Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11]2)=[CH:7][CH:6]=1.[C:30]1(=[O:40])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32][NH:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:40]=[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32][N:31]1[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11]2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCCBr)cc2)nc1-c1ccccc1
Reactant: O=c1[nH]ncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1cn(Cc2ccc(OCCn3ncc4ccccc4c3=O)cc2)nc1-c1ccccc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 128.6 %

Procedure:
A mixture of ethyl 3-[1-[4-(2-bromoethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (1050 mg), 1(2H)-phthalazinone (530 mg), potassium carbonate (1000 mg) and N,N-dimethylformamide (15 ml) was stirred at 90° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-[2-[1-oxophthalazin-2(1H)-yl]ethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (1460 mg, yield 90%). This was recrystallized from acetone-hexane. Melting point: 155–156° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:15]2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:15]2)[CH2:12][CH2:13]1)(=[O:42])[CH3:41]
Reactant: Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
To N-(2-(3-(4-(2-aminophenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)-3,4-dichlorobenzamide (Example #4.149, 0.050 g, 0.10 mmol) in DCM (1 mL) was sequentially added triethylamine (0.044 mL, 0.32 mmol) and acetic anhydride (10.9 μL, 0.116 mmol). The reaction mixture was stirred at room temperature for about 16 h. The solvent was removed in vacuo and the residue purified by RP-HPLC (10% acetonitrile/0.05M aqueous ammonium acetate, buffered to pH 4.5 for 3 min., 5% to 60% acetonitrile/0.05M aqueous ammonium acetate over 6 min at 22.5 mL/min with 2.5 mL/min. acetonitrile at-column dilution; APCI positive mode detection; Xterra prep. MS C18. 19×50 mm column) to afford N-(2-(3-(4-(2-acetamidophenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)-3,4-dichlorobenzamide (0.0075 g, 0.014 mmol). RP-HPLC (Table 1, Method a) Rt 1.92 min; nm/z: (M+H)+ 517.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][CH2:9][S:10]([C:13]1[CH:18]=C(C)[CH:16]=[C:15]([C:20](=[O:37])[N:21]([C:23]2[N:24]=[N:25][C:26]([Cl:36])=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH3:22])[CH:14]=1)(=[O:12])=[O:11])(C)(C)C.C1(OC)C=CC=CC=1.[F:47][C:48]([F:53])([F:52])[C:49](O)=O>ClCCl>[Cl:36][C:26]1[N:25]=[N:24][C:23]([N:21]([CH3:22])[C:20]([C:15]2[CH:14]=[C:13]([S:10]([CH2:9][CH2:8][CH2:7][C:6]([OH:38])=[O:5])(=[O:12])=[O:11])[CH:18]=[C:49]([C:48]([F:53])([F:52])[F:47])[CH:16]=2)=[O:37])=[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:27]=1
Reactant: Cc1cc(C(=O)N(C)c2nnc(Cl)cc2-c2ccccc2C)cc(S(=O)(=O)CCCC(=O)OC(C)(C)C)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Cc1ccccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)CCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-{3-[(6-chloro-4-o-tolyl-pyridazin-3-yl)-methyl-carbamoyl]-5-methyl-benzenesulfonyl}-butyric acid tert-butyl ester (0.055 g, 89.9 μmol) in dichloromethane (1.5 mL) were added anisole (10.7 mg, 10.8 μL, 98.8 μmol) and trifluoroacetic acid (512 mg, 346 μL, 4.49 mmol) and the light yellow solution was stirred at room temperature for 3.5 hours. The reaction mixture was evaporated to dryness and the residue treated with toluene and again completely evaporated. The product was purified by preparative HPLC (Gemini NX column) using a gradient of methanol:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless foam (0.037 g; 74%). MS (ESI+): m/z=556.09 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[CH:15]=O)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[N:6]1[C:5]2[N:10]3[CH:14]=[CH:13][CH:12]=[C:11]3[CH2:15][NH:1][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1cccn1-c1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: c1cnc2c(c1)NCc1cccn1-2
Reaction time: 3 h
Yield: 134.8 %

Procedure:
To a suspension of 8.0 g of 1-(3-nitro-2-pyridinyl)-1H-pyrrole-2-carboxaldehyde in 150 ml of ethyl acetate is added 800 mg of 10% Pd/C. The mixture is shaken in a Parr hydrogenator for 3 hours and then filtered through diatomaceous earth. The filtrate is concentrated under vacuum to give 8.5 g of solid. The solid is purified by chromatography over silica gel with solvent hexane-ethyl acetate (2:1) as solvent to give 2.6 g of product as white crystals, m.p. 92°-94° C. and 1.6 g of pyrido[3,2-a]pyrrolo[1,2-a]pyrazine as tan needles, m.p. 88° C. to 90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44](O)=[O:45])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.[CH3:60][C:61]1([S:64]([NH2:67])(=[O:66])=[O:65])[CH2:63][CH2:62]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([NH:67][S:64]([C:61]4([CH3:60])[CH2:63][CH2:62]4)(=[O:66])=[O:65])=[O:45])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)O)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3(C)CC3)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Compound 2d (130 mg, 0.198 mmol) was dissolved in DCM (10 ml). EDAC (46 mg, 0.238 mmol) was added and the reaction mixture was stirred at RT for 2.5 h. Methyl cyclopropanesulfonic amide (30 mg, 0.3218 mmol) and DBU (63 μl, 0.416 mmol) were added and the mixture was stirred at RT over night. 5% Citric acid was added and the organic layer was washed with brine, dried, filtered and evaporated. The material was used directly in the following step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[O:10]1[CH:11]=[CH:12][N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: COc1ccc(-c2ncco2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ncco2)cc1
Yield: 94.9 %

Procedure:
The title compound (0.52 g, 95%) was prepared from the product of step 1 (0.6 g, 3.4 mmol) and boron tribromide (1M in methylene chloride, 10.3 ml, 10.3 mmol) using the procedure of Example 146, step 2; 1HNMR (400 MHz, DMSO-d6) δ 8.1 (s, 1H), 7.81 (d, J=8.8 Hz, 2H), 7.30 (s, 1H), 6.92 (d, J=9.2 Hz, 2H), MS (APCI+) 162 (M+1, 100);
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]=O)=[CH:21][CH:22]=3)[C:17]3[CH:26]=[C:27]([Cl:30])[CH:28]=[N:29][C:16]2=3)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:31]([CH3:34])([O-:33])=[O:32]>>[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]=[CH:34][N+:31]([O-:33])=[O:32])=[CH:21][CH:22]=3)[C:17]3[CH:26]=[C:27]([Cl:30])[CH:28]=[N:29][C:16]2=3)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 89.5 %

Procedure:
Solid ammonium acetate (121 mg, 1.1 equiv. 1.56 mmol) was added to solution of 9-benzenesulfonyl-3-chloro-9H-pyrido[2,3-b]indole-6-carbaldehyde (524 mg, 1.42 mmol) in nitromethane (5.5 mL). The mixture was vigorously stirred and boiled at 100° C. for 2 h. Then the mixture was cooled in an ice bath and concentrated under reduced pressure. Trituration of the crude residue from ethanol followed by filtration afforded 14 (528 mg, 89.5%), 1H-NMR (300 MHz, CDCl3): δ 8.81 (d, 1H, J=1.6 Hz), 8.70 (d, 1H, J=2.3 Hz), 8.65 (d, 1H, J=2.3 Hz), 8.42 (d, 1H, J=8.8 Hz), 8.25 (s, 2H), 8.17 (dd, 1H, J=1.6, 8.9 Hz), 8.09 (d, 1H, J=7.2 Hz), 8.09 (d, 1H, J=8.8 Hz), 7.71 (t, 1H, J=7.4 Hz), 7.60 (d, 1H, J=8.1 Hz), 7.58 (t, 1H, J=7.4 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 148.7 (C), 146.0 (CH), 139.4 (C), 138.7 (CH), 137.9 (CH), 137.3 (C), 135.2 (CH), 130.9 (CH), 129.8 (2 CH), 129.5 (CH), 127.3 (C), 127.1 (2 CH), 126.5 (C), 123.8 (CH), 122.2 (C), 118.9 (C), 115.0 (CH), MS (ESI) m/z 414 [M+H+]
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N+:14]([O-])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([C:22]#[N:23])(C)C.C(N(CC)CC)C.C(O)C>CCCCCC.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:22]#[N:23])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc[n+]([O-])cc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCc1ccnc(C#N)c1

Procedure:
A solution of 28.6 g of 4-(tert-butyl-dimethylsilyloxyethyl)-pyridine-N-oxide, 60.3 ml of trimethylsilyl cyanide and 31.5 ml triethylamine is stirred under nitrogen at reflux for 3 hours. The dark solution is cooled in an ice bath, 30 ml of ethanol added, followed by 400 ml ethyl acetate and 200 ml hexane. The solution is washed twice with 150 ml of water, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using ethyl acetate/hexane (1:10) to yield 4-(tert-butyl-dimethylsilyloxyethyl)-2-cyanopyridine.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3].ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH:22]3[O:37][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: CCCCCC=Cc1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCCCCC1OC1c1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Reaction time: 3 h

Procedure:
1.5 g (3.98 mmoles) of the compound from Example 1 is dissolved at 0° C. in 40 ml of dry chloroform. To it is added 0.98 g (3.98 mmoles) of 70% m-chloroperbenzoic acid. The mixture is allowed to come to room temperature and is stirred for 3 hours longer. It is washed 3 times with 30 ml portions of 10% sodium bisulfite solution and twice with 30 ml portions of 1 N NaOH solution, dried over MgSO4, and evaporated under vacuum. The residue (1.6 g) was chromatographed on silica gel with toluene/ethyl acetate 95:5 as eluant.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.C(Cl)(Cl)[Cl:30].ClN1C(=O)CCC1=O>C(#N)C>[Cl:30][C:14]1[N:13]=[C:12]([C:15]([NH2:17])=[O:16])[C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=2)=[N:10][C:9]=1[NH:8][C@H:5]1[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]1
Reactant: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)cnc2C(N)=O)c1
Reactant: ClC(Cl)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(Cl)nc2C(N)=O)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 111) (298 mg), chloroform (40 mL) and acetonitrile (10 mL), N-chlorosuccinimide (108 mg) was added and stirred at 70° C. for 8 hours. After the reaction liquid was cooled, silica gel was added, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform:methanol=10:0 to 10:1). The resulting crude product was solidified from chloroform and collected by filtration. The resulting solid was heated with ethyl acetate and washed with ethyl acetate to give 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (189 mg) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[C:10]([C:12]3[C:26]([F:27])=[CH:25][C:15]4[C:16]([C:19]5[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=5)=[N:17][O:18][C:14]=4[CH:13]=3)[C:9]([CH3:28])=[C:8]([F:29])[CH:7]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1.CCOCC>C(Cl)(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[C:10]([C:12]3[C:26]([F:27])=[CH:25][C:15]4[C:16]([C:19]5[CH:20]=[CH:21][N+:22]([O-:39])=[CH:23][CH:24]=5)=[N:17][O:18][C:14]=4[CH:13]=3)[C:9]([CH3:28])=[C:8]([F:29])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1cc2onc(-c3ccncc3)c2cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1cc2onc(-c3cc[n+]([O-])cc3)c2cc1F
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 72.2 %

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-[5-fluoro-3-(4-pyridinyl)-1,2-benzisoxazol-6-yl]-4-methylbenzamide (Example 3, 12 mg) in chloroform (1 ml) under nitrogen was treated with M-CPBA (10 mg) and the mixture was stirred at 60° C. for 40 min. Further m-CPBA (10 mg) was added and stirring was continued for 1 h. The solution was applied to an Isolute amino cartridge (1 g) which was eluted with chloroform/methanol (100:0 to 90:10) to give a glass. Trituration using a small quantity of ether gave the title compound as a white powder (9 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:35][CH2:34][NH:33][C:32]2=[O:36])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N[C@@H]1CCCC[C@H]1N.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([N:33]3[CH2:34][CH2:35][N:31]([C:28]4[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=4)[C:32]3=[O:36])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NCCN1c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](/C=C/c2ccc(I)cc2)COC1(C)C
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@@H](/C=C/c2ccc(N3CCN(c4ccc(F)cc4)C3=O)cc2)COC1(C)C
Temperature: 180 °C
Yield: 66.7 %

Procedure:
A stirred suspension of (S)-4-[(E)-2-(4-iodo-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (250 mg, example 3(a)), 1-(4-fluorophenyl)imidazoline-2-one (320 mg, CAS 53159-75-4), caesium carbonate (418 mg), trans-1,2-diaminocyclohexane (0.14 ml), dibenzylideneacetone (54 mg) and copper(I) triflate benzene complex (58 mg) in dioxane (3 ml) under an atmosphere of argon in a sealed tube was heated at 180° C. for 40 min under microwave irradiation. The mixture was then cooled to room temperature and was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-((E)-2-{4-[3-(4-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-phenyl}-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (187 mg, 67%) as an off-white solid. MS (ISP): 504.2 ([M+Na]+), 426.2 ([M+H—C4H8]+).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5].[OH:11][C:12]1(CC#N)C[CH2:16][CH2:15][CH2:14][CH2:13]1>>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[O:1][C:2]1([CH2:3][C:4]#[N:5])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: N#CCC1(O)CCCCC1
Reactant: CCCCCC(O)CC#N
Product: N#CCC1(OC2CCCCO2)CCCCC1

Procedure:
This compound is prepared essentially by the same method as described in Example 1, Step A-2, except that the 3-hydroxycaprylonitrile is replaced by 2-(1-hydroxycyclohexyl)acetonitrile. This method provides the title compound as a pale yellow liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.[N:19]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[N:19]1([CH:24]2[CH2:29][CH2:28][N:27]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([B:4]4[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]4)=[CH:17][CH:16]=3)=[O:15])[CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Reaction time: 0.33 h
Yield: 32.9 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid (9.80 mmol, 2.43 g), 4-(1-pyrrolidinyl)piperidine (10.77 mol, 1.66 g), 1-hydroxybenzotriazole (16.67 mmol, 2.25 g), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19.57 mmol, 3.75 g) in DMF (30 mL) was stirred overnight at 60° C. Upon removal of DMF on rotavap, the residue was taken into mixture of EtOAc and H2O. The combined organic layers from extraction were stirred with aq. 2N HCl for 20 min and the aqueous layer was purified by reverse phase prep-HPLC to furnish the desired boronic acid (1.24 g. 42%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:12]([NH:22][CH:23]([CH2:27]O)[CH:24]([CH3:26])[CH3:25])[N:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:12]([N:22]2[CH:23]([CH:24]([CH3:26])[CH3:25])[CH2:27][O:8][CH:7]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:11]=1
Reactant: O=Cc1ccccn1
Reactant: CC(C)C(CO)Nc1cc(C(F)(F)F)c(C#N)c(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)C1COC(c2ccccn2)N1c1cc(C(F)(F)F)c(C#N)c(Cl)n1

Procedure:
Pyridine-2-carboxaldehyde (207 mg, 1.9 mmol) was added to a toluene solution (15 mL) of 2-chloro-6-[[1-(hydroxymethyl)-2-methyl-propyl]amino]-4-(trifluoromethyl)pyridine-3-carbonitrile (400 mg, 1.3 mmol) (Compound 13) followed by a catalytic amount of para-toluene sulfonic acid (50 mg). The reactants were refluxed for 6 hours in a Dean-Stark apparatus, concentrated under reduced pressure, adsorbed onto silica and purified using a neutral alumina column, eluting with a mobile phase of 10% ethyl acetate in hexane. 2-Chloro-6-[4-isopropyl-2-(2-pyridyl)oxazolidin-3-yl]-4-(tri fluoromethyl) pyridine-3-carbonitrile (Compound 12) was isolated as a solid in 20% yield. mp 112-115° C.
Reaction SMILES: COC1C=CC(C(O[O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:27])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]=2[NH:28][C:29](=[O:38])[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=O)=CC=1.[OH-].[Na+]>CO>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]([NH:28][C:12]2[C:13]([NH:17][C:18](=[O:27])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:14][CH:15]=[CH:16][C:11]=2[OH:10])=[O:38])=[CH:35][CH:34]=1
Reactant: COc1ccc(C(=O)Nc2cccc(OOC(=O)c3ccc(OC)cc3)c2NC(=O)c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)Nc2cccc(O)c2NC(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.9 %

Procedure:
A solution of 2,3-bis[(4-methoxybenzoyl)amino]phenoxy 4-methoxybenzoate (7.75 g, 14.7 mmol) in methanol (100 mL) was cooled to ice-water bath temperature and 5 N aqueous sodium hydroxide solution (3.0 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 72 hr. The reaction mixture was concentrated in vacuo and the resulting solid was dissolved in methylene chloride and washed with dilute aqueous hydrochloric acid, water, and saturated sodium chloride solution. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. Recrystallization of the residue from diethyl ether/hexane gave 2.3 g (40%) of the title product. mp 208-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([C:17]([O:19]C)=[O:18])=[CH:11][CH:12]=2)[N:7]=1.[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([C:17]([OH:19])=[O:18])=[CH:11][CH:12]=2)[N:7]=1
Reactant: COC(=O)c1ccc2c(=O)[nH]c(Cc3cccc(Cl)c3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2c(=O)[nH]c(Cc3cccc(Cl)c3)nc2c1
Yield: 93.3 %

Procedure:
A mixture of 336 mg of methyl 2-(3-chlorobenzyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate which was synthesized in Production Example 1, 3.0 mL of aqueous 1N sodium hydroxide solution and 6 mL of ethanol was heated for 2.5 hours under reflux. The reaction solution was allowed to cool off, and to which 3.0 mL of 1N hydrochloric acid and 5 mL of water were added. Whereupon precipitated crystals were recovered by filtration, washed with water and through-flow dried under heating, to provide 300 mg of the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](OC)=[O:11].[H-].[Na+]>>[OH:11][CH:10]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: N#CCc1ccccc1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Product: N#CC(=CO)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Phenylacetonitrile (10 g, 85.4 mmol) and methyl formate (67 ml) were dissolved in TIIF (250 ml) in a reaction vessel, and then NaH (2.6 g, 106.7 mmol) was added thereto at 0° C. The solution was stirred at room temperature for 12 hr. After completion of the reaction, the reaction mixture was washed with distilled water and acidified with 1 N HCl to adjust the pH to 5 or less. Thereafter, the resulting solution was extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4, followed by filtration. The filtrate was concentrated under reduced pressure to give 12.3 g (84.7 mmol, quant.) of the title compound.