Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]=[C:13]=[O:14])=[C:4]([F:15])[CH:3]=1.[NH2:16]/[C:17](/[CH3:25])=[C:18](/[F:24])\[C:19](OCC)=[O:20]>C(OCC)C>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([N:12]2[C:19](=[O:20])[C:18]([F:24])=[C:17]([CH3:25])[NH:16][C:13]2=[O:14])=[C:4]([F:15])[CH:3]=1
Reactant: CCOC(=O)/C(F)=C(/C)N
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Solvent: CCOCC
Product: Cc1[nH]c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)c1F
Reaction time: 16 h

Procedure:
A solution of 6.00 g of 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate in 100 ml of absolute diethyl ether is added dropwise while stirring at room temperature during 1 hour to a solution of 4.00 g of ethyl 3-amino-2-fluorocrotonate and the reaction mixture is stirred for 16 hours. The mixture is then evaporated to dryness under reduced pressure, the residue is dissolved in 50 ml of absolute dimethylformamide and the solution is added while stirring at room temperature to a solution of 1.31 g of a 55% sodium hydride dispersion in 50 ml of dimethylformamide and 100 ml of isopropyl alcohol. The mixture is subsequently stirred at room temperature for 4 hours, adjusted to pH ~4 with concentrated acetic acid and concentrated under reduced pressure. The residue is poured into 1 l of water and extracted twice with 200 ml of ethyl acetate each time, and the organic phases are washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using ethyl acetate/n-hexane as the eluent and subsequently recrystallized from ethyl acetate/diethyl ether. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5 -fluoro-6-methyl-2,4(1H,3H)-pyrimidinedione, m.p. 162°-164° C.
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(O[N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:50]=[C:49]([N:51]3[CH2:56][CH2:55][CH:54]([OH:57])[CH2:53][CH2:52]3)[CH:48]=[CH:47][C:27]=2[C:28]([NH:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[O:29])[CH2:21][C:20]1=C=O)(C)(C)C.FC1C=CC(C(NC2C=CC=CC=2C(NC2C=CC(Cl)=CN=2)=O)=O)=C(OC2CCN([C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])CC2)C=1.OC1CCNCC1>>[C:96]([O:95][C:93]([N:19]1[CH2:20][CH2:21][CH:22]([O:25][C:26]2[CH:50]=[C:49]([N:51]3[CH2:52][CH2:53][CH:54]([OH:57])[CH2:55][CH2:56]3)[CH:48]=[CH:47][C:27]=2[C:28]([NH:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[O:29])[CH2:23][CH2:24]1)=[O:94])([CH3:99])([CH3:98])[CH3:97]
Reactant: CC(C)(C)ON1CCC(Oc2cc(N3CCC(O)CC3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1=C=O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: OC1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCC(O)CC3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
Using methods substantially equivalent to those described in Example 4-F except that the workup used saturated aqueous citric acid instead of water, 2-[2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(4-hydroxypiperidin-1-yl)benzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide (196 mg, 0.30 mmol, 39%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide and 4-hydroxypiperidine.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:14]#[C:15]Br>C(Cl)Cl>[C:15]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)#[N:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CBr
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a solution of 1-Boc-piperazine (25 g, 0.13 mol) in anhydrous DCM (500 mL) at 0° C. was added TEA (52 mL, 0.40 mol) followed by a solution of cyanogen bromide (28.5 g, 0.27 mol) in anhydrous DCM (250 mL) slowly over a period of 30 min. The reaction mixture was stirred at RT for 16 hours and washed with a 10% aqueous solution of sodium bicarbonate, water and brine. The organic layer was dried and the solvent was removed under vacuum. The residue was purified by chromatography using chloroform/methanol (95/5) as eluent to afford 15 g (57%) of the title compound as a solid. TLC-Chloroform/methanol (9/1): Rf=0.7.
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[CH3:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[CH3:11]>>[CH3:4][C:5]1[CH:6]=[CH:7][C:8]([CH:2]([CH3:3])[CH3:1])=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccccc1C
Reactant: C=CC
Product: Cc1ccc(C(C)C)cc1C

Procedure:
o-xylene is reacted with propene to give 1,2-dimethyl-4-isopropylbenzene,
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:6]1[C:7](OC)=[O:8])=[O:4].[NH3:15]>CO>[OH:14][C@@H:11]1[CH:6]2[C:7](=[O:8])[NH:15][CH2:2][C:3](=[O:4])[N:5]2[CH2:13][CH2:12]1
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)CCl
Reactant: N
Solvent: CO
Product: O=C1NCC(=O)N2CC[C@H](O)C12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl (3S)-1-(chloroacetyl)-3-hydroxy-L-prolinate (D69, 1.48 g, 6.7 mmol) in 10 ml of MeOH and 60 ml of a saturated solution of NH3 in MeOH was stirred for 48 h at rt. The solvent was evaporated under reduced pressure, to afford a solid. Analysis indicated this to be the title compound as a pair of diastereoisomers. After a short chromatography column (CHCl3/MeOH 8/2 as eluent) the title compound was isolated as a foamy solid (1 g). Yield 88%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:30][C:31](=[O:41])[C:32]2[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[C:4]([CH:42]=O)[CH:3]=1.Cl.[NH2:45][OH:46].C(N(CC)CC)C>CN(C=O)C.CO.C(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:30][C:31](=[O:41])[C:32]2[CH:33]=[CH:34][C:35]([N:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=2)=[C:4](/[CH:42]=[N:45]/[OH:46])[CH:3]=1
Reactant: NO
Reactant: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c(C=O)cc2Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c(/C=N/O)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
The reaction mixture of N-(4-chloro-2-formyl-5-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)phenyl)-4-(dimethylamino)benzamide (Example 115, 7.7 mg, 0.013 mmol), hydroxylamine hydrochloride (1.8 mg, 0.026 mmol) and triethylamine (3.6 μL, 0.026 mmol) in DMF (1.2 mL), MeOH (0.240 mL) and DCM (0.240 mL) was stirred at RT overnight. The product was purified by preparative HPLC (10 mM NH4OAc AcCN/H2O) to give 2.7 mg of the title compound. 1H-NMR (DMSO-d6, 400 MHz) δ 11.46 (1H, br. s.), 8.48 (1H, s), 8.31 (1H, s), 7.87 (2H, d, J=9.0 Hz), 7.58 (1H, s), 7.55-7.44 (2H, m), 7.18 (1H, d, J=8.3 Hz), 7.10 (1H, t, J=7.5 Hz), 6.81 (2H, d, J=9.0 Hz), 3.75 (3H, s), 3.03 (6H, s). HPLC/MS (Method H): (ES+) m/z (M+H)+=617; Rt=1.98 min.
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:8][CH2:9][CH:10]=O>ClCCCl.CC(O)=O.[OH-].[Na+]>[Cl:8][CH2:9][CH2:10][N:5]1[CH2:6][CH2:7][C@H:3]([F:2])[CH2:4]1
Reactant: FC1CCNC1
Reactant: O=CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: F[C@H]1CCN(CCCl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 3-fluoropyrrolidine hydrochloride (0.59 g, 4.7 mmol) in 1,2-dichloroethane (8.2 mL) and AcOH (0.54 mL) was added chloroacetaldehyde (0.74 mL, 4.7 mmol, 50% in H2O solution) and Na(AcO)3BH (3.7 g, 17 mmol). The reaction mixture was stirred at ambient temperature for 1 h, and then the reaction mixture was diluted with 1 N NaOH and extracted with CH2Cl2 (3×50 mL). The organics were washed with brine (2×25 mL), dried (Na2SO4) and concentrated to yield the title compound (0.242 g, 33%) as a red-orange oil: 1H NMR (500 MHz, DMSO-d6) δ 5.24-5.11 (m, 1H), 4.25-4.23 (m, 1H), 3.60 (t, J=7.0 Hz, 2H), 2.95-2.82 (m, 4H), 2.60-2.56 (m, 1H), 2.20-2.04 (m, 2H); ESI MS m/z 152 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(OC(=O)C)(=O)C>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:12][C:11]2[C:2]([CH:1]=[CH:20][C:19]3[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=3)=[N:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1nc2ccccc2nc1C
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(C=Cc2nc3ccccc3nc2C=Cc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
In 200 ml of acetic anhydride, 16 g of 2,3-dimethylquinoxaline and 30 g of p-nitrobenzaldehyde were heated under reflux for 30 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.S(OC)(O[CH3:15])(=O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:15])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2cn[nH]c12
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: Cn1cc2cccc(Br)c2n1
Yield: 72.7 %

Procedure:
A solution of 7-bromo-1H-indazole (3; 1.71 g, 8.67 mmol) and dimethyl sulfate (0.90 mL, 9.5 mmol) in 30 mL of toluene was stirred at 110° C. for 4 h, then allowed to cool. The mixture was carefully washed with 30 mL of a saturated aqueous NaHCO3 solution, dried over MgSO4, filtered (rinsing with diethyl ether), and concentrated to an orange oil Column chromatography (0→50% EtOAc/hexanes) afforded 7-bromo-2-methyl-2H-indazole (6: R=Me; 1.33 g, 73%) as a light tan solid.
Reaction SMILES: C1[N:5]([CH2:6][O:7]CCO)[C:4]2NC(N)=[N:13][C:14](=O)[C:3]=2N=1.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=[CH:19][CH:18]=1>C(O)C>[NH2:13][C:14]1[CH:3]=[C:4]2[C:18]([CH2:19][C:6](=[O:7])[NH:5]2)=[CH:17][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1nc(=O)c2ncn(COCCO)c2[nH]1
Solvent: CCO
Product: Nc1ccc2c(c1)NC(=O)C2
Yield: 3626.2 %

Procedure:
2,4-dinitrophenylacetic acic (10 g; 44 mmol) was dissolved in ethanol (200 mL) and purged with N2. 10% Pd/C (400 mg) was added and the reaction hydrogenated at 45 psi for 2 hours. The reacton was then transferred to a RBF and p-toluenesulfonic acid (150 mg) was added and the reaction heated at reflux overnight. The reaction was then filtered through celite to remove catalyst and concentrated. The product crashed out and was filtered as tan crystals 4.68 g (72% yield). 1H NMR (DMSO-d6, 400 MHz) δ 3.20 (s, 2H), 4.97 (br s, 2H), 6.07 (m, 2H), 6.76 (d, J=8.7 Hz; 1H), 10.05 (s, 1H); HPLC ret. time: 2.123 min. LRMS (M+) 148.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][CH:4]=1.O.NN>CO>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][NH2:9])=[CH:5][CH:4]=1
Reactant: COc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CO
Solvent: O
Product: COc1ccc(CON)cc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-methoxybenzyloxy)isoindoline-1,3-dione (200 mg, 0.706 mmol) in MeOH (5 mL) was added hydrazine monohydrate (35.3 mg, 0.706 mmol). The reaction mixture was stirred at 65° C. for 1 h. The solvent was removed in vacuo, and the resulting residue was diluted with EtOAc (5 mL). After stirring for 20 min, the mixture was filtered. The filtrate was concentrated in vacuo to afford the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 7.30 (m, 2H), 6.90 (m, 2H), 4.63 (m, 2H), 3.81 (s, 3H).
Reaction SMILES: C(O[N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:30]=[C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:28]=[CH:27][C:14]=2[C:15]([NH:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])=[O:16])[CH2:8][C:7]1=C=O)(C)(C)C.[C:38]([O:42][C:43](N1CCC(OC2C=C(N3CCCC3)C=CC=2C(O)=O)CC1)=[O:44])([CH3:41])([CH3:40])[CH3:39].NC1C=CSC=1C(OC)=O>>[C:38]([O:42][C:43]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:30]=[C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:28]=[CH:27][C:14]=2[C:15]([NH:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])=[O:16])[CH2:10][CH2:11]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)O)CC1
Reactant: COC(=O)c1sccc1NC(=O)c1ccc(N2CCCC2)cc1OC1CCN(OC(C)(C)C)C(=C=O)C1
Agent: COC(=O)c1sccc1N
Product: COC(=O)c1sccc1NC(=O)c1ccc(N2CCCC2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 58 %

Procedure:
Using methods substantially equivalent to those described in Example 12-C, methyl 3-[2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-thiophene-2-carboxylate was prepared in a 58% yield from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoic acid and methyl 3-aminothiophene-2-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]=[O:22])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[CH3:25]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:30]3[CH:29]=[N:28][C:27]([O:26][CH2:24][CH3:25])=[CH:32][CH:31]=3)=[CH:16][C:15]=2[CH:21]=[O:22])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2C=O)c1
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4′-bromo-2′-formyl-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and 2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:5]([CH:27]=[O:28])=[C:6]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[C:16]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])[N:17]=[CH:18]3)=[CH:13][CH:12]=2)[C:7]([CH3:10])=[CH:8][CH:9]=1>C1COCC1.C(OCC)(=O)C>[F:3][C:4]1[C:5]([CH2:27][OH:28])=[C:6]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[C:16]([NH:21][C:22]([CH:24]4[CH2:25][CH2:26]4)=[O:23])[N:17]=[CH:18]3)=[CH:13][CH:12]=2)[C:7]([CH3:10])=[CH:8][CH:9]=1
Reactant: Cc1ccc(F)c(C=O)c1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(CO)c1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 40 °C
Yield: 40.8 %

Procedure:
Sodium borohydride (11 mg, 0.29 mmol) was added to a solution of N-[7-(3-fluoro-2-formyl-6-methyl-phenyl)-3-isoquinolyl]cyclopropanecarboxamide (50 mg, 0.14 mmol) in THF (1 mL). The reaction mixture was heated at 40° C. for 1 hour and then diluted with ethyl acetate (40 mL) and washed with water (40 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water w/0.1% NH4OH, 14 minutes). Desired fractions were combined and evaporated in vacuo to afford the title compound as an off-white solid (20 mg, 40%). 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 9.14 (s, 1H), 8.50 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.89 (s, 1H), 7.54 (dd, J=8.5, 1.4 Hz, 1H), 7.31 (dd, J=8.3, 5.8 Hz, 1H), 7.20-7.12 (m, 1H), 4.79 (t, J=4.9 Hz, 1H), 4.25-4.10 (m, 2H), 2.13-2.03 (m, 1H), 1.99 (s, 3H), 0.91-0.79 (m, 4H). LCMS (Method E): RT=4.648 min, M+H+=351.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(#N)C.[Br:23][C:24]1[CH:25]=[C:26](/[CH:29]=[CH:30]/[CH:31]=O)[O:27][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.O.C(#N)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:31]/[CH:30]=[CH:29]/[C:26]4[O:27][CH:28]=[C:24]([Br:23])[CH:25]=4)[CH2:15][C:14]3=[O:19])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C/C=C/c1cc(Br)co1
Reactant: Nc1ncnc2cc(CN3CCNCC3=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncnc2cc(CN3CCN(C/C=C/c4cc(Br)co4)CC3=O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a solution of 1-(4-amino-quinazolin-7-ylmethyl)-piperazin-2-one (50 mg, 0.20 mmol), EXAMPLE 72.in 3 mL of acetonitrile is added 3-(4-bromo-furan-2-yl)-(E)-propenal (43 mg, 0.22 mmol), prepared as described in EXAMPLE 18, 2 drops of HOAc and sodium triacetoxyborohydride (62 mg, 0.29 mmol). The solution is stirred at room temperature for 16 hours. After this time, the solution is diluted with water/acetonitrile. The crude material is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 80% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are combined and lyopholized to give the title compound (48 mg, 0.07 mmol) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ9.75 (bs, 2H), 8.85 (s, 1H), 8.60 (d, 1H), 7.95 (s, 1H), 7.69 (s, 1H), 7.62 (d, 1H), 6.80 (s, 1H), 6.65 (d, 1H), 6.19 (dt, 1H), 4.80 (s, 2H), 3.70 (m, 4H), 3.50 (m, 2H), 3.28 (m, 2H), ESI MS [M+H]+=441,443 (Br pattern).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[C:16](=[O:22])[N:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1.[NH4+].[Cl-]>CO.[Zn]>[NH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:2]=[N:3][N:4]2[CH2:14][C:15]1[C:16](=[O:22])[N:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1
Reactant: Cn1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Cn1cccc(Cn2ncc3c(N)cccc32)c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
3-((3-Iodo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one (0.26 g, 0.63 mmol) was added to MeOH (6 mL) and cooled to 0° C. Zinc (0.21 g, 3.2 mmol) was added to the reaction mixture. Saturated aqueous NH4Cl (6 mL) was added drop-wise and the reaction mixture was stirred for 90 minutes at ambient temperature. The reaction was diluted with MeOH (50 mL), stirred for 5 minutes and filtered. The filtrate was diluted with saturated NH4OAc and the MeOH was removed under vacuum. The aqueous mixture was extracted with CHCl3. The organic layer was washed with brine, dried over MgSO4 and concentrated to provide 3-((4-amino-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one (0.12 g, 71% yield) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:11](C(O)=O)=[C:10](O)[C:9]2[C:4](=[C:5]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[N:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:26].C([O-])(O)=O.[Na+]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]([Cl:26])[C:9]2[C:4](=[C:5]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[N:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(-c3ccc(Cl)cc3Cl)nccc2c(O)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(Cl)c2ccnc(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 230 °C

Procedure:
A solution of 2-methyl-3-carboxy-4-hydroxy-8-(2′,4′-dichlorophenyl)-1,7-naphthyridine (0.41 g, 1.2 mmole) in diphenyl ether (0.4 ml) is stirred and heated to 230° C. for 1.5 h. The solution is allowed to cool to r.t., and POCl3 (0.8 ml) is added. This mixture is heated to 100° C. for 2 h, then allowed to cool to r.t., and poured into 5% NaHCO3. This is extracted with EtOAc, the organic phase washed with brine, dried and concentrated. The product is purified by flash chromatography on silica gel to give the title compound D7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C([O:39][C:40]([CH3:45])([CH3:44])[C:41](Cl)=[O:42])(=O)C.O[Li].O>CC(N(C)C)=O.O.CCOC(C)=O>[OH:39][C:40]([CH3:45])([CH3:44])[C:41]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:19][CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1)=[O:42]
Reactant: Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(O)C(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0.1 %

Procedure:
To a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine (1.0 g, 2.8 mol) 249(a) and DIPEA (0.5 mL, 1 eq.) in anhydrous DMA (5 mL) was added dropwise 2-acetoxy-2-methylpropionyl chloride (3 mol, 1.05 eq., 0.44 mL) at 0° C. The mixture was stirred for 20 min at room temperature. The solution was diluted with water and EtOAc. The organic layer was concentrated in vacuo. The residue 366(a) was suspended in MeOH (10 mL) and a solution of LiOH—H2O (8.3 mmol, 3 eq. 0.35 g) in water (3 mL) was added. The reaction was complete within 20 min and then was neutralized. The organic solvent was removed in vacuo. The residue was purified to afford 2-hydroxy-2-methyl-N-(4-(2-(4-morpholino-phenylamino)pyrimidin-4-yl)phenyl)propanamide (366) (1.0 g, 85% yield) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6): 9.86 (s, 1H), 9.41 (s, 1H), 8.47 (d, 1H), 8.12 (d, 2H), 7.94 (d, 2H), 7.68 (d, 2H), 7.30 pm (d, 1H), 6.94 (d, 2H), 5.82 (s, 1H), 3.75 (m, 4H), 3.08 (m, 4H), 1.38 (s, 6H); MS (EI) m/z for C22H23N5O3HCl: 434.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[CH2:30]Cl)[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>C(#N)C>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[CH2:30][N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])[CH:8]=2)[N:3]=1
Reactant: CCNCC
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3CCl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN(CC)Cc1ccc(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg of [2-amino-6-(2-chloromethyl-5-fluorophenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone are dissolved in 5 ml of acetonitrile. 301 mg of caesium carbonate and 73 μl of diethylamine are added, and the mixture is stirred at 80° C. for 16 h. After cooling to 25° C., the mixture is filtered, and the filtrate is evaporated to dryness. The residue is taken up in 5 ml of ethyl acetate, the solution is washed with 5 ml of 2N sodium hydroxide solution, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).