Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[CH2:15][CH2:14]2)=O)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:21]1([CH3:26])[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH:16]1[CH2:15][CH2:14][N:13]([CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:18][CH2:17]1
Reactant: Cc1ccccc1OC1CCN(C(=O)C(=O)c2c[nH]c3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1OC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
A solution of 8.7 g of 1-(indol-3-ylglyoxyloyl)-4-(o-tolyloxy)piperidine in 80 ml. of tetrahydrofuran is added dropwise to a stirred suspension of 4.2 g of lithium aluminum hydride in 120 ml. of tetrahydrofuran. After addition is complete, the mixture is stirred and refluxed for 3 hours under nitrogen. The reaction mixture is then cooled and excess hydride is carefully destroyed with water. The mixture is filtered, the filter cake washed with tetrahydrofuran, and the tetrahydrofuran is removed under reduced pressure to give an oil. The oil is evacuated at about 3 mm. overnight, and then rubbed with a glass rod in the presence of hexane to give a white solid. the solid is recrystallized from a benzene and hexane mixture (charcoal treatment) to give off-white crystals. These crystals are recrystallized from an isopropanol and water mixture to give white flakes of 3-{2-[4-(o-tolyloxy)piperidyl]ethyl}indole, m.p. 88°-90° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[O:13]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:18][CH:15]1[CH2:16][CH2:17][O:13][CH2:14]1
Reactant: NC1CCOC1
Reactant: CS(=O)(=O)c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(NC2CCOC2)c(Br)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 69.2 %

Procedure:
A mixture of 2-bromo-1-fluoro-4-methylsulfonylbenzene (0.8 g, 3.16 mmol), oxolan-3-amine (1.38 g, 15.8 mmol) and K2CO3 (0.87 g, 6.32 mmol) in DMSO (15 mL) was stirred at 100° C. for 5 hrs. It was cooled to r.t. and water (50 mL) was added. The mixture was extracted with EtOAc (50 mL×3) and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE: EA=50:1˜3:1) to give the title compound (0.7 g, yield: 69.16%). 1H NMR (CDCl3, 400 MHz) δ 8.00 (d, J=1.2 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 5.03 (d, J=6.4 Hz, 1H), 4.23-4.13 (m, 1H), 4.07-3.98 (m, 2H), 3.96-3.87 (m, 1H), 3.83-3.76 (m, 1H), 3.03 (s, 3H), 2.43-2.32 (m, 1H), 1.98-1.88 (m, 1H). LCMS (M+H)+=320.0 (M+H)+, 322.0
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:26](=[O:27])[N:25]([CH3:28])[C:16]2[N:17]=[C:18](S(C)(=O)=O)[N:19]=[CH:20][C:15]=2[CH:14]=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-])=O)[C:31]=1[NH2:39].CC(C)([O-])C.[K+]>CN(C=O)C.CCOC(C)=O>[NH2:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[C:31]=1[NH:39][C:18]1[N:19]=[CH:20][C:15]2[CH:14]=[C:13]([C:3]3[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[Cl:12])[C:26](=[O:27])[N:25]([CH3:28])[C:16]=2[N:17]=1
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: COc1cc(OC)c(Cl)c(-c2cc3cnc(S(C)(=O)=O)nc3n(C)c2=O)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4c(C)cccc4N)nc3n(C)c2=O)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
To a mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (9) (1.0 g, 2.26 mmol) and 2-methyl-6-nitrobenzenamine (684 mg, 4.5 mmol) in DMF (20 mL), potassium tert-butoxide (756 mg, 6.75 mmol) was added at ˜10° C., and the reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with EtOAc (150 mL), and the organic phase was separated, washed with water (2×150 mL) and then brine (150 mL), dried over sodium sulfate, filtered, and concentrated. The residue was recrystallizated with EtOAc to give 2-(2-amino-6-methylphenylamino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (10) (810 mg, yield 70%) as a yellow solid. MS (ES+) C23H19Cl2N5O5 requires: 515, 517. found: 516, 518 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[OH-].[Na+].[CH2:10]([NH2:12])[CH3:11]>>[O:4]1[CH2:5][CH2:6][O:7][CH:3]1[CH2:2][NH:12][CH2:10][CH3:11]
Reactant: ClCC1OCCO1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Product: CCNCC1OCCO1
Reaction time: 18 h

Procedure:
A 40% by weight aqueous solution of ethylamine (100 ml) and 2-chloromethyl-1,3-dioxolane (35 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer. The reaction mixture is stirred for a period of about 18 hours. After this time sodium hydroxide (18 grams) is added with stirring over a period of about 4 hours. Stirring is then continued for an additional period of about 16 hours. The organic phase of the reaction mixture is then separated, washed with aqueous potassium carbonate and dried over anhydrous magnesium sulfate. The dried product is then distilled under reduced pressure to yield the desired product N-(1,3-dioxolan-2-ylmethyl)-N-ethylamine.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])=[CH:20][CH:21]=1
Reactant: N#Cc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ccc(C(=O)N2CCCCc3ccccc32)cc1

Procedure:
To a degassed solution of the cyanobenzoyl benzaz pin from Example 1A (1.50 g, 5.43 mmol) in methanol (50 ml) were added concentrated hydrochloric acid (1.4 ml, 16.2 mmol) and 10% palladium-on-carbon (1.15 g). Hydrogen gas was bubbled through the mixture for 5 h at room temperature. The catalyst was removed by filtration through a pad of celite and the filtrate was evaporated in vacuo. The residue was partitioned between EtOAc and water. The aqueous layer was basified by addition of saturated sodium bicarbonate solution and extracted with dichloromethane (2 times). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 1.12 g (74%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)[CH2:21][CH2:22]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: c1ccc(CN2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(Cc3ccccn3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-[(2-pyridyl)-methyl]-piperazine (0.097 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was heated at 45° C. for 20 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.163 g, 83%); 1H-NMR (500 MHz, DMSO-d6) 2.57 (br s, 4H, piperazine N(CH2)2), 3.08 (br s, 4H, piperazine N(CH2)2), 3.65 (s, 2H, NCH2), 6.97 (s, 2H, NH2), 7.26 (ddd, J=7.45, 4.80, 1.00 Hz, 1H), 7.46 (d, J=7.80 Hz, 1H), 7.77 (td, J=7.66, 1.80 Hz, 1H) and 8.48 (dm, J=4.09 Hz, 1H) (pyrid-2-yl protons), 8.16 (s, 1H, 6-H);
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@H:25]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:24]1=[O:48])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:49]N(P(N(C)C)(N(C)C)=O)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1.C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@H:25]([CH:43]([CH3:49])[C:44]([O:46][CH3:47])=[O:45])[C:24]1=[O:48])[CH2:21][CH3:22])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@H](CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@H](C(C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-((3S,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetate (Example 127, Step C) was azetroped with toluene 3× and then dissolved in THF (14 mL) under Ar and the mixture was cooled to −78° C. HMPA (236 μL, 1.356 mmol) and LHMDS (1.0M in THF) (1356 μL, 1.356 mmol) were added under Ar at −78° C. The mixture was stirred at −78° C. for 30 min. The mixture color turned light yellow. Then iodomethane (110 μL, 1.763 mmol) was added and the reaction mixture was allowed to slowly warm to room temperature. The mixture was quenched with sat. NH4Cl and the layers were separated. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2×50 g stacked VersaPak I-style, Spherical, Supelco, Bellenfonte, Pa.; eluent: 20 to 30% MtBE in hexanes) to give the title compound as the less polar, major diastereomer. The retention time of the less polar diastereomer is 0.871 min (80-100% MeCN +0.1% TFA in water +0.1% TFA, over 1 minute). The retention time of the more polar diastereomer is 0.841 min (80 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 1 minute).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[CH2:22]([O:21][C:19](=[O:20])[C:17]#[C:16][C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=1)[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: C#Cc1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
LDA solution (2M) in THF (20.71 mL, 41.436 mmol) was added to a stirred solution of 1-bromo-4-ethynyl-benzene (3 g, 16.57 mmol) in dry THF (40 mL) at −70° C. and stirred for 30 min. Ethyl chloroformate (11.81 mL, 74.58 mmol) was added and the mixture was allowed to warm to ambient temperature. Stirring was continued for 2 h. The mixture was cooled, and quenched with saturated NH4Cl solution. THF was evaporated under reduced pressure and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated and purified over normal silica gel column chromatography using EtOAc-hexane as eluting solvent to get (4-bromo-phenyl)-propynoic acid ethyl ester (2.9 g, 69.13% yield) as a light yellow liquid. GC-MS: 253 (M+H); 1H-NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.0 Hz, 3H). 4.28 (q, J=7.0 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9]O)[N:6]=[N:7][CH:8]=1.[CH2:11]([C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)[CH3:12]>>[CH2:11]([C:13]1[N:14]([CH2:9][C:5]2[N:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:15]=[CH:16][N:17]=1)[CH3:12]
Reactant: COc1cnnc(CO)c1
Reactant: CCc1ncc[nH]1
Product: CCc1nccn1Cc1cc(OC)cnn1

Procedure:
The title compound, MS: m/e=219.3 (M+H+), was prepared from (5-methoxy-pyridazin-3-yl)-methanol and 2-ethylimidazole.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl[CH2:12]Cl.C[Mg]Br>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: ClCCl
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Product: Cc1ncnc2[nH]ccc12
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (17, 5.03 g, 32.8 mmol) in 100 mL of toluene, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.627 g, 0.328 mmol) was added under nitrogen. After stirring for 10 minutes, methylmagnesium bromide (62.9 mL, 3.00 M in ether, 189 mmol) was added slowly. The reaction was heated at 55° C. overnight, then cooled to −70 to −80° C. and quenched by adding ammonium chloride dropwise. Then 1N hydrochloric acid was added and the pH was adjusted to 7-8 with addition of saturated sodium bicarbonate. This was extracted 3× with ethyl acetate. The combined organic layer was washed with saturated ammonium chloride and brine, then dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane, then methanol and dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a tan solid (18). MS (ESI) [M+H′]′=134.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].[NH:8]1[CH:12]=[CH:11][CH2:10][CH2:9]1>>[N+:1]([CH2:3][C:4]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:6])#[C-:2]
Reactant: C1=CNCC1
Reactant: [C-]#[N+]CC(=O)OC
Product: [C-]#[N+]CC(=O)N1CC=CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
Prepared in accordance with Method B with methyl isocyanoacetate (1.00 g, 10.10 mmol) and dihydro-1H-pyrrole (1.01 mL, 15.15 mmol). The reaction mixture was stirred 5 h at 50° C. and concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10% aqueous citric acid (2×25 mL), dried over MgSO4, filtered and evaporated. 2-Isocyano-1-(2H-pyrrol-1(5H)-yl)ethanone SLA 07178 was obtained (1.0 g, 73% yield) as a yellow solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]([C:34]1[CH:39]=[C:38]([CH3:40])[C:37]([C:41](C)(C)[O:42][SiH2]C(C)(C)C)=[CH:36][N:35]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]([C:34]1[CH:39]=[C:38]([CH3:40])[C:37]([CH2:41][OH:42])=[CH:36][N:35]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc1C(C)(C)O[SiH2]C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
Tetrabutylammonium fluoride (13.9 g, 44.1 mmol) was added to a solution of 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-(tert-butyl-dimethyl-silanyloxymethyl)-4-methylpyridin (10.0 g, 24.3 mmol) in THF (100 mL). The reaction mixture was stirred for 3 h at room temperature. Concentration under reduced pressure followed by flash chromatography (hexane/EtOAc, 50:50) gave 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-hydroxymethyl-4-methylpyridin (5.0 g, 67%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].C>O.C(O)CO>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: O=C(O)c1ccccc1Nc1ccc(F)cc1
Temperature: 125 °C
Yield: 37.3 %

Procedure:
4-Fluoroaniline (1.86 gm; 20 mmol), 2-chlorobenzoic acid (1.56 gm; 10 mmol), ethylene glycol (5 ml) and anhydrous sodium carbonate (1.1 gm; 10 mmol) were placed in a reaction vessel and stirred until effervescence ceased. Cupric chloride (100 mg; 0.75 mmol) dissolved in 2 ml of water was added to the reaction mixture which was then heated to 125° C. for 6 hrs. The reaction was allowed to cool and water (30 ml) and charcoal were added. The mixture was filtered and then acidified to pH 2 with conc. hydrochloric acid. The precipitate was collected by filtration, washed with water and then re-dissolved in 1M sodium hydroxide solution. Material was re-precipitated by the addition of acetic acid, filtered off, washed with aqueous acetic acid, then water and finally dried under vacuum over phosphorous pentoxide to give 862 mg (37%) of N-(4-fluorophenyl)anthranilic acid.
Reaction SMILES: NC1C=CC(F)=NC=1.Br.FC1C=CC(OC)=CN=1.Cl.[F:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.[N+:28]([O-])([OH:30])=[O:29]>S(=O)(=O)(O)O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.[F:20][C:21]1[CH:22]=[C:23]([N+:28]([O-:30])=[O:29])[C:24]([OH:27])=[N:25][CH:26]=1
Reactant: O=[N+]([O-])O
Agent: Br
Agent: COc1ccc(F)nc1
Agent: Cl
Product: O=[N+]([O-])c1cc(F)cnc1O
Temperature: 25 °C
Yield: 53 %

Procedure:
5-Fluoro-2-hydroxypyridine (5-fluoro-2-pyridone) was prepared from commerially available 5-amino-2-fluoropyridine as described by Nesnow and Heidelberger (J. Heterocyclic Chem., 10, 779 (1973)) except that refluxing 48% hydrobromic acid was used to carry out the final hydrolysis of 2-fluoro-5-methoxypyridine rather than the literature conditions (25% hydrochloric acid in a sealed glass tube at 145° C.). 5-Fluoro-2-hydroxypyridine (11.16 g, 98.7 mmol) was added in portions to concentrated sulfuric acid (90 mL) at 0° C. Fuming nitric acid was then added dropwise. The reaction mixture was allowed to warm to room temperature and was then heated at 55°-60° C. for 3 hours. The mixture was cooled to room temperature and was then poured into ice/water. The yellow product was collected by filtration, washed with water and dried in the air to yield 8.24 g (53%) of the title compound. The filtrate was adjusted to pH 2 by the addition of solid NaHCO3 and was extracted with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated to yield an additional amount of the title compound (1.71 g, 11%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O=S(Cl)Cl>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([O:6][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5]
Reactant: COc1cc(O)c(C(=O)O)cc1OC
Reactant: Oc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1C
Product: COc1cc(O)c(C(=O)Oc2ccccc2)cc1OC
Yield: 64 %

Procedure:
In 10 g of xylene were suspended 1.0 g of compound (2a) and 522 ma of phenol, to which 460 μL of SOCl2 was then added dropwise before heating to reflux for 3 hours, followed by further adding 184 μL of SOCl2 and additionally heating to reflux for one hour. The reaction solvent was distilled off, followed by adding methanol to the residue before stirring. The precipitated crystal was collected by filtration to provide 880 mg of phenyl 2-hydroxy-4,5-dimethoxybenzoate (3a) at a yield of 64%.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][S:18][C:17]([CH3:22])([CH3:21])[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH3:21][C:17]1([CH3:22])[CH2:16][N:15]([C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=2)=[O:32])[CH2:20][CH2:19][S:18]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC1(C)CN(C(=O)CN(C(=O)CN)c2ccccc2)CCS1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCSC(C)(C)C2)c2ccccc2)c1
Yield: 62.8 %

Procedure:
The procedure is analogous to that described in Example 81, but 0.7 g of 2-amino-N-[2-(2,2-dimethylthiomorpholino)-2-oxoethyl]-N-phenylacetamide and 0.28 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from an ethyl acetate/acetonitrile mixture (80/20 by volume), 0.6 g of N-[2-(2,2-dimethylthiomorpholino)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 186° C. is obtained.
Reaction SMILES: C(Cl)(Cl)(Cl)F.[CH:6]([O:15][C:16](Cl)([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8].[F:20][C:21]([F:33])([F:32])[CH:22]([O:27]C(F)(F)F)[C:23]([F:26])([F:25])[F:24]>>[F:8][C:7]([F:10])([F:9])[CH:6]([O:15][C:16]([F:18])([F:17])[O:27][CH:22]([C:23]([F:26])([F:25])[F:24])[C:21]([F:33])([F:32])[F:20])[C:11]([F:14])([F:13])[F:12]
Reactant: FC(F)(F)OC(C(F)(F)F)C(F)(F)F
Reactant: FC(F)(Cl)OC(C(F)(F)F)C(F)(F)F
Solvent: FC(Cl)(Cl)Cl
Product: FC(F)(OC(C(F)(F)F)C(F)(F)F)OC(C(F)(F)F)C(F)(F)F

Procedure:
Fractionation of the combined products afforded 23.2 g of a mixture, boiling point up to 39.5° C. shown by 1H and 19F NMR and GC to contain mainly CFCl3 and (CF3)2CHOCF2Cl along with a small amount of trifluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether. There was then distilled 120.1 g, boiling point 40° to 45° C., identified by GC and NMR as chlorodifluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether. Next came 2.7 g, boiling point 75° to 79° C., of dichlorofluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether, identified by GC and NMR. Finally, there was obtained 24.4 g of 2,6-bis(trifluoromethyl)1,1,1,4,4,7,7,7-octafluoro-3,5-dioxaheptane, ((CF3)2CHOCF2OCH(CF3)2), boiling point 89° to 94° C., identified by GC and NMR analyses. NMR and mass spectroscopic (MS) analyses of (CF3)2CHOCF2OCH(CF3)2 are as follows: 1H-NMR (CDCl3) δ4.78 (septet, JHF, 5.4 Hz, OCH(CF3)2); 19F-NMR (CDCl3) Φ-60.9 (m, 2F, OCF2O), -74.3 (m, 12F, CF3). MS, m/e 364.966156 (M+ -F; mass meas. C7H2F13O2), 314.9808 (M+ -CF3), 216.983002 (mass meas. (CF3)2CHOCF2+), 150.9758 (CF3CHCF3+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][OH:12])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([Cl:18])=[N:11][OH:12])=[CH:6][C:5]=1[C:13]([F:15])([F:14])[F:16]
Reactant: COC(=O)c1ccc(C=NO)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C(Cl)=NO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.7 %

Procedure:
To a solution of 4-(hydroxyimino-methyl)-2-trifluoromethyl-benzoic acid methyl ester (Example I11) (3.90 g) in N,N-dimethylformamide (20 ml) was added N-chlorosuccinimide (“NCS”) (2.318 g). The reaction mixture was stirred at ambient temperature for 45 minutes. The reaction mixture was poured into water (400 ml). The solids were isolated by filtration and dried to give 4-(chloro(hydroxyimino)methyl)-2-trifluoromethyl-benzoic acid methyl ester (4.21 g) as an off-white powder. 1H-NMR (CDCl3, 400 MHz): 9.00 (s, 1H), 8.24-8.04 (m, 3H), 3.96 (s, 3H).