Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[CH2:10][O:9]C(C)(C)[O:7][C@H:6]1[CH:13]=[CH2:14])C=C.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[OH:9][CH2:10][C@H:5]1[C@@H:6]([OH:7])[CH:13]=[CH:14][CH2:1][O:4]1
Reactant: C=CCO[C@H]1COC(C)(C)O[C@H]1C=C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC[C@@H]1OCC=C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cis-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane (50 mg, 0.29 mmol) in MeOH (5 mL) was added a solution of methanolic HCl (0.5 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The mixture was stirred for 30 min at ambient temperature. Aqueous saturated NaHCO3 (5 mL) was added and the mixture was diluted with EtOAc (50 mL). The organic layer was washed with saturated NaHCO3 (30 mL). The aqueous layer was washed with EtOAc (30 mL×2). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and the residue was purified by flash chromatography with 100% EtOAc
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.O>[N:32]([CH2:20][C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[N+:33]=[N-:34]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC(=O)OC(C)(C)C)Nc2ccc(C#N)c(Cl)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](CN=[N+]=[N-])Nc1ccc(C#N)c(Cl)c1
Yield: 105.4 %

Procedure:
1,1-Dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-{[(4-methylphenyl)sulfonyl]oxy}butanoate (35.0 g, 76 mmol) and sodium azide (9.83 g, 150 mmol) in DMF (150 mL) were stirred at 65° C. for 2.25 h. After cooling, the reaction was diluted with cold H2O (500 mL) and extracted with Et2O (3×). The combined organic extracts were washed with H2O (3×), treated with charcoal and dried (MgSO4), filtered and the solvent evaporated. The residue was dissolved in a small amount of Et2O and filtered through a short plug of silica gel. Evaporation of the filtrate afforded the titled compound (26.9 g, >100%) as an oil. 1H-NMR (CDCl3) δ: 1.46 (9H, s), 2.58 (2H, m), 3.56 (2H, d, J=5.2 Hz), 3.99 (1H, m), 6.54 (1H, d, J=8 Hz), 6.99 (1H, s), 7.43 (1H, d, J=8.8 Hz). LC-MS (ES) m/e 336.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]([CH3:10])[C:7](Cl)=[O:8])=[O:4].[C:11]1(=[O:30])[N:15]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=[O:25])[C:13]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:12]12.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:1][O:2][C:3](=[O:4])[CH2:5][CH:6]([C:7](=[O:8])[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][CH2:16][N:15]2[C:11](=[O:30])[C:12]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:13]3[C:14]2=[O:25])=[CH:24][CH:23]=1)[CH3:10]
Reactant: COC(=O)CC(C)C(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)CC(C)C(=O)c1ccc(CCCN2C(=O)c3ccccc3C2=O)cc1

Procedure:
8.2 g (50 mmol) of 3-methoxycarbonyl-2-methyl-propionic acid chloride and 13.3 g (50 mmol) of 3-phthalimidopropyl-benzene are reacted with 26 g of aluminum chloride in 1,2-dichloroethane analogously to Example 4(a). The oil obtained crystallizes from ethanol as beige coloured crystals.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[NH:6][C@H:7]2[CH3:12].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:13][O:14][Si:15]([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:17])[CH3:16])[N:6]([C:31](=[O:32])[CH2:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[Cl:22])[C@H:7]2[CH3:12]
Reactant: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(Br)cccc21
Reactant: O=C(O)Cc1c(F)cccc1Cl
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: ClCCl
Product: C[C@H]1c2cccc(Br)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(F)cccc1Cl
Reaction time: 3 h
Yield: 81.6 %

Procedure:
Dissolve (1S,3R)-5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline (1.85 g, 4.99 mmol) and 2-chloro-6-fluorophenylacetic acid (1.04 g, 5.49 mmol) in dichloromethane (50 mL). Add 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.85 g, 7.49 mmol) and diisopropylethylamine (1.3 mL, 7.49 mmol) at rt. Stir 3 hours. Add water and extract with dichloromethane three times. Combine the dichloromethane extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 5-60%) to give the title compound as a white foam (2.2 g, 4.07 mmol). MS (m/z): 540.2 (M+1).
Reaction SMILES: S1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:3][CH2:2]1.O[O:22][S:23]([O-:25])=O.[K+].[OH-].[Na+]>CO.O>[O:22]=[S:23]1(=[O:25])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)=[CH:3][CH2:2]1
Reactant: COC(=O)c1ccc(C2=CCSc3ccccc32)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C2=CCS(=O)(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Methyl 4-(2H-1-benzothiopyran-4-yl)benzoate from reaction 33b (0.77 g, 2.75 mmol) was dissolved in methanol (30 mL) cooled to 0° C. and Oxone® (6.76 g, 11.1 mmol) in water (7 mL) was added. The reaction was stirred for 1 h at 0° C. and then allowed to warm to room temperature and stir for another hour. The reaction was diluted with water, pH adjusted to pH=8 with 1 N sodium hydroxide. This was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate and concentrated to give methyl 4-(1,1-dioxido-2H-1-benzothiopyran-4-yl)benzoate (0.784 g, 91%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24](O)=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[CH2:35]([N:37](CC)[CH2:38]C)C.CNC>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24](=[O:25])[N:37]([CH3:38])[CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)c1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-carboxynitrobenzene (3.4 g) in dichloromethane (60 ml) were added isobutyl chloroformate (1.4 ml) and triethylamine (1.5 ml) in an ice bath and the mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture was added 50% aqueous dimethylamine (1.1 ml) and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/methanol=19/1 as an eluant to give the desired compound (3.1 g, yield 83%) as a pale yellow amorphous solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]([C:17]([CH3:23])([CH3:22])[C:18]([O:20]C)=O)=[N:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=O.C[O-].[Na+].O>CO>[N:9]([C:10]([CH3:15])([CH3:16])[C:11]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13])=[N:8][C:17]([CH3:23])([CH3:22])[C:18]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:20]
Reactant: NC1CCCCC1
Reactant: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(N=NC(C)(C)C(=O)NC1CCCCC1)C(=O)NC1CCCCC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
47.3 Grams of cyclohexylamine is mixed with 50 g of dimethyl 2,2'-azobis (2-methylpropionate) and 20 g of 28% sodium methoxide solution in methanol is dropwise added thereto under stirring, following by conducting a reaction at room temperature with stirring for 6 hours and keeping standing overnight. 100 Milliliter of water is added to the reaction solution and cooled to 10° C. to precipitate crystals. The crystals are recovered by filtration and dried to give 59.4 g (yield 81 %) of 2,2'-azobis (N-cyclohexyl-2-methylpropionamide) as yellow crystals. The solubility is shown in Table 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC([O-])(C)C.[K+].[Cl:16][C:17]1[C:18]([C:24]([NH2:26])=[O:25])=[N:19][CH:20]=[CH:21][C:22]=1Cl>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:22]2[CH:21]=[CH:20][N:19]=[C:18]([C:24]([NH2:26])=[O:25])[C:17]=2[Cl:16])=[C:4]([F:9])[CH:3]=1
Reactant: NC(=O)c1nccc(Cl)c1Cl
Reactant: Nc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1nccc(Oc2ccc(N)cc2F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution of 4-amino-2-fluorophenol (254 mg, 2.0 mmol) in DMF (5 mL) was added t-BuOK (359 mg, 3.2 mmol). The mixture was stirred at rt for 30 minutes. 3,4-dichloropicolinamide (420 mg, 2.2 mmol) was then added, and the mixture was microwaved at 120° C. for 2 hours. The mixture was cooled to rt, quenched with 25 mL of water. The resulted solution was extracted with EtOAc (30 mL×3) and the combined organic phases were washed with brine (30 mL×3), dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as a pale yellow solid (306 mg, 54.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][C@H:12]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]2)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][C@H:12]2[CH2:13][CH2:14][C@@H:15]([OH:18])[CH2:16][CH2:17]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@H]1CC[C@@H](O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)cc1O[C@H]1CC[C@@H](O)CC1

Procedure:
4-Fluoro-2-(cis-4-hydroxycyclohexyloxy)-nitrobenzene (2.00 g) in methanol (15.0 ml) was hydrogenated under 50 psi hydrogen using palladium on charcoal (5%) as catalyst (300 mg) at RT for 2 h. The catalyst was filtered off; the solvent was removed in vacuo to yield the desired product as 95% pure oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=[O:12])[CH:7]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=1
Reactant: CCOC(=O)c1cc(Cc2cccc(F)c2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Cc2cccc(F)c2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Ethanol (3 mL) was added to the mixture of ethyl 5-(3-fluorobenzyl)isoxazole-3-carboxylate (0.688 g; 2.82 mmol) and 1M sodium hydroxide (10.5 mL; 10.5 mmol). The mixture was stirred overnight at room temperature and was concentrated under reduced pressure to remove ethanol. The aqueous solution was acidified by addition of 6N hydrochloric acid to pH 0-1. The formed precipitate was collected by filtration and was dried. 0.5026 g (82%) of 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid was obtained as a white solid, which was directly used in the next step.
Reaction SMILES: [CH3:1][C:2]12[O:8][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3]2.[OH-].[NH4+:10]>O>[NH2:10][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1([CH3:1])[OH:8]
Reactant: [NH4+]
Reactant: CC12CCCCC1O2
Agent: [OH-]
Solvent: O
Product: CC1(O)CCCCC1N
Temperature: 50 °C

Procedure:
To a solution of 1-methyl-7-oxabicyclo[4.1.0]heptane, 30a, (1.0 g, 7.1 mmol) in water was added ammonium hydroxide (6.0 mL, 154.1 mmol). The mixture was heated to 50° C. for 48 hours. The mixture was diluted with water, extracted with EtOAc and then twice with 20% MeOH/CHCl3. The organic phases were dried (MgSO4), filtered and concentrated in vacuo to provide the desired product, 30b, as an amorphous white solid.
Reaction SMILES: C(O[C:9]([C:11]1[O:36][C:14]2=[CH:15][CH:16]=[C:17]3[C:21]([N:20]([CH2:22][C@@H:23]([NH:25][C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH3:24])[N:19]=[CH:18]3)=[C:13]2[CH:12]=1)=[O:10])C1C=CC=CC=1.[Cl-].[NH4+].[CH2:39]([CH2:41][NH2:42])[OH:40]>>[CH2:29]([O:28][C:26](=[O:27])[NH:25][C@@H:23]([CH3:24])[CH2:22][N:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]3[O:36][C:11]([C:9](=[O:10])[NH:42][CH2:41][CH2:39][OH:40])=[CH:12][C:13]3=2)[CH:18]=[N:19]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCCO
Reactant: C[C@@H](Cn1ncc2ccc3oc(C(=O)OCc4ccccc4)cc3c21)NC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Product: C[C@@H](Cn1ncc2ccc3oc(C(=O)NCCO)cc3c21)NC(=O)OCc1ccccc1
Yield: 57 %

Procedure:
A stirred solution of the product from Step A, Example 2 (0.44 g, 0.91 mmol) in ethanolamine was heated at 80° C. for 8 h. A saturated aqueous solution of ammonium chloride (20 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried and evaporated to a residue, which was purified by chromatography (silica, 60% ethyl acetate in hexane) to give an oil (0.23 g, 57%): MS (ES) m/z 437 (M+); 1H NMR (CDCl3) δ 8.00 (s, 1H), 7.69 (d, 1H, J=8.0 Hz), 7.22-7.30 (m, 7H), 5.30 (brs, 1H), 5.03 (m, 2H), 4.63 (m, 1H), 4.40 (m, 1H), 4.15 (m, 1H), 3.85 (m, 2H), 3.65 (m, 2H), 1.26 (d, 3H, J=8.0 Hz).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].[CH:13]1([CH:19]=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(=O)C>C(O)C>[CH2:6]([O:5][C:1]([NH:2][N:3]=[CH:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CC1CCCCC1
Reactant: NNC(=O)OCc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(NN=CC1CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
Benzyl carbazate (25 g, 150.44 mmoles) was dissolved in 200 mL ethanol under a nitrogen atmosphere in a round bottom flask equipped with magnetic stirring. Cyclohexanecarbaldehyde (17.7 g, 158 mmoles) and acetic acid (1 mL) were added to the solution and the mixture was stirred at room temperature for 8 h. The resultant solid precipitate was filtered, washed with hexanes, crystallized from ethyl acetate, and dried overnight on the open bench to provide 28.87 g (73.7% yield) white crystalline N′-cyclohexylmethylene-hydrazinecarboxylic acid benzyl ester. Rf=0.67 (1:3 hexanes:ethyl acetate), 1H NMR (400 MHz, CDCl3) δ 7.8 (1H, br s), 7.4 (5H, m), 7.1 (1H, br s), 5.3 (2H, s), 2.4 (1H, m), 1.7-1.9 (4H, m), 1.3 (6H, m); HRMS (ESI) m/z calcd for C15H21N2O2 [M+H]+ 261.1603, found 261.1592, calcd for C15H20NaN2O2 [M+Na]+ 283.1426, found 283.1417.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH:26]=[CH:25][CH:24]=[C:23]2C=O)[CH:19]=[CH:20][CH:21]=1>C(O)C>[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH:26]=[CH:25][CH:24]=[C:23]2[CH:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=3)[NH:10][C:9]2=[O:14])[CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cccn1-c1cccc(Cl)c1
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Solvent: CCO
Product: CC(=O)Nc1ccc2c(c1)C(c1cccn1-c1cccc(Cl)c1)C(=O)N2
Yield: 17 %

Procedure:
By carrying out the procedure as in Example 1, but starting with 1.05 g (5 mmol) of 5-acetylaminoindolin-2-one in 150 ml of ethanol and 0.95 g (10 mmol) of 3-[N-(3-chlorophenyl)pyrrole-2-carboxaldehyde, 0.32 g (17%) of 3-[N-(3-chlorophenyl)pyrrol-2-yl]-5-acetylaminoindolin-2-one is obtained in the form of an orange solid whose characteristic is the following: melting point=251° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O.Cl>[CH2:22]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1
Temperature: 105 °C
Reaction time: 21.5 h

Procedure:
4-Hydroxybenzaldehyde (8.00 g, 6.55×10−2 mol), 1-bromododecane (16.50 ml, 6.87×10−2 mol), K2CO3 (9.05 g, 6.55×10−2 mol) and dry DMF (100 ml) were added to a two-neck round-bottom flask. The reaction mixture was stirred at 105° C. for 21.5 h under Ar. After cooling, the solution was diluted with H2O, 2M HCl and extracted three times with CH2Cl2. The combined organic layers were washed with aqueous NaHCO3, H2O and dried over Na2SO4. The product was chromatographed on silica gel with 1:1 hexane:CH2Cl2 as the eluent. Yield=19.02 g (100% based on 8.00 g of 4-hydroxybenzaldehyde). 1H NMR (250 MHz, CDCl3): δ 9.88 (s, 1H, —CHO), 7.83 (d, 2H, J=8.8 Hz, Ph), 6.99 (d, 2H, J=8.7 Hz, Ph), 4.04 (t, 2H, J=6.5 Hz, OCH2), 1.82 (quint, 2H, J=6.9 Hz, OCH2CH2), 1.40-1.54 (m, 2H, —CH2—), 1.16-1.40 (m, 16H, —CH2—), 0.88 (t, 3H, J=6.5 Hz, —CH3). CI MS m/z: 291.232 ((M+H)+) (calcd 291.232).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:15])[C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:5][CH:4]=1.[N+:16]([O-])([O-:18])=[O:17].[NH4+]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:15])[C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc2c(=O)c(C#N)c[nH]c2c1
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2[nH]cc(C#N)c(=O)c2cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a suspension of 10 g (49.6 mmol) of 1,4-dihydro-7-methoxy-4-oxo-3-quinolinecarbonitrile in 160 ml of trifluroacetic anhydride was added 6 g (74.9 mmol) of ammonium nitrate over a period of 3 hours. The mixture was stirred an additional two hours. Excess anhydride was removed at reduced pressure at 45° C. The residue was stirred with 500 ml of water. The solid was collected and washed with water. The solid was dissolved in 1000 ml of boiling acetic acid and the solution was treated with decolorizing charcoal. The mixture was filtered and concentrated to a volume of 300 ml. Cooling gave a solid which was collected giving 5.4 g of 1,4-dihydro-7-methoxy-6-nitro-4-oxo-3-quinolinecarbonitrile as a brown solid: mass spectrum (electrospray, m/e): M+H 246.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[NH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:40][CH2:39][CH:36]1[CH2:37][CH2:38][N:33]([C:15](=[O:17])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:31])([F:32])[F:30])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:34][CH2:35]1
Reactant: OCC1CCNCC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCC(CO)CC3)ccc21
Yield: 80.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]amide (73 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (75 mg), 4-piperidinemethanol (20 mg), HBTU (73 mg), and DIEA (42 uL), with a modification of General Procedure F where DIEA was slowly added to the reaction mixture as the last reagent. LC/MS: m/z 563.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.48 (t, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.79 (d, 1H), 7.67 (bs, 1H), 7.51 (d, 1H), 7.37 (d, 1H), 4.37 (d, 1H), 4.14 (d, 2H), 3.92 (d, 1H), 3.67 (s, 3H), 3.27 (d, 2H), 3.02 (t, 1H), 2.58 (t, 1H), 1.78-1.55 (m, 3H), 1.20-0.90 (m, 2H), —OH and —NH proton signal was not observed.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][P:7]([OH:10])([OH:9])=[O:8])[C:2]([OH:4])=[O:3].[OH-].[K+:12]>O>[CH2:1]([NH:5][CH2:6][P:7]([O-:10])([OH:9])=[O:8])[C:2]([OH:4])=[O:3].[K+:12]
Reactant: O=C(O)CNCP(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNCP(=O)([O-])O

Procedure:
The procedure of Example 1 is followed using 519.30 g of glyphosate acid, 324.20 g of deionized water, and 224.60 g KOH pellets. The resulting potassium glyphosate concentrate (1068.10 g) has 44.0% acid equivalents. The final pH of the concentrate, measured as a 10% solution in deionized water, is 4.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2F)(=[O:19])=[O:18])=[CH:13][N:12]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)(=[O:19])=[O:18])=[CH:13][N:12]=1
Reactant: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)nc1)c1ccccc1F
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CCN(c2ccccc2S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
2-[(E)-2-(2,4-Difluorophenyl)vinyl]-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 1, 30 mg, 0.08 mmol) and 1-methylpiperazine (22 μL, 0.20 mmol) were combined in acetonitrile (0.5 mL) and heated to 100° C. for 5 minutes in a Smith synthesiser microwave reactor. Further 1-methylpiperazine (44 μL, 0.40 mmol) was added and the reaction heated to 150° C. for 10 minutes, then to 170° C. for 10 minutes. The reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid and brine, dried over MgSO4 and evaporated in vacuo to give the title compound which was dissolved in ethyl acetate and treated with ethereal HCl to give the hydrochloride salt (10 mg, 25%). δH (500 MHz, MeOD) 9.15 (1H, d, J 2.1), 8.30 (1H, dd, J=1.5, 7.9), 8.25 (1H, dd, J=2.3, 8.4 Hz), 7.96 (1H, d, J=16.3 Hz), 7.84–7.76 (3H, m), 7.56 (1H, td, J=1.1, 7.6 Hz), 7.50 (1H, d, J=7.9 Hz), 7.37 (1H, d, J=16.2 Hz), 7.07–7.03 (2H, m), 3.53 (2H, d, J=12.2 Hz), 3.21–3.14 (2H, m), 3.10 (4H, d, J=6.6 Hz), 3.03 (3H, s); m/z (ES+) 456 [MH+].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12]2[C:21]3[CH:22]=[CH:23][NH:24][C:25](=[O:26])[C:20]=3[C:19]3[C:14](=[CH:15][CH:16]=[N:17][CH:18]=3)[N:13]=2)=[C:6]([Cl:27])[CH:5]=1)(=[O:3])[CH3:2].[CH3:28][Mg]Br>C1COCC1>[Cl:27][C:6]1[CH:5]=[C:4]([C:1]([OH:3])([CH3:28])[CH3:2])[CH:9]=[C:8]([Cl:10])[C:7]=1[NH:11][C:12]1[C:21]2[CH:22]=[CH:23][NH:24][C:25](=[O:26])[C:20]=2[C:19]2[C:14](=[CH:15][CH:16]=[N:17][CH:18]=2)[N:13]=1
Reactant: CC(=O)c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of 6-[(4-acetyl-2,6-dichlorophenyl)amino]pyrido[4,3-c]-1,6-naphthyridin-10(9H)-one (Examples 144 and 145, Step 3) (1.3 g, 3.26 mmol) in THF (30 mL) at 0° C. under nitrogen atmosphere was added methyl magnesium bromide (11.6 mL, 1.4 M in THF/toluene) and the reaction mixture stirred for 30 min. The solution was quenched with 1 N citric acid, diluted with 1:1 THF/EtOAc, and neutralized with saturated NaHCO3. The organic layer was concentrated, triturated with diethyl ether, and filtered to afford the desired product as a yellow powder.