Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]=[C:15]=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][S:9]([CH2:12][Cl:13])(=[O:11])=[O:10].[CH3:17][NH:18][CH3:19].O.ClC1C=C(N(C)C(NC)=O)C=CC=1OS(CCl)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([N:18]([CH3:19])[CH3:17])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][S:9]([CH2:12][Cl:13])(=[O:11])=[O:10]
Reactant: O=C=Nc1ccc(OS(=O)(=O)CCl)c(Cl)c1
Reactant: CNC
Agent: CNC(=O)N(C)c1ccc(OS(=O)(=O)CCl)c(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=O)Nc1ccc(OS(=O)(=O)CCl)c(Cl)c1

Procedure:
20 g of 3-chloro-4-chloromethylsulfonyloxy-phenylisocyanate (alternative name: chloromethanesulfonic acid 2-chloro-4-isocyanato-phenyl ester) were dissolved in 100 ml of acetone and 10 ml of a 45% strength dimethylamine solution were added, whilst cooling. After addition of water, N-(3-chloro-4-chloromethylsulfonyloxy-phenyl)-N,N'-dimethylurea precipitated: it was filtered off and dried.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]2[N:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:7]=[C:6]([CH3:21])[C:5]1=2.[CH3:22]I>O1CCCC1>[CH3:22][O:3][CH:4]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]2[N:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:7]=[C:6]([CH3:21])[C:5]1=2
Reactant: Cc1nn(-c2ccccn2)c2c1C(O)CC(C)(C)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CC(C)(C)Cc2c1c(C)nn2-c1ccccn1
Reaction time: 0.08 h
Yield: 81.3 %

Procedure:
0.11 g (2.04 mmol) of 55% sodium hydride in oil were added to a solution of 4-hydroxy-1-(2-pyridyl)-3,6,6-trimethyl-4,5,6,7-tetrahydroindazole (0.35 g, 1.36 mmol), prepared as described in example 12, in dry tetrahydrofuran (5 ml) maintained under magnetic stirring and inhert atmosphere at 0° C. After 5 minutes, 0.13 ml (2.04 mmol) of methyl iodide were added, the reaction mixture was allowed to warm to room temperature and after 3.5 hours further 0.13 ml of methyl iodide were added. Stirring was continued for about 24 hours, additional sodium hydride (0.11 g) and methyl iodide (0.13 ml) were added and after 2.5 hours the solvent was evaporated. The residue was chromatographed on silica gel (cyclohexane:ethyl acetate=90:10), to yield the title compound as a colourless solid (0.3 g, 82%): m.p. 66-68° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:40])([F:39])[C:20]1[C:25]([C:26](O)=[O:27])=[CH:24][N:23]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:21]=1.COC(=O)C1C(C(F)(F)F)=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:26]([C:25]2[CH:24]=[N:23][C:22]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)=[CH:21][C:20]=2[C:19]([F:18])([F:39])[F:40])=[O:27])=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Agent: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)cc2C(F)(F)F)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 108B]) by saponification in analogy to example 53B]) to give 2-methyl-2-[4-({[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as amorphous light yellow solid.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Br:16][CH2:17][C:18](Br)=[O:19].O>ClCCl>[Br:16][CH2:17][C:18]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([F:9])[C:2]=1[F:1])=[O:19]
Reactant: O=C(Br)CBr
Reactant: Nc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)Nc1cccc(F)c1F
Reaction time: 5 h

Procedure:
To a mixture of 2,3-difluoroaniline (630 mg) and potassium carbonate (1.01 g) in dichloromethane (30 mL) was added bromoacetyl bromide (0.86 mL). The reaction mixture was stirred for 5 h then water was added and the phases separated. The organic layer was concentrated to give a 2:1 mixture of the sub-titled compound and bromoacetyl bromide. The residue was dissolved up in dichloromethane and washed with water. The volatiles were evaporated to give the sub-titled compound (1.15 g) as an off-white solid that was used without further purification.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[F:12])[CH2:7]Br>CO>[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[F:12])[CH2:7][CH2:1][NH2:2]
Reactant: CN
Reactant: Fc1ccc(CBr)cc1Br
Solvent: CO
Product: NCCc1ccc(F)c(Br)c1
Reaction time: 91 h
Yield: 58.9 %

Procedure:
To 40% solution of methylamine in methanol (100 ml) with being stirred under ice cooling was added dropwise 3-bromo-4-fluorobenzylbromide (13.04 g; 48.7 mmol) in methanol (10 ml). The mixture was brought to room temperature, and stirred for 91 hours. The reaction mixture was concentrated under reduced pressure, and the residue was taken up in water. The mixture was alkalinized with sodium hydroxide, followed by extraction with ether (160 ml). The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:0→10:1), to thereby yield 6.25 g of the target compound (yield: 58.9%).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:4]2[C:3](=[O:8])[C@H:2]([CH3:1])[NH:6][C:5]2=[O:7])=[CH:13][CH:12]=1
Reactant: COc1ccc(CCl)cc1
Reactant: C[C@@H]1NC(=O)NC1=O
Product: COc1ccc(CN2C(=O)N[C@@H](C)C2=O)cc1

Procedure:
Using (S)-5-methylimidazolidine-2,4-dione (2.00 g) and 4-methoxybenzyl chloride (2.85 mL) and by the reaction and treatment in the same manner as in Preparation Example 51, the title compound (3.13 g) was obtained.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1.C(N(CC)CC)C>C(O)CCC>[Cl:14][C:15]1[N:16]=[N:17][C:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)nn2)CC1

Procedure:
A mixture of 13.52 g of tert-butyl 1-piperazinecarboxylate, 10.81 g of 3,6-dichloropyridazine and 20 ml of triethylamine in 100 ml of n-butanol is heated at reflux for 5 hours. It is concentrated under vacuum and the residue is chromatographed on silica gel, eluting with a DCM/AcOEt (90/10; v/v) mixture. This gives 14 g of the expected product, which is used as it is.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C[O-].[Na+].[CH3:29][O:30][CH:31]([O:35][CH3:36])N(C)C>CO>[CH3:29][O:30][CH:31]([O:35][CH3:36])[N:23]1[CH2:24][CH2:25][CH:20]([C:16]2[NH:15][CH:19]=[CH:18][N:17]=2)[CH2:21][CH2:22]1
Reactant: COC(OC)N(C)C
Reactant: c1c[nH]c(C2CCNCC2)n1
Agent: C[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: COC(OC)N1CCC(c2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of the dihydrochloride salt of 4-(1H-imidazol-2-yl)piperidine (0.448 g, 0.002M) in methanol (15 ml) which contained sodium methoxide (0.004M) was stirred at room temperature for about 5 minutes and dimethylformamide dimethyl acetal (10 ml) was added and the mixture was heated at 80° C. for 8 hrs. The excess of dimethylformamide dimethylacetal was removed to give 4-(1H-imidazol-2-yl)-1-piperidine carboxaldehyde dimethylacetal. This acetal was then dissolved in 6 ml of chloroform. To a mixture of 6-aminopenicillanic acid (0.388 g, 0.0018M) and diisopropylethylamine (0.2 ml) in CHCl3 (20 ml) was added the chloroform solution of the above piperidine carboxaldehyde dimethylacetal at 0° C. The reaction was stirred at 0° C. for 1 hr and room temperature for 3 hrs. After this period, the solvent was removed and the residue dissolved in water (15 ml). The aqueous solution, washed with ethylacetate, was acidified to pH 3 with dil. HCl and purified on Sephadex LH 20 to give [2S-(2alpha,5alpha,6beta)]-6-[[[4-(1H-imidazol-2-yl)-1-piperidinyl)methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride trihydrate (0.245 g, 26% yield).
Reaction SMILES: [F:1][CH:2]([F:36])[CH2:3][N:4]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[O:34][CH3:35])C(=O)C1C=C(C(F)(F)F)N=C(C(F)(F)F)C=1.[F:37]C1C(F)=CC(B(O)O)=C(OC)C=1>CCCCCCC.CCOC(C)=O>[F:1][CH:2]([F:36])[CH2:3][NH:4][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[C:31]([F:37])[C:30]([F:33])=[CH:29][C:28]=1[O:34][CH3:35]
Reactant: COc1cc(F)c(F)cc1B(O)O
Reactant: COc1cc(F)ccc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-amine (example 153, intermediate b) and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown solid (73%). MS (ESI): m/z=301.10 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([OH:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.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>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:24]2[CH:25]=[CH:26][C:21]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[N:4][C:3]=1[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
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: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)nc1C(=O)Nc1cccnc1
Temperature: 75 °C
Yield: 75.7 %

Procedure:
Pd(PPh3)4 (1.05 g, 0.91 mmol) was added to a to a solution of 3-amino-6-bromo-N-pyridin-3-ylpyrazine-2-carboxamide (2.0 g, 6.8 mmol), 4-carboxyphenylboronic acid (1.12 g, 6.7 mmol), and sodium carbonate (2.88 g, 27.2 mmol) in tetrahydrofuran/water, (1:1, 240 mL), and the resulting mixture was heated at 75° C. for 16 days. The solvent was evaporated and the residue dissolved in water. The aqueous phase was washed with ethyl acetate and then neutralized (pH 7) using HCl (10% aq.). The formed crystals were filtered off and dried in vacuo to give 1.7 g (77% yield) of the title compound: MS (ES) m/z 336 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.B(O)O.[C:40]([O-:43])([O-])=O.[Na+].[Na+].CO>O1CCOCC1.C(Cl)Cl.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>[CH3:33][C:32]1[CH:31]=[C:30]([CH3:34])[NH:29][C:28](=[O:35])[C:27]=1[CH2:26][NH:25][C:24]([C:4]1[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[CH:7]=[C:2]([C:10]2[CH:11]=[N:12][C:13]([CH:40]=[O:43])=[CH:14][CH:9]=2)[CH:3]=1)=[O:36]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 152.6 %

Procedure:
Tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl) carbamoyl)-2-methylphenyl)(methyl)amino)piperidin-1-carboxylate (0.5 g, 0.892 mmol), (6-formylpyridin-3-yl))boronic acid (0.31 g, 1.33 mmol) and Pd(PPh3)4 (0.103 g, 0.082 mmol) in 1,4-dioxane (10 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (0.34 g, 3.21 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using 5% MeOH in DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-formylpyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate (0.40 g, 87.9%).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28]([NH2:30])=[O:29]>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:30]=[C:28]([CH2:27][C:21]3[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[O:29][CH:15]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Reactant: NC(=O)Cc1c(Cl)cccc1Cl
Product: O=C(O)COc1ccc(Br)cc1-c1coc(Cc2c(Cl)cccc2Cl)n1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 2-(2,6-dichlorophenyl)acetamide according to GP5 and GP3: LC/MS (an 10p8) Rt 2.75 min, m/z 456/458/460 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17]/[CH:18]=[N:19]/[S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])=[CH:11][CH:10]=2)[CH2:4][O:3]1.[CH:27]([Mg]Br)=[CH2:28]>C1COCC1>[CH3:1][C:2]1([CH3:26])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH:18]([NH:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH:27]=[CH2:28])=[CH:13][CH:14]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCC/C=N/S(=O)C(C)(C)C)cc2)O1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(CCCc1ccc(OC[C@@H]2COC(C)(C)O2)cc1)NS(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-Methyl-propane-2-sulfinic acid [4-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-but-(E)-ylidene]-amide (4.51 g, 11.8 mmol) in THF (120 ml) at 0° C. is added vinylmagnesium bromide (11.8 ml of a 1 M solution in THF, 11.8 mmol) dropwise. After addition is complete, the mixture is stirred at 0° C. for 30 minutes then quenched with sat. aq. NH4Cl solution (20 ml). This mixture is allowed to warm to room temperature and diluted with water (50 ml) and EtOAc (50 ml). The organic phase is separated, dried (MgSO4) and concentrated in vacuo. Purification by chromatography (SiO2, EtOAc/iso-hexane) affords 2-Methyl-propane-2-sulfinic acid {4-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-1-vinyl-butyl}-amide as a mixture of diastereomers as a gum; [M+H]+ 410.39
Reaction SMILES: [C:1]([O:10][CH2:11][C@@H:12]([O:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:13][S:14][CH2:15][C@H:16]([NH:24][C:25]([O:27][CH2:28][CH:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[C:17]([O:19]C(C)(C)C)=[O:18])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O[C@H](COC(=O)CCCCCCCCCCC)CSC[C@@H](C(O)=O)NC(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=O)CCCCCCCCCCC>>[CH:31]1[C:30]2[CH:29]([CH2:28][O:27][C:25](=[O:26])[NH:24][C@H:16]([C:17]([OH:19])=[O:18])[CH2:15][S:14][CH2:13][C@H:12]([O:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:11][O:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1
Reactant: CCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCC
Agent: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Product: CCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCC

Procedure:
The product was prepared from (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropylthio)propane-1,2-diyl dioctanoate by following the procedure described for compound 6.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([CH:8]1[CH2:13][CH:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=1[Cl:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1c(Cl)cccc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1c(Cl)cccc1Cl)N1CCC(NCc2ccnc3ccccc23)CC1Cc1ccccc1

Procedure:
138 mg (0.230 mmol) of (2R*,4S*)-2-benzyl-1-(2,6-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 40 with 18.4 mg (0.460 mmol) of sodium hydroxide in 1.5 ml of tetrahydrofuran and 1.5 ml of methanol. The title compound ##STR68## is obtained (56 mg, 48%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.50, FD-MS: M+ =503, 505.
Reaction SMILES: C(C1C=NC(C2C=CC(O[CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:46])([F:45])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=CC=2)=NC=1)CCCCCCC.[CH2:49]([O:57][C:58]1[CH:59]=[N:60][C:61]([C:64]2[CH:69]=[CH:68][C:67]([OH:70])=[CH:66][CH:65]=2)=[N:62][CH:63]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]>CN(C)C=O>[CH2:49]([O:57][C:58]1[CH:63]=[N:62][C:61]([C:64]2[CH:65]=[CH:66][C:67]([O:70][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:47])([F:48])[C:32]([F:45])([F:46])[O:33][C:34]([F:43])([F:44])[C:35]([F:41])([F:42])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=[CH:68][CH:69]=2)=[N:60][CH:59]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-chloropropane (5.2 g, 10.9 mmol, Example 24) with 5-octyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 10.0 mmol) in dimethylformamide and stirring at 120° C. overnight. The resulting product was further purified by Kugelrohr distillation (b.p. 195-210° C. at 0.3 torr), followed by recrystallization from ethanol and additional distillation (yield of 3.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1>CO.O.O.[Sn](Cl)Cl.Cl>[NH2:16][C:15]1[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COc1ccc(Nc2ncccc2N)cc1
Reaction time: 3 h
Yield: 89.5 %

Procedure:
6.6 g (27 mmol) of 2-(4-methoxyphenyl)amino-3-nitropyridine was dissolved in methanol (150 mL). A solution in which tin (II) chloride dihydrate was dissolved in 12 N hydrochloric acid (40 mL) was prepared, and this solution was added dropwise to the reaction solution at 0° C. over 5 minutes. The reaction solution was returned to room temperature, and then stirred for 3 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and water (100 mL) was added. The reaction solution was adjusted to pH 12 using a 10% aqueous solution of sodium hydroxide, subsequently filtered, and extracted with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the inorganic matter was separated by filtration. The solvent was distilled off under reduced pressure, to obtain 5.2 g (yield: 90%) of 3-amino-2-(4-methoxyphenyl)aminopyridine as orange-colored crystals.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([O:9][CH2:10]/[C:11](/[C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)=[C:12](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[C:13]([OH:15])=[O:14])=[O:8].[CH2:32](I)[CH3:33].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([O:9][CH2:10]/[C:11](/[C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=1)=[C:12](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[C:13]([O:15][CH2:32][CH3:33])=[O:14])=[O:8]
Reactant: CCI
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCBr)=C(/C(=O)O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C(\COC(=O)OCCCCBr)c1ccc(S(C)(=O)=O)cc1)c1ccccc1

Procedure:
A solution of 5 mmol of (2Z)-4-{[(4-bromobutoxy)carbonyl]oxy}-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid with 3 mL of EtI in 30 mL of DMF was stirred with 5 mmol of K2CO3 at rt for 30 min. The reaction was quenched with sat. NH4Cl/H2O, extracted with EtOAc, Dried over Na2SO4, evaporated, and purified by flash chromatography (5–50% EtOAc/hexane) to afford 2.7 g of the titled compound. 1H NMR (acetone-d6, 500 MHz): δ 7.80 (d, 2 H), 7.48 (d, 2 H), 7.22–7.17 (m, 3 H), 7.15–7.08 (m, 2 H), 5.30 (s, 2 H), 4.32 (m, 4 H), 3.54 (t, 2 H), 3.12 (s, 3 H), 1.95–1.84 (m, 2 H), 1.83–1.70 (m, 2 H) 1.31 (t, 3 H).