Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][CH:8]([O:37][Si:38]([CH2:43]C)([CH2:41][CH3:42])[CH2:39][CH3:40])[C:9]([CH3:36])([CH3:35])[C:10](=[O:34])[CH:11]([CH3:33])[CH:12]([O:24]C(OCC(Cl)(Cl)Cl)=O)[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]>[Zn].C1COCC1.CC(O)=O>[C:1]([O:5][C:6](=[O:45])[CH2:7][CH:8]([O:37][Si:38]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH3:43])[C:9]([CH3:35])([CH3:36])[C:10](=[O:34])[CH:11]([CH3:33])[CH:12]([OH:24])[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[Si](CC)(CC)OC(CC(=O)OC(C)(C)C)C(C)(C)C(=O)C(C)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)COCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[Si](C)(CC)OC(CC(=O)OC(C)(C)C)C(C)(C)C(=O)C(C)C(O)C(C)COCc1ccccc1
Yield: 1022.2 %

Procedure:
To a solution of 71 (22.9 mg, 3.2 μmol) in 1:1 THF/AcOH (1.4 mL) was added Zn (5.0 mg, 7.8 μmol, nanosize). The mixture was sonicated for 15 min. More Zn (5.0 mg, 7.8 μmol, nanosize) was added, followed by sonication for a further 15 min. The suspension was filtered through a celite pad, washing with EtOAc several times. The filtrates were washed with sat. NaHCO3, brine, dried over MgSO4 and concentrated under vacuum. The crude residue was passed through a short plug of silica gel eluting with hexane/EtOAc 4:1 to give 17.1 mg (99% yield) of 71a as colorless oil: 1H NMR (400 MHz, CDCl3) δ (m, 6H), 0.96 (t, J=7.9 Hz, 9H), 0.97 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H), 1.11 (s, 3H), 1.26 (s, 3H), 1.44 (s, 9H), 1.84-1.90 (m, 1H), 2.21 (dd, J=6.7 and 17.0 Hz, 1H), 2.36 (dd, J=6.7 and 17.0 Hz, 1H), 3.24-3.29 (m, 1H), 3.44-3.52 (m, 2H), 3.67 (dd, J=3.9 and 8.9 Hz, 1H), 4.36 (dd, J=3.5 and 6.5 Hz, 1H), 4.50 (d, J=12.0 Hz, 1H), 4.54 (d, J=12.0 Hz, 1H), 7.32-7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 5.0, 6.9, 9.7, 13.9, 20.2, 21.8, 28.0, 36.3, 40.8, 41.5, 53.7, 72.5, 72.9, 73.2, 73.6, 80.7, 127.4, 127.5, 128.2, 138.6, 171.0, 221.4; IR (film, NaCl, cm−1) 3502, 2959, 2875, 1731, 1683, 1456, 1366, 1154, 1098, 996, 739; LRMS (ESI) calcd for C30H52O6SiCl3Na [M+Na+] 559.3, found 559.3; [α]23D=−41.0 (c=0.4, CHCl3).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11]1[CH:38]=[CH:37][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[N+:39]([CH3:42])([O-:41])=[O:40]>>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH2:42][N+:39]([O-:41])=[O:40])[CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[O:26])=[CH:21][CH:22]=2)=[CH:37][CH:38]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(COC(=O)/C=C/c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Agent: CN(C)C(=N)N(C)C
Product: COc1ccc(COC(=O)CC(C[N+](=O)[O-])c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
1,1,3,3-tetramethylguanidine (0.31 mL, 2.48 mmol) was added to 40.2 (5 g, 12.4 mmol) in nitromethane (20 mL). The mixture was stirred at room temperature for 3 hours, at 50° C. for 3 hours, and at 100° C. for 8 hours. Nitromethane was removed under vacuum and the crude product was purified by flash chromatography to give 40.3 (4.5 g). MS ESI (pos.) m/e: 466 (M+H). 1HNMR (CDCl3) δ 7.37 (d, 2H), 7.19 (d, 2H), 7.12 (d, 2H), 6.92 (m, 6H), 5.01 (s, 2H), 4.97 (s, 2H), 4.68 (m, 1H), 4.59 (m, 1H), 3.96 (m, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 2.77 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:13][C:10]2([CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14](OC)=[O:15])[CH:8]=2)[O:3]1.CC(C[AlH]CC(C)C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1(C)C=CC=CC=1.ClCCl>[CH3:1][C:2]1([CH3:18])[CH2:13][C:10]2([CH2:11][CH2:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]=[O:15])[CH:8]=2)[O:3]1
Reactant: COC(=O)c1ccc2c(c1)C1(CC1)CC(C)(C)O2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1(C)CC2(CC2)c2cc(C=O)ccc2O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Methyl 2,2-dimethyl-2,3-dihydrospiro[chromene-4,1′-cyclopropane]-6-carboxylate (33.0 mg, 0.13 mmol) was dissolved in dry toluene (1.34 mL), and cooled to −78° C. DIBAL-H (536 μL, 0.54 mmol) was added dropwise via a syringe. The reaction mixture was stirred for 2 hours at −78° C. It was then quenched with methanol (500 μL) at the same temperature, and diluted with EtOAc (15.0 mL). The organic layer was washed with water (10.0 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford the crude alcohol, which was used directly to the next step. The crude alcohol was dissolved in dichloromethane (4.00 mL) and Dess-Martin periodinane (114 mg, 0.27 mmol) was added in one portion at room temperature. The resulting mixture was stirred at room temperature for 1 hour and concentrated under vacuum on silica gel. It was then purified by silica gel chromatography eluting with 0-15% EtOAc/hexanes to give the desired product as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[O:21]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:40][C:37]2[CH:38]=[CH:39][C:34]([C:31]3[CH:32]=[CH:33][C:28]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:29][CH:30]=3)=[CH:35][CH:36]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: Oc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccc(Oc4ccccc4)cc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4′-phenoxy-biphenyl-4-ol from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C31H30O6 [M+NH4]+: 516, [M+Na]+: 521.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([C:44](=[O:51])[CH2:45][N:46]2[CH:50]=[N:49][N:48]=[N:47]2)[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:40][CH2:39][N:38]([C:44](=[O:51])[CH2:45][N:46]4[CH:50]=[N:49][N:48]=[N:47]4)[CH2:43][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(Cn1cnnn1)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)Cn2cnnn2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-piperazin-1-yl-2-tetrazol-1-yl-ethanone (Enamine) to give the title compound. HR-MS (ES, m/z) calculated for C36H41Cl2N9O3 [(M+H)+] 718.2782, observed 718.2788.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH3:12])[C:7](=O)[CH2:6][CH2:5]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:25]([NH2:29])(=[O:28])[CH:26]=[CH2:27]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3([CH3:12])[C:7](=[CH:6][CH2:5][C:4]=2[CH:3]=1)[NH:29][C:25](=[O:28])[CH2:26][CH2:27]3
Reactant: CC1C(=O)CCc2cc(F)ccc21
Reactant: C=CC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC12CCC(=O)NC1=CCc1cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.4 %

Procedure:
To 6-fluoro-1-methyl-2-tetralone (7.06 g; 39.6 mmol) in a round bottomed flask was added p-toluenesulfonic acid (1.23 g; 6.5 mmol) and the mixture was stirred at room temperature under nitrogen for 15 minutes. Acrylamide (5.62 g; 79.2 mmol) was added and the reaction mixture was heated to 88°-90° C. under nitrogen for three days. The mixture was diluted with ethyl acetate and water and stirred at room temperature for 1 hour. The resulting layers were separated. The organic layer was washed three times with water, dried over MgSO4 and concentrated to a viscous oil. The crude product was crystallized from ethyl acetate to afford 1.59 g (17% yield) of the subtitle compound. Melting point 202° C.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[C:10]2[C:11](=O)[O:12]C(=O)[NH:14][C:9]=2[CH:8]=[CH:7][CH:6]=1>O.CCOC(C)=O>[NH2:14][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH3:3])[C:10]=1[C:11]([NH:2][CH3:1])=[O:12]
Reactant: CN
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(N)cccc1OC
Temperature: 25 °C
Reaction time: 36 h
Yield: 70.1 %

Procedure:
Phosgene (4.72 ml, 8.97 mmol; 20% in toluene) was added dropwise to a solution of 2-amino-6-methoxybenzoic acid (1 g, 5.98 mmol) in 2N aqueous sodium hydroxide (6.28 ml, 12.56 mmol) and water (15 ml) cooled to 0° C. over a period of 15 minutes, maintaining the temperature at 0-5° C. The resulting suspension was stirred at 0° C. for 15 minutes. The precipitate was collected by filtration, washed with water, followed by a small amount of acetonitrile and ether and dried under vacuum at 40° C. to afford 5-methoxy-1H-3,1-benzoxazine-2,4-dione (0.760 g, 65.8%) as a beige solid. 40% aqueous methylamine (1.57 ml, 18.1 mmol) was added to a stirred suspension of 5-methoxy-1H-3,1-benzoxazine-2,4-dione (700 mg, 3.62 mmol;) in water (5 ml). The resulting solution was stirred at room temperature for 36 hours. The mixture was diluted with EtOAc, washed sequentially with saturated aqueous sodium carbonate, water and brine. The organic layer was dried over MgSO4 and evaporated to afford 2-amino-6-methoxy-N-methylbenzamide (457 mg, 70.0%) as a white solid. 1H NMR spectrum (500 MHz, DMSO): 2.73 (d, 3H), 3.73 (s, 3H), 5.79 (bs, 2H), 6.19 (d, 1H), 6.30 (d, 1H), 6.99 (dd, 1H), 7.98 (q, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]([N+:24]([O-:26])=[O:25])=[C:15]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[N:14]=1>>[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH:11][C:13]2[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]([N+:24]([O-:26])=[O:25])=[C:15]([NH:27][C:28]3[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=3)[N:14]=2)[CH3:10])=[N:7][CH:8]=1
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2cc(C)[nH]n2)c1[N+](=O)[O-]
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Product: CCOC(=O)c1nc(N[C@@H](C)c2ncc(F)cn2)nc(Nc2cc(C)[nH]n2)c1[N+](=O)[O-]

Procedure:
The title compound was prepared using a procedure similar to the one described for the synthesis of Intermediate 18 using [(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amine hydrochloride (Intermediate 15) and ethyl 2-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-5-nitropyrimidine-4-carboxylate (Intermediate 48) as the starting materials. LCMS: 432 [M+1].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC(=O)c1ccc(N)cc1
Yield: 30.7 %

Procedure:
A solution of ethyl 4-(4-nitrophenyl)-4-oxobutyrate (1.4 g, 5.6 mmol) and 10% palladium on carbon (0.18 g) in ethanol (50 ml) was shaken under hydrogen (50 psi) for 2 hours then filtered and concentrated in vacuo. The residue was absorbed onto silica gel (5 g) from an ethyl acetate solution and purified by chromatography on silica gel (100 g) eluting with ethyl acetate:hexane (1:2) to give ethyl 4-(4-aminophenyl)-4-oxobutyrate (0.38 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ: 1.17 (t, J=7 Hz, 3H, CH3), 2.56 (t, J=6.5 Hz, 2H, CH2), 3.10 (t, J=6.5 Hz, 2H, CH2), 4.04 (q, J=7 Hz, ester CH2), 6.04 (br s, 2H, NH2), 6.57 (d, J=9 Hz, 2H, Ar), 7.69 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C12H15NO3 :C, 65.I4; H, 6.83; N, 6.33. Found: C, 65.23; H, 6.85; N, 6.32.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>C(Cl)Cl.CN(C=O)C>[C:12]([C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([NH:36][CH2:35][C:34]1[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=1)=[O:7])(=[O:14])[CH3:13]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C(C)=O)cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-Methoxy-5-acetylbenzoic acid (Step B, 2.5 g, 12.8 mmol), HOBt.H20 (2.08 g, 15.4 mmol), and EDC (3.70 g, 19.3 mmol) in CH2Cl2 (20 ml) and DMF (5 ml) was added 4-(Trifluoromethyl)benzylamine (2.48 g, 14.1 mmol), and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure and then redissolved in ethyl acetate. The organic layer washed with 3% K2CO3, 1 N HCl, and brine, dried over Na2SO4, filtered and concentrated. The purification was done by flash chromatography on silica gel column (chloroform:methanol 95:5) to provide the title compound as white solid.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:20])([CH3:19])[CH:8]2[C:11]2[C:12]([S:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N#[O+].[CH3:28][S:29]SC.C[S-].[Na+]>C(#N)C.CCOCC>[CH3:19][C:7]1([CH3:20])[CH2:6][C:5]2[C:9](=[CH:10][C:2]([S:29][CH3:28])=[CH:3][CH:4]=2)[CH:8]1[C:11]1[C:12]([S:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=1
Reactant: CSc1ncncc1C1c2cc(N)ccc2CC1(C)C
Reactant: CSSC
Agent: C[S-]
Agent: F[B-](F)(F)F
Agent: N#[O+]
Solvent: CCOCC
Solvent: CC#N
Product: CSc1ccc2c(c1)C(c1cncnc1SC)C(C)(C)C2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 1.0 g (3.5 mmol) of 5-(6-amino-2,2-dimethylindan-1-yl)-4-methylthiopyrimidine in 25 mL of dry acetonitrile at 5° C. was added with stirring 1.0 g (7.0 mmol) of nitrosonium tetrafluoroborate. After 30 min the resulting solution was poured with stirring into a solution of 20 g (0.20 mol) of dimethyl disulfide in 100 mL of acetonitrile. After 2 hr, 0.50 g of sodium methanethiolate was added and the reaction mixture was heated with stirring to 60° C. for 16 hr. The mixture was cooled and poured into 600 mL of ether with stirring. The ethereal phase was recovered and was washed with water (2×100 mL), dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 500 mg (45 percent of theory) of the title compound as a light gold oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:12](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[CH3:12][O:10][C:9]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=1)=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred suspension of 4-nitro-3-pyrazolecarboxylic acid (1 g) in dichloromethane under nitrogen at 0° C. was treated with oxalyl chloride (1.11 ml) followed by dimethylformamide (5 drops). The reaction mixture was warmed to room temperature and stirred overnight. Methanol (10 ml) was added and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure and azeotroped with toluene twice to yield 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.3 g) as a pale green solid. LC-MS (Method H): RT=1.94 minutes, 170.23 (M−H)−.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].Cl[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:3][CH2:2][CH2:1][OH:4]
Reactant: Clc1ccccn1
Reactant: OCCO
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: OCCOc1ccccn1
Reaction time: 48 h

Procedure:
Ethylene glycol (30.1 g, 484 mmol), 2-chloropyridine (10.0 g, 88 mmol), powdered potassium hydroxide (9.9 g, 176.13 mmol), and 18-crown-6 ether (9.3 g, 35 mmol) were dissolved in anhydrous toluene (500 mL) under a N2 atmosphere. The reaction mixture was stirred vigorously and heated to reflux. After 48 h, the reaction reached 50% conversion. The reaction mixture was concentrated in vacuo to approximately 100 mL volume then diluted with water (100 mL). After stirring for 0.5 h, the organic layer was separated and the aqueous layer was extracted with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by Jones column chromatography (100% hexanes to 50% ethyl acetate/hexanes) to give 2-(pyridin-2-yloxy)ethanol as a dark brown oil containing 15% w/w of 18-crown-6 ether. 1H NMR (d6-DMSO, 400 MHz): δ 8.14 (ddd, J=5.0, 2.0, 1.2 Hz, 1H), 7.68 (ddd, J=9.4, 7.2, 2.4 Hz, 1H), 6.95 (ddd, J=8.0, 4.8, 1.2 Hz, 1H), 6.80 (ddd, J=8.4, 1.0, 1.0 Hz, 1H), 4.83 (t, J=5.6 Hz, 1H), 4.26 (t, J=5.2 Hz, 2H), 3.70 (dt, J=10.4, 5.2 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][O:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[CH:19]=1.[S:26](=O)(=[O:29])([OH:28])[OH:27]>CC(C)=O>[C:3]1([CH3:9])[CH:4]=[CH:5][C:6]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:7][CH:2]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][O:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[CH:19]=1
Reactant: O=S(=O)(O)O
Agent: CC(C)c1nnc2ccc(-c3ocnc3-c3cc(F)ccc3F)cn12
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 6-[4-(2,5-Difluoro-phenyl)-oxazol-5-yl]-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine (5.0 g, 15 mmol) slurried in acetone (50 ml) was added sulfuric acid (850 μl). The resulting slurry was heated to reflux to form a solution and was then cooled and stirred at room temperature for 12 hours and filtered to yield 4.2 grams of 6-[4-(2,5-Difluoro-phenyl)-oxazol-5-yl]-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine p-toluenesulfonate.
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8]([C:10](=[C:13]([C:15]2[C:16]([C:22]([F:25])([F:24])[F:23])=[N:17][N:18]([CH3:21])[C:19]=2[Cl:20])[OH:14])[C:11]#[N:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28]([O:30][CH2:31]Cl)[CH3:29]>C1COCC1>[C:1]([C:5]1[O:6][CH:7]=[C:8]([C:10](=[C:13]([C:15]2[C:16]([C:22]([F:23])([F:24])[F:25])=[N:17][N:18]([CH3:21])[C:19]=2[Cl:20])[O:14][CH2:31][O:30][CH2:28][CH3:29])[C:11]#[N:12])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOCCl
Reactant: Cn1nc(C(F)(F)F)c(C(O)=C(C#N)c2coc(C(C)(C)C)n2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCOC(=C(C#N)c1coc(C(C)(C)C)n1)c1c(C(F)(F)F)nn(C)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.4 %

Procedure:
0.6 g of 2-{2-tert-butyloxazol-4-yl}-3-(5-chloro-3-trifluoromethyl-1-methyl-pyrazol-4-yl)-3-hydroxyacrylonitrile was dissolved in 5 ml of THF, and 0.07 g of 60% sodium hydride was added thereto with cooling with ice, and then stirred for 15 minutes at room temperature. 0.17 g of ethoxymethyl chloride was added thereto and stirred for 6 days at room temperature. The reaction mixture was poured into ice water, extracted with ethyl acetate, and washed with saturated saline. The resulting product was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residual product was purified through silica gel thin-layer chromatography (ethyl acetate:n-hexane=1:4) to obtain 0.1 g of the intended compound in vitreous state.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:9]=1)[C:5]#[N:6].C(NCBr)(O[C:16](C)([CH3:18])[CH3:17])=O>>[CH3:11][N:10]([CH3:12])[C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([C:16]([CH3:18])=[CH2:17])[CH:9]=1)[C:5]#[N:6]
Reactant: CN(C)c1cc(Br)cc(C#N)c1
Reactant: CC(C)(C)OC(=O)NCBr
Product: C=C(C)c1cc(C#N)cc(N(C)C)c1

Procedure:
3-(dimethylamino)-5-(prop-1-en-2-yl)benzonitrile was synthesized from 3-bromo-5-(dimethylamino)benzonitrile following the general procedure as described for the Cbz protected Boc aminomethyl bromide.
Reaction SMILES: C[C:2](=[CH2:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].C(Cl)C=C[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[C:12]1([CH:8]=[CH:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=C(C)CCC(C)=O
Reactant: ClCC=Cc1ccccc1
Solvent: CCO
Product: CC(=O)CCC=Cc1ccccc1

Procedure:
The synthesis was similar to that used for 5-methyl-5-hexen-2-one. Materials that were used: cinnamyl chloride (100 g, 0.655 mole, Acros Organic), pentadione (72 g, 0.72 mole), and ethanol (460 mL). Product, 70-75° C., 0.1 mmHg, 48 g (42%). 1H-NMR (CDCl3, δ): 2.15 (s, 3H); 2.16 (m, 2H); 2.60 (m, 2H); 6.17 (m, 1H), 6.42 (d, 1H), 7.2-7.33 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:5]=[C:4](Cl)[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.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.[Pd]>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:5]=[C:4]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1c(Cl)cc(Cl)nc1-c1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(Cl)c(C#N)c(-c3ccc(Oc4ccccc4)cc3)n2)cc1
Temperature: 90 °C
Reaction time: 19 h
Yield: 25.5 %

Procedure:
A mixture of 4,6-dichloro-2-(4-phenoxyphenyl)nicotinonitrile (56.8 mg, 0.166 mmol), 4-methoxyphenylboronic acid (26.2 mg, 0.172 mmol), potassium phosphate (0.052 mL, 0.629 mmol) and palladium tetrakis(triphenylphosphine) (9.5 mg, 8.22 μmol) in N,N-dimethylformamide (2 mL) was pumped under vacuum and backfilled with nitrogen twice, and heated to 90° C. under nitrogen. After 19 h at 90° C., the mixture was concentrated. The residue was purified by preparative TLC (30% ethyl acetate in hexanes, Whatman PARTISEL® PLK5F, Silica Gel 150 A with Fluorescent Indicator, size: 20×20 cm, layer thickness: 1000 μM) to give 4-chloro-6-(4-methoxyphenyl)-2-(4-phenoxyphenyl)nicotinonitrile as white solid (17.5 mg, 26% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (2H, δ, J=9.04 Hz), 7.99-8.05 (2H, m), 7.76 (1H, s), 7.40 (2H, t, J=7.91 Hz), 7.19 (1H, t, J=7.40 Hz), 7.12 (4H, dd, J=8.16, 4.14 Hz), 7.02 (2H, δ, J=9.03 Hz), 3.89 (3H, s); MS (ES+) m/z: 413 (M+H); LC retention time: 4.488 min (analytical HPLC Method A).