Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]([CH2:43][CH2:44][OH:45])C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)=[C:25]([CH:28]=1)[C:26]#[N:27].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:26]([C:25]1[CH:28]=[C:21]([NH:20][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)[C:13]=2[CH3:14])=[O:17])[CH:22]=[CH:23][C:24]=1[N:29]1[CH2:30][CH2:31][CH:32]([NH:35][CH2:43][CH2:44][OH:45])[CH2:33][CH2:34]1)#[N:27]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N(CCO)C1CCN(c2ccc(N)cc2C#N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)Nc2ccc(N3CCC(NCCO)CC3)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 9.2 %

Procedure:
The reaction and treatment in the same manner as in Example 64 were conducted using 1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid (1.94 g) and 5-amino-2-[4-(N-tert-butoxycarbonyl-2-hydroxyethylamino)piperidin-1-yl]benzonitrile (2.59 g) and the resulting mixture was further stirred in trifluoroacetic acid (10 ml) under ice-cooling for 1 h. The reaction mixture was treated with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of dimethylformamide-water to give the title compound (0.34 g), melting point: 202° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([O:32][CH:33]([CH3:35])[CH3:34])[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:37][S:38]([O:17][C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)[C@H:15]([O:32][CH:33]([CH3:34])[CH3:35])[C:14]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:36])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OC(C(=O)N1C(=O)OCC1Cc1ccccc1)C(O)c1cccc(OCc2ccccc2)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)O[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](OS(C)(=O)=O)c1cccc(OCc2ccccc2)c1
Reaction time: 2 h

Procedure:
12.9 g of 4-Benzyl-3-(3-(3-benzyloxyphenyl)-3-hydroxy-2-isopropoxy propionyl]oxazolidin-2-one was dissolved in 30 ml of pyridine, and 3.06 ml of methanesulfonyl chloride was dropwise added thereto under ice-cooling. After stirring was continued at room temperature for 2 hours, the reaction solution was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated, to give 3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-1(R)-(3-benzyloxyphenyl)-2(S)-isopropoxy-3-oxopropyl methanesulfonate. This product was then dissolved in 300 ml of ethanol, and 2 g of 10% palladium carbon was added, and the mixture was stirred overnight under hydrogen atmosphere at room temperature. The reaction solution was filtered, and the filtrate was concentrated. The residue was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate, The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 5.87 g of the title compound as a colorless oil in the 2:1→3:2 hexane-ethyl acetate fraction.
Reaction SMILES: [C:1]1([N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:27]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:34]5[CH:43]=[CH:42][C:41]6[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=6)[CH:35]=5)[N:21]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: Nc1nccc(-c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccnc(Nc5ccc6ccccc6c5)n4)cc3)cc2)cc1
Yield: 76.3 %

Procedure:
4-(4′-Diphenylaminobiphenyl-4-yl)pyrimidine-2-amine (100 mg, 0.24 mmol), 2-bromonaphthalene (54.6 mg, 0.264 mmol), dichlorobis(triphenylphosphine)palladium(II) (17 mg, 0.024 mmol), Xantphos (14 mg, 0.024 mmol) and sodium t-butoxide (35 mg, 0.36 mmol) were added in toluene (3 mL), and refluxed under nitrogen atmosphere for 14 hours. This solution was cooled, and the precipitated solid was washed with cold toluene and water to obtain the title compound (99 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=[C:11]2[C:19]2[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].O>ClCCl>[NH2:25][C:20]1[C:19]([C:11]2[N:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:46]([NH:45][C:42]4[CH:43]=[CH:44][C:39]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:40][CH:41]=4)=[O:47])=[CH:9][CH:8]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: NCc1ccc(-n2c(-c3cccnc3N)nc3cccnc32)cc1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)NCc2ccc(-n3c(-c4cccnc4N)nc4cccnc43)cc2)cc1
Yield: 14.2 %

Procedure:
3-(3-(4-(aminomethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine HCl salt (63 mg, 0.2 mmol) was suspended in dichloromethane (2 mL). Diisopropylethylamine (0.07 mL, 0.4 mmol) was added. After everything went into solution 1-tert-butyl-4-isocyanatobenzene (32 mg, 0.2 mmol) were added. After 20 min water (10 mL) was added and diluted with dichloromethane (10 mL). The organic phase was separated and dried over Na2SO4. After filtration the solvent was removed under reduced pressure and it was purified by silica gel chromatography (0-20% methanol in dichloromethane) to yield the desired product (14 mg, 15% yield). Mp. 210-212° C.; 400 M Hz 1H NMR (CD3OD) δ: 8.32 (dd, J=0.8 Hz and 2.4 Hz, 1H), 8.19 (dd, J=0.6 Hz and 3.8 Hz, 1H), 7.98-7.94 (m, 1H), 7.55-7.49 (m, 2H), 7.45-7.37 (m, 3H), 7.35-7.24 (m, 5H), 6.48-6.23 (m, 1H), 4.48 (s, 2H), 1.29 (s, 9H); LCMS [M+H]: 492.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1cccs1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)c4cccs4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.068 mMol) 2-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13](Br)[S:12][CH:11]=1)=[O:9].CC1(C)C(C)(C)OB([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[N:29]([S:36]([C:39]3[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH:28]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCOC(C)=O.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[N:29]([S:36]([C:39]3[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH:28]=2)[S:12][CH:11]=1)=[O:9]
Reactant: COc1cccc(CNC(=O)c2csc(Br)c2)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cccnc32)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(CNC(=O)c2csc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncccc34)c2)c1
Yield: 45 %

Procedure:
N-(3-Methoxybenzyl)-5-bromothiophene-3-carboxamide (100 mg, 0.3 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (122 mg, 0.3 mmol), potassium carbonate (125 mg, 0.9 mmol), and tetrakis(triphenylphosphine) palladium (0) (20 mg) were combined in 4 mL DME, 1 mL water, and heated to 160° C. in the microwave for 10 minutes. The reaction mixture was diluted with EtOAc and water. The organic layer was filtered through celite and concentrated to an oil which was purified by column chromatography on silica (20 to 60% EtOAc/hexanes) to give the product as a brown oil, 0.07 g, 0.14 mmol, 45% yield. MH+ 518.0
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17])[C:4]=2[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:22]>C1COCC1>[CH3:22][N:14]([CH2:13][C@@H:11]1[CH2:12][C@H:10]1[C:9]1[C:4]2[CH2:3][CH2:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)[C:15](=[O:18])[CH2:16][CH3:17]
Reactant: CI
Reactant: CCC(=O)NC[C@@H]1C[C@H]1c1cccc2c1CCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)N(C)C[C@@H]1C[C@H]1c1cccc2c1CCO2
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
To a solution of (trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl]methyl]propanamide (120 mg, 0.6 mmol) in THF (1.5 mL) was added sodium hydride (30 mg of 60%, 0.75 mmol). The mixture was allowed to stir for 0.5 h and iodomethane (140 mg, 1 mmol) was added. After stirring for 18 h, the solution was concentrated in vacuo. The residue was dissolved in acetonitrile and washed with hexane. The acetonitrile solution was concentrated in vacuo and the residue purified by chromatography on silica eluting with ethyl acetate-hexane (2:8) to give the product as an amber oil (90 mg, 69%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][N:6]=[C:5]([Cl:13])[CH:4]=1.Cl.[NH2:15][C@@H:16]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C(N(CC)C(C)C)(C)C.C(O)CCC>>[Cl:13][C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:11])[N:15]([C@@H:16]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:17][N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[CH2:2][C:3]=2[CH:4]=1
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)c1cnc(Cl)cc1CBr
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1C[C@H](CC1CCCCC1)N1Cc2cc(Cl)ncc2C1=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
A mixture of methyl 4-(bromomethyl)-6-chloronicotinate (200.0 mg, 0.7561 mmol) (prepared according to Example 119, Steps A, B and C), 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione hydrochloride (244 mg, 0.754 mmol) (prepared from Example 79, Step A) and N,N-diisopropylethylamine (0.526 mL, 3.02 mmol) in 1-butanol (5.0 mL, 55 mmol) was stirred at 140° C. for 2 h under microwave irradiation. Direct purification on prep.HPLC afforded 182 mg (55.1% yield) of the desired product. LC-MS found: 438.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH:3]([CH3:5])[CH3:4]>[Pd]>[CH2:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Product: CC(C)CCN1CCN(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 250-mL round bottom flasked is added 10% Pd/C (100 mg) and 1-isopentyl-4-(4-nitrophenyl)piperazine (1.0 g, 3.6 mmol). The flask is sealed with a septum, and flushed with a slow stream of N2. EtOH (30 mL) is then added via syringed into the flask. The flask is again flushed with N2 and then it is fitted with a balloon of hydrogen. An outlet needle is inserted through the septum and the flask is flushed with hydrogen before the outlet needle is removed. The resulting slurry is stirred vigorously under the H2 atmosphere at rt. After 24 h the yellow color of the solution dissipated and the hydrogen balloon is removed. The flask is flushed with nitrogen, DCM (10 mL) is added to the reaction mixture, and the resulting slurry stirred at rt for 1.5 h. The reaction is filtered through a filtration tube packed with a short column of Celite, the Celite washed with DCM (2×20 mL), and the combined filtrate evaporated to dryness on a rotary evaporator. The product is air dried for 48 h and then it is dried under vacuum for 2 h to provide crude 4-(4-isopentylpiperazin-1-yl)aniline (1.16 g, 120% recovery due to the incomplete removal of the solvent, >80% purity as determined by LC/MS analysis @ UV 254 nm detection). The crude product was used in the next step without further purification. LCMS-ESI (m/z): calcd for C15H25N3, 247; [M+H]+ found, 248.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[C:13]2=[O:18])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][C:7]2=[O:11].[CH:19]1([O:22][C:23]2[N:28]=[CH:27][C:26](O)=[CH:25][CH:24]=2)[CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:19]1([O:22][C:23]2[N:28]=[CH:27][C:26]([O:17][C@@H:14]3[CH2:15][CH2:16][N:12]([C:4]4[CH:5]=[C:6]5[C:10](=[C:2]([F:1])[CH:3]=4)[CH2:9][CH2:8][C:7]5=[O:11])[C:13]3=[O:18])=[CH:25][CH:24]=2)[CH2:21][CH2:20]1
Reactant: Oc1ccc(OC2CC2)nc1
Reactant: O=C1CCc2c(F)cc(N3CC[C@H](O)C3=O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2c(F)cc(N3CC[C@@H](Oc4ccc(OC5CC5)nc4)C3=O)cc21
Reaction time: 2 h

Procedure:
To a mixture of (S)-1-(7-fluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)-3-hydroxy-pyrrolidin-2-one (80 mg), 6-cyclopropoxy-pyridine-3-ol (53.4 mg), triphenylphosphine (polymer, 126 mg) and THF (1.5 mL) was added DIAD (97 mg). The mixture was shaken for 2 hours and filtered. The filtrate was concentrated and the residue purified by preparative HPLC to provide Example 3-13. 1H-NMR (400 MHz, DMSO) δ 8.02 (1H, d, J=3.1 Hz), 7.99 (1H, d, J=11.1 Hz), 7.78 (1H, s), 7.55 (1H, dd, J=9.0, 3.1 Hz), 6.83 (1H, d, J=9.0 Hz), 5.25 (1H, dd, J=8.3, 8.3 Hz), 4.13 (1H, m), 3.97 (1H, m), 3.86 (1H, m), 3.10 (2H, m), 2.72 (2H, m), 2.70 (1H, m), 2.14 (1H, m), 0.74 (2H, m), 0.64 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH3:30][C:31]([CH3:33])=[O:32].[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:31]([OH:32])([CH3:33])[CH3:30])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(N(Cc1ccccc1)Cc1ccccc1)C(C)(C)O
Reaction time: 8 h
Yield: 52.4 %

Procedure:
A solution of 11.3 g (40.0 mmol) dibenzylamino-acetic acid ethyl ester in 107 ml tetrahydrofuran and 107 ml toluene was stirred at −70° C. with 22 ml (44 mmol) lithium diisopropylamide (2M in heptane) for 30 minutes. 3.40 ml (46 mmol) acetone were added and stirring was continued overnight. The mixture was allowed to warm to room temprature, aqueous ammonium chloride solution was added. Extraction with diethylether and chromatography on silicagel with diethylether/heptane 1/2 yielded 7.16 g (52%) 2-dibenzylamino-3-hydroxy-3-methyl-butyric acid ethyl ester, MS m/e (%): 342.3 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].N[C@H:14](C(O)=O)[C@H](CC)C>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:7]([CH3:9])[CH2:8][CH3:14])[C:10]([OH:12])=[O:11])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O

Procedure:
(2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid was synthesized similar to N-methoxycarbonyl-L-Valine, using L-isoleucine instead of L-Valine.
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[CH:7][CH:6]=1.[ClH:20].[CH:21]([NH2:24])([CH3:23])[CH3:22]>C(O)CC>[ClH:20].[OH:1][CH:2]([CH2:19][NH:24][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[CH:7][CH:6]=1
Reactant: CCCOC(=O)CCc1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Agent: Cl
Solvent: CCCO
Product: CCCOC(=O)CCc1ccc(OCC(O)CNC(C)C)cc1
Yield: 56 %

Procedure:
A solution of 1.5 g (0.006 mole) of n-propyl 3-[4-(2,3-epoxypropoxy)phenyl]propionate in 10 mL of isopropylamine and 20 mL of n-propanol was heated to reflux for 4 hours. The reaction medium was then evaporated under reduced pressure to provide the crude free amine as an oil. The oil was dissolved in n-propanol and treated with ethereal HCl and provided 1.2 g (56%) of white crystals: mp 88°-92° C. The NMR spectrum of the product was consistent with the assigned structure and the elemental analysis data was consistent with the molecular formula C18H30NO4Cl.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[N:33]1([CH2:39][CH2:40]O)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:40][CH2:39][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(COC(C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: OCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(COC(C(=O)OCCN2CCOCC2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 35.1 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (14) (0.5 g, 1.2 mmol) dissolved in 5 mL of anhydrous dichloromethane (DCM) was reacted with 0.14 mL (0.2 g, 0.14 mmol) of oxalyl chloride. After completion of the reaction, a solution of 0.37 g (2.8 mmol) of 2-morpholin-4-yl ethanol in anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using ethyl acetate as eluent to provide 0.22 g (35% yield) of the title compound (27a) as a colorless oil. Rf=0.67 (EtOAc). 1H NMR (400 MHz, CDCl3): δ=1.07 (s, 3H), 1.09 (s, 3H), 2.26-2.32 (m, 2H), 2.53-2.70 (m, 6H), 3.22-3.26 (m, 2H), 3.65-3.69 (m, 6H), 3.82 (s, 3H), 3.84 (s, 1H), 4.02 (d, J=9.2 Hz, 1H), 4.19 (d, J=8.8 Hz, 1H), 4.30-4.38 (m, 3H), 4.59 (d, J=9.2 Hz, 1H), 6.88 (d, J=7.2 Hz, 2H), 7.27 (d, J=6.8 Hz, 2H) ppm. MS (ESI) m/z 529.09 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:32])=[O:5])[S:12][CH:13]=3)=[CH:24][CH:23]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.7 %

Procedure:
2-[(4-{2-[(4′-Fluorobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (351 mg) obtained in Example 34-1 was dissolved in dichloromethane (2 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (293 mg) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][CH3:28])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C(O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:27]([CH3:28])[CH2:2][CH2:3][CH:4]2[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]3[CH:13]=[CH:14][CH:15]=[N:16][C:6]=3[O:5]2)=[CH:21][CH:20]=1
Reactant: CNCCc1ccc(OC)cc1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN(C)CCC2CN(C)C(=S)c3cccnc3O2)cc1
Reaction time: 8 h

Procedure:
To 40 ml of absolute ethanol was added 5.0 g (0.0195 mole) of 2-(2-chloroethyl-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione and 3.65 g (0.022 mole) of 4-methoxy-N-methylbenzene-ethanamine and 2.5 g (0.0195 mole) of diisopropylethylamine. After ~6 hr heating at reflux 3.15 g (0.022 mole) of 4-methoxy-N-methylbenzeneethanamine was added and heating was continued overnight. After removing the solvent by rotary evaporation, the residue was taken up in 100 ml of methylene chloride and the solution was washed with 2×50 ml of 1N sodium hydroxide and 50 ml of water, dried over sodium sulfate and filtered. The solution was then treated with 10 ml of acetic anhydride overnight. The methylene chlordide was extracted with 3×100 ml of hydrochloric acid. The combined aqueous extracts were washed with 2×100 ml of chloroform made basic with concentrated sodium hydroxide and extracted into 3×100 ml of chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give 2.8 g (37%) of yellow, analytically pure crystals, m.p. 75°-78° C.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[C:21]2[N:22]=[CH:23][N:24]=[C:25]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]#[N:34])[CH2:29][CH2:28]3)[C:20]=2[S:19][CH:18]=1.[NH4+].[Cl-].[N-:37]=[N+:38]=[N-:39].[Na+]>O>[N:34]1[NH:37][N:38]=[N:39][C:33]=1[N:30]1[CH2:31][CH2:32][CH:27]([O:26][C:25]2[C:20]3[S:19][CH:18]=[C:17]([C:8]4[CH:9]=[CH:10][C:11]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:12][C:7]=4[F:6])[C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:28][CH2:29]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCN(C#N)CC4)ncnc23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCN(c5nn[nH]n5)CC4)ncnc23)c(F)c1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
2.5 ml of dimethylformamide was added to 200 mg 4-(7-(2-fluoro-4-methanesulfonyl-phenyl)thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-carbonitrile of Example 75, and 33 mg of NH4Cl and 45 mg of NaN3 45 mg were added thereto with stirring. The mixture was stirred at 100° C. for 12 hr. The resulting mixture was cooled to room temperature, added with water and stirred. The solid thus obtained was filtered to obtain 120 mg of the title compound.