Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28].Cl>O1CCCC1.CCCCCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C:25](=[O:29])[CH2:26][CH2:27][CH3:28])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CCCC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 1.27 ml, 2.00 mmol) was added to a tetrahydrofuran (10 ml) solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (606 mg, 2.00 mmol) obtained in Example 5. The temperature of the resulting mixture was then raised to room temperature. After cooling to −78° C., butyryl chloride (0.218 ml, 2.10 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at −78° C. for 1.5 hours, and added with 1N hydrochloric acid (2.0 ml). The temperature of the mixture was then raised to room temperature. The reaction mixture was extracted with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (10% ethyl acetate-hexane). The solid thus obtained was recrystallized from hexane, whereby the title compound (330 mg, 44%) was obtained as colorless needle crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:21])([F:20])[F:22])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1cccc(Cl)n1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3cccc(Cl)n3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 6-chloro-2-pyridinol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 226.4-227.4° C. 1H NMR (acetone-d6 /300 MHz) 7.99 (m, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 7.30 (d, 1H, J=7.7 Hz), 7.16 (d, 1H, J=8.0 Hz), 7.10 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.3 (d, J=7.2 Hz). FABLRMS m/z 404 (M-H). ESHRMS m/z 405.9853 (M+H, Calc'd 405.9861). Anal. Calc'd for C16H8Cl2F3NO4 : C, 47.32; H, 1.99; N, 3.45; Cl, 17.46. Found: C, 47.26; H, 1.93; N, 3.35; Cl, 17.19.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:46])[C@@H:15]([NH:28]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].N1CCOCC1>CN(C=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:46])[C@@H:15]([NH2:28])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCCCOCc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a solution of 650 mg (S)-4-[6-Benzyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoyl]-piperazine-1-carboxylic acid butyl ester in 3.6 ml DMF were added at room temperature 0.91 ml morpholine. After stirring for 2 h the reaction mixture was evaporated and the crude product thus obtained used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[NH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>CO.O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1n[nH]c2ccc(C(=O)OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNC(=O)c1n[nH]c2ccc(C(=O)O)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of methyl 3-(methylcarbamoyl)-1H-indazole-5-carboxylate (400 mg, 1.7 mmol) in methanol (10 mL) and water (10 mL), was added lithium hydroxide monohydrate (0.36 g, 8.5 mmol). The reaction was heated to 60° C. and was stirred overnight. The methanol was removed under reduced pressure and the remaining residue was acidified to pH=4 with 1 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (350 mg, 94%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ): 13.99 (s, 1 H), 8.85 (s, 1 H), 8.47-8.48 (m, 1 H), 7.94-7.96 (m, 1 H), 7.65-7.68 (m, 1 H), 2.82 (d, J=4.4 Hz, 3 H).
Reaction SMILES: [S:1]=[P:2]1(Cl)[NH:6][CH2:5][CH:4]([CH3:7])[O:3]1.C1(C)C=CC=CC=1.[CH3:16][CH2:17][O-:18].[Na+]>C(O)C>[S:1]=[P:2]1([O:18][CH2:17][CH3:16])[NH:6][CH2:5][CH:4]([CH3:7])[O:3]1
Reactant: CC1CNP(=S)(Cl)O1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOP1(=S)NCC(C)O1
Reaction time: 2 h
Yield: 82.8 %

Procedure:
18 g (0.1 mol) of 2-thioxo-2-chloro-5-methyl-1,3,2-oxazaphospholane were initially introduced into 100 ml of toluene, and a solution of 0.1 mol of sodium ethylate in ethanol was added dropwise at an internal temperature of between 10° and 15° C. The reaction mixture was stirred for a further two hours, washed with water, dried and filtered and the filtrate was distilled. 15 g (83% of theory) of 2-thioxo-2-ethoxy-5-methyl-1,3,2-oxazaphospholane were obtained as a colorless liquid of boiling point 78° C./0.01 mbar and of refractive index nD23 : 1.5041.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=O)[NH:4][N:3]=1.S([O-])(O)=O.[Na+].O.[CH3:15][C:16]1([CH3:29])[C:25]2[C:20](=[CH:21][C:22]([NH2:27])=[C:23]([NH2:26])[CH:24]=2)[NH:19][C:18](=[O:28])[CH2:17]1>C(O)C>[CH3:15][C:16]1([CH3:29])[C:25]2[CH:24]=[C:23]3[NH:26][C:7]([C:5]4[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=4)=[N:27][C:22]3=[CH:21][C:20]=2[NH:19][C:18](=[O:28])[CH2:17]1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Reactant: Cc1cc(C=O)[nH]n1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2nc3cc4c(cc3[nH]2)C(C)(C)CC(=O)N4)[nH]n1

Procedure:
1.5 g. (13.6 mmole) 3-methyl-1H-pyrazole-5-aldehyde was stirred with 4.5 g. sodium hydrogen sulphite in 9 ml. water for 3 hours at 60° C. The evaporation residue was stirred with 2.79 g. (13.6 mmole) 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2-one and 40 ml. ethanol for 3 hours at 60° C. while passing through air. Half of the ethanol was distilled off, water was added and the residue was filtered off with suction and recrystallized from ethyl acetate/methanol to give 3.3 g. (82.5% of theory) of the title compound; m.p. 242°-245° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[C:14]([CH:22]2[CH:31]3[CH2:32][CH:33]=[CH:34][CH:30]3[C:29]3[CH:28]=[C:27]([C:35](=[O:37])[CH3:36])[CH:26]=[CH:25][C:24]=3[NH:23]2)=[CH:15][C:16]2[O:20][CH2:19][O:18][C:17]=2[CH:21]=1)(C)C.O>CO>[C:12]([C:13]1[C:14]([CH:22]2[CH:31]3[CH2:32][CH:33]=[CH:34][CH:30]3[C:29]3[CH:28]=[C:27]([C:35](=[O:37])[CH3:36])[CH:26]=[CH:25][C:24]=3[NH:23]2)=[CH:15][C:16]2[O:20][CH2:19][O:18][C:17]=2[CH:21]=1)#[CH:11]
Reactant: CC(=O)c1ccc2c(c1)C1C=CCC1C(c1cc3c(cc1C#C[Si](C)(C)C)OCO3)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1cc2c(cc1C1Nc3ccc(C(C)=O)cc3C3C=CCC31)OCO2
Reaction time: 2 h
Yield: 74.6 %

Procedure:
Potassium carbonate (0.058 g, 0.42 mmol) was added to the 1-[4-(6-trimethylsilanylethynyl-benzo[1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-yl]-ethanone (0.090 g, 0.21 mmol) in methanol (4 mL) and stirred for 2 hr. The reaction mixture poured into water (25 mL) and the product was extracted with chloroform (3×5 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 10% EtOAc/Hexanes to give the product as a colorless solid (0.056 g, 75%)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[N:32][NH:33]3)O1>>[NH:33]1[C:34]2[C:30](=[C:29]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[S:10][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][C:6]=4[N:7]=3)[CH:37]=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC(=O)Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
The crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)acetamide (46 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 24.2 mg of 163. MS (Q1) 395 (M)+
Reaction SMILES: [NH3:1].[CH2:2]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][C:10]=2[F:19])=[C:6]([O:22][CH3:23])[CH:5]=1)[CH3:3]>C1COCC1.C(OCC)(=O)C>[CH2:2]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:1])(=[O:17])=[O:16])=[CH:11][C:10]=2[F:19])=[C:6]([O:22][CH3:23])[CH:5]=1)[CH3:3]
Reactant: CCc1ccc(Oc2ccc(S(=O)(=O)Cl)cc2F)c(OC)c1
Reactant: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(S(N)(=O)=O)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
Conc. NH3 (5.0 mmol; 0.28 mL) was slowly added to a solution of 4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzenesulfonyl chloride (1.0 mmol; 344 mg) in THF (5 mL), under argon at 0° C. The reaction was stirred overnight with slow warming to room temperature. Diluted with ethyl acetate (5 mL), the mixture was washed with HCl (1N), and sat. NH4Cl. The organic phase was dried over MgSO4, concentrated. The residue was purified by chromatography (dichloromethane/ethyl acetate gradient) to yield the title compound as an off-white solid (108 mg; 0.33 mmol; 33%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C@@H:3]2[CH2:7][CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C@@H:2]12.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([N:4]1[CH2:5][CH2:6][O:1][C@@H:2]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][C@@H:3]12)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)OCC[C@H]1NCCO[C@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCO[C@@H]2c3ccccc3OCC[C@H]21
Reaction time: 8 h

Procedure:
To a stirred solution of 2.41 g of trans-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine, prepared in accordance with Example 2, and 3.5 ml of triethylamine dissolved in 50 ml of methylene chloride is added dropwise a solution of 0.85 ml of acetyl chloride dissolved in 25 ml of methylene chloride. The mixture is stirred overnight, washed with a dilute hydrochloric acid solution and dried over anhydrous magnesium sulfate. The volatiles are removed by evaporation leaving an oil which yields the compound trans-4-acetyl-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine having a mp. of 97°-98° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCOCC1
Reactant: Nc1cccc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Brc1cccc(NC2CCOCC2)c1
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To a solution of 3-Bromo-phenylamine (0.54 ml, 5 mmol) and tetrahydro-4H-pyran-4-one (0.5 g, 5 mmol) in DCE (20 ml) was added sodium triacetoxyborohydride (1.48 g, 7 mmol) and acetic acid (0.3 g). The mixture was stirred for 18 h before being quenched with 1N NaOH (10 ml). The mixture was partitioned between Et2O and H2O, the aqueous layer further extracted with Et2O, the organics combined, dried (MgSO4), filtered and the solvent removed in vacuo to give a colourless liquid. Purification using silica column chromatography (0-80% EtOAc/hexane gradient) afforded the title compound as a white solid (0.81 g). MS: [M+H]+=256,258
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[C:14](=O)[CH3:15])C.[CH3:18][NH2:19]>CO.[O-]S([O-])(=O)=O.[Mg+2].ClCCl>[CH3:18][N:19]1[C:14](=[CH2:15])[C:6]2[C:5](=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:8][CH:7]=2)[C:4]1=[O:3]
Reactant: CCOC(=O)c1c(C(C)=O)cccc1[N+](=O)[O-]
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: C=C1c2cccc([N+](=O)[O-])c2C(=O)N1C
Reaction time: 0.25 h

Procedure:
Ethyl-2-acetyl-6-nitrobenzoate (11.12 g) is suspended in a mixture of MeOH (70 mL) and MgSO4. Methylamine (2 molar in THF, 28.13 mL) is added dropwise and the solution is stirred for 15 min at this temperature. Then it is preheated to 70° C. for 18 h. The solvent is eliminated in vacuo, the residue is taken up in dichloromethane (100 mL), washed with sodium chloride solution (10%) dried on magnesium sulphate, filtered off from the desiccant and the solvent is eliminated in vacuo. For purification it is recrystallised from toluene (250 mL).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([CH3:26])[C:9]([CH2:21][O:22]C(=O)C)=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>CCO.O>[OH:22][CH2:21][C:9]1[C:8]([CH3:26])=[C:7]2[C:12](=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C:10]=1[CH3:20])[NH:4][CH2:5][CH2:6]2
Reactant: CC(=O)OCc1c(C)c2c(c(NC(=O)C(C)(C)C)c1C)N(C(C)=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(CO)c(C)c(NC(=O)C(C)(C)C)c2c1CCN2
Yield: 52.2 %

Procedure:
N-(1-Acetyl-5-acetoxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (7.5 g) was dissolved in EtOH (70 ml) and a solution of NaOH (8.3 g) in water (20 ml) was added, which was followed by refluxing for 10 hr. EtoH was evaporated under reduced pressure and CHCl3 (200 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate and CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=1/0-10/1) to give 3.0 g of N-(5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8](=[O:17])[C:7]1=[O:18].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[O:17]=[C:8]1[C:7](=[O:18])[NH:6][CH2:11][CH2:10][N:9]1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CN1CCN(Cc2ccc(OC)cc2OC)C(=O)C1=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN1CCNC(=O)C1=O
Yield: 77.4 %

Procedure:
A mixture of 10.5 g of methyl [4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin-1-yl]acetate, 42 ml of trifluoroacetic acid and 21 ml of anisole was refluxed for 4 hours. The reaction mixture was cooled to room-temperature and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent; chloroform:methanol=6:1) to obtain 4.5 g of methyl (2,3-dioxopiperazin-1-yl)acetate as colorless crystals.
Reaction SMILES: BrN1[C:6](=O)[CH2:5][CH2:4][C:3]1=[O:8].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=C(C)C=C[C:31]=1[F:37]>C(Cl)(Cl)(Cl)Cl>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[C:4]([CH:3]=[O:8])[CH:5]=[CH:6][C:31]=1[F:37]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)ccc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(C=O)ccc1F
Temperature: 25 °C
Yield: 19.9 %

Procedure:
Add N-bromosuccinimide (2.46 g, 13.86 mmol) and benzoyl peroxide (0.152 g, 0.630 mmol) to a solution of 2-fluoro-5-methyl-benzoic acid methyl ester (1.06 g, 6.30 mmol) in carbon tetrachloride (50 mL). Heat the mixture at reflux for 4 h. Cool the mixture to room temperature and wash with saturated aqueous sodium bicarbonate solution (10 mL) and brine (10 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Dissolve the resulting residue in dimethylsulfoxide (30 mL) and heat at reflux for 16 h. Cool the mixture to room temperature and dilute with water (100 mL) and ethyl acetate (100 mL). Extract the aqueous layer with ethyl acetate (3×100 mL). Wash the combined organic layers with water (3×100 mL), followed by brine (100 mL). Dry the organic layer over anhydrous sodium sulfate, filter and concentrate. Purify the residue by chromatography over silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as a tan solid (0.228 g, 20%). 1H NMR (CDCl3, 300 MHz) δ 3.89 (s, 3H), 7.31-7.44 (m, 1H), 8.05-8.12 (m, 1H), 8.44-8.53 (m, 1H), 10.00 (s, 1H); TLC Rf=0.65 (3:1 Hexanes/Ethyl Acetate).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].Cl[CH2:13][CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:15][CH:14]=[CH2:13])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: C=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C(C)(C)C)cc1

Procedure:
A mixture of 45 g 4-(1,1-dimethylethyl)phenol, 30 g 3-chloro-1-propene, 50 g anhydrous potassium carbonate and 250 ml 2-butanone was refluxed for 15 hours, after which time the solvent was removed in a rotary evaporator. Water was added to dissolve the potassium salts and the product extracted twice with ether. The ether layer was dried, removed, and the product distilled. The 50 grams of 1-(1,1-dimethylethyl)-4-(2-propenyloxy)benzene was found to boil at 70°-75° C. at 0.2 mm Hg, listed in Table 1 as compound I-4)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:23][OH:24]>C(O)(C)C>[OH:24][NH:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(NO)nc3ccccc23)cc1
Temperature: 130 °C
Yield: 40.5 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and hydroxylamine hydrochloride (6.7 mg, 0.10 mmol) in isopropanol was heated by microwave at 130° C. for 20 min. The solvent was evaporated under reduced pressure. The product was isolated by preparative TLC as white solid (6 mg, 40%) using acetone:hexane (1:1) as eluent. 1H NMR (CDCl3): 7.65 (d, J=8.4 Hz, 1H), 7.47 (ddd, J=8.4, 6.9 and 1.8 Hz, 1H), 7.08 (d, J=8.7 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.88-6.75 (m, 2H), 3.86 (s, 3H), 3.48 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:14][C:15]([F:35])([F:34])[C:16]1[N:17]=[C:18]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:19]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:20]=1.C(N(CC)CC)C>CN1CCCC1=O>[CH3:12][C@H:11]1[C:3]2[C:2]([N:31]3[CH2:30][CH2:29][CH:28]([C:18]4[N:19]([CH2:21][CH2:22][N:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[CH:20]=[C:16]([C:15]([F:34])([F:35])[F:14])[N:17]=4)[CH2:33][CH2:32]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9](=[O:13])[CH2:10]1
Reactant: FC(F)(F)c1cn(CCN2CCCC2)c(C2CCNCC2)n1
Reactant: C[C@@H]1CC(=O)Nc2ncnc(Cl)c21
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: C[C@@H]1CC(=O)Nc2ncnc(N3CCC(c4nc(C(F)(F)F)cn4CCN4CCCC4)CC3)c21
Temperature: 130 °C
Yield: 70.2 %

Procedure:
Add (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (28.30 g, 143.20 mmol), 4-(4-trifluoromethyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine (49.83 g, 1.10 eq) and triethylamine (43.47 g, 3.0 eq) in N-methylpyrrolidinone (86 mL). Heat the reaction mixture to 130° C. Cool the reaction mixture to room temperature after 2 hours. Pour the reaction mixture over ice/water (500 mL) with stirring. Extract with ethyl acetate (4×200 mL). Wash the organics with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate and concentrate in vacuo. Suspend the solid in hexanes and stir for 30 minutes. Filter and dry under vacuum. Add 75% methyl tert-butyl ether in hexanes (800 mL) and heat to reflux. Cool the mixture to room temperature. Filter, wash with 75% methyl tert-butyl ether in hexanes (200 mL), and dry under vacuum at 40° C. to give the title compound (48.00 g, 70%). MS (ES) m/z=478 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:13]([CH2:14][CH3:15])[CH2:11][CH3:12])[C:5]#[N:6]
Reactant: CCNCC
Reactant: N#Cc1ccc(F)c(Cl)c1
Solvent: O
Product: CCN(CC)c1ccc(C#N)cc1Cl
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A sealed tube with 3-chloro-4-fluorobenzonitrile (0.366 g, 2.4 mmol) and diethylamine (0.6 mL, 5.8 mmol) was heated to 100° C. for 8 hours. The reaction was allowed to cool to room temperature and water (5 mL) was added. The solution was extracted with dichloromethane (2×5 mL), dried over magnesium sulfate and concentrated in vacuo to afford 3-chloro-4-diethylaminobenzonitrile as an oil (0.38 g). This was reacted as described in Methods A-C (Examples 1-3) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.89 (dd, 1H), 8.26 (d, 1H), 8.11 (ddd, 1H), 7.97 (dd, 2.2 Hz, 1H), 7.53 (d, 1H), 7.27 (dd, 1H), 7.15 (d, 1H), 3.86 (b, 2H), 3.20 (q, 4H), 3.03 (t, 2H), 1.91 (quint, 2H), 1.08 (t, 6H); MS (m/e) calculated for C21H26ClN5 383, found 384.3 (M+H).
Reaction SMILES: [C:1]([C:4]([CH2:8][CH3:9])([CH3:7])[CH2:5][CH3:6])(=[O:3])[CH3:2].[O:10]=[CH:11][C:12]([Cl:15])([Cl:14])[Cl:13]>C(O)(=O)C>[Cl:13][C:12]([Cl:15])([Cl:14])[CH:11]([OH:10])[CH2:2][C:1](=[O:3])[C:4]([CH2:8][CH3:9])([CH3:7])[CH2:5][CH3:6]
Reactant: CCC(C)(CC)C(C)=O
Reactant: O=CC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCC(C)(CC)C(=O)CC(O)C(Cl)(Cl)Cl

Procedure:
A 30 g. portion of the product of Example 1, 1-acetyl-1-ethyl-1-methylpropane, was combined with 38.4 g. of chloral and 36 ml. of acetic acid, and was stirred under reflux, under nitrogen, for 4 days. The solvent was then carefully removed under vacuum to obtain 39 g. of the crude product as an amber, viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]1.[O:20]=[C:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25]([C:31](O)=[O:32])=[CH:26][CH:27]=2)[NH:22]1>>[O:20]=[C:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25]([C:31]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][N:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:14][CH2:13]3)=[O:32])=[CH:26][CH:27]=2)[NH:22]1
Reactant: COc1ccccc1N1CCN(CCCCO)CC1
Reactant: O=C1CCc2ccc(C(=O)O)cc2N1
Product: COc1ccccc1N1CCN(CCCCOC(=O)c2ccc3c(c2)NC(=O)CC3)CC1

Procedure:
4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate (23c) (Scheme 4) was synthesized from the compound 21c and the carboxylic acid 22 according to the protocol described for the compound 23a (Example 35). Off-white solid, 0.085 g (13%). 1H NMR (400 MHz, CDCl3): δ 1.66-1.72 (m, 2H); 1.78-1.84 (m, 2H); 2.47 (t, J=7.6 Hz, 2H); 2.63-2.67 (m, 6H); 3.01 (t, J=7.2 Hz, 2H); 3.09 (broad s, 4H); 3.84 (s, 3H); 4.34 (t, J=6.8 Hz, 2H); 6.83-7.00 (m, 4H); 7.21 (d, J=8.0 Hz, 1H); 7.47 (s, 1H); 7.66 (dd, J=1.6, 8.0 Hz, 1H); 8.61 (broad s, 1H). MS (ESI): m/z=438.20 (M+H+).