Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]([OH:26])=O)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:24]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[O:26])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: CN1CCNCC1
Reactant: Cc1cc(C(=O)O)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 58.2 %

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (35 mg, 0.096 mmol), 1-methylpiperazine (12 μL, 0.11 mmol), EDCI (20 mg, 0.11 mmol), HOBT (14 mg, 0.11 mmol) were stirred in DMF (5 mL) for 18 hours at room temperature. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated to yield 25 mg of a brown solid (70%). 1H NMR (300 MHz, CDCl3): δ 7.34-7.37 (m, 2H), 7.19-7.24 (m, 4H), 4.79 (s, 2H), 4.24 (s, 2H), 3.84 (br s, 2H), 3.44 (br s, 2H), 2.79 (s, 3H), 2.55 (br s, 2H), 2.36 (s, 5H).
Reaction SMILES: [H-].[Na+].CS(C)=O.[C:7]([O:11][C:12](=[O:51])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[C:41]=2[Cl:50])[CH2:25][CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=1)([CH3:10])([CH3:9])[CH3:8].[CH3:52][O:53][C:54](=[O:57])[CH2:55]Br>CN(C=O)C>[CH3:52][O:53][C:54](=[O:57])[CH2:55][N:13]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:51])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:48])([F:49])[F:47])[C:41]=2[Cl:50])[CH2:25][CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of sodium hydride (18.8 mg, 0.47 mmol, 60% in mineral oil) in anhydrous DMF (10 mL) at 0° C. and DMSO (10 ml) was added dropwise a solution of (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-carbamic acid tert-butyl ester (150 mg, 0.235 mmol) in DMF (5 ml). The solution was stirred at 0° C. for 20 minutes and was then treated with bromo-acetic acid methyl ester (72 mg 0.47 mmol). The resulting solution was warmed to room temperature and stirred for 6 hours. The reaction mixture was poured into ice water (30 ml). The mixture was extracted with EtOAC (3×) and the combine organic layers were washed with saturated aqueous sodium bicarbonate (2×), brine (×), dried over sodium sulphate, and filtered. The ethyl acetate filtrate was concentrated to afford the title compound as an oil. MS(ES) m/e 711.2 (M+).
Reaction SMILES: [CH3:1][C:2]([C:4]([O:6][CH2:7][CH2:8][O:9]C)=[O:5])=[CH2:3].CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C(C)=CC=CC=1>[CH3:3][C:2]([C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])=[CH2:1]
Reactant: C=C(C)C(=O)OCCOC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1C
Product: C=C(C)C(=O)OCCO
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A 0.5% of aqueous solution of 88% hydrolyzed polyvinylalcohol (90 ml) was introduced into a 100 ml reactor and allowed to stand under a nitrogen atmosphere for 15 min. The monomer phase containing poly(ethylene glycol)methyl ether methacrylate (2.77 g), PLA cross-linker (0.7 g) and 1 wt % AIBN solubilized in 4.3 ml of xylene was degassed by bubbling nitrogen through the solution for 15 min. The monomer phase was added to the aqueous phase at 50° C. and agitated by means of a propeller type stirrer at an appropriate velocity so as to obtain monomer droplets of desired diameter. The temperature was increased to 80° C. and stirred for 5 h. The mixture was filtered hot and washed with water and acetone. Then, beads were freeze dry. Size 390±100 μm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[S:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[S:23][C:22]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Cc1ccc(C(=O)O)s1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)s1
Yield: 73.6 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 21.0 mg (0.10 mMol) 5-methyl-2-thienoic acid, 13.0 mg (74%) of the title compound were recovered.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)cc1F
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A166) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:9]2[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]([C@@H:13]([NH2:15])[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][C:5]=1[O:22][CH3:23].Cl[C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][N:29]2[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:3][C:4]1[C:9]2[N:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11]([C@@H:13]([NH:15][C:25]3[N:33]=[CH:32][N:31]=[C:30]4[C:26]=3[N:27]=[CH:28][N:29]4[CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][C:5]=1[O:22][CH3:23]
Reactant: COc1ccc2nc([C@H](C)N)n(-c3ccccc3)c2c1Br
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c2c1Br
Temperature: 90 °C
Yield: 45.9 %

Procedure:
To a solution of (S)-1-(7-bromo-6-methoxy-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (0.75 g, 1.8 mmol) in IPA (10 mL) was added 6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (0.56 mg, 2.34 mmol) and DIPEA (1.2 mL, 7.2 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to give the title compound as a white solid (453 mg, 44%). LCMS (Method C): RT=3.22 min, [M+H]+=548 & 550.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[N:4][C:5]2[N:6]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=1[NH2:8].CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CN(C=O)C>[Br:1][C:2]1[C:3]([CH:22]2[CH2:27][CH2:26][CH2:25][N:24]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23]2)=[N:4][C:5]2[N:6]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=1[NH2:8]
Reactant: Nc1c(Br)c(C2CCCNC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-bromo-5-(piperidin-3-yl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (HCl salt, 46 mg, 0.10 mmol) in DMF (2.0 mL) was added DIEA (0.10 mL, 0.30 mmol) and methylsulfonyl chloride (14 mg, 0.12 mmol). The reaction mixture was stirred at rt for 3 h and concentrated in vacuo. The residue was purified by prep-LC to give the title compound. LC/MS RT=2.49 min. Mass calculated for, M+H 486.05, observed 389.17.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[C:4]([Cl:19])[N:3]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:19][C:4]1[N:3]=[C:2]2[O:18][C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)nc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc3ccc(Cl)nc3o2)cc1
Temperature: 160 °C
Yield: 59 %

Procedure:
N-(2,6-Dichloro-pyridin-3-yl)-4-methoxy-benzamide (3.86 g, 13.0 mmol) and K2CO3 (1.80 g, 13 mmol) were combined in DMF (15 mL) and heated by microwave to 160° C. for 30 minutes. The resulting mixture was poured into water (100 mL) causing the formation of a precipitate which was collected by filtration and washed with additional water before drying overnight in vacuo. The resulting solid was purified with silica gel flash chromatography (0-60% EtOAc in hexanes) to afford 5-chloro-2-(4-methoxy-phenyl)-oxazolo[5,4-b]pyridine (2.0 g, 7.67 mmol, 59.1% yield) which was used in subsequent reactions without further purification. ES MS (M+H+)=261.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=3[CH:18]=[C:19]([CH3:30])[CH:20]=2)=[CH:23][CH:24]=1
Reactant: CN
Reactant: COc1ccc(-c2cc(C)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Product: CNCC1Cc2cc(C)cc(-c3ccc(OC)cc3)c2O1

Procedure:
The title compound was prepared (0.075 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(4-methoxyphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.45 mmol) and methylamine (0.112 g, 4.5 mmol). mp 235-238° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH3:21][C:22]([N:30]1[CH:34]=[C:33]([N+:35]([O-])=O)[N:32]=[CH:31]1)([CH3:29])[CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:29][C:22]([N:30]1[CH:34]=[C:33]([NH:35][C:15](=[O:17])[CH:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])[N:32]=[CH:31]1)([CH3:21])[CH2:23][N:24]1[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(C)(CN1CCCC1)n1cnc([N+](=O)[O-])c1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 2) was reacted with 1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)-4-nitro-1H-imidazole to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 24.3, 26.6, 28.2, 28.8, 28.9, 29.8, 36.6, 52.8, 56.0, 59.1, 60.9, 67.3, 100.8, 101.1, 101.3, 104.8, 110.7, 110.9, 112.5, 131.2, 137.3, 172.4; MS m/z 474.3 (M+1).
Reaction SMILES: CC(C)=CC[O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1>C1(OC)C=CC=CC=1>[CH3:7][CH:8]([C:16]1[CH:15]=[C:9]([CH:8]=[CH:7][C:6]=1[OH:5])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:9]([CH3:15])=[CH2:10]
Reactant: CCOC(=O)c1ccc(OCC=C(C)C)cc1
Solvent: COc1ccccc1
Product: C=C(C)C(C)c1cc(C(=O)OCC)ccc1O
Yield: 53.7 %

Procedure:
Ethyl 4-(3-methyl-but-2-enyloxy)-benzoate (2.23 g, 9.53 mmol) was dissolved in anisole (8 ml) and the mixture stirred and held at reflux for 4 days. The solvent was removed in vacuo and the residue subjected to column chromatography on silica. Elution with 20% ethyl acetate in petroleum ether afforded ethyl 3-(1,2-dimethyl-allyl)-4-hydroxy-benzoate (600 mg, 27%) as a colorless solid. 1H NMR (DMSO-d6) 10.32 (1H, br s), 7.67 (1H, dd), 7.62 (1H, s), 6.90 (1H, d), 4.90 (1H, s), 4.85 (1H, s), 4.25 (2H, q), 3.75 (1H, q), 1.61 (3H, s), 1.30 (3H, t), 1.26 (3H, d). MS: [M+H]+ 235.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[F:24][C:25]1[C:26]([CH3:32])=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[C:26]=2[CH3:32])=[N:3][CH:4]=1
Reactant: Cc1c(O)cccc1F
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(F)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-fluoro-2-methylphenol: 1H-NMR (CDCl3) δ 8.57 (1H, d, J=2.3 Hz), 8.14 (1H, d, J=7.5 Hz), 8.10 (1H, d, J=2.3 Hz), 8.00 (2H, d, J=8.3 Hz), 7.43 (2H, d, J=8.3 Hz), 7.25 (1H, m), 7.03 (1H, t, J=8.3 Hz), 6.91 (1H, d, J=8.1 Hz), 5.40 (1H, m), 3.90 (3H, s), 2.06 (3H, s), 1.60 (3H, d, J=7.5 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][P:14]([C:19]([F:36])([F:35])[CH:20]([OH:34])[CH2:21][C:22]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[O:32][CH3:33])([CH3:24])[CH3:23])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12].C(N(CC)CC)C>ClCCl>[CH2:16]([O:15][P:14]([C:19]([F:35])([F:36])[C:20](=[O:34])[CH2:21][C:22]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[O:32][CH3:33])([CH3:23])[CH3:24])(=[O:18])[O:13][CH2:11][CH3:12])[CH3:17]
Reactant: CCOP(=O)(OCC)C(F)(F)C(O)CC(C)(C)c1cc(F)ccc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(F)(F)C(=O)CC(C)(C)c1cc(F)ccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
A solution of oxalyl chloride (2.2 mL, 2.0M in dichloromethane) was diluted with dichloromethane (3.0 mL) and cooled in a dry ice/acetone bath. To this solution was added a solution of DMSO (0.7 mL) in dichloromethane (2.5 mL) dropwise. After 10 minutes, a solution of the [1,1-difluoro-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]phosphonic acid diethyl ester (1.10 g) in dichloromethane (3 mL) was added and the mixture was stirred for 15 minutes. Triethylamine (4.0 mL) was added, the cooling bath was removed, the reaction mixture was allowed to warm to room temperature and quenched with water and diluted with hexanes. The organic layer was separated, washed with water, dried, filtered, and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluent: hexanes to hexanes-ethyl acetate (2:1) gradient) to give [1,1-difluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentyl]phosphonic acid diethyl ester as an oil (1.0 g, 91%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)cc1
Product: Fc1ccc(CNc2nc(-n3ccnc3)nc3sc4c(c23)CCCC4)cc1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:25])[C:7](=[O:24])[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:25][CH:6]1[C:7](=[O:24])[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=[C:10]2[CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:2]([N:32]4[CH2:36][CH2:35][CH2:34][CH:33]4[CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[CH:3][C:4]=3[N:5]12
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(Br)cc3N21
Reactant: CC(C)(C)OC(=O)NCC1CCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(N4CCCC4CNC(=O)OC(C)(C)C)cc3N21
Temperature: 25 °C

Procedure:
A mixture of 6-bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #1, Step E, 0.050 g, 0.117 mmol), cesium carbonate (0.076 g, 0.235 mmol), tert-butyl (pyrrolidin-2-ylmethyl)carbamate (0.047 g, 0.235 mmol), Pd(OAc)2 (0.008 g, 0.035 mmol) and BINAP (0.022 g, 0.035 mmol) in toluene (2 mL) was heated at reflux overnight. The reaction mixture was cooled to ambient temperature, filtered and concentrated in vacuo to give crude tert-butyl ((1-(1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)pyrrolidin-2-yl)methyl)carbamate as brown solid, which was used for next step without further purification.
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>C(#N)C.C(O)(=O)C>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][N:21]([CH3:3])[CH2:20][CH:17]2[CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:19][CH2:18]2)[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC(CNCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A 37% aqueous solution of formaldehyde (5 ml; 67 mmol) and sodium cyanoborohydride (314 mg; 5.0 mmol) were added to a solution in acetonitrile (20 ml) of N,N-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]amine (1.0 g; 2.4 mmol) synthesized by the above process, and the mixture was stirred at room temperature for 15 minutes. Acetic acid was then added to the solution to adjust the pH to about 5, and the mixture was stirred further for 48 hours at room temperature. The reaction mixture was brought to pH about 10 by addition of aqueous 2.5N sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 989 mg (yield: 95%) of N,N-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]methylamine as a colorless oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11](F)[C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.CC[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>CC#N>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([N:4]4[CH2:1][CH2:2][CH:30]([CH2:29][NH:26][CH2:27][CH3:28])[CH2:5]4)[C:12]=3[C:14]([F:15])([F:16])[F:17])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C(F)(F)F)C1
Yield: 193.1 %

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylic acid (0.20 g, 0.61 mmol) 3-((N-ethylamino)methyl)pyrrolidine (0.20 g, 1.6 mmol) and NEt3 (0.20 g, 2 mmol) were refluxed with stirring under N2 in CH3CN (2 mL) for 2 hours. When the reaction mixture had cooled to 20° the yellow solid was collected by vacuum filtration, washed with water (5 mL) and ether (5 mL), and then dried at 110°/0.2 mm to give 1-cyclopropyl-7-(3-((N-ethylamino) methyl)pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylic acid (0.26 g, 97%) as a light yellow solid; mp 239°-241° C. C21H23N3O3F4 requires C, 57.14; H, 5.22; N, 9.52; F, 17.23%. Found, C, 56.77; H, 4.98; N, 9.34; F, 16.95%. Nmr (TFA) δ 9.37 (1 H, s, H 2), 8.02 (1 H, d, J=13.8 Hz, H 5), 7.2-7.5 (2 H, br s, NH+2), 4.45-4.55 (1 H, m, H 1 pyrrolidinyl), 4.1-4.4 (2 H, m, H 5 pyrrolidinyl), 3.9-4.1 (2 H, m, H 1 cyclopropyl +pyrrolidinyl, 3.3-3.65 (4 H, m, CH2s ethylaminomethyl), 2.9-3.1 (1 H, m, H 3 pyrrolidinyl), 2.5-2.65 (1 H, m, H 4 pyrrolidinyl), 1.9-2.1 (1 H, m, H 4 pyrrolidinyl), 1.5-1.8 (5 H, m and t, J=7.1 Hz, cyclopropyl and CH3), 0.95-1.4 (2 H, m, cyclopropyls). Ir (KBr) 1629, 1456, 1360 cm-1. MS 442 (4, M H⊕), 441 (4, M⊕).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:11][C:10]1[C:2]2[NH:1][C:13](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)oc(=O)[nH]c12

Procedure:
The compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of 2-amino-3-methylbenzoic acid with triphosgene in THF produced 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione, which was treated with tert-butylamine and DMAP in DMF to produce 2-amino-N-tert-butyl-3-methylbenzamide. Reaction of the benzamide with CDI in THF produced 3-tert-butyl-8-methylquinazoline-2,4(1H,3H)-dione, which was reacted with methyl 3-(bromomethyl)benzoate and MeONa in DMF, followed by treatment with hydrochloric acid aqueous solution, to produce 8-methyl-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione. Coupling of the acid with 2-(piperazin-1-yl)pyrimidine in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 8-methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione.