Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([Cl:13])[CH:5]=[C:6]([CH:10](Cl)[CH3:11])[C:7]=1[O:8][CH3:9].[I:15][C:16]1[C:24]2[C:19](=[N:20][CH:21]=[N:22][C:23]=2[NH2:25])[NH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:10]([N:18]2[C:19]3=[N:20][CH:21]=[N:22][C:23]([NH2:25])=[C:24]3[C:16]([I:15])=[N:17]2)[CH3:11])[CH:5]=[C:4]([Cl:13])[C:3]=1[CH3:14]
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(I)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 3-bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene (0.60 g, 2.0 mmol, from Example 167, Step 3), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (590 mg, 2.2 mmol, from AnaSpec), cesium carbonate (0.98 g, 3.0 mmol) and potassium iodide (30 mg, 0.2 mmol) in N,N-dimethylformamide (8 mL) was stirred at 140° C. for 1 h. The mixture was cooled down and then the solvent was completely removed. The residue was stirred with CH2Cl2 (30 mL) at room temperature for 20 min and then filtered. The filtrate was concentrated and the product (0.65 g, 63%) was purified by chromatography eluting with CH2Cl2/EtOAc (max. EtOAc 60%). LCMS calculated for C15H15BrClIN5O (M+H)+: m/z=521.9; Found: 521.9.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=O)[NH:12][CH2:13][C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:22](O[C@H]1CC[C@H](C2N3C=CN=C(Cl)C3=CN=2)CC1)(=O)C>>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:22])[C:14]3=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Reactant: CC(=O)O[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Product: CC(=O)O[C@H]1CC[C@H](c2ncc3c(C)nccn32)CC1

Procedure:
(Trans)-4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl acetate (2.8 g) was transformed into (trans)-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (2.2 g) using the procedure described in example 1 step 1b using a reaction temperature of 60° C. for 16 hours. Reaction of the latter compound (2.6 g) yielded (trans)-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (1.6 g) using the procedure described in example 2 step 2d.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:14]([O-])=O)[C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:17].[Sn].[OH-].[Na+]>Cl.O>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([NH2:14])[C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:17]
Reactant: Cc1nc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cc(N)c(N)cc2n1C
Temperature: 10 °C

Procedure:
1,2-Dimethyl-5,6-dinitrobenzimidazole was reduced with tin in hydrochloric acid. The solution obtained from the reduction was diluted with water, cooled to 10° C., and treated with 40% NaOH. The precipitate which formed was filtered, washed with water and recrystallized from alcohol to yield 1,2 dimethly-5,6 diaminobenzimidazole.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:5]2[C:10]([F:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:30][N:31]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[F:11][C:10]1[C:5]2[C:4]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)=[N:3][C:2]([NH:36][C:33]3[CH:34]=[CH:35][N:31]([CH3:30])[N:32]=3)=[N:7][C:6]=2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=1
Reactant: C[Si](C)(C)CCOCn1cc(F)c2c(Oc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Reactant: Cn1ccc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1ccc(Nc2nc(Oc3cccc([N+](=O)[O-])c3)c3c(F)cn(COCC[Si](C)(C)C)c3n2)n1
Temperature: 140 °C
Yield: 95.2 %

Procedure:
To a solution of 2-chloro-5-fluoro-4-(3-nitrophenoxy)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (483 mg, 1.1 mmol), in 1,4-dioxane (12 mL) was added 1-methyl-1H-pyrazol-3-amine (128 mg, 1.32 mmol), Cs2CO3 (717 mg, 2.2 mmol), Xantphos (66 mg, 0.11 mmol) and Pd2(dba)3 (101 mg, 0.11 mmol). The reaction vial was flushed with nitrogen, capped, stirred and heated at 140° C. in a microwave reactor for 45 min. After removing the reaction solvent, the residue was partitioned in EtOAc (120 mL) and water (20 mL). The organic layer was separated, washed with water (20 mL) and brine (10 mL), dried over Na2SO4 and evaporated. Purification via flash chromatography with a gradient of 0%-50% EtOAc in heptanes afforded the title compound (523 mg, 95% yield) as a thick oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (s, 1H) 8.28-8.32 (m, 1H) 8.26 (d, J=8.06 Hz, 1H) 7.90-7.95 (m, 1H) 7.81-7.88 (m, 1H) 7.45 (br. s., 1H) 7.32 (d, J=2.27 Hz, 1H) 5.52 (s, 2H) 3.74 (s, 3H) 3.55-3.66 (m, 2H) 0.94 (t, J=8.18 Hz, 2H) 0.00 (s, 9H). m/z (APCI+) for C22H26FN7O4Si 500.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:4][CH:5]=2)[C:12](=[O:26])[CH:13]=1
Reactant: C1CCNC1
Reactant: O=c1cc(OCc2cccc(F)c2)ccn1CCc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: O=c1cc(OCc2cccc(F)c2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 120 mg (0.29 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(3-fluoro-benzyloxy)-1H-pyridin-2-one (example 8.1b) in 2.0 mL DMF is added at RT 95 μL (1.15 mmol) pyrrolidine. The reaction mixture is stirred overnight at RT and is directly transferred to a reverse HPLC for purification (Waters symmetry; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.O=[C:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[C:18](OC)=[O:19]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[C:18](=[O:19])[O:9][C:4]=2[CH:3]=1
Reactant: COC(=O)C1CNCCC1=O
Reactant: Cc1ccc(O)cc1C
Agent: Cl
Product: Cc1cc2oc(=O)c3c(c2cc1C)CCNC3
Yield: 84.2 %

Procedure:
Prepared by the method described in Example 1 from 3,4-dimethylphenol (10.0 g, 0.082 moles) and methyl 4-oxo-3-piperdinecarboxylate hydrochloride (11.3 g, 0.058 moles). Recrystallization from 2-methoxyethanol yielded the product (11.2 g), mp 172°-l74° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19](=[O:29])[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:27][OH:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19](=[O:29])[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[CH:27]=[O:28])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1CO)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C[C@@H]1CCCC[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 96.7 %

Procedure:
A solution of oxalyl chloride (2.6 mL, 29.4 mmol) in dichloromethane (80 mL) at −78° C. was treated with a solution of dimethyl sulfoxide (4.3 mL, 60.8 mmol) in dichloromethane (10 mL) over 5 minutes. The mixture was stirred for 40 min, then treated with a solution of benzyl[(1R,2R)-2-(hydroxymethyl)cyclohexyl]carbamate (5.0 g, 19 mmol) in dichloromethane (20 mL) over 5 minutes. The mixture was stirred for 45 minutes, then was treated with triethylamine (8.6 mL, 61.7 mmol) and allowed to warm to room temperature. After 60 minutes, the mixture was washed with water, then with brine, and dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography using 30% ethyl acetate in hexane to provide a white solid (4.8 g, 97%).
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH2:10][CH:9]([NH:15]C(=O)C)[CH2:8]2)(=O)C.[ClH:22]>>[ClH:22].[Br:14][C:13]1[CH:12]=[C:11]2[C:7]([CH2:8][CH:9]([NH2:15])[CH2:10]2)=[C:6]([N+:19]([O-:21])=[O:20])[C:5]=1[NH2:4]
Reactant: CC(=O)Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(NC(C)=O)C2
Agent: Cl
Product: Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(N)C2
Yield: 93 %

Procedure:
N-(5-Acetylamino-6-bromo-4-nitro-indan-2-yl)-acetamide (1 g, 2.8 mmol) was stirred in 3N HCl (80 mL) at reflux for 3 h. The resulting solid was collected by filtration and dried in vacuo. Additional material was obtained by evaporation of the filtrate to give a combined yield of 93% of the yellow orange product (0.8 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14].[NH2:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][C:21]#[N:22]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:11]1[C:20]([C:21]#[N:22])=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:15]([CH3:16])=[C:12]1[C:13]#[N:14]
Reactant: N#CC=C(N)C(F)(F)F
Reactant: CC(=O)/C(C#N)=C/c1cc2cn[nH]c2cc1F
Product: CC1=C(C#N)C(c2cc3cn[nH]c3cc2F)C(C#N)=C(C(F)(F)F)N1

Procedure:
Following the procedure described for Example 4, 200 mg (0.87 mmol) (2E)-2-[(6-fluoro-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 6A) were treated with 3-amino-4,4,4-trifluorobut-2-enenitrile. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient, final mixture 90:10 v/v) to yield 115 mg (40% of th.) of the racemic title compound.
Reaction SMILES: [N:1]1([S:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]3[CH2:22][CH2:21][C:20](=O)[CH2:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][C:27]=1[O:35][CH3:36]>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([NH:34][CH:20]2[CH2:21][CH2:22][C@@H:18]([C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][S:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)(=[O:9])=[O:8])=[CH:17][CH:16]=3)[CH2:19]2)[CH3:33])=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: COc1cc([C@@H](C)N)ccc1F
Reactant: O=C1CC[C@@H](c2ccc(CCS(=O)(=O)N3CCOCC3)cc2)C1
Agent: Cl
Product: COc1cc([C@@H](C)NC2CC[C@@H](c3ccc(CCS(=O)(=O)N4CCOCC4)cc3)C2)ccc1F

Procedure:
General procedure B was followed using (3R)-3-{4-[2-(morpholine-4-sulfonyl)-ethyl]-phenyl}-cyclopentanone (preparation 49) as the ketone and (1R)-1-(4-fluoro-3-methoxyphenyl)ethylamine hydrochloride as the amine. 1H NMR (300 MHz, DMSO) δ 7.23-7.04 (m, 6H), 6.92-6.83 (m, 1H), 3.82 (s, 3H), 3.80-3.68 (m, 1H), 3.66-3.55 (m, 4H), 3.37-3.26 (m, 2H), 3.22-3.10 (m, 4H), 3.06-2.78 (m, 4H), 2.20-1.13 (m, 6H), 1.23 (d, J=6.6 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:19]=[C:18]2[C:9]([O:10][CH2:11][CH2:12][N:13]3[C:17]2=[N:16][C:15]([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[C:22]([CH3:28])[N:21]=2)=[CH:14]3)=[CH:8][N:7]=1)=[CH2:5])C.CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:28][C:22]1[N:21]=[C:20]([C:15]2[N:16]=[C:17]3[N:13]([CH:14]=2)[CH2:12][CH2:11][O:10][C:9]2[C:18]3=[CH:19][C:6]([C:4](=[O:3])[CH3:5])=[N:7][CH:8]=2)[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=1
Reactant: C=C(OCC)c1cc2c(cn1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)c1cc2c(cn1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 60 °C
Reaction time: 1.25 h
Yield: 78.2 %

Procedure:
A mixture of 13-(1-ethoxyethenyl)-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,12-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (900 mg, 2.36 mmol) and 4-methylbenzenesulfonic acid (204 mg, 1.18 mmol) in acetone (20 mL) was stirred at 60° C. for 75 min. After removal of the solvent, the residue was purified by reverse phase Combi-flash eluting with a 23-27% gradient of CH3CN in 0.3% NH4HCO3 to give the desired product (650 mg, 74% yield) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.49 (s, 1H), 8.07 (s, 1H), 5.69 (m, 1H), 4.68-4.59 (m, 4H), 2.63 (s, 3H), 2.29 (s, 3H), 1.49 (s, 6H). LCMS m/z [M+H]+ 353.3
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:29][C:30]1[C:31]([CH:40]=O)=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2>C1COCC1.C(OC(C)C)(C)C>[Br:2]/[CH:3]=[CH:40]\[C:31]1[C:30]([CH3:29])=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1
Reactant: Cc1cc2ccccc2nc1C=O
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: Cc1cc2ccccc2nc1/C=C\Br
Temperature: -75 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a suspension of (bromomethyl)triphenylphosphonium bromide (3.06 g, 7.01 mmol) in 30 mL of THF, potassium tert-butoxide (0.78 g, 7.01 mmol) was added portionwise at −75° C. under argon. After completion of the addition, the mixture was stirred for 1 h a −75° C. Then, a solution of 3-methylquinoline-2-carbaldehyde (1 g, 5.84 mmol) in 20 mL of THF was added. The reaction mixture was stirred for 5 h at −75° C. and then allowed to warm up to room temperature overnight. For work-up, the reaction mixture was diluted with diisopropyl ether (1:1) and the precipitate formed was sucked off. The filtrate was concentrated and triturated in diisopropyl ether. The precipitate was sucked off. The filtrate was purified by column chromatography (normal phase, eluent: cyclohexane/EA) to give 492.5 mg (34%) of the title compound as yellow solid. LC-MS: m/e 248.0 (M+H)+; Rt 1.561 min.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:37])=[C:5]([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)[O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].Cl>>[Cl:1][C:2]1[S:3][C:4]([Cl:37])=[C:5]([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)[O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2c(Cl)sc(Cl)c2C(OC2CCCCO2)c2cccc(Cl)c2)cc1
Agent: Cl
Product: C[C@H](NC(=O)c1c(Cl)sc(Cl)c1C(OC1CCCCO1)c1cccc(Cl)c1)c1ccc(C(=O)O)cc1

Procedure:
Methyl 4-{(1S)-1-[({2,5-dichloro-4-[(3-chlorophenyl)(tetrahydro-2H-pyran-2-yloxy)methyl]-3-thienyl}carbonyl)amino]ethyl}benzoate from Example 8, Step 4 (21.3 mg, 0.0365 mmol) was reacted under conditions similar to Example 1, Step 11. The reaction mixture was neutralized with 25% aq. NH4OAc (instead of an acidification with 1N HCl). The desired product was obtained as a white foam and was used without further purification. MS (−APCI): m/z 566 (M−1)−
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:19])[C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:19][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:10]=2[O:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:5]=[CH:4][N:3]=1
Reactant: CN1CCN(CCCO)CC1
Reactant: Oc1ccc2ncnc(Cl)c2c1OC1CCOCC1
Product: CN1CCN(CCCOc2ccc3ncnc(Cl)c3c2OC2CCOCC2)CC1

Procedure:
Using an analogous procedure to that described in the last paragraph of the portion of Note [10] immediately above that is concerned with the preparation of starting materials, 4-chloro-6-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (1.12 g) was reacted with 1-(3-hydroxypropyl)-4-methylpiperazine to give 4-chloro-6-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.56 g); NMR Spectrum: (CDCl3) 1.85-2.2 (m, 6H), 2.32 (s, 3H), 2.35-2.7 (m, 10H), 3.42 (m, 2H), 4.05 (m, 2H), 4.25 (m, 2H), 4.65 (m, 1H), 7.75 (d, 1H), 7.85 (d, 1H), 8.9 (s, 1H); Mass Spectrum: M+H+ 421 and 423.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH2:36][CH3:37])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[CH2:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>CN(C=O)C.C(Cl)Cl>[CH2:36]([C:13](=[CH:14][CH2:15][C:16]1[C:17]([OH:29])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[CH2:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])[CH2:12][NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])[CH3:37]
Reactant: CCOP(=O)(CCNCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CC)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(=CCc1c(O)c2c(c(C)c1CC)COC2=O)CNCCP(=O)(O)O
Temperature: 25 °C
Yield: 44.7 %

Procedure:
(2-{2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (24.9 mg, 0.045 mmol) was dissolved in DMF (0.5 mL) and DCM (0.5 mL). Trimethylsilyl bromide (68.7 mg, 0.449 mmol) was added and the reaction was stirred at room temperature. After 20 hrs the reaction was quenched with MeOH (0.15 mL). The solvents were evaporated in vacuo and the crude material was purified by RP-HPLC (eluent: water/MeCN). The product-containing fractions were combined and lyophilized to yield 8.0 mg of the free phosphonic acid [MS: 498 M++1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1.[O:17]1CCOCC1>>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[C:7]([C:10](=[O:17])[C:11]([O:13][CH3:14])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: C1COCCO1
Reactant: COC(=O)Cc1coc2cc(OC)ccc12
Product: COC(=O)C(=O)c1coc2cc(OC)ccc12
Yield: 85 %

Procedure:
A mixture of methyl 2-(6-methoxybenzofuran-3-yl)acetate (0.500 g, 2.27 mmol) and SeO2 (0.303 g, 2.73 mmol) in 1,4-dioxane (10 mL) was refluxed for 2 days and then filtered. The filtrate was concentrated in vacuo and the residue was purified on a silica gel column to give methyl 2-(6-methoxybenzofuran-3-yl)-2-oxoacetate (0.452 g, 85%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:5][CH:4]=1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:8]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(CCNC(C)=O)cc1
Solvent: CC(=O)O
Product: COc1ccc(CCNC(C)=O)cc1[N+](=O)[O-]
Temperature: 32.5 °C
Reaction time: 1 h

Procedure:
A solution of 70 g of N-[2-(4-methoxyphenyl)ethyl]acetamide in 330 mL of acetic acid was introduced slowly into 350 mL of 70% nitric acid so that the temperature was between 30-35° C. The addition process took 1 hour. The mixture was stirred at 30-35° C. for additional 40 minutes and was then poured into 1500 mL of ice water. The resulting slurry was extracted with chloroform (2×400 mL). The organic phase was extracted with a saturated aqueous solution of NaHCO3 (2×400 mL) and then with water (2×400 mL). The solvent was then removed by rotary evaporation to produce 65 g of N-[2-(4-methoxy-3-nitrophenyl)ethyl]acetamide, which was further purified by recrystallization from ethyl acetate to yield 48 g (55.6% yield) of yellow crystals. 1HNMR (DMSO-d6) spectrum was consistent with the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH2:18])[CH:12]=1>>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[CH:12]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: NCc1cccnc1
Product: O=C(NCc1cccnc1)c1cccc(Br)c1
Yield: 73 %

Procedure:
Using Preparation Method 1, 3-bromobenzoic acid was reacted with 3-pyridylmethylamine. The resulting reaction mixture was purified using SiO2 with CH2Cl2/MeOH 95:5 to give N-(3-pyridylmethyl)-3-bromobenzamide as thick yellow oil (73%). NMR 1H (ppm, CDCl3): 8.44 (s, 1H), 8.41 (d, J4=3.9 Hz, 1H), 7.92 (s, 1H), 7.69 (d, J3=7.8 Hz, 1H), 7.64 (d, J3=7.8 Hz, 1H), 7.57-7.54 (m, 2H), 7.24-7.18 (m, 2H), 4.55 (d, J3=5.9 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=1)[CH2:13][CH3:14])[CH2:7]2.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>C1COCC1>[CH2:24]([O:23][C:17]1[CH:16]=[C:15]([CH:12]([N:8]2[C:9](=[O:11])[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[CH2:7]2)[CH2:13][CH3:14])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[CH3:25]
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc(C(CC)N2Cc3cccc(N)c3C2=O)ccc1OC
Solvent: C1CCOC1
Product: CCOc1cc(C(CC)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Yield: 76 %

Procedure:
A solution of 7-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (1.0 g, 2.9 mmol) and cyclopropanecarbonyl chloride (0.32 mL, 3.5 mmol) in THF (10 mL) was heated to reflux for 40 min. The solvent was removed in vacuo. The residue was extracted with ethyl acetate (50 mL) and sodium hydrogen carbonate (sat, 50 mL). The organic layer was washed with brine (50 mL) and dried over MgSO4. The solvent was removed in vacuo and the residue was purified with chromatography (Silica Gel) to cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (900 mg, 76% yield): mp, 107–109° C.; 1H NMR (CDCl3) δ 0.84–0.92 (m, 2H, CH2), 0.99 (t, J=7 Hz, 3H, CH3), 1.02–1.13 (, 2H, CH2), 1.44 (t, J=7 Hz, 3H, CH3), 1.64–1.73 (m, 1H, CH), 2.00–2.16 (m, 2H, CH2), 3.86 (s, 3H, CH3), 4.00 (d, J=17 Hz, 1H, CHH), 4.09 (q, J=7 Hz, 2H, CH2), 4.27 (d, J=17 Hz, 1H, NCHH), 5.33 (dd, J=7, 9 Hz, 1H, NCH), 6.83–6.95 (m, 3H, Ar), 7.00 (d, J=8 Hz, 1H, Ar), 7.42 (t, J=8 Hz, 1H, Ar), 8.42 (d, J=8 Hz, 1H, Ar), 10.67 (s, 1H, NH); 13C NMR (CDCl3) δ 8.19, 11.18, 14.78, 16.18, 24.54, 45.64, 55.53, 55.97, 64.58, 111.46, 112.91, 116.68, 117.67, 119.51, 131.96, 132.94, 138.02, 141.37, 148.54, 149.04, 169.55, 172.70; Anal Calcd for C24H28N2O4: C, 70.57; H, 6.91; N, 6.86. Found: C, 70.54; H, 6.91; N, 6.86.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:21]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: c1ccc(C2CCNC2)nc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC(c4ccccn4)C3)c(F)cc2c1=O
Yield: 85 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.25 g, 4.7 mmol) and 2-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.57 g, 85%) as an off-white solid, mp 216°-219° C.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=O)[C:7]2=[O:15].Cl.[C:17]1([NH:23][C:24](=[O:27])[NH:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=[N:26][NH:25][C:24]([NH:23][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:27])[C:7]2=[O:15]
Reactant: NNC(=O)Nc1ccccc1
Reactant: COc1ccc2c(=O)c(=O)c(=O)c2c1
Agent: Cl
Solvent: O
Product: COc1ccc2c(=O)c(=NNC(=O)Nc3ccccc3)c(=O)c2c1

Procedure:
5-methoxyindan-1,2,3-trione, monohydrate, 4-phenyl semicarbazide hydrochloride