Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[CH2:43][OH:44].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=3)[N:4]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)=[CH:36][C:35]=1[CH2:43][OH:44]
Reactant: OCc1cc(B(O)O)ccc1F
Reactant: O=[N+]([O-])c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1ccc(F)c(CO)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
A suspension of 3-bromo-5-nitro-1-trityl-1H-indazole 1 (6 g, 12.41 mmol), 4-fluoro-3-hydroxymethylphenylboronic acid 10AV (2 g, 12.87 mmol), Pd(dppf)Cl2 (800 mg, 0.98 mmol) and K3PO4 (6 g, 28.30 mmol) in 124 mL of dioxane/H2O (25:6) was heated to 80° C. for overnight. After removal of most of the solvent, the black residue was diluted with EtOAc (250 mL) and H2O (60 mL). The resulting mixture was filtered through a pad of Celite. Additional 150 mL of EtOAc was used to wash the Celite cake. The filtrates were combined. The aqueous layer was separated and the organic layer was washed with brine, dried (MgSO4) and concentrated to give crude 3-(4-fluoro-3-hydroxymethylphenyl)-5-nitro-1-trityl-1H-indazole 11AV (8.2 g) as a greenish yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].[F:19][C:20]([F:39])([F:38])[C:21]1[CH:22]=[C:23]([C:31]2[O:35][N:34]=[C:33]([CH2:36]Cl)[N:32]=2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N>CCOC(C)=O>[F:39][C:20]([F:19])([F:38])[C:21]1[CH:22]=[C:23]([C:31]2[O:35][N:34]=[C:33]([CH2:36][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[N:32]=2)[CH:24]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:26]=1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
A mixture of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.040 g, 0.16 mmol), 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole (0.058 g, 0.17 mmol), Cs2CO3 (0.057 g, 0.17 mmol) and CH3CN (4 mL) was stirred at 75° C. for 1.5 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), and brine (15 mL). The organic portion was dried (MgSO4), filtered, and concentrated. The concentrated material was treated with 10% Et2O in hexanes (10 mL) and stirred for 2 h. The resulting solid was filtered, rinsed with hexanes, and dried to afford the title compound (0.070 g, 81%) as a light tan solid: 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 2H), 8.50 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 6.59 (s, 1H), 5.90 (s, 2H), 2.90 (t, J=7.5 Hz, 2H), 1.79-1.70 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); MS m/z 547 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([CH:21]([CH3:23])[CH3:22])[C:3]([N:5]1[CH2:10][CH2:9][C@@:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[C@:7]([OH:20])([CH3:19])[CH2:6]1)=[O:4].[F:24][C:25]1([F:33])[CH2:29][CH2:28][C@@H:27]([C:30](O)=[O:31])[CH2:26]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C@@:8]2([OH:11])[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:30]([C@@H:27]3[CH2:28][CH2:29][C:25]([F:33])([F:24])[CH2:26]3)=[O:31])[CH:21]([CH3:23])[CH3:22])[CH2:6][C@@:7]2([OH:20])[CH3:19])=[CH:13][CH:14]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)[C@@](C)(O)C1
Reactant: O=C(O)[C@@H]1CCC(F)(F)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NC(=O)[C@@H]1CCC(F)(F)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)[C@@](C)(O)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
To a mixture of (R)-2-amino-1-((3S,4S)-4-(4-chlorophenyl)-3,4-dihydroxy-3-methylpiperidin-1-yl)-3-methylbutan-1-one (22.49 g, 66.0 mmol), (R)-3,3-difluorocyclopentanecarboxylic acid (10.21 g, 68.0 mmol) in CH2Cl2 (300 mL) and DMF (75 mL) were added HOBT (12.50 g, 82 mmol), EDC (15.65 g, 82 mmol) and Hunig's base (23.76 mL, 136 mmol). The reaction was stirred for 20 h at rt then concentrated to remove the CH2Cl2. Ethyl acetate was added and the organic layer was washed twice with 1N HCl, twice with saturated sodium carbonate and three times with water. The organic layer was dried over sodium sulfate and concentrated to give a glass solid which was crystallized from CH3CN to give (R)—N—((R)-1-((3S,4S)-4-(4-chlorophenyl)-3,4-dihydroxy-3-methylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3,3-difluorocyclopentanecarboxamide (31.03 g, 65.6 mmol, 99% yield).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:18][C:17](=[O:33])[C@@H:16]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39])=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[Cl:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][C@H:16]1[C:17](=[O:33])[O:18][C@H:19]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:15]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCCCCCl)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1O[C@H](c2ccccc2)[C@H](c2ccccc2)N[C@H]1CCCCCCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of TFA in DCM (20%, 60 mL) is added at 0° C. to (3S,5S,6R)-3-(5-chloro-pentyl)-2-oxo-5,6-diphenyl-morpholine-4-carboxylic acid tert-butyl ester (8.0 g, 17.5 mmol). The reaction mixture is slowly warmed up to room temperature and stirred for 4 hours. The reaction mixture is poured into a saturated K2CO3 solution, the two phases are separated and the water phase is extracted with DCM twice. The combined organic phases are dried over anhydrous Na2SO4 and removal of the solvent under reduced pressure affords 6.0 g of (3S,5S,6R)-3-(5-Chloro-pentyl)-5,6-diphenyl-morpholin-2-one trifluoroacetate.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9]C.I.CI>>[OH:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: I
Solvent: CI
Product: O=C(O)Cc1ccc(O)c(O)c1

Procedure:
The preparation of the above compound can be carried out according to the information set forth in the Berichte der deutschen chemischen Gesellschaft 42: 2949, incorporated herein by reference. In the present case, the compound was prepared from the commercially available 3,4-dimethoxyphenylacetic acid. A mixture of 115 gm (587 mmol) of 3,4-dimethoxyphenylacetic acid, 1052 gm (2.35 mol) of 57% hydroiodic acid, and 14 gm of red phosphorus was agitated for 1.5 hours at 95° C. and for an additional 1.5 hours at 105° to 110° C., during which time the calculated amount (166.5 gm) of methyliodide was distilled off. After cooling of the mixture, removal of the red phosphorus by filtration, evaporation of the solution, and taking up of the residue in ether, the ether solution was treated with concentrated NaHSO3 solution and activated charcoal. After drying of the light-yellow solution with Na2SO4 and evaporation, the residue was suspended in methylene chloride, the residual water was removed by azeotropic distillation, and, after the suspension was cooled, the solid product was removed by suction filtration and dried at 50° C. An amount of 63 gm of 3,4-dihydroxyphenylacetic acid, with a melting point of 126° to 129° C., was obtained (64% of theory).
Reaction SMILES: [Sn].C(Cl)/C=C(/CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)\C.[CH3:23][C:24]1[C:33]([CH3:34])=[C:32]2[C:27]([CH2:28][CH2:29][C:30]([CH2:36][CH2:37][CH2:38][CH:39]([CH2:41][CH2:42][CH2:43][CH:44]([CH2:46][CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[CH3:45])[CH3:40])([CH3:35])[O:31]2)=[C:26]([CH3:52])[C:25]=1[OH:53].[C:54](OC(=O)C)(=[O:56])[CH3:55].N1C=CC(C)=CC=1>[Cl-].[Zn+2].[Cl-]>[CH3:34][C:33]1[C:24]([CH3:23])=[C:25]([O:53][C:54]([CH3:55])=[O:56])[C:26]([CH3:52])=[C:27]2[CH2:28][CH2:29][C@:30]([CH2:36][CH2:37][CH2:38][C@@H:39]([CH2:41][CH2:42][CH2:43][C@@H:44]([CH2:46][CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[CH3:45])[CH3:40])([CH3:35])[O:31][C:32]=12
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Cl-]
Agent: [Sn]
Solvent: Cc1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Yield: 95 %

Procedure:
2.279 of TMHQ, 0.368 g of metallic tin powder and 0.041 g of zinc chloride were suspended in 15 ml of trichlene in an atmosphere of nitrogen. A solution of 4.939 g of phytyl chloride in 10 ml of trichlene was dripped into said suspension over a period of 2.5 hours under agitation and reflux. The reaction mixture was subjected to reflux under agitation for another 2 hours to obtain a reaction mixture containing dl-α-tocopherol which was substantially achromatic. To the reaction mixture was added 13.0 ml of acetic anhydride and 0.219 g of γ-picoline and the mixture was subjected to reflux for 2.5 hours. The lower boiling fractions were distilled off from the reaction mixture under reduced pressure. The reaction mixture was extracted with n-hexane in an amount of 50 ml, and the extract was washed 4 times with an aqueous solution of 2% sodium hydrosulfite, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 7.167 g of dl-α-tocopheryl acetate which was a substantially achromatic viscous liquid. The absorbance of this crude dl-α-tocopheryl acetate was measured: E415 mμ40%EtOH =0.041. Estimation of this crude dl-α-tocopheryl acetate by liquid chromatography with the use of n-nonane as the standard indicated that its purity was 93.8% and the yield was 95.0%.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][CH2:19][CH3:20])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=2)[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH2:18][CH2:19][CH3:20]
Reactant: CCCc1c(OC)cc(CP(=O)(OCC)OCC)cc1OC
Reactant: O=Cc1cccc(F)c1
Product: CCCc1c(OC)cc(C=Cc2cccc(F)c2)cc1OC

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-1-propylbenzyl)phosphonate and 3-fluorobenzaldehyde in the same way as described in Example 21.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Br[C:15]1[S:19][CH:18]=[N:17][CH:16]=1>>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:15]2[S:19][CH:18]=[N:17][CH:16]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: COc1ccc(B(O)O)cc1C=O
Reactant: Brc1cncs1
Product: COc1ccc(-c2cncs2)cc1C=O

Procedure:
The title compound was prepared by employing the method described in Example 111, Step A with (3-formyl-4-methoxyphenyl)boronic acid and the known 5-bromothiazole (E. J. Trybulski and H. J. Brabander, U.S. Pat. No. 4,990,520, 1991). NMR (400 MHz, CDCl3): δ 10.48 (s, 1H), 8.76 (s, 1H), 8.04 (s, 1H), 8.01 (d, 1H, J=2 Hz), 7.75 (dd, 1H, J=9,2 Hz), 7.05 (d, 1H, J=9 Hz), 3.97 (s, 3H). Mass spectrum (NH3 /CI): 220 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8](=[O:16])[CH:7]=1.O>C(O)(=O)C>[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8](=[O:16])[C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2ccccc2[nH]1
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2c(O)c1[N+](=O)[O-]
Temperature: 40 °C
Yield: 98 %

Procedure:
Fuming nitric acid (262 mL) was added at about 20° C. to a suspension of 4-hydroxy-2(l H)-quinolinone (1.0 Kg) in acetic acid (7.57 L). The mixture was heated at 40° C. for 2.5 h. The resulting solution was cooled to about 20° C. and poured into 8 L of water. The resulting mixture was stirred for 20 rain, filtered, washed with water until the filtrate was neutral, and dried. The product 4-hydroxy-3-nitro-2(I H)-quinolinone was isolated in 98% yield and showed only one spot upon analysis by thin layer chromatography (silica gel, 20:80 (V/V) chloroform in methanol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[OH:19]O>C(O)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:19]
Reactant: OO
Reactant: Cc1ccc(CSc2c(O)cc(C)oc2=O)cc1
Solvent: CC(=O)O
Product: Cc1ccc(CS(=O)c2c(O)cc(C)oc2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
4-Hydroxy-6-methyl-3-(p-methylbenzylthio)-2-pyrone (10.5 g., 0.0400 mol), 30% hydrogen peroxide (5.14 g., 0.0440 mol), and 50 ml. glacial acetic acid were combined and stirred at room temperature for 20 hours. The reaction mixture was poured into 250 ml. ice-water and the recovered white precipitate was collected and dried. The solids were recrystallized from toluene to give 3.9 g. (35 percent) of the desired compound as a pale pink crystalline solid, m.p. 156°-158°C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][NH:4][C:3]1=[O:10].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N1CCOCC1)C.[Cl:42][C:43]1[C:48]([F:49])=[C:47]([F:50])[CH:46]=[CH:45][C:44]=1[CH2:51][NH2:52]>ClCCl>[Cl:42][C:43]1[C:48]([F:49])=[C:47]([F:50])[CH:46]=[CH:45][C:44]=1[CH2:51][NH:52][C:7]([CH:6]1[CH2:5][NH:4][C:3](=[O:10])[N:2]1[CH3:1])=[O:9]
Reactant: CN1C(=O)NCC1C(=O)O
Reactant: NCc1ccc(F)c(F)c1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)NCC1C(=O)NCc1ccc(F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.1 %

Procedure:
A mixture of 3-methyl-2-oxo-4-imidazolidinecarboxylic acid (115 mg, 0.8 mmol), 1-hydroxybenzotriazole hydrate (147 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.96 mmol) and N-ethyl morpholine (0.613 ml, 4.8 mmol) in dichloromethane (18 ml) was stirred at room temperature for 10 minutes. A solution of [(2-chloro-3,4-difluorophenyl)methyl]amine (142 mg, 0.8 mmol) in dichloromethane (2 ml) was added and the reaction stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (60 ml) and the mixture was washed with 3N citric acid solution (30 ml). The organic phase was separated, washed with brine, dried and evaporated. The residue was purified by mass-directed automated HPLC to give N-[(2-Chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (95 mg, 39%). LC/MS [M+H]+=304, retention time=1.99 minutes.
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:17]([O-:20])(=[O:19])C.[K+].C(N)=O>>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([CH3:2])[C:17]([OH:20])=[O:19])=[CH:9][CH:8]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(C(OC)(OC)C(C)Br)cc1
Agent: [K+]
Solvent: NC=O
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 95 °C
Reaction time: 6 h
Yield: 4960 %

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(4-methoxyphenyl)-propane (3.6 g; 13 mmol), potassium acetate (2.5 g; 0.25 mmol) and formamide (25 ml) is heated at 95° C. under stirring for 6 h. The reaction mixture is worked up as described in example 1a to give 2-(4-methoxyphenyl)-propionic acid (2.2 g; 12.4 mmol; yield 96%), m.p. 56°-57° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:14])=O)=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[NH:58]1[C:66]2[C:61](=[C:62]([CH2:67][NH2:68])[CH:63]=[CH:64][CH:65]=2)[CH:60]=[N:59]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:14])[NH:68][CH2:67][C:62]2[CH:63]=[CH:64][CH:65]=[C:66]3[C:61]=2[CH:60]=[N:59][NH:58]3)=[CH:8][C:9]=1[C:10]#[N:11])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1C#N
Reactant: NCc1cccc2[nH]ncc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.7 %

Procedure:
To a solution of 3-Cyano-thiophene-2,5-dicarboxylic acid 2-methyl ester (240 mg, 1.14 mmol) in anhydrous DMF (6 mL) was added triethylamine (0.64 mL, 4.56 mmol), HBTU (0.52 g, 1.36 mmol), HOBT (0.180 mg, 1.36 mmol), and C-(1H-Indazol-4-yl)-methylamine dihydrochloride (300 mg, 1.36 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 30-100% EtOAc in hexane to afford the desired product (0.2627 g, 67% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:20])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=S(Cl)[Cl:23]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([Cl:23])=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Cl)ccc2C1

Procedure:
To a suspension of 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester (96 mg, 0.348 mmol) in toluene (4 mL) is added SOCl2 (254 μL, 10 eq.). The mixture is heated to reflux for 3 hours. All the solvent is removed under reduced pressure. The residue is redissolved in toluene and evaporated to dryness twice to remove excess HCl and is dried under high vacuum for 2 hours to give crude 6-chlorocarbonyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21](O)[CH:22]=2)[CH:17]=1)=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:25]=[CH:24]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1

Procedure:
A mixture of cis-4-tert-butylcyclohexanol (927 mg, 0.00593 mol), 6-hydroxy-naphthalene-2-carboxylic acid methyl ester (1.00 g, 0.00494 mol) and triphenylphosphine (1560 mg, 0.00593 mol) in toluene (10 mL, 0.1 mol) was heated to reflux, and diisopropyl azodicarboxylate (1.17 mL, 0.00593 mol) was added dropwise and was stirred and refluxed for 6 hours. The mixture was taken up into dichloromethane and was purified via column chromatography with ethyl acetate:hexane (0:100 to 40:60) to give methyl 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthoate as a white solid (0.95 g, 56%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.01 (dd, J=8.7, 1.7 Hz, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.17 (m, 2H), 4.34 (m, 1H), 3.97 (s, 3H), 2.30 (m, 2H), 1.92 (m, 2H), 1.52-1.14 (m, 5H), 0.91 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([NH2:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:15][CH:16](Cl)[C:17](=O)[CH3:18]>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]3[O:13][CH:18]=[C:17]([CH2:16][Cl:15])[N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)C(Cl)Cl
Reactant: NC(=O)C=Cc1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Product: ClCc1coc(C=Cc2ccc3c(c2)OCO3)n1
Yield: 75.9 %

Procedure:
49.0 g (256 mmol) 3-Benzo[1,3]dioxol-5-yl-acrylamide, 44.4 g (350 mmol) dichloro acetone and 300 ml toluene were kept at reflux temperature for 48 h with continuous removal of water by applying a Dean-Stark trap. After removal of solvents in vacuo, the residue was treated with 600 ml of a 1:1 mixture of water/isopropanol. After filtration the precipitate was washed first with isopropanol, then with heptane. Drying at 40° C. in vacuo gave 51.2 g (76%) 2-(2-Benzo[1,3]dioxol-5-yl-vinyl)-4-chloromethyl-oxazole.
Reaction SMILES: C(OC1C=CC([Cl:12])=CC=1)(=O)C=C.[C:13]([O-:26])(=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CCCCCC.[C:27]([O-:40])(=O)[CH2:28][CH2:29]CCCCCCCCC.C([Sn+2]CCCC)CCC>>[C:27]([O:26][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[Cl:12])(=[O:40])[CH:28]=[CH2:29]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: C=CC(=O)Oc1ccc(Cl)cc1
Agent: CCCC[Sn+2]CCCC
Product: C=CC(=O)Oc1ccccc1Cl
Reaction time: 8 h

Procedure:
A solution was prepared containing 98.86 wt. % 4-chlorophenyl acrylate and 1.14 wt. % dibutyltin dilaurate. 0.017 g of this solution was added to a vial containing 0.2519 g diisocyanate-terminated polypropylene glycol (MW=2471), 0.047 g α,ω-dihydroxypolypropylene glycol (MW=425), 0.051 g 4-chlorophenyl acrylate, and 0.00063 g Ciba CGI-784 (photoinitiator). The mixture was thoroughly mixed and allowed to cure overnight at room temperature, while protected from light. The polymerization was a step polymerization of the isocyanate groups with the hydroxyl groups to form a polyurethane with dissolved chlorophenyl acrylate monomer. The mixture appeared clear and transparent to the naked eye. Upon exposure to an intense tungsten light, which initiated polymerization of the acrylate monomer, the sample remained clear and transparent, indicating the compatibility of the monomer and the matrix polymer.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](I)[CH3:11].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH3:11]
Reactant: O=Cc1cccc(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (3.0 g, 24.6 mmol), ethyl iodide (5.9 ml, 73.8 mmol) and K2CO3 (3.4 g, 24.6 mmol) in 50 ml of acetone was stirred at +40° C. for 6 h and at RT overnight. The mixture was filtered and evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 15:100) to give 3-ethoxybenzaldehyde.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2.[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][CH:7]1[CH:6]2[CH2:9][CH2:10][N:3]([CH2:4][CH2:5]2)[CH:2]1[CH3:1]
Reactant: CC1C(=O)C2CCN1CC2
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNC2C3CCN(CC3)C2C)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Methyl-1-aza-bicyclo[2.2.2]octan-3-one (500 mg, 3.59 mmol) and 2,4-dimethoxybenzyl amine (1.2 g, 7.18 mmol) were dissolved in anhydrous 1,2-dichloroethane (10 ml). Sodium triacetoxyborohydride (1.1 g, 5.0 mmol) followed by glacial acetic acid (0.21 ml, 3.59 mmol) and the resultant foamy suspension was stirred at ambient temperature for 12 hours. The reaction was quenched by the addition of 1M NaOH, and the layers were separated. The aqueous phase was extracted further with ethyl acetate. The organic portions were combined, dried (Na2SO4), filtered and concentrated in vacuo. The crude reaction mixture was purified by chromatography [eluent gradient: 10-30% MeOH/Et3N (9:1) in EtOAc) to give pure (2,4-dimethoxy-benzyl)-(2-methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-amine.