Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]=[N:3][CH:4]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:6](C)([CH2:7]N=C=O)[CH2:5]1.C1N2CCN(CC2)C1.C1(=O)OC(C)C[O:26]1>>[N-:3]=[C:2]=[O:1].[N-:3]=[C:2]=[O:1].[O:26]=[C:4]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:6]([CH3:7])=[CH:5]1
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: CC1COC(=O)O1
Agent: C1CN2CCN1CC2
Product: CC1=CC(=O)CC(C)(C)C1
Product: [N-]=C=O
Temperature: 131 °C
Reaction time: 0.13 h

Procedure:
A mixture of 861 parts of isophorone diisocyanate, 535.95 parts of propylene carbonate and 2.15 parts of Dabco TMR* is stirred and gradually heated. When the temperature reaches 55° C. heating is discontinued. The exothermic reaction raises the temperature to 131° C. in 15 minutes. After cooling to 89° C., 5.8 parts of a 10% solution of Dabco TMR* in propylene carbonate is added. The temperature rises to 90° C. in 8 minutes. After heating to 132° C. it is allowed to cool. 1397.1 parts of this product, the tri-isocyanato-isocyanurate formed from 3 moles of isophorone di-isocyanate as a 61.4% solids solution in propylene carbonate, having an NCO content of 10.94% is stirred while 366.8 parts of 3,5-dimethylpyrazole is added, cooling as required, to keep the temperature below 80° C. followed by 463.4 parts of the monomethyl ether of propylene glycol. The mixture is stirred at 50° C. and a clear solution formed which solution is then allowed to cool. The IR Spectrum shows NCO absent.
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(#N)C.N1C=CC=CC=1>[C:18]1([C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCOCCOCCOCCOCCO
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: OCCOCCOCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
10 g of pentaethyleneglycol was dissolved in a mixture of 100 mL of acetonitrile and 30 mL of pyridine, to which 11 g of trityl chloride were added at 0° C., and then the solution was stirred overnight at room temperature. The reaction solution was mixed with iced water and subjected to extraction with ethyl acetate, and then the organic layer washed with water and concentrated under reduced pressure after drying. The residue was purified with silica gel column chromatography to obtain 6 g of the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4](Cl)=[O:5].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[N:24][CH:25]=1.N1C=CC=CC=1.Cl>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[N:24][CH:25]=1)=[O:5]
Reactant: O=C(Cl)c1c(F)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: COC(=O)c1ccc(N)cn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2c(F)cc(C(F)(F)F)cc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
A solution of 2-fluoro-4,6-bis(trifluoromethyl)benzoyl chloride (1.0 g, 3.39 mmol) and dichloromethane (5.0 mL) was added drop-wise to a mixture of methyl 5-aminopyridine-2-carboxylate (619.9 mg, 4.07 mmol), pyridine (824.1 μL, 10.18 mmol) in dichloromethane (20.00 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl and dichloromethane. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a tan solid. The product was purified on column chromatography eluting with 10-100% ethyl acetate in hexanes to obtain methyl 5-[[2-fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (850 mg, 61%) as a white solid. ESI-MS m/z calc. 410.05, found 411.0 (M+1)+; Retention time: 0.62 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.48-8.41 (m, 1H), 8.34 (dd, J=8.6, 2.6 Hz, 1H), 8.20 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 3.89 (s, 3H) ppm.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].N12CCCN=C1CCCCC2.CC1C=CC([C:24]2[C:25]([F:53])=[C:26]([CH:30]=[C:31]([Cl:52])[C:32]=2[O:33][C:34]2[CH:35]=[N:36][C:37]([O:44][CH2:45][C:46]([F:51])([F:50])[CH:47]([F:49])[F:48])=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)[C:27]([O-])=[O:28])=CC=1>C(#N)C>[Cl:52][C:31]1[C:32]([O:33][C:34]2[CH:35]=[N:36][C:37]([O:44][CH2:45][C:46]([F:51])([F:50])[CH:47]([F:48])[F:49])=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)=[CH:24][C:25]([F:53])=[C:26]([CH:30]=1)[C:27]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:28]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(-c2c(F)c(C(=O)[O-])cc(Cl)c2Oc2cnc(OCC(F)(F)C(F)F)c(C(F)(F)F)c2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(OCC(F)(F)C(F)F)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
Methanesulphonamide (89.54 mg, 0.94 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL, 1.03 mmol) were added to 4-methylphenyl-5-chloro-4-(6-(2,2,3,3-tetrafluoropropoxy)-5-(trifluoromethyl)pyridin-3-yloxy)-2-fluorobenzoate (Preparation 263, 475 mg, 0.86 mmol) in acetonitrile (5 mL) and the reaction mixture was stirred for 18 hours at room temperature. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate and water, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase chromatography (acetonitrile/water both with 0.1% formic acid) to give the title compound as a white solid (303 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:13]=2[C:14]#[N:15])=[CH:6][C:5]([S:20]([N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)(=[O:22])=[O:21])=[C:4]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH:3]=1.C(#N)C.[OH2:40].CO>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:13]=2[C:14]#[N:15])=[CH:6][C:5]([S:20](=[O:22])(=[O:21])[N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[C:4]([CH:3]=1)[O:31][CH2:32][CH2:33][CH2:34][C:35]([OH:40])=[O:36]
Reactant: CN(c1ccccn1)S(=O)(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCCO
Reactant: O
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: CN(c1ccccn1)S(=O)(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4-hydroxy-butoxy)-N-methyl-N-pyridin-2-yl-benzenesulfonamide (45 mg, 0.083 mmol) in a mixture of DCM (0.3 mL), acetonitrile (0.3 mL) and water (0.4 mL) was added NaIO4 (54 mg, 0.25 mmol) and RuCl3 (2.7 mg, 0.013 mmol). After stirring at rt for 20 minutes, 0.5 mL of methanol was added. The mixture was stirred for 5 minutes, filtered, and purified by prep. LCMS to afford 4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-pyridin-2-yl-sulfamoyl)-phenoxy]-butyric acid 18-1. MS: 555.1 (M+H)+; tR=7.61 min (method 2).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.N1([C:20](N2C=NC=N2)=[O:21])C=NC=N1.[CH3:27][O:28][CH:29]([O:49][CH3:50])[C:30]1[C:39]([CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][C:42]2=[O:48])=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1>CN(C=O)C>[C:6]([C:5]1[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:9][C:2]([NH:1][C:20]([N:33]2[C:32]3[C:37](=[CH:38][C:39]([CH2:40][N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][C:42]4=[O:48])=[C:30]([CH:29]([O:49][CH3:50])[O:28][CH3:27])[N:31]=3)[CH2:36][CH2:35][CH2:34]2)=[O:21])=[N:3][CH:4]=1)#[N:7]
Reactant: O=C(n1cncn1)n1cncn1
Reactant: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2
Reactant: COCCNc1cc(N)ncc1C#N
Solvent: CN(C)C=O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 481 mg, 2.50 mmol) in anhydrous DMF (1.5 ml) was added drop wise over 10 minutes to a mixture of di(1H-1,2,4-triazol-1-yl)methanone (410 mg, 2.50 mmol) and DMF (1.5 ml) cooled at 0° C. After stirring for 45 minutes at 0° C. the reaction mixture was allowed to warm to room temperature and after a further 90 minutes at room temperature a solution of 1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one (intermediate 81, 418 mg, 1.00 mmol) in DMF (2 ml) was added. The reaction mixture was stirred for 17.5 h at room temperature, quenched by the addition of MeOH and evaporated. The residue was applied to a 80 g RediSep® silica column as a DCM solution and purified by normal phase chromatography, eluting with a gradient from DCM to 2% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as an orange foam. 1H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H), 8.27 (s, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 6.93 (t, 1H), 5.45 (s, 1H), 4.65 (s, 2H), 3.94-3.89 (m, 2H), 3.54-3.50 (m, 2H), 3.40-3.35 (m, 2H), 3.38 (s, 6H), 3.29 (s, 3H), 3.20-3.16 (m, 2H), 3.05 (s, 2H), 2.86-2.80 (m, 2H), 2.61-2.55 (m, 2H), 2.22 (s, 3H), 1.94-1.88 (m, 2H). (UPLC-MS 6) tR 0.72; ESI-MS 553.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=1.F[B-](F)(F)F.[N:28]1(OC(N(C)C)=[N+](C)C)[C:32]2[CH:33]=CC=C[C:31]=2N=N1.C(N(CC)C(C)C)(C)C.C(N)(C)C>CN(C=O)C>[CH:32]([NH:28][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:19][CH:18]=1)=[O:22])([CH3:33])[CH3:31]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)NC(C)C)s1
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (77 mg, 0.24 mmol) in DMF (3 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (86 mg, 0.27 mmol), N,N-diisopropyl ethyl amine (208 μL, 1.21 mmol) and isopropylamine (16 mg, 0.27 mmol). The resulting reaction mixture was stirred for 2 h and then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 1:1 to 0:1) afforded the title compound (81 mg, 93%) as an off white solid. MS: m/e=357.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@H:10]1[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][C@@H:11]1[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O1CCOCC1.O>S(=O)(=O)(O)O>[O:14]=[C:13]1[CH2:12][C@H:11]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:10]([C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:19][CH2:18]1
Reactant: O=C(N[C@H]1CC2(CC[C@@H]1c1cc(F)c(F)cc1F)OCCO2)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of benzyl [(7S,8R)-8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-yl]carbamate (315 mg, 0.75 mmol) in sulfuric acid (15 mL, 1:1 in water) was added 1,4-dioxane (30 mL). The mixture was stirred at room temperature for 1 h. The resulting mixture was poured into water (70 ml) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated to yield the title compound. LC/MS 378.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[O:31])=[CH:26][CH:25]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(C(=O)N2CCCC2)cc1)C(=O)OC
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)N2CCCC2)cc1
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.39 g), 3-oxo-2-[4-(pyrrolidine-1-carbonyl)benzyl]pentanoic acid methyl ester (1.0 g), polyphosphoric acid (2 g) and dioxane (20 mL) was heated at 120° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (9:1 by volume) to afford title compound, 0.25 g.
Reaction SMILES: [OH:1][C@@H:2]([CH2:24][OH:25])[CH2:3][C:4]1[CH:5]=[C:6]([F:23])[C:7]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[N:8][CH:9]=1.Cl.C(OCC)C>ClCCl.O1CCOCC1>[F:23][C:6]1[CH:5]=[C:4]([CH2:3][C@@H:2]([OH:1])[CH2:24][OH:25])[CH:9]=[N:8][C:7]=1[N:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C[C@@H](O)CO)cc2F)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: OC[C@H](O)Cc1cnc(N2CCNCC2)c(F)c1
Yield: 114.3 %

Procedure:
A solution of 13 (1.40 g, 3.94 mmol) in dichloromethane (10 mL) was stirred with 4 mol/L HCl in dioxane (25 mL) in a closed vessel overnight at room temperature. The resulting suspension was stirred for 1 h with ethyl ether. The solid precipitated was collected by filtration and washed several times with ethyl ether to afford 1.15 g (yield 100%) of 14 as a pale yellow foam (HCl salt). The identity of compound 14 was confirmed by LC/MS and was used directly for the next step. LC/MS (M+1) 256.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([O:8][O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])(O)=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1C=CC=CC=1>[Cl:19][C:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([O:8][O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])=[O:2]
Reactant: CC(C)(C)OOC(=O)c1ccccc1C(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)OOC(=O)c1ccccc1C(=O)Cl

Procedure:
To a suspension of t-butyl o-(carboxy)peroxybenzoate (16.2g. 0.06 moles) in 100 ml. of benzene at +6° to +24° C but preferably at +6° to +10° C was added in a single portion phosphorous pentachloride (12.6g. 0.06 moles).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6]([O:8][C:9](OCC)(OCC)[CH3:10])[CH3:7].C(OC(=O)C)(=O)C>>[CH2:6]([O:8][C:9](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH3:10])[CH3:7]
Reactant: CCOC(C)(OCC)OCC
Reactant: N#CCC#N
Solvent: CC(=O)OC(C)=O
Product: CCOC(C)=C(C#N)C#N

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed malononitrile (20.4 g, 309.09 mmol, 1.00 equiv) at room temperature. To the resulting mixture was then added 1,1,1-triethoxyethane (50 g, 308.64 mmol, 1.00 equiv), in portions at room temperature. To the resulting mixture was then added acetic anhydride (72 g, 705.88 mmol, 2.28 equiv), in portions at room temperature. The resulting solution was heated to reflux for 3 hr. The resulting mixture was concentrated under vacuum, then cooled with a water/ice bath. The solids were collected by filtration to yield 2-(1-ethoxyethylidene)malononitrile as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:18]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]=[N:16][N:15]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:45])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:45][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:18]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture containing 11 g of the compound prepared in step B, 140 ml of carbon tetrachloride, 4.12 g of NBS and 0.4 g of benzoyl peroxide is refluxed for 3 hours. After it has returned to RT, it is filtered and the filtrate is then evaporated. The residue is taken up in 30 ml of isopropyl ether. The precipitate formed is filtered off and then dried under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH:8]=[CH:12][N:13]([CH3:15])[CH3:14])[S:5][CH:6]=1
Reactant: CC(=O)c1cc(Br)cs1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1cc(Br)cs1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A mixture of 1-(4-bromo-2-thienyl)ethanone (48.8 mmol) and N,N-dimethylformamide dimethyl acetal (73.1 mmol) was refluxed overnight and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure and dried in vacuo to afford 12.6 g (99% yield) of 1-(4-bromo-2-thienyl)-3-(dimethylamino)prop-2-en-1-one which was used in the next step without further purification.
Reaction SMILES: [S:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:26]([S:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1)(=[O:3])=[O:2])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: COC(=O)c1ccc(S(=O)O)cc1
Reactant: CCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)OC)cc1
Temperature: 70 °C

Procedure:
Methyl 4-sulfinobenzoate (4), (12.7 g, 63.43 mMole) and 1-bromododecane (17.4 g, 69.77 mMole) were dissolved in dimethylformamide (100 mL). Potassium carbonate (10.5 g, 76.12 mMole) was added and the mixture heated to 70° C. for 3 hours with good stirring. At the end of this period of time the mixture was cooled and carefully poured into ice cold 2N-HCl (500 mL). The crude methyl 4-dodecylsulfonylbenzoate, a white solid, was filtered off, washed well with water and used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.C1COCC1.CCN(C(C)C)C(C)C.Cl[CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>CCOC(C)=O>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]2[N:6]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COc1cc2[nH]cnc2cc1Cl
Reactant: COCCOCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCCOCn1cnc2cc(Cl)c(OC)cc21
Reaction time: 18 h
Yield: 65.4 %

Procedure:
To a mixture of 5-chloro-6-methoxy-1H-benzoimidazole (0.320 g, 1.75 mmol) and THF (10 mL), was added DIPEA (0.850 mL, 4.9 mmol) followed by 1-chloromethoxy-2-methoxy-ethane (0.310 g, 2.45 mmol) at 23° C. After stirring for 18 h, EtOAc (50 mL) was added. The organic layer was washed with brine (20 mL), dried, filtered, and concentrated under reduced pressure to afford (0.31 g) of crude material which was used without further purification in the next reaction.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4](=[O:29])[C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[C:7]([F:27])[C:6]=1[F:28].[OH-].[Na+]>CO.O1CCCC1.O>[F:11][C:10]1[C:9]([F:12])=[C:8]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:7]([F:27])=[C:6]([F:28])[C:5]=1[C:4](=[O:29])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(=O)c1c(F)c(F)c(OCCOc2ccc3ccccc3c2)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1c(F)c(F)c(OCCOc2ccc3ccccc3c2)c(F)c1F
Yield: 38.3 %

Procedure:
A solution of 2,3,5,6-tetrafluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from dichloromethane-hexane provided 0.185 g of purified 2,3,5,6-tetrafluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a yellow solid, mp 146°-148° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][O:29][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:26][CH:27]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CO)cc3)c2CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(COS(C)(=O)=O)cc3)c2CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-(4-hydroxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (170 mg, 0.391 mmol) in anhydrous DCM under nitrogen, add methanesulfonyl chloride (33 μL, 0.426 mmol) and triethylamine (61 μL, 0.44 mmol) and continue stirring for 2 h. Dilute with water (5 mL) and extract three times with DCM. Wash the combined organic extracts with brine, dry over anhydrous Na2SO4, and concentrate in vacuo to obtain the desired intermediate that was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.[NH2:14][OH:15]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[CH:5]=[N:14][OH:15]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: NO
Product: COc1ccc(C=NO)c(OC)c1

Procedure:
2,4-Dimethoxybenzoic acid is reacted with hydroxylamine to form 2,4-dimethoxybenzaldoxime. 2,4-Dimethoxybenzaldoxime is reacted with diphosphorus pentoxide to form 2,4-dimethoxybenzonitrile. 2,4-Dimethoxybenzonitrile is reacted with boron trichloride to form 2,4-dihydroxybenzonitrile.