Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:15]([F:18])([F:17])[F:16])([O-:14])[C:4]([F:13])([C:9]([F:12])([F:11])[F:10])[C:5]([F:8])([F:7])[F:6].[K+].[F:22][C:23](=[CH2:27])[C:24](Cl)=[O:25]>C(OCC)C>[F:22][C:23](=[CH2:27])[C:24]([O:14][C:3]([C:15]([F:16])([F:17])[F:18])([C:4]([F:13])([C:5]([F:8])([F:7])[F:6])[C:9]([F:12])([F:11])[F:10])[C:2]([F:19])([F:20])[F:1])=[O:25]
Reactant: C=C(F)C(=O)Cl
Reactant: [O-]C(C(F)(F)F)(C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CCOCC
Product: C=C(F)C(=O)OC(C(F)(F)F)(C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Yield: 71.7 %

Procedure:
A solution of 213.6 g (0.571 mol) of potassium perfluoro-2,3-dimethyl-2-butanolate in 250 ml of dry diethyl ether was added dropwise with stirring at a temperature of 25°0 C. to a solution of 62 g (0.571 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 100 ml of dry diethyl ether in the course of 1 hour, and a colorless solid precipitated. The reaction mixture was stirred at a temperature of 25° C. for a further hour, and the solid was filtered off. The filtrate had added to it 0.01 g of hydroquinone monomethyl ether and was then distilled under reduced pressure. 167 g (72 percent of theory) of perfluoro-2,3-dimethyl-2-butyl α-fluoroacrylate having a boiling point of 43° C. (under 20 mbar) were obtained.
Reaction SMILES: [NH:1]([C:3]([C@@H:5]([C@@H:14]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)O)[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4])[NH2:2].[N+:34]([C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1)([O-:36])=[O:35]>CO>[CH2:7]([O:6][C@@H:5]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:23]([CH2:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:4][CH:3]1[NH:1][N:2]=[CH:41][C:40]1[CH:43]=[CH:44][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NNC(=O)[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Solvent: CO
Product: O=[N+]([O-])c1ccc(C=NNC2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
2.4 g (5.55 mmoles) of 1-hydrazino-2,3,5-tri-O-benzyl-D-ribose are dissolved in 10 ml of absolute methanol. 0.84 g (5.55 mmoles) of p-nitrobenzaldehyde (dissolved in 8 ml of absolute methanol) are added to the solution. Stirring is carried out at room temperature and after approximately 5 minutes a yellow flaky precipitate appears. After 24 hours the precipitate is drawn off by suction and dried. Yield: 2.4 g (76 %). Melting point: 93° C. (from methanol).
Reaction SMILES: [CH:1]1([P:7]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)([C@@H:9]2[CH2:13][NH:12][C@H:11]([CH2:14][P:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)[CH2:10]2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][N:36]=[C:37]=[O:38]>C(Cl)Cl>[CH3:35][NH:36][C:37]([N:12]1[CH2:13][C@@H:9]([P:7]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:10][C@H:11]1[CH2:14][P:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:38]
Reactant: O=P(C[C@@H]1C[C@H](P(=O)(C2CCCCC2)C2CCCCC2)CN1)(c1ccccc1)c1ccccc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1C[C@@H](P(C2CCCCC2)C2CCCCC2)C[C@H]1CP(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Using 300 mg (0.60 m-mol) of (2S,4S)-4-dicyclohexylphosphinyl-2-diphenylphosphinylmethylpyrrolidine, the reaction and after-treatment were carried out in the same manner as described in Example 2(b) to obtain CPM. This CPM was dissolved in 8 ml of methylene chloride and 38 mg (0.66 m-mol) of methyl isocyanate was slowly added dropwise to the solution under ice-cooling. The mixture was stirred in a stream of argon for 2 hours at room temperature. The reaction liquid was concentrated at a lower temperature under reduced pressure, and the residue was dried. This product was recrystallized from methanol to obtain 292 mg (yield: 96%) of MCCPM as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=[O:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]=[CH:6][C:5]3=[O:12])=[O:22])=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Nc1ccc2occc(=O)c2c1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc2occc(=O)c2c1
Yield: 99.1 %

Procedure:
To the slurry of 6-aminochromone (3.0 g, 18.6 mmol) stirred and heated to 80° C. in toluene (200 mL) was added 4-chlorophenyl isocyanate (3.2 g, 20.5 mmol) and the mixture was refluxed for 18 hrs. The reaction mixture was cooled and the precipitate was filtered and washed with methanol. The residue was dried in vacuo to afford a yellow powder (5.8 g, 99%) of 1-(4-chloro-phenyl)-3-(4-oxo-4H-chromen-6-yl)-urea. LCMS m/z (%)=315 (M+H, 35Cl 100), 317 (M+H37Cl 32.2) 1H NMR (400 MHz, DMSO-d6) δ: 9.098 (bs, 1H), 8.94 (bs, 1H), 8.28-8.30 (d, J=5.99 Hz, 1H), 8.20-8.21 (d, J=2.69 Hz, 1H), 7.81-7.84 (dd, J=9.0, 2.75 Hz, 1H), 7.62-7.64 (d, J=9.07 Hz, 1H), 7.52-7.55 (dd, J=6.84, 2.16 Hz, 2H), 7.35-7.37 (dd, J=6.85, 2.11 Hz, 2H), 6.33-6.34 (d, J=5.98 Hz, 1H).
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[NH:38])SC)=[CH:31][CH:30]=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][NH2:40]>ClCCl.CO>[CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:39][NH2:40])=[NH:38])=[CH:31][CH:30]=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)NCc1ccc(C(=N)SC)cc1
Solvent: CO
Solvent: ClCCl
Product: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)NCc1ccc(C(=N)NN)cc1
Reaction time: 18 h
Yield: 60.7 %

Procedure:
N-(Benzylsulfonyl)-D-isoleucyl-N1-{4-[imino-(methylthio)methyl]benzyl}-L-methioninamide (49 mg, 0.084 mmol) was dissolved in dichloromethane (2 ml) and methanol (2 ml), to which hydrazine (0.020 ml, 0.624 mmol) was then added and stirred for 18 hours. The solvent was distilled off under reduced pressure and the residue was purified by preparative HPLC to give N-(benzylsulfonyl)-D-isoleucyl-N1-{4-[hydrazino(imino)methyl]benzyl}-L-methioninamide (29 mg, 0.051 mmol; yield 61%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CS(C)=O>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CNCCN1
Reactant: Clc1cccnc1Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Clc1cccnc1N1CCNCC1
Temperature: 80 °C

Procedure:
2,3-Dichloropyridine (15.0 g, 101.6 mmol), piperazine(9.78 g, 113.70 mmol), and triethylamine (14.36 g, 141.95 mmol) were dissolved in 300 mL of DMSO and the resulting mixture was heated at about 80° C. for about 24 h. The reaction mixture was then cooled to room temperature and extracted with a saturated aqueous sodium bicarbonate solution. The organic layer was dried, concentrated, and purified using a silica gel column eluted with a gradient elution from ethyl acetate to 2:1 ethyl acetate:methanol to provide N-(3-chloropyridin-2-yl)-piperazine (compound 1) as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl.CN.[CH2:16]([N:18](CC)CC)C.O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([S:9]([NH:18][CH3:16])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: CN
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
Commercially available 3,4-difluorophenylsulfonylchloride (117 μL, 0.87 mmol) was dissolved in dichloromethane (5 mL), and methylamine hydrochloride (49 mg, 0.73 mmol) and triethylamine (203 μL, 1.45 mmol) were added, followed by stirring at room temperature for 2 hours. To the reaction solution, water (15 mL) was added, extraction was carried out twice with dichloromethane (15 mL), and washing was carried out with saturated brine (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, followed by vacuum drying, to afford the desired compound (44.7 mg, yield 30%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]=[C:24]=[O:25].Cl>C(Cl)Cl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:24](=[O:25])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: CCCCCCCNCCCCCO
Reactant: O=C=Nc1ccc(F)cc1F
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCN(CCCCCO)C(=O)Nc1ccc(F)cc1F
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Part C. To a solution of N-(5-hydroxypentyl) heptylamine (11.65 g, 0.0578 mol) in methylene chloride (75 mL) under a nitrogen atmosphere cooled to 0°, 2,4-difluorophenylisocyanate (8.97 g, 0.0578 mol) was added slowly. The reaction mixture was stirred for 1 hour, poured into 1 N aqueous HCl (200 mL) and was extracted with ethyl acetate (300 mL). The combined organic layer was washed with water, brine, dried over magnesium sulfate and was concentrated to give N'-(2,4-difluorophenyl)-N-heptyl-N-5-hydroxypentylurea as a pale yellow oil (20.0 g, 0.056 mol). 1H NMR (CDCl3) δ 8.03 (m, 1H), 6.88-6.59 (m, 2H), 6.45 (bs, 1H), 3.68 (t, 2H), 3.33(m, 4H), 1.81-1.22(m, 16H), 0.907(t,3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[C:26]1(B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C2=CCCCC2)Cc2ccccc2C1
Yield: 21.6 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (491 mg, 1.09 mmol) and 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (937 μL, 4.36 mmol) in EtOH (10 mL) and dioxane (10 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 240 mg, 0.11 mmol) and 2M aqueous solution of K2SO4 (2.18 mL, 4.36 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (140) as white solid (95 mg, 22%).
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([N:12]([NH2:18])C(OCC)=O)[C:9]2[C:4](=[CH:5][C:6]([CH3:20])=[C:7]([CH3:19])[CH:8]=2)[N:3]=1.CN(C)[CH:23]=[O:24]>>[CH3:20][C:6]1[C:7]([CH3:19])=[CH:8][C:9]2[C:10]3[N:11]([C:23](=[O:24])[NH:18][N:12]=3)[C:2](=[O:1])[NH:3][C:4]=2[CH:5]=1
Reactant: CCOC(=O)N(N)c1nc(O)nc2cc(C)c(C)cc12
Reactant: CN(C)C=O
Product: Cc1cc2[nH]c(=O)n3c(=O)[nH]nc3c2cc1C
Temperature: 25 °C

Procedure:
1.0 g (0.0030 mol) of ethyl 2-hydoxy-6,7-dimethyl-quinazolin-4-yl-carbazate in 57 ml of dimethylformamide was boiled under reflux for 2 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off and dried in a vacuum. There were obtained white crystals which were recrystallized from dimethylformamide/methanol. Yield: 0.43 g (52%) of 8,9-dimethyl-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as yellowish crystals; m.p. >350° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[C:9]([CH:12]=C)[CH:8]=[CH:7][C:6]=2[C:5]2=[N:14][O:15][C:16]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])=[C:4]2[CH2:3]1.[O:32]=[O+][O-].C(N(CC)CC)C>ClCCl>[CH3:1][N:2]1[C:11]2[CH:10]=[C:9]([CH:12]=[O:32])[CH:8]=[CH:7][C:6]=2[C:5]2=[N:14][O:15][C:16]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])=[C:4]2[CH2:3]1
Reactant: C=Cc1ccc2c(c1)N(C)Cc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1Cc2c(noc2-c2onc(-c3ccccc3)c2C(F)(F)F)-c2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-methyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydroisoxazolo[4,3-c]quinoline (Preparation 77F, 0.020 g, 0.047 mmol) in Dichloromethane (5 mL) at −78° C. was passed ozone from an ozone generator until the solution turned a deep blue. The reaction mixture then was purged with oxygen until the blue color disappeared, then with nitrogen for five minutes. The reaction mixture was allowed to warm to room temperature and triethylamine (5.07 μl, 0.036 mmol) was added. The reaction mixture was stirred at room temperature for fifteen minutes, and then concentrated under vacuum to give 5-methyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydroisoxazolo[4,3-c]quinoline-7-carbaldehyde as a tan solid. (0.015 mg, 0.035 mmol, 74%). The product had an HPLC ret. time=3.61 min. (condition B). LC/MS M+1=426.1 min
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([C:6]1[C:11](Cl)=[N:10][N:9]2[C:13]([NH2:16])=[N:14][N:15]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].[O-:19][CH2:20][CH3:21].[Na+]>C(O)C>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([C:6]1[C:11]([O:19][CH2:20][CH3:21])=[N:10][N:9]2[C:13]([NH2:16])=[N:14][N:15]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC[O-]
Reactant: CCN(CC)C(=O)c1cc2nnc(N)n2nc1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2cc1C(=O)N(CC)CC
Reaction time: 8 h
Yield: 98.5 %

Procedure:
N,N-Diethyl-3-amino-6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-7-carboxamide (W2.019, 50 mg) was initially charged in ethanol (5 ml) and admixed with sodium ethoxide (28 mg) while stirring. After stirring at RT for 7 h and leaving to stand overnight, the solvent was drawn off and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 51 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH:14]=O.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[CH3:1][O:2][C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1/[CH:14]=[C:24]1\[C:25](=[O:29])[NH:26][C:27]2[C:23]\1=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=2
Reactant: COC(=O)C(C)(C)COc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)C(C)(C)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 66.6 %

Procedure:
3-(4-chloro-2-formyl-phenoxy)-2,2-dimethyl-propionic acid methyl ester (6.7 g, 25 mmol) and 6-Chloro-1,3-dihydro-indol-2-one (4.35 g, 25 mmol) were mixed in 20 mL of anhydrous methanol. Then pyrrolidine (2 mL, 25 mmol) was added dropwise at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration and dried to give title compound as yellow solid (Yield: 7 g, 67%).
Reaction SMILES: [CH3:1][SiH:2]([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].C(O)C.[CH2:12]([O:16][CH2:17][CH:18]=[CH2:19])[CH:13]1[O:15][CH2:14]1>C(O)(=O)C>[CH2:12]([O:16][CH2:17][CH2:18][CH2:19][Si:2]([CH3:1])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5])[CH:13]1[O:15][CH2:14]1
Reactant: C=CCOCC1CO1
Reactant: CCO[SiH](C)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: CCO[Si](C)(CCCOCC1CO1)OCC
Temperature: 85 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Again, to the apparatus of Example 3 were pressure charged 49.6 lb [22.5 kg] (168.2 mol) of methyldiethoxysilane from a 10 gallon Pope can. After addition of the 20.0 g of CPA ethanol solution (15 ppm Pt) and 21.0 ml (460 ppm) of acetic acid through the handhole, the reactor was kept under nitrogen purge, sealed and heated to 85° C. Allyl glycidyl ether (50.6 lb [23 kg], 20 mole % excess or 210.8 mol) was added through a line to the mixture in the reactor from a pressurized can. The AGE was added at a rate that kept the reaction temperature between 85 and 95° C. After two hours, the addition was complete and the hydrosilation lites were stripped. The crude product was vacuum distilled at 104-121° C. (3-7 mm Hg) to yield 75.5 pounds (31.23 kg) of γ-glycidoxypropylmethyldiethoxysilane with an average purity of 99.0%. This represents a conversion of 82.3%. Again present were the silane scrambled products γ-glycidoxy-propyldimethyl(ethoxy) silane (0.39% by GC) and γ-glycidoxypropyltriethoxysilane (0.27% by GC).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.BrC[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=O>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[C:6]3=[C:5]([OH:11])[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]3[O:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: O=C(CBr)c1ccc(F)cc1
Product: Oc1cc(O)c2c(-c3ccc(F)cc3)coc2c1
Yield: 27 %

Procedure:
This compound was prepared using Method B from 3,5-dimethoxyphenol and 2-bromo-1-(4-fluorophenyl)ethanone: Yield 27% following procedures B.2, B.3 and B.5; m.p. 125° C. (dec.); IR 3508, 1612, 1508, 1455, 1240, 1121, 1090, 1048 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.84 (s, 1H), 9.36 (s, 1H), 7.77 (s, 1H), 7.70 (dd, J=8.1 Hz, 5.9 Hz, 2H), 7.20 (t, J=8.8 Hz, 2H), 6.41 (s, 1H), 6.25 (s, 1H); 13C NMR (126 MHz, δ ppm, CD3OD) 163.7 (d, J=243.9 Hz), 160.2, 157.7, 153.6, 140.4, 132.0 (d, J=7.9 Hz), 130.4 (d, J=3.3 Hz), 123.3, 115.6 (d, J=21.6 Hz), 109.2, 99.1, 91.0.
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH2:17][CH2:18][N:19]([C:31]2[N:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][N:32]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:39]([Cu])#[N:40]>CN(C=O)C>[C:39]([C:2]1[CH:16]=[C:15]([CH2:17][CH2:18][N:19]([C:31]2[N:32]=[CH:33][C:34]([CH2:37][CH3:38])=[CH:35][N:36]=2)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:40]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ncc(CC)cn2)cc1Br
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ncc(CC)cn2)cc1C#N

Procedure:
A solution of ethyl 2-[2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (from step 1 in the previous example) (188 mg; 0.32 mmol) in DMF (2 ml) was treated with CuCN (37 mg; 0.41 mmol) and heated to reflux overnight under a nitrogen atmosphere. Upon cooling, the reaction mixture was filtered through a plug of silica gel and eluted with DMF. The filtrate was concentrated and partitioned between dichloromethane and brine. The organic phase was dried over MgSO4, filtered and concentrated to afford ethyl 2-[2-cyano-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (153 mg), which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[C:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:7][CH:6]=[C:5]([O:20]C)[N:4]=1.[BrH:22].CCOCC>C(O)(=O)C>[BrH:22].[O:19]=[C:10]1[C:11]2[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:14])[N:9]1[C:8]1[C:3]([OH:2])=[N:4][C:5]([OH:20])=[CH:6][CH:7]=1
Reactant: COc1ccc(N2C(=O)c3ccccc3C2=O)c(OC)n1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1c1ccc(O)nc1O
Temperature: 70 °C
Reaction time: 54 h
Yield: 71 %

Procedure:
1,3-Dioxo-2-(2,6-dihydroxypyridin-3-yl)-isoindoline hydrobromide (7) was prepared and isolated as follows. To a flask were added 2,6-dimethoxy-3-phthalimidopyridine (150 mg, 0.528 mmol) and hydrogen bromide solution in acetic acid (30%, 6 ml). The mixture was stirred at an 70° C. oil bath under N2 for 54 h. The mixture was cooled to room temperature, dry ether was added, and the supernatant liquid was decanted. Then ethyl acetate was added, solid precipitated, filtered and washed with ethyl acetate to afford 7 (126 mg, 71%) as a white solid: 1H NMR (CD3OD) δ 7.83-7.77 (m, 4H), 6.37 (d, J=8.1 Hz, 1H), 6.37 (d, J=8.1 Hz, 1H); MS (CI/CH4) 256 [M]+; HRMS (DEI) m/z calcd for C13H8N2O4 256.0484. found 256.0483.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[CH:14]=[N:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[F:20][C:17]([F:18])([F:19])[C:12]1[N:13]=[CH:14][C:15]2[CH2:16][NH:8][CH2:9][C:10]=2[N:11]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(C(F)(F)F)nc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ncc2c(n1)CNC2
Yield: 100 %

Procedure:
3.4 mmol of 2-Trifluoromethyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester was dissolved in a mixture of 20 ml dichloromethane and 3 g trifluoroacetic acid. The mixture was hold at 45° C. for 3 hours and concentrated to give the title compound as a waxy solid. Yield=100%. MS (m/e): 190.3 ([M+H]+, 100%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C@H:21]([CH3:25])[C:22](O)=[O:23])[CH:15]=[CH:14]2.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C@H:21]([CH3:25])[C:22]([O:1][CH2:2][C:3]([CH2:7][OH:8])([CH3:4])[CH2:5][OH:6])=[O:23])[CH:15]=[CH:14]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC(CO)(CO)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2cc([C@H](C)C(=O)OCC(C)(CO)CO)ccc2c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 65.4 %

Procedure:
To a stirred solution of 1,1,1-tris(hydroxymethyl)ethane (13.1 g, 109 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 5.00 g, 21.7 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (4.80 g, 25 mmol), and N,N-dimethylaminopyridine (DMAP, 20 mg, catalytic amount) in acetonitrile (200 mL) was added triethylamine (4.2 mL, 30 mmol). The reaction mixture was stirred at ambient temperature for 25 hours, filtered, and the filtrate was concentrated to dryness. The residue was diluted with EtOAc, washed with 1N HCl (2×), saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The resulting material was purified by crystallization (2×) from EtOAc/Hexanes (1:3 v:v) to give the title compound (4.72 g, 66% yield) as white flakes. Mp 105° C. 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=2.0 Hz, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.66 (s, 1H), 7.39 (dd, J=8.5, 1.7 Hz, 1H), 7.17-7.10 (m, 2H), 4.25 (d, J=11.3 Hz, 1H), 4.09 (d, J=11.3 Hz, 1H), 3.90 (s, 3H), 3.88 (q, J=7.1 Hz, 1H), 3.46-3.25 (m, 4H), 2.65-2.55 (m, 2H), 1.60 (d, J=7.1 Hz, 3H), 0.67 (s, 3H). 13C NMR (75 MHz, CDCl3) δ175.8, 157.7, 135.3, 133.8, 129.2, 128.9, 127.3, 126.0, 119.2, 105.6, 67.7. 67.5, 66.8, 55.3, 45.6, 40.9, 18.1, 16.7. LRMS (API-TIS) m/z 350.2 ((M+NH4)+).