Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl.C1(C2C=CC=CC=2)C=CC=CC=1N[C:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:19](=[O:23])[CH:18](CCN3CCC(C4C=CC=CC=4)CC3)[CH2:17][CH2:16][C:15]=2[CH:14]=1)=[O:12].[CH3:44]I.CN([CH:49]=[O:50])C>>[CH3:44][O:23][CH:19]1[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:11]([O:50][CH3:49])=[O:12])[CH:22]=[CH:21][C:20]1=2
Reactant: O=C(Nc1ccccc1-c1ccccc1)c1ccc2c(c1)CCC(CCN1CCC(c3ccccc3)CC1)C2=O
Reactant: CN(C)C=O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc2c(c1)CCCC2OC
Temperature: 0 °C
Yield: 63 %

Procedure:
Sodium hydride (80% oil dispersion, 28 mg, 0.93 mmol) was added to a solution of 2 (0.19 g, 0.93 mmol) in DMF (2 mL) stirring at 0° C. Methyl iodide (0.13 g, 58 mL, 0.93 mmol) was added. After stirring at 0° C. for 2 hours and at ambient temperature for 30 minutes, additional sodium hydride (14 mg, 0.47 mmol) and methyl iodide (29 mL, 0.47 mmol) were added. After stirring an additional 3 hours, the reaction was quenched with 0.1N HCl and transferred to a separatory funnel with CH2Cl2. Extraction with CH2Cl2 (2×40 mL) and drying over MgSO4 afforded 0.33 g of crude product after evaporation of the solvent. Flash chromatography (silica, 25 mm dia, 10% EtOAc/hexane) afforded 0.13 g (63%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Cl:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=O)=[CH:19][CH:18]=1>>[Cl:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=2)[CH2:10][CH3:11])=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)c1ccc(O)c(F)c1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)c(F)c1
Yield: 87.5 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-(3-fluoro-4-hydroxyphenyl)propan-1-one (255 mg, 1.52 mmol) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (629 mg, 2.27 mmol) to give 549 mg desired product (88% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([O:13]CC)=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].CO.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1cn(C)c(=O)c(C)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cl)c(C(=O)O)cn(C)c1=O
Reaction time: 0.67 h
Yield: 100 %

Procedure:
To a solution of ethyl 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (172 mg, 0.75 mmol) dissolved in a 4:1 mixture of THF:MeOH (5 mL) (v:v), was added a aqueous solution of LiOH (1.52 mmol, 1M). After stirring for 40 min, the reaction mixture was acidified to pH ˜1 with HCl(1N, aq) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered and concentrated under the reduced pressure to give an off-white solid as the title compound. (163 mg, 100% yield). MW m/z: 202.3 (MW+1), 204.2 (MW+1+Cl pattern); 200.4 (MW−1), 202.4 (MW−1+Cl pattern). 1H NMR (DMSO-d6, 300 Hz): δ ppm 12.97 (s, 1H), 8.42 (s, 1H), 3.48 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].ClC1C=CC(O[CH2:13][C:14]#[N:15])=CC=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>CN(C)C=O>[CH3:18][N:19]([CH3:29])[C:20]1[N:21]=[C:22]([CH2:13][C:14]#[N:15])[C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc([N+](=O)[O-])c(CC#N)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a stirred solution of potassium tert-butoxide (12.34 g, 110 mmol, 2.2 eq) in anhydrous dimethylformamide (100 mL) at -10° C. was added dropwise a solution of (4-chlorophenoxy)acetonitrile (9.22 g, 55 mmol, 1.1eq) and 2-dimethylamino-5-nitropyridine (Pfaltz and Bauer, Inc., 8.36 g, 50.0 mmol) in anhydrous dimethylformamide (50 mL). The resultant deep purple-colored solution was stirred at -10° C. under nitrogen for 1hour. Then an aqueous 5% HCL solution (85 mL) added dropwise to the reaction solution at 0° C., and the precipitated solid was filteredand dried to yield Compound 5c (8.60 g, 41.7 mmol, 83%) as a yellow solid: mp, 156.0-158.0° C.; IR (KBr) 2240, 1600, 1580, 1530, 1485, 1420, 1385, 1335 cm-1 ; 1H NMR (CDCl3) δ 8.25 (d, J=9.0 Hz, 1H), 6.45 (d, J=9.6 Hz, 1H), 4.38 (s, 2H), 3.25 (br s, 6H); LRMS (m/z,relative intensity) 207 (13), 206 (M+, 100), 191 (54), 189 (26), 177 (88), 160 (35), 159 (22), 145 (94), 134 (30), 131 (24), 119 (29), 118 (59), 93 (27). Anal. calcd. for C9H10N4O2 : C, 52,42; H, 4.89; N, 27.17; found: C, 52.19; H, 4.93; N, 26.93.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(N(CC)CC)C>[CH:38]1([N:37]([CH3:36])[CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:24]=[CH:23][C:22]4[CH2:21][C@@H:20]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[C:19]5[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=5[C:17]=4[N:16]=3)=[CH:10][CH:9]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(F)cc2)C3)cc1
Reactant: CNC1CCCCC1
Solvent: CCN(CC)CC
Product: CN(CCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(F)cc2)C3)cc1)C1CCCCC1

Procedure:
This was synthesized by using (S)-4-(6-(4-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-methylcyclohexanamine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=160-162° C. 1H NMR (DMSO-d6) 400 MHz δ 10.37 (brs, 1H), 9.68 (s, 1H), 8.32-8.36 (m, 2H), 7.80 (d, J=7.8 Hz, 2H), 7.50-7.52 (m, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.10-7.17 (m, 4H), 4.43 (t, J=6.6 Hz, 1H), 3.27-3.30 (m, 5H), 3.01-3.13 (m, 2H), 2.73 (d, J=4.6 Hz, 3H), 2.03-2.09 (m, 2H), 1.99 (s, 1H), 1.81 (d, J=12.1 Hz, 2H), 1.61 (d, J=12.5 Hz, 1H), 1.40-1.44 (m, 3H), 1.27-1.32 (m, 3H), 1.09-1.17 (m, 2H). LCMS m/e 507 [M+H].
Reaction SMILES: [N+](C1C=C(C=CC=1)O[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][CH2:23][CH3:24])([O-])=O.[H][H].[CH2:30]([OH:32])[CH3:31]>[Pt]>[CH2:11]([NH:10][C:9]1[CH:31]=[C:30]([CH:24]=[CH:23][CH:22]=1)[O:32][C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[N:8]([CH2:20][CH:19]([CH3:14])[CH3:18])[C:9]([CH2:22][CH2:23][CH3:24])=[N:10][C:11]=3[C:12]([NH2:21])=[N:13][C:14]=2[CH:15]=1)[CH3:12]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1Oc1cccc([N+](=O)[O-])c1
Reactant: CCO
Reactant: [H][H]
Agent: [Pt]
Product: CCCc1nc2c(N)nc3cc(Oc4cccc(NCC)c4)ccc3c2n1CC(C)C
Reaction time: 1 h

Procedure:
1-(2-Methylpropyl)-7-(3-nitrophenoxy-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.254 g, 0.606 mmol), prepared as described in Example 37, was stirred in ethanol (10 mL), and 5% platinum on carbon (0.025 g) was added. The reaction was placed under a positive pressure of hydrogen and stirred for one hour. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 98:2 to 95:5). The product was recrystallized from acetonitrile to provide 0.032 g of 7-(3-ethylaminophenoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as square, orange crystals, mp 168-174° C.
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[NH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl.CO>[CH:1]1([CH2:7][N:16]2[C:17]3[C@:18]4([CH3:28])[C:25]([CH3:27])([CH3:26])[C@@H:21]([CH2:20][CH2:19]4)[C:22]=3[C:23](=[O:24])[N:15]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CCCCC1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccccc2)n1CC1CCCCC1
Temperature: 100 °C
Yield: 4.1 %

Procedure:
A mixture of cyclohexylmethyl bromide (2.1 mL, 15 mmol), (4R,7S)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 395 mg, 1.47 mmol) and tetra-n-butylammonium iodide (400 mg, 1.08 mmol) in N,N-dimethylformamide (4 mL) was heated in an oil-bath at 100° C. for 64 h. Additional quantities of in N,N-dimethylformamide (2 mL), cyclohexylmethyl bromide (2.1 mL, 15 mmol), and tetra-n-butylammonium iodide (400 mg, 1.08 mmol) were added and the mixture was heated at 135° C. for 20 h. An additional quantity of cyclohexylmethyl bromide (2.1 mL, 15 mmol) was added and the mixture was heated at 135° C. for 6 days. The reaction mixture to cooled to room temperature and then diluted with dichloromethane (150 mL) and washed with water (5×30 mL), aqueous sodium thiosulfate solution (2×30 mL) and brine (30 mL). The organic extract was dried (magnesium sulfate), filtered, evaporated, and the residue purified on an Isco 40 g column, eluting with 15-100% ethyl acetate/hexanes and then held under high vacuum to give an orange gum. This was treated with charcoal in methanol in a warm water bath, and the resulting mixture was filtered, evaporated and held under high vacuum to give (4R,7S)-1-(cyclohexyl)methyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (22 mg, 4%) as a yellow gum. ES(+)-MS (M+H) 365.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])=[CH:7][C:6]=1[NH2:19])[CH:2]=[CH2:3].[C:20]([S:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[C@H:26]([C:35](O)=[O:36])[CH2:25]1)(=[O:22])[CH3:21].NC1C=C(C=CC=1)C=CC(OCC=C)=O>>[C:20]([S:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[C@H:26]([C:35](=[O:36])[NH:19][C:6]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:18][CH:17]=[C:8](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH:7]=2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: C=CCOC(=O)C=Cc1ccc(OCC=C)c(N)c1
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Agent: C=CCOC(=O)C=Cc1cccc(N)c1
Product: C=CCOC(=O)/C=C/c1ccc(OCC=C)c(NC(=O)[C@@H]2C[C@H](SC(C)=O)CN2C(=O)OCC=C)c1

Procedure:
Allyl 4-allyloxy-3-aminocinnamate was condensed with (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-carboxypyrrolidine by the method described in example 1 for allyl 3-aminocinnamate to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(6-allyloxy-3-(E-2-allyloxycarbonyl-1-ethenyl)phenylcarbamoyl)pyrrolidine.
Reaction SMILES: [CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([O:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:22]([CH3:24])[CH3:23])(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Product: CC(=O)Oc1ccc(C)cc1[C@H](CCN(C(C)C)C(C)C)c1ccccc1

Procedure:
A solution of 2-[(1R)-3-(Diisopropylamino)-1-phenylpropyl]-4-methylphenol (0.9 g) in acetylchloride (20 ml) is stirred at room temperature for 18 h. The acetyl chloride is evaporated, ether is added, and the precipitate of 2-(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenyl acetate hydrochloride is filtered off; mp 126-130° C., Anal Calcd for C24H33NO2.HCl: C, 71.35; H, 8.48; Cl, 8.78; N, 3.47. Found: C, 71.02; H, 8.30; Cl, 8.64; N, 3.43. [α]D (c=1, MeOH) +11°.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:37])=[N:4][CH:5]=1)[CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1
Reactant: N#Cc1ncc(N[C@H](Cc2cccs2)C(N)=O)nc1Nc1ccc2ncccc2c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@H](Cc2cccs2)C(N)=O)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-(thiophen-2-yl)propanamide (40 mg, 0.096 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (11 mg). MS 434.3 (M+H); UV 204.2, 265.8, 298.4, 357.9 nm; t 0.453 min.
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]1)(=O)=O.O[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>O>[F:13][C:10]1([F:14])[CH2:11][CH2:12][CH:7]([CH2:6][O:5][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH:19]=[O:20])[CH2:8][CH2:9]1
Reactant: O=Cc1cccc(O)c1
Reactant: CS(=O)(=O)OCC1CCC(F)(F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=Cc1cccc(OCC2CCC(F)(F)CC2)c1
Reaction time: 1 h

Procedure:
Mesylate 142 (0.9 g, 3.94 mmole), 3-hydroxybenzaldehyde (0.577 g, 4.73 mmole), K2CO3 (0.817 g, 5.91 mmole) and NMP (5 ml) were heated at 70° C. overnight. H2O (30 ml) and hexanes (50 ml) was added and stirred for 1 hr. The organic layer was dried over Na2SO4 and evaporated. Purification by flash chromatography (20% ether/hexanes gradient) gave 3-((4,4-difluorocyclohexyl)methoxy)benzaldehyde (143) as an oil. Yield (0.559 g, 56%): 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.51-7.46 (m, 2H), 7.41-7.40 (m, 1H), 7.25 (dt, J=6.8, 2.8 Hz, 1H), 3.91 (d, J=6.0 Hz, 2H), 2.06-1.98 (m, 5H), 1.89-1.73 (m, 5H), 1.37-1.27 (m, 2H).
Reaction SMILES: [CH2:1]=[O:2].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.[OH-].[Na+]>C(O)C>[OH:2][CH2:1][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]2)=[N:11]1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(c2nn(CO)c3ccccc23)CC1
Yield: 38 %

Procedure:
A solution of 0.52 g of paraformaldehyde, 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole, 15 ml of ethanol and 0.34 ml of 5% aqueous sodium hydroxide was refluxed for 3 hrs. The ethanol was removed in vacuo and the residue diluted with water. The aqueous suspension was extracted with dichloromethane (2×, 50 ml) and the combined extracts were washed with water and dried over anhydrous magnesium sulfate. The dichloromethane was evaporated in vacuo to yield an oil, which crystallized upon standing. The solid was recrystallized twice from ethyl acetate to yield 1.3 g (57.8%) of product, mp 128°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:12])(O)[CH3:10])=[CH:4][CH:3]=1.[Cl:13][CH2:14][C:15]#[N:16].S(=O)(=O)(O)[OH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Cl:13][CH2:14][C:15]([NH:16][C:9]([CH3:12])([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:18]
Reactant: CC(C)(O)Cc1ccc(Cl)cc1
Reactant: N#CCCl
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(Cc1ccc(Cl)cc1)NC(=O)CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the crude alcohol (184 mg, 0.996 mmol) and chloroacetonitrile (150 mg, 1.99 mmol) in acetic acid (3.0 mL) was cooled to 0° C. Concentrated sulfuric acid (1.0 mL) was added to the solution dropwise while keeping the reaction temperature below 10° C. After stirring at room temperature for 1 hour, the resulting solution was poured onto ice and basified by the addition of solid potassium carbonate to pH>8. The mixture was extracted with ethyl acetate and the combined organic fractions were washed with water, dried over sodium sulfate and concentrated under vacuum to give 150 mg of 2-chloro-N -(1-(4-chlorophenyl)-2-methylpropan-2-yl)acetamide as yellow solid. The crude material was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:40])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]3[N:18]([C:32]4[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=4)[C:35]#[N:36])[C:19](=[O:31])[N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH:21]([CH3:22])[C:15]3=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1.[OH-:41].[Na+].C(#N)C1C=CC=CC=1.OO>CS(C)=O>[CH3:40][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]3[N:18]([C:32]4[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=4)[C:35]([NH2:36])=[O:41])[C:19](=[O:31])[N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH:21]([CH3:22])[C:15]3=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: [OH-]
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCN(C)C)c4)ncc3C2C)cc1
Agent: OO
Agent: [Na+]
Solvent: N#Cc1ccccc1
Solvent: CS(C)=O
Product: COc1ccc(N2C(=O)N(c3cccc(C(N)=O)c3)c3nc(Nc4cccc(CCN(C)C)c4)ncc3C2C)cc1
Reaction time: 4 h

Procedure:
(±)-3-[7-[3-(2-Dimethylamino-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (92.7 mg; 0.17 mmol) (from Example 6 supra) was dissolved in dimethyl sulfoxide (1.0 mL) and the resulting solution was cooled in an ice-water bath. Aqueous sodium hydroxide (1 M; 300 μL; 0.30 mmol) was added, resulting in the precipitation of the benzonitrile. Aqueous hydrogen peroxide (30%; 53 μL; 0.52 mmol) was then added. The benzonitrile went back into solution and the product then precipitate out of solution. After 4 hours, the reaction was diluted with water. The solid was collected, washed with water and dried. Recrystallization from dichloromethane-ether gave (±)-3-[7-[3-(2-dimethylamino-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzamide. (Yield 72.9 mg; 76.1%). Melting Point: 215–230° C. HR-MS(ES+) m/z Calculated for C31H33N7O3 ([M+H]+): 552.2718; Found: 552.2722.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[CH3:15]OS(OC)(=O)=O>>[Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH3:15])[C:6]=2[CH:11]=1
Reactant: COS(=O)(=O)OC
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2o1
Product: Cn1c(=O)oc2cc([N+](=O)[O-])c(Cl)cc21

Procedure:
5-Chloro-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one was prepared by the procedure described in Example 2, step 2 starting from 5-chloro-6-nitrobenzo[d]oxazol-2(3H)-one (1.75 g, 8.1 mmol) substituting iodomethane for dimethylsulfate. The crude product was recrystallised from methanol to afford an orange solid (0.6 g, 32%), which was taken through to the next step with no further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:22]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[C:30](=[O:35])[NH:31][CH:32]([CH3:34])[CH3:33]>>[F:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:22]=2)[CH:27]=[CH:28][C:29]=1[C:30](=[O:35])[NH:31][CH:32]([CH3:33])[CH3:34]
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Reactant: CC(C)NC(=O)c1ccc(B(O)O)cc1F
Product: CC(C)NC(=O)c1ccc(-c2ccc3oc(C4CCN(C(=O)OC(C)C)CC4)nc3c2)cc1F
Yield: 17.8 %

Procedure:
Following the General Procedure-3, the titled compound (45 mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and 3-fluoro-4-(isopropylcarbamoyl)phenylboronic acid (120 mg, 0.54 mmol) as a grey solid. M.P.: 147-150° C. MS (m/z): 468.4 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[C:10]([N:17]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[N:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O[C:30]1[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=1)[O:33][C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:1]([N:8]1[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[C:10]([N:17]([CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:25][CH2:26][CH2:27][O:28][C:30]2[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=2)[O:33][C:34]([CH3:40])([CH3:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(O)c1
Reactant: CCCCCCCn1nc(N(CCCO)CCCC(F)(F)F)c(=O)n(C)c1=O
Product: CCCCCCCn1nc(N(CCCOc2cccc(OC(C)(C)C(=O)OCC)c2)CCCC(F)(F)F)c(=O)n(C)c1=O

Procedure:
Compound 51 (oil) is prepared from triazine 9m and from intermediate 10b according to synthesis method 3 using Mitsunobu coupling conditions such as those described for example 33.
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH3:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH2:13]>>[C:9]1([CH3:8])[CH:16]=[CH:15][CH:14]=[C:11]([CH2:12][NH:13][CH:3]=[CH:4][C:5](=[O:7])[CH3:6])[CH:10]=1
Reactant: Cc1cccc(CN)c1
Reactant: COC=CC(C)=O
Product: CC(=O)C=CNCc1cccc(C)c1

Procedure:
The title compound 62 is prepared according to the procedure reported in step A of Example 18 with 4-methoxy-3-buten-2-one (0.1 g, 1 mmol) and 3-methylbenzylamine (0.125 g, 1 mmol) as reactants. Yellow oil. (Yield 0.19 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:17][O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2)=[O:23]>>[ClH:1].[OH:33][C:28]1[NH:29][C:30]2[C:26]([C:27]=1[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:6][N:7]=1)=[CH:25][C:24]([C:22]([NH:21][CH2:20][CH2:19][O:18][CH3:17])=[O:23])=[CH:32][CH:31]=2
Reactant: O=S(=O)(c1ccc(Cl)nc1)N1CCOCC1
Reactant: COCCNC(=O)c1ccc2c(c1)CC(=O)N2
Product: COCCNC(=O)c1ccc2[nH]c(O)c(-c3ccc(S(=O)(=O)N4CCOCC4)cn3)c2c1
Product: Cl
Yield: 7 %

Procedure:
Starting materials: 4-[(6-chloropyridin-3-yl)sulfonyl]morpholine and N-(2-methoxyethyl)-2-oxoindoline-5-carboxamide. Yield: 7%: 1H NMR (DMSO-d, 400 MHz) δ 10.85 (s, 1H), 8.45 (m, 2H), 7.99 (s, 1H), 7.74 (s, 2H), 7.58 (m, 1H), 6.94 (d, J=8 Hz, 1H), 3.65 (m, 4H), 3.45 (m, 4H), 3.27 (s, 3H), 3.00 (m, 4H); MS (ES) m/z 461 (M++1).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.O=[C:20]([CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH2:27][CH2:28][CH3:29])[NH:13][C:14]2=[N:15][NH:16][CH:17]=[C:18]12)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1C=O
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2OC(C)C)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-isopropyloxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.