Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18](Cl)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10].[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][OH:35])=[CH:30][CH:29]=1.CC(C)([O-])C.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CN1CCCC1=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:35][CH2:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][O:26][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)=[CH:33][CH:32]=2)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: OCc1ccc(COC2CCCCO2)cc1
Reactant: O=S(=O)(Nc1nccnc1Cl)c1cccc(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=S(=O)(Nc1nccnc1OCc1ccc(COC2CCCCO2)cc1)c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
2,3-Dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28a) (0.1 g), [4-(tetrahydro-2-pyranyloxymethyl)phenyl]methanol (0.27 g) and potassium tert-butoxide (2 mL of a 1M solution in tetrahydrofuran) in N-methylpyrrolidinone (1 mL) was stirred at 50° C. After 2 h, aqueous citric acid was added and the mixture extracted with ethyl acetate. The organic solution was washed with water and brine and evaporated to dryness. Used directly.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[Cl:11][C:12]1(Cl)[CH2:17][O:16][CH2:15][CH2:14][O:13]1>>[Cl:11][CH2:12][CH2:17][O:16][CH2:15][C:14]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:13]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: ClC1(Cl)COCCO1
Product: O=C(COCCCl)Nc1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 1.12 g (8.12 mmol) of 3-nitroaniline and 1.11 g of 2-chlorodioxene (contains 6% of 2,2-dichlorodioxane) is heated at 80° C. with stirring for 24 hours, giving 2.1 g of 2-(2-chloroethoxy)-N-(3-nitrophenyl)acetamide as brownish oil. ESI 259.
Reaction SMILES: [F:1][CH:2]([F:11])[C@@H:3]([C@H:5]1[CH2:9][O:8][C:7](=[O:10])[NH:6]1)[CH3:4].[F:12][C:13]1[N:18]=[C:17](F)[CH:16]=[CH:15][N:14]=1.[H-].[Na+]>CN(C=O)C.C(OC(=O)C)C.[Cl-].[Na+].O.O>[F:11][CH:2]([F:1])[C@@H:3]([C@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:15]1[CH:16]=[CH:17][N:18]=[C:13]([F:12])[N:14]=1)[CH3:4]
Reactant: C[C@@H](C(F)F)[C@H]1COC(=O)N1
Reactant: Fc1ccnc(F)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](C(F)F)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a solution of (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (223 mg, 1.35 mmol) and 2,4-difluoropyrimidine (157 mg, 1.35 mmol) in DMF (4.09 mL) was added sodium hydride (60% wt.; 70.2 mg) in three portions at <0° C. (sodium chloride/ice). After the first portion of sodium hydride the mixture was stirred for ˜5 min. The remaining two portions of sodium hydride were added over ˜5 min and stirring was continued for 30 min. The mixture was diluted with ethylacetate (10 mL), stirred for 5 min and further slowly diluted with brine/water (1/1; 10 mL). The mixture was allowed to warm to 5° C. and poured into a mixture of brine/water (1/1; 20 mL) and ethylacetate (20 mL). The aqueous layer was separated and extracted with ethylacetate (25 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane] to provide (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (207 mg) as a white solid.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[NH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24]>O>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:18]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc2ccccc2n1CCCCCl

Procedure:
0.30 g of sodium hydride (60% oily) was added to a dimethylformamide (20 ml) solution of 1.0 g of 1H-quinolin-2-one while being stirred under ice-cooling and stirred at room temperature for 0.5 hour, and after that 1.6 ml of 1-bromo-4-chlorobutane was added and stirred at room temperature for 14 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate and, after washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), and 1.02 g of 1-(4-chlorobutyl)-1H-quinolin-2-one was obtained in the form of colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](F)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[NH2:33][C@H:34]([CH2:38][CH3:39])[C:35]([OH:37])=[O:36]>CN1C(=O)CCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)Cl>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([NH:33][C@H:34]([CH2:38][CH3:39])[C:35]([OH:37])=[O:36])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(F)nc21
Reactant: CC[C@@H](N)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC[C@@H](Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1)C(=O)O
Temperature: 160 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)-amine (151 mg, 0.5 mmol) was dissolved in NMP (5 mL) and DBU (1.5 mL, 10 mmol). (R)-(−)-2-Aminobutyric acid (99% ee/GLC; 1.03 g, 10 mmol) was then added and the mixture was stirred under N2 at 160° C. for 1 h. After cooling, the mixture was diluted with citric acid (10% aq solution) and CH2Cl2 (25 mL each). The phases were separated and the organic fraction was extracted with brine (2×10 mL), dried over MgSO4, filtered, and evaporated. The residue was redissolved in MeCN and was fractionated by preparative RP-HPLC (Vydac 218TP1022, 9 mL/min, 22.5-32.5% MeCN in H2O containing 0.1% CF3COOH over 40 min). Appropriate fractions were pooled and lyophilised to afford the pure title compound (137 mg, 74.4%) as an amorphous off-white solid. Anal. RP-HPLC (Vydac 218TP54, 1 mL/min): tR=16.04 min (0-60% MeCN), 15.95 min (22.5-32.5% MeCN in H2O containing 0.1% CF3COOH over 20 min), purity: >98% (λ=214 nm). 1H-NMR (d6-DMSO, 300 MHz) δ: 0.95 (t, J=7.3 Hz, 3H, CH2CH3); 1.51 (d, J=6.7 Hz, 6H, CH(CH3)2); 1.78 (m, J=7.3 Hz, 2H, CH2CH3); 4.27 (m, 1H, CHCH2); 4.64 (hept., J=6.7 Hz, 1H, CH(CH3)2); 4.69 (m, 2H, CH2Ph); 7.25-7.41 (m, 6H, ArH). DE-MALDI-TOF MS (α-cyano-hydroxy-cinnamic acid matrix): [M+H]+=369.41. FAB-MS: [M+H]+=369.2033 (C19H25N6O2 requires 369.2039).
Reaction SMILES: [CH2:1]([C:10]([OH:12])=[O:11])[CH:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH:13]1(O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1.CCCCCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:13]1([O:5][C:4]([CH2:3][CH:2]([C:7]([O:9][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:8])[CH2:1][C:10]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:11])=[O:6])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)CC(CC(=O)O)C(=O)O
Reactant: OC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: O=C(CC(CC(=O)OC1CCCCC1)C(=O)OC1CCCCC1)OC1CCCCC1
Yield: 83.4 %

Procedure:
A mixture of 1,2,3-propanetricarboxylic acid (25 g), cyclohexanol (55 g), and p-toluenesulfonic acid (100 mg) in toluene (500 mL) was refluxed for 2 days and water removed from the reaction mixture. After reaction was complete, solvent was removed in vacuuo to yield a viscous oil. The crude material was redissolved in heptane and passed through a pad of silica gel to obtain 1,2,3-propanetricarboxylic acid tricyclohexyl ester (50 g) as a pale yellow oil.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH:12]=[CH:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O.O.[CH2:23]([OH:26])[CH2:24][OH:25]>>[C:1]([N:9]1[CH2:13][C@@H:12]([O:25][CH2:24][CH2:23][OH:26])[C@H:11]([Br:14])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=C(c1ccccc1)N1CC=CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Product: O=C(c1ccccc1)N1C[C@@H](Br)[C@H](OCCO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
95 g (0.55 mol) of 1-benzoyl-3-pyrroline are dissolved in 380 g of ethylene glycol, and 101 g (0.57 mol) of N-bromosuccinimide are added in 5 g portions over a period of 2 hours at room temperature. The mixture is then stirred overnight at room temperature and poured into water, followed by extraction with methylene chloride, drying over magnesium sulphate and concentration of the solution. The residue (188 g) was chromatographed with ethyl acetate on silica gel.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:34][C:30]1[CH:29]=[C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH3:27])[O:25][N:24]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Reactant: NCC(F)(F)F
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (119 mg, 94 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 2 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (122 mg, 99%) which was obtained as a white solid. MS: m/e=410.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:17][C:18](=[O:28])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN1C(=O)CCC1.O>[CH2:1]([O:17][C:18](=[O:28])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCCCCCCCl
Reactant: CCCCCCCCCCCCCCCCOC(=O)C=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCCCCCCOC(=O)C=Cc1ccc(OCCCCCCO)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
3-(4-Hydroxy-phenyl)-acrylic acid hexadecyl ester (4.8 g, 12.4 mmol) was dissolved in 100 ml of NMP. To this was added 6-chlorohexanol (2.19 g, 16 mmol), anhydrous potassium carbonate (1.7 g, 12 mmol) and a catalytic amount of potassium iodide. The reaction was stirred at 90° C. for 18 hours. Water was added to the cooled solution, which was subsequently extracted with 3×100 mls of ethyl acetate. The combined organics were washed with water (2×100 mls), water/brine (100 ml, 50:50) and brine solution and then dried over magnesium sulfate. The concentrated product was purified by silica gel chromatography eluting with 25% ethyl acetate in hexane to give 2.6 g white solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[CH2:9]([O:16][NH:17][C:18]([C@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[S:26]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([F:44])[CH:42]=3)[NH:37][CH:36]=2)[CH2:31][CH2:30]1)(=[O:28])=[O:27])=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:9]([O:16][N:17]([CH3:1])[C:18]([C@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[S:26]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([F:44])[CH:42]=3)[NH:37][CH:36]=2)[CH2:31][CH2:30]1)(=[O:28])=[O:27])=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(NOCc1ccccc1)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(OCc1ccccc1)C(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reaction time: 2 h
Yield: 71 %

Procedure:
Anhydrous potassium carbonate (736 mg, 5.33 mmol) and iodomethane (0.133 ml, 2.13 mmol) were added to a solution of N-benzyloxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (549 mg, 1.07 mmol) [prepared as described in Step 3 above] in dimethylformamide (11 ml) at RT. After 2 h, the reaction mixture was diluted with ethyl acetate (50 ml) and then washed with 0.1 M HCl, brine and dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed (PTLC, SiO2, 40% ethyl acetate/hexanes) to give N-benzyloxy-N-methyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (71%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:28]I>C1COCC1>[F:1][C:2]1[C:16]([CH2:17][N:18]([CH3:28])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1cc2c(cc1F)ncn2C1CCCCO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1cc2c(cc1F)ncn2C1CCCCO1)C(=O)OC(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a mixture of tert-butyl (5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-6-yl)methylcarbamate (200 mg, 0.57 mmol) in anhydrous THF (2 mL) cooled to −60° C. was added NaH (60% in mineral oil, 21.6 mg, 0.9 mmol). After stirring at −60° C. for 30 min, CH3I (127 mg, 0.9 mmol) was added, followed by stirring at RT overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (3:1) to afford tert-butyl (5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-6-yl)methyl(methyl)carbamate as white solid (170 mg, 97%). MS (ESI): m/z=364 [M+1]+.
Reaction SMILES: [C:1]([O:21][CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[N:25]([OH:30])[C:24]([CH3:32])([CH3:31])[CH2:23]1)(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)=[O:7].OO.[C:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>C(#N)C>[C:1]([O:21][CH:22]1[CH2:23][C:24]([CH3:32])([CH3:31])[N:25]([O:30][CH2:36][C:35]([CH3:38])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:37])[C:26]([CH3:29])([CH3:28])[CH2:27]1)(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH2:36][C:35]([CH3:38])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:37])[C:11]([CH3:19])([CH3:18])[CH2:10]1)=[O:7]
Reactant: CC1(C)CC(OC(=O)CCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CC(C)(C)c1ccccc1
Agent: OO
Solvent: CC#N
Product: CC(C)(CON1C(C)(C)CC(OC(=O)CCCCC(=O)OC2CC(C)(C)N(OCC(C)(C)c3ccccc3)C(C)(C)C2)CC1(C)C)c1ccccc1

Procedure:
The title compound is prepared from the reaction of bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) adipate, aqueous hydrogen peroxide, ferric chloride hexahydrate; acetonitrile, and tert-butylbenzene following a procedure similar to that of Example 6.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)cccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 59.3 %

Procedure:
A mixture of 2-amino-6-nitrobenzoic acid (11.9 g, 65.3 mmol), methyl p-toluenesulfonate (15.1 g, 81.1 mmol) and triethylamine (6.60 g, 65.3 mmol) in DMF (170 ml) was stirred under N2 at 60° for 18 hours. After removing DMF at 60° and 0.2 mm pressure, the residue was dissolved in ETOAc and washed with a saturated solution of NaHCO3 followed by a saturated aqueous solution of NaCl. The EtOAc extract was dried (Na2O4), filtered and concentrated under reduced pressure. Flash chromatography over silica gel and elution with 50% toluene-50% CHCl3 gave methyl 2-amino-6-nitrobenzoate (7.6 g, 59.4%), m.p. 105°-107°.
Reaction SMILES: [CH3:1][OH:2].[C:3]([OH:6])(=[O:5])[CH3:4]>>[C:3]([O:6][CH3:1])(=[O:5])[CH3:4].[CH:1]([O:5][CH3:3])=[O:2]
Reactant: CC(=O)O
Reactant: CO
Product: COC(C)=O
Product: COC=O

Procedure:
Next, 1 μl (2.47×10-5 mol) of methanol was introduced into the reactor at a temperature of 200° C. by using helium gas as a carrier (flow rate: 25 ml/min). Thus, 0.0001×10-5 mol of acetic acid, 0.003×10-5 mol of methyl acetate and 0.02×10-5 mol of methyl formate were formed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:7](=[O:20])[CH:6]=[C:5]2[CH3:21].[H-].[Na+].[CH3:24]O.Cl.[C:27](=O)([O:31]CC)[O:28]CC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:7](=[O:20])[CH:6]=[C:5]2[CH:21]([CH3:24])[C:27]([OH:31])=[O:28]
Reactant: Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccc(Cl)cc12
Reactant: CO
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C(=O)O)c1cc(=O)n(Cc2ccc(Cl)cc2)c2ccc(Cl)cc12
Yield: 43 %

Procedure:
6-Chloro-1-(4-chlorobenzyl)-1,2-dihydro-4-methyl-2-oxoquinoline (7.9 g.) was added to a suspension of sodium hydride (6.0 g., 60% w/w dispersion in oil, washed as in Example 1) in diethyl carbonate (100 ml.). The mixture was then stirred and heated under reflux for 3 hours. A small quantity of methanol was added to the cooled suspension to destroy any remaining sodium hydride, and the mixture was then poured into ether (1 l.) to give a solid which was collected and washed well with ether. This solid (16 g.) was suspended in dimethylformamide (40 ml.), and methyl iodide (30.0 g.) was added. The mixture was stirred at room temperature for 1 hour and then heated under reflux on the steam-bath for 1 hour. The mixture was cooled and poured into water (200 ml.) to give an oil which was extracted into ethyl acetate, washed three times with water, and, after drying over magnesium sulphate, was recovered by evaporation under reduced pressure. The residual oil (4.8 g.), which comprised diethyl α-[6-chloro-1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-yl]-α-methylmalonate, was dissolved in a mixture of ethanol (50 ml.) and aqueous 40% w/v sodium hydroxide (4ml.), and heated under reflux for 2 hours. The resultant suspension was poured into water (200ml.) to give a solution which was adjusted to pH 3 by addition of concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water, drained well, and recrystallised from aqueous ethanol to give α-[6-chloro-1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-yl]propionic acid, m.p. 192.5-193.5° C., (decomposition) in 43% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=2[C:10]([CH3:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:25][NH2:26])[CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([Cl:20])[N:14]=[CH:15][C:16]([C:17](=[O:19])[NH:26][CH2:25][CH:22]3[CH2:24][CH2:23]3)=[C:11]2[C:10]([CH3:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)O)c12
Reactant: NCC1CC1
Product: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)NCC3CC3)c12

Procedure:
Prepared in a similar manner to Example 11 (b) from 7-chloro-3-methyl-pyrrolo[2,3-c]pyridine-1,4-dicarboxylic acid 1-tert-butyl ester using cyclopropylmethylamine (167 μl) instead of morpholine to give the title compound as a pale brown foam (389 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26](C3CCCCO3)[N:25]=[CH:24]4)=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:26]1[C:27]2[C:23](=[CH:22][C:21]([CH2:20][CH2:19][C:16]3[CH:17]=[N:18][C:13]([NH:12][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([F:11])[F:10])=[C:2]([Cl:1])[CH:3]=4)=[N:14][CH:15]=3)=[CH:29][CH:28]=2)[CH:24]=[N:25]1
Reactant: FC(F)Oc1ccc(Nc2ncc(CCc3ccc4c(cnn4C4CCCCO4)c3)cn2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)Oc1ccc(Nc2ncc(CCc3ccc4[nH]ncc4c3)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To N-(3-chloro-4-(difluoromethoxy)phenyl)-5-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)pyrimidin-2-amine (0.075 g, 0.150 mmol) in DCM (5 mL) was added TFA (0.116 mL, 1.500 mmol) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated and the crude product purified by preparative HPLC on a Symmetry C18 column (19×300 mm, 7 μm) using 0-100% mobile phase B (ACN) in mobile phase A (10 mM ammonium acetate) to give 5-(2-(1H-indazol-5-yl)ethyl)-N-(3-chloro-4-(difluoromethoxy)phenyl)pyrimidin-2-amine as an off white solid (0.012 g, 19% yield). 1HNMR 400 MHz, DMSO-d6: δ 2.85 (t, J=15.60 Hz, 2H), 2.99 (t, J=14.80 Hz, 2H), 6.95-7.31 (m, 3H), 7.46 (d, J=8.40 Hz, 1H), 7.54 (s, 1H), 7.65-7.68 (m, 1H), 7.98 (s, 1H), 8.08 (d, J=2.80 Hz, 1H), 8.36 (s, 2H), 9.76 (s, 1H), 12.95 (s, 1H). LCMS (ES-API), RT: 2.15 min, m/z 414 (M−H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH2:21](I)[CH3:22]>>[F:20][C:2]([F:19])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:21][CH3:22])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: CCI
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Product: CCOC(=O)c1c(OCC)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 77 %

Procedure:
This material was prepared following the procedure of Example 4 in 77% yield from product of Example 2 and ethyl iodide as a white solid; mp 57°-59° C.