Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23](C(OC(C)(C)C)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][C:18]=1[F:38])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O)CC#C.[C:44]([C:46]1[CH:50]=[CH:49][S:48][CH:47]=1)#[CH:45]>>[C:1]([O:8][C:9]1[CH:14]=[C:13]([C:45]#[C:44][C:46]2[CH:50]=[CH:49][S:48][CH:47]=2)[CH:12]=[CH:11][C:10]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:19][C:18]=1[F:38])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C#Cc1ccsc1
Reactant: CC(C)(C)OC(=O)Oc1cc(Br)ccc1Oc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Agent: C#CCCO
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C#Cc3ccsc3)cc2OC(=O)OC(C)(C)C)c(F)c1

Procedure:
According to the procedure of example 11 (a) except substituting 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine by O,N,N-triBoc-2-(4-amino-2-fluorophenoxy)-5-bromophenol (0.62 mmol; 363 mg) and 3-butyn-1-ol by 3-ethynylthiophene (1.55 mmol; 153 μL), the title compound was obtained as a yellow solid (60%, 195 mg) after purification on silica gel (cyclohexane/ethyl acetate gradient).
Reaction SMILES: [C:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:14])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27]C1C=CC(NC(N)=S)=CC=1.BrCC(=O)C(OCC)=O>>[Cl:27][C:4]1[CH:5]=[CH:6][C:1]([NH:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:14])[N:12]=2)=[CH:2][CH:3]=1
Reactant: COc1cc(C(=O)c2csc(Nc3ccccc3)n2)cc(OC)c1OC
Reactant: NC(=S)Nc1ccc(Cl)cc1
Agent: CCOC(=O)C(=O)CBr
Product: COc1cc(C(=O)c2csc(Nc3ccc(Cl)cc3)n2)cc(OC)c1OC

Procedure:
(2-((4-Chlorophenyl)amino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (5d) was prepared using the same method as used for 5a from 1-(4-chlorophenyl)thiourea and ethyl bromopyruvate. Melting point: 165-166° C. 1H NMR (500 MHz, CDCl3) δ 7.60 (s, br, 1H), 7.56 (s, 1H), 7.47 (s, 2H), 7.38 (d, 2H), 7.31 (d, 2H), 3.94 (s, 3H), 3.89 (s, 6H). MS: 402.9 (M−1)−; 427.0 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:12]([C:13](OC)=[O:14])=[C:11]([CH:17]([CH3:19])[CH3:18])[O:10][N:9]=2)=[C:6]([Cl:20])[CH:5]=[CH:4][N:3]=1.[H-].C([Al+]C(C)C)(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH:17]([CH3:18])[CH3:19])[O:10][N:9]=2)=[C:6]([Cl:20])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1c(-c2c(Cl)ccnc2Cl)noc1C(C)C
Agent: CC(C)[Al+]C(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1onc(-c2c(Cl)ccnc2Cl)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A solution of methyl 3-(2,4-dichloro-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (1.32 g, 4.2 mmol) in THF (11.7 mL) was stirred at a 0° C. as a 1.5 M solution of diisopropylaluminum hydride in toluene (9 mL, 13.4 mmol) was added; the solution was allowed to warm to room temperature and stirred overnight. A 10% aqueous solution of Rochelle's salt was added and the solution was then allowed to stir for three hours. The layers were separated and the organic layer was washed with brine. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexane to ethyl acetate gradient elution) to yield [3-(2,4-dichloro-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methanol (1.20 g, 94% 0.2 ethyl acetate). 1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, J=5 Hz, 1H), 7.78 (d, J=5 Hz, 1H), 4.94 (t, J=5 Hz, 1H), 4.20 (d, J=5 Hz, 2H), 3.34 (septet, J=7 Hz, overlapping water), 1.29 (d, J=7 Hz, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16](C(=O)C)[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH:2]=1.[BH4-].[Na+].[C:25](O)(=[O:27])[CH3:26]>C(O)C>[CH3:26][CH:25]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:9]2[N:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[CH:15][CH:16]=1)[OH:27]
Reactant: CC(=O)c1cccc(Nc2nccc(-c3cccnc3)n2)c1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reaction time: 3 h

Procedure:
A 1.45 g portion of 1-[3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone was dissolved with stirring in 220 ml of ethanol. A 125 mg portion of sodium borohydride was added and stirring continued for 3 hours. A 63 mg portion of sodium borohydride was added and stirring continued overnight. A 2 ml portion of glacial acetic acid was added and the mixture evaporated. The solid was triturated with water, dried and recrystallized from 30 ml of ethanol giving 710 mg of the desired product, mp 145°-147° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]3=[O:33])=[CH:19][C:18]=2[F:34])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:42][C:43]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][C@H:50]([NH:54][C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])[C:51](O)=[O:52])=[O:44])=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]3=[O:33])=[CH:19][C:18]=2[F:34])([O:14][C:51](=[O:52])[CH:50]([NH:54][C:55]([O:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)=[O:56])[CH2:49][CH2:48][CH2:47][CH2:46][NH:45][C:43]([O:42][CH2:41][C:38]2[CH:37]=[CH:36][CH:35]=[CH:40][CH:39]=2)=[O:44])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1

Procedure:
A suspension of 96 mg of 4-{4-[5-(5S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (MW: 481.52, 0.2 mmol), 195 mg of Z-Lys (Z)—OH (MW: 414.46, 0.4 mmol) and 49 mg of 4-dimethylaminopyridine (MW: 122.17, 0.4 mmol) in 2 ml dichloromethane was treated under stirring at room temperature with 115 mg N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (MW: 191.70, 0.6 mmol). The reaction mixture was stirred over night. The mixture was diluted with 20 ml ethyl acetate and the organic layer washed successively with 10 ml 1 N aqueous hydrochloric acid, 20 ml water and 20 ml brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated to dryness. The residue was purified by chromatography on silica, using a 9/1 dichloromethane/methanol mixture as eluent to leave a colorless sticky oil. Yield: 150 mg, 88%. MS: 878.8 (M+H)+, Method ESI+.
Reaction SMILES: Cl[S:2]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6]([OH:8])=[O:7])(=[O:4])=[O:3].[CH2:18]([OH:20])[CH3:19].C(N(CC)CC)C.O>C(OCC)C>[CH2:18]([O:20][S:2]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6]([OH:8])=[O:7])(=[O:3])=[O:4])[CH3:19]
Reactant: CCO
Reactant: O=C(O)C(c1ccc2c(c1)CCO2)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CCOS(=O)(=O)C(C(=O)O)c1ccc2c(c1)CCO2
Temperature: 20 °C
Reaction time: 1 h

Procedure:
α-Chlorosulfonyl(2,3-dihydro-5-benzofuranyl)acetic acid (5 mmole) is added to 30 ml of ethyl ether. To this mixture is added 5 mmole of ethanol in 10 ml of ethyl ether which contains 10 mmole of triethylamine. The mixture is stirred at 20° C. for about 1 hour and 50 ml of water is added. The pH is adjusted to about 6.5 and the layers separated. The organic layer is dried over magnesium sulfate, filtered and evaporated to give α-ethoxysulfonyl(2,3-dihydro-5-benzofuranyl)acetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20](Cl)[N:19]=[C:18]([Cl:23])[N:17]=2)=[CH:11][C:10]=1[Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[OH-].[Na+].O>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([NH:32][CH:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:19]=[C:18]([Cl:23])[N:17]=2)=[CH:11][C:10]=1[Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCCC1
Reactant: Clc1nc(Cl)nc(Nc2ccc(OCc3ccccc3)c(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Clc1nc(Nc2ccc(OCc3ccccc3)c(Cl)c2)nc(NC2CCCCCC2)n1

Procedure:
To 160b (1.0010 g, 2.6 mmol) dissolved in acetone (25 mL) was added a solution of N-cycloheptylamine (0.35 mL, 2.6 mmol) in acetone (5 mL) followed by addition of 2.5 N NaOH (1.0 mL, 2.6 mmol) and water (2.5 mL). The reaction mixture was allowed to stir at reflux for 3 hours under nitrogen. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine and dried over potassium carbonate. After filtering, the sample was concentrated by rotary evaporation and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 70:30 hexanes:ethyl acetate) yielded a white solid (160c, 855 mg, 72%), mp 110° C.; HPLC: Inertsil ODS-3V C18, 30:70 [KH2PO4 (0.01M, pH 3.2): CH3CN], 264 nm, Rt 47.3 min, 94.7% purity; MS (TOF MS ES+): m/z 535 (44.7), 460 (73.3), 458 (M+H, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[S:8][C:7]=1N)=[O:5])[CH3:2].N(OC(C)(C)C)=O.[Cl-].[NH4+]>[Cu](Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[S:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C2CCCCC2)sc1N
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Product: CCOC(=O)c1csc(C2CCCCC2)c1
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
2-Amino-5-(cyclohexyl)-thiophene-3-carboxylic acid ethyl ester (1.79 g, 7 mmol) was added to a mixture of t-butyl nitrite (10.5 mmol) and copper (II) chloride (7 mmol) in IMS (100 mL). The reaction mixture was stirred for 30 minutes then saturated aqueous ammonium chloride (7 mL) was added and the resulting solution stirred overnight. The solvent was then evaporated under vacuum and the residue partitioned between ethyl acetate and water. The organic solution was separated and dried with magnesium sulphate, filtered and the solvent evaporated to give the title compound as an orange oil (1.28 g). 1H NMR δ (ppm) (CHCl3-d): 7.9 (s, 1H), 7.2 (s, 1H), 4.3 (q, 2H), 2.8 (m, 1H), 2.1 (m, 2H), 1.9 (m, 2H), 1.7-1.2 (m, 9H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([Cl:10])[N:4]=1.[CH3:11][NH:12][CH3:13]>O1CCOCC1.O>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:10])[CH:6]=[C:7]([N:12]([CH3:13])[CH3:11])[N:8]=1
Reactant: CNC
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(Cl)cc(N(C)C)n1
Yield: 97.9 %

Procedure:
To a solution of 46 g 2-methylthio-4,6-dichloropyrimidine in 250 ml dioxane, were added at room temperature and over a period of 10 minutes, 65.6 ml of 40% dimethylammonia-solution in water and the mixture was stirred for one hour. The solvent was evaporated and the residue purified on silica gel with toluene as eluent to give 57.0 g (97.9%) of 2-methylthio-4-chloro-6-(N,N-dimethylamino)-pyrimidine of m.p. 102° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([O:10][CH3:11])=[O:9].C([O-])(=O)C.[Na+].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:2][C@H:3]2[CH2:7][CH2:6][CH2:5][C@H:4]2[C:8]([O:10][CH3:11])=[O:9])=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
Methyl (1R,2S)-2-aminocyclopentanecarboxylate hydrochloride (4.32 g, 24.15 mmol) was dissolved in methanol (120 mL). Sodium acetate (3.96 g, 48.3 mmol) was added followed by 4 Å powdered molecular sieves (5.0 g) and 4-fluoro-benzaldehyde (2.55 mL, 24.15 mmol). Sodium cyanoborohydride (3.04 g, 48.3 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (400 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (100 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, methyl (1R,2S)-2-(4-fluoro-benzylamino)-cyclopentanecarboxylate (5.38 g, 21.4 mmol, 89%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.55-1.72 (2H, m), 1.89 (3H, m), 2.05 (1H, m), 2.97 (1H, m), 3.32 (1H, m), 3.71 (3H, s), 3.77 (2H, m), 7.00 (2H, m), 7.28 (2H, m). LC-MS (ESI) calcd for C14H18FNO2 251.13, found 252.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:40][C@H:41]([CH2:58][C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=1)[C:42]([N:44]([CH2:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:54][CH2:55][CH2:56][OH:57])[CH3:45])=[O:43].C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[NH:40][C@@H:41]([C:42](=[O:43])[N:44]([CH2:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:54][CH2:55][CH2:56][OH:57])[CH3:45])[CH2:58][C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCc1ccccc1OCCO)C(=O)[C@H](N)Cc1ccc2ccccc2c1
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (95 mg, 0.39 mmol) was dissolved in dichloromethane (1 ml) and N,N-dimethylformamide (1 ml). 1-Hydroxy-7-azabenzotriazole (55 mg, 0,39 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (75 mg, 0.39 mmol) was added. The reaction mixture was stirred for 20 min at 0° C. A solution of (2R)-2-amino-N-{2-[2-(2-hydroxyethoxy)pheny]ethyl}-N-methyl-3(2naphthyl)propionamide (155 mg, 0.39 mmol) in dichloromethane (1 ml) and ethyldiisopropylamine (0.07 ml, 0.39 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (30 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (30 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate solution (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crued product was purified by flash chromatography on silica (12 g), using ethyl acetate/heptane (2:1) as eluent to give 147 mg of {(3E)-4-[(1R)-1-(N-{2-[2-(2-hydroxyethoxy)phenyl]ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl]-1,1-dimethylbut-3-enyl}carbamic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[OH:14])=[O:4].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:3](=[O:4])[CH2:2][O:14][C:7]=2[CH:8]=1
Reactant: COc1ccc(NC(=O)CCl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)OCC(=O)N2
Yield: 101 %

Procedure:
2-Chloro-N-(2-hydroxy4-methoxy-phenyl)-acetamide (390.0 g, 0.18 mol) and powdered potassium carbonate (27.6 g, 0.2 mol) were added to 1000 mL acetone, and the reaction mixture was refluxed under nitrogen for eight hours. The reaction mixture was cooled, solids were removed by filtration, and the liquid was concentrated under reduced pressure to give 32.56 g of crude 7-Methoxy-4H-benzo[1,4]oxazin-3-one. (M+H)=180.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][CH:19]1[CH2:21][CH2:20]1)[CH:13]([OH:17])[C:14](O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:23]1C(=O)CC[C:24]1=O.C(Cl)CCl.CN>C(Cl)Cl.C1COCC1>[CH:19]1([CH2:18][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]([OH:17])[C:14]([NH:23][CH3:24])=[O:15])[CH2:21][CH2:20]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(N[C@@H](CC1CC1)C(O)C(=O)O)OCc1ccccc1
Agent: CN
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNC(=O)C(O)[C@H](CC1CC1)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of (3S)-3-(benzyloxycarbonylamino)-4-cyclopropyl-2-hydroxybutanoic acid (180 mg, 0.26 mmol) in DCM (20 mL) was added HOSu (105 mg, 0.92 mmol), EDC (175 mg, 0.92 mmol). After stirred for 30 minutes, methylamine in THF (2 N, 0.92 mL) was added to above mixture. The reaction mixture was stirred for 18 hours and then concentrated in vacuo. The residue was purified by Gilson Prep to afford title compound (50 mg). 1H-NMR (CDCl3): δ 7.53-7.26 (m, 5H), 6.83 (NH, 1H), 5.25 (NH, 1H), 5.05 (m, 2H), 4.25-3.89 (m, 3H), 2.70 (m, 3H), 1.4 (m, 1H), 0.86 (m, 1H), 0.61 (m, 1H), 0.38 (m, 2H), 0.33 (m, 2H). (M+1) 307.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].CC(O)=O>O1CCOCC1.O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([N:8]2[CH2:9][CH2:10][C:11]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[NH:13][C:12]=3[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)=[O:28])=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 3-(4-fluorobenzoyl)-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester (543 mg, 1.42 mmol) in 1,4-dioxane (8 mL) was added aqueous sodium hydroxide (114 mg in 2 mL Of water). The mixture was stirred for 1 hour at 20° C. Solvent was then removed under high vacuum to give a crude product, which was redissolved in water and acidified with AcOH. Solid was collected by filtration and washed with water and dried under high vacuum to give 3-(4-fluorobenzoyl)-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole-5-carboxylic acid (421 mg, 84%); MS (ES): 353 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[N:6][CH:5]=[CH:4][N:3]=1.O.[NH2:18][NH2:19]>C(O)CCC>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][N:6]=2)[NH:19][N:18]=1
Reactant: NN
Reactant: Fc1ccccc1C#Cc1nccnc1Cl
Solvent: CCCCO
Solvent: O
Product: Fc1ccccc1Cc1n[nH]c2nccnc12

Procedure:
A solution of 550 mg (2.36 mmol) of 2-chloro-3-[(2-fluorophenyl)ethynyl]pyrazine from example 13A and 592 mg (11.8 mmol) of hydrazine hydrate in 12 ml of n-butanol is heated in a microwave at 140° C. for 30 min. The solution is then concentrated in vacuo, and the residue is purified by preparative HPLC. 150 mg (26% of theory) of the desired compound are obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.Br.NC(N)=[S:16]>O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[CH2:9][CH2:10][SH:16])=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: CC(CCO)c1ccc(I)cc1
Agent: Br
Solvent: O
Product: CC(CCS)c1ccc(I)cc1
Yield: 41 %

Procedure:
70 g of 3-(p-iodophenyl) butanol was combined in solution with 138 g of hydrobromic acid (48%) and 20 g thiourea in 100 ml of water and the thiol product vacuum distilled at 126° and 0.18 mm Hg. A 41% yield of 3-(p-Iodophenyl) butane thiol was confirmed having a refractive index of n25D = 1.6071 and nmr, ir and gc readings commensurate with the structure of the desired product.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CN(C)C=O.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1>O.C(O)(=O)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)OCC)c1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
50 g (0.31 mol) of diethyl malonate were added, a little at a time, at not more than 50° C. to a mixture of 7.5 g (0.31 mol) of sodium hydride and 50 ml of dimethylformamide, with ice-cooling. After the mixture had cooled to room temperature (approximately 25° C.), it was treated with g (0.173 mol) of 2-chloro-3-nitropyridine. After approximately 15 hours, the reaction mixture was diluted with water, acidified using acetic acid and extracted using ethyl acetate. The organic phases were combined, washed and dried, and the solvent was removed under reduced pressure. The excess malonic ester was distilled off at elevated temperature and reduced pressure ("high vacuum"). This gave 43 g (66%) of the title compound as a yellow oil (purity approximately 75%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:31])=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][C:6]1[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]2[N:13]([C:14]=1[C:15](O)=[O:16])[CH:12]=[CH:11][C:10]([C:18]([O:20][CH3:21])=[O:19])=[CH:9]2.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.[Cl-].[Na+].O.CC(=O)OCC>[CH3:21][O:20][C:18]([C:10]1[CH:11]=[CH:12][N:13]2[C:8]([CH:9]=1)=[C:7]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:6]([CH2:5][C:4]1[CH:28]=[CH:29][CH:30]=[C:2]([F:1])[C:3]=1[CH3:31])=[C:14]2[C:15]([N:42]1[CH2:43][CH2:44][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:38])[CH2:40][CH2:41]1)=[O:16])=[O:19]
Reactant: COC(=O)c1ccn2c(C(=O)O)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution of the crude compound obtained in step 4 (0.420 g, 0.69 mmol), 1-tert-butoxycarbonyl-piperazine (0.142 g, 0.76 mmol) and triethylamine (0.48 ml, 2.78 mmol) in 3.5 ml of DMF cooled at 0° C., was added TBTU (0.490 g, 1.53 mmol) in small portions, and the mixture was stirred at room temperature overnight. 10 ml of EA and 20 ml of brine were then added, the aqueous phase was separated and extracted twice with EA. The combined organic phases were washed with water, 1 N hydrochloric acid, water, an saturated solution of sodium hydrogencarbonate and brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 100:0, then 70:30) to give 0.162 g of the title compound as a beige solid.