Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4].[Na+].O=C1O[C@H]([C@H](CO)O)C(O)=C1O.[Na].COC(C1C=CC(O)=CC=1)=O.[Na].C(OC(C1C=CC(O)=CC=1)=O)CC>O>[CH2:11]([OH:12])[C@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: CCCOC(=O)c1ccc(O)cc1
Agent: COC(=O)c1ccc(O)cc1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A formulation with 1.5% of the freeze-dried NOE powder from Example 1, 0.05% sodium ascorbate and 0.02% ascorbic acid as antioxidants, 0.1% methylparaben sodium and 0.01% propylparaben sodium as preservatives (Table 5) was prepared under aseptic conditions following the method given in Example 2A. A 2000 mL glass cylinder was weighed and tarred, and the following ingredients (Table 5) except water were weighed and added directly into the glass cylinder. Type I water was added to the mixture and the volume of the mixture was adjusted to 1000 mL. The pH of the solution was approximately 6.49. The freeze-dried powder in 10 mL vials with the ingredients in Table 5 was reconstituted with 10 mL sterile water forming a clear solution within a minute.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[N:22]([C:33](=[O:34])[CH2:32][N:31]([CH3:36])[CH3:30])[CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc(OC[C@@H]2C[C@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: CN(C)CC(=O)O
Product: COc1cc(OC[C@@H]2C[C@H](O)CN2C(=O)CN(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 83 %

Procedure:
The procedure described in Example 30 was repeated using (3S,5S)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (157 mg) with N,N-dimethylglycine (43 mg) to give the title compound as a white solid in 83% yield; NMR spectrum (DMSO-d6) 10.03 (s, 1H), 8.46 (s, 1H), 8.19 (dd, 1H), 7.76-7.71 (m, 1H), 7.43 (t, 1H), 6.83 (d, 1H), 6.75 (d, 1H), 5.27-5.26 (m, 1H), 4.72-4.67 (m, 1H), 4.61-4.56 (m, 1H), 4.41-4.40 (m, 1H), 4.34-4.29 (m, 1H), 3.93 (s, 3H), 3.78 (dd, 1H), 3.52 (br d, 1H), 3.14 (d, 1H), 2.99 (d, 1H), 2.26-2.17 (m, 7H), 1.95-1.90 (m, 1H); Mass spectrum MH+ 50
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)C>Cl.O=[Pt]=O.C(Cl)(Cl)Cl>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(OCCN2CCOCC2)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: NCc1ccc(OCCN2CCOCC2)cc1
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of 4-[2-(4-morpholinyl)ethoxy]benzonitrile (0.93 g, 4 mmol), ethanol (100 mL), CHCl3 (4 mL) and PtO2 (100 mg) was hydrogenated at 45 psi on a Parr hydrogenator for 8 hours. Concentrated HCl (2-3 drops) was then added to the reaction mixture and the hydrogenation was continued for another 10 hours. The catalyst was removed by filtration, the filter cake was washed with ethanol and then the filtrate was evaporated to dryness. The residue was dissolved in water and then was saturated with solid K2CO3. The mixture was extracted with CH2Cl2 and then the CH2Cl2 layer was dried over K2CO3 and evaporated to afford 0.75 g (79%) of 4-[2-(4-morpholinyl)ethoxy]phenylmethylamine.
Reaction SMILES: N[C:2]1[C:3]2[C:26]([CH3:28])([CH3:27])[C:25](=[O:29])[NH:24][C:4]=2[N:5]=[C:6]([C:8]2[C:9]3[CH2:23][CH2:22][CH2:21][C:10]=3[N:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[N:12]=2)[N:7]=1.N(OCCC(C)C)=O.[I:38]I.[I-].[Cs+]>C(COC)OC.[Cu]I>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:11]1[C:10]2[CH2:21][CH2:22][CH2:23][C:9]=2[C:8]([C:6]2[N:7]=[C:2]([I:38])[C:3]3[C:26]([CH3:27])([CH3:28])[C:25](=[O:29])[NH:24][C:4]=3[N:5]=2)=[N:12]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(N)c21
Reactant: II
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: [Cs+]
Solvent: COCCOC
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(I)c21
Temperature: 100 °C
Reaction time: 0.67 h

Procedure:
285 mg (0.68 mmol) of 4-amino-2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one were initially charged in absolute dimethoxyethane, and 800 mg (6.83 mmol) of isopentyl nitrite, 87 mg (0.34 mmol) of iodine, 39 mg (0.21 mmol) of copper(I) iodide and 177 mg (0.68 mmol) of caesium iodide were added. The mixture was stirred at 100° C. for 40 min. The mixture was concentrated on a rotary evaporator, and the residue was taken up in dichloromethane and washed with 5% aqueous sodium thiosulphate solution and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, concentrated and purified by means of preparative HPLC (eluent: acetonitrile/water with 0.1% acetic acid, gradient 20:80→100:0). 148 mg (40% of theory) of the target compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.4 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (59.4 mg, 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[C:11]1([C:15]([O:17]C)=O)[CH2:14][CH2:13][CH2:12]1>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:11]1([CH2:14][CH2:13][CH2:12]1)[C:15](=[O:17])[NH:8]2
Reactant: COC(=O)C1(c2c(F)cccc2[N+](=O)[O-])CCC1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1Nc2cccc(F)c2C12CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of methyl 1-(2-fluoro-6-nitrophenyl)cyclobutanecarboxylate (3.11 g) in acetic acid (60 mL) was added zinc (16.1 g), and the mixture was stirred overnight at room temperature. The zinc was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.30 g).
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([CH3:21])([S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH3:21][C:5]([S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:22])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccccc1)S(=O)(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(Cc1ccccc1)(C(=O)O)S(=O)(=O)c1cccs1

Procedure:
2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid was prepared according to the general method as outlined in example 9. Starting from 2-methyl-3-phenyl-2-(thiophen-2-sulfonyl)-propionic acid ethyl ester (5.0 g, 15 mmol), ethanol (30 mL) and 10 N sodium hydroxide (10 mL). Yield 5.6g MS 310.0 (M+H).
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)(Cl)Cl>[C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C2CCCN2C(=O)c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1CCCC1c1cccc(O)c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To a solution of 1-benzoyl-2-(3-methoxyphenyl)pyrrolidine (1.0 g) in chloroform (40 ml) was added boron tribromide (99%, 1.0 ml) at -10° C., under nitrogen. The cooling bath was removed after 15 mins, and the reaction mixture was allowed to warm to ambient temperature. Crushed ice was added to the reaction mixture followed by 5:1-chloroform/2-propanol. The layers were separated, and the aqueous phase was extracted with 5:1-chloroform/2-propanol (2 times). The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was crystallized from dichloromethane/petroleum ether to give 0.89 g (94%) of product. Recrystallization from 2-propanol/methanol gave the analytical sample, mp 167°-169° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][OH:19])[CH2:15][O:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[F:8][C:6]1[C:5]([F:9])=[C:4]([O:19][CH2:18][CH:16]2[CH2:15][O:14][C:13]([CH3:20])([CH3:12])[O:17]2)[C:3]([F:11])=[C:2]([F:1])[N:7]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: CC1(C)OCC(CO)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC1(C)OCC(COc2c(F)c(F)nc(F)c2F)O1
Temperature: 60 °C
Yield: 94.8 %

Procedure:
To pentafluoropyridine (2.0 g, 12 mmol) dissolved in DMSO was added 2,2-dimethyl-1,3-dioxolane4-methanol (solketal) (1.5 mL, 12 mmol) and Cs2CO3 (3.8 g, 12 mmol). The slurry was heated in an oil bath at 60° C. for 1 day. The reaction was partitioned with water and ethyl acetate, washed with water and brine, dried (Na2SO4) and the solvent was removed to give 2,3,5,6-tetrafluoro-4-[[(2,2-dimethyl)dioxolan-4-yl]methoxy]pyridine (3.2 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[C:22]([CH2:34][CH:35]=[C:36]([CH3:39])[CH2:37]O)=[C:23]([O:32][CH3:33])[C:24]([CH3:31])=[C:25]2[C:29]=1[C:28](=[O:30])[O:27][CH2:26]2.C(Br)(Br)(Br)[Br:41]>ClCCl>[Br:41][CH2:37][C:36]([CH3:39])=[CH:35][CH2:34][C:22]1[C:21]([OH:20])=[C:29]2[C:25]([CH2:26][O:27][C:28]2=[O:30])=[C:24]([CH3:31])[C:23]=1[O:32][CH3:33]
Reactant: BrC(Br)(Br)Br
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CO)C(=O)OC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1CC=C(C)CBr)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
Polymer-supported triphenylphosphine (3 mmol/g, 0.5 g) was soaked in dichloromethane (10 mL) for 1 hour 7-Hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one 1A (100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) were sequentially added and the mixture was shaken for 1 hour at room temperature. More carbon tetrabromide (143 mg, 0.43 mmol) was added and the mixture was shaken further for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (0% to 60% ethyl acetate/hexanes) to afford 6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one 3B as an oil (52 mg, 42%); 1H NMR (300 MHz, CDCl3) δ 1.95 (s, 3H), 2.16 (s, 3H), 3.44 (d, J=7.2 Hz, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s, 2H), 5.68 (t, J=7.2 Hz, 1H), 7.71 (brs, 1H) ppm.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([NH:24][C:25]([C:27]2[C:32]([CH3:33])=[N:31][CH:30]=[CH:29][N:28]=2)=[O:26])[CH:10]=[CH:11][C:12]=1[C:13]([O:22][CH3:23])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:4]([CH3:6])[CH3:5].[C:34](Cl)(=[O:40])[O:35][CH2:36][CH:37]([CH3:39])[CH3:38].Cl>C1COCC1>[CH2:36]([O:35][C:34]([N:24]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:22][CH3:23])([C:18]([F:20])([F:21])[F:19])[C:14]([F:17])([F:16])[F:15])=[C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=1)[C:25]([C:27]1[C:32]([CH3:33])=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])=[O:40])[CH:37]([CH3:39])[CH3:38]
Reactant: COC(c1ccc(NC(=O)c2nccnc2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc(N(C(=O)OCC(C)C)C(=O)c2nccnc2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Sodium hydride (32 mg, 60% by weight, 0.8 mmol) was suspended in THF (10 ml) and a THF solution (5 ml) of N-{3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pheny}-3-methylpyrazine-2-carboxamide (300 mg, 0.67 mmol) was dropwise added thereto. The reaction solution was stirred at room temperature for 30 minutes, and was dropwise added with a THF (2 ml) solution of isobutyl chlorocarbonate (110 mg, 0.8 mmol) and stirred for 2 hours. The reaction solution was poured into a diluted HCl solution, followed by extracting with ethyl acetate, and washing with water. The solution was dried over magnesium sulfate, and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=3:1) to obtain 0.33 g of the desired compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[C:24]3[C:19](=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]([C:29]([F:32])([F:31])[F:30])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[F:32][C:29]([F:30])([F:31])[C:17]1[CH:16]=[C:15]([C:11]2([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:24]2[C:19](=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: OC1(c2cc(C(F)(F)F)nc3c(C(F)(F)F)cccc23)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: OC1(c2cc(C(F)(F)F)nc3c(C(F)(F)F)cccc23)CCNCC1
Yield: 62.4 %

Procedure:
A solution of 1-benzyl-4-(2,8-bis(trifluoromethyl)-4-quinolinyl)-4-piperidinol (480 mg, 1.06 mmol) and palladium hydroxide (100 mg) in MeOH (25 mL) was stirred vigorously under an atmosphere of hydrogen (using balloons) for 3 h, filtered through a pad of celite and concentrated in vacuo. The resulting viscous syrup was triturated with ether to give the title compound (241 mg, 63%) as a pale-grey solid: mp 210-220° C. (dec); IR νmax (Nujol)/cm−1 3406, 2924, 1458, 1313, 1154 and 823; NMR δH (400 MHz, DMSO-d6) 1.89 (2H, d, J 13.1 Hz), 2.11-2.19 (2H, m), 2.85 (2H, br d, J 10.0 Hz), 3.05-3.10 (2H, m), 5.73 (1H, s), 7.90 (1H, t, J 8.6 Hz), 8.03 (1H, s), 8.34 (1H, d, J 7.0 Hz) and 9.34 (1H, d, J 8.3 Hz).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]I.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[S:8][CH2:7]1
Reactant: O=C1CSCN1CCCCBr
Reactant: ICCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1N(CCCCBr)CSC12CCCCC2
Temperature: -65 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(4-bromobutyl)-4-thiazolidinone (25 g) in tetrahydrofuran (350 ml) cooled to -60° C., was added 1,5-diiodopentane (100 g). The resulting slurry was allowed to cool to -65° C. and a solution of lithium bis(trimethylsilyl)amide in hexanes (220 ml) was added dropwise over a period of 30 minutes while maintaining the internal temperature at or below -55° C. The resulting mixture was stirred for 15 minutes and the internal temperature allowed to rise to 0° C. 0.5N HCl (500 ml) was added to quench the reaction and the mixture was concentrated in vacuo to remove the THF. The aqueous mixture was extracted twice with 250 ml portions of ether, washed with water (400 ml) and brine (400 ml), dried (Na2SO4) and concentrated to a liquid. The liquid was chromatographed on silica gel (elution with 20% ethyl acetate/hexane) to give a liquid.
Reaction SMILES: C(C1(C)C(=O)NC([C:10]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=N1)(C)C.C(N)(C)C>O>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:19]([C:20]([OH:22])=[O:21])[CH:10]=1
Reactant: CC(C)C1(C)N=C(c2nc3ccccc3cc2C(=O)O)NC1=O
Solvent: CC(C)N
Solvent: O
Product: O=C(O)c1cnc2ccccc2c1

Procedure:
An aqueous solution containing 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)3-quinolinecarboxylic acid (12.44 g, 88.42% pure) and isopropylamine (2.83 g) in 11 liters of water to provide the equivalent of from 0.5 to 4 grams per hectare of the 3-quinolinecarboxylic acid, is added to a spray tank containing a 46% aqueous solution of (2-chloroethyl)trimethylammonium chloride containing choline chloride to provide the equivalent of from 920 to 1610 grams per hectare of this active ingredient. Water is then added to provide a total spray volume of from 100 to 400 liters per hectare.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(F)ccc43)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-n3ncc4cc(F)ccc43)nc12
Reaction time: 15 h
Yield: 27.8 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-fluoro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 249 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL Jan. 10, 1960 of a solution of ammonium hydroxide/methanol/dichloromethane was added. After 1 h the mixture was concentrated in vacuo then purified by chromatography (silica, 24 g Analogix column, 0-5% methanol containing 10% ammonium hydroxide in dichloromethane) to give 2-(5-fluoro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (24.4 mg, 28%). MS: (M+H)+=353; 1H NMR (DMSO-d6) δ: 9.02 (s, 1H), 8.56-8.61 (m, 2H), 8.53 (d, J=0.8 Hz, 2H), 8.42 (d, J=3.0 Hz, 1H), 7.78 (dd, J=8.8, 2.3 Hz, 1H), 7.62 (s, 1H), 7.49 (d, J=2.5 Hz, 1H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:6][CH2:7][CH2:8][C:9]1([CH3:28])[CH2:18][CH2:17][C:16]2[C:11](=[C:12]3[CH:26]4[CH2:27][CH:23]([CH2:24][CH2:25]4)[C:13]3=[C:14]([O:19]COC)[CH:15]=2)[O:10]1)(=[O:5])[OH:4].[CH3:29]O>Cl>[CH3:29][O:4][P:3]([CH2:6][CH2:7][CH2:8][C:9]1([CH3:28])[CH2:18][CH2:17][C:16]2[C:11](=[C:12]3[CH:26]4[CH2:27][CH:23]([CH2:24][CH2:25]4)[C:13]3=[C:14]([OH:19])[CH:15]=2)[O:10]1)(=[O:5])[O:2][CH3:1]
Reactant: COCOc1cc2c(c3c1C1CCC3C1)OC(C)(CCCP(=O)(O)OC)CC2
Reactant: CO
Agent: Cl
Product: COP(=O)(CCCC1(C)CCc2cc(O)c3c(c2O1)C1CCC3C1)OC

Procedure:
190 mg of 6-methoxymethoxy-dimethyl phosphonate derivative from Step 3 was treated with a mixture of 20 mL of MeOH and 20 drops of concentrate HCl for overnight. After removal of most of the solvent, ethyl acetate was added and then washed with water, and dried over MgSO4. After the removal of solvents the residue was purified by flash column chromatography on silica gel (10% MeOH I DCM) to afford 90 mg of [3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propyl]-phosphonic acid dimethyl ester. 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.38 (s, 1H), 5.32 (s, 1H), 3.72-3.82 (m, 6H) 3.50-3.54 (m, 2H), 2.62-2.68 (m, 4H), 1.70-1.84 (m, 12H), 1.22-1.28 (s, 3H) MS: 381 (M+H+, 100%), 403 (M+Na+, 36%)
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)=[O:4].S(C)C.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:3]2[CH2:2][O:4]2)=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(CCl)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc([C@@H]2CO2)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Under nitrogen atmosphere, 2-chloro-1-(4-fluoro-3-nitrophenyl)ethanone (5.4667 g) which can be prepared according to the method described in Reference example 64, etc. was dissolved in dehydrated THF (100 mL), added with 1 mol/L-(R)—CBS-toluene solution (7.5 mL; manufactured by Sigma-Aldrich Co.), followed by cooling to 0° C. To the resulting solution, BH32.SMe2 (10 mL; manufactured by Sigma-Aldrich Co.) was added dropwise over 10 minutes and the mixture was stirred at 0° C. for 2 hours. An aqueous solution of ammonium chloride was added to the reaction solution and extraction was carried out twice with ethyl acetate. The organic layer was washed once with brine, dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was added with 2-propanol (100 mL) and an aqueous solution of 1 mol/L-sodium hydroxide (25 mL; manufactured by Kanto Chemical Co., Inc.), and the mixture was stirred at 0° C. for 10 minutes. The reaction solution was poured to water and extracted twice with ethyl acetate. The organic layer was washed once with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (“COLUMN-8”; n-hexane:ethyl acetate=88:12→67:33) to obtain the title compound (4.2885 g, optical purity; 92% ee).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].[OH-].[K+].[CH2:15](Cl)[C:16](=[CH2:18])[CH3:17]>CO>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][C:16](=[CH2:15])[CH3:18])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: C=C(C)CCl
Reactant: Cc1ccc(O)c2c1CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=C(C)COc1ccc(C)c2c1C(=O)CC2

Procedure:
Into a solution of 15 g of 4-methyl-7-hydroxy-1-indanone and 7.95 g of potassium hydroxide in 200 ml of methanol was added 13.55 ml of methallyl chloride, and the mixture was refluxed by heating for 11 hours. The insoluble matters in the reaction mixture were removed by filtration, then the solvent was removed by evaporation. The residue obtained was purified by means of a silica gel column chromatography (eluent: n-hexane: dichloromethane=1:1) to obtain 9 g of 4-methyl-7-methallyloxy-1-indanone.