CCOCC1>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH:15][C:16]1([C:17]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C1OC(c2ccco2)=NC12CCCCC2
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)C1(NC(=O)c2ccco2)CCCCC1)C(=O)O
Yield: 12.5 %

Procedure:
10 ml of N-methylmorpholine was added to 1.0 g (9.1 mmol) of L-valine and 2.0 g (9.1 mmol) of 2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with a 10% aqueous potassium hydrogensulfate solution and then saturated brine, followed by drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and it was purified by silica gel chromatography to obtain 384 mg (12.5%) of the title compound.