Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1SC2C(O)=C(C(OC)=O)N(C)S(=O)(=O)C=2C=1.NC1C=CC=CN=1.[Cl:26][C:27]1[S:31][C:30]([C:32]([OH:34])=[O:33])=[C:29]([S:35](=[O:39])(=[O:38])[NH:36][CH3:37])[CH:28]=1.C.ClC1SC2C(O)=C(C(=O)NC3C=CC=CN=3)N(C)S(=O)(=O)C=2C=1>OCC(CO)O.C1(C)C(C)=CC=CC=1>[Cl:26][C:27]1[S:31][C:30]([C:32]([O:34][CH3:2])=[O:33])=[C:29]([S:35](=[O:38])(=[O:39])[NH:36][CH3:37])[CH:28]=1
Reactant: COC(=O)C1=C(O)c2sc(Cl)cc2S(=O)(=O)N1C
Reactant: CNS(=O)(=O)c1cc(Cl)sc1C(=O)O
Agent: CN1C(C(=O)Nc2ccccn2)=C(O)c2sc(Cl)cc2S1(=O)=O
Agent: Nc1ccccn1
Solvent: OCC(O)CO
Solvent: Cc1ccccc1C
Product: CNS(=O)(=O)c1cc(Cl)sc1C(=O)OC
Reaction time: 12 h

Procedure:
1200 ml. of absolute xylene are placed in a 2 liter volume flask and 11 g. of 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno[2,3-e]-1,2-thiazine-1,1-dioxide are added while stirring. 4.42 g. of 2-aminopyridine are next added and the solution is then boiled under reflux until all the starting product has been shown by thin layer chromatography to have reacted (about 4 hours). A gentle stream of nitrogen is passed through the mixture during boiling under reflux, in order to entrain the methanol that is formed. After the end of the reaction, the solution is cooled to about 120°, activated charcoal is added, and the solution is boiled for an additional short time. A hot water funnel is filled with glycerol and preheated to 120°, and the hot reaction solution at 120° is then filtered through this funnel. When the temperature of the solution has fallen to 70°, the solution is then scratched, whereupon small orange crystals begin to separate out. When cold, the solution is kept for 12 hours in an icebox (-5°) and the precipitate that has separated out is filtered under suction and washed with xylene. The product is dried in vacuo (1 mm, 120°, 2 hours). The orange to yellow crystals thus obtained are 6-chloro-4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl)-2H-thieno[2,3-e]-1,2-thiazine-1,1-dioxide with a melting point of 225°-230° (with decomposition).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:59]1([C:64]2[CH:71]=[CH:70][C:67]([CH2:68][NH2:69])=[CH:66][CH:65]=2)[CH:63]=[CH:62][N:61]=[CH:60]1>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:69][CH2:68][C:67]3[CH:66]=[CH:65][C:64]([N:59]4[CH:63]=[CH:62][N:61]=[CH:60]4)=[CH:71][CH:70]=3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCc1ccc(-n2ccnc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCc3ccc(-n4ccnc4)cc3)cs2)c1-c1ccc(F)cc1
Yield: 46.4 %

Procedure:
A solution of 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (50 mg, 0.14 mmol), HATU (106 mg, 0.28 mmol), DIEA (0.049 mL, 0.28 mmol) and 4-(1H-imidazol-1-yl)benzylamine (96 mg, 0.56 mmol) in DMF (2.0 mL) was stirred at room temperature for 14 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 50→70% ethyl acetate/hexane) to give the title compound (33.4 mg, 0.065 mmol, 46.7%) as a white powder.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]2[N:17]3[C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N+:21]([O-])=[CH:20][C:19]=4[N:29]=[C:16]3[CH2:15][O:14][CH2:13]2)=[CH:7][CH:6]=1)(=O)C.[OH-].[NH4+:31].C1(C)C=CC(S([Cl:41])(=O)=O)=CC=1.C(Cl)(Cl)Cl>C(Cl)Cl.Cl.O>[ClH:41].[NH2:31][C:20]1[C:19]2[N:29]=[C:16]3[CH2:15][O:14][CH2:13][C@H:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=4)[N:17]3[C:18]=2[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [NH4+]
Reactant: CC(=O)Oc1ccc(C[C@H]2COCc3nc4c[n+]([O-])c5ccccc5c4n32)cc1
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1nc2ccccc2c2c1nc1n2[C@@H](Cc2ccc(O)cc2)COC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4-{[(11S)-5-Oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methyl}phenyl acetate (3.08 g, 7.91 mmol) was dissolved in 100 mL of CH2Cl2 and treated with 10 mL of concentrated ammonium hydroxide solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (1.51 g, 7.91 mmol) was carefully added. Rapid stirring continued for 1 hour. The reaction mixture was then treated with 20 mL of H2O and the layers were separated. The aqueous portion was extracted with CH2Cl2 (5×25 mL). The combined organic layers were washed with saturated NaHCO3 solution. Methanol was added to the organic layer to aid in solubility. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown solid. Chromatography (SiO2, 20-40% CMA/CHCl3) gave a yellow solid. This material was dissolved in 100 mL 6 N aqueous HCl, and the solution was heated at 50° C. overnight. The reaction mixture was cooled and treated with concentrated ammonium hydroxide until pH=11 and then diluted with 200 mL H2O. The solution was extracted with 9:1 mixture of CH2Cl2/methanol (3×150 mL). The combined organic layers were washed sequentially with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a white solid. Crystallization from ethanol containing HCl gave 4-{[(11S)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methyl}phenol hydrochloride (0.47 g) as an off white solid, mp>240° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][NH:7][NH:6]1)=[O:4].[CH3:11][S:12][C:13]1[N:18]=[C:17]([C:19](Cl)=[O:20])[CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([S:12][CH3:11])[N:18]=2)=[O:20])[NH:6]1)=[O:4]
Reactant: CSc1nccc(C(=O)Cl)n1
Reactant: COC(=O)C1CCCNN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCCN(C(=O)c2ccnc(SC)n2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
To a solution of hexahydro-pyridazine-3-carboxylic acid methyl ester (1.5 g, 8.3 mmol) in CH2Cl2 (80 mL) is added 2-methylsulfanyl-pyrimidine-4-carbonyl chloride, 16, (1.41 g, 7.5 mmol) and triethylamine (1.2 mL, 8.3 mmol). The mixture is stirred at room temperature for 3 hours. The reaction solution is then diluted with1 N HCl (100 mL) and the organic phase is decanted. The aqueous phase is extracted with additional solvent and the organic layers are combined, dried, and concentrated in vacuo. The crude product is purified over silica(ethyl acetate/hexane 1:1) to afford 0.9 g (36% yield) of the desired product as a yellow solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[CH:11][CH:10]=2)O1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[C:35]([C:49]([OH:51])=[O:50])[C:36]3[C:41](I)=[N:40][N:39]([CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][O:44]4)[C:37]=3[N:38]=2)=[CH:29][C:28]=1[C:52]([O:54][CH3:55])=[O:53]>>[CH2:16]([O:15][C:13]([C:12]1[CH:11]=[CH:10][C:9]([C:41]2[C:36]3[C:35]([C:49]([OH:51])=[O:50])=[CH:34][C:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[C:28]([C:52]([O:54][CH3:55])=[O:53])[CH:29]=4)=[N:38][C:37]=3[N:39]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[N:40]=2)=[CH:24][CH:23]=1)=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(-c2cc(C(=O)O)c3c(I)nn(C4CCCCO4)c3n2)ccc1F
Reactant: CC1(C)OB(c2ccc(C(=O)OCc3ccccc3)cc2)OC1(C)C
Product: COC(=O)c1cc(-c2cc(C(=O)O)c3c(-c4ccc(C(=O)OCc5ccccc5)cc4)nn(C4CCCCO4)c3n2)ccc1F
Yield: 66 %

Procedure:
Obtained according to the process described in Step 3.1, using benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and 6-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid [described in Step 1.7], in the form of a yellow solid (yield: 66%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:13][N:14]([C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1)[C@H:15]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]2[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:24]([CH3:26])=[CH:25][C:16]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C.C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=1)[CH2:13][N:14]([C@H:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:17]2[CH:22]=[C:23]([C:27]([F:28])([F:29])[F:30])[C:24]([CH3:26])=[CH:25][C:16]1=2)[C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1ccncc1)CCC[C@@H]2N(Cc1cc(F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 0.08 h
Yield: 87.9 %

Procedure:
Add pyridine-4-carboxaldehyde (0.065 mL, 0.69 mmol) to a solution of (S)-(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-yl)-amine (0.12 g, 0.23 mmol) in 1,2-dichloroethane (10 mL) and acetic acid (0.02 mL) at room temperature under nitrogen and stir for 5 min. Add sodium triacetoxy borohydride (0.29 g, 1.38 mmol) and stir for 12 h. Dilute the mixture with methylene chloride (30 mL) and wash with saturated aqueous sodium bicarbonate solution (2×10 mL). Extract the combined aqueous washes with methylene chloride (20 mL) and wash the combined organic extracts with brine (20 mL) and dry over anhydrous sodium sulfate. Remove the solvents under reduced pressure and purify by silica gel column (gradient eluent, 0-5% MeOH in ethyl acetate) to give the title compound (0.12 g, 87%). MS (ES+): 594 (M+H).
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].O1CCOCC1.Cl[CH2:18][C:19](=[O:21])[CH3:20]>O>[C:1]1([S:7]([CH2:18][C:19](=[O:21])[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(=O)CCl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)CS(=O)(=O)c1ccccc1
Temperature: 50 °C
Yield: 60.3 %

Procedure:
Sodium benzenesulfinate (50 g, 304.6 mmol) was dissolved in water (200 ml). A dioxane solution (200 ml) of chloroacetone (29.6 g, 319.9 mmol) was added and the solution was stirred and heated to 50° C. for 22 hours then cooled to approximately 25° C. The solution was extracted with methylene chloride (2X, 250 ml), the methylene chloride layers were combined and washed with saturated aqueous sodium bicarbonate solution (1X, 250 ml) and water (1X, 250 ml) then the aqueous wash solutions were combined and extracted with methylene chloride (2X, 100 ml). All of the methylene chloride layers were combined and washed with saturated aqueous sodium chloride solution (1X, 150 ml), dried over sodium sulfate, filtered and concentrated in vacuo to a solid. The solid was dissolved in diethyl ether (800 ml) with gentle heating and then the solution was stirred and allowed to cool to room temperature. The solution was slowly cooled to 0° C. with stirring, causing the product to crystallize. The resulting crystals were collected by filtration, washed with cold diethyl ether, and dried in vacuo at 35° C. for 4 hours to yield 36.43 g of (phenylsulfonyl)acetone. The filtrate was concentrated to approximately one-eighth of its volume in vacuo and was gradually cooled below room temperature to induce crystallization, then stirred overnight at room temperature. The resulting crystals were collected by filtration, washed with cold diethyl ether, and dried in vacuo at 35° C. for 8 hours to yield an additional 14 g of the (phenylsulfonyl)acetone: n.m.r. (90 MHz, CDCl3): δ 2.39 (s, 3), 4.17 (s, 2), 7.55-7.95 (m, 5); m.p. 56°-58° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][C:18](=O)[NH:17][CH2:16][CH:15]2[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)=[CH:10][CH:9]=1>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)=[CH:10][CH:9]=1
Reactant: O=C1CC(c2ccc(F)cc2)C(COc2ccc3c(c2)OCO3)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(C2CCNCC2COc2ccc3c(c2)OCO3)cc1
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of lithium aluminium hydride in tetrahydrofuran (1.0M solution, 2 ml, 2.0 mmol) was added over ten minutes to a well stirred solution of 4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine-6-one (0.41 g, 0.96 mmol) in tetrahydrofuran (7 ml), maintaining the temperature below 25° C. The reaction solution was stirred for 2 hours and then quenched first of all with water (0.16 ml), then with 15% aqueous sodium hydroxide solution (0.1 ml), and finally with water again (0.4 ml). The reaction mixture was stirred for 0.5 hours to complete the precipitation, diluted with dichloromethane (30 ml) and filtered. The filtrate was evaporated in vacuo to give the title product with a trans/cis ratio=72:28. Yield 90%.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:15][CH2:16][CH3:17])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1.CC(C)([O-])C.[K+]>>[C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:2]([OH:1])([CH3:4])[CH3:3])[N:6]=[C:7]2[CH2:15][CH2:16][CH3:17])=[CH:25][CH:24]=1)#[N:33]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 95.3 %

Procedure:
Following a procedure similar to that as described in Example 68(a), but using 4.01 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9), 5.0 g of 4'-bromomethylbiphenyl-2-carbonitrile and 1.97 g of potassium t-butoxide. 6.86 g of the title compound were obtained as crystals, melting at 92°-93° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24][CH3:25])[CH:19]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:34]1([CH2:37][C:38](O)=[O:39])[CH2:36][CH2:35]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:34]1([CH2:37][C:38]([NH:2][C@@H:3]2[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:26])[C:11]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]=3[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24][CH3:25])[CH:19]=3)[CH2:5][CH2:4]2)=[O:39])[CH2:36][CH2:35]1
Reactant: CSc1cccc(Oc2ncccc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: O=C(O)CC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncccc2C(=O)N[C@H]2CC[C@@H](NC(=O)CC3CC3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-(cis-4-Aminocyclohexyl)-2-[3-(methylsulfanyl)phenoxy]nicotinamide hydrochloride (100 mg, 0.25 mmol) was dissolved in dimethylformamide (1.7 ml) and triethylamine (106 μl, 0.76 mmol) was added followed by cyclopropylacetic acid (28 mg, 0.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (97 mg, 0.51 mmol) and 1-hydroxybenzotriazole (38 mg, 0.28 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate solution (5 ml) and extracted with ethyl acetate (3×10 ml). The organic phase was washed with brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethyl ether to give N-{cis-4-[(cyclopropylacetyl)amino]cyclohexyl}-2-[3-(methylsulfanyl)phenoxy]nicotinamide (99 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:17]([O-:20])([O-:19])=O.[K+].[K+].Br[CH2:24][C@H:25]([CH3:28])[CH2:26][OH:27].C(OC(C)C)(C)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.O>[C:4]([OH:27])(=[O:8])/[CH:5]=[CH:15]/[C:17]([OH:20])=[O:19].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C@@H:25]([CH3:28])[CH2:26][OH:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: C[C@H](CO)CBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CC#N
Solvent: O
Product: C[C@@H](CO)CN1CCC(c2noc3cc(F)ccc23)CC1
Product: O=C(O)/C=C/C(=O)O

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (14.5 g, 65 mmol), K2CO3 (10 g, 72 mmol). (R)-(-)-3-bromo-2-methyl-1-propanol (10 g, 65.3 mmol), tetrabutylammonium hydrogen sulfate (1,27 g, phase transfer catalyst) in acetonitrile (300 ml) and H2O (5 ml) was heated at reflux for 6 hours. The mixture was cooled and the solvent was removed on rotary evaporator. The residue was extracted into methylene chloride (DCM), and the insolubles were filtered. After concentration of the extract, the crude product was purified by flash chromatography over a silica gel column (SiO2, 150 g; eluted with DCM, 11; 2% CH3OH in DCM, 1.6). The material thus purified weighed 17 g (89%). The sample for testing was prepared by treatment of a sample (2.28 g) with fumaric acid (953 mg) in ethanol. The crystals fonned slowly upon addition of isopropyl ether. These were collected and dried: weight 1.84 g, m.p.=114°-115° C.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[Cl:25][CH2:26][C:27](Cl)=[O:28].CCN(CC)CC>C1COCC1>[Cl:25][CH2:26][C:27]([NH:24][C:8]1[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[N:10][C:11]([CH3:13])=[CH:12][C:7]=1[O:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:28]
Reactant: O=C(Cl)CCl
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1NC(=O)CCl

Procedure:
The title compound was prepared by acylation of 4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine with chloroacetyl chloride, NEt3 in THF at room temperature. A tan solid was isolated, mp. 79-82° C. Anal. For C22H30ClN3O2 calc. C, 65.41; H, 7.49; N, 10.40; found: C, 65.56; H, 7.62; N, 10.98.
Reaction SMILES: O[N:2]=[C:3]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[CH:5]([C:6](=[O:30])[O:7][C:8]3[C@H:9]4[C@:21]([CH3:29])([CH2:22][CH2:23][C:24]=32)[C@@H:12]([C@@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:10]4)[CH2:4]1.S(Cl)(Cl)=[O:32].C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:28][C@:25]12[CH2:26][CH2:27][NH:2][C:3](=[O:32])[CH2:4][C@@H:5]1[C:6](=[O:30])[O:7][C:8]1[C@@H:9]3[CH2:10][CH2:11][C@H:12]([C@@H:13]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:20])[C@@:21]3([CH3:29])[CH2:22][CH2:23][C:24]=12
Reactant: CC(C)CCC[C@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=NO)CC1C(=O)O3
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCNC(=O)C[C@@H]1C(=O)O3
Reaction time: 1 h
Yield: 27.9 %

Procedure:
Compound 3 (41.5 mg, 0.0999 mmol) obtained in Example 3 was dissolved in 1,4-dioxane (3.0 mL), and thionyl chloride (21.9 μL, 0.300 mmol) was added thereto at room temperature, followed by stirring for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative thin layer chromatography to obtain the title compound (11.6 mg, 28%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:39](Cl)(Cl)=[O:40].[Cl-].[NH4+].CC[N:47](C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:39]([NH2:47])=[O:40])=[CH:3][CH:4]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]2[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]=2[CH3:26])[CH2:13][CH2:14]1)#[N:38]
Reactant: O=C(Cl)Cl
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(N)cc2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(NC(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of COMPOUND 142 (61 mg, 0.12 mmol) in toluene (1 mL) was added phosgene (20% in toluene, 82 μL, 0.15 mmol) and the resultant slurry was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was dissolved in DMF (1 mL). To the solution were added ammonium chloride (33 mg, 0.62 mmol) and DIPEA (120 μL, 0.69 mmol) and the mixture was stirred at room temperature for 17 hours to afford COMPOUND 158 as a white solid (24 mg, 36%) following work-up and purification. 1H NMR (CDCl3) δ 1.00-1.15 (m, 5H), 1.55 (m, 1H), 1.71 (m, 3H), 2.16 (m, 1H), 2.30 (s, 6H), 2.56 (m, 1H), 2.75-2.87 (m, 3H), 3.29 (m, 1H), 3.57 (m, 1H), 3.79-3.90 (m, 3H), 4.63 (s, 2H), 6.41 (s, 1H), 6.50 (d, 2H, J=7.8 Hz), 6.92-7.04 (m, 5H), 7.43 (s, 3H), 7.52 (br s, 1H), 8.38 (br s, 1H). 13C NMR (CDCl3) δ 13.81, 19.54, 29.41, 30.68, 31.30, 40.24, 43.99, 48.69, 52.49, 57.30, 60.85, 112.86, 114.97, 119.39, 125.05, 127.70, 128.84, 129.63, 130.41, 130.90, 131.39, 134.47, 138.87, 142.42, 146.09, 158.05, 170.39. ES-MS m/z 553 (M+H). Anal. Calcd. for C33H40N6O2.0.85CH2Cl2.0.1C6H14: C, 65.31; H, 6.86; N, 13.27. Found. C, 65.38; H, 6.66; N, 13.07.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:24])OCC2C=CC=CC=2)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6](F)[CH:7]=1.[CH3:25][O:26][C:27]1[CH:36]=[C:35]2[C:30](CCC[CH:34]2[NH2:37])=[CH:29][CH:28]=1.C(N(CCC)C([C:44]1[CH:45]=[C:46]([CH:50]=[C:51](CC)[CH:52]=1)[C:47]([OH:49])=O)=O)CC>>[CH2:9]([C@H:10]([NH:14][C:15](=[O:24])[C:2]1[CH:3]=[CH:4][C:5]([O:49][CH2:47][C:46]2[CH:45]=[CH:44][CH:52]=[CH:51][CH:50]=2)=[CH:6][CH:7]=1)[C@H:11]([OH:12])[CH2:13][NH:37][CH2:34][C:35]1[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:36]=1)[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc2c(c1)C(N)CCC2
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2ccc(OCc3ccccc3)cc2)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl 1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and 4-(benzyloxy)benzoic acid (IX), the title compound is obtained, MH+=511.