Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C:37]1([O:40]C(=O)C)[CH2:39][CH2:38]1)=[O:36]>>[OH:40][C:37]1([C:35]([N:2]2[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:33][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:6][CH2:7]2)=[O:36])[CH2:39][CH2:38]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)cc1F
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)C5(O)CC5)CC4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A166) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([CH:2]([NH:1][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:19][CH:20]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:12][CH:11]=1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: COC(=O)C(N)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)c1ccc(C(C)(C)C)cc1)c1ccc(Br)cc1
Reaction time: 4 h
Yield: 87.7 %

Procedure:
Prepared using General Procedure 7. To a stirring solution of methyl 2-amino-2-(4-bromophenyl)acetate (421 mg, 1.5 mmol), 4-(tert-butyl)benzoic acid (321 mg, 1.8 mmol), and DIEA (831 μl, 4.5 mmol) in DMF (3 mL) cooled to 0° C. was slowly added a solution of HATU (380 mg, 1.65 mmol) in DMF (1.5 mL) in a drop-wise fashion. The reaction mixture was allowed to warm slowly and stirring continued for 4 h. The reaction mixture was poured onto ice-water and the solid was filtered. The solid was dissolved in DCM (10 mL), dried over MgSO4 and evaporated to afford 532 mg (88%) of methyl 2-(4-bromophenyl)-2-(4-(tert-butyl)benzamido)acetate. LCMS-ESI (m/z) calculated for C20H22BrNO3: 403.0. found 404.1 [M+H]+, tR=3.61 min. (Method 16).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH:8]=1)[OH:7].C(O)(=O)[C:11](O)=[O:12].C1(C=O)C(C)=CC=CC=1O>O>[CH:8]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1].[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH:8]=1)[OH:7].[CH2:11]=[O:12]
Reactant: O=C(O)C(=O)O
Agent: Cc1cc(O)cc(O)c1
Agent: Cc1cccc(O)c1C=O
Solvent: O
Product: C=O
Product: Cc1cccc(O)c1
Temperature: 60 °C

Procedure:
Into a reactor equipped with a thermometer, an agitator, a reflux cooler and a dropping funnel were charged 108 parts of m-cresol, 108 parts of water and 1.1 parts of potassium hydroxide, and 142 parts of 37% aqueous formaldehyde solution was added dropwise to the mixture in 2 hours while agitating the resulting mixture at 60° C. After completion of the addition of the formaldehyde solution, an agitation was further continued for 3 hours at 60° C., and then the mass was cooled to obtain a homogeneous transparent resol type precondensate of m-cresol. Into another reactor having the same equipments as described above were charged 248 parts of 5-methylresorcin, 290 parts of water and 2.5 parts of oxalic acid. Then, the above obtained m-cresol-formaldehyde reaction liquid was added dropwise to the 5-methylresorcin solution in 2 hours while agitating the resulting mixture at 60° C. After completion of the addition, the resulting mixture was further agitated at 60° C. for 3 hours, and then water in the reaction liquid was removed. The residue was poured into a distillation vessel, and unreacted m-cresol and 5-methylresorcin were removed by a distillation under reduced pressure to obtain a m-cresol/5-methylresorcin/formaldehyde cocondensate.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-:3].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)([CH3:10])[CH3:9].[C:12](O)(=O)[CH3:13]>ClC(Cl)=C>[CH3:9][C:8]([CH3:10])([CH2:13][CH2:12][Cl:3])[CH:7]=[C:6]([Cl:1])[Cl:5]
Reactant: [Cl-]
Reactant: CC(C)(Cl)CCCl
Reactant: CC(=O)O
Agent: [Al+3]
Solvent: C=C(Cl)Cl
Product: CC(C)(C=C(Cl)Cl)CCCl
Temperature: -10 °C

Procedure:
20 g of aluminum chloride are dissolved in 2,300 g of 1,1-dichloroethene, while stirring and cooling to -10° C. Thereupon, 1,286 g of 1,3-dichloro-3-methylbutane are added dropwise in the course of 3 hours, and simultaneously, at intervals of 15 minutes, further 3 g portions of aluminum chloride are added in measured amounts to the mixture, a reaction temperature of between 0° and +5° C. being maintained by cooling. After the end of the reaction, 60 ml of acetic acid are added dropwise to the reaction mixture. Thereafter, the product mixture is filtered over sodium sulphate, and is then metered into a distillation apparatus, the trough temperature being kept at 120° C., and a pressure of 1 mbar being maintained; the distillate is cooled and condensed by means of a dry ice/acetone mixture. The crude distillate is then fractionally distilled in vacuo in a Vigreux column. 1,650 g of 3,3-dimethyl-1,1,5-trichloro-1-pentene of boiling point 59° to 63° C./0.1 mm Hg are obtained. 1,1-Dichloro-3,3-dimethyl-1,4-pentadiene
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.C(Cl)(Cl)(Cl)Cl.C(=O)=O.[CH:26](=[O:28])[CH3:27].Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[C:8]([CH:26]([CH3:27])[OH:28])[S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: CC=O
Reactant: Oc1cc2ccsc2c(Cl)c1Cl
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 4 h

Procedure:
To a solution of 25 g of 6,7-dichloro-5-hydroxybenzo[b]thiophene in 145 ml of dried tetrahydrofuran at -25° to -30° is added 110 ml of 2.5M n-butyllithium maintaining a temperature below -21°. After the addition, the carbon tetrachloride-dry ice bath is replaced with an ice-water bath and the mixture is stirred at 0°-5° for 4 hrs. A solution of 7.5 ml of freshly distilled acetaldehyde in 10 ml tetrahydrofuran is added dropwise. And additional 2 ml of acetaldehyde is added and the solution is stirred for 1 hr. The solution is poured onto 500 ml of a cold 5% hydrochloric acid solution and the mixture is extracted with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and solvent is removed to give a solid. Recrystallization from ethyl acetate and hexane gives 20 g of 6,7-dichloro-5-hydroxy-α-methylbenzo[b]thiophene-2-methanol, mp 173°-174°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[C@H:10]([OH:36])[CH2:9]1)=O)(C)(C)C.Cl.[CH2:38](Cl)Cl>CO.O1CCOCC1>[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[C:17]4[CH:34]=[CH:35][C:14]([C@H:11]5[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]5[OH:36])=[CH:15][C:16]=4[O:25][CH2:24][CH2:23][N:22]3[CH:21]=2)=[N:30][C:29]([CH3:38])=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3O)cc1OCC2
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2ccc([C@H]4CCNC[C@H]4O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of cis-racemic-3-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (17 mg, 0.36 mmol) in DCM (1 mL) and methanol (0.6 mL) was added 4M HCl in dioxane (1.5 mL) slowly and the reaction mixture stirred at RT for 2.5 h before being concentrated in vacuo. The resultant residue was triturated in diethyl ether to give racemic cis-4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-3-ol which was resolved as the (3R,4S) enantiomer 328 as a white solid (10 mg, 67%). MS RT 2.47, [M+H]+=409. 1H NMR (DMSO-d6) δ: 8.92 (1 H, br, d), 8.33 (1 H, d, J=8.30 Hz), 7.97 (1 H, s), 7.08 (1 H, d, J=8.36 Hz), 6.96 (1 H, d, J=1.66 Hz), 5.79 (1 H, t, J=6.59 Hz), 4.50 (4 H, d, J=7.99 Hz), 4.06 (1 H, s), 3.27 (2 H, m), 3.17 (2 H, m), 2.97 (2 H, d, J=14.58 Hz), 2.32-2.27 (1H, m), 2.29 (3 H, s), 1.74 (1 H, d, J=13.43 Hz), 1.46 (6 H, d, J=6.59 Hz)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[C:9]([O:30][CH3:31])=[CH:10][C:11]([O:28][CH3:29])=[C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:13]=1)=[O:7].Cl.[NH:33]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[C:36](=[O:43])[NH:35][C:34]1=[O:44].[I-].[Na+].C(N(CC)CC)C>CN(C=O)C>[O:44]=[C:34]1[NH:35][C:36](=[O:43])[C:37]2([CH2:42][CH2:41][N:40]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]3[C:9]([O:30][CH3:31])=[CH:10][C:11]([O:28][CH3:29])=[C:12]([NH:14][S:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)(=[O:17])=[O:16])[CH:13]=3)=[O:7])[CH2:39][CH2:38]2)[NH:33]1
Reactant: COc1cc(OC)c(C(=O)CCCCCl)cc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1NC(=O)C2(CCNCC2)N1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(=O)CCCCN2CCC3(CC2)NC(=O)NC3=O)cc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 115 °C
Yield: 38.2 %

Procedure:
A mixture of N-[5-(5-chloropentanoyl)-2,4-dimethoxyphenyl]-4-trifluoromethylbenzenesulfonamide (0.8 g, 1.7 mmol), prepared as in Example 14, 1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (0.55 g, 2.7 mmol), prepared as in Example 16, sodium iodide (0.4 g, 2.7 mmol), triethylamine (0.5 g, 5 mmol) in DMF (approximately 5 mL) was heated 16 hours at 115° C. The mixture was concentrated and the residue was stirred with water and the solids were collected, dried and purified by column chromatography eluting with methylene chloride/methanol+ammonium hydroxide (95:5) to give N-{5-[5-(2,4-dioxo -1,3,8-triazaspiro[4.5]dec-8-yl)pentanoyl]-2,4-dimethoxyphenyl}-4-trifluoromethylbenzenesulfonamide (0.4 g, 0.65 mmol), m.p. 226° C. The free base was recrystallized from a solution of hydrogen chloride in ethanol to give N-{5-[5-(2,4-dioxo-1,3,8-triazaspiro[4.5]dec-8-yl)pentanoyl]-2,4-dimethoxyphenyl}-4-trifluoromethylbenzenesulfonamide hydrochloride (0.37 g, 0.57 mmol), m.p. 277°-278° C. (dec).
Reaction SMILES: [S:1]1(=[O:9])(=[O:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3][NH:2]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:10][S:11]([N:5]1[CH2:6][CH2:7][S:1](=[O:9])(=[O:8])[NH:2][CH2:3][CH2:4]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=S1(=O)CCNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCNS(=O)(=O)CC1

Procedure:
To a solution of 1,2,5-thiadiazepane 1,1-dioxide (0.10 g, 0.67 mmol) in methylene chloride (2 mL) at −10 C was added methane sulfonyl chloride (0.06 mL, 0.77 mmol) and triethylamine (0.108 mL, 0.77 mmol). After 72 hr the reaction was quenched with NaHCO3 (sat. aq.) and extracted into methylene chloride. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified by chromatography (SiO2, EtOAc/CH2Cl2: 1:1) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C=O)C.C(OCC)(=O)C>[CH3:18][N:19]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:15](=[O:17])/[CH:14]=[CH:13]/[C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[CH:32][CH:33]=1)[CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: Cc1ccc(-c2ccc(/C=C/C(=O)O)o2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(/C=C/C(=O)Nc3ccc(CN(C)C4CCOCC4)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.1 %

Procedure:
To a solution of (E)-3-[5-(4-methylphenyl)furan-2-yl]acrylic acid (200 mg), 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (212 mg) and triethylamine (0.15 ml) in DMF (10 ml) was added diethyl cyanophosphate (0.16 ml) at 0° C., and the mixture was stirred at room temperature for 3 hours. To the mixture was added ethyl acetate, and the mixture was washed with water and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:50→1:25→1:10) to give (E)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-3-[5-(4-methylphenyl)furan-2-yl]acrylic amide (Compound 210) (87 mg) as brown amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17](O)=[O:18])=[N:9]2)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:51][C@@H:52]([CH:55]([CH3:57])[CH3:56])[CH2:53][OH:54]>C(C#N)(C)=O>[OH:54][CH2:53][C@@H:52]([NH:51][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)[N:9]=1)=[O:18])[CH:55]([CH3:57])[CH3:56]
Reactant: O=C(O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)[C@H](N)CO
Agent: CC(=O)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](CO)NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@H]1C[C@@H]21
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of (1aR,5aR)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (68.9 mg, 0.25 mmol), HATU (95 mg, 0.25 mmol) and Et3N (25.3 mg, 0.25 mmol) in AcCN (5 mL) was added (S)-2-amino-3-methylbutan-1-ol (25.3 mg, 0.25 mmol) at room temperature. The reaction was stirred overnight and concentrated. The residue was diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was concentrated. The residue was purified by column chromatography to give the title compound (72 mg) as a white solid. LCMS m/z=361.5 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.45 (dd, J=7.9, 4.6 Hz, 1H), 1.04 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H), 1.22-1.27 (m, 1H), 2.01-2.08 (m, 1H), 2.24-2.30 (m, 1H), 2.78-2.82 (m, 1H), 2.96 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.5, 6.3 Hz, 1H), 3.75-3.88 (m, 3H), 7.02 (d, J=7.8 Hz, 1H), 7.21 (dd, J=5.4, 1.8 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 8.36 (d, J=5.4 Hz, 1H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl.O1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: C1=COCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
to a vigorously stirred solution of N-hydroxyphthalimide (10.0 g, 61.4 mmol) in CH2Cl2 (70 mL) and dioxane (80 mL) was added dihydropyran (6.16 mL, 67.6 mmol) and p-toluenesulfonic acid (200 mg). The resulting solution was stirred overnight at room temperature. The reaction was quenched by slow addition of saturated NaHCO3 (100 mL). After separation, the organic layer was washed with brine and dried over Na2SO4. Solvent removal under vacuum yielded 13.4 g (88%) of 2-(tetrahydro-2H-pyran-2-yloxy)isoindoline-1,3-dione as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=[CH:14][C:15]([OH:17])=[O:16])[CH2:7][CH2:6]2.O>C(O)(=O)C.O.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][C:15]([OH:17])=[O:16])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(=CC(=O)O)C2=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)CCC(CC(=O)O)C2=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
Zinc (493 g, 7536 mmol) was added to a solution of 1A (350 g, 1507 mmol) in acetic acid-water mixture (1 L+420 mL), and the mixture was stirred at 100° C. for 3 h. The reaction mixture was then filtered over celite bed, and the organic layer was removed under reduced pressure to give a residue. Water (5 L) was added to the residue. The resulting solids were filtered off and dried under vacuum to afford the title compound (280 g, 77%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 12.2 (bs, 1H), 7.8 (d, J=8.4 Hz, 1H), 6.9 (m, 2H), 3.8 (s, 3H), 3.1 (m, 1H), 3.0-2.8 (m, 2H), 2.7 (m, 1H), 2.4 (m, 1H), 2.2 (m, 1H), 1.9 (m, 1H). ESI-MS m/z: 235 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:12][CH:13]([CH3:15])[CH3:14].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1
Reactant: CC(C)CBr
Reactant: Oc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(Br)nc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
2-Bromo-5-hydroxypyridine (2 mmol) is dissolved in DMF (10 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min 1-Bromo-2-methylpropane (1.1 eq.) is added and the reaction solution is stirred 3 days at 100° C. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. 2-Bromo-5-isobutoxy-pyridine is obtained after reversed phase column chromatography (water/acetonitrile+0.1% TFA) as a yellow oil in a yield of 19%; HPLC (method C): 2.08 min; LC-MS (method A): 2.05 min, 241.95 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].BrCC[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:10].[CH2:26]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:26]2[C:27]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:23]=[CH:24][C:25]=2[CH2:11][CH3:12])[CH:4]=1)[CH2:27][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCCc1cccc2ccccc12
Reactant: CCBr
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCC[n+]1cn(-c2c(CC)ccc3ccccc23)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 1-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: [OH2:1].[NH2:2][NH2:3].F[C:5]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=[O:14])=[CH:9][C:6]=1[C:7]#[N:8]>CCO>[N+:13]([C:10]1[CH:9]=[C:6]2[C:5](=[CH:12][CH:11]=1)[NH:3][N:2]=[C:7]2[NH2:8])([O-:14])=[O:1]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: O
Reactant: NN
Solvent: CCO
Product: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C

Procedure:
Hydrazine monohydrate (17.5 mL, 362 mmol) was added to a hot (50° C.) solution of 2-fluoro-5-nitrobenzonitrile (30 g, 181 mmol) in EtOH (500 mL). The mixture was heated at reflux for 4 hours then allowed to cool to room temperature, whereupon the product precipitated from solution. The filtrate was concentrated and the residue partitioned between EtOAc and saturated ammonium chloride solution. The organic phase was separated, dried over magnesium sulfate and concentrated to obtain further product. The combined product (32.2 g, quant.) was taken on to the following step without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:16])[CH:7](O)[C:8]1[C:9](=O)[CH2:10][CH:11]([CH3:13])[CH:12]=1)[CH2:2][CH2:3][CH3:4].O.C1(C)C=CC(S(O)(=O)=[O:25])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6](=[O:16])[CH:7]=[C:8]1[CH2:12][CH:11]([CH3:13])[C:10](=[O:25])[CH2:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(O)C1=CC(C)CC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)C=C1CC(=O)C(C)C1
Temperature: 15 °C
Reaction time: 2 h
Yield: 1072.9 %

Procedure:
Into a 5-L, 3-necked, round-bottomed flask equipped with a condenser, thermometer and nitrogen inlet were added 154.8 g (0.68 M) alpha-hydroxy-4-methyl-3-oxo-cyclopentene acetic acid butyl ester (as prepared by Example 4), 2.3 L of toluene, and 12.9 g (0.068 M) of p-toluenesulfonic acid monohydrate. The resulting reaction mixture was stirred at 75°-78° C. for 61/2 hours under nitrogen. When the reaction was complete, the mixture was cooled to 15° C., poured into a separatory funnel, washed with three 1-L portions of a total of 3 L of water, dried (MgSO4) and evaporated to give 153 g of the homogeneous 4-methyl-3-oxo-cyclopentylidene acetic acid butyl ester bp 82°-84° C./0.05 mm Hg, as a red oil for use in Example 8.
Reaction SMILES: Br[C:2]1[C:3]([F:15])=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:16](C([Sn])=C(CCCC)CCCC)[CH2:17]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:15][C:3]1[C:2]([CH:16]=[CH2:17])=[C:12]([F:13])[C:11]([F:14])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(F)c(F)c(Br)c1F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(F)c(F)cc(C(=O)OCC)c1F

Procedure:
In 30 ml of toluene was dissolved 3.04 g of ethyl 3-bromo-2,4,5-trifluorobenzoate, and to the solution were added 5.11 g of tributylvinyltin and 0.25 g of tetrakis(triphenylphosphine) palladium (0), after which the resulting mixture was heated under reflux for two hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by a column chromatography (eluent: n-hexane:ethyl acetate=100:1), to obtain a colorless, oily ethyl 2,4,5-trifluoro-3-vinylbenzoate. The oily product thus obtained was dissolved in a mixed solvent of 62 ml of methanol and 12 ml of methylene chloride, and thereafter, at -50° C., an ozone gas was blown thereinto for three hours and subsequently a nitrogen gas was blown thereinto for 30 minutes. The temperature of this solution was elevated to -20° C., and thereafter, 0.81 g of sodium borohydride was added thereto, after which the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was added to a mixed solvent of 400 ml of ethyl acetate and 600 ml of ice water and the pH was adjusted to 1 with 6N hydrochloric acid, after which the organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluent: n-hexane:ethyl acetate=4:1), to obtain 1.70 g of a colorless, oily ethyl 3-hydroxymethyl-2,4,5-trifluorobenzoate.