Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)c(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)c(F)c2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of ethyl(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(cycloheptylidene)methyl]phenyl}-2-propenoate (134) (0.22 g, 0.56 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract washed with brine and dried over Na2SO4. Upon concentration, light brown foam was obtained. It was triturated with hexanes (contains 1% MeOH) to give compound 135 as a pale yellow solid (0.171 g, 84%). mp 164-165° C. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (br s, 8H), 2.10-2.30 (m, 4H), 6.45 (d, J=15.9 Hz, 1H), 6.70-6.78 (m, 1H), 6.80-6.90 (m, 1H), 7.14 (d, J=8.2 Hz, 2H), 7.53 (d, J=16.2 Hz, 1H), 7.59 (d, J=8.0 Hz, 2H), 9.74 (s, 1H), 12.35 (s, 1H). LCMS (ES): m/z 367 (M+H)+, m/z 365 (M−H)−. Anal. Calcd for C23H23FO3. 0.1H2O: C, 75.02; H, 6.35; Found: C, 74.93; H, 6.44.
Reaction SMILES: [Br:1]CC(C1C=C2C(=CC=1)C(=O)OCC2)=O.C(N1CCN[C@H](CO)C1)(OC(C)(C)C)=O.[CH:31]([N:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][CH3:36])([CH3:33])[CH3:32]>C1COCC1>[BrH:1].[CH3:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH:31]([CH3:33])[CH3:32]
Reactant: O=C(CBr)c1ccc2c(c1)CCOC2=O
Agent: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
6-(Bromoacetyl)-3,4-dihydro-1H-isochromen-1-one (˜1.54 g, ˜5.72 mmol, presence of α-chloroketone was noted, ˜10%) and commercially available (S)-4-N-BOC-2-hydroxymethylpiperazine (1.24 g, 5.72 mmol) were added to a round bottom flask and diluted with THF (50 mL). Diisopropylethylamine (1.30 mL, 7.44 mmol) was then introduced and the mixture left stirring for 14 h at RT during which time a considerable amount of solid had formed (presumably HBr salt of DIPEA). The reaction mixture was diluted with EtOAc, then washed with saturated NH4Claq followed by H2O. Both aqueous layers were sequentially back extracted once with another portion of EtOAc, the organics were then combined, dried with MgSO4, filtered, and concentrated in vacuo. The recovered crude product was subjected to purification by flash chromatography (Biotage, 50% EtOAc/Hex) to afford the title compound.
Reaction SMILES: NC1C(C(N)=[O:9])=C(N2CCC(C3N(C)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1.[NH2:34][C:35]1[C:40]([C:41]#[N:42])=[C:39]([N:43]2[CH2:48][CH2:47][CH:46]([C:49]3[N:50]([CH2:62][CH2:63][N:64]4[CH2:67][CH2:66][CH2:65]4)[CH:51]=[C:52]([C:54]4[CH:59]=[CH:58][C:57]([F:60])=[C:56]([Cl:61])[CH:55]=4)[N:53]=3)[CH2:45][CH2:44]2)[N:38]=[CH:37][N:36]=1>>[NH2:34][C:35]1[C:40]([C:41]([NH2:42])=[O:9])=[C:39]([N:43]2[CH2:44][CH2:45][CH:46]([C:49]3[N:50]([CH2:62][CH2:63][N:64]4[CH2:65][CH2:66][CH2:67]4)[CH:51]=[C:52]([C:54]4[CH:59]=[CH:58][C:57]([F:60])=[C:56]([Cl:61])[CH:55]=4)[N:53]=3)[CH2:47][CH2:48]2)[N:38]=[CH:37][N:36]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCN2CCC2)CC1
Product: NC(=O)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=499, obsd.=499).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:12])=[N:8][C:9]=2Cl)[N:4]([CH3:13])[N:3]=1.[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CN(C=O)C>C(Cl)Cl.O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:12])=[N:8][C:9]=2[NH:22][CH2:21][CH2:20][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:4]([CH3:13])[N:3]=1
Reactant: NCCN1CCOCC1
Reactant: Cn1nc(Br)c2c(Cl)nc(N)nc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nc(Br)c2c(NCCN3CCOCC3)nc(N)nc21
Temperature: 50 °C

Procedure:
3-Bromo-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 14) (750 mg, 2.8 mmol), 2-(4-morpholinyl)ethylamine (0.44 ml, 3.3 mmol) and DMF (30 ml) are mixed together and heated to 50° C. overnight. After cooling to room temperature the reaction mixture is diluted with DCM (60 ml) and water (40 ml) and the aqueous portion is extracted with a further 40 ml DCM. The organic portions are combined, dried over MgSO4, filtered and concentrated in vacuo. The crude residue is dry loaded onto silica and purification by flash chromatography eluting with DCM then MeOH:DCM (5:95) affords the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:23]4=[C:24]([CH2:31][CH3:32])[C:25]([C:27]([O:29]C)=[O:28])=[CH:26][N:22]4[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:23]4=[C:24]([CH2:31][CH3:32])[C:25]([C:27]([OH:29])=[O:28])=[CH:26][N:22]4[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(C(=O)OC)cn2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1c(C(=O)O)cn2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c12
Yield: 59 %

Procedure:
Methyl 4-(1-benzyl-1H-indazol-5-ylamino)-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (51.3 g, 0.12 mol) was dissolved in THF (750 mL) and the solution added to a 2 L round bottomed flask equipped with a reflux condenser. Methanol (250 mL) was then added to the flask followed by a solution of lithium hydroxide monohydrate (60.8 g, 1.45 mol) in water (300 mL). The reaction was then heated to reflux for 20 hrs. HPLC analysis of the mixture after this time indicated that the reaction was complete. The reaction was then cooled and the mixture concentrated under reduced pressure. Water (200 mL) was then added to the residue and the resulting solution extracted with ethyl acetate (2×100 mL). Hydrochloric acid (2N) was then added to the aqueous solution until a pH of 3-4 was obtained. This resulted in the formation of a thick white precipitate, which was filtered off. The filter cake was then slurried in ethyl ether (1 L), re-filtered and dried, affording 29.2 g of 4-(1-benzyl-1H-indazol-5-ylamino)-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid. The filtrate was combined with the original ethyl acetate extract and the solvents removed under reduced pressure. Purification of the residue by trituration with a 2:1 mixture of ether and ethyl acetate (500 mL) followed by filtration and drying, afforded a further 13.4 g of the desired acid. The combined total yield of 4-(1-benzyl-1H-indazol-5-ylamino)-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid was 42.6 g (86%) and the material had an HPLC purity of 98.2%.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=1[CH:13]=[O:14].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Br:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:15][C:12]=1[CH:13]=[O:14]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1
Temperature: 80 °C
Yield: 78 %

Procedure:
To a solution of 6-chloro-nicotinonitrile (3.5 g, 25.0 mmol, 1.0 eq.), 2-bromo-5-hydroxy-benzaldehyde (5.0 g, 25.0 mmol, 1.0 eq.) in DMF (40.0 mL) was added K2CO3 (4.1 g, 30.0 mmol, 1.2 eq.) under nitrogen atmosphere. The mixture was heated at 80° C. overnight. After cooling to room temperature, the mixture was poured into EtOAc (30 mL) and H2O (30 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×20 mL). Combined organic extracts was washed with brine (30 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 6-(4-bromo-3-formyl-phenoxy)-nicotinonitrile as a white solid. 1H NMR(CHLOROFORM-d) δ: 10.35 (s, 1H), 8.43 (dd, J=2.3, 0.6 Hz, 1H), 7.98 (dd, J=8.6, 2.3 Hz, 1H), 7.69-7.77 (m, 2H), 7.30 (dd, J=8.6, 3.0 Hz, 1H), 7.12 (dd, J=8.6, 0.8 Hz, 1H). Amount obtained, 5.92 g, 78% yield.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].CN(CCN(C)C)C.[I:30]I>C1COCC1>[F:13][C:10]1[C:9]([I:30])=[C:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:7]([F:6])=[CH:12][CH:11]=1
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccc1F
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1c(F)ccc(F)c1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
nBuLi (5.67 mL, 14.2 mmol) was added to a solution of tert-butyl (2,5-difluorophenyl)carbamate (1.08 g, 4.73 mmol) and TMEDA (2.14 mL, 14.2 mmol) in THF (21.6 mL) at −78° C. over 20 minutes, ensuring the internal temperature remained below −70° C. The resulting solution was stirred at −78° C. for 1 h. Iodine (3.60 g, 14.2 mmol) in THF (10 mL) was added dropwise over 30 min, also ensuring the internal temperature remained below −70° C. The resulting reaction was stirred for 1 h at −78° C., The reaction was quenched at −78° C. with water and the reaction warmed to room temperature. 10% Sodium thiosulfate was added until the iodine color dissipated and the mixture was then extracted with ethyl acetate (3×50 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated. The crude material was purified on silica gel, eluting 0-60% EtOAc in hexanes over 28 minutes to afford tert-butyl (3,6-difluoro-2-iodophenyl)carbamate (1.14 g, 3.20 mmol) as a white crystalline solid. MS (ESI): m/z=300.2 (M+H-[t-Bu]).
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].[C:15]1([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[OH:30][CH:29]([C:28]1[CH:31]=[CH:32][C:25]([O:24][CH2:23][CH2:22][CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:26][CH:27]=1)[CH2:13][C:12]#[N:14]
Reactant: CC#N
Reactant: O=Cc1ccc(OCCCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCC(O)c1ccc(OCCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To dry tetrahydrofuran (14 mL), n-butyl lithium (0.94 mL; a 1.6 M hexane solution) and dry acetonitrile (0.082 mL) were successively dropped at −78° C. After stirring for 30 minutes, a solution of 4-(3-phenylpropoxy)benzaldehyde (300 mg) in dry tetrahydrofuran (3 mL) was dropped into the mixture at −78° C. The reaction mixture was stirred at room temperature for 1 hour, then poured into ice-water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with a mixed solvent of diethyl ether and hexane and filtered to give the title compound (238 mg) having the following physical properties.
Reaction SMILES: Cl.N[C@H:3]1[CH2:7][O:6][CH2:5][C@@H:4]1[OH:8].C([N:11](CC)CC)C.[C:16](OC([O-])=O)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>ClCCl.CCOCC>[C:16]([C@H:3]1[CH2:7][O:6][CH:5]([NH2:11])[C@@H:4]1[OH:8])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCN(CC)CC
Reactant: N[C@H]1COC[C@@H]1O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H]1COC(N)[C@@H]1O
Temperature: 20 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
(3R,4S)-4-Amino-3-hydroxytetrahydrofuran hydrochloride (Scott et al, J. Org. Chem., 62, 4197 (1997); 0.75 g, 5.37 mmol) in dichloromethane (10 ml) was treated with triethylamine (0.8 ml) and t-butyl dicarbonate (1.3 g). The reaction was stirred at 20° C. for 18 h. The reaction mixture was diluted with ether (20 ml) washed with water, 5% aqueous citric acid and brine, dried and partially evaporated under reduced pressure, to give a white solid. This was collected, washed with hexane and dried under reduced pressure to give the title compound, (0.64 g, 58%). NMR (CDCl3) 1.45 (9H, s), 3.0 (1H, bs), 3.6 (1H, dd), 3.7 (1H, dd), 3.95 (1H, m), 4.1 (2H, m), 4.28 (1H, m), 4.7 (1H, bm).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][C:5]1([OH:17])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:19](Cl)(=[O:21])[CH3:20].C(N(CC)CC)C.[CH:30]1([NH:36][S:37]([OH:40])(=[O:39])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1>[CH:30]1([NH:36][S:37](=[O:38])(=[O:39])[OH:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1.[C:19]([O:17][C:5]1([CH2:4][CH2:3][N:2]([CH3:1])[CH3:18])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:21])[CH3:20]
Reactant: CN(C)CCC1(O)CCCCC1c1ccccc1
Reactant: CC(=O)Cl
Agent: O=S(=O)(O)NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC1(CCN(C)C)CCCCC1c1ccccc1

Procedure:
The procedure of Example I (c) is followed using 7.5 g of 1-(2-Dimethylaminoethyl)-2-phenylcyclohexanol (Example XIV) and 8 ml of acetyl chloride with 18 ml triethylamine giving 11.8 g crude acetate which is treated with 12 g cyclohexanesulfamic acid in tetrahydrofuran to give 6.7 g pure product, m. 140°-1°.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)=O>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2].O>[C:20]1([C:19]2[NH:8][CH:9]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:18]=2[C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: C1=C(c2ccccc2)N1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1ccccc1)c1c(-c2ccccc2)c[nH]c1-c1ccccc1
Temperature: 20 °C

Procedure:
With stirring, 3.0 g of 2-phenylazirine are added dropwise to a solution of 5.6 g of dibenzoylmethane, 10 ml of acetone and 0.1 g of nickel acetylacetonate at 50° C. The mixture is then heated at reflux for 30 minutes, cooled to 20° C., and 25 ml of water are added. The precipitated crystals are filtered with suction, washed with water, and dried to constant weight.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[C:4]#[N:5].[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+].CC(N1CCCC1)(C)C(N)C1C=CC=CC=1>C(OCCCC)CCC.C1COCC1.CO>[NH2:5][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([N:2]([CH3:10])[CH3:1])([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: [Li]c1ccccc1
Reactant: CCC(C#N)(CC)N(C)C
Agent: CC(C)(C(N)c1ccccc1)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(C(N)c1ccccc1)N(C)C
Yield: 88 %

Procedure:
The title compound (11.12 g, 88%) was prepared from 2-(dimethylamino)-2-ethylbutanenitrile D19 (8.05 g, 0.0575 mol) and phenyllithium in dibutylether (64 ml of a 1.8M solution; 0.115 mol) in THF (350 ml), followed by reaction with sodium borohydride (3.9 g, 0.103 mol) in methanol (300 ml) in a similar manner to that described in D5. 1H NMR (CDCl3) δ: 0.72 (3H, t, J=7.6 Hz), 0.97 (3H, t, J=7.6 Hz), 1.40-1.68 (4H, m), 1.70 (2H, br, m), 2.43 (6H, s), 4.09 (1H, s), 7.19-7.43 (5H, m).
Reaction SMILES: CO[C:3]1[C:6](=O)[C:5](=[O:8])[C:4]=1[O:9]C.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([F:19])[CH:13]=1.Cl.[Cl:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[C:31]([C@H:32]3[CH2:36][CH2:35][CH2:34][NH:33]3)=[N:30][N:29]=[C:28]2[CH3:37])=[CH:24][CH:23]=1>CO.CCN(C(C)C)C(C)C>[Cl:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[C:28]([CH3:37])=[N:29][N:30]=[C:31]2[C@H:32]2[CH2:36][CH2:35][CH2:34][N:33]2[C:3]2[C:4](=[O:9])[C:5](=[O:8])[C:6]=2[NH:16][C:15]2[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][C:14]=2[F:19])=[CH:24][CH:23]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1c(OC)c(=O)c1=O
Reactant: Cc1nnc([C@H]2CCCN2)n1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc([C@H]2CCCN2c2c(Nc3ccc(Cl)cc3F)c(=O)c2=O)n1Cc1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Dimethoxycyclobutenedione (28 mg) and the 4-chloro-2-fluoroaniline (30 mg) were dissolved in methanol (1 ml) and DIEA (0.035 ml). The reaction was stirred at 75° C. overnight. (R)-4-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole hydrochloride (58 mg) was added and stirring and heating was continued overnight. Flash chromatography purification (0-10% methanol/DCM) afforded the desired product as residue (11 mg, 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH3:20])[CH2:17][O:18][CH3:19])[C:10]=1[NH2:21].[C:22](OC)(=[O:26])[C:23]([CH3:25])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:21]=[C:23]([CH3:25])[C:22](=[O:26])[N:15]([CH:16]([CH3:20])[CH2:17][O:18][CH3:19])[C:11]=2[N:12]=[CH:13][CH:14]=1
Reactant: COC(=O)C(C)=O
Reactant: COCC(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1N
Solvent: Cc1ccccc1
Product: COCC(C)n1c(=O)c(C)nc2c(-c3ccc(Cl)cc3Cl)ccnc21
Yield: 2.1 %

Procedure:
4-(2,4-Dichloro-phenyl)-N2-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine (0.13 g, 0.40 mmol) was dissolved in toluene (20 mL), followed by methyl pyruvate (0.081 g, 0.80 mmol) and heated at reflux overnight. The reaction was concentrated in vacuo and purified by reverse phase prep HPLC to yield 3.2 mg (2%) of 8-(2,4-dichloro-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 9): 1H NMR (300 MHz, CD3OD): δ 8.6 (d, 1H), 7.6 (s, 1H), 7.4–7.25 (m, 3H), 4.4 (m, 1H). 3.8 (m, 1H), 3.3 (s, 3H), 2.4 (s, 3H), 1.6 (d, 2H), 1.25 (s, 2H). MS (AP) m/z 378.3 [(M+H)+, 100].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][N:8]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:9]1[N:14]=[CH:13][N:12]=[C:11]2[NH:15][N:16]=[CH:17][C:10]=12.C1(C)C=CC(S([O:35][CH2:36][CH:37]2[CH2:41]OC(C)(C)[O:38]2)(=O)=O)=CC=1>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][N:8]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:9]1[N:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:41][CH:37]([OH:38])[CH2:36][OH:35])[N:16]=[CH:17][C:10]=12
Reactant: Clc1cccc(CN(c2ncnc3[nH]ncc23)C2CCCC2)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCC(O)Cn1ncc2c(N(Cc3cccc(Cl)c3)C3CCCC3)ncnc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a suspension of 1.5 g (30 mmole) 50% sodium hydride in 50 ml. N,N-dimethylformamide are added dropwise 9.6 g. (30 mmole) 4-[N-(3-chlorobenzyl)-cyclopentylamino]-1H-pyrazolo[3,4-d]pyrimidine (compound of Example 1) in 25 ml. N,N-dimethylformamide. The reaction mixture is stirred for 1 hour at 80° C., 10.0 g. (35 mmole) 4-(4-toluenesulphonyloxymethyl)-2,2-dimethyl-1,3-dioxolan in 25 ml. N,N-dimethylformamide are added thereto, the reaction mixture is further stirred for 3 hours at 80° C. and evaporated in a vacuum. The residue is taken up in water, extracted with dichloromethane and the extract evaporated. The residue is mixed with 300 ml. 0.1N hydrochloric acid, heated under reflux for 10 hours, allowed to cool, washed with diethyl ether and the aqueous phase rendered alkaline with aqueous sodium hydroxide solution. After extraction with dichloromethane and evaporation of the extract, there are obtained 8.2 g. of crude product which is purified by chromatography on silica gel (elution agent: dichloromethane/methanol; 9:1 v/v). 4.1 g. (34% of theory) of the title compound are eluted which, after trituration with diethyl ether, melts at 98°-100° C.
Reaction SMILES: [CH:1]1([C:4](OC)=O)C[CH2:2]1.[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O)([O-:10])=[O:9].[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>>[C:11]([C:12]1[CH:13]([C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N+:8]([O-:10])=[O:9])[C:24]2[C:20](=[N:21][NH:22][CH:23]=2)[NH:19][C:13]=1[CH:4]1[CH2:1][CH2:2]1)#[N:8]
Reactant: COC(=O)C1CC1
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Product: N#CC1=C(C2CC2)Nc2n[nH]cc2C1c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from methyl cyclopropanecarboxylate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:22][NH:23][CH3:24].[CH2:25](O)C>>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C1CCC(c2ccccc2)=NN1Cc1ccccc1
Reactant: CNC
Agent: Cl
Product: CN(C)CC1CC(c2ccccc2)=NN(Cc2ccccc2)C1=O

Procedure:
A mixture of 2-benzyl-6-phenyl-4,5-dihydro-3(2H)-pyridazinone (23.9 g) paraformaldehyde (5.0 g), and dimethylamine hydrochloride (8.0 g) in 200 ml of ethanol is heated under reflux for 4 hours. The ethanol is removed by distillation on the rotary evaporator and the residue is rendered basic with ammonium hydroxide solution. This is extracted with dichloromethane. The dichloromethane is concentrated on the rotary evaporator and the residue is chromatographed on silica gel with 2% methanol/chloroform to give 2-benzyl-4-(dimethylaminomethyl)-6-phenyl-4,5-dihydro3(2H)-pyridazinone. This is dissolved in 500 ml of methanol and catalytically hydrogenated at 3 atmospheres pressure over 5% paladium on charcoal. The catalyst is removed by filtration and the methanol is concentrated to give 4-(dimethylaminomethyl)-6-phenyl-4,5-dihydro-3(2H)-pyridazinone. This compound is treated with bromine in acetic acid according to the procedure of Example 1 to give 4-(dimethylaminomethyl)-6-phenyl-3(2H)-pyridazinone.