Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].[Mg].II.C(OC([N:20](C(OC(C)(C)C)=O)[C@H:21]([CH2:32][CH2:33]/[CH:34]=[CH:35]/[N+:36]([O-])=O)[C:22](OCC1C=CC=CC=1)=[O:23])=O)(C)(C)C>C(OCC)C>[NH2:20][C@@H:21]1[CH2:32][CH2:33][CH:34]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=2[Cl:9])[CH2:35][NH:36][C:22]1=[O:23]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC/C=C/[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: Clc1cccc(Br)c1Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: N[C@@H]1CCC(c2cccc(Cl)c2Cl)CNC1=O
Temperature: 25 °C
Yield: 176.3 %

Procedure:
To a slurry of 1-bromo-2,3-dichlorobenzene (1.46 g, 6.46 mmol) in diethyl ether (10 mL) was added magnesium (0.157 g, 6.46 mmol) and a crystal of iodine. This mixture was refluxed for 3 h, and then cooled to room temperature. A solution of benzyl (2R,5E)-2-[bis(tert-butoxycarbonyl)amino]-6-nitrohex-5-enoate (0.50 g, 1.08 mmol) in diethyl ether (10 mL) was cooled to 0° C., and 2.0 mL of the Grignard solution prepared above was added. After 1 and 2 h, respectively, 2.0 and 1.0 mL of the Grignard solution was added. The reaction was quenched with a saturated aqueous solution of ammonium chloride, the phases separated and the organic phase washed with saturated aqueous sodium potassium tartrate and brine. The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue that was purified by silica gel chromatography (0%→3% methanol/dichloromethane) to give the title compound (0.52 g). MS 411.0 (M+1-2Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:20]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:20])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: NC(=S)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 64 %

Procedure:
To a stirred mixture of 14.9 grams (0.102 mole) of 4-chlorobenzamide in 800 ml of toluene was added 20.6 grams (0.051 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent). This mixture was stirred and heated at reflux for two hours. The reaction mixture was allowed to cool slowly to room temperature. Approximately 600 ml of toluene was evaporated from the mixture under reduced pressure, leaving a residual liquid. This liquid was purified by column chromatography on silica gel, eluting with methylene chloride:ethyl acetate (60:40), to yield 5.6 grams of 4-chlorophenylthiocarboxamide as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]([O-:20])([O-:19])=O.[K+].[K+].[CH:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:30][C:31](Cl)=[O:32])=[CH:25][CH:24]=1.O>ClCCl>[CH2:10]([N:9]([C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:31]([O:30][CH2:29][C:26]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)=[O:32])=[CH:7][C:2]=1[F:1])[C:17](=[O:20])[O:19][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(NCc2ccccc2)c(F)c1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(N(Cc2ccccc2)C(=O)OCc2ccccc2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 152 %

Procedure:
7 g (217.3 mmol) of N-(2-fluoro-4-aminophenyl)-N-benzyl amine (4) obtained from the aforesaid process was dissolved in 500 mL dichloromethane, then 60 g (434.6 mmol) of K2CO3 was added thereto, with stirring in an ice bath for 10 minutes. 92 mL (652 mmol) Cbz-Cl was dropped slowly to the mixture over 1 hour and then the mixture was warmed to room temperature. After completion of the reaction, 200 mL water was added to the reaction solution under stirring for 1 hour. The resultant mixture was allowed to stand for separation, and the dichloromethane layer was washed in sequence with 10% diluted hydrochloric acid and NaHCO3 solution. The obtained dichloromethane layer was rotary evaporated to afford a light yellow oil, which was purified with column chromatography to obtain 80 g of a white solid, with a yield of 76.2%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.C1([C:21](=[O:30])[CH2:22][C:23]2[CH:24]=[C:25](C)[CH:26]=[CH:27][CH:28]=2)C=CC=CC=1>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:21](=[O:30])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: Clc1cc(Cl)cc(Br)c1
Reactant: Cc1cccc(CC(=O)c2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 18.3 %

Procedure:
To a solution of 1-bromo-3,5-dichlorobenzene (1 g, 4.4 mmol) in anhydrous THF (10 mL) was added n-BuLi (339 mg, 5.3 mmol) at −78° C. After being stirred for 30 minutes, a solution of N-methoxy-N-methyl-2-phenyl-acetamide (prepared following step 1 of Intermediate 4) (790 mg, 4.4 mmol) in THF (5 mL) was added, and the mixture was stirred for 3 hours. When TLC indicated that starting material was consumed, the reaction mixture was diluted with water (50 mL), and extracted with EtOAc (20 mL×3). The combined organic layer was dried over Na2SO4, concentrated in vacuum, and purified by column chromatography (PE:EtOAc=50:1) to afford 1-(3,5-dichlorophenyl)-2-phenylethanone (213 mg, yield 19.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:28])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)=[O:17])[CH2:13][CH2:12][N:11]([C:29]([C:31]3[NH:32][C:33]4[C:34](=[O:40])[CH2:35][CH2:36][CH2:37][C:38]=4[CH:39]=3)=[O:30])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:43]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:28])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][N:19]=3)=[O:17])[CH2:13][CH2:12][N:11]([C:29]([C:31]3[N:32]([CH3:43])[C:33]4[C:34](=[O:40])[CH2:35][CH2:36][CH2:37][C:38]=4[CH:39]=3)=[O:30])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)c1ccc(C(F)(F)F)cn1)[C@@H]1CCN(C(=O)c2cc3c([nH]2)C(=O)CCC3)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccc(C(F)(F)F)cn1)[C@@H]1CCN(C(=O)c2cc3c(n2C)C(=O)CCC3)C[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of the compound (0.060 g) obtained in Example 642 in DMF (1 mL) was added sodium hydride (0.005 g) and the mixture was stirred for 10 min. Methyl iodide (0.020 mL) was added at 0° C. and the mixture was stirred at room temperature. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 30→70% ethyl acetate/hexane) to give the title compound (0.020 g, 33%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]([CH2:17][O:18][CH2:19][CH2:20][Cl:21])=[O:16])[CH3:11].N1CCCCC1>C(O)(C)C.C(O)(=O)C.N1CCCCC1>[CH2:10]([O:12][C:13](=[O:22])[C:14](=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])[C:15]([CH2:17][O:18][CH2:19][CH2:20][Cl:21])=[O:16])[CH3:11]
Reactant: CCOC(=O)CC(=O)COCCCl
Reactant: O=Cc1ccccc1Cl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)COCCCl
Yield: 97 %

Procedure:
16.64 g (0.118 mole) of 2-chloro-benzaldehyde (V) and 24.7 g (0.118 mole) of ethyl-4-(2-chloroethoxy)-acetoacetate (IV) are reacted in 365 ml of isopropanol in the presence of a piperidine acetate catalyst [10 g (11.8 millimoles) of piperidine+0.7 g (11.8 millimoles) of acetic acid] at room temperature for 10 hours. The reaction mixture is evaporated, the residual oil is dissolved in dichloro methane, washed with water and dried. The organic phase is evaporated in vacuo. Thus 37.9 g of the desired product are obtained in the form of a yellow oil, yield 97%.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].[O-:26][C:27]#[N:28].[K+]>C(O)(=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH:24][C:27]([NH2:28])=[O:26])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(CN)ccc2-3)n(C(C)C)n1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(CNC(N)=O)ccc2-3)n(C(C)C)n1

Procedure:
Following the procedures for 542, C-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine 532 was reacted with potassium cyanate in acetic acid and water to give 524. MS (ESI+) 399.1.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][O:27]1>>[CH3:23][N:24]([CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][O:27]1)[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: CNC[C@H]1CCCO1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(C[C@H]1CCCO1)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-N-methyl-1(tetrahydrofuran-2-yl)methanamine (1.2 equiv) to give 174 (18.4 mg, M+1 411.1)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C([O-])([O-])=O.[K+].[K+].[C:28]1([CH:34]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:35][NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[C:39]=2[Cl:48])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[C:49]1([CH:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:35][N:36]([CH2:2][CH2:3][CH2:4][OH:5])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[C:39]=2[Cl:48])[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: FC(F)(F)c1cccc(CNCC(c2ccccc2)c2ccccc2)c1Cl
Reactant: OCCCBr
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a stirring solution of 3-bromo-propanol (77 ul, 0.84 mmol) in acetonitrile (10 ml) was added Nal (0.25 g, 1.7 mmol) and K2CO3 (0.23 g, 1.7 mmol). The mixture was stirred at 85° C. for 1 h, and then N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine (0.43 g, 1.12 mmol) was added. The reaction mixture was heated at 85° C. overnight. Solvent was removed, the residue was washed with H2O, and extracted twice with EtOAc. The EtOAc extracts were dried over Na2SO4, filtered, and concentrated. The crude mixture was purified by preparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H2O, UV detection at 254 nm) to give 225 mg (60%) of the title compound as a white solid. MS (ESI) 448.0 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].[BrH:14]>O>[Br:14][C:3]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=1[I:1]
Reactant: Cc1ccc(N)c(I)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)c(I)c1
Temperature: 0 °C
Yield: 81.8 %

Procedure:
2-Iodo-4-methylaniline (100 g, 450 mmol) was suspended in the mixture of water (200 mL) and HBr (48%, 300 mL). The mixture was refluxed for 15 min. Then the mixture was cooled to 0° C., and NaNO2 (31.05 g, 0.45 mol) in water (150 ml) was added dropwise at such a rate that the temperature did not exceed 5° C. The diazonium solution wad stirred for a further 30 min at 0-5° C. and then added slowly to a stirred mixture of CuBr (64.5 g, 0.45 mol) in HBr (48%, 250 mL) and water (250 ml) at room temperature. The mixture was poured into ice and extracted with CH2Cl2 (500 ml×3). The methylene chloride layer was washed with brine, dried over Na2SO4, and evaporated in vacuum to give the crude product (109 g, yield 81.8%). It can be further purified by column chromatography eluting with petroleum ether. MS: 297 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[NH:27][CH:28]([CH:32]([CH3:34])[CH3:33])[C:29]([OH:31])=[O:30].[C:35]([C:43]1[N:48]=[C:47]([CH2:49][OH:50])[CH:46]=[CH:45][CH:44]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O:12][CH2:49][C:47]2[CH:46]=[CH:45][CH:44]=[C:43]([C:35](=[O:42])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:48]=2)=[O:11])=[CH:6][CH:7]=1.[F:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[NH:27][CH:28]([CH:32]([CH3:34])[CH3:33])[C:29]([O:31][CH2:35][C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([C:49](=[O:50])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:48]=1)=[O:30]
Reactant: CC(C)C(Nc1ccc(Cl)cc1)C(=O)O
Reactant: O=C(c1ccccc1)c1cccc(CO)n1
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)OCc1cccc(C(=O)c2ccccc2)n1
Product: CC(C)C(Nc1ccc(Cl)cc1)C(=O)OCc1cccc(C(=O)c2ccccc2)n1

Procedure:
Following the procedure of Example 1, the acid chloride of each of 2-(4-chlorophenylamino)-3-methylbutanoic acid and 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with (6-benzoyl-2-pyridyl)methanol to yield (6-benzoyl2-pyridyl)methyl 2-(4-chlorophenylamino)-3-methylbutanoate and (6-benzoyl-2-pyridyl)methyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[C:8](=O)[CH2:9][CH3:10].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2]1[C:3]([O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[C:8](=[N:24][OH:25])[CH2:9][CH3:10]
Reactant: NO
Reactant: CCC(=O)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC(=NO)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of 1-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-one (330 mg, 1.11 mmol), hydroxylamine hydrochloride (230.4 mg, 3.33 mmol), and sodium acetate (273 mg, 3.33 mmol) in ethanol (25 ml) was stirred at room temperature over a weekend. The mixture was concentrated to dryness, then diluted with water, and extracted with chloroform. The organic layer was separated, dried over sodium sulfate and concentrated to dryness to give 306 mg of a mixture of the title (E) and (Z)-isomers as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[O:4].C(Cl)(=O)C(Cl)=O.[CH:20]([O:23][C:24](=[O:28])[CH2:25][NH:26][CH3:27])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C>ClCCl.CN(C1C=CN=CC=1)C.CN(C)C=O>[C:3]([O:2][CH3:1])(=[O:4])/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11](=[O:13])[N:26]([CH3:27])[CH2:25][C:24]([O:23][CH:20]([CH3:22])[CH3:21])=[O:28])=[O:8]
Reactant: CNCC(=O)OC(C)C
Reactant: COC(=O)/C=C/C(=O)OCC(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)OCC(=O)N(C)CC(=O)OC(C)C
Yield: 26.8 %

Procedure:
Following general procedure B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetic acid (23) (0.50 g, 2.65 mmol) was activated with oxalyl chloride (0.30 mL, 0.40 g, 3.18 mmol) in dichloromethane (DCM) at ca. 0° C. and in the presence of a catalytic amount of N,N-dimethylformamide (DMF). A DCM solution of the freshly prepared crude acid chloride was reacted ca. 0° C. (ice bath) with sarcosine isopropyl ester (H-Sar-OiPr) (0.41 g, 3.18 mmol) and diisopropylethylamine (DIEA) (0.41 mL, 0.304 g, 2.35 mmol) in DCM and in the presence of 4-(N,N-dimethyl)aminopyridine (DMAP) (0.10 g, 0.82 mmol). After aqueous work-up and isolation, and purification by silica gel flash chromatography afforded 0.214 g (27% yield) of the title compound (35) as a pale-yellow solid. 1H NMR (CDCl3, 400 MHz, all rotamers): δ 6.94-6.90 (m, 2H), 5.09-4.99 (m, 1H), 4.89-4.79 (2s, 2H), 4.07-3.95 (2s, 2H), 3.78 (s, 3H), 3.04-2.98 (2s, 3H), 1.27-1.21 (m, 6H). MS (ESI): m/z 302.04 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[CH:20]=[CH:21]/[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH2:1]([N:4]([CH2:5][CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[CH:20]=[CH:21]/[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)[CH2:2][CH3:3]
Reactant: CCCNCCC
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2s1
Product: CCCN(CCC)CCCCOc1ccccc1/C=C/c1nc2ccccc2s1
Yield: 35 %

Procedure:
Reaction of this product (5.0 g, 14.5 mmol) with dipropylamine produced 2.1 g (35% yield) of the named compound as the HCl salt, mp 155°-156° C. IR(KBr): 3400, 1600 cm-1. MS: 409(MH+). 1H NMR (CD3OD): δ 8.19-6.99 (m, 10H), 4.10 (t, J=5.2 Hz, 2H), 3.12(m, 6H), 1.85(m, 8H), 1.02 (m, 6H).
Reaction SMILES: [F:1][CH:2]([F:34])[O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]([C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])[CH2:16][CH3:17])[CH:11]=[CH:10][C:5]=1[C:6]([NH:8][OH:9])=[NH:7].C(N(CC)C(C)C)(C)C.Cl[C:45](OC1C=CC=CC=1)=[O:46].O>O1CCCC1>[F:34][CH:2]([F:1])[O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]([C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])[CH2:16][CH3:17])[CH:11]=[CH:10][C:5]=1[C:6]1[NH:7][C:45](=[O:46])[O:9][N:8]=1
Reactant: CCC(Oc1ccc(C(=N)NO)c(OC(F)F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(Oc1ccc(-c2noc(=O)[nH]2)c(OC(F)F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 315 mg of 2-difluoromethoxy-N-hydroxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzamidine in 6.5 mL of tetrahydrofuran at 0° C. was added 1.5 mL of N,N-diisopropylethylamine followed by 0.08 mL of phenyl chloroformate. The resulting mixture was stirred for 5 minutes at 0° C. then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved 6.5 mL of tetrahydrofuran and 0.3 mL of N,N-diisopropylethylamine. The resulting solution was heated in a sealed tube to 150° C. under microwave irradiation for 15 minutes. After allowing it to cool down to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (diisopropyl ether 100 followed by a gradient from dichloromethane 100 to dichloromethane 90/methanol 10) to give 31 mg of 3-(2-difluoromethoxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-4H-1,2,4-oxadiazol-5-one.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=[CH:28][C:29]#[N:30]>>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]2[CH:10]=[C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:28]=[C:29]([NH2:30])[N:12]2[N:13]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Reactant: N#CC=Cc1ccccn1
Product: Nc1cc(-c2ccccn2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, MS m/e (%): 278 (M+H+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(2-pyridinyl)-2-propenenitrile.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[C:18]([F:27])=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH3:26])=[CH:20]4)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>CN(C=O)C>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[C:18]([F:27])=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][C:21]([CH3:26])=[CH:20]5)=[N:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:28][CH3:29])[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCBr
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Yield: 100 %

Procedure:
A solution of 7-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (0.25 g, 0.543 mmol) and 1-acetylpiperazine (0.208 g, 1.63 mmol) in DMF (4 ml) was stirred at 80° C. for 2.5 hours. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and the resulting solid was filtered, washed with diethyl ether and dried under vacuum to give 7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (0.25 g, 0.543 mmol).
Reaction SMILES: [C:1](O[C:6]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH2:10][O:11][CH3:12])=O)(C)(C)C.[C:16]([O:20][C:21]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH2:25][O:26][CH3:27])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH3:6][NH:8][C@@H:9]([C:13]([NH2:23])=[O:15])[CH2:10][O:11][CH3:12].[C:16]([O:20][C:21]([N:23]([CH3:1])[C@@H:24]([C:28]([OH:30])=[O:29])[CH2:25][O:26][CH3:27])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CN[C@H](COC)C(N)=O
Product: COC[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C

Procedure:
N2,O-dimethyl-D-serinamide was prepared by methylating N-(tert-butoxycarbonyl)-O-methyl-D-serine using an analogous method to that described in Example 7 for the methylation of N-(tert-butoxycarbonyl)-O-methyl-L-serine, to give N-(tert-butoxycarbonyl)-N,O-dimethyl-D-serine; 1H NMR spectrum: (DMSO d6, 100° C.) 1.40 (s, 9H), 2.77 (s, 3H), 3.26 (s, 3H), 3.67 (m, 2H), 4.51 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.N1[CH2:20][CH2:19][CH2:18][CH2:17]1.O.C(O[CH2:26][CH3:27])(=O)C>CO>[CH:26]1([CH:27]=[C:11]2[CH2:10][CH2:9][C:8]3[N:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]=3[C:2]2=[O:1])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc2c(n1)CCCC2=O
Reactant: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2c(n1)CCC(=CC1CCCC1)C2=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 58 %

Procedure:
In a dried reaction flask, methyl 5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylate (1.97 g, 9.6 mmol), cyclopentylcarbaldehyde (2.05 mL, 19.20 mmol), and pyrrolidine (1.6 mL, 19.39 mmol) were dissolved in methanol (19 mL) at room temperature. In the protection from light and under the nitrogen atmosphere, the mixture was stirred at room temperature for 6 hr. To the mixture were added water and ethyl acetate. The mixture was extracted with ethyl acetate. The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to obtain a pale yellow solid (1.589 g) in 58.0% yield.