Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([CH2:31][CH2:32][C:33](Cl)=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[C:25]1([CH2:31][CH2:32][C:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C(CCc1ccccc1)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 29.2 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.16 mmol) obtained in Example 1, (3), and 3-phenylpropionyl chloride (28 μL, 0.19 mmol), the title compound (21 mg, yield 29%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16](=[O:19])[NH:17][N:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.[Br:22][CH2:23][CH2:24]Br>CN(C=O)C.O>[Br:22][CH2:23][CH2:24][N:17]1[C:16](=[O:19])[N:14]2[CH:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[CH:11]=[CH:12][C:13]2=[N:18]1
Reactant: O=c1[nH]nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Reactant: BrCCBr
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(CCBr)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Temperature: 95 °C

Procedure:
6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (synthesized according to Example 1, 500 mg, 1.69 mmol) was dissolved in 5 ml DMF and 1,2 dibromoethane (1.0 mL, 11.8 mmol) was added. The reaction was heated to 95° C. overnight. The reaction was cooled, diluted with water/EtOAC and the layers were separated. The organic layer was washed with NaHCO3. The organics were dried (MgSO4), filtered, concentrated and purified by flash chromatography (Rf=0.46, 1:1 hexanes:EtOAc) to afford 2-(2-bromoethyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. To a solution of 2-(2-bromoethyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.124 mmol) in 1 mL DMF was added K2CO3 (51 mg, 0.372 mmol) and 4-phenyl-1H-imidazole (36 mg, 0.249 mmol) and the reaction was heated to 85° C. for 24-72 hours until the SM was consumed. The reaction was concentrated and purified by reverse phase HPLC to afford compound 100 (24 mg, 41%). GS-490257. C24H18F3N5O2, m/z (ESI)=466.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:17]1([C:23](Cl)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([NH:1][C:23](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1ccc(Cl)cc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(Cl)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4-chlorobenzonitrile (7.25 g, 47.5 mmol), in anh. pyridine (38 mL, 475 mmol) and DCM (300 mL) cooled in an ice-H2O bath under Ar was added PhCOCl (5.8 mL, 50 mmol) dropwise. The reaction was allowed to slowly warm to rt within the cooling bath and then was stirred at rt overnight. The reaction mixture was washed (H2O, 2 M aq HCl (2×), H2O, brine), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a white solid; MS (ES+): m/z 257.1 (100) [MH+]; HPLC: tR=3.27 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[CH:9]([CH:12]=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:29]=[C:27]([NH:26][C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:30])[F:31])=[CH:25][CH:24]=4)[N:28]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: N=C(N)Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc2c(s1)C(=O)C(C=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc2c(s1)-c1nc(Nc3ccc(C(F)(F)F)cc3)ncc1CC2
Yield: 8.1 %

Procedure:
A mixture of 2-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazole-6-carbaldehyde (200 mg, 1.02 mmol), N-(4-trifluoromethyl-phenyl)-guanidine nitrate (273 mg, 1.02 mmol), NaOH (41 mg, 1.02 mmol) and 2-methoxyethanol (1.25 mL) was heated under reflux for 16 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) followed by crystallisation from EtOAc gave the pure title compound as a white crystalline solid (30 mg, 8%): mp 212-213° C. Anal. RP-HPLC: tR 21.8 min (10-70% MeCN, purity 95%). 1H-NMR (CDCl3): δ 8.17 (s, 1H, Py-H), 7.71 (d, 2H, J 8.4, Ph-H), 7.52 (d, 2H, J 8.4, Ph-H), 7.16 (s, 1H, NH), 3.04 (t, 2H, J 6.6, CH2), 2.94 (t, 2H, J 6.6, CH2), 2.72 (s, 3H, CH3). MS (ESI−): m/z 360.95 (M−H)+.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[C:3](C2N=C(C=O)C3C(C=2)=C[C:13]([O:17]C)=[C:12](OC)C=3)[CH:2]=1.[BH4-].[Na+].C[C:32]([CH3:34])=[O:33]>C(O)C>[CH3:12][CH2:13][O:17][C:32]([CH3:34])=[O:33].[CH3:5][CH2:6][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: COc1cc2cc(-c3cccc(-c4ccccc4)c3)nc(C=O)c2cc1OC
Reactant: CC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC
Product: CCOC(C)=O
Reaction time: 1 h
Yield: 61 %

Procedure:
3-([1,1′-Biphenyl]-3-yl)-6,7-dimethoxyisoquinoline-1-carboxaldehyde (160 mg) in 7 mL ethanol was treated slowly with NaBH4 (50 mg, 3 eq.) at room temperature. Reaction was stirred for 1 hour then 2 mL acetone was added and solution was filtered through filter paper. Filtrate was concentrated then re-dissolved in DCM and washed with H2O. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 50% EtOAc/hexane yielding product as a yellow solid (98 mg, 61% yield). 1H NMR (400 MHz) (CDCl3) δ 8.36-8.35 (m, 1H), 8.13-8.11 (m, 1H), 7.98 (s, 1H), 7.73 (d, J=8 Hz, 2H), 7.68-7.66 (m, 1H), 7.60 (t, J=16 Hz, 1H), 7.51 (t, J=16 Hz, 2H), 7.42 (t, J=12 Hz, 1H), 7.22 (s, 1H), 7.09 (s, 1H), 5.35 (bs, 1H), 5.32 (s, 2H), 4.08 (s, 3H), 4.07 (s, 3H). 13C NMR (100 MHz) (CDCl3) δ 154.65, 141.81, 141.21, 129.19, 128.82, 127.44, 127.29, 127.25, 125.55, 125.51, 119.82, 115.35, 105.87, 101.29, 61.41, 56.14, 56.09.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.C(N(CC)CC)C.Cl[C:27](OC1C=CC=CC=1)=[O:28].[CH2:36]([N:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][NH2:42])[CH3:37]>O1CCCC1.CN(C)C=O>[CH2:36]([N:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][NH:42][C:27]([NH:11][C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:2]=2[CH3:1])[CH:10]=[CH:9][N:8]=1)=[O:28])[CH3:37]
Reactant: CCN(CC)CCCN
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2C)ccn1
Yield: 96.9 %

Procedure:
To a solution of 4-(2-methyl-4-nitrophenoxy)pyridin-2-ylamine and triethylamine (500 mg) in tetrahydrofuran (50 ml) was added phenyl chloroformate (0.384 ml, 4.08 mmol) dropwise while stirring in an ice bath, followed by stirring for 0.5 hr. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (20 ml) and N,N-diethyl-1,3-propanediamine (1.28 ml) were then added, followed by stirring at room temperature for 2 hrs. The reaction mixture was partitioned between ethyl acetate (150 ml) and water (100 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:1, then ethyl acetate) to provide the titled compound (794 mg, 96.9%) as a pale yellow oil.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[CH3:8][C:9]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:23]=[C:22]([CH3:32])[C:10]=1[O:11][C:12]1[C:13]2N[N:20]=[N:19][C:14]=2[N:15]=[C:16](Cl)[N:17]=1.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1.FC(F)(F)CO>>[CH3:8][C:9]1[CH:25]=[C:24]([C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[CH:23]=[C:22]([CH3:32])[C:10]=1[O:11][C:12]1[N:17]=[C:16]([NH:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[N:15]=[C:14]2[NH:19][N:20]=[CH:2][C:13]=12
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(Cl)nc2nn[nH]c12
Reactant: N#Cc1ccc(N)cc1
Solvent: OCC(F)(F)F
Product: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2[nH]ncc12
Temperature: 90 °C

Procedure:
Trifluoroacetic acid (8 eq) is added to a suspension of 7-(2,6-dimethyl-4-(pyridin-4-yl)phenoxy)-5-chloro-1H-[1,2,3]triazolo[4,5-d]pyrimidine (1 eq) and 4-aminobenzonitrile (4 eq) in 2,2,2-trifluoroethanol (1 ml/0.1 mmol) in a sealed tube. The resulting mixture is heated at 90° C. for 3 days. The reaction is cooled to room temperature, concentrated to dryness and purified by silica gel chromatography.
Reaction SMILES: [C:1]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11](=[O:16])[CH:10]=[CH:9]2)([O:3]C)=[O:2].[OH-:17].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.O>[C:11](/[CH:10]=[CH:9]\[C:8]1[CH:7]=[C:6]([CH2:5][C:1]([OH:3])=[O:2])[CH:15]=[CH:14][C:13]=1[O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:16])=[O:17]
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1ccc2oc(=O)ccc2c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)/C=C\c1cc(CC(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.63 g (12.06 mmoles) of 6-carbomethoxymethylcoumarin in 50 ml of ethanol is added 2.41 g (60.30 mmoles) of NaOH in 3 ml of H2O. The reaction mixture is heated to reflux for 8 hours after which time 40 ml (3.36 moles) of benzylbromide is added. The reaction mixture is stirred at room temperature for 12 hours after which time the reaction mixture is concentrated in vacuo. The crude product is taken up in H2O, washed with ethylacetate (2 times) and acidified to pH 3-4 with concentrated HCl. The resulting white precipitate is collected to yield cis-3-carboxyvinyl-4-benzyloxyphenylacetic acid which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10](F)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>CN(C)C=O.O>[F:1][C:2]1[CH:11]=[C:10]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc([N+](=O)[O-])c(NCc2ccc(OC)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of methyl 2,4-difluoro-5-nitrobenzoate (35 g, 161.20 mmol) in N,N-dimethylformamide (1000 ml) was added DIEA (41.3 g, 319.56 mmol). Then (4-methoxybenzylamine (28.72 g, 209.64 mmol) was added dropwise with stirring for 1 hour at 25° C. The reaction mixture was diluted with water (2 L). The solids were collected by filtration to afford methyl 2-fluoro-4-(4-methoxybenzylamino)-5-nitrobenzoate as a yellow solid (44 g, 82%).
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([S:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1>C(O)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([S:18]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)=[O:1])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: OO
Reactant: CCNC(=O)Nc1ccc(Sc2ccc(OC)c(-c3cccc(Cl)c3)c2)cc1
Solvent: CC(=O)O
Product: CCNC(=O)Nc1ccc(S(=O)c2ccc(OC)c(-c3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of 10% v/v 30% aqueous hydrogen peroxide (w/w) (1 mL) in glacial acetic acid (9 mL) was made. To a slurry of the above compound (P-448) (41.3 mg, 0.100 mmol) in acetic acid (300 uL) was added the hydrogen peroxide solution (96.7 uL, 0.100 mmol hydrogen peroxide). The solution was stirred for 1 hour at room temperature. The solvent was removed under vacuum, and the residue purified by silica gel thin layer chromatography (eluting with 10% acetone in dichloromethane), triturated with diethyl ether (5 mL), filtered, and dried to give the product (P-449) (29.3 mg, 68% yield) as a brown gum. 1H NMR (400 MHz, DMSO-d6) 7.55-7.44 (m, 5H), 7.36-7.32 (m, 5H), 7.20 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.27 (m, 1H), 3.84 (s, 3H), 3.29-3.22 (m, 2H), 1.12 (t, J=7.4 Hz, 1H) ppm. LCMS=97.6% purity. MS (APCI+)=429.1 (M+1).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:28])([CH3:27])[C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20](S(C)(=O)=O)=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:29].[Na+].O.Cl>O1CCOCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:28])([CH3:27])[C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20]([OH:29])=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(S(C)(=O)=O)nn23)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(O)nn23)c1
Temperature: 80 °C
Yield: 37 %

Procedure:
7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (800 mg, 1.92 mmol) was dissolved in 1,4-dioxane (5.00 mL) and 5.00 M sodium hydroxide in water (5.00 mL, 25.0 mmol) was added. The reaction was heated at 80° C. for 2 hours and then acidified to pH 6 with conc. HCl. The product was then extracted with DCM (100 mL) and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol as a yellow solid (252 mg, 37%). m.p.=194-195° C.; LCMS (m/e) 356 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 8.27 (d, 1H, J=7.7 Hz), 8.07 (s, 1H), 7.52-7.44 (m, 1H), 7.40 (d, 1H, J=7.6 Hz), 7.17 (d, 1H, J=5.1 Hz), 7.05 (d, 1H, J=5.1 Hz), 4.84 (s, 2H), 0.97 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][C:12]3[C:20]4[C:19]([C:21]([O:23]C)=[O:22])=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][N:13]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.O.[OH-].[Li+:27]>O1CCCC1.O>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][C:12]3[C:20]4[C:19]([C:21]([O-:23])=[O:22])=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][N:13]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Li+:27]
Reactant: COC(=O)c1cccc2[nH]nc(CNCC34CCN(CC3)CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cccc2[nH]nc(CNCC34CCN(CC3)CC4)c12
Yield: 136.8 %

Procedure:
A mixture of methyl 3-((quinuclidin-4-ylmethylamino)methyl)-1H-indazole-4-carboxylate (2.9 g, 8.9 mmol) from Step A above and lithium hydroxide monohydrate (1.1 g, 26.7 mmol) in tetrahydrofuran/water (1:1, 30 mL) was stirred at reflux until the reaction was complete by LC-MS. The solvent was removed under reduced pressure to give lithium 3-((quinuclidin-4-ylmethylamino)methyl)-1H-indazole-4-carboxylate as a brown solid (3.9 g, quantitative yield): 1H NMR (500 MHz, CD3OD) δ 7.49 (d, J=8.5 Hz, 1H), 7.43 (d, J=7.0 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 4.17 (s, 2H), 2.82 (t, J=8.0 Hz, 6H), 2.26 (s, 2H), 1.42 (t, J=8.0 Hz, 6H); MS (ESI+) m/z 315 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]([CH3:15])[CH2:9][NH:10][C:11](=[O:14])[CH2:12]Cl)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.O>FC(F)(F)C(O)=O>[CH3:15][C@H:8]1[CH2:9][NH:10][C:11](=[O:14])[CH2:12][N:7]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16]
Reactant: C[C@@H](CNC(=O)CCl)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CNC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
(S)-tert-butyl(1-(2-chloroacetamido)propan-2-yl)carbamate (7.5 g, 29.9 mmol) was dissolved in trifluoroacetic acid (30 mL) and stirred for 10 minutes. The reaction mixture was concentrated, dissolved in THF (321 mL) and potassium carbonate (20.7 g, 149.5 mmol) was added and the reaction mixture was refluxed for 12 hours. To the reaction mixture was added (Boc)2O (7.7 mL, 35.9 mmol) and the reaction mixture was refluxed for an additional 5 hours. The reaction mixture was cooled to rt and water was added. The reaction mixture was extracted with EtOAc. The organic layers were combined, dried with Na2SO4, filtered, concentrated and purified by flash column chromatography (0-100% EtOAc in hexanes) to provide the desired compound (5 g, 78%). 1H NMR (600 MHz, DMSO) δ 8.00 (s, 1H), 4.17 (s, 1H) 3.94 (d, J=17.8 Hz, 1H), 3.58 (d, J=17.9 Hz, 1H), 3.43-3.34 (m, 1H), 3.98 (ddd, J=12.7, 4.9, 2.5 Hz, 1H), 1.43-1.38 (s, 9H), 1.10 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:40])[N:5]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:13])=[N:7]2.C(N(CC)[OH:44])C>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:40])[N:5]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]([NH2:36])=[O:44])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH3:13])=[N:7]2
Reactant: CCN(O)CC
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#N)c3)c(=O)c12
Solvent: ClCCl
Product: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C(N)=O)c3)c(=O)c12
Temperature: 50 °C
Yield: 97 %

Procedure:
A 100-mL, three-neck, round bottomed flask equipped with a magnetic stirrer and a reflux condenser was purged with nitrogen and charged with compound 141 (219 mg, 0.40 mmol) and anhydrous methylene chloride (15 mL). N,N-Diethylhydroxylamine (146 mg, 1.64 mmol) was added to the resulting solution, and the reaction mixture was heated for 16 h at 50° C., cooled to ambient temperature, and then evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography to give a 97% yield of compound 143 as a white solid. m.p. 195-197° C.; 1H NMR (CDCl3) δ (ppm) 8.34 (d, 1H, J=10.9 Hz), 7.59-8.06 (m, 7H), 7.28 (m, 1H), 6.95 (bs, 1H), 6.00 (bs, 2H), 5.60 (s, 2H), 5.28 (bs, 1H), 3.62 (t, 2H, J=8.4 Hz), 2.85 (s, 3H), 1.53 (dd, 3H, J 6.7, 10.8 Hz), 0.96 (t, 2H, J=8.3 Hz), 0.01 (s, 9H); m/z=571 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:17])[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].I[CH3:21]>CN(C)C=O.CCOCC>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:17][CH3:21])[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH2:10]2)[C:6]=1[CH3:7]
Reactant: CI
Reactant: Cc1c(Br)cnn1CC1(O)CCCC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC1(Cn2ncc(Br)c2C)CCCC(C)(C)C1
Reaction time: 0.17 h

Procedure:
A solution of EXAMPLE 157B (0.62 g) was dissolved in N,N-dimethylformamide (10 mL) and treated with NaH (0.062 g, 60% in mineral oil). After 10 minutes, iodomethane (0.16 mL) was added. After 1 hour, additional sodium hydride (0.5 eq.) and iodomethane (0.5 eq.) were added and stirring was continued at room temperature for 3 hours. The reaction was diluted with ether (75 mL) and washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 1.5% to 15% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: Cl[Si:2]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].C1(NC2CCCCC2)CCCCC1.Cl[SiH3].Cl.[OH:28][CH2:29][CH:30]([CH2:32][OH:33])[OH:31]>>[CH2:4]([O:3][Si:2]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[O:28][CH2:29][CH:30]([CH2:32][OH:33])[OH:31])[CH3:5]
Reactant: CCO[Si](Cl)(OCC)OCC
Reactant: OCC(O)CO
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Agent: [SiH3]Cl
Product: CCO[Si](OCC)(OCC)OCC(O)CO
Yield: 90 %

Procedure:
Glycerol (GL) was reacted with chlorotriethoxysilane (CTS) in a 1:1 ratio at 0° C. in a 50/50 mixture of ethanol/cyclomethicone, using a 1:1 ratio of dicyclohexylamine to chlorosilane as the HCl scavenger. The resulting product, 1-triethoxysilylglycerol, was obtained in 90% yield and was dissolved to a 10% by weight solution in a 50/50 by volume mixture of ethanol/cyclomethicone.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]1([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:16][Cl:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C(C2C=CC=CC=2)(CCBr)C#N)C=CC=CC=1>>[ClH:17].[C:8]1([CH:14]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:15][CH2:16][N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCCC(c1ccccc1)c1ccccc1
Reactant: C1CCNCC1
Agent: Cl
Agent: N#CC(CCBr)(c1ccccc1)c1ccccc1
Product: c1ccc(C(CCN2CCCCC2)c2ccccc2)cc1

Procedure:
Repetition of the procedure detailed in Example 12 using piperidine hydrochloride and 1,1-diphenyl-3-chloropropane in place of the 2-azabicyclo[2.2.2]octane hydrochloride and 2,2-diphenyl-4-bromobutyronitrile affords 1-(3,3-diphenylpropyl)piperidine hydrocloride, melting at about 216° - 217° C., and represented by the following structural formula. ##STR13##
Reaction SMILES: C(C(C1C=CC=C(C2C=CC(OC)=C(OC)C=2)N=1)O)#N.[C:21]([CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[N:26]=1)[OH:24])#[N:22].[Cl:39][C:40]1[CH:41]=[CH:42][C:43]2[S:47][C:46]([CH:48]([CH:52]([CH3:54])[CH3:53])[C:49]([OH:51])=[O:50])=[CH:45][C:44]=2[CH:55]=1>>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]2[S:47][C:46]([CH:48]([CH:52]([CH3:53])[CH3:54])[C:49]([O-:51])=[O:50])=[CH:45][C:44]=2[CH:55]=1.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]2[S:47][C:46]([CH:48]([CH:52]([CH3:53])[CH3:54])[C:49]([O:24][CH:23]([C:21]#[N:22])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[F:38])[N:26]=3)=[O:50])=[CH:45][C:44]=2[CH:55]=1
Reactant: N#CC(O)c1cccc(Oc2ccccc2F)n1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Agent: COc1ccc(-c2cccc(C(O)C#N)n2)cc1OC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2F)n1)c1cc2cc(Cl)ccc2s1
Product: CC(C)C(C(=O)[O-])c1cc2cc(Cl)ccc2s1

Procedure:
The alcohol, cyano [6-(3,4-dimethoxyphenyl)-2-pyridyl] methanol and cyano [6-(2-fluorophenoxy)-2-pyridyl]methanol, is reacted with the acid chloride of 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid to yield cyano[6-(3,4-dimethoxy-phenoxy)-2-pyridyl]methyl 2-(5-chloro-2-benzothienyl-3-methylbutanoate and cyano[6-(2-fluorophenoxy)-2-pyridyl]methyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]=[O:6].[CH3:7][OH:8].O=O>O>[C:1]([OH:4])(=[O:3])[CH:2]=[CH2:5].[C:5]([O:8][CH3:7])(=[O:6])[CH:1]=[CH2:2]
Reactant: CC(=O)O
Reactant: C=O
Reactant: CO
Agent: O=O
Solvent: O
Product: C=CC(=O)O
Product: C=CC(=O)OC

Procedure:
A reaction feed comprising acetic acid (9.1%), formaldehyde (17.3%), methanol (6.7%), water (38%), oxygen (4.06%), and nitrogen (24.8%) was passed through a fixed bed reactor comprising the Catalyst 1 and Comparative Catalyst A. The reaction was conducted at three temperatures, 340° C., 355° C., and 370° C. Acrylic acid and methyl acrylate (collectively, “acrylates”) were produced. The conversions, selectivities, and space time yields are shown in Table 4.