Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[C:29]=1[OH:30])[CH:25]=O)[CH3:20].[NH2:34][C:35]([NH2:37])=[O:36].Cl>CCO.CCOC(C)=O>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:25]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[NH:37][C:35](=[O:36])[NH:34]2)[CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[C:29]=1[OH:30])[CH3:20]
Reactant: COc1cccc(CC(=O)c2ccc(F)cc2)c1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(C2NC(=O)NC(c3ccc(F)cc3)=C2c2cccc(OC)c2)cc([N+](=O)[O-])c1O
Yield: 19.7 %

Procedure:
A mixture of 1-(4-fluorophenyl)-2-(3-methoxyphenyl)ethanone (Intermediate 53) (200 mg, 0.82 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (157 mg, 0.74 mmol), urea (134 mg, 2.23 mmol), concentrated HCl (0.06 mL, 0.74 mmol) in EtOH (5 mL) was refluxed overnight. Followed standard aqueous/EtOAc workup procedure, then purified by preparative HPLC to give Compound 108 (70 mg, yield 20%). 1H NMR (DMSO-d6 300 MHz): δ 10.29 (s, 1H), 8.77 (s, 1H), 7.55 (s, 1H), 7.45 (s, 1H), 7.27-7.24 (m, 2H), 7.20 (s, 1H), 7.15-7.09 (m, 2H), 6.99-6.94 (m, 1H), 6.59 (d, J=7.2 Hz, 1H), 6.39 (d, J=6.3 Hz, 2H), 5.22 (s, 1H), 4.07-4.05 (m, 2H), 3.49 (s, 3H), 1.33 (t, J=6.6 Hz, 3H); MS (ESI): m/z 479.9 [M+1]+.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[O:32]=[C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30](=[O:31])[N:22]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccccc2C)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccccc1-c1csc(N2C(=O)c3ccccc3C2=O)c1C(=O)O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-(2-methylphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 10, Part D). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1Nc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1-bromo-4-fluoro-3-nitrobenzene (2270 mg, 10.01 mmol), aniline (3 ml) and DMF (20 ml) was heated at 100° C. under an atmosphere of Nitrogen for 7 h. The mixture was then concentrated in vacuo, and the residue triturated with heptane (30 ml) to give the desired product. 18 NMR (400 MHz, CDCl3) δ=7.11 (d, 1H, J=9.2 Hz), 7.25-7.29 (m, 3H), 7.40-7.45 (m, 3H), 8.35 (d, 1H, J=2.4 Hz) and 9.45 (brs, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.[NH2:14][C@H:15]([C:20]([NH:22][C@H:23]([CH:36]=[O:37])[CH2:24][C:25](=[N:31][NH:32][C:33]([NH2:35])=[O:34])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18].CCN=C=NCCCN(C)C.CCOCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:14][C@H:15]([C:20]([NH:22][C@H:23]([CH:36]=[O:37])[CH2:24][C:25](=[N:31][NH:32][C:33]([NH2:35])=[O:34])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:21])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:13]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
1-Methylindole-2-carboxylic acid (70 mg, 0.4 mmol) and 3(S)-(Leucinyl)amino-4-oxobutanoic acid, t-butyl ester semicarbazone (131 mg, 0.4 mmol) were dissolved in methylene chloride (2 mL) and both DMAP (49 mg, 0.40 mmol) and EDAC (107 mg, 0.56 mmol) were added to the solution under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and an additional 3 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution. The ethyl acetate solution was washed successively with 5% KHSO4 solution, saturated with sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated in vacuo to give a crude solid. Trituration of the solid with ether afforded the title product as a white powder (156 mg, 80%). TLC: (methanol/methylene chloride: 5/95, silica gel): Rf=0.42; 1H NMR (CDCl3+CD3OD): δ 8.18 (s, 1H), 7.66-7.11 (m, 6H), 6.97 (s, 1H), 6.32 (d, J=7.7, 1H), 4.95-4.88 (m, 1H), 4.70-4.62 (m, 1H), 4.03 (s, 3H), 2.82-2.56 (m, 2H), 1.87-1.58 (m, 3H), 1.38 (9H), 1.00 (t, J-6.3, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2S(C2C=CC=CC=2)(=O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(O)C=CC=CC=1>Br>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(CC1CCCCN1S(=O)(=O)c1ccccc1)c1ccc(Cl)cc1
Agent: Br
Solvent: Oc1ccccc1
Product: Cl
Product: O=S(=O)(CC1CCCCN1)c1ccc(Cl)cc1

Procedure:
A mixture of 45.1 g (0.109 mole) of 2-[[(4-chlorophenyl)sulfonyl]methyl]-1-phenylsulfonylpiperidine and 200 ml of phenol in 200 ml of 48% hydrobromic acid was refluxed for 1 hr. The reaction mixture was quenched in water and 50% sodium hydroxide was added until the solution was basic (pH>10). The mixture was extracted with methylene chloride. The methylene chloride phase was separated, extracted with dilute aqueous sodium hydroxide followed by several portions of dilute sulfuric acid. The acidic phase was separated, basified with solid sodium carbonate and extracted with methylene chloride. This methylene chloride solution was dried over sodium sulfate and evaporated to remove solvent in vacuo to give an oil, the free base of the title compound. The free base was dissolved in methanol and converted to the hydrochloride salt with ethereal hydrogen chloride and the salt was recrystallized from methanol-diethyl ether to give 22.82 g (67.5%) white crystalline solid, m.p. 223.5°-224.5° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:19]2[CH:18]=[CH:17][C:16]([S:13]([C:6]3([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)(=[O:14])=[O:15])=[CH:21][CH:20]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(C(=O)O)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1

Procedure:
4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylic acid was prepared starting from 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylic acid ethyl ester (4.3 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (100 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.5 g (86%); white solid; mp 185° C.; MS:410(M+H)+
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C]=[O:18].B(F)(F)F>C(OCC)(=O)C.CC(C)=O>[CH3:9][C:1]1[CH:2]=[CH:3][C:4]([C:7]([OH:18])=[O:8])=[CH:5][CH:6]=1
Reactant: [C]=O
Reactant: Cc1ccc(C=O)cc1
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)O)cc1

Procedure:
As described above, p-tolualdehyde, starting material of the present invention, is synthesized through reaction of toluene with carbon monoxide in the presence of a catalyst of HF--BF3 or HCl--AlCl3, and the resulting crude p-tolualdehyde is in a form of complex with the catalyst. After passage through the ordinary step of decomposing the complex, the crude p-tolualdehyde is purified to a purity of about 99% by distillation. Th resulting p-tolualdehyde has a sufficient quality as an industrial raw material for the ordinary reaction processes other than the process of the present invention. That is, even if the resulting p-tolualdehyde as such is autooxidized with air under pressure in a solvent of acetone or ethyl acetate in the absence of catalyst, a long induction period is required for the start of reaction, and even if the reaction is started, a sufficient reaction rate cannot be obtained. Even with a sufficient time, the per-p-toluic acid yield is low, and thus the resulting p-tolualdehyde of purity of about 99% is not industrially preferable as the starting material for the present invention.
Reaction SMILES: [OH-].[K+].CO.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[CH:11]=[CH:10]2>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[CH:11]=[CH:10]2
Reactant: CCOC(=O)C(C)c1ccc2cc(OC)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 25 °C

Procedure:
A solution of 6.0 g. of potassium hydroxide, 6 ml. of water and 60 ml. of methanol is added to the ethyl 2-(6-methoxy-2-naphthyl)propionate, and the mixture is heated at reflux for 45 minutes, cooled to ambient temperature, acidified and mixed with 60 ml. of water. Methanol is removed by evaporation in vacuo, and the resultant solution is extracted with two 60 ml. portions of methylene chloride. The combined methylene chloride extracts are evaporated to dryness to yield 2-(6-methoxy-2-naphthyl)propionic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.O1CCCC1.S(Cl)(Cl)(=O)=O.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>N1C=CC=CC=1>[F:19][C:3]1[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cccc(C(=O)c2c[nH]c3ncncc23)c1F
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncncc23)c1F
Temperature: 60 °C
Reaction time: 48 h

Procedure:
The (3-amino-2-fluoro-phenyl)-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (39, 20.0 mg, 0.078 mmol) is further reacted, for example, by adding 0.5 mL of tetrahydrofuran, 50 μL of pyridine, and an appropriate sulfonyl chloride (e.g. ethanesulfonyl chloride 40, 0.078 mmol). The reaction vial is allowed to stir at room temperature or in an oil bath at 60° C. After 1-3 days, the solvents are removed under vacuum, the residue dissolved in 0.5 mL dimethyl sulfoxide, and the material purified by C18 reversed phase HPLC, eluting with 20-100% acetonitrile (with 0.1% trifluoroacetic acid) in water (with 0.1% trifluoroacetic acid) at a flow rate of 20 mL/min. Ethanesulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-0036) was prepared by this protocol using ethanesulfonyl chloride 40 in step 4. MS (ESI) [M+H+]+=349.1.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:15]=[C:16]([C:26]2[O:27][C:28](=[O:38])[C:29]3[N:35]=[C:34]([Cl:36])[CH:33]=[C:32]([CH3:37])[C:30]=3[N:31]=2)[N:17]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1.O>C1COCC1.O.C(OCC)(=O)C>[Cl:36][C:34]1[N:35]=[C:29]([C:28]([N:4]([CH3:3])[NH:5][CH3:6])=[O:38])[C:30]([NH:31][C:26]([C:16]2[N:17]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:18]=[C:14]([Br:13])[CH:15]=2)=[O:27])=[C:32]([CH3:37])[CH:33]=1
Reactant: Cc1cc(Cl)nc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: CNNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CNN(C)C(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.3 %

Procedure:
1,2-Dimethylhydrazine dihydrochloride (176 mg) and potassium carbonate (366 mg) were suspended in THF (8 mL) and 10 drops of water, 2-[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-6-chloro-8-methyl-pyrido[3,2-d][1,3]oxazin-4-one (example 7, step 4) (300 mg) was added and the reaction mixture was stirred for 20 h at room temperature. Water and ethyl acetate were added, the layers were separated and the aqueous layer was 2× extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, chloroform/ethyl acetate=1:1, Rf=0.13) to afford 300 mg of the title compound of the formula
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].CC(O)(C)C.[CH:13]1[C:26]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][C:14]=1[C:27]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[N:30]=[C:29]([C:39]([F:42])([F:41])[F:40])[CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:13]1[C:26]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][C:14]=1[C:27]1[N:31]([C:32]2[CH:33]=[CH:34][C:35]([NH:38][S:2]([NH2:5])(=[O:4])=[O:3])=[CH:36][CH:37]=2)[N:30]=[C:29]([C:39]([F:42])([F:40])[F:41])[CH:28]=1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc3c(ccc4ccccc43)c2)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: NS(=O)(=O)Nc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc3c(ccc4ccccc43)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Chlorosulfonyl isocyanate (1 mmol) was added dropwise to an ice-cold solution of t-BuOH (1 mmol) in CH2Cl2, which was then added to a mixture of 4-(5-phenanthren-2-yl-3-trifluoromethyl-pyrazol-1-yl)-phenylamine (1 mmol), generated from step d, and triethylamine (1.5 mmol) in CH2Cl2. The reaction mixture was stirred at 25° C. for 1 h, and concentrated. The residue was treated with 20% trifluoroacetic acid in CH2Cl2 for 3 h, washed with 10% NaHCO3, dried, and concentrated. The residue was purified by flash column chromatograph to give 36 as off-white solid in 78% yield. 1H NMR (DMSO-d6) δ 7.35-7.15 (m, 7H), 7.46 (dd, J=1.8, 8.7 Hz, 1H), 7.73-7.65 (m, 2H), 7.88 (dd, J=9, 33.6 Hz, 2H), 8.00-8.05 (m, 1H), 8.09 (d, J=1.8 Hz, 2H), 8.82 (m 2H), 9.89 (br s, 1H). HRMS exact mass of C24H17F3N4O2S, (M+Na)+. 505.0922 amu; found: 505.0902 amu. Anal. calcd C 59.75, H 3.55, N 11.61; found C 59,98, H 3.71, N 11.51.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17]>CO>[Cl:4][C:5]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:2][NH:3][C:15]=1[CH2:16][CH3:17]
Reactant: CCC(=O)C(CCCCCCOc1ccc(OC)cc1Cl)C(=O)CC
Reactant: NN
Solvent: CO
Solvent: O
Product: CCc1n[nH]c(CC)c1CCCCCCOc1ccc(OC)cc1Cl

Procedure:
Hydrazine hydrate (15.7 ml, 0.32 m) was added over a 20 min. period to a slurry of 100 g. (0.272 m) of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-heptanedione in 300 ml of methanol. The internal temperature rose to a maximum of 50° C. during the addition. The reaction mixture was heated at reflux for one hour, and the solvent was then removed in vacuo. The residue was dissolved in 300 ml of methylene dichloride and the resulting solution was washed with three 100 ml portions of water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to leave 100 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-diethyl-1H-pyrazole as a colorless oil.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:34])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:68]([O:75][C:76]([N:78]1[CH2:83][CH2:82][NH:81][CH2:80][CH2:79]1)=[O:77])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:68]([O:75][C:76]([N:78]1[CH2:83][CH2:82][N:81]([C:31](=[O:32])[CH2:30][NH:29][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:34])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:28])[CH2:80][CH2:79]1)=[O:77])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: O=C(O)CNC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)OCc2ccccc2)CC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
To a solution of 3.34 g ({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-acetic acid in 100 ml DMF were added 1.9 ml DIPEA, 2.7 g HATU and 1.4 ml 1-benzyloxycarbonylpiperazine. After stirring for 1 h it was diluted with ethyl acetate and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/methanol gradient.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:13])[C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.C[O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:3]=[N+:4]([O-:13])[C:5]3[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:20][CH:19]=1)([OH:17])=[O:15]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: [O-][n+]1nc(Cl)nc2ccc(O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(-c2nc3ccc(O)cc3[n+]([O-])n2)cc1

Procedure:
3-chloro-7-hydroxybenzo[e][1,2,4]triazine 1-oxide (2 mmol) was mixed with 1.0 equivalent of 4-(methoxycarbonyl)phenylboronic acid and 2 equivalents of K2CO3 in 20 ml of 50% dioxane/water. A catalytic amount of Pd(PPh3)4 was added and the mixture was heated to reflux for 2 hours. The reaction was concentrated and re-dissolved in 20 ml water and 5 ml 1N NaOH was added to hydrolyze the ester. The mixture was extracted with DCM (3×10 ml). The aqueous layer was filtered and the filtrate was neutralized with 1N HCl to pH=5. The precipitate was filtered and washed with water and dried. 500 mg of product was obtained. 1H NMR (DMSO-d6 400 MHz): δ 11.38 (s, 1H), 8.44 (d, 2H), 8.15 (m, 3H), 7.67 (d, 1H), 7.60 (s, 1H). MS (ESI): m/z 284.5 [M+1]+.
Reaction SMILES: NO.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH:17]([NH2:19])[CH3:18])[CH2:14][CH2:15]O)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(O)(=O)C.CCCCCC>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:14][CH2:15][NH:19][CH:17]2[CH3:18])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(N)C(CCO)c1ccc(C(C)(C)C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: NO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1NCCC1c1ccc(C(C)(C)C)cc1

Procedure:
4.2 g (0.018 mol) of the aminoalcohol prepared in (c), 4.69 g (0.018 mol) of triphenylphosphine and 3.1 g (0.018 mol) of diethyl azodicarboxylate were dissolved in 100 mL THF. 2 drops of glacial acetic acid were added and the solution refluxed for two hours. During this time the initially red solution became yellow. On cooling, hexane was added dropwise until precipitation started. The mixture was then cooled in the freezer and the crystalline precipitate filtered off. The solvent was removed under reduced pressure and the residue taken up in chloroform and washed with water. The organic layer was dried with MgSO4, filtered, the solvent evaporated off under reduced pressure and the residue vacuum distilled (130° C. at 2 mm Hg) to afford 3.0 g (77 percent of theoretical) of the crude product in the form of a mobile oil. The NMR and IR spectra of the product were consistent with the expected structure and indicated a mixture of the two possible diastereoisomers were present in a ratio of 3:1.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C.[C:29]1([CH3:44])[CH:34]=[CH:33][C:32]([S:35]([O:38][C@H:39]([CH3:43])[C:40](Cl)=[O:41])(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[C:29]1([CH3:44])[CH:30]=[CH:31][C:32]([S:35]([O:38][C@H:39]([CH3:43])[C:40]([N:1]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[CH2:3][C@H:2]2[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:41])(=[O:36])=[O:37])=[CH:33][CH:34]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CC2=C(CCCC2)N1
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)N2C3=C(CCCC3)C[C@H]2C(=O)OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
Introduce into a reactor 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate and 1.5 litres of dichloromethane, and then bring the temperature of the reaction mixture to 0° C. and add 201 ml of diisopropylethylamine, followed by 202 g of (1R)-2-chloro-1-methyl-2-oxoethyl p-toluenesulphonate. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water. The solution of benzyl (2S)-1-[(2R)-2-{p-toluenesulphonyloxy}propionyl]-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate so obtained is used as it is in the following Step.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].N1(C2CCCCCCCCCC2)CCCCCCCCCN1.Cl[CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50]>CS(C)=O>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:12][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])=[O:11]
Reactant: C[Si](C)(C)CCl
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Solvent: CS(C)=O
Product: C[Si](C)(C)COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
18.1 g (0.05 mol) of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitro-benzoic acid are dissolved in 100 ml of dimethylsulphoxide. 9.8 g of diazabicycloundecane are added at 20° C., while cooling. The mixture is stirred for a further half hour. 7.4 g (0.06 mol) of chloromethyl-trimethylsilane are then added dropwise at 20° C., and the mixture is heated at 100° C. for 20 hours. The reaction mixture is thereafter concentrated, and the residue is taken up in toluene. The organic phase is washed successively with dilute hydrochloric acid, aqueous sodium hydroxide solution and water, and is then dried and evaporated down. The residue is dissolved in ligroin, the solution is stirred under active charcoal, the latter is filtered off under suction over kieselguhr, and the filtrate is then concentrated. 20 g (89% of theory) of trimethyl-silyl-methyl 5-(2-chloro-4-trifluoromethyl-phenoxy)-2-nitro-benzoate are obtained as a viscous oil.