Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:32])[C@H:7]([CH3:31])[CH2:8][C@@H:9]1[O:13]C(C)(C)[N:11](C(OC(C)(C)C)=O)[C@H:10]1[CH2:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([OH:28])=O)[CH2:2][CH2:3][CH3:4].[CH3:33][O:34][CH2:35][CH2:36][CH:37]1[CH2:42][NH:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[O:38]1>>[CH2:1]([NH:5][C:6](=[O:32])[C@H:7]([CH3:31])[CH2:8][C@H:9]([OH:13])[C@@H:10]([NH2:11])[CH2:23][C:24]([CH3:29])([CH3:30])[CH2:25][C:26]([N:41]1[C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[O:38][CH:37]([CH2:36][CH2:35][O:34][CH3:33])[CH2:42]1)=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: COCCC1CNc2ccccc2O1
Reactant: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CC(=O)O
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(CCOC)Oc2ccccc21

Procedure:
Starting from 230 mg of 3-[N-tert-butoxycarbonyl-4(S)-(3-carboxy-2,2-dimethylpropyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-methyl-propionic acid (N-butyl)amide and 193 mg of 2(R,S)-methoxyethyl-3,4-dihydro-2H-1,4-benzoxazine, the title compound is obtained via (4O,5N-isopropylidene)-5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[2(R,S)-methoxyethyl-3,4-dihydro-2H-1,4-benzoxazin-4-ylcarbonyl]-octanoic acid (N-butyl)amide (analogously to Example 1a); Rf (A)=0.19; Rt (VI)=36.6/36.9 min) and 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[2(R,S)-methoxyethyl-3,4-dihydro-2H-1,4-benzoxazin-4-ylcarbonyl]-octanoic acid (N-butyl)amide (Rf (X)=0.36; Rt (VI)=30.6 min; FAB-MS: (M+H)+ =592) in a manner analogous to that described in Example 1) as a diastereomer mixture:Rf (V)=0.32; Rt (VI)=23.7/24.1 min; FAB-MS: (M+H)+ =492.
Reaction SMILES: [C:1]([CH:3]([Na])[C:4](=[O:6])[CH3:5])#[N:2].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]>CN(C=O)C.[Cl-].[NH4+]>[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH:3]([C:4](=[O:6])[CH3:5])[C:1]#[N:2]
Reactant: Cc1ccccc1CBr
Reactant: CC(=O)C([Na])C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)C(C#N)Cc1ccccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
To a solution of (1-cyano-2-oxopropyl)sodium (525 mg, 5 mmol) in DMF (15 mL) was added 1-(bromomethyl)-2-methylbenzene (648 mg, 3.5 mmol) dropwise over a period of 15 min at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. Then this solution was diluted with saturated aq. ammonium chloride solution. This solution was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, concentrated under reduced pressure. The residue was purified by a silica gel chromatography (petroleum ether/ethyl acetate=15/1) to give the titled product (181 mg, 28%) as a colorless oil; LC/MS: MS (ES+) m/e 188 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 2.35 (s, 3H), 2.38 (s, 3H), 3.06 (dd, J=9.6, 14.1 Hz, 1H), 3.28 (dd, J=5.4, 14.1 Hz, 1H), 3.60 (dd, J=5.4, 9.6 Hz, 1H), 7.18-7.22 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=3)[CH:7]=1.Cl[C:23]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:25][N:24]=1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:19][N:10]1[C:11]2[C:16](=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=2)[CH:17]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[S:25][N:24]=3)[CH:3]=[CH:4][C:5]=2[CH3:21])[C:9]1=[O:20]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2C
Reactant: Clc1nsc(-c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3nsc(-c4ccccc4)n3)ccc1C)c(=O)n2C
Reaction time: 10 h

Procedure:
3-(5-Amino-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 15 (30 mg, 0.107 mmol), 3-chloro-5-phenyl-1,2,4-thiadiazole (41 mg, 0.21 mmol) and TsOH (10 mg) were heated at 100° C. in dioxane (2 ml). After 10 h, the solution was cooled and filtered. The mixture was purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-phenyl-1,2,4-thiadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (G1). MS m/z 440.5 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30](=[O:34])[CH2:31][C:32]#[N:33])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:35][C:36]([N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)([CH3:39])[CH:37]=O.N1CCCC1.[Si](Cl)(C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30]([C:31](=[CH:37][C:36]([CH3:39])([N:40]3[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]3)[CH3:35])[C:32]#[N:33])=[O:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CN1CCN(C(C)(C)C=O)CC1
Reactant: N#CCC(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: CN1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a mixture of 3-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidin-1-yl]-3-oxo-propanenitrile (100.6 mg, 0.220 mmol) and 2-methyl-2-(4-methylpiperazin-1-yl)propanal (118.2 mg, 0.660 mmol) in DCM (5 mL) in an ice bath was added pyrrolidine (0.11 mL, 1.32 mmol) and TMS-Cl (0.11 mL, 0.880 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was loaded on silca gel plate, purified by MeOH:CH2Cl2 to obtain 2-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile (19 mg) as a white powder. LC-MS (ES, m/z): 610 [M+H]
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:31])=[CH:24][C:25]([C:29]#[N:30])=[N:26]2)=[CH:21][CH:20]=1>C(#N)C>[Cl:31][C:23]1[C:22]2[C:27](=[CH:28][C:19]([CH2:18][N:5]3[C:4](=[O:6])[CH2:3][CH2:2][C:1]3=[O:7])=[CH:20][CH:21]=2)[N:26]=[C:25]([C:29]#[N:30])[CH:24]=1
Reactant: N#Cc1cc(Cl)c2ccc(CBr)cc2n1
Reactant: O=C1CCC(=O)N1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)c2ccc(CN3C(=O)CCC3=O)cc2n1
Temperature: 100 °C

Procedure:
To a room temperature solution of succinimide (4.22 g, 42.6 mmol, 1.2 equiv.) in anhydrous acetonitrile (89 mL, 0.4 M) was added Hunig's base (12.4 ml, 71.0 mmol, 2.0 equiv.) and 7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4, 10.0 g, 35.5 mmol). The resulting mixture was warmed in the microwave to 100° C. for 1 h. The reaction was then cooled to 0° C. and a precipitate formed. The solids were then collected by vacuum filtration and washed with cold acetonitrile to afford 4-chloro-7-[(2,5-dioxopyrrolidin-1-yl)methyl]quinoline-2-carbonitrile (2-5) which was taken to the next step without further purification. LRMS m/z (M+H)+ 300.2. found, 300.0 required.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].[OH-].[Na+]>>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CNc1ccccc1
Product: CN(c1ccccc1)S(=O)(=O)c1ccccc1Br

Procedure:
Freshly distilled N-methylaniline (b.p. 196° C.) is prepared. To 1.07 g (0.01 mole) of the N-methylaniline is added 2.56 g (0.01 mole) of 2-bromobenzenesulfonyl chloride (98 w/w %). The mixture is stirred until hot. Ten percent sodium hydroxide is then added dropwise with stirring until the solution is slightly alkaline, and 2-bromo-N-methylbenzenesulfonanilide is formed as a viscous red-brown liquid. It is washed with water several times until the wash water is neutral to litmus paper. A viscous red-brown liquid is extracted with ether, and the ether layer is dried over magnesium sulfate, filtered and the solvent removed by evaporation. The yield of red-brown oil is 2.30 g (70% yield). 1H NMR (deuterioacetone): δ 7.1-8 (m, 9 ArH), 3.3 (s, 3H, N—CH3).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[C:16]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C@@H:31]([C:33]([OH:35])=[O:34])[NH2:32])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>>[CH2:19]([O:18][C:16]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C@H:31]([NH:32][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:33]([OH:35])=[O:34])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(NCCCC[C@H](Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O)OCc1ccccc1
Yield: 43 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with N(ε)-Cbz-L-lysine to provide the title compound in 43% yield as yellow needles (recrystallization from EtOH/water).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18].O>C(Cl)(Cl)Cl>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][Cl:18])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1CCC(CCl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
In 20 ml of chloroform was dissolved 2.19 g (10 mmol) of N-benzoyl-4-hydroxymethylpiperidine (C) and to the resulting solution was added 2.08 g (10 mmol) of phosphorus pentachloride. The resulting mixture was stirred at room temperature for 1 hour. After the completion of the reaction, thereto was added 20 ml of chloroform and the resulting mixture was poured into 50 ml of iced water to separate an organic layer. The organic layer was washed with 50 ml of a saturated aqueous solution of sodium hydrogencarbonate and dried over 4 g of anhydrous magnesium sulfate. Then, the solvent was removed by distillation to obtain 3.03 g of an oily matter. The oily matter was subjected to silica gel column chromatography (stationary phase: 50 g of Silicagel 60 available from Merck KGaA). The fraction eluted with a hexane/ethyl acetate mixture (1:1 (v/v)) was collected. The solvent was removed by distillation from the obtained fraction to obtain 1.33 g of N-benzoyl-4-chloromethylpiperidine (D) as a colorless crystal. The NMR spectrum of this compound coincided with that of the product in Example 3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[CH:6][N:7](C)C)[CH3:2].C(OC(=O)C(C(=O)C1C=CC=CC=1)=CN(C)C)C>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:7][O:18][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Product: CCOC(=O)c1cnoc1-c1ccc(Cl)cc1
Yield: 49 %

Procedure:
The procedure of Example 15 was employed utilizing ethyl-2-(4'-chlorobenzoyl)-3-dimethylaminopropenoate in lieu of ethyl-2-benzoyl-3-dimethylaminopropenoate to yield ethyl-5-(4'-chlorophenyl)-4-isoxazolecarboxylate (3.7 g.; 49% yield) having a melting point of 58°-60° C. and the following analysis:
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([C:20]([OH:22])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:27]1([NH:29][C:20]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[CH:17]([CH3:19])[CH3:18])=[O:22])[CH2:28][CH2:26]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2C(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 164.1 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-isopropyl-1H-1,2,3-triazole-4-carboxylic acid (512 mg, 1.69 mmol) obtained in Example 92a), HOBt (116 mg, 0.847 mmol, 0.5 eq.) and cyclopropylamine (0.157 ml, 2.20 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 9.0 ml), WSC (398 mg, 2.03 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, the residue was diluted with ethyl acetate-hexane (2:1, 45 ml), and the mixture was washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (3:2, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (476 mg, 1.39 mmol, 91.4%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH2:13])=[O:12])[CH:2]=1.C([NH:21][C@@H:22]([C:31]([OH:33])=[O:32])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH2:13])=[O:12])[CH:2]=1.[NH2:21][C@@H:22]([C:31]([OH:33])=[O:32])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Agent: NC(=O)c1cnc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CCc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 57.6 %

Procedure:
N-Boc-D-homophenylalanine Quinoline-3-amide (2.6 g, 6.42 mmol, procedure 1A) was treated with trifluoroacetic acid (15 mL) at 25° C. for 1 hr. The solution was concentrated to dryness and treated with diethyl ether (10 mL). The solid was filtered and dried. It was dissolved in water (180 mL) and neutralized to pH=7.5 with saturated solution of sodium bicarbonate. The mixture was stirred for 1 hr and the solid was filtered and dried giving the title compound (1.30 g) as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][CH2:9][CH2:8][N:6]3[CH:7]=[C:2]([C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)[CH:3]=[CH:4][C:5]3=[O:23])=[CH:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(OCCn3cc(Br)ccc3=O)ccnc2c1
Reactant: OB(O)c1cccs1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc2c(OCCn3cc(-c4cccs4)ccc3=O)ccnc2c1
Temperature: 85 °C

Procedure:
A mixture of 5-bromo-1-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridin-2(1H)-one (50 mg, 133 μmol), thiophene-2-boronic acid (34 mg, 267 μmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) (8 mg, 11 μmol), and Na2CO3 (2M, 200 μl, 400 μmol) in DME (0.5 mL) were heated to 85° C. for 1 h. The reaction mixture was partitioned between CH2Cl2 (10 mL) and 5% NaHCO3 (5 mL). The aqueous layer was further extracted with CH2Cl2 (5 mL) and the combined organics were dried with brine and MgSO4. The concentrated organic residue was purified on 4 g silica eluting with 0-2.5% MeOH/CH2Cl2. The product was isolated as an off white solid. MS (ESI pos. ion) m/z (MH+): 379. Calc'd exact mass for C21H18N2O3S: 378. 1H NMR (400 MHz, Chloroform-d) δ ppm 3.92 (s, 3H) 4.53 (s, 4H) 6.62-6.67 (m, 2H) 7.24-7.28 (m, 1H) 7.34 (d, J=2.54 Hz, 1H) 7.63 (dd, J=9.49, 2.64 Hz, 1H) 7.79 (d, J=2.54 Hz, 1H) 8.00 (d, J=9.19 Hz, 1H) 8.66 (d, J=5.28 Hz, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1C[CH2:5][CH2:6][N:7]2[C:12](=[O:25])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24].BrC1C2[O:33]CCNC=2C=CC=1>>[Br:1][C:2]1[C:3]2[O:33][CH2:5][CH2:6][N:7]([C:12](=[O:25])[CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=3[CH3:24])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(Br)cccc32)c1C
Reactant: Brc1cccc2c1OCCN2
Product: Cc1cccc(OCCCC(=O)N2CCOc3c(Br)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one except that 5-bromo-1,2,3,4-tetrahydroquinoline, HCl salt was replaced by 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine. LCMS, [M+H]+=404.1. 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.0 Hz, 1H), 7.26-7.21 (m, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.78-6.71 (m, 2H), 6.64 (d, J=8.1 Hz, 1H), 4.36-4.28 (m, 2H), 3.98 (t, J=5.8 Hz, 2H), 3.95-3.90 (m, 2H), 2.80 (t, J=7.2 Hz, 2H), 2.24 (s, 3H), 2.19 (dt, J=13.1, 6.4 Hz, 2H), 2.02 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([CH2:34][C:35]#[N:36])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:64])(=O)=O)CCCCCCCCCCCCCCC>>[C:35]([CH2:34][CH:10]([CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:64])(=[O:7])=[O:6])#[N:36]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CC#N)CNS(=O)(=O)CCCCl
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CC#N)CNS(=O)(=O)CCCI

Procedure:
1-(3-Chloropropylsulfonylamino)-2-cyanomethyl-3-octadecylcarbamoyloxypropane IIIn2 is allowed to react by the same procedure as described in (5). The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:12][C@H:11]([CH2:13][O:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10]1)(OC(C)(C)C)=O.[ClH:26]>O>[ClH:26].[ClH:26].[NH2:15][O:14][CH2:13][C@H:11]1[CH2:12][C@H:9]([NH2:8])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](CON2C(=O)c3ccccc3C2=O)C1
Agent: Cl
Solvent: O
Product: NOC[C@H]1C[C@H](N)C1

Procedure:
Analogously to Example 6, starting from 7.25 g (0.02093 mol) of 2-[trans-3-(N-BOC-amino)-cyclobutylmethoxy]-1H-isoindole-1,3(2H)-dione, 35 ml of water and 30 ml of concentrated hydrochloric acid, the title compound is obtained, m.p. 198° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:4][C:3]=1[O:23]C(=O)C1C=CC=CC=1.C[O-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[C:15]2[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=2)=[CH:4][C:3]=1[OH:23]
Reactant: N#Cc1ccc(N(Cc2ccc(Cl)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(N(Cc2ccc(Cl)c(O)c2)n2cnnc2)cc1
Temperature: 25 °C

Procedure:
A solution of benzoic acid 2-chloro-5-{[(4-cyano-phenyl)-[1,2,4]triazol-4-yl-amino]methyl}-phenyl ester (CAB02139, 1.13 g, 2.63 mmol) and sodium methoxide (500 mg) in methanol (20 mL) and water (5 mL) was heated to reflux for 30 minutes. After cooling to room temperature most of the solvent was removed under reduced pressure and concentrated sodium bicarbonate solution (20 mL) and ethyl acetate (50 mL) were added. The organic layer was separated, dried over sodium sulphate and the solvent was removed under reduced pressure. The resulting white powder was refluxed in to ethyl acetate (10 mL, product did not dissolve completely). After cooling to room temperature the product was filtered off and dried under high vacuum. Yield-412 mg (48%) white powder. 1H-NMR (400 MHz, d6-DMSO) δ=4.97 (s, 2H), 6.71-6.75 (m, 3H), 6.84 (d, J=2.0 Hz, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.75 (d, J=9.0 Hz, 2H), 8.76 (s, 2H), 10.21 (s, 1H, —OH). LRMS (FAB+): 326.1 (100, [M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22][O:23]S(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O-].[Na+].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22][O:23][CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
18.1 To a stirred solution of 200 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (example 17.2) at r.t. in 5 ml THF under an argon atmosphere were added 78 mg sodium methylate. The resulting suspension was heated to reflux for 4 hrs, then treated again with 78 mg sodium methylate and 1.5 ml MeOH and refluxed overnight. The reaction mixture was cooled to r.t. and concentrated. The crude product was purified by column chromatography (silica gel, gradient: cyclohexane->cyclohexane/EtOAc 35:65) to give (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless gum. MS 375.0 ([M+H]+)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH:7]([S:11]C(=O)C)[CH2:6]2)[O:4][CH2:3][CH2:2]1.C[O-].[Na+].O1CCCC1.OP([O-])(O)=O.[K+]>C(OCC)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH:7]([SH:11])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)SC1CC2(CCS1)OCCO2
Agent: C[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: SC1CC2(CCS1)OCCO2
Reaction time: 0.33 h
Yield: 80.5 %

Procedure:
A mixture of 0.56 g of product from Example 395, 0.60 ml of 4.37M sodium methoxide and 10 ml of tetrahydrofuran is stirred in an ice bath for 20 minutes. Ethyl acetate is added followed by 0.5M potassium phosphate monobasic. The organic layer is dried and concentrated in vacuo to give 0.37 g of the desired product as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:10])[C:6](F)=[N:7][CH:8]=1)#[N:2].[CH3:11][CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:10][C:5]1[C:6]([N:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[CH3:11])=[N:7][CH:8]=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: CC1CCCN1
Reactant: Cc1cc(C#N)cnc1F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)cnc1N1CCCC1C
Yield: 101.4 %

Procedure:
A solution of 5-cyano-2-fluoro-3-methylpyridine (Molekula, 400 mg; 2.94 mmol) in 1-butanol (1 mL), 2-methylpyrrolidine (Acros, 300 mg; 3.53 mmol) and DIEA (1.52 mL; 8.82 mmol) was heated at 90° C. for 18 hours. Reaction mixture was partitioned between EtOAc and water and washed with water to give the title compound as a yellow oil (600 mg, quantitative). HPLC (Method A) Rt 1.99 min (Purity: 96.1%). LC/MS (Method B): 202.1 (M+H)+.