Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:34][C:31]3[S:32][CH:33]=[C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[N:30]=3)=[O:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: COc1cccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)c1
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3nc(-c4ccccn4)cs3)cc2)c1

Procedure:
4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (12) (100 mg, 0.31 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with 50-100% EtOAc in hexanes. The resulting solid was triturated with diethyl ether to give 4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 56 mg (41%). 1H-NMR: 8.64-8.61 (m, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.94-7.88 (m, 3H), 7.71 (d, J=8.5 Hz, 2H), 7.36 (ddd, 7.5, 5.0, 1.0 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 6.92-6.88 (m, 1H), 6.71-6.67 (m, 2H), 3.70 (s, 3H), 3.20 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[C@@H:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16])(=O)=O.Cl>C(#N)C>[CH3:18][O:17][C:15](=[O:16])[C@H:14]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNc1ccccc1
Reactant: COC(=O)[C@@H](OS(C)(=O)=O)c1ccccc1
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@@H](c1ccccc1)N(C)c1ccccc1
Temperature: 120 °C
Yield: 26.6 %

Procedure:
N-methylaniline (299 ul, 2.76 mmol) is added to a solution of (S)-methyl 2-(methylsulfonyloxy)-2-phenylacetate (I5) (450 mg, 1.84 mmol) in acetonitrile (10 mL). The reaction is heated at 120° C. for 15 minutes (microwave irradiation). 2N HCl (5 mL) is added and the mixture is extracted with EtOAc. The organic phase is dried over sodium sulphate and the solvent is evaporated to dryness. The crude is purified by flash chromatography on silica gel (Petroleum ether/Et2O=9/1) to obtain intermediate I121 as an orange amorphous solid (125 mg, 27% yield).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH3:19])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:20]([NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:27]([O:29][C:30](=O)[C:25]=12)=[O:28])(=[O:22])[CH3:21].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:20]([NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:25]=1[C:30](=[O:29])[N:1]([CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH3:19])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])[C:27]2=[O:28])(=[O:22])[CH3:21]
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC(F)F
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 43.3 %

Procedure:
3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid was prepared by the procedure of Example 4 from 3-amino-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (2.7 g, 13 mmol), 3-acetamido-phthalic anhydride (4.0 g, 14.5 mmol) and sodium acetate (1.2 g, 14.5 mmol) in acetic acid (50 ml) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (2.6 g, 45%) as yellowish solid. mp 89-91° C.; 1H NMR (CDCl3): δ 1.42 (t, J=7.5 Hz, 3H, OCH2CH3), 2.51 (s, 3H, CH3CO), 3.19 (dd, J=5.8, 15.5 Hz, 1H, CH2), 3.79 (dd, J=8.4, 15.5 Hz, 1H, CH2), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 5.65-5.71 (m, 1H, CHN), 6.52 (t, JH-F=75 Hz, 1H, CF2H), 7.03-7.11 (m, 3H, Ar), 7.45 (d, J=7.5 Hz, 1H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 8.72 (d, J=8.3 Hz, 1H, Ar), 9.46 (s, 1H, NHCO). 13C NMR (CDCl3): δ 14.6, 24.8, 35.6, 50.3, 64.7, 98.4, 99.1, 111.8, 113.5, 115.2, 115.9, 118.2, 120.1, 120.2, 122.7, 125.0, 131.0, 136.0, 136.5, 137.4, 138.1, 140.0, 140.1, 140.2, 150.6, 167.4, 169.5, 169.7, 175.1; Anal. Calcd. for C22H20F2N2O7+0.17H2O: C, 56.77; H, 4.40; N, 6.06, H2O, 0.66; Found: C, 56.60; H, 4.43; N, 6.02; H2O, 0.66.
Reaction SMILES: N1C=CC=CC=1.[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1.[CH2:14]([NH2:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>ClCCl>[CH2:14]([NH:26][C:7](=[O:13])/[CH:8]=[CH:9]\[C:10]([OH:12])=[O:11])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCCCCN
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)/C=C\C(=O)O
Temperature: 25 °C
Yield: 96.5 %

Procedure:
30 g of pyridine are added to a solution of 83 g of maleic anhydride in 700 ml of dichloromethane at room temperature. A solution of 122 g of n-dodecyl-amine and 70 g of pyridine in 800 ml of dichloro-methane is then added dropwise in 15 min, during which the temperature rises to 39° C. The mixture is then refluxed for 30 min, cooled to 25° C. and 210 ml of 32% by weight aqueous hydrochloric acid are cautiously added. The aqueous phase is separated off at 35° C., and the organic phase is washed three times with 200 ml of water each time at 35° C., dried over sodium sulfate and crystallized at 10° C. 180 g (96%) of N-dodecylmaleamic acid are obtained in the form of colorless waxy crystals. The product is pure by NMR and gives a clear solution in dilute sodium hydroxide solution.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[N:12]=[C:13]([S:22][CH3:23])[N:14]=[N:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[S:24]1[CH:28]=[CH:27][C:26]2[C:29]([NH2:33])=[CH:30][CH:31]=[CH:32][C:25]1=2>C1COCC1>[S:24]1[CH:28]=[CH:27][C:26]2[C:29]([NH:33][C:11]3[N:12]=[C:13]([S:22][CH3:23])[N:14]=[N:15][C:16]=3[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:30][CH:31]=[CH:32][C:25]1=2
Reactant: Nc1cccc2sccc12
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nnc(SC)nc1Nc1cccc2sccc12
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Diisopropylethylamine (0.10 ml) was added to a solution of ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (70 mg) and benzo[b]thiophen-4-amine (70 mg) in THF (1 ml), and the reaction solution was stirred at room temperature for 35 minutes. The solvent was evaporated under vacuum, and then the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain ethyl 5-(benzo[b]thiophen-4-ylamino)-3-(methylthio)-1,2,4-triazine-6-carboxylate as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.COC1C=CC(CCl)=CC=1.[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1[NH:24][CH:25]=[CH:26][N:27]=1>>[S:4]1[CH:5]=[CH:6][N:7]=[C:3]1[CH2:2][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1[NH:27][CH:26]=[CH:25][N:24]=1
Reactant: BrCc1nccs1
Reactant: c1c[nH]c(-c2ncc[nH]2)n1
Agent: COc1ccc(CCl)cc1
Product: c1c[nH]c(-c2nccn2Cc2nccs2)n1

Procedure:
If the procedure of Example 1 is repeated using 2- bromomethylthiazole rather than 4-methoxybenzyl chloride of Example 1, the products obtained are title compounds (7) and (8).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[NH:24]1[C:32]2[C:27](=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:31]=2)[CH:26]=[CH:25]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[C:27]6[CH:26]=[CH:25][NH:24][C:32]6=[N:31][CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5[nH]ccc5c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 39 mg, 0.105 mmol) and 7-azaindole-5-boronic acid pinacol ester (ABCR, Karlsruhe, Germany, 31 mg, 0.127 mmol) to give the title compound as a white solid. (HPLC: tR 2.35 min (Method A); M+H=410 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 11.75 (s, br, 1H), 8.95 (s, 1H), 8.38-8.28 (m, 1H), 8.22-8.15 (m, 1H), 8.13-8.03 (m, 2H), 8.01-7.95 (m, 1H), 7.59-7.51 (m, 2H), 6.55-6.47 (m, 1H), 3.93 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[N:22]1([C:2]2[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:7]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3ccnc3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.2) (0.16 g, 0.5 mmol) and commercially available imidazole (0.034 g, 0.5 mmol) according to the general procedure IVa. Obtained as a white solid (0.07 g, 39%). MS (EI) 358.0 [(M)+]; mp 162° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[CH:20][N:21]3S(C3C=CC(C)=CC=3)(=O)=O)=[CH:17][CH:16]=2)[C:11]1=[O:34].CO>C(O)C.C(Cl)(Cl)Cl>[NH:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N:12]3[CH2:13][CH2:14][N:10]([C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:4]=4[CH3:3])[C:11]3=[O:34])[CH:23]=2)[CH:19]=[CH:20]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(N4CCN(c5cnccc5C)C4=O)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1N1CCN(c2ccc3cc[nH]c3c2)C1=O
Temperature: 90 °C
Yield: 47.1 %

Procedure:
10% NaOH solution (10 mL) was added to a solution of 1-(4-methyl-pyridin-3-yl)-3-[1-(toluene-4-sulfonyl)-1H-indol-6-yl]-imidazolidin-2-one (I-144a: 94 mg) in ethanol (10 mL). The resulting mixture was heated to reflux at 90° C. for 1 hour. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried and concentrated. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 29 mg of the product (47.54% yield).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:44]1[CH:49]=[CH:48][N:47]=[CH:46][N:45]=1.[NH2:50][C:51]1[C:55]([C:56](=[O:58])[NH2:57])=[CH:54][N:53]([C:59]2([CH2:72][C:73]#[N:74])[CH2:64][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:61][CH2:60]2)[N:52]=1>CC(O)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:56]([C:55]1[C:51]([NH:50][C:44]2[CH:49]=[CH:48][N:47]=[CH:46][N:45]=2)=[N:52][N:53]([C:59]2([CH2:72][C:73]#[N:74])[CH2:64][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:69])([CH3:70])[CH3:71])=[O:66])[CH2:61][CH2:60]2)[CH:54]=1)(=[O:58])[NH2:57]
Reactant: Brc1ccncn1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(N)n2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccncn3)n2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
K3PO4 (75 mg, 0.35 mmol), X-Phos (21 mg, 0.043 mmol), 4-bromopyrimidine (34 mg, 0.22 mmol) and tert-butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Intermediate 35-1) (50 mg, 0.14 mmol) were suspended in t-BuOH (3 mL) and degassed with argon for 5 minutes in a microwave vial. The catalyst, Pd2(dba)3 (20 mg, 0.022 mmol), was added and then the mixture was heated at 80° C. for 2 hours. The mixture was then cooled to ambient temperature, Si-DMT (0.10 g) was added and the resulting mixture was allowed to stir for 1 hour. The mixture was filtered and passed through a C18 silica plug. The column was washed with acetonitrile (4 mL) and then the column eluent was evaporated to dryness in vacuo. The crude material was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, passed through a 6 mL Silicycle Carbonate cartridge, and lyophilized to afford the title compound, Example #13-1, as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].CN(CCN(C)C)C.[Li]CCCC.CON(C)[C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[NH4+].[Cl-]>C(OC)(C)(C)C>[C:32]([C:4]1[C:3]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][CH:5]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)c1Cl
Reactant: CON(C)C(=O)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: CC(C)(C)C(=O)Nc1c(C(=O)c2ccccc2)ccc(Cl)c1Cl
Temperature: -23 °C
Reaction time: 1.5 h

Procedure:
To a cool (−23° C.), stirred solution of N-(2,3-dichlorophenyl)pivalamide (Shimada, I. et al., Bioorganic & Medicinal Chemistry, 16:1966-1982 (2008)), compound #12; 2.10 g, 8.53 mmol) and TMEDA (1.0 ml, 6.63 mmol) in t-BuOMe (21 ml) under N2 was added n-BuLi (7.9 ml, 19.75 mmol, 2.5M in pentane) via syringe over 15 min. The reaction mixture was stirred for 90 min. To the cool reaction mixture was added a solution of N-methoxy-N-methylbenzamide (2.46 g, 14.89 mmol) in t-BuOMe (11 ml) via cannula over 30 min, then the reaction mixture was allowed to warm to room temperature as the bath warmed. To the reaction mixture was added saturated NH4Cl, then the precipitated solid was collected by filtration, washed with water, and air dried overnight to afford Intermediate A25A (2.75 g, 88%) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.04 (1H, br. s.), 7.76-7.83 (2H, m), 7.54-7.62 (1H, m), 7.43-7.49 (2H, m), 7.41 (1H, d, J=7.7 Hz), 7.35 (1H, d, J=7.7 Hz), 1.14 (9H, s).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[Li+].[OH-].[Na+]>CN(C=O)C.C1COCC1.O>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc(F)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(N2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 4-fluorobenzoate (Lancaster 14154; 500 mg; 3.24 mmol; 1 eq.) and piperidine (Fluka 80640; 828.62 mg; 9.73 mmol; 3 eq.) in DMF (2 mL) was stirred at 50° C. for 16 hours. The reaction mixture was then passed through a short pad of silica and the obtained solution evaporated in vacuo to give a colourless oil. The oil was taken up in THF (15 mL) and lithium hydroxide (388.41 mg; 16.22 mmol; 5 eq.) was added followed by water (15 mL). The reaction mixture was stirred at room temperature for 6 hours then at 60° C. for 16 hours. NaOH (155.5 mg, 6.48 mmol, 2 eq) was then added and the reaction mixture was refluxed for 24 hours. After cooling, the solution was diluted with water and washed with Et2O. The aqueous layer was then acidified to pH 5-6 with acetic acid and the formed precipitate was collected by filtration, washed with water and dried under high vacuum to afford the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.[BH3-]C#N.[Na+].C(OCC)C>CO.[Cl-].[Zn+2].[Cl-].O>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH2:18][CH2:19][N:20]([CH:25]4[CH2:26][O:23][CH2:24]4)[CH2:21][CH:22]=3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(C3=CCNCC3)cn2)c1=O
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: Cn1cc(Br)cc(Nc2ccc(C3=CCN(C4COC4)CC3)cn2)c1=O
Temperature: 50 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
A mixture of 200d (500 mg, 1.4 mmol), oxetan-3-one (298 mg, 4.2 mmol), NaBH3CN (261 mg, 4.2 mmol), and 1 mol/L zinc chloride in ethoxyethane (4 mL, 4.2 mmol) in methanol (20 mL) was stirred at 50° C. for 5 hours. Water (20 mL) was added to the reaction and the resulting mixture was extracted with dichloromethane (3×50 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 10:1 methylene chloride/methanol to afford 200e (450 mg, 78%) as a yellow solid. MS-ESI: [M+H]+ 419.1
Reaction SMILES: [NH2:1][C:2]1[C:16]([Br:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:5].[C:18](=O)(OC(Cl)(Cl)Cl)[O:19]C(Cl)(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Br:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:3]2[C:2]=1[NH:1][C:18](=[O:19])[N:6]([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[C:4]2=[O:5]
Reactant: Nc1c(Br)cccc1C(=O)NC1CCOCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CCOCC1
Temperature: 90 °C

Procedure:
A solution of 2-amino-3-bromo-N-(tetrahydro-2H-pyran-4-yl)benzamide (515a, 1.54 g, 5.15 mmol), bis(trichloromethyl) carbonate (0.764 g, 2.57 mmol), and triethylamine (3.59 mL, 25.7 mmol) in DCM (51.5 mL) was refluxed for 16 h. Toluene (50 mL) was added to the clear solution; this mixture was partially concentrated to remove the DCM. More bis(trichloromethyl) carbonate (0.764 g, 2.57 mmol) was added, and the yellow solution was heated to 90° C. for 1 h. The reaction mixture was concentrated to give 8-bromo-3-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione (515b) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.56-1.62 (m, 2H) 2.87 (qd, J=12.39, 4.69 Hz, 2H) 3.52 (td, J=12.03, 1.76 Hz, 2H) 4.10 (dd, J=11.54, 4.69 Hz, 2H) 5.11 (tt, J=12.18, 3.96 Hz, 1H) 7.11 (t, J=8.02 Hz, 1H) 7.79 (dd, J=7.82, 1.17 Hz, 1H) 8.09 (s, 1H) 8.11 (s, 1H). MS (ESI, pos. ion) m/z: 325.0/326.9 (M+1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[C:31]1([S:37]([N:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42](B(O)O)=[CH:41]2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH2:15][CH2:14]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:42]1[C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:40]([S:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:39])=[O:38])[CH:41]=1)=[N:3][C:4]=2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Reactant: Cn1c(CN2CCC(N3CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(CN2CCC(N3CCOCC3)CC2)nc2c(N3CCOCC3)nc(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)nc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a degassed suspension of 4-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine (249 mg, 0.571 mmol), 1-(phenylsulfonyl)-3-indoleboronic acid (189 mg, 0.628 mmol), 2M Na2CO3 aqueous solution (0.571 mL, 1.0 mmol) in toluene (5 mL) and ethanol (2 mL) was added Pd(PPh3)4 (33 mg, 0.029 mmol). The suspension was then stirred under nitrogen at 100° C. for 18 hours. The reaction mixture was then diluted with EtOAc and water. The layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (25% MeOH in DCM) to give the title compound as a white solid (357 mg, 95.2%). LCMS: M+H+=657.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12]C)[CH:10]=2)[N:5]=[CH:4][N:3]=1.NC(C(O)=[O:30])CCSC.[OH-].[Na+]>CS(O)(=O)=O>[CH3:22][N:19]1[CH2:20][CH2:21][CH:16]([CH2:15][O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([OH:30])=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[OH:12])[CH2:17][CH2:18]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: CSCCC(N)C(=O)O
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(COc2cc3ncnc(O)c3cc2O)CC1
Temperature: 150 °C
Yield: 71 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazoline (see Journal of Medicinal Chemistry, 2002, 45, 1300-12, 9.8 g, 30 mmol), D,L-methionine (7.15 g, 48 mmol) and methanesulphonic acid (50 ml) was heated at 150° C. for 32 hours. The reaction mixture was allowed to cool to room temperature. The pH was adjusted to 8 with aqueous sodium hydroxide then, aqueous sodium hydrogen carbonate and concentrated to half the original volume. The resultant solid was filtered and washed with water and then dried for 16 hours at 60° C. to give 7-[(1-methylpiperidin-4-yl)methoxy]quinazoline-4,6-diol (6.16 g, 71% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1>O1CCCC1.[Pd]>[CH3:1][CH:2]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: Cc1coc2ccc(O)cc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1COc2ccc(O)cc21
Yield: 81.3 %

Procedure:
3-Methyl-benzofuran-5-ol (prepared as above in EXAMPLE III) (245 g, 1.6 mol) was added in tetrahydrofuran (THF) (450 mL) and hydrogenated with palladium on carbon (Pd/C) (5%, 2.4 g) under hydrogen (H2) (200 psi) at 145° C. for about 8 hours till gas chromatograph (GC) analysis showed completion of the reaction. The obtained mixture was filtered and distilled to afford 3-methyl-2,3-dihydro-benzofuran-5-ol (190 g, 1.3 mol).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([Cl:12])[CH:5]=1)=[O:3].[H-].[Na+].C([O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1)C>CN(C=O)C>[Cl:12][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:17])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: COc1ccc(C(C)=O)cc1Cl
Reactant: CCOC(=O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CC(=O)c2cccnc2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-chloro-4-methoxy acetophenone (3.0 g, 16.30 mmol) in DMF (15 mL) was added 60% NaH [0.717 g (0.430 g, 17.93 mmol)] at 0° C. under a nitrogen atmosphere. The mixture was stirred for 30 min and a solution of nicotinic acid ethyl ester (2.95 g, 19.56 mmol) in DMF (10 mL) was added slowly to it. The mixture was stirred at temperature in the range of 20-40° C. for 12 hour. It was then poured into ice-cold water (100 mL) and stirred for 15 minutes. The solid was filtered and dried to give the desired compound.