Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:25])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:24])[C:21]([OH:23])=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:28](CC)CC)[CH3:27].ClC(OCC(C)C)=O.C(N)C>C1COCC1.O>[CH2:1]([N:8]([CH3:25])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:24])[C:21]([NH:28][CH2:26][CH3:27])=[O:23])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)C(=O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2 [(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-2-oxoacetic acid (98 mg) in THF (3 ml) was cooled to -20° C. Triethylamine (188 μl) and isobutyl chloroformate (77 μl) were added dropwise to the solution. The mixture was stirred for 20 mins at the same temperature. An aq. solution of ethylamine (70%; 200 μl) was added dropwise to the solution at the same temperature. The solution was stirred for 1 hr, while the temperature of the solution was raised to room temperature gradually. Water was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2 --CH3OH) to give the title compound (62 mg) having the following physical data:
Reaction SMILES: [CH2:1]([C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26](Cl)=[O:27])[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2].[NH2:33][CH2:34][CH:35]([OH:38])[CH2:36][NH2:37]>C(Cl)Cl>[CH2:1]([C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([NH:33][CH2:34][CH:35]([OH:38])[CH2:36][NH2:37])=[O:27])[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2]
Reactant: NCC(O)CN
Reactant: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)Cl)C1
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)NCC(O)CN)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a solution of (R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxy pentyl)piperidine-1-carbonyl chloride (<0.05 mmol) in CH2Cl2, there was added excess 1,3-diaminopropan-2-ol (˜0.1 mL). The resulting solution was stirred at rt for 1 h, the CH2Cl2 was removed, and the residue was purified by prep HPLC to give (3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-(3-amino-2-hydroxypropyl)piperidine-1-carboxamide (10.0 mg, 39%) as its TFA salt. 1H NMR (400 MHz, CD3OD): 7.64 (d, 1H), 7.32 (d, 1H), 7.04-7.20 (m, 4H), 6.74 (d, 1H), 6.56 (d, 1-H), 4.40 (d, 1H), 3.82 (m, 2H), 3.26 (t, 2H), 3.24 (s, 3H), 2.96 (m, 1H), 2.78 (m, 2H), 2.62 (q, 2H), 2.40 (m, 2H), 1.94 (m, 1H), 1.22-1.64 (m, 7H), 1.08 (t, 3H), 0.98 (m, 1H); MS m/z 514 (M+H+).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH:14]=[CH2:15])[CH:6]=1)=[S:3].[S:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C(N(CC)CC)C>C(OCC)C>[S:16]1[CH2:20][CH2:19][N:18]([C:2](=[S:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH:14]=[CH2:15])[CH:6]=2)[CH2:17]1
Reactant: C1CSCN1
Reactant: C=CCOc1cc(OC(=S)Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCOc1cc(OC(=S)N2CCSC2)ccc1Cl
Reaction time: 4 h
Yield: 66.5 %

Procedure:
O-(3-Allyloxy-4-chlorophenyl) chlorothioformate (2.63 g) was dissolved in 60 ml of diethyl ether. To this solution were added with stirring 1.01 g of thiazolidine and 1.42 ml of triethylamine. The resulting mixture was stirred for 4 hours and then washed with water. The solvent was distilled off from the ether layer. The residue was recrystallized from methanol to give 2.1 g of O-(3-allyloxy-4-chlorophenyl) 3-thiazolidinecarbothioate [Compound (33)]. The product had a melting point of 103.6°-105.6° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)C(C)C)(C)C.Cl.[N:21]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][N:23]=[CH:22]1>C(#N)C>[N:21]1([CH:26]2[CH2:31][CH2:30][N:29]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH2:28][CH2:27]2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1cn(C2CCNCC2)cn1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1N1CCC(n2ccnc2)CC1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
A solution of 1-fluoro-2-nitro-benzene (0.32 mmol, 34 μL), N,N-diisopropylethylamine (1.6 mmol, 0.28 mL) and HCl salt of 4-Imidazol-1-yl-piperidine (0.53 mmol, 0.10 g) in ACN (2 mL) was irradiated using microwave for 10 minutes at a temperature of 180° C. The solution was then cooled to room temperature and concentrated in vacuo and the resulting residue was purified using column chromatography on silica gel to provide 4-Imidazol-1-yl-1-(2-nitro-phenyl)-piperidine (71 mg, 81% yield). To the solution of this nitro compound in EtOAc (15 mL) was added Pd on carbon (5% Pd, 55 mg). The resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for about 15 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to provide compound 41A (54 mg, 86% yield). HPLC-MS RT=0.63 minutes, mass calculated formula C14H18N4 242.15, observed LCMS m/z 243.30 (M+H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: COc1cc(C#N)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1Oc1ccc(Cl)cc1Cl
Reaction time: 22 h

Procedure:
30.8 g of 4-fluoro-3-methoxybenzonitrile, 39.1 g of 2,4-dichlorophenol and 78.2 g of caesium carbonate are dissolved in 180 ml of dimethylformamide and stirred at 120° for 22 h. After cooling, the solution is diluted with diethylether, washed with water, an 1N aqueous solution of sodium hydroxide, an 1N aqueous solution of hydrogen chloride and finally with brine. The organic phase is dried over magnesium sulfate and evaporated to yield 4-(2,4-dichlorophenoxy)-3-methoxybenzonitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9](=O)[CH3:10])=[CH:3][CH:2]=1.[NH2:13][C:14]1[C:18]([C:19]#[N:20])=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[NH:16][N:15]=1>C(O)(=O)C>[CH3:10][C:9]1[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:15]2[N:16]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[C:18]([C:19]#[N:20])=[C:14]2[N:13]=1
Reactant: N#Cc1c(N)n[nH]c1N1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)CC(=O)c1ccncc1
Solvent: CC(=O)O
Product: Cc1cc(-c2ccncc2)n2nc(N3CCN(Cc4ccccc4)CC3)c(C#N)c2n1

Procedure:
A mixture of 4.8 g (0.03 moles) of 1-(4-pyridyl)-1,3-butanedione [J. Chem. Soc. (1950) p 1680], 8.4 g (0.03 moles) of 3-amino-5-(4-phenylmethyl-1-piperazinyl)-4-pyrazolecarbonitrile (prepared as described in Example 1) and 100 ml of glacial acetic acid was stirred at reflux for 18 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[S:12])=[C:5]([CH3:38])[CH:4]=1.Br[CH2:40][C:41](OC)=[O:42]>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N:10]2[C:41](=[O:42])[CH2:40][S:12]/[C:11]/2=[N:13]/[N:14]=[CH:15]\[C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:29][CH:28]=4)[N:23]=3)=[CH:20][CH:21]=2)=[C:5]([CH3:38])[CH:4]=1
Reactant: COc1cc(C)c(NC(=S)N/N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C)c1
Reactant: COC(=O)CBr
Solvent: O
Solvent: CCO
Product: COc1cc(C)c(N2C(=O)CS/C2=N/N=C\c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C)c1
Temperature: 70 °C
Yield: 76.1 %

Procedure:
To a solution of (E)-N-(4-methoxy-2,6-dimethylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazine-carbothioamide (250 mg, 0.462 mmol) in EtOH (5 mL) was added methyl bromoacetate (100 mg, 0.65 mmol), and the mixture was heated to 70° C. for 4 h. The mixture was allowed to cool to room temperature and diluted with water (1 mL). The precipitate was vacuum filtered, giving the title compound as a white solid (204 mg, 76%): mp 188-190° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.33 (s, 1H), 8.22 (d, J=8.1 Hz, 2H), 7.90-7.70 (m, 4H), 7.39 (d, J=8.7 Hz, 2H), 6.72 (s, 2H), 4.01 (s, 2H), 3.87-3.73 (s, 3H), 2.18 (s, 6H); ESIMS m/z 581 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][N:9]([CH:14]([CH3:16])[CH3:15])[S:10](=[O:13])(=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][Cl:22]>CN(C=O)C>[Cl:22][CH2:21][CH2:20][N:11]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=2[CH2:8][N:9]([CH:14]([CH3:16])[CH3:15])[S:10]1(=[O:13])=[O:12]
Reactant: ClCCBr
Reactant: CC(C)N1Cc2c(F)cccc2NS1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1Cc2c(F)cccc2N(CCCl)S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-fluoro-3-(1-methylethyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide (0.22 g, 0.9 mmol) in dry DMF (15 ml) was added via cannula to a flask containing NaH (25 mg, 0.99 mmol) and DMF (7 ml) in argon atmosphere, and stirred for 2 hours at room temperature. 1-Bromo-2-chloroethane (0.19 ml, 2.25 mmol,) was then added dropwise and the mixture stirred at room temperature for 4 days. Then, the mixture was extracted with EtOAc (3×50 ml). The combined organic extracts were washed with water (1×100 ml) and then brine (1×100 ml), dried over Na2SO4 and solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc:Hexane 1:4) affording pure 1-(2-chloroethyl)-5-fluoro-3-(1-methylethyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([O:18][C:19]([N:21]([C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH2:36]Br)=[CH:31][N:30]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OCC)(=O)C>CN(C=O)C>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:36][C:32]1[CH:31]=[N:30][C:29]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[CH:34][C:33]=1[CH3:35])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C)C(=O)OCC
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
To a suspension of NaH (0.24 g, 6.0 mmol, 60%) in DMF (5 mL) was added diethyl malonate (0.91 mL, 6.0 mmol) and the mixture was stirred for 15 min. A solution 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-bromomethyl-4-methyl-pyridin (2.0 g, 5.0 mmol) in DMF (5 mL) was added and the resulting solution stirred for 120 min at 60 ° C. Ethyl acetate was added and the mixture was washed with water and brine and dried. After evaporation of the solvent, the crude product was purified by flash chromatography (CH3OH/CH2Cl2, 1:100→1:20) to give a pure fraction 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-4-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.15 g, 48%) and an impure fraction 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]4-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.1 g).
Reaction SMILES: C(OC([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([CH3:16])[N:14]=[CH:15][C:10]=2[CH2:9]1)=O)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>ClCCl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[CH3:16][C:13]1[N:14]=[CH:15][C:10]2[CH2:9][NH:8][CH2:18][CH2:17][C:11]=2[N:12]=1
Reactant: Cc1ncc2c(n1)CCN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc2c(n1)CCNC2

Procedure:
Reaction of the product from Step A above with trifluoroacetic acid in dichloromethane according to the procedure outlined for Intermediate 28, Step C afforded the title compound as a light orange powder. LC/MS 150.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:27][CH:28]2[CH2:30][CH2:29]2)=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: BrCC1CC1
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCC2CC2)nn1
Temperature: 25 °C
Reaction time: 60 h
Yield: 94 %

Procedure:
A solution of n-butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylate (reference example 3) (0.286 g, 0.69 mmol) in DMF (3.5 ml) was treated with bromomethylcyclopropane (0.1 g, 0.78 mmol) and potassium carbonate (0.473 g, 3.4 mmol). The reaction was allowed to stir at ambient temperature for 60 hours. The solvent was evaporated at reduced pressure (vacuum pump) and the residue partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×10 ml). The organic layers were combined dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant ethyl acetate/hexane) to give the title compound as a pale yellow oil (0.3 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:35])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=2[CH:34]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].[CH2:36]([O:38][C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43](Br)[N:42]=1)=[O:40])[CH3:37]>>[CH2:36]([O:38][C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:6]2[CH:5]=[CH:4][C:3]([CH:17]([CH3:35])[C:18]([OH:23])([C:24]3[CH:25]=[CH:26][C:27]4[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=4[CH:34]=3)[C:19]([F:22])([F:20])[F:21])=[C:2]([Cl:1])[CH:7]=2)[N:42]=1)=[O:40])[CH3:37]
Reactant: CCOC(=O)c1cccc(Br)n1
Reactant: CC(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Product: CCOC(=O)c1cccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)n1

Procedure:
The title compound was prepared in analogy to Example 186, step 2 from 5-{2-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-hydroxy-1-trifluoromethyl-propyl}-3-methyl-3H-benzooxazol-2-one (obtained in Example 186, step 1) with ethyl-6-bromopyridine-2-carboxylate [CAS Reg. No. 21190-88-5]. MS (m/e)=535.2 [M+H+].
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([OH:3])=[O:2].[NH2:14][C:15]1[C:16](=[O:29])[N:17]([CH2:26][CH2:27][CH3:28])[C:18](=[O:25])[N:19]([CH2:22][CH2:23][CH3:24])[C:20]=1[NH2:21]>CO.C(O)(=O)C>[NH2:21][C:20]1[N:19]([CH2:22][CH2:23][CH3:24])[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH3:28])[C:16](=[O:29])[C:15]=1[N:14]=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Solvent: CC(=O)O
Solvent: CO
Product: CCCn1c(N)c(N=Cc2ccc(OCC(=O)O)cc2)c(=O)n(CCC)c1=O

Procedure:
A representative synthesis of benzylidene adduct is given. Compound A (1.51 g, 8.37 mmol) was dissolved in a mixture of methanol (35 ml) and acetic acid (5 ml) in a 50 ml boiling flask on a steam bath. To this was added a methanolic solution (60 ml) of freshly synthesized 5,6-diamino-1,3-dipropyluracil. After heating 15 minutes, the volume was reduced by evaporation until crystallization occurred. Ether (40 ml) was added and the nearly white solid was collected. Yield 2.80 g (86%), mp 179°-180° C. Analysis (C19H24N4O5): calc. 58.60% C, 6.21% H, 14.39% N; found 58.72% C, 6.16% H, 14.43% N.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:16])[NH:11]2.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O.N1CCCCC1>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccccn2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccccn4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 70 °C

Procedure:
A mixture of 4-pyridin-2-yl-1,3-dihydroindol-2-one (31.5 mg, 0.15 mmol), 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (37.4 mg, 0.15 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 70° C. for 6 hours. The reaction was concentrated and the residue was re-crystallized from ethyl acetate and hexane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:13]2[CH2:15][CH2:14]2)=[N:7][NH:8][C:9]=1[CH:10]1[CH2:12][CH2:11]1)=[O:4].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[C:20](I)[CH:21]=[CH:22][CH:23]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:13]2[CH2:15][CH2:14]2)=[N:7][N:8]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([C:17]([F:26])([F:25])[F:16])[CH:23]=2)[C:9]=1[CH:10]1[CH2:12][CH2:11]1)=[O:4]
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: COC(=O)c1c(C2CC2)n[nH]c1C1CC1
Product: COC(=O)c1c(C2CC2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1

Procedure:
The title compound was prepared by reaction of intermediate 16B 3,5-dicyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester with 3-trifluoromethlyiodobenzene in analogy to intermediate 6A. MS: 367.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC(C)([O-])C.[K+].[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1.5 h

Procedure:
25 g of 4-amino-3-nitro-phenol are dissolved in 250 ml of dimethylformamide and 18.5 g of potassium tert.butoxide are added in batches whilst cooling with ice. The mixture is stirred for a further 1.5 hours, then 18.5 ml of ethylbromoacetate are added dropwise, whilst cooling with water, and the mixture is stirred for a further 16 hours at ambient temperature. The solvent is evaporated off in vacuo and the residue is taken up with a mixture of 500 ml of ethyl acetate, 250 ml of tetrahydrofuran and 750 ml of water and the organic phase is washed with saturated saline solution. The aqueous phases are extracted with ethyl acetate, the organic phases are combined and evaporated down and the residue is purified by column chromatography (neutral aluminium oxide; eluant:methylene chloride). Yield: 29 g (75% of theory),
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([CH:12]3[O:20][CH:19]4[CH:14]([O:15][Si](C(C)(C)C)(C(C)(C)C)[O:17][CH2:18]4)[CH:13]3[O:29][C:30](=[O:32])[CH3:31])[C:6]=2[N:7]=1.N1C=CC=CC=1>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([CH:12]3[CH:13]([O:29][C:30](=[O:32])[CH3:31])[CH:14]([OH:15])[CH:19]([CH2:18][OH:17])[O:20]3)[C:6]=2[N:7]=1
Reactant: CC(=O)OC1C2O[Si](C(C)(C)C)(C(C)(C)C)OCC2OC1n1c(=O)sc2cnc(N)nc21
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)OC1C(O)C(CO)OC1n1c(=O)sc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 17 (2.28 g, 4.73 mmol) in 10 mL anhydrous methanol was added 327 μL HF/Pyridine. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated and purified by flash chromatography (0-10% MeOH—CH2Cl2) yielding 1.47 g (90%) 18: 1H NMR (400 MHz, DMSO-d6) δ 8.38 (1H, s), 6.86 (2H, bs), 5.82 (1H, d, J=4.68 Hz), 5.76-5.78 (1H, m), 5.34 (1H, d, J=7.8 Hz), 4.60 (1H, t, J=5.46 Hz), 4.27-4.31 (1H, m), 3.96-4.00 (1H, m), 3.61-3.72 (2H, m), 2.03 (3H, s); [M]+ @ m/z 343.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH:26]=4)[N:19]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][O:31][C:27]1[CH:26]=[C:25]([NH:24][C:20]2[N:19]=[C:18]([C:17]3[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:43](=[O:44])[CH2:42][C:38]5[S:37][CH:41]=[CH:40][CH:39]=5)[CH:3]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:23]=[CH:22][N:21]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4ccc(F)c(N)c4)nn4ccccc34)n2)c1
Reactant: O=C(Cl)Cc1cccs1
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4ccc(F)c(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Yield: 37 %

Procedure:
The title compound was prepared 4-[2-(3-amino-4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine and 2-thiopheneacetyl chloride using the acylation conditions described in Example 36, Step H to generate, after HPLC purification, the desired product as a TFA salt in 37% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 9.62 (s, 1H), 8.85 (d, J=6.8 Hz, 1H), 8.49 (d, J=8.7 Hz, 1H), 8.27 (d, J=5.5 Hz, 2H), 7.61 (s, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.30-7.39 (m, 3H), 7.19 (t, J=8.0 Hz, 2H), 7.13 (t, J=6.9 Hz, 2H), 6.96-6.98 (m, 1H), 6.60 (d, J=6.1 Hz, 1H), 6.55 (d, J=5.3 Hz, 1H), 4.25-4.26 (m, 2H), 3.99 (s, 2H), 3.50 (m, 2H), 2.85 (s, 6H). ES-LC/MS m/z=608 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26][NH2:27]>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:27][CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([CH3:21])[CH:30]=[CH:29][CH:28]=2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: Cc1cccc(CCN)c1
Product: COc1cc(CNCCc2cccc(C)c2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 78.9 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 3-methylphenethylamine (0.0248 g, 0.184 mmol) gives the title compound (0.0568 g, 78.9%): TOF MS ES+ 392.2 (M+H)+, HRMS calcd for C23H26N3O3 392.1974 (M+H)+, found 392.1975, time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.7 min, 97.6% purity.