Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7]1.[CH3:18][N:19]1[C:24]([CH3:26])([CH3:25])[CH2:23]C(O)[CH2:21][C:20]1([CH3:29])[CH3:28].[NH2-].[Li+].CO>CCCCCCC>[CH3:18][N:19]1[C:24]([CH3:26])([CH3:25])[CH2:23][CH:1]([O:2][C:3](=[O:17])[CH2:4][NH:5][CH:6]2[CH2:7][C:8]([CH3:16])([CH3:15])[N:9]([CH3:14])[C:10]([CH3:13])([CH3:12])[CH2:11]2)[CH2:21][C:20]1([CH3:29])[CH3:28]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: COC(=O)CNC1CC(C)(C)N(C)C(C)(C)C1
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCCC
Solvent: CO
Product: CN1C(C)(C)CC(NCC(=O)OC2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Yield: 78.6 %

Procedure:
To the same flask as used in Example 1 were added 24.2 g (0.1 mole) of N-(1,2,2,6,6-pentamethyl-4-piperidinyl)glycine methyl ester, 18.7 g (0.11 mole) of 1,2,2,6,6-pentamethyl-4-piperidinol, 0.23 g of lithium amide and 100 g of heptane. The temperature was raised with stirring, and reaction was carried out at 98° to 105° C. for 6 hours, during which methanol was removed from the reaction system by means of the Deanstark trap. After completion of the reaction, water was added to the reaction solution to dissolve the product in the heptane layer. The heptane layer was separated, and heptane in the layer was removed by distillation to obtain 30 g of N-(1,2,2,6,6-pentamethyl-4-piperidinyl)glycine(1,2,2,6,6-pentamethyl-4-piperidinyl)ester as a pale yellow liquid. Yield, 79% based on N-(1,2,2,6,6-pentamethyl-4-piperidinyl)glycine methyl ester. A pale yellow oily product was obtained by the subsequent column chromatographic separation.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[C@@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([NH:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[C@@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=[O:42])[CH3:41]
Reactant: Cc1cccc(-c2c(F)cccc2[C@H](OCCN)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a round-bottom flask were added (R)-tert-butyl 2-((S)-(2-aminoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (280 mg, 0.63 mmol), triethylamine (0.19 mL, 1.89 mmol) and anhydrous CH2Cl2 (15 mL). The mixture was cooled in an ice bath and a solution of acetyl chloride (49.2 mg, 0.045 mL, 0.63 mmol) was added. The reaction mixture was allowed to warm slowly to rt and stirred until the reaction was complete (ca 1˜2 h). The solvent was removed by evaporation, and the residue was purified by preparative tlc to give (R)-tert-butyl 2-((S)-(2-acetamidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (202 mg, 66%). 1H NMR (300 MHz, CDCl3): δ=1.45 (s, 9 H), 1.93 (s, 3 H), 2.38 (s, 3 H), 2.87˜3.2 (m, 6 H), 3.32˜3.92 (m, 5 H), 4.28 (d, 1 H), 7.01˜7.25 (m, 3 H), 7.28˜7.37 (m, 4 H), 9.41-9.54 (s, 1 H). MS (E/Z): 487 (M+H+)
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:26]([O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32])[CH3:27]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[O:28][CH2:26][CH3:27])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccccc1C(=O)N[C@@H]1CCc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.43 mmol) and triethylamine (90 μL, 0.65 mmol) in methylene chloride (15 mL) was added dropwise 2-ethoxybenzoyl chloride (84 mg, 0.45 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 110 mg (64%) of the title compound as white solid: [α]21D −36° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 393 (15, M+). The hydrochloride salt was precipitated out of diethyl ether and 110 mg (59% yield) of white crystals were isolated; mp sinters at 176° C.
Reaction SMILES: ClS(C1C=CC(C(O)=O)=CC=1)(=O)=O.CC1OC(C)CNC1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.[CH3:36][CH:37]1[CH2:42][N:41]([S:43]([C:46]2[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][CH:47]=2)(=[O:45])=[O:44])[CH2:40][CH:39]([CH3:55])[O:38]1>>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:50](=[O:51])[C:49]2[CH:53]=[CH:54][C:46]([S:43]([N:41]3[CH2:40][CH:39]([CH3:55])[O:38][CH:37]([CH3:36])[CH2:42]3)(=[O:45])=[O:44])=[CH:47][CH:48]=2)=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC1CN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC(C)O1
Agent: CC1CNCC(C)O1
Agent: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: CC1CN(S(=O)(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC(C)O1

Procedure:
1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 616 μL of 2,6-dimethylmorpholine via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 120 mg of 4-(2,6-dimethylmorpholinosulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2,6-dimethylmorpholinosulfonyl)benzamide. MS (Q1) 486.3 (M)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Cl)nc(N2CCCCC2)c1
Yield: 99.6 %

Procedure:
A solution of methyl 2,6-dichloroisonicotinate (1 g, 4.85 mmol), piperidine (0.61 g, 7.28 mmol), K2CO3 (1.38 g, 9.7 mmol) in acetonitrile (20 mL) was heated at 90° C. for 20 h. After completion of reaction, reaction mass was filtered, filtrate concentrated and purified by column to obtain pure methyl 2-chloro-6-(piperidin-1-yl)isonicotinate (1.23 g, 90%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22]([O:24][C:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([CH2:37]O)[CH:35]=2)[C@H:30]([N:41]([CH2:46][C:47]2[CH:52]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:50]=[C:49]([C:57]([F:60])([F:59])[F:58])[CH:48]=2)[C:42]([O:44][CH3:45])=[O:43])[CH2:29][C@@H:28]1[CH3:61])=[O:26])[CH3:23]>ClCCl.C(Cl)(Cl)Cl>[CH2:22]([O:24][C:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([CH2:37][Br:20])[CH:35]=2)[C@H:30]([N:41]([CH2:46][C:47]2[CH:52]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:50]=[C:49]([C:57]([F:60])([F:59])[F:58])[CH:48]=2)[C:42]([O:44][CH3:45])=[O:43])[CH2:29][C@@H:28]1[CH3:61])=[O:26])[CH3:23]
Reactant: BrBr
Reactant: CCOC(=O)N1c2cc(CO)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1c2cc(CBr)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 71.5 %

Procedure:
To a solution of triphenylphosphine (0.457 g, 1.74 mmol) in anhydrous dichloromethane (15 mL) at 0° C. was slowly added bromine (84 μL, 1.6 mmol). After the reaction was stirred at 0° C. for 20 min, a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-hydroxymethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 85) (0.630 g, 1.09 mmol) in dichloromethane (15 ml) was added. The reaction was stirred at 0° C. for 20 min, then at room temperature for 3 h. The reaction mixture was then diluted with chloroform and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 10-15% ethyl acetate/hexanes as eluent afforded the title product (0.500 g, 72%): MS m/z 642.1 (M+ +1); 1H NMR (CDCl3) δ 1.15 (d, 3H), 1.3 (t, 3H), 3.8 (s, 3H), 3.85 (s, 3H), 6.4 (s, 1H), 7.4 (s, 1H), 7.7 br, 2H), 7.8 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:14])[CH:11]=2)[NH:6]1)=[O:4].[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:27][CH3:28])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N=C=NC(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:14])[CH:11]=2)[N:6]1[C:24](=[O:25])[C@@H:23]([NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH3:28])=[O:4]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C1Cc2cc(Cl)ccc2N1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(Cl)cc2C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-chloroindoline-2(R/S)-carboxylic acid methyl ester (1.2 g, 5.69 mmol) and N-t-butoxycarbonyl-2(S)-aminobutyric acid (1.27 g, 6.25 mmol) dissolved in dried dichloromethane (10 ml) under nitrogen at 10° C., was added diisopropylcarbodiimide (0.98 ml, 6.30 mmol). The mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was evaporated under vacuum to afford a brown solid which was purified by column chromatography on silica gel using 20:1 dichloromethane: diethyl ether as eluent. A white foam was obtained which was the mixture of two diastereomers. The two diastereomers were separated by column chromatography on silica gel using 7:3 petroleum spirit:diethyl ether as eluent, and the pure (S,S) form was obtained as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[C:13](O)(=O)CC(O)=O.Cl.O>C(N(CC)CC)C>[C:5]([C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([F:1])[C:3]=1[C:8]([OH:7])=[O:9])(=[O:6])[CH3:13]
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1cccc(F)c1C(=O)O

Procedure:
9 g of 3-fluorophthalic anhydride and 6.8 g of malonic acid are mixed in 80 ml of triethylamine and heated in an oil bath at 71-72° until evolution of gas ceases. The reaction mixture is mixed with 50 ml of 10% HCl/H2O and extracted with ether. The ether is evaporated off and the resulting black oil chromatographed on a column using 1 l of 20% of ethylacetate/hexane followed by 1 l of 30% ethylacetate/hexane to yield first the 3fluoro-isomer followed by the desired 6-fluoro isomer; m.p. 76-81.5°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16][CH2:15]1)[CH:6]=[C:5]2[S:26][CH2:27][C@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]1.[CH:41]1([NH:44][C:45](=[O:63])[C:46]2[CH:51]=[C:50](B3OC(C)(C)C(C)(C)O3)[C:49]([CH3:61])=[C:48]([F:62])[CH:47]=2)[CH2:43][CH2:42]1>>[Si:19]([O:18][CH2:17][C:14]1([CH2:13][N:7]2[CH:6]=[C:5]([S:26][CH2:27][C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:50]4[CH:51]=[C:46]([C:45](=[O:63])[NH:44][CH:41]5[CH2:42][CH2:43]5)[CH:47]=[C:48]([F:62])[C:49]=4[CH3:61])[CH:3]=3)[C:8]2=[O:12])[CH2:15][CH2:16]1)([C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CSc2cn(CC3(CO[Si](C)(C)C(C)(C)C)CC3)c(=O)c3ccc(Br)cc23)C1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3(CO[Si](C)(C)C(C)(C)C)CC3)cc(SC[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1
Yield: 102.1 %

Procedure:
tert-Butyl (3S)-3-{[(6-bromo-2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopropyl]methyl}-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfanyl]methyl}piperidine-1-carboxylate (Example 63d, 109 mg) was reacted with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (45 mg) by the method of Example 58d to afford the subtitle compound (110 mg) as a colourless oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N(CC)CC)C.[CH3:19][CH:20]([CH3:29])[CH2:21][C:22](=[O:28])[CH2:23][CH2:24]C(O)=O.[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:19][CH:20]([CH3:29])[CH2:21][C:22](=[O:28])[CH2:23][CH2:24][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)CC(=O)CCC(=O)O
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)CCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Add benzyl chloroformate (0.712 g, 4.17 mmol), triethylamine (0.464 g, 4.59 mmol), and 4-dimethylaminopyridine (0.051 g, 0.42 mmol) to a solution of 6-methyl-4-oxo-heptanoic acid (0.66 g, 4.17 mmol) in dichloromethane (13 mL) at 0° C. Stir at 0° C. for 1 hour. Add saturated aqueous ammonium chloride (30 mL). Extract with dichloromethane (1×50 mL). Dry organic phase over magnesium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with 0-50% ethyl acetate in hexane to provide 0.87 g (84.1%) of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.[OH-].[NH4+:29]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH2:29])=[O:13])=[CH:14][C:15]([C:19]#[N:20])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(N)=O)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the cyanobenzoxazinone product of Example 5, Step F) (100 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added dropwise ammonium hydroxide (0.5 mL, 12.8 mmol) at room temperature. The reaction mixture was then stirred for five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (36 mg), with a melting point above 255° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:16])[C@H:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:16])[C@H:10]([O:15][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[C:11]([O:13][CH3:14])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](O)[C@H](O)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 72 h
Yield: 72.4 %

Procedure:
Under argon atmosphere, a solution of 955 mg of methyl (2S,3R)-3-(2,4-difluorophenyl)-2,3-dihydroxypropionate dissolved in 30 ml of dichloromethane was cooled to 0° C., and to the solution was added 940 mg of p-toluenesulfonyl chloride and 624 mg of triethylamine. After the mixture was stirred at 0° C. for 3 days, the reaction mixture was washed with water and dried, and the solvent was removed. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to obtain 1.15 g of methyl (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-(p-toluenesulfonyloxy)propionate.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[NH:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:15]
Reactant: c1cncc(CC2CCCN2)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCCC1Cc1cccnc1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 3-(pyrrolidin-2-ylmethyl)pyridine (50.5 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H21N3O2: 349.1426, found 349.1693.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH2:17][CH2:18][CH3:19])[C:4]([NH:6][C:7]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[O:9][N:8]=1)=[O:5])[CH3:2].[CH3:20]I>>[CH2:1]([N:3]([CH2:16][CH2:17][CH2:18][CH3:19])[C:4]([N:6]([CH3:20])[C:7]1[CH:11]=[C:10]([C:12]([CH3:13])([CH3:15])[CH3:14])[O:9][N:8]=1)=[O:5])[CH3:2]
Reactant: CCCCN(CC)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: CI
Product: CCCCN(CC)C(=O)N(C)c1cc(C(C)(C)C)on1

Procedure:
The reaction is effected as in Example 171 by using 1-ethyl-1-butyl-3-(5-t-butyl-3-isoxazolyl)urea and methyl iodide to give 1-ethyl-1-butyl-3-methyl-3-(5-t-butyl-3-isoxazolyl)urea as an oil boiling at 140° to 145° C (bath temperature)/0.67 mm Hg.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([I:12])[CH:11]=1)[NH:8][C:7](=[S:13])[N:6]([CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][O:16]1)[C:5]2=[O:20].[CH2:21](I)[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([I:12])[CH:11]=1)[N:8]=[C:7]([S:13][CH2:21][CH2:22][CH3:23])[N:6]([CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][O:16]1)[C:5]2=[O:20]
Reactant: O=c1c2cc(I)cc(I)c2[nH]c(=S)n1CC1CCCO1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2c(I)cc(I)cc2c(=O)n1CC1CCCO1
Yield: 88.3 %

Procedure:
A mixture of the title compound of Step A (0.86 g, 1.67 mmol), n-propyl iodide (0.85 g, 5.02 mmol) and potassium carbonate (2.3 g, 16.7 mmol) was stirred in dimethylformamide (20 mL) at ambient temperature for approximately 4 h. The reaction mixture was then concentrated to dryness in vacuo and partitioned between 200 mL each of ethyl acetate and water. The organic phase was then separated, washed with saturated aqueous NaCl, and dried over Na2SO4. Concentration in vacuo provided 0.82 g of the title compound of Step B, a compound of the invention, as a solid melting at 108-111° C. 1H NMR (300 MHz, CDCl3): δ 1.10 (t,3H), 1.63-1.80 (m,1H), 1.80-2.14 (m,5H), 3.24-3.45 (m,2H), 3.70-3.80 (m,1H), 3.90-4.00 (m,1H), 4.10-4.21 (m,2H), 4.35-4.47 (m,1H), 8.44 (d,1H), 8.48 (d,1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([S:32](=[O:38])(=[O:37])[NH:33][CH:34]2[CH2:36][CH2:35]2)=[CH:28][C:22]=1[C:23]([N:25]=[C:26]=[O:27])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([S:32]([NH:33][CH:34]2[CH2:36][CH2:35]2)(=[O:38])=[O:37])=[CH:28][C:22]=1[C:23]1[NH:25][C:26](=[O:27])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Reactant: O=C=NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c(-c2cc(S(=O)(=O)NC3CC3)ccc2Cl)nn1-c1ccc(C(F)(F)F)cc1
Yield: 60.5 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 0.050 g, 0.18 mmol), 2-chloro-5-(N-cyclopropylsulfamoyl)benzoyl isocyanate (step-4 of Intermediate-40, 0.108 g, 0.36 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.050 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 0.40-0.42 (m, 2H), 0.50-0.54 (m, 2H), 2.17-2.21 (m, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.92-7.98 (m, 2H), 8.15-8.21 (m, 4H), 12.84 (s, 1H); MS (m/z): 457.15 (M+H+).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[C:18]1([C:15]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][N:8]([CH3:7])[C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:17][CH2:16]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CNCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N(C)CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 8.943531518538547e+16 %

Procedure:
Diketene (0.98 mL, 12.7 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 1-[3-(N-methylamino)propyl]-4,4-diphenylpiperidine (2.61 g, 8.46 amol, 1.00 equiv) in anhydrous toluene (30 mL) under argon, and stirring was continued for 1 hour. After removal of the solvent, the residue was purified by flash chromatography (SiO2, EtOAc-MeOH-isopropylamine 9:1:0 to 6:1:0.1) to afford 2.97 g (89%) of brown oil, which was characterized spectroscopically.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH2:24][CH3:25])[N:14]([CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[CH:27]([B-](F)(F)F)=[CH2:28].[K+]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH2:24][CH3:25])[N:14]([CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH:27]=[CH2:28])=[CH:5][C:4]=2[N:3]=1
Reactant: C=C[B-](F)(F)F
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCNS(C)(=O)=O
Agent: [K+]
Product: C=Cc1ccc2c(c1)nc(N)c1nc(CCCC)n(CCNS(C)(=O)=O)c12

Procedure:
N-[2-(4-Amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide was coupled with potassium vinyltrifluoroborate according to the procedure described in Part D of Examples 440–455 and recrystallized from acetonitrile to provide N-[2-(4-amino-2-butyl-7-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide as an off-white solid.