Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:28][OH:29].O>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([NH:28][OH:29])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(CC(=O)NO)N2Cc3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (15.0 g, 42.7 mmol) and N,N′-carbonyldiimidazole (7.27 g, 44.8 mmol) in tetrahydrofuran (50 mL) under nitrogen was stirred at room temperature for 2 hours. To the resulting solution was added hydroxylamine hydrochloride (3.86 g, 55.5 mmol). The resulting suspension was stirred for 18 hours. To the suspension was added water (150 mL) and stirring was continued for 1 hour. The suspension was filtered, the solid was washed with water (5×30 mL) and ether (2×20 mL), and then was dried in a vacuum oven overnight (60° C., <1 torr) to give 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propion-amide as a white solid (13.0 g, 82% yield): mp, 167-168° C.; 1H NMR (DMSO-d6) δ1.29 (t, J=6.9 Hz, 3H, CH3) 2.81-2.86 (m, 2H, CH2), 3.72 (s, 3H, CH3), 3.96-4.04 (m,2H, CH2), 4.13 (d, J=17.5 Hz, 1H, CHH), 4.54 (d, J=17.5 Hz, 1H, NCHH), 5.73 (t, J=7.9 Hz, 1H, NCH), 6.84-6.92 (m, 3H, Ar), 7.43-7.68 (m, 4H, Ar), 8.83 (br.s, 1H, OH), 10.61 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.68, 35.04, 46.22, 51.20, 55.44, 63.73, 111.85, 112.19, 119.21, 122.78, 123.43, 127.83, 131.29, 131.85, 132.27, 141.67, 147.85, 148.42, 165.99, 166.82. Anal. Calcd for C20H22N2O5: C, 64.85; H, 5.99; N, 7.56. Found: C, 64.73; H, 6.17; N, 7.36.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][N:16]=[C:17]([CH3:18])[C:11]=2[N:10]=[C:9]1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:27]Br.CCOC(C)=O>C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][N:16]=[C:17]([CH3:18])[C:11]=2[N:10]=[C:9]1[CH:19]([Br:27])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1nc2c(C)nsc2c(=O)n1Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCC(Br)c1nc2c(C)nsc2c(=O)n1Cc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 6-benzyl-3-methyl-5-propyl-6H-isothiazolo[4,5-d]pyrimidin-7-one (method 59) (208 mg, 0.69 mmol) and sodium acetate (0.5 g, 5 mmol) in acetic acid (10 mL) at 100° C., a solution of the bromine (0.232 g, 1.46 mmol) in acetic acid (20 mL) was added dropwise [The next drop of Bromine was added only after the previous drop had reacted completely by monitoring the decolorization] over a period of 30 min. The reaction mixture was cooled after the addition and the TLC (eluent 10% EtOAc in hexanes) and MS showed the complete disappearance of the SM and only the product. The reaction mixture was poured into ice water and extracted with EtOAc (3×30 mL) and the organic layers were combined and washed with 2% sodium thiosulfate solution (30 mL), water (50 mL), brine (50 mL) and dried (Na2SO4). Concentration of the organic layer provided the product and it was pure enough to be used in the next step. Yield 260 mg (99%). 1H NMR (300 MHz) δ 0.77 (t, 3H), 2.20-2.54 (m, 2H), 2.70 (s, 3H), 4.67 (t, 1H), 4.95 (d, 1H), 6.25 (d, 1H) 7.10-7.19 (m, 2H), 7.30-7.39 (m, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[CH2:16][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH:24]([NH:27][C:28](=[O:42])[CH:29]([CH:39]([OH:41])[CH3:40])[CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25][CH3:26])=[N:19][N:18]=1.C(N(CC)CC)C>>[C:39]([CH:29]([CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:28]([NH:27][CH:24]([C:20]1[C:21](=[O:23])[NH:22][C:17]([CH2:16][C:15]2[CH:43]=[CH:44][C:45]([O:46][CH3:47])=[C:13]([O:12][CH3:11])[CH:14]=2)=[N:18][N:19]=1)[CH2:25][CH3:26])=[O:42])(=[O:41])[CH3:40]
Reactant: CCC(NC(=O)C(CCCc1ccccc1)C(C)O)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCC(NC(=O)C(CCCc1ccccc1)C(C)=O)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O

Procedure:
Analogously to Example 40A, 440 mg (305 mmol) of oxalyl chloride, 550 mg (7.00 mmol) of dimethyl sulphoxide, 920 mg (1.82 mmol) of N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}-2-(1-hydroxyethyl)-5-phenyl-pentanamide and 1.82 g (18 mmol) of triethylamine are reacted to give 2-acetyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}-5-phenylpentanamide.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[C:4]([OH:5])[CH:3]=1.O.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:5][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:6]=1[O:7][CH3:8])[C:1]([O:12][CH3:14])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(C(=O)O)cc1O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(OC)c(O)c1

Procedure:
A 25 g quantity of isovanillic acid was suspended in 250 ml of methanol, and 1.5 g of p-toluenesulfonic acid monohydrate was added. The mixture was heated and refluxed overnight. After completion of the reaction, methanol was distilled off under reduced pressure. The residue was neutralized with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. After washing with saturated brine twice, the organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 24.5 g of white crystalline methyl 3-hydroxy-4-methoxybenzoate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:5]([F:21])[CH:4]=1)[CH3:2].[CH3:22][C:23]1([CH3:31])[O:28][CH2:27][CH:26]([O:29][NH2:30])[CH2:25][O:24]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[CH3:22][C:23]1([CH3:31])[O:28][CH2:27][CH:26]([O:29][NH:30][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([F:19])[C:10]=2[NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[F:21])[CH2:25][O:24]1
Reactant: CC1(C)OCC(ON)CO1
Reactant: CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(Nc2c(C(=O)NOC3COC(C)(C)OC3)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a stirring solution of the product of Example 1, Step D, 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid (0.480 g, 1.626 mmol) in dichloromethane (15 mL) is added the product of Example 33, Step B, O-(2,2-dimethyl-[1,3]dioxan-5-yl)-hydroxylamine (0.287 g, 1.951 mmol), triethylamine (0.41 mL, 2.927 mmol), and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.02 g, 1.951 mmol) and allowed to stir at ambient temperature for 75 minutes. The reaction mixture was concentrated in vacuo and the affording residue was partitioned between ethyl acetate and water. The organic layers were washed twice with saturated sodium carbonate solution and twice with brine. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo. N-(2,2-Dimethyl-[1,3]dioxan-5-yloxy)-2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-benzamide was isolated via silica column chromatography in 4:1 hexanes/ethyl acetate affording a white foam (0.423 g, 61.4%).
Reaction SMILES: [NH2:1][C:2](=[C:10]([C:15](=O)[CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.CNS(C)(=O)=O.C(O)(C)(C)C.[C:31]([N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])#[N:32].CC(C)([O-])C.[Na+]>>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:32]=[C:31]([N:33]([S:34]([CH3:37])(=[O:36])=[O:35])[CH3:38])[N:1]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Reactant: CN(C#N)S(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: CNS(C)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 50 °C
Reaction time: 19.9 h
Yield: 68.1 %

Procedure:
2.97 g (11.2 mmol) of methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate were introduced into 2.45 g (22.4 mmol) of N-methyl-methanesulphonamide (MMSA) and 4.19 g (55.9 mmol) of tert-butanol together with 4.51 g (36.6 mmol) of N-cyano-N-methylmethanesulphonamide (CMMSA). 2.22 g (22.4 mmol) of sodium tert-butoxide were added to this suspension at room temperature in portions. An orange-coloured suspension was obtained. It was heated to 50° C. and stirred at 50° C. for 19.9 h. The suspension was poured onto 20 g of ice water, and the precipitate was filtered off and washed with water (2×5 ml). After drying in a high vacuum, 2.91 g of methyl 4-(4-fluoro-phenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methyl-amino)pyrimidine-5-carboxylate were obtained in the form of a pale beige solid having a concentration of 76.4% (HPLC), which corresponds to a yield of 52.1%.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:11]([C:13]([OH:15])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][CH:25](Cl)[CH3:26])[CH3:23]>C(Cl)Cl>[C:1]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:11]([C:13]([O:15][CH:22]([O:24][CH2:25][CH3:26])[CH3:23])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(c1ccccc1)C(O)C(=O)O)c1ccccc1
Reactant: CCOC(C)Cl
Solvent: ClCCl
Product: CCOC(C)OC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1

Procedure:
reacting said N-benzoyl-3-phenyl-isoserine with 1-chloroethyl ethyl ether and tertiary amine in methylene chloride to form-N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine for the C13 side chain;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10](O)=[O:11])=[C:4]([F:13])[CH:3]=1.S(Cl)([Cl:16])=O.CN(C=O)C>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10]([Cl:16])=[O:11])=[C:4]([F:13])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1c(F)cc(Br)cc1F
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1c(F)cc(Br)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a solution of 2-(4-bromo-2,6-difluorophenyl)acetic acid (0.3 g, 1.195 mmol) in sulfurous dichloride (5 mL, 1.195 mmol) was added DMF (9.25 μL, 0.120 mmol). The resulting mixture was stirred at 60° C. After 2 h, LCMS analysis showed the starting material had disappeared and the solvent was removed in vacuo to give 2-(4-bromo-2,6-difluorophenyl) acetyl chloride (0.35 g, 0.832 mmol, 69.6% yield). To a solution of 4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (0.347 g, 1.113 mmol) and Et3N (0.225 g, 2.227 mmol) in DCM (30 mL) was added 2-(4-bromo-2,6-difluorophenyl)acetyl chloride (0.3 g, 1.113 mmol). The resulting mixture was stirred at 25° C. After LCMS analysis showed the starting material had disappeared, the mixture was washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC (PE/EA=3/1) to give N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluoro phenyl)acetamide (110 mg, 0.196 mmol, 17.6% yield): 1H NMR (400 MHz, CD3OD) δ 7.81 (d, J=2.8 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.32-7.25 (m, 7H), 7.15 (d, J=8.8 Hz, 1H), 4.61 (s, 2H), 4.23 (t, J=4.6 Hz, 2H), 3.84 (t, J=4.6 Hz, 2H), 3.77 (s, 2H); ES-LCMS m/z 546.0 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[CH3:32][N:33]1[CH:37]=[N:36][N:35]=[C:34]1[CH:38]([NH2:40])[CH3:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:40][CH:38]([C:34]1[N:33]([CH3:32])[CH:37]=[N:36][N:35]=1)[CH3:39])=[O:4]
Reactant: CC(N)c1nncn1C
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1)c1nncn1C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 17 mg, 0.039 mmol), (R/S)-1-(4-methyl-4H-1,2,4-triazol-3-yl)ethanamine (7.46 mg, 0.059 mmol), 4-methylmorpholine (15.95 mg, 0.158 mmol), and HATU (19.48 mg, 0.051 mmol) were dissolved in DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=12.2 min) to provide 2-hydroxy-N-(1-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (8 mg, 0.014 mmol, 34.6% yield) as a racemic mixture of diastereomers. LCMS=540.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.90 (1 H, s), 8.16 (2 H, d, J=8.36 Hz), 7.52-7.77 (7 H, m), 5.36 (1 H, q), 5.21 (1 H, s), 3.62 (3 H, s), 1.69 (3 H, d, J=7.04 Hz); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:17]([OH:23])=[CH:16][C:15]=2[CH:24]([CH3:26])[CH3:25])=[O:12])[CH2:6][CH2:5]1.[CH:27](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C.[OH-].[Na+]>C(#N)C.CO>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:19]([CH:20]([CH3:21])[CH3:22])=[CH:18][C:17]([O:23][CH3:27])=[CH:16][C:15]=2[CH:24]([CH3:26])[CH3:25])=[O:12])[CH2:6][CH2:5]1
Reactant: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CN1CCN(CCO)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: COc1cc(C(C)C)c(NC(=O)CN2CCN(CCO)CC2)c(C(C)C)c1
Reaction time: 12 h
Yield: 82.8 %

Procedure:
Into a solution of the acetamide (640 mg, 1.76 mmol) in a mixed solvent (10 ml) of methanol and acetonitrile (1:4) were dropped N,N-diisopropylethylamine (0.43 ml, 2.46 mmol) and trimethylsilyl diazomethane (1.23 ml, 2.46 mmol) and the mixture was stirred for 12 hours. The residue obtained by evaporation of the solvent was made alkaline by adding 2N sodium hydroxide and then extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom to provide 550 mg (yield 83%) of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-(2,6-diisopropyl-4-methoxyphenyl)acetamide as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][CH:8]=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>>[F:29][C:17]([F:16])([F:28])[C:18]1[CH:19]=[C:20]([S:24]([NH:13][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][O:5][CH2:4][CH2:3][C:2]([F:1])([F:14])[F:15])[N:12]=2)(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(COCCC(F)(F)F)n1
Product: O=S(=O)(Nc1cccc(COCCC(F)(F)F)n1)c1cccc(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(3,3,3-Trifluoro-propoxymethyl)-pyridin-2-ylamine (0.075 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.092 g) as a light yellow gum (0.048 g). MS (ESI−): 427.1 ([M−H]−).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:13]([OH:26])[CH2:14][N:15]([CH2:24][CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@@H:12]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C@@H:13]([OH:26])[CH2:14][N:15]([CH2:24][CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18]
Reactant: CCN(C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN(C[C@H](O)[C@@H](N)Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 82.4 %

Procedure:
A solution of crude tert-butyl 2-((2S,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate (502 mg, 1.1 mmol) in MeOH (10 mL) was added to 10% Pd/C (5.2 mg) and stirred in a hydrogen atmosphere (@ ambient pressure) for 6 h. The reaction was filtered through Celite and the filtrate concentrated under reduced pressure to yield crude tert-butyl 2-((25,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate (293 mg). MS (ESI+) for C17H29N3O3 m/z 324.2 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=O)[CH2:19][C:20](OCC)=[O:21]>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([OH:21])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Product: N#Cc1ccnc(-n2nc(-c3ccccc3F)cc2O)c1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-(2-fluorophenyl)-3-oxopropanoate according to the procedure for the preparation of Example 3, part A. 1H NMR (300 MHz, DMSO-d6): δ 6.15-6.17 (1H, m), 7.13-7.41 (4H, m), 8.07-8.12 (1H, m), 8.34 (1H, s), 8.48-8.50 (1H, m), 11.64 (1H, s). [M+H] Calc'd for C15H9FN4O, 281; Found, 281.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[N:13][C:12]1=[O:22].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:34][NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[Cl:43]>ClCCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=2[Cl:43])[CH3:34])=[O:8])=[CH:4][C:3]=1[N:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[N:13][C:12]1=[O:22]
Reactant: CNc1cccc(F)c1Cl
Reactant: Cc1cc(C(F)(F)F)nc(=O)n1-c1cc(C(=O)O)ccc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nc(=O)n1-c1cc(C(=O)N(C)c2cccc(F)c2Cl)ccc1Cl
Reaction time: 0.67 h
Yield: 25.1 %

Procedure:
To a stirred solution of 4-chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoic acid (50 mg, 0.151 mmol) in anhydrous 1,2-dichloroethane (0.5 mL) at room temperature was added oxalyl chloride (23 mg, 0.181 mmol) followed by a catalytic amount of DMF. After stirring for 40 mins, a solution of N-methyl-2-chloro-3-fluoroaniline 29-1 (30 mg, 0.188 mmol) in 1,2-dichloroethane (0.5 mL), followed by 4-(dimethylamino)pyridine (22 mg, 0.179 mmol) were added and the mixture was stirred for 12 h. Direct purification via reverse phase preparative LCMS gave 4-chloro-N-(2-chloro-3-fluoro-phenyl)-N-methyl-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzamide 30-1 (18 mg, 25%) as a colorless solid. MS: 350.5, tR=8.75 min (method 3); 1H NMR (CDCl3) δ 7.50 (1H, m), 7.44 (1H, dd, J=8.4, 1.8 Hz), 7.31 (1H, m), 7.26 (1H, s), 6.95 (1H, dd, J=9, 2.1 Hz), 6.79 (1H, m), 6.55 (1H, s), 3.46 (3H, s), 1.93 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]#[N:28])=[N:19][CH:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC>>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[N:19][CH:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1nc2c(C)cccc2n1Cc1ccc(-c2ccccc2C#N)nc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Product: CCCc1nc2c(C)cccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Yield: 46 %

Procedure:
A mixture of 4-methyl-2-propyl-1-[[2-(2-cyanophenyl)-5-pyridinyl]methyl]-1H-benzimidazole (0.87 g, 2.39 mmol), NaN3 (0.77 g, 11.94 mmol), and tri-n-butyltin chloride (3.88 g, 11.94 mmol) in xylenes (20 mL) was heated under reflux for 20 h. The reaction mixture was concentrated and 2N HCl was added. The mixture was extracted with ether (discarded) and adjusted to pH 5 with 50% NaOH. The aqueous phase was extracted with CH2Cl2, and the extracts were washed with water, dried, and concentrated. Purification by flash chromatography (5% MeOH/CH2Cl2) and recrystallization from EtOH/EtOAc/ether gave 0.45 g (45%) of product as a white solid, mp 169°-170° C.
Reaction SMILES: [CH2:1]([N:8]1C2C(=CC=CC=2)C(C2OC(C(O)=O)=CC=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[F:26][C:27]1[CH:42]=[CH:41][CH:40]=[CH:39][C:28]=1[C:29]([C:31]1[O:35][C:34]([C:36]([OH:38])=O)=[CH:33][CH:32]=1)=[O:30].C(NN)C1C=CC=CC=1>CO.C(O)(=O)C>[CH2:1]([NH:8][N:9]=[C:36]([C:34]1[O:35][C:31]([C:29](=[O:30])[C:28]2[CH:39]=[CH:40][CH:41]=[CH:42][C:27]=2[F:26])=[CH:32][CH:33]=1)[OH:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2F)o1
Agent: NNCc1ccccc1
Agent: [K]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(c1ccc(C(O)=NNCc2ccccc2)o1)c1ccccc1F

Procedure:
1-Benzyl-3-(5-carboxy-2-furyl)indazole, potassium salt: 70.26 g (0.3 mol) of 5-(2-fluorobenzoyl)furan-2-carboxylic acid were initially charged in 350 ml of methanol, 109.95 g (0.9 mol) of benzylhydrazine were added and the mixture was, after addition of 8 ml of glacial acetic acid, heated under reflux for 6 h. For work-up, the mixture was concentrated using a rotary evaporator, the residue was taken up in 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The aqueous phase was acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The residue that remained after drying and concentration using a rotary evaporator was recrystallized from ethyl acetate/n-hexane. The 68.3 g (0.20 mol) of 5-(2-fluorobenzoyl)furan-2-carboxylic acid benzylhydrazone (m.p.: 147° C. (decomp.)) obtained in this manner were dissolved in 400 ml of DMF, 45.38 g (0.40 mol) of potassium tert-butoxide were introduced and the mixture was heated under reflux for 30 minutes. The precipitate was filtered off with suction, washed with dichloromethane and recrystallized from ethanol/water (95:5). This gave 57.7 g (54%) of the title compound. The corresponding cyclization of the precursor which was still contained in the mother liquor gave 25.9 g of product. m.p.: >300° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14](Cl)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]>>[CH3:1][O:2][C:3](=[O:20])[CH:4]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][CH2:22][OH:21])[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: OCCc1ccccc1O
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Cl)c(Cl)c1=O
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2ccccc2CCO)c(Cl)c1=O
Yield: 48 %

Procedure:
In an analogous manner to the reaction outlined in Intermediate 19 step 1, starting from 3-cyclopentyl-2-(4,5-dichloro-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester and 2-(2-hydroxy-ethyl)-phenol afforded 2-{5-chloro-4-[2-(2-hydroxy-ethyl)-phenoxy]-6-oxo-6H-pyridazin-1-yl}-3-cyclopentyl-propionic acid methyl ester (10.1 g, 48%).