Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@H:28]4[CH2:33][CH2:32][C@H:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].CO.[OH-].[Li+].O>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@H:28]4[CH2:33][CH2:32][C@H:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(-c3cnc4[nH]cc([C@H](C)c5c(OC)ccc(F)c5Cl)c4c3)c2C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@H](C(=O)O)CC4)c3C)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl trans-4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-methyl-1H-pyrazol-1-yl)cyclohexanecarboxylate (20.0 mg, 0.0371 mmol) in MeOH (3 mL, 70 mmol) was added lithium hydroxide (4.44 mg, 0.186 mmol) and H2O (1 mL, 60 mmol). The mixture was stirred at rt for 2 h. The organic solvent was removed in vacuo, and the material was extracted with DCM and water (pH=2). The organic layer was concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=511.19/513.19 (100/50) [MH+]. HPLC: tR=1.44 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].NC1C=CC=CC=1C(F)(F)F.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:23])([F:24])[F:25])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1cc2ncnc(Nc3ccccc3C(F)(F)F)c2cn1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (300 mg, 1.56 mmol), 2-aminobenzotrifluoride hydrochloride (1.00 g, 5.06 mmol) and 2-aminobenzotrifluoride (2.00 g, 12.4 mmol) is stirred at 160° C. for 10 min. The resulting product is neutralized with excess NaHCO3, dissolved in MeOH/CHCl3, dried onto silica gel and chromatographed over silica gel (6-7% MeOH/CH2Cl2) to give 7-amino-4-(2-trifluoromethylanilino)pyrido(4,3-d]pyrimidine (194 mg, 41%) as a cream solid, mp (MeOH/CHCl3/light petroleum) 126-130° C. (dec.). 1H NMR (DMSO) δ 10.60 (1H, brs), 9.17 (1H, brs), 8.13 (1H, brs), 7.76, 7.69 (1H, 1H, m, m), 7.45 (2H, m), 6.66 (2H, brs), 6.36 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:36][C:37]4[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25]
Reactant: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dimethylurea, 50 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine hydrochloride (49 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 37 mg (yield 60%) of the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH3:13].[CH2:14]([N:21]1[C:29]2[C:28](Cl)=[N:27][C:26]([NH2:31])=[N:25][C:24]=2[CH:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN1C(=O)CCC1.O>[NH2:31][C:26]1[N:27]=[C:28]([O:3][C:4]2[C:5]([CH3:13])=[CH:6][C:7]([C:8]#[N:9])=[CH:10][C:11]=2[CH3:12])[C:29]2[N:21]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:22]=[CH:23][C:24]=2[N:25]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: Nc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(N)nc2ccn(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a stirred suspension of NaH (155 mg, 6.47 mmol) in dry NMP (4 mL) was added 4-hydroxy-3,5-dimethylbenzonitrile (570 mg, 3.88 mmol), and the mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (400 mg, 1.55 mmol) in dry NMP (4 mL) and heated at 160° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1-1:4) to give the product as a light yellow solid (342 mg, 60%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[N:10]1([C:16]2[C:21](=[O:22])[NH:20][CH:19]=[C:18]3[CH2:23][N:24]([CH2:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[C:25](=[O:26])[C:17]=23)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(#N)C.O>[CH2:8]([N:20]1[C:21](=[O:22])[C:16]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:17]2[C:25](=[O:26])[N:24]([CH2:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:23][C:18]2=[CH:19]1)[CH3:9]
Reactant: CCI
Reactant: O=C1c2c(c[nH]c(=O)c2N2CCOCC2)CN1CCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Temperature: 60 °C
Yield: 35.4 %

Procedure:
Potassium carbonate (2.5 g, 18.09 mmol), iodoethane (0.103 ml, 1.281 mmol) and 7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (0.5 g, 1.281 mmol, see Example 15) were suspended in acetonitrile (30 ml). The suspension was heated in a three-neck round bottom flask at about 60° C. for about 2 h. After cooling to r.t. LC-MS analysis indicated complete conversion. The reaction mixture was diluted with water. The aqueous layer was extracted with DCM (2×100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give a yellow solid which was purified by preparative HPLC to give the title compound (190 mg, 0.454 mmol, 35.5 yield) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:16]=[CH2:17])[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(O)(=O)C>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][CH3:17])[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: C=Cc1cccc2cccc(C(=O)OCC)c12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cccc2cccc(CC)c12
Yield: 94.6 %

Procedure:
A solution of 8-vinyl-naphthalene-1-carboxylic acid ethyl ester (1.1 g) in EtOH (25 ml) was treated with acetic acid (1 ml) and Pd/C (270 mg; 10%) and hydrogenated at normal pressure overnight. The catalyst was filtered off. The filtrate was concentrated. The crude product was isolated by chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 3:2) to give 8-ethyl-naphthalene-1-carboxylic acid ethyl ester (1.05 g) as colorless liquid. MS (ISP): 229.3 ((M+H)+.).
Reaction SMILES: Cl.[CH2:2](N(CC)CC)C.C=O.[C:11]1([CH2:17][CH2:18][CH:19]=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:17]([C:18](=[CH2:2])[CH:19]=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CCCc1ccccc1
Reactant: CCN(CC)CC
Agent: C=O
Agent: Cl
Product: C=C(C=O)Cc1ccccc1
Temperature: 20 °C
Yield: 71 %

Procedure:
To a mixture of triethylamine hydrochloride 27.5 g (0.20 mol) and 37% formalin 16.3 g (0.201 mol) was added dropwise β-phenylpropionaldehyde 25 g (0.183 mol) at 20° to 35° C. and the mixture was reacted at 110° to 115° C. for 4 hours. After the completion of the reaction, the reaction mixture was cooled to 20° C. and extracted with 100 ml of diethyl ether. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was distilled to give 2-benzyl-2-propenal (bp10 : 99° to 101° C.) in a yield of 71%.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.Br[CH2:26][CH2:27][Cl:28]>>[CH3:1][C:2]1([CH3:24])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH:9]2[CH2:26][CH2:27][Cl:28])[CH:4]=[N:3]1
Reactant: CC1(C)N=CC2=C3N=C(c4ccc(Cl)cc4)N=C3C(=O)CC2C1=O
Reactant: ClCCBr
Product: CC1(C)N=CC2=C3N=C(c4ccc(Cl)cc4)N=C3C(=O)C(CCCl)C2C1=O

Procedure:
Prepared analogous to Example 23 from 7.5 gm of 7,7-dimethyl-2-(4-chloro phenyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione and 6.9 gm of 1-bromo-2-chloro-ethane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:20]2[O:21][C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH:9]=[C:8]4[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:7]=3)=[N:18][N:19]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Reactant: C1COCCN1
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(N5CCOCC5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 130 °C
Yield: 48 %

Procedure:
The solution of 5-(3-(6-chloropyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (1.0 g, 1.70 mmol) and morpholine (0.178 g, 2.05 mmol) was taken in sealed tube and heated at 130° C. for 5 h, then cooled to RT and poured in cooled ice water (5 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and concentrated to give N-(4-methoxybenzyl)-5-(3-(6-morpholinopyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (0.52 g, 48%) as an off-white solid. MS (ESI, pos. ion) m/z: 637 (M+1); 1H NMR (DMSO-d6, 400 MHz): δ ppm 8.95 (s, 1H), 8.51 (s, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.85-7.82 (m, 1H), 7.72-7.64 (m, 2H), 7.42-7.39 (m, 3H), 7.32 (d, J=8.4 Hz, 2H), 6.9 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 1H), 4.3 (s, 2H), 3.75 (m, 8H), 3.56 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[F:21][C:22]1([CH2:26][OH:27])[CH2:25][NH:24][CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:24]3[CH2:25][C:22]([F:21])([CH2:26][OH:27])[CH2:23]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: OCC1(F)CNC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC(F)(CO)C1
Yield: 42.1 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 20 mg, 70.4 μmol) was reacted with (3-fluoroazetidin-3-yl)methanol (CAN 1268520-93-9, 8.87 mg, 84.4 μmol) to obtain the title compound (11 mg, 42%) as colorless liquid, MS (ESI): m/e=372.2 [MH+].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7]>[Rh].C(O)C>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7]
Reactant: O=C(c1ccco1)N1CCCNCC1
Agent: [Rh]
Solvent: CCO
Product: O=C(C1CCCO1)N1CCCNCC1

Procedure:
N-[2-Furoyl)homopiperazine (33.0 g.) in 200 ml. of ethanol was hydrogenated over 5% rhodium-on-carbon catalyst at three atmospheres pressure. The catalyst was removed by filtration and the product distilled to give the desired product, B.P. 135° at 1 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.[Br:14]Br.O>C(O)(=O)C>[Br:14][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]=1[C:11]([OH:13])=[O:12]
Reactant: BrBr
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1[nH]c2ccc(Cl)cc2c1Br
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
To a solution of 5-chloro-1H-indole-2-carboxylic acid (2.0 g, 10.2 mmol) in acetic acid (24 mL) was added a solution of bromine (0.53 mL, 10.2 mmol) in acetic acid (16 mL). After 20 minutes, the mixture was poured into water and extracted with chloroform twice. The combined extracts were washed with water twice and brine, dried over magnesium sulfate and concentrated. The product was obtained as a solid (2.5 g, 89%).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH:14]=[CH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:28])[C:18]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[C:20]([O:21][CH3:22])[CH:19]=1>C(#N)C>[C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH2:14][CH2:15][N:28]([CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:16])[CH2:17][C:18]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[C:20]([O:21][CH3:22])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN)cc1OC
Reactant: C=CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: CC#N
Product: COc1ccc(CN(CCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)CCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc1OC
Yield: 10.9 %

Procedure:
A solution of 1.0 g (4.44 mmol) (R)-1-acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester and 0.33 ml (2.22 mmol) veratrylamine in 25 ml acetonitrile was stirred for 16 h at 80° C. Concentration in vacuo and flash chromatography (gradient: 0-10% MeOH in EtOAc) afforded 150 mg (10%) of the title compound as a light brown oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.Cl[CH2:19][O:20][CH2:21][CH3:22]>CC#N>[CH2:21]([O:20][CH2:19][N:6]1[CH:7]=[C:2]([F:1])[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:5]1=[O:8])[CH3:22]
Reactant: CCOCCl
Reactant: Oc1ncc(F)c(NCc2ccccc2F)n1
Solvent: CC#N
Product: CCOCn1cc(F)c(NCc2ccccc2F)nc1=O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A 25 mL screw-top vial was charged with 5-fluoro-4-(2-fluorobenzylamino)pyrimidin-2-ol (49.7 mg, 0.210 mmol), CH3CN (1 mL), and BSA (0.054 mL, 0.0221 mmol), and the mixture was agitated on an rotary shaker at 65° C. for 30 min. After cooling to room temperature, (chloromethoxy)ethane (0.022 mL, 0.237 mmol) was added, and the resulting mixture was agitated on a rotary shaker at room temperature for 16 h. The crude reaction mixture was concentrated in vacuo and was purified by normal phase chromatography (gradient, 0 to 25% MeOH/CH2Cl2) to afford 1-(ethoxymethyl)-5-fluoro-4-(2-fluorobenzylamino)-pyrimidin-2(1H)-one (55.0 mg, 89%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 8.60 (t, J=5.8 Hz, 1H), 8.05-7.95 (m, 1H), 7.40-7.26 (m, 2H), 7.26-7.10 (m, 2H), 5.01 (s, 2H), 4.59 (d, J=5.9 Hz, 2H), 3.49 (q, J=7.0 Hz, 2H), 1.09 (dd, J=9.0, 5.0 Hz, 3H); ESIMS m/z 296 ([M+H]+), m/z 294 ([M−H]−).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10](=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:22])[CH:8]=2)[NH:3]1.C(N(CC)C(C)C)(C)C.[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37]Cl>ClCCl>[O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10](=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:8]=2)[NH:3]1
Reactant: COCCOCCl
Reactant: CCOC(=O)CCCCn1c(=O)[nH]c2ccc(O)cc2c1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCn1c(=O)[nH]c2ccc(OCOCCOC)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
To a suspension of ethyl 2,4-dioxo-6-hydroxy-1,2,3,4-tetrahydroquinazoline-3-valerate (3.50 g, 11.8 mmol) obtained in Reference Example 149 in dichloromethane (35.0 ml), N,N-diisopropylethylamine (2.05 ml, 17.7 mmol) and 2-methoxyethoxymethyl chloride (2.02 ml, 17.7 mmol) were added dropwise with cooling on ice, and the reaction mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was combined with water and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure to give the title compound (3.68 g, 79%). Recrystallization from ethyl acetate-ethyl ether yielded a colorless crystal having a melting point of 105 to 107° C.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)(=[O:3])[CH3:2].[Br:27]Br>>[Br:27][CH2:2][C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:14][C:7]=2[O:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Reactant: BrBr
Product: CS(=O)(=O)Nc1cc2occ(C(=O)CBr)c(=O)c2cc1Oc1ccccc1

Procedure:
3-Acetyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with bromine to obtain 3-(2-bromoacetyl)-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. It was reacted with thioformamide to obtain 7-methylsulfonylamino-6-phenoxy-3-(thiazol-4-yl)-4H-1-benzopyran-4-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH:21]([C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1)([CH3:23])[CH3:22]
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cccc(C(C)C)c2o1
Product: CC(C)c1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 5384.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (41 mg, 0.26 mmol) and 2-(but-3-ynyl)-7-isopropyl-benzo[d]oxazole (55 mg, 0.26 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 4.2 mg (14 mmol, 6%) of 7-isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[CH:19][N:18]=[CH:17]1.[CH2:23]=[O:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]1[CH2:23][OH:24]
Reactant: C=O
Reactant: Cc1cncn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Product: Cc1cnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1, 2',5 -dichloro-2-(5-methylimidazol-1-yl)benzophenone is heated in a bomb to 150° C. with 37% aqueous formaldehyde solution to give 2',5-dichloro-2-[2-(hydroxymethyl)-5-methylimidazol-1-yl]benzophenone.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
6 g of Boc-Phe-PAM resin (substitution 0.36 mmol/g) was suspended and shaken in TFA/CH2Cl2 (1:1 by volume, 3×50 mL) 10 min. each time at room temperature to remove the Boc-group. The product was isolated by filtration and washed (3×50 mL each) with CH2Cl2 8% DIEA in CH2Cl2 and CH2Cl2 to give the free base of Phe-PAM-resin. This was subjected to sequential solid phase synthesis using the Fmoc-protocol. All couplings were performed using the DCC/HOBt procedure. At step 7 the Fmoc-amino acid, DCC, and HOBt were added with the corresponding reaction times as follows: Fmoc-Asp(OtBu)-OH (2.46 g, 6 mmol), DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. Fmoc-Met-OH (2.2 g, 6 mmol), DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. Fmoc-Trp-OH (2.6 g, 6 mmol), DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. Fmoc-Gly-OH (1.8 g, 6 mmol), DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min. Fmoc-Met-OH (2.2 g, 6 mmol), DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. At this point the peptide-resin was dried under high vacuum to provide 7.98 g of Fmoc-Met-Gly-Trp-Met-Asp(OtBu)-Phe-PAM resin.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[C:10](Br)[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[C:10]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)Cc1cc(Br)ccc1[N+](=O)[O-]
Product: CCOC(=O)Cc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
Under argon, a mixture of [5-bromo-2-nitro-phenyl]acetic acid ethyl ester (2.02 g, 7.00 mmol) and 1-methyl-piperazine (1.40 g, 14.0 mmol) is heated at 65° C. for 24 h. The reaction mixture is partitioned between CH2Cl2 (25 mL) and H2O (25 mL), and the aqueous layer is extracted with CH2Cl2 (2×25 mL). The combined organic layers are washed with brine (25 mL), dried over Na2SO4, and concentrated at reduced pressure. The crude product is purified by FCC(CH2Cl2/MeOH 97.5:2.5) to afford the title compound as a yellow oil. ES+-MS: 308 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:18])[C:11]([CH2:16][OH:17])=[CH:12][O:13]2)=[CH:8][CH:7]=1.Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1>CN(C)C=O>[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:15]=[C:14]5[C:9]([C:10](=[O:18])[C:11]([CH2:16][OH:17])=[CH:12][O:13]5)=[CH:8][CH:7]=4)[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=c1c(CO)coc2cc(OCCCCl)ccc12
Agent: Cl
Solvent: CN(C)C=O
Product: O=c1c(CO)coc2cc(OCCCN3CCC(c4noc5cc(F)ccc45)CC3)ccc12
Yield: 37.4 %

Procedure:
By the procedure described above, starting from 2.0 g (7.5 mmoles) of 7-(3-chloropropoxy)-3-(hydroxymethyl)chromen-4-one and 1.93 g (7.5 mmoles) of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, a solid was obtained by crystallization of the crude product from dimethylformamide to yield 1.27 g of 7-[3-[4-(6-fluoro-1,2-benzisoxazole-3-yl)piperidin-1-yl]propoxy]-3-(hydroxymethyl)-chromen-4-one, mp 200°-202° C.