Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH3:25])=[N:16][N:17]=3)[CH:14]=2)=[CH:5][C:4]=1[N+:26]([O-])=O.[NH4+].[Cl-:30]>C(O)C.O.Cl.C(OCC)(=O)C.[Fe]>[ClH:30].[NH2:26][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH3:25])=[N:16][N:17]=3)[CH:14]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1-c1nnc2ccc(-c3ccc(OC)c([N+](=O)[O-])c3)cn12
Reactant: [Cl-]
Agent: [Fe]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2ccc3nnc(-c4ccccc4OC)n3c2)cc1N
Temperature: 70 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
A mixture of 6-(4-methoxy-3-nitrophenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (80 mg, 0.21 mmol), iron (59 mg, 1.06 mmol) and NH4Cl (6 mg, 0.11 mmol) in ethanol (10 mL) and water (10 ml) was stirred for 3 h at 70° C. The mixture was concentrated under reduced pressure at 50° C. to remove ethanol, and was extracted with ethyl acetate (40 mL×4). The combined organic phase were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a product. The product was dissolved in HCl/ethyl acetate (2M, 20 mL), stirred at room temperature for 30 min, and concentrated to dryness to give the title compound (7.45 mg, 10.2% yield) as yellow solids. 1H NMR (DMSO-d6): 8.14 (m, 1H), 8.05 (dd, J=9.6 and 0.9 Hz, 1H), 7.88 (dd, J=9.6 and 1.5 Hz, 1H), 7.71-7.58 (m, 4H), 7.35 (d, J=8.1 Hz, 1H), 7.26-7.19 (m, 2H), 3.92 (s, 3H), 3.89 (s, 3H). MS: m/z 347.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][S:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1cccc(-c2scnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COc1cccc(-c2scnc2C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Br[CH2:11][Cl:12].C(N(CC)CC)C>>[Cl:12][CH2:11][S:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: ClCBr
Reactant: OCc1ccc(S)cc1
Solvent: CCN(CC)CC
Product: OCc1ccc(SCCl)cc1

Procedure:
4-Mercaptobenzyl alcohol (see J.Chem.Soc 1963 p 1947) (5.0 mmol) was dissolved in bromochloromethane (100 mmol) and triethylamine (5 mmol) added dropwise. The resultant mixture was stirred for 1 hour at room temperature, washed with water and the dried (MgSO4) organic solution evaporated to leave the product. Yield 0.94g (95%) 1H NMR (CDCl3, δ): 2.03 (OH), 4.65 (CH2O), 4.90 (CH2S), 7.1-7.4 (Ph). The product needed no further purification for use in Example 33.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[CH:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:39][CH:40]=1
Reactant: CN(C)C(=O)CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CN(C)C(=O)CN1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N,N-dimethyl-acetamide was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine in General Procedure A. Purification on silica yielded 163. NMR 400 MHz (CDCl3): 2.61 (8H, b, CH2), 2.94 (3H, s, CH3), 3.07 (3H, s, CH3), 3.19 (2H, s, CH2), 3.82 (2H, s, CH2), 3.87-3.89 (4H, m, CH2), 4.01-4.04 (4H, m, CH2), 4.60 (2H, s, CH2), 6.56 (1H, d (J=9.03), ar), 7.26 (1H, s, ar), 8.45 (1H, dd (J=8.45, 2.29), ar), 9.15 (1H, d (J=1.78), ar). MH+=497.21
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][C:15](N)=[O:16]>O>[N+:1]([C:4]1[CH:12]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:13][C:15](=[O:16])[NH:14][C:9]2=[O:11])([O-:3])=[O:2]
Reactant: NC(N)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 160 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A mixture of 5 g (27.4 mmol) of 5-nitroanthranilic acid and 22.9 g (274.0 mmol) of urea was heated to 160° C. and the melt stirred overnight. The reaction mixture was allowed to cool to 100° C. and 5 mL of water was added to dissolve the urea. The solid was filtered and suspended in 100 mL of 0.5 N NaOH and heated to boiling for 40 min to allow formation of the sodium salt. Then the mixture was cooled down and the pH was adjusted with 1 M HCl until pH=5. The precipitate was filtered off and washed with water and dried in vacuo to give 5.12 g of the title compound. 1H NMR (DMSO-d6) δ 11.7 (s, 2H), 8.6 (s, 1H), 8.45(d, 1H), 7.4 (d, 1H); LC-MS (ESI+; 208 ([M+H]+)).
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:30])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([C:21]([NH:23][C:24](=[CH2:29])[C:25]([O:27]C)=[O:26])=[O:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:3][CH:2]=1.O.O.[OH-].[Li+].Cl>C1COCC1>[C:1]1([CH3:31])[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:30])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([C:21]([NH:23][C:24](=[CH2:29])[C:25]([OH:27])=[O:26])=[O:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:6]=1
Reactant: C=C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(C)cc3)cc2)no1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(C)cc3)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
Methyl 2-(3-(4-(3-p-tolylureido)phenyl)isoxazole-5-carboxamido)acrylate (125 mg, 0.298 mmol) was dissolved in THF and water in 2:1 ratio. Lithium hydroxide monohydrate (19 mg, 0.447 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. Crude compound was purified by washing with methanol to get 60 mg (50%) white solid as the required compound. MS: ES (+): m/z 407(M+1); 1HNMR (DMSO-d6, 300 MHz) δ: 9.732 (s, 1H), 8.989 (s, 1H), 8.714 (s, 1H), 7.894 (d, 2H), 7.784 (s, 1H), 7.638 (d, 2H), 7.377 (d, 2H), 7.121 (d, 2H), 6.232 (s, 1H), 5.921 (s, 1H), 5.918 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:9][CH:10]=[O:11])[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[K+].Cl>CO.O>[CH3:1][C:2]([CH3:12])([CH2:9][CH:10]=[O:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(C)(C)CC=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CC=O)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a solution of 1.50 g (8.71 mmol) of ethyl 3,3-dimethyl-5oxopentanoate in 50 mL of methanol and 1 mL of water was added 1.0 g (17.8 mmol) of potassium hydroxide. The reaction mixture was stirred at room temperature for 411/2 hours. The reaction mixture was diluted with water and then made acidic by the addition of aqueous hydrochloric acid. The resulting solution was extracted with methylene chloride repeatedly. The combined organic layer was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Removal of the solvent afforded 1.05 g of 3,3-dimethyl-5-oxopentanoic acid, 84% crude yield. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:44])[NH:30][C:31]3[CH:36]=[CH:35][C:34](C4C=CC=CC=4)=[C:33]([CH3:43])[CH:32]=3)=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([CH:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:44])[NH:30][C:31]3[CH:36]=[CH:35][C:34]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)=[C:33]([CH3:43])[CH:32]=3)=[CH:25][N:24]=2)[CH2:21][CH2:22]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4)c(C)c3)cn2)CC1
Reactant: COc1cccc(B(O)O)c1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4cccc(OC)c4)c(C)c3)cn2)CC1

Procedure:
5′-(3′-Methoxy-2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from F-(4-iodo-3-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and 3-methoxyphenyl boronic acid following a method similar to the one described in the synthesis of 5′-(2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester, above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C28H31N3O4 [M+H]+: 474.2388. Found: 474.2388.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[C:9]1([CH2:15][SH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:15]([S:16][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Fc1cncc(Br)c1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cncc(SCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of 3-bromo-5-fluoropyridine (522 mg) in toluene (5 mL) were added phenylmethanethiol (370 mg), N,N-diisopropylethylamine (831 mg), tris(dibenzylideneacetone)dipalladium(0) (108 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (138 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered through silica gel. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane→hexane-ethyl acetate=10:1) to give the title compound as an orange oil (yield 587 mg, 90%).
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:18])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn].Cl.C(OCC)(=O)C>C(O)(C)C.CCCCCC>[CH2:1]([N:8]1[CH2:9][C:10]2[C:15](=[C:14]([CH3:18])[CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c1C(=O)N(Cc1ccccc1)C2=O
Agent: Cl
Agent: [Sn]
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1cccc2c1C(=O)N(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 4.2 %

Procedure:
A mixture of 2-benzyl-4-methyl-isoindole-1,3-dione (0.500 g, 2 mmol), tin (0.59 g, 5 mmol) and concentrated HCl (2 mL) in isopropanol (10 mL) was heated at reflux for 2.5 h. After this time, the reaction mixture was cooled to ambient temperature, the solids removed by filtration and the filtrate concentrated. The resulting material was dissolved in dichloromethane (20 mL) and the solution washed with brine (7 mL). The organic solution was separated, dried over anhydrous MgSO4, filtered, and concentrated to afford a mixture of regio isomers. Silica gel column chromatography of this mixture using 25% ethyl acetate in hexane afforded 2-benzyl-7-methyl-2,3-dihydro-isoindol-1-one (0.02 g, 9%); 1H NMR (300 MHz, CDCl3): δ ppm) 2.68 (s, 3H), 4.23 (s, 2H), 4.77 (s, 2H), 7.15-7.40 (m, 8H) and GC-MS: m/z 237 (M)+, 160 (M−77)+; and 2-benzyl-4-methyl-2,3-dihydro-isoindol-1-one (0.02 g, 9%); 1H NMR (300 MHz, CDCl3): δ (ppm) 2.68 (s, 3H), 4.23 (s, 2H), 4.77 (s, 2H), 7.15-7.40 (m, 8H) and GC-MS: m/z 237 (M)+, 160 (M−77)+.
Reaction SMILES: C(#N)C.[ClH:4].[CH3:5][N:6]([CH3:13])[CH2:7]/[CH:8]=[CH:9]/[C:10](O)=[O:11].C(Cl)(=O)C([Cl:17])=O.C(OC)(=O)C(OC)=O>CN(C)C=O>[ClH:17].[CH3:5][N:6]([CH3:13])[CH2:7][CH:8]=[CH:9][C:10]([Cl:4])=[O:11]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: COC(=O)C(=O)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C)CC=CC(=O)Cl

Procedure:
A 1 L multi-neck flask equipped with agitator, thermometer, addition funnel, and nitrogen protection is charged with acetonitrile (0.67 kg, 0.85 L) followed by adding dimethylformamide (0.00086 kg, 0.91 mL, d=0.944 g/mL). At ambient temperature, is added 4-dimethylaminocrotonic acid hydrochloride (0.0709 kg) and the mixture stirred until homogeneous. Cool the reaction mixture to (0–10° C.) and add oxalyl chloride (0.0473 kg, 0.0325 L, d=1.45 g/mL) dropwise over (20 minutes) at (0–10° C.) followed by a rinse with acetonitrile (0.02 kg, 0.03 L). The temperature (0–10° C.) is maintained for about (20 minutes). The temperature of the reaction mixture is adjusted to (22–26° C.) over (20 minutes) and maintained over (2 hours). The temperature of reaction mixture is adjusted to (40–45° C.) and held for about (5 minutes). Cool the light suspension to about (20–25° C.) and check for reaction completion by high-pressure liquid chromatography (HPLC). The reaction is complete when there is ≦15% of the starting material (4-dimethylaminocrotonic acid hydrochloride) present and/or ≦2% of oxalyl chloride (detected as the dimethyl oxalate).
Reaction SMILES: [S:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:10])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].S(C1C=CC(C(Cl)=O)=CC=1)(=O)(=O)N.FC1C(O)=C(F)C(F)=C(F)C=1F.N1C=CC=CC=1.[NH2:56][C:57]([NH2:59])=[NH:58]>CO>[S:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([NH:58][C:57]([NH2:59])=[NH:56])=[O:10])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: N=C(N)N
Reactant: NS(=O)(=O)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Agent: NS(=O)(=O)c1ccc(C(=O)Cl)cc1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: c1ccncc1
Solvent: CO
Product: N=C(N)NC(=O)c1ccc(S(N)(=O)=O)cc1

Procedure:
is obtained analogously to the procedure given in Example 1 from pentafluorophenyl 4-sulfamoylbenzoate, prepared from 4-sulfamoylbenzoyl chloride and pentafluorophenol in the presence of 1 mol of pyridine, with guanidine in methanol as reaction medium.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)=[O:12]>>[OH:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)=[O:12]
Reactant: Cc1cc(Nc2ncnc3cccc(OCCNC(=O)CO)c23)ccc1O
Reactant: ClCc1ccccn1
Product: Cc1cc(Nc2ncnc3cccc(OCCNC(=O)CO)c23)ccc1OCc1ccccn1
Yield: 27 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and 2-hydroxy-N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]acetamide to give the title compound as a yellow solid in 27% yield; NMR spectrum (DMSO-d6) 2.27 (s, 3H), 3.71 (q, 2H), 3.77 (d, 2H), 4.38 (t, 2H), 5.20 (s, 2H), 5.49 (t, 1H), 6.98 (d, 1H), 7.14 (d, 1H), 7.31 (d, 1H), 7.35 (dd, 1H), 7.45 (d, 1H), 7.56 (m, 2H), 7.68 (t, 1H), 7.85 (td, 1H), 8.17 (t, 1H), 8.41 (s, 1H), 8.57 (d, 1H), 9.75 (s, 1H); Mass spectrum MH+ 460.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(Cl)CCl>CN(C=O)C.O>[C:14]([N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:1]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: O=C(O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (2.0 g. 11.6 mmole) in dry DMF (20 mL) at RT was added benzoic acid (1.56 g, 12.77 mmole), 1-hydroxybenzotriazole hydrate (1.72 g, 12.77 mmole) and diisopropylethylamine (1.65 g, 12.77 mmole). After 10 min, EDC (2.44 g, 12.77 mmole) was added and the reaction was allowed to stir for 12 hr. The reaction contents were poured into H2O (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (3.0 g. 94%) as a white solid: MS (ES) m/e 277 (M+H)+.
Reaction SMILES: C=C.[C:3](=[O:6])([OH:5])[OH:4].[CH:7]([CH:9]=[CH2:10])=[CH2:8]>>[CH2:7]=[CH2:8].[C:3]1(=[O:5])[O:4][CH2:10][CH:9]([CH:7]=[CH2:8])[O:6]1
Reactant: O=C(O)O
Reactant: C=CC=C
Agent: C=C
Product: C=CC1COC(=O)O1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
Upon removal from the glove box, the flask was evacuated and backfilled with ethylene. The catalyst was dissolved in CH2Cl2 (25 mL) and immediately treated with vinyl ethylene carbonate (5 mL). The resulting orange solution was stirred at 23° C. under an ethylene atmosphere (1 atm) for 20 hours. A small amount of polymer had precipitated out of solution. The polymerization was quenched with MeOH and acetone leaving gray oil adhering to the walls of the flask. The polymer was washed several times with acetone and MeOH to remove any remaining monomer. The polymer was dissolved in CH2Cl2 and transferred to a storage jar. The solvent was left to evaporate and the resulting oily polymer was dried in vacuo at ~80° C. for 3 days to afford a tacky solid (2.15 g, 1100 TO). 1H NMR was consistent with a copolymer containing approximately 96.5 weight % ethylene and 3.5 weight % vinyl ethylene carbonate monomer units.; Mn 40,000 g /mol ; Mw 92,000 g /mol ; DSC Tg -68° C., Tm -38° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([Cl:25])=[CH:6][C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:3][C:4]1[C:5]([Cl:25])=[CH:6][C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13][C:9]=3[N:10]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:11]=2[CH:12]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Cl)c(Cl)cc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3cc(Cl)c(Cl)cc31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.34 g, 8.5 mmol) was added to a solution of tert-butyl 8,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (2.00 g, 5.63 mmol) in DMF (30 mL). After 20 min, ethyl bromoacetate (1.25 mL, 11.3 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 4 h and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography with heptane/EtOAc (3:1) to give 2.10 g (84%) of a pale yellow solid: mp 137.5-139.5° C.; IR (diffuse reflectance) 2985, 1742, 1687, 1473, 1411, 1377, 1367, 1341, 1318, 1249, 1218, 1193, 1167, 1118, 922 cm−1; MS (CI) m/z 441 (M+H+), 404, 402, 387, 385, 343, 341, 339, 307, 52, 51; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 57.13; H, 6.05; N, 6.24.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH2:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.C(#N)C>>[CH3:15][N:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1
Reactant: Oc1ccc(OCCCCCBr)cc1
Reactant: CCNc1ccccc1
Solvent: CC#N
Product: CN(CCCCCOc1ccc(O)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 12.3 %

Procedure:
To a solution of compound 14a (150 mg, 0.57 mmol) and N-ethylaniline (0.07 mL, 0.63 mmol) in acetonitrile (5.0 mL) diisopropylethylamine (0.24 mL, 1.73 mmol) was added dropwise. After the addition was complete the reaction was stirred at 60° C. for 12 hours. The reaction mixture was concentrated, purified by column chromatography to isolate the required compound 14 as a colorless oil (20 mg, 0.07 mmol, 12% yield). MS (ESI, positive) m/z calcd. for C18H24NO2 [M+H]+: 286.18, found: 285.95. 1H NMR (CDCl3, 400 MHz) δ 7.28 (t, J=8.8 Hz, 2H), 6.70-6.85 (m, 7H), 4.72 (s, 1H), 3.93 (t, J=6.4 Hz, 2H), 3.36 (t, J=7.6 Hz, 2H), 2.95 (s, 3H), 1.85-1.78 (m, 2H), 1.65-1.71 (m, 2H), 1.47-1.55 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=1[O:11][CH3:12])[CH2:6][OH:7].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=1[O:11][CH3:12])[CH2:6][O:7][S:24]([CH3:23])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1cc(CO)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1cc(COS(C)(=O)=O)cc(OC)c1OC
Yield: 51.6 %

Procedure:
To a stirred solution of 3,4-dimethoxy-5-propylbenzylalcohol (171 mg, 0.82 mmol) in CH2Cl2 (5.0 mL) at room temperature was added triethylamine (0.23 mL, 1.63 mmol) followed by methanesulfonyl chloride (95 μL, 1.22 mmol, 1.5 eq.). After 30 min the reaction mixture was diluted with hexanes (20 mL) and filtered through a pad of silica gel. The pad was then washed with 25% EtOAc in hexanes (100 mL). The combined organic filtrate was then concentrated to give methanesulfonic acid 3,4-dimethoxy-5-propylbenzyl ester (122 mg) as oil, which was used without further purification.
Reaction SMILES: [H-].[Na+].[Cl-].[Cl:4][C:5]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:6]=1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:32]([CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1)=O.[Cl-].[NH4+]>CS(C)=O>[Cl:4][C:5]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:6]=1/[CH:7]=[CH:32]/[CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Cc1cccc(Cl)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Cc1cccc(Cl)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
264 mg of sodium hydride (55%) was added to a solution of 2.65 g of (2-chloro-6-methylbenzyl)(triphenyl)phosphonium chloride in 20 ml of dimethylsulfoxide, followed by stirring at ambient temperature for 1 hour. After 994 mg of tert-butyl 4-formylpiperidine-1-carboxylate was added to the reaction mixture, the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 645 mg of tert-butyl 4-[(E)-2-(2-chloro-6-methylphenyl)vinyl]piperidine-1-carboxylate as an oil.