Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[F:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:11]([CH3:10])(=[O:13])=[O:12]
Reactant: Nc1ccc(O)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(O)cc1F
Temperature: 0 °C
Reaction time: 72 h

Procedure:
4-Amino-3-fluorophenol (0.254 g; 2.0 mmol) was dissolved in 10 ml of dry pyridine under nitrogen and cooled to 0° C. Methanesulfonyl chloride (0.17 ml; 2.1 mmol) was added dropwise and stirred for three days at room temperature. The reaction was evaporated, 25 ml of toluene added and evaporated again. Toluene evaporation was repeated. Residue was dissolved in 25 ml of EtOAc, washed with 20 ml of water and evaporated to dryness to give red-brown solid N-(2-fluoro-4-hydroxyphenyl)methanesulfonamide. 1H NMR (400 MHz, DMSO-d6): 2.93 (3H, s), 6.56-6.66 (2H, m), 7.14 (1H, t, J=9.0 Hz), 9.17 (1H, s), 9.98 (1H, s).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[C-:8].[CH3:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>O1CCCC1>[CH2:18]([C:19]1[O:20][CH:8]=[N:7][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CCCCCC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCc1ocnc1C(=O)OC
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
50.1 g of potassium t-butoxide are dissolved in 500 ml of tetrahydrofuran, and 37.0 g of methyl α-isocyanoacetate are added dropwise thereto at -50° C. to -40° C. The mixture is stirred at the same temperature for 30 minutes. 50.0 g of n-caproyl chloride are gradually added to the mixture at -50° C. to -40° C., and the mixture is stirred at the temperature below -30° C. for 20 hours. After the reaction, the mixture is treated in the same manner as described in Preparation 1-(1). 40 g of 5-n-pentyl-4-methoxycarbonyloxazole are thereby obtained as oil. Yield: 54.3%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH2:9]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH2:22][CH:21](CS([O-])(=O)=O)[CH2:20][CH2:19]2)=[N:16][CH:17]=1)[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH2:9]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([O:1][C:2]3[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=3)[CH2:20][CH2:19]2)=[N:16][CH:17]=1)[CH2:10][CH3:11]
Reactant: O=c1cc(O)cc[nH]1
Reactant: CCCc1cnc(N2CCC(CS(=O)(=O)[O-])CC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Temperature: 100 °C
Yield: 40.6 %

Procedure:
A stirring suspension of 4-hydroxypyridin-2(1H)-one (5.23 g, 47.1 mmol, Aldrich), 1-(5-propylpyrimidin-2-yl)piperidin-4-ylmethanesulfonate (11.7 g, 39.2 mmol), potassium carbonate (12.5 g, 90.0 mmol, EMD) and DMSO (48 mL) was heated at 100° C. for 3 hours and then cooled to room temperature. The resulting mixture was diluted with H2O and extracted with EtOAc (2×). The organic layers were combined and concentrated in vacuo to a brown solid. The solid was purified by flash chromatography (SiO2, 100% EtOAc and then SiO2, 10% MeOH in CH2Cl2) to yield 5.00 g of desired product as an off-white solid. MS (ESI) 315 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][C:13]([OH:15])=[O:14].CO.Cl[CH2:19]Cl>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][C:13]([O:15][CH3:19])=[O:14]
Reactant: COc1cc([N+](=O)[O-])ccc1CC(=O)O
Reactant: ClCCl
Solvent: CO
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(2-methoxy-4-nitrophenyl)acetic acid (step 2, 1.2 g, 5.5 mmol) in methanol/dichloromethane (11 ml, 1/1) was added trimethylsillyldiazomethane (2 M, 5.6 ml, 11.8 mmol) and stirred for 10 min at room temperature. The mixture was quenched with saturated citric acid aqueous solution and the extracted with ethyl acetate (3×20 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to give 1.2 g of title compound as orange solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1>>[CH3:22][C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1I
Reactant: OB(O)c1cccnc1
Product: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cccnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 13 using 3-iodo-4-methyl-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 13.1) and pyridin-3-ylboronic acid to afford a yellow oil. UPLC-MS (Condition 1) tR=2.27 min, m/z=373.0 [M+H]+, m/z=371.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 7.36 (d, J=8.6 Hz, 2H) 7.49-7.55 (m, 2H) 7.83-7.92 (m, 2H) 7.83-7.92 (m, 2H) 7.94 (dd, J=7.8, 1.7 Hz, 1H) 8.63 (dd, J=4.8, 1.3 Hz, 1H) 8.67 (d, J=1.7 Hz, 1H) 10.37 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.B([O-])([O-])O.[Na+].[Na+]>CO>[N:10]1([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(O)c1
Agent: [Na+]
Agent: [O-]B([O-])O
Solvent: CO
Product: Oc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
3-Hydroxybenzaldehyde (III) (0.246 mol, 30 g) was dissolved into 150 ml of methanol. Piperidine (IV) (0.6 mol, 52 g) was added to the solution and the mixture was stirred at room temperature to dissolution. To the solution was added under ice cooling sodium hydrogen borate (0.247 mol, 9.4 g) while stirring over 1 hour, followed by continued stirring for 1 hour at room temperature. The reaction mixture was concentrated under vacuum. The residue was dissolved in 200 ml of 3N hydrochloric acid and washed twice with 50 ml of ethyl acetate. The water layer was alkalinized (pH 10) with about 50 ml of concentrated aqueous ammonia to deposit crystals. The crystals were collected by filtration, washed with water, dried under vacuum, and recrystallized from a mixed solvent of acetone and n-hexane, to obtain 40 g of 3-piperidinomethylphenol (V) (yield: 84.7%). m.p. 135°-138° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=O)#[N:2].[CH3:18][NH:19][NH2:20]>CCO>[NH2:2][C:1]1[N:19]([CH3:18])[N:20]=[C:4]([C@@H:6]2[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)CC#N
Reactant: CNN
Solvent: CCO
Product: Cn1nc([C@@H]2CCCN2C(=O)OC(C)(C)C)cc1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
tert-Butyl (2S)-2-(2-cyanoacetyl)pyrrolidine-1-carboxylate (5.8 g, 24.3 mmol), was dissolved in EtOH (100 mL). Methylhydrazine (1.8 mL, 35 mmol) was added and the resulting mixture was heated, for about 12 h, at about 80° C. After cooling to rt, the mixture was concentrated in vacuo. The residue was taken up in toluene (50 mL) and stirred overnight. The precipitated solid was collected by filtration and washed with toluene (2 mL) and diethyl ether to afford tert-butyl (2S)-2-(5-amino-1-methyl-pyrazol-3-yl)pyrrolidine-1-carboxylate (4.43 g, 16.3 mmol, 68%), as white solid: 1H-NMR (CDCl3, Bruker 400 MHz, rotamers) δ 1.35 and 1.45 (9 H, br. s), 1.70-2.24 (4 H, m), 3.36-3.53 (4 H, m), 3.60 (3 H, br s), 4.70-4.78 and 4.83-4.90 (1 H, m), 5.35 and 5.41 (1H, br s).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[I:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=2)[CH3:2].CN(C=O)C.[CH2:21](I)[CH3:22]>C(OCC)(=O)C>[CH2:21]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=2)[C:11]([I:12])=[C:3]1[CH2:1][CH3:2])[CH3:22]
Reactant: CCI
Reactant: CCc1[nH]c2cc([N+](=O)[O-])ccc2c1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1c(I)c2ccc([N+](=O)[O-])cc2n1CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
Add to a solution of 2-ethyl-3-iodo-6-nitro-1H-indole (0.30 g, 00.95 mmol) in anhydrous DMF (5 mL) sodium hexamethyldisilylamide (1.0M in THF, 1.0 mL, 1.00 mmol) dropwise followed by ethyl iodide (0.23 mL, 2.85 mmol) and stir 3 hours at ambient temperature. Quench the reaction with 1N HCl and add ethyl acetate. Wash the organic layer 2×1N HCl, 1× brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 20% ethyl acetate hexane to afford 0.28 g (86%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20](O)=[O:21])=[N:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[C:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)=[N:26][CH:27]=[C:28]([CH2:30][NH2:31])[CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[F:23][C:24]1[C:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)=[N:26][CH:27]=[C:28]([CH2:30][NH:31][C:20]([C:17]2[N:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[CH:15][CH:16]=2)=[O:21])[CH:29]=1
Reactant: NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)nc2)CC1
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: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid 49-4 (92 mg, 0.3 mmol), (3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methanamine 84-2 (81 mg, 0.3 mmol) and HATU (114 mg, 0.3 mmol) in DMF (1.5 mL) was added DIEA (0.15 mL, 0.9 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (100 mL), washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, and eluted with 5% methanol in dichloromethane to give tert-butyl 4-(6-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate 49-5 as a pale yellow oil. MS m/z 561.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24]Cl)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:26]#[N:27])=[C:4]([F:28])[CH:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[I-].[Na+]>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:26]#[N:27])=[C:4]([F:28])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cc1OCCCCl
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cc1OCCCN1CCOCC1
Yield: 98.1 %

Procedure:
A mixture of 1 g (2.38 mmol) of 4-(4-Chloro-2-fluoro-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile, 3.1 g (35.7 mmol) of morpholine, and 0.07 g of sodium iodide in 20 ml ethylene glycol dimethyl ether refluxed for 7 hr. The solvent was removed and the residue was mixed with warm ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and ether-hexane was added. One standing, the crystals were deposited giving 1.1 g of the title compound as a off-white solid: mass spectrum (electrospray, m/e) M+H 470.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8]([N+:13]([O-])=O)=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[H][H].O>[Ni].C(O)C>[NH2:13][C:8]1[C:9]([F:12])=[C:10]([F:11])[C:2]([Cl:1])=[C:3]([F:16])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: O=C(O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Nc1c(F)c(F)c(Cl)c(F)c1C(=O)O

Procedure:
63.9 g (0.25 mol) of 3-chloro-2,4,5-trifluoro-6-nitrobenzoic acid and 15 g of Raney nickel are suspended in 450 ml of ethanol. Hydrogenation is carried out at 10°-15° C. under a hydrogen pressure of 5-10 bar until the uptake of hydrogen has ended. The crude reaction mixture is poured onto 1 l of water. The carboxylic acid which has precipitated is dissolved by addition of 10% strength sodium hydroxide solution. When the catalyst has been filtered off with suction, a pH of 2-3 is established by addition of half-concentrated hydrochloric acid. The precipitate is filtered off with suction, washed with water and dried over KOH in a desiccator.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C@@H:17]([O:35][C:36]([N:38]2[CH2:43][CH2:42][CH:41]([N:44]3[CH2:50][CH2:49][C:48]4[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=4[NH:46][C:45]3=[O:55])[CH2:40][CH2:39]2)=[O:37])[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[CH:11][C:10]=1[CH3:56])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C@@H:17]([O:35][C:36]([N:38]2[CH2:39][CH2:40][CH:41]([N:44]3[CH2:50][CH2:49][C:48]4[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=4[NH:46][C:45]3=[O:55])[CH2:42][CH2:43]2)=[O:37])[C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]3)[CH2:24][CH2:25]2)=[O:19])=[CH:11][C:10]=1[CH3:56]
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(C(=O)O)CC3)CC2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(C(=O)O)CC3)CC2)cc(C)c1O

Procedure:
100 mg (0.13 mmol) 1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylic acid in 10 mL MeOH were combined with 30 mg 10% Pd/C and hydrogenated at 50° C. and 3 bar hydrogen for 2 h. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i. vac. The residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:5]([NH:6][CH:7]2[CH2:9][CH2:8]2)=[C:4]([O:15][CH3:16])[CH:3]=1>C(O)C.C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:5]([NH:6][CH:7]2[CH2:9][CH2:8]2)=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1NC1CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(Br)cc(N)c1NC1CC1
Temperature: 60 °C

Procedure:
4-bromo-N-cyclopropyl-2-methoxy-6-nitroaniline (1.05 g, 3.66 mmol) and iron powder (1.43 g, 25.6 mmol) were suspended in ethanol (19 mL) and acetic acid (9.5 mL). The stirred mixture was heated to 60° C. for 1 h and was diluted with EtOH (20 mL EtOH). Celite (15 g) was added and the mixture was filtered through a pad of Celite with EtOH. The filtrated was concentrated in vacuo. The crude residue was taken up in and concentrated once from 30 mL EtOH to afford crude 4-bromo-N1-cyclopropyl-6-methoxybenzene-1,2-diamine that was used immediately in the following step. LCMS-ESI+ (m/z): [M+H]+ calcd for C10H14BrN2O: 257.03; found: 257.15.
Reaction SMILES: F[C:2]1[C:9]([C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:19][CH3:20])[CH:3]=1.O.[NH2:22][NH2:23].O>O1CCCC1.CO>[F:17][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:2](=[CH:3][C:4]([O:19][CH3:20])=[C:5]([C:6]#[N:7])[CH:8]=3)[NH:23][N:22]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(F)c(C(=O)c2cccc(F)c2)cc1C#N
Reactant: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2[nH]nc(-c3cccc(F)c3)c2cc1C#N

Procedure:
A total of 203 mg of 4-fluoro-5-(3-fluoro-benzoyl)-2-methoxy-benzonitrile obtained in Production Example II-1-c was dissolved in 3 ml of tetrahydrofuran and 3 ml of methanol, 7.4 ml of hydrazine monohydrate was added at room temperature under stirring, and the mixture was stirred at room temperature for 14 hours. Then, water was added and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated. The resulting crystals were washed with diethyl ether, to give 172 mg of the title compound as pale yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:21])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=1.[OH-].[Na+].Cl.C(O)(=O)C>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:21])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccn2)cc1
Reaction time: 16 h
Yield: 86.6 %

Procedure:
A solution of methyl 4-(2-pyridylureido)phenylacetate (5.7 g, 20.0 mmol) in methanol (20 mL) was treated with 1 N NaOH (40 mL). The reaction was stirred for 16 h, then acidified carefully with 1 N HCl to pH 7 then with acetic acid to pH 3. The product was filtered and washed with methanol then ether to give 4-(2-pyridyl)ureidophenylacetic acid (4.7 g, 87%) as a white powder: 1H NMR (CD3SOCD3, 300 MHz, ppm) 10.62 (bs, 1H), 9.53 (bs, 1H), 8.39 (d, 1H), 7.82 (t, 1H), 7.63-7.55 (m, 1H), 7.33-7.27 (d, 2H), 7.14-7.08 (m, 1H), 3.62 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6](O)[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:22]([O:27]C)([O:25][CH3:26])[O:23][CH3:24]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])/[CH:6]=[C:7](\[CH2:9][CH2:10][CH2:11][CH3:12])/[CH2:8][P:22]([O:25][CH3:26])([O:23][CH3:24])=[O:27])[CH3:2]
Reactant: C=C(CCCC)C(O)C(NC=O)C(=O)OCC
Reactant: COP(OC)OC
Agent: O=S(Br)Br
Product: CCCC/C(=C\C(NC=O)C(=O)OCC)CP(=O)(OC)OC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-hexanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(hexen-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester,which is hydrolysed in a manner analogous to that described in Example 15 to 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester. Reaction of the 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite analogously to Example 1 yields E-2-formylamino-4-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: FC1C=CC(S(=O)(=O)NC(F)(F)F)=CC=1C(O)=O.[OH:19][CH:20]([CH:48]1[CH2:52][O:51]C(C)(C)[O:49]1)[CH2:21][NH:22][C:23](=[O:47])[C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([C:31](=[O:38])[NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:25]=1[O:39]CC1C=CC=CC=1.O>CO.Cl.[C].[Pd]>[OH:19][CH:20]([CH:48]([OH:49])[CH2:52][OH:51])[CH2:21][NH:22][C:23](=[O:47])[C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([C:31](=[O:38])[NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:25]=1[OH:39]
Reactant: CC1(C)OCC(C(O)CNC(=O)c2cc(F)cc(C(=O)NCC(F)(F)F)c2OCc2ccccc2)O1
Agent: [Pd]
Agent: Cl
Agent: O=C(O)c1cc(S(=O)(=O)NC(F)(F)F)ccc1F
Solvent: O
Solvent: CO
Product: O=C(NCC(O)C(O)CO)c1cc(F)cc(C(=O)NCC(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.95 g (13.5 mmol) of 2 benzyloxy-5-fluoro-3-(2,2,2-trifluoroethylcarbamoyl)-benzoic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in 20 ml of methanol, 5 ml of water and 5 ml of IN hydrochloric acid is added and stirred for 3 hours at room temperature. The solution is then adjusted to pH 6.3 by addition of anion exchanger Amberlite IRA 67, 200 mg of palladium-carbon (10%) is added and hydrogenated for 1 hour at normal pressure. The catalyst is then filtered off, the filtrate is evaporated to dryness in a vacuum and the residue is chromatographed on silica gel 60 (Merck) with dichloromethane/methanol. 3.76 g (9.77 mmol)=72.4% of the theoretical yield of the compound is obtained as an amorphous solid.
Reaction SMILES: [H-].[K+:2].[H-].[Na+].CC1C=CC(N)=CC=1.[CH3:13][C:14]1[CH2:18][C:17]([CH3:19])=[C:16]([CH3:20])[C:15]=1[CH3:21]>O1CCCC1>[CH3:13][C:14]1[CH:18]([K:2])[C:17]([CH3:19])=[C:16]([CH3:20])[C:15]=1[CH3:21]
Reactant: CC1=C(C)C(C)=C(C)C1
Reactant: [K+]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccc(N)cc1
Solvent: C1CCOC1
Product: CC1=C(C)C([K])C(C)=C1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium hydride (containing mineral oil; the content of sodium hydride: 35%) (3.00 g) was suspended in tetrahydrofuran (18 ml), and then 4-methylaniline (0.056 g) was dropwise added to the suspension at 10° C., followed by stirring for 10 minutes. Thereafter, the solution of tetramethylcyclopentadiene (1.22 g) dissolved in tetrahydrofuran (6 ml) was dropwise added to the suspension, and heated to 25° C., followed by stirring for one hour. Thus, tetramethylcyclopentadienylpotassium was obtained. To this solution, the solution of (2-allyloxy-3-tert.-butyl-5-methylphenyl)chlorodimethylsilane (3.99 g; purity: 70.7%; pure compound: 2.82 g) dissolved in tetrahydrofuran (3 ml) was dropwise added, followed by stirring for one hour.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.C(N(CC)C(C)C)(C)C.[NH:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1>C(#N)C>[F:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([F:1])[C:7]=1[N:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: C1CSCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1

Procedure:
A solution of 3,4,5-trifluoronitrobenzene (5.00 g, 28.24 mmol) in acetonitrile (60 mL) was cooled to 0° C. and treated with N,N-diisopropylethylamine (7.38 mL, 42.35 mmol) followed by thiomorpholine (2.98 mL, 29.65 mmol). The ice bath was removed and the reaction mixture stirred at room temperature under nitrogen for approximately 24 hrs, during which additional thiomorpholine (0.1 eq) was added. The solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate, washed with 1N hydrochloric acid (until the washings were acidic), saturated aqueous sodium bicarbonate and saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound, mp 104-105° C.
Reaction SMILES: C([NH:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[S:8](=[O:17])(=[O:16])[C:7]2[S:18][C:19]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:20][C:6]1=2)(=O)C.CO.[ClH:27].CCOCC>C(O)C>[ClH:27].[NH2:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[S:8](=[O:17])(=[O:16])[C:7]2[S:18][C:19]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:20][C:6]1=2
Reactant: COCCCC1CC(NC(C)=O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: CCOCC
Product: COCCCC1CC(N)c2cc(S(N)(=O)=O)sc2S1(=O)=O

Procedure:
A solution of 4-acetamido-5,6-dihydro-6-(3-methoxypropyl)-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (7.3 g), (prepared employing substantially the same procedures as described in Example 10, Steps A through I), methanol (70 ml.) and 6N HCl (70 ml.) was heated at reflux for 18 hours then evaporated at reduced pressure to a volume of 20 ml. The reaction mixture was made basic with aqueous NaHCO3 and extracted wth ethyl acetate (2×80 ml.). The organic phase was washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was crystallized from ethanol (20 ml.) to remove the cis isomer and the product thus obtained was redissolved in hot ethanol, treated with an excess of ethanolic HCl and ether to provide 1.0 g of the title compound which melts at 262° C.