Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=13)[N:8]=[CH:7][N:6]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]1[OH:29])[C:5]2=[O:30].[Cl-].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][Zn+])=[CH:35][N:34]=1>ClCCl>[Cl:32][C:33]1[N:34]=[CH:35][C:36]([CH2:39][C:2]2[CH:3]=[C:4]3[C:9](=[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=24)[N:8]=[CH:7][N:6]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH:17]2[OH:29])[C:5]3=[O:30])=[CH:37][CH:38]=1
Reactant: Clc1ccc(C[Zn+])cn1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc3c(cc(Br)c4ccccc43)c2=O)C(O)C1
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cnc3c(cc(Cc4ccc(Cl)nc4)c4ccccc43)c2=O)C(O)C1
Temperature: 90 °C

Procedure:
To a dry 25 mL round bottom flask containing tert-butyl rac-(3R,4R)-4-(6-bromo-4-oxobenzo[h]quinazolin-3(4H)-yl)-3-hydroxypiperidine-1-carboxylate (0.163 g, 0.344 mmol) under N2(g) was added (2-chloro-5-pyridyl)methylzinc chloride (0.5 M in THF, 2.06 mL, 1.03 mmol) and tetrakis (triphenylphosphine)palladium (0) (10 mol %). The reaction was heated to reflux at 90° C. for 20 h, cooled to room temperature, and diluted with dichloromethane. Hexanes were added to the solution and the resultant beige precipitate was collected via filtration, washed with dichloromethane and hexanes, and dried on high vac to provide crude tert-butyl rac-(3R,4R)-4-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]-3-hydroxypiperidine-1-carboxylate that gave a mass ion (ES+) of 520.9 for M+H+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:37]1([NH:42][C:23](=[O:24])[CH:22]([N:8]2[CH2:9][CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[CH:7]2[CH2:6][C:5]2[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NC1CCCC1
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NC2CCCC2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with cyclopentylamine.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[OH:13].[CH3:15][N:16]([CH3:19])[CH:17]=O.[CH3:20]OC(OC)N(C)C>O>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])/[CH:11]=[CH:15]/[N:16]([CH3:19])[CH3:17])=[CH:6][C:5]=1[O:13][CH3:20]
Reactant: CN(C)C=O
Reactant: CC(=O)c1ccc(OC(F)F)c(O)c1
Reactant: COC(OC)N(C)C
Solvent: O
Product: COc1cc(C(=O)/C=C/N(C)C)ccc1OC(F)F
Temperature: 140 °C

Procedure:
Into a 1-necked flask were added 1-[4-(difluoromethoxy)-3-hydroxyphenyl]ethanone (0.317 g, 1.57 mmol), 16 mL of N,N-dimethylformamide, and N,N-dimethylformamide dimethy acetal (0.25 mL, 1.9 mmol). The mixture was heated to 140° C. overnight and after cooling to room temperature, poured into 50 mL water and extracted 3×50 mL ethyl acetate. The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 50% ethyl acetate in hexanes to 100% ethyl acetate over 30 minutes to give (2E)-1-[4-(difluoromethoxy)-3-methoxyphenyl]-3-(dimethylamino)prop-2-en-1-one (51 mg, 0.188 mmol) as a yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH:25]1([CH2:28]Br)[CH2:27][CH2:26]1>CN(C=O)C.CO>[CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:28][CH:25]3[CH2:27][CH2:26]3)[N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC2CC2)c1
Reaction time: 18 h

Procedure:
A solution of N-cyclopropyl-3-(1H-indazol-5-yl)-4-methylbenzamide (Example 17) (0.10 g) in dry DMF (3 ml) was treated with sodium hydride (60% oil dispersion, 0.017 g) under nitrogen. After 5 min cyclopropylmethyl bromide (0.04 ml) was added and the yellow solution was stirred at room temp. for 18 h. Methanol (2 drops) was added and the solvent was evaporated. The residue was purified by column chromatography on silica eluting with cyclohexane:ethyl acetate (2:1 to 1:1) to give the title compound (0.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=NC2CCCCC2)[CH:10]=[C:11]2[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])(=O)/C=C/C([O-])=[O:27]>C(O)(C)C.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:27])[CH:10]=[C:11]2[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(C(C=C2CCCN2)=NC2CCCCC2)cc1Cl
Reactant: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C(C=C1CCCN1)c1ccc(Cl)c(Cl)c1

Procedure:
With the use of 76.8 g (0.3 mole) of 3',4'-dichloro-2-(2-pyrrolidinylidene)-acetophenone, there is obtained in an analogous manner 2-[2-(3,4-dichlorophenyl)-2-(cyclohexylimino)-ethylidene]-pyrrolidine-(1:1)-fumarate, m.p. 208°-209° (from isopropanol/ether).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[CH:19]=O)([O-:3])=[O:2].[CH3:21][CH:22]1[CH2:27][N:26]([C:28]2[CH:29]=[C:30]([NH2:35])[C:31]([NH2:34])=[CH:32][CH:33]=2)[CH2:25][CH2:24][O:23]1.S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[CH3:21][CH:22]1[O:23][CH2:24][CH2:25][N:26]([C:28]2[CH:33]=[CH:32][C:31]3[NH:34][C:19]([C:7]4[C:6]5[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=5)[N:9]([CH:13]5[CH2:18][CH2:17][CH2:16][CH2:15][O:14]5)[N:8]=4)=[N:35][C:30]=3[CH:29]=2)[CH2:27]1
Reactant: CC1CN(c2ccc(N)c(N)c2)CCO1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1CN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc([N+](=O)[O-])cc45)nc3c2)CCO1
Temperature: 70 °C
Yield: 55.5 %

Procedure:
5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (150 mg, 0.545 mmol) and 4-(2-methylmorpholino)benzene-1,2-diamine (113 mg, 0.545 mmol) were dissolved in THF (10 mL) and 2N HCl (1 drop) was added. The solution was heated at a gentle reflux for 30 min. Then, 1N sodium bisulfite (104 mg, 1 mmol; 2 mL of a 1N solution) was added and heated at reflux (70° C.) overnight. The solution was cooled to room temperature, and diluted with ethyl acetate (40 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (140 mg). 1H NMR: (400 MHz, CDCl3): δ 9.56 (d, 1H, J=1.6 Hz), 8.28 (m, 1H), 7.74 (d, 1H, J=8.8 Hz), 7.64 (m, 1H), 7.36 (m, 1H), 7.03-6.96 (m, 1H), 5.75 (dd, 1H, J=2.8 and 6.4 Hz), 3.99 (m, 2H), 3.79 (m, 3H), 3.38 (m, 2H), 2.84 (m, 1H), 2.51 (m, 2H), 2.11 (m, 2H), 1.86 (m, 1H), 1.74 (m, 2H), 1.22 (d, 3H, J=6.4 Hz).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:46])[CH:6]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=1)[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:27]4[O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:26]=4[CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9].Cl>O1CCCC1.CO.O>[CH:25]1[C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][C:27]=2[C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH2:7][CH:6]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:43])([F:44])[F:45])[CH:37]=4)[C:5]([OH:46])=[O:4])=[CH:15][CH:14]=3)=[CH:21][CH:20]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)C(CC(=O)c1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(CC(Cc1cccc(C(F)(F)F)c1)C(=O)O)c1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 25 °C

Procedure:
2 N Sodium hydroxide solution (1 mL) was added dropwise to a stirred solution of methyl-4-(4′-dibenzofuran-4-ylbiphen-4-yl)-4-oxo-2-(3-trifluoromethy-benzyl)butyrate (220 mg) in tetrahydrofuran (5 mL) and methanol (2 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (5 mL), and acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with water, sat'd aq NaCl, dried over anhyd MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (5-10% methanol in methylene chloride) afforded the title compound has a white solid (190 mg). Rf: 0.60 (10% methanol in dichloromethane); 1H-NMR (CDCl3, 300 MHz): δ 8.06 (4H, m, Ar—H), 7.96 (2H, m, Ar—H), 7.77 (4H, t, J=9 Hz, Ar—H), 7.62 (2H, t, J=9 Hz, Ar—H), 7.47 (6H, m, Ar—H), 7.37 (1H, t, J=8 Hz, Ar—H), 3.46 (2H, m), 3.26 (1H, dd, J=16, 7 Hz), 3.12 (1H, m), 3.02 (1H, dd, J=16, 8 Hz); ESI-LCMS e/z calcd for C36H25F3O4:578.583, found 579 (M+H)+, 601 (M+Na)+.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=1)[CH3:22].C(O)(=O)C.[Na]>CCCCCC.C(OCC)(=O)C>[CH2:21]([O:23][C:24]([C:25]1[CH:26]=[C:27]([NH:31][C@H:2]2[CH2:11][CH2:10][C@@H:9]3[C@@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]3)[CH2:3]2)[CH:28]=[CH:29][CH:30]=1)=[O:32])[CH3:22]
Reactant: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Reactant: CCOC(=O)c1cccc(N)c1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCOC(=O)c1cccc(N[C@H]2CC[C@H]3CN(C(=O)OC)[C@H](C(=O)OCC)C[C@H]3C2)c1
Yield: 91.1 %

Procedure:
Following the procedures from Example 1A, and using ethyl 6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate (11.4 g, 40.28 mmol), 3-aminobenzoic acid ethyl ester (3.5 g, 21.2 mmol), glacial acetic acid (5.0 mL, 84.0 mmol), and sodium triacethoxyborohydride (12.58 g, 59.36 mmol) flash chromatography (silica gel, hexane-ethyl acetate 3:1) afforded 8.35 g (92% yield) of the title compound.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH:2]=[CH2:3].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=1[Cl:23].C1(C)C=CC=CC=1.C1(N(C)C2CCCCC2)CCCCC1>C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:15][C:16]1[CH:21]=[C:20](/[CH:3]=[CH:2]/[CH2:1][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[C:5]2=[O:14])[CH:19]=[CH:18][C:17]=1[Cl:23]
Reactant: C=CCN1C(=O)C(=O)c2ccccc21
Reactant: Clc1ccc(I)cc1Cl
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C1C(=O)N(C/C=C/c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 80 °C
Yield: 83.9 %

Procedure:
A mixture of 1-allyl-1H-indole-2,3-dione (1.00 g, 5.34 mmol), Pd(P(t-Bu)3)2 (0.0819 g, 0.16 mmol), 1,2-dichloro-4-iodobenzene (1.458 g, 5.34 mmol), dry toluene (10 mL), and N-cyclohexyl-N-methylcyclohexanamine (1.23 mL, 5.86 mmol) in an oven-dried sealed tube under an atmosphere of N2 was heated for 16 h at 80° C. The reaction was cooled, diluted with CH2Cl2, and loaded directly onto a silica gel column that had been packed with CH2Cl2. The column was eluted with a gradient of 100% CH2Cl2 to 95:5 CH2Cl2:EtOAc. The appropriate fractions were combined to provide the title compound as an orange solid (1.489 g, 84%). 1H NMR (600 MHz, CHLOROFORM-D) δ ppm 4.52 (d, J=5.9 Hz, 2H), 6.19 (dt, J=15.9, 5.9 Hz, 1H), 6.56 (d, J=15.6 Hz, 1H), 6.91 (d, J=7.9 Hz, 1H), 7.09-7.20 (m, 2H), 7.37 (d, J=8.2 Hz, 1H), 7.42 (s, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.64 (d, J=7.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[N:10]([CH2:17][CH:18]([OH:34])[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])[CH2:22][CH2:21]3)[N:9]=2)=[CH:4][C:3]=1[CH3:35].Cl[C:37](=[O:42])[C:38]([O:40][CH3:41])=[O:39].CO.C(Cl)Cl>C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[C:37]([N:14]1[CH2:15][CH2:16][C:11]2[N:10]([CH2:17][CH:18]([OH:34])[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])[CH2:22][CH2:21]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:35])[CH:4]=3)[C:12]=2[CH2:13]1)=[O:42]
Reactant: Cc1cc(-c2nn(CC(O)CN3CCN(c4ccccc4C#N)CC3)c3c2CNCC3)ccc1Cl
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2CC(O)CN2CCN(c3ccccc3C#N)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
2-(4-{3-[3-(4-Chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile (58 mg, 0.118 mmol) was dissolved in CH2Cl2 (0.59 mL) and treated with methyl chlorooxoacetate (16 mg, 0.129 mmol). The reaction mixture was allowed to stir for 18 h at room temperature. Column chromatography (silica, 2-10% MeOH/CH2Cl2) gave (3-(4-chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-oxo-acetic acid methyl ester (54 mg, 79%) as a white solid. MS (electrospray): m/z 577.3 (577.2, calculated for C30H33ClN6O4, [M+H]+). 1H NMR (400 MHz, CDCl3): 7.32-7.62 (m, 5H), 7.14 (t, J=7.6 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 4.59-4.80 (m, 3H), 4.12-4.28 (m, 2H), 3.92 (s, 3H), 3.78-3.86 (m, 2H), 3.44-3.60 (m, 5H), 3.15-3.40 (m, 4H), 2.83-3.05 (m, 2H), 2.41 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Cl)[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[C:14]([NH2:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([C:14]2[O:21][C:5]([C:4]([OH:3])=[O:13])=[C:6]([C:7]([F:8])([F:9])[F:10])[N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:1]([O:3][C:4]([CH:5]1[O:21][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:22][C:6]1([OH:11])[C:7]([F:10])([F:9])[F:8])=[O:13])[CH3:2]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: NC(=O)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1OC(c2ccccc2)=NC1(O)C(F)(F)F
Product: O=C(O)c1oc(-c2ccccc2)nc1C(F)(F)F
Temperature: 25 °C
Yield: 75.5 %

Procedure:
2-Phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid was prepared according to the procedure described in Bioorg. Med. Chem. Lett. 2003, 13, 1517. A solution of 2-chloro-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (436 mg, 2 mmol) and benzamide (484 mg, 4 mmol) in ethanol (6 mL) in a sealed tube was heated at 120 degrees for 30 h. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography (silica gel 60, 230-400 mesh, 0-80% ethyl acetate in hexane for 25 min) to give 4-hydroxy-2-phenyl-4-trifluoromethyl-4,5-dihydro-oxazole-5-carboxylic acid ethyl ester as an off-white solid (229 mg, 38% yield). LCMS calcd for C13H12F3NO4 (m/e) 303, obsd 304 (M+H). The ester was dehydrated by heating with 2 mL of phosphorus oxychloride at 80 degree overnight. The reaction mixture was cooled and concentrated. The resulting residue was mixed with THF and concentrated again to remove remaining POCl3. The oily residue was quenched with water and extracted with DCM (2×). The organic layer was concentrated. The crude product was purified by flash chromatography (silica gel 60, 230-400 mesh, 0-50% ethyl acetate in hexane for 25 min) to yield 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid ethyl ester as an off-white solid (160 mg, 75% yield). The ester was hydrolyzed by stirring with lithium hydroxide monohydrate in a mixed solvent of 3:1:1 of THF:MeOH:water (3 mL) at RT for 4 h. The reaction was concentrated and water was added. The pH of the solution was adjusted to ˜1-2 with 1 N HCl. The white precipitate was collected by centrifugation and washed with water. After drying under vacuum, 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid was obtained as a white solid (141 mg, 98% yield. LCMS calcd for C11H6F3NO3 (m/e) 257, obsd 258 (M+H).
Reaction SMILES: [Na].[CH2:2]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[CH2:4].[CH3:16][O:17][CH2:18][CH2:19]Br>C(O)C.O>[CH3:16][O:17][CH2:18][CH2:19][C:5]([CH2:2][CH:3]=[CH2:4])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: COCCBr
Agent: [Na]
Solvent: CCO
Solvent: O
Product: C=CCC(CCOC)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Metallic sodium (15 g, 230 mmol) was dissolved in dry ethanol (250 mL) with cooling in an ice bath, under nitrogen, and diethyl allylmalonate (Lancaster Synthesis, Windham, Mass.) (105 g, 525 mmol) in absolute ethanol (50 mL) was added dropwise under nitrogen. The mixture was stirred at room temperature for 1 h. and 2-bromoethyl methyl ether (87.57 g, 630 mmol) in absolute ethanol (50 mL) was then added dropwise. The mixture was heated at reflux for 3 h and then cooled to room temperature. The precipitate solid was filtered and washed with ethanol (2×100 mL). The residue obtained upon concentration of the filtrate was diluted with water (1 L). The mixture was extracted with ether (2×150 mL), dried over MgSO4 and concentrated to give the diester ether 2 (118 g, 87%) as a viscous liquid. IR (KBr) υmax 3069, 2971, 2927, 1734, 1640, 1459, 1443, 1382, 1361, 1284, 1223, 1196, 1119, 1077, 1031, 922, 856 cm−1: 1HNMR (CDCl3) δ1.24 t, J=7.0 Hz, 6 H), 2.17 (t, J=6.4 Hz, 2 H), 2.68 (d, J=7.1 Hz, 2 H), 3.2 (s, 3 H), 3.41 (t, J=6.5 Hz, 2 H), 4.17 (dis q, 4 H), 5.04-5.12 (m, 2 H), 5.63-5.79 (m, 1 H); 13CNMR (CDCl3) δ13.98, 32.05, 37.31, 55.08, 58.52, 61.13, 68.34, 118.93, 132.49, 170.17; mass spectrum (EI), m/z (rel itensity) 259 (M++1.16), 227 (20), 213 (19), 200 (37), 185 (13), 167 (17), 154 (25), 153 (65), 139 (38), 125 (25), 108 (100), 81 (30), 79 (31), 67 (23), 59 (23), 53 (23).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:11]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=1)(=[O:13])=[O:12].Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:11]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:27][CH:28]=1
Reactant: NCCc1ccccc1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(CN(CCc2ccccc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from 2-phenylethanamine, methyl 4-(chlorosulfonyl)-benzoate (Example 5-10c) and 1-(chloromethyl)-4-methoxybenzene. MS (M−H, 424.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.51 (m, 2H), 3.23 (m, 2H), 3.74 (s, 3H), 4.31 (s, 2H), 4.31 (s, 2H), 6.92 (m, 2H), 6.98 (m, 2H), 7.20-7.27 (m, 5H), 7.85 (m, 2H), 8.06 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH:16]([CH3:18])[CH3:17])C(C#N)O)C1C=CC=CC=1.Cl.C1([O:27]C)C=CC=CC=1.[O:29]1[CH2:34][CH2:33][O:32]CC1>>[NH2:10][CH:11]([CH:16]([CH3:18])[CH3:17])[C@H:33]([OH:32])[C:34]([OH:29])=[O:27]
Reactant: C1COCCO1
Reactant: COc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(O)C#N
Agent: Cl
Product: CC(C)C(N)[C@H](O)C(=O)O
Temperature: 110 °C

Procedure:
To a solution of ((S)-2-Cyano-2-hydroxy-1-isopropyl-ethyl)-carbamic acid benzyl ester (10) (5.1 g, 19.5 mmol) in 1,4-dioxane (90 mL) was added conc. HCl (90 mL) and anisole (1.5 equiv.) and the mixture was heated to 110° C. for 18 h. The reaction mixture was cooled to ambient temperature and concentrated under vacuum to remove the dioxane. The mixture was then washed with EtOAc and the residue further concentrated under vacuum at 40° C. to remove the conc HCl. Any residual water was removed by azeotroping with toluene. The residue was washed with Et2O (2×50 mL) to afford hydroxyl acid (11) as a gummy solid (crude, mixture of diastereoisomers). 1H NMR (400 MHz, DMSO-d6): δ 8.20 (1H, brs), 7.96 (1H, brs), 4.42 (1H, d J=3.0 Hz), 4.17 (1H, d J=4.0 Hz), 3.17-3.05 (2H, m), 1.98-1.86 (2H, m), 0.96-0.86 (6H, m); m/z 148 (MH)+.
Reaction SMILES: [CH2:1]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:2]1[O:4][CH2:3]1.O>CC(O)=O.C1COCC1>[CH2:1]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8])[C@H:2]1[O:4][CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CO1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Yield: 48.3 %

Procedure:
Using the (R,R)-(salen)Co(II) precatalyst of 1 (91 mg, 0.15 mmol, 0.005equiv), (+/−)-(tert-butyldimethylsilyl) glycidyl ether (5.64 g, 30.0 mmol), AcOH (32 mL, 0.6 mmol, 0.02 equiv), 0.3 mL THF, and H2O (297 mL, 16.5 mmol, 0.55 equiv) and a procedure analogous to the one outlined for 5b, (S)-(tert-butyldimethylsilyl) glycidyl ether 5c (2.72 g, 14.5 mmol, 48%) was obtained as a clear oil by vacuum distillation of the reaction mixture (30° C., 0.5 Torr). The product was determined to be present in >99% ee by derivatization through ring opening with 2-napthalenethiol in methanol using 1 equiv TEA at 0° C. and direct analysis of the 2-napthylsulfide thus obtained (Chiralcel OD, 99.25:0.75 hexanes:EtOH, 1 mL/min, 230 nm).
Reaction SMILES: IC.[Cl:3][C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[OH:18])[N:5]=1.[OH-].[K+].[CH3:21]S(C)=O>O>[Cl:3][C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[O:18][CH3:21])[N:5]=1
Reactant: CS(C)=O
Reactant: O=[N+]([O-])c1ccc(-n2cnc(Cl)n2)c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.6 %

Procedure:
Iodomethane (0.860 mL, 13.82 mmol) was added to a mixture of 2-(3-chloro-1H-1,2,4-triazol-1-yl)-5-nitrophenol (1.33 g, 5.53 mmol), potassium hydroxide (0.388 g, 6.91 mmol), and DMSO (25 mL). The mixture was left to stir at rt for 24 h. The reaction mixture was poured into water (250 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified using silica gel column chromatography (0-1% MeOH/chloroform, linear gradient over 72 min, flow 25 mL/min). The pure fractions were combined and concentrated to afford 3-chloro-1-(2-methoxy-4-nitrophenyl)-1H-1,2,4-triazole (0.924 g, 3.63 mmol, 65.6% yield) as a light yellow solid. LC-MS (M+H)+=255.0. 1H NMR (500 MHz, CDCl3) δ ppm 8.35 (s, 1H) 7.36 (d, J=8.55 Hz, 1H) 6.29-6.34 (m, 2H) 3.80 (s, 3H) 2.46 (s, 3H).