Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.ClCCl>O>[CH3:1][O:2][C:3](=[O:16])[C:4]([CH3:6])([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[CH:11][CH:12]=1)[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 88.6 %

Procedure:
In a reaction vessel, 2-[4-(2-hydroxy-ethyl)-phenyl]-2-methyl-propionic acid methylester (2 g) prepared in the Examples 1-3, triethylamine (1.1 g), p-toluenesulfonylchloride (1.9 g) and dichloromethane (20 mL) were introduced, and the mixture was reacted at room temperature for 1 hour. Distilled water (50 mL) was added thereto, and the mixture was stirred to separate layers. The separated organic layer was dehydrated with Na2SO4, and then condensed by filtration to obtain 2-methyl-2-{4-[2-(toluene-4-sulfonyloxy)-ethyl]-phenyl}-propionic acid methylester (3.0 g, yield 91%).
Reaction SMILES: [NH3:1].O.[CH2:3]([CH:7]1[CH2:13][C:12](=[O:14])[O:11][C:9](=[O:10])[CH2:8]1)[CH:4]([CH3:6])[CH3:5]>C(OC)(C)(C)C>[C:9]([CH2:8][CH:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:13][C:12]([OH:11])=[O:14])(=[O:10])[NH2:1]
Reactant: N
Reactant: CC(C)CC1CC(=O)OC(=O)C1
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)CC(CC(N)=O)CC(=O)O
Temperature: 15 °C

Procedure:
Aqueous ammonia (308 g of 28% ammonium hydroxide, 5.06 mol), water (431 g), and methyl tert-butyl ether (200 g) are combined and cooled to 15° C. 3-Isobutylglutaric acid anhydride is added and the reaction mixture is allowed to warm to 50° to 60° C. The reaction mixture is cooled to 20°-25° C. The solvent is evaporated and the pH of the solution is adjusted to 1.0 with concentrated hydrochloric acid. Water (200 mL) is added and the mixture is filtered. The solid is washed with water (200 mL). The solid is dried under reduced pressure to give 408 g of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid as an off-white solid. (±)-3-(Carbamoylmethyl)-5-methylhexanoic acid has a melting point in the range of about 107.5° to about 108.5° C. 1H-NMR (DMSO-d6, 200 MHz): δ 0.84 (d, 6H, J=6.5 Hz), 1.07-1.17 (m, 2H), 1.50-1.72 (m, 1H), 1.98-2.25 (m, 5H), 6.75 (s, 1H), 7.30 (s, 1H), 11.6 (s, 1H). IR (KBr): 592.0, 655.7, 700.0, 1010.5, 1133.9, 1214.9, 1241.9, 1278.6, 1294.0, 1427.1, 1461.8, 1585.2, 1668.1, 1700.9, 2514.7, 2622.7, 2962.1, 3220.5, 3367.1 cm-1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].Cl[C:20]1C=CC(S(C(C)C)(=O)=O)=C[C:21]=1C(O)=O.N1CCCC1>>[CH2:1]([S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:20][CH3:21]
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Solvent: C1CCNC1
Product: CCCS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Yield: 63 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(propane-2-sulfonyl)-benzoic acid and pyrrolidine and obtained in 63% yield. MS (m/e): 296.2 (MH−, 100%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].C1(C)C=CC=CC=1.[CH3:15][O:16][C:17](=[O:31])[C:18]1[CH:23]=[C:22]([CH:24]=[CH2:25])[C:21]([C:26]([F:29])([F:28])[F:27])=[CH:20][C:19]=1[NH2:30].N1C=CC=CC=1>C(Cl)Cl>[CH3:15][O:16][C:17](=[O:31])[C:18]1[CH:23]=[C:22]([CH:24]=[CH2:25])[C:21]([C:26]([F:28])([F:27])[F:29])=[CH:20][C:19]=1[NH:30][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3]
Reactant: CC(C)OC(=O)Cl
Reactant: C=Cc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=Cc1cc(C(=O)OC)c(NC(=O)OC(C)C)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Add a 1.0 M solution of isopropyl chloroformate in toluene (183.0 mL, 183.0 mmol) to a 0° C. cooled solution of 2-amino-4-trifluoromethyl-5-vinyl-benzoic acid methyl ester (34.47 g, 140.58 mmol) and pyridine (35.0 mL, 429.20 mmol) in methylene chloride (500 mL). Allow the mixture to stir for 2 h at 0° C. then 16 h at room temperature under an atmosphere of N2. Wash the mixture with saturated aqueous sodium bicarbonate solution (2×200 mL) followed by aqueous 2 N HCl solution (2×200 mL). Wash the combined organic extracts with brine (20 mL) and dry over anhydrous sodium sulfate. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0 to 15%), to provide the title compound as an off-white solid (40.50 g, 87%): TLC Rf 0.62 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.32-1.33 (m, 6H), 3.89 (s, 3H), 5.21-5.27 (m, 1H), 5.41-5.44 (m, 1H), 5.63-5.70 (m, 1H), 7.03-7.11 (m, 1H), 8.23 (s, 1H), 8.89 (s, 1H), 10.32 (bs, 1H).
Reaction SMILES: BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2CCCCC.[CH2:28]([O:30][C:31](=[O:55])[CH2:32][N:33]1[C:41]2[C:36](=[CH:37][C:38]([Cl:42])=[CH:39][CH:40]=2)[C:35](O)([C:43]2[C:44]([OH:52])=[CH:45][C:46]3[O:50][CH2:49][CH2:48][C:47]=3[CH:51]=2)[C:34]1=[O:54])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:55])[CH2:32][N:33]1[C:41]2[C:36](=[CH:37][C:38]([Cl:42])=[CH:39][CH:40]=2)[CH:35]([C:43]2[C:44]([OH:52])=[CH:45][C:46]3[O:50][CH2:49][CH2:48][C:47]=3[CH:51]=2)[C:34]1=[O:54])[CH3:29]
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl[5-chloro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (94%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.30-7.24 (m, 2H), 6.72 (d, 1H), 6.66 (s, 1H), 6.39 (s, 1H), 5.05 (s, 1H), 4.53-4.46 (m, 4H), 4.21 (q, 2H), 3.14-2.94 (m, 2H), 1.25 (t, 3H); MS (ES+) m/z 388.8 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[C:8]([C:11]([NH2:13])=O)[CH:9]=2)[C:4]([CH3:16])([CH3:15])[CH:3]1[CH3:17].S(Cl)(Cl)=O.[OH-].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[C:8]([C:11]#[N:13])[CH:9]=2)[C:4]([CH3:16])([CH3:15])[CH:3]1[CH3:17]
Reactant: Cc1cc2c(cc1C(N)=O)C(C)(C)C(C)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cc2c(cc1C#N)C(C)(C)C(C)C2(C)C

Procedure:
The crude product from Step III was dissolved in 250 ml. of benzene in a 50-ml. flask equipped with mechanical stirrer, cooling bath, thermometer, addition funnel, condenser, and static nitrogen head. Thionyl chloride (72 ml.) was added gradually with cooling over six mimutes at 24° to 30° C. The mixture was then heated to reflux for about 4 hours, and after cooling, 150 ml. of 5% sodium hydroxide solution was added at between 32° and 50° C., with cooling, over 16 minutes. The entire contents of the reaction flask were transferred to a separatory funnel and washed twice with 500 ml. of 5% sodium hydroxide solution. The washings were extracted in succession with 50 ml. of benzene. The organic phases were combined and flash evaporated on a rotary evaporator for one hour at 50° C. 10 mm. Hg to yiedl 30.6 g. of crude nitrile. The infrared spectrum (mineral oil mull) showed a medium intensity nitrile band at 2400 cm-1. The crude nitrile was taken up in 100 ml. of benzene and run onto a 1 1/8 inch by 35 inch chromatography column (wet-packed with 400 g. of MCB grade 923 silica gel using benzene as packing solvent). Pure nitrile was collected after 525 ml. of benzene were eluted from the column. A 5 g. portion of the chromatographed nitrile was recrystallized from hexane. The recrystallized nitrile was dissolved in 30 ml. of methanol, 2 g. of Draco K-9 activated carbon added, and the slurry filtered. After repeating the carbon treatment, the product was again recrystallized from hexane. The recrystallized product melted at 70.2° to 72.8° C. NMR spectrum (CDCl3 with TMS reference):
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][C@H:9]([CH3:11])[CH2:8][CH2:7][C@H:6]1[C:12]([OH:14])=O)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][C@H:9]([CH3:11])[CH2:8][CH2:7][C@H:6]1[C:12]([Cl:18])=[O:14])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
To a solution of (1R,2S,4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid (109 mg, 0.54 mmol) in dichloromethane (2.7 ml) was added oxalyl chloride (545 ul, 1.09 mmol) followed by 1 drop of dimethylformamide. The reaction mixture was stirred for 4 h at room temperature. The solvents were then removed to obtain 119 mg (99%) of (1R*,2S*,4R*)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid chloride.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:20]([NH:21][C@H:10]1[CH2:11][CH2:12][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:20]([NH:21][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: c1ccc(C(N[C@H]2CC[C@@H](c3ccccc3)CC2)c2ccccc2)cc1
Product: c1ccc(C(N[C@H]2CC[C@H](c3ccccc3)CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
To a solution of 4-phenylcyclohexanone (500 mg, 2.87 mmol) and diphenylmethanamine (526 mg, 2.87 mmol) in DCE (4 mL) at 0° C. was added sodium triacetoxyborohydride (912 mg, 4.30 mmol) by portions slowly. A white suspension resulted and was stirred for 5 min before the ice-water bath was removed. The reaction was stirred at rt for 1.5 h. The reaction was quenched with water carefully, then saturated NaHCO3 was added carefully and the aqueous was extracted with DCM (3×). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by ISCO flash chromatography (0-100% hexane/EtOAc) to give Intermediate 30A (734 mg, 2.149 mmol, 74.9% yield) and trans-N-benzhydryl-4-phenylcyclohexanamine (191 mg, 0.559 mmol, 19.49% yield), LC-MS (ESI) m/z 342.1 (M+H), RT=1.76 min (Method B). 1H NMR (400 MHz, chloroform-d) δ ppm 7.37 (4 H, d, J=7.33 Hz), 7.23-7.31 (6 H, m), 7.11-7.23 (5 H, m), 4.91 (1 H, s), 2.80-2.88 (1 H, m), 2.46-2.56 (1 H, m), 1.74-1.90 (4 H, m), 1.60-1.70 (2H, m), 1.47-1.59 (2 H, m).
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[O:17][CH3:18])[CH2:9][CH2:8]1)C.[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.C(OC)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:16][C:12]1[C:11]([O:17][CH3:18])=[C:10]([C:7]2([CH2:6][C:5]([OH:19])([C:22]([F:24])([F:23])[F:21])[CH:4]=[O:20])[CH2:8][CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(=O)CC1(c2cccc(Cl)c2OC)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1c(Cl)cccc1C1(CC(O)(C=O)C(F)(F)F)CC1
Reaction time: 8 h
Yield: 35.6 %

Procedure:
6.18 g (20.83 mmol) of ethyl-3-[1-(3-chloro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate is dissolved in 33 ml of tetrahydrofuran and mixed with 3.55 g (24.99 mmol) of (trifluoromethyl)-trimethylsilane. After 51 mg of tetrabutylammonium fluoride is added, the batch is stirred overnight. The reaction mixture is diluted with methyl tert-butyl ether, washed once with water and then with brine. After conventional working-up, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). The isolated 5.65 g (66.4%) of product is mixed in 76 ml of tetrahydrofuran with 4.34 g (13.75 mmol) of tetrabutylammonium fluoride, and it is stirred for one hour at room temperature. After the reaction mixture is mixed with water, it is extracted with methyl tert-butyl ether. After conventional working-up, the residue is chromatographed on a Flashmaster. 2.39 g (47.4%) of the desired compound: ethyl-2-[1-(3-chloro-2-methoxyphenyl)-cyclopropylmethyl]-3,3,3-trifluoro-2-hydroxypropionate is isolated.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][C:15]=1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30]>>[Cl:13][C:14]1[S:18][C:17]([S:19]([NH:1][C:2]2[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)(=[O:21])=[O:20])=[CH:16][C:15]=1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30]
Reactant: O=S(=O)(Cl)c1cc(-c2cc(F)ccc2F)c(Cl)s1
Reactant: CCOC(=O)c1sc(N)nc1C
Product: CCOC(=O)c1sc(NS(=O)(=O)c2cc(-c3cc(F)ccc3F)c(Cl)s2)nc1C
Yield: 20 %

Procedure:
The product was prepared from ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate (9 mg, 0.050 mmol) and 5-chloro-4-(2,5-difluorophenyl)thiophene-2-sulfonyl chloride (Intermediate 20) (17 mg, 0.050 mmol) according to the General Procedure 9, described in Example 123, using a slightly modified reaction temperature of 60° C. and a reaction time of one week. The title compound was obtained in 20% yield (4.7 mg). 1H NMR (500 MHz, CDCl3) δ ppm 1.36 (t, J=7.11 Hz, 3 H) 2.62 (s, 3 H) 4.32 (q, J=7.11 Hz, 2 H) 7.05-7.11 (m, 1 H) 7.13 (td, J=9.02, 4.63 Hz, 1 H) 7.16 (ddd, J=8.55, 5.62, 3.07 Hz, 1 H) 7.60 (d, J=1.83 Hz, 1 H). MS (ESI+) m/z 479 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][NH:2][CH2:3][C:4]([O:6][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])=[O:5]
Reactant: CNCC(=O)O
Reactant: OCc1ccccc1
Product: CNCC(=O)OC(=O)c1ccccc1

Procedure:
Following the procedure described in Example 7 above, MeNHCH2COOH is esterified with benzyl alcohol to provide MeNHCH2COOBz (22).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([OH:20])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH3:28])=[O:6].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl>[C:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([OH:20])[C:16]([F:17])([F:18])[F:19])=[CH:10][C:9]=1[CH3:28])=[O:6])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C(O)(c2ccc(F)cc2)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C(O)(c2ccc(F)cc2)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-amino-N-{2,6-dimethyl-4-[2,2,2-trifluoro-1-(4-fluoro-phenyl)-1-hydroxy-ethyl]-phenyl}-benzamide (0.064 g, 0.15 mmol) (Example I4) in absolute dichloromethane (2 ml), at 20° C., was added a solution of benzoyl chloride (0.021 g, 0.15 mmol) in dichloromethane (0.5 ml). After 10 minutes, the suspension was treated with a solution of pyridine (0.016 g, 0.2 mmol) in dichloromethane (0.5 ml). The solution was stirred at 20° C. for 2 hours. The reaction mixture was quenched by addition of water (2 ml) and a few drops of aqueous hydrochloric acid (1M). The phases were separated and the aqueous phase was extracted with dichloromethane. The organic phases were dried over sodium sulfate, filtered through a plug silica gel which was further washed with ethyl acetate and concentrated. The residue was triturated in hexanes, filtered, washed with pentane and dried to yield the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Br[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C(C)(C)CBr
Reactant: CC(C)Oc1ncc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cn1ncc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 48 h
Yield: 22 %

Procedure:
A mixture of 5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indazole (D110) (335 mg, 0.94 mmol), ethyl 3-bromo-2,2-dimethylpropanoate (D98) (197 mg, 0.94 mmol) and K2CO3 (130 mg, 0.94 mmol) in DMF (5 ml) was stirred at 80° C. for 48 hours. The reaction mixture was then cooled to room temperature and partitioned between EtOAc and water (30 ml). The organic phase was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [20% ethyl acetate/cyclohexane] gave the title compound (100 mg, 22%) as a colourless solid. MS (ES) C24H26ClN5O4 requires 483, found 484 [M+H]+
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:20][C:16]=2[N:17]=[CH:18][N:19]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]2[C:15]3[C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])=[N:19][CH:18]=[N:17][C:16]=3[O:20][C:21]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCNC(=O)OC(C)(C)C)c23)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCN)c23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 380 mg (0.76 mmol) of the compound from Stage 1 in 5 ml methylene chloride and add 0.4 ml anisole and then 5.5 ml trifluoroacetic acid. Stir for 2 h at room temperature. Dilute the mixture with dichloromethane and wash with sodium hydrogencarbonate solution until reaction is neutral. After washing the organic phase with saturated sodium chloride solution, dry over magnesium sulphate. The residue left after concentration by evaporation is dissolved in ethanol and concentrated by evaporation; this operation is repeated three times. 349 mg (82% of theor.) of the title compound is obtained as a yellowish foam.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH2:15][C:16](Cl)=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:19]([C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([OH:31])[CH2:29][CH3:30])[C:22]=1[NH2:23])[CH3:20]>>[CH2:19]([C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([O:31][C:16](=[O:17])[CH2:15][CH:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:6][C:5]3[C:14]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:29][CH3:30])[C:22]=1[NH:23][C:16](=[O:17])[CH2:15][CH:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:20]
Reactant: CCc1cccc(C(O)CC)c1N
Reactant: O=C(Cl)CC1c2ccccc2Oc2ccccc21
Product: CCc1cccc(C(CC)OC(=O)CC2c3ccccc3Oc3ccccc32)c1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Example 21, but using 2.2 equivalents of 2-(9H-xanthenyl)acetyl chloride and one equivalent of 2-ethyl-6-(1-hydroxypropyl)aniline, the title compound was obtained as a foam-like material.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O[N:14]1[C:18]2N=CC=CC=2N=[N:15]1.CC1C=C(C)C2C(=C([O:35][CH2:36][C:37]3[C:38](Cl)=[C:39](S(N4CCC[C@H]4C(NCCN)=O)(=O)=O)[CH:40]=[CH:41][C:42]=3[Cl:43])C=CC=2)N=1.[OH-:59].[Na+]>CN(C)C=O.O>[ClH:43].[NH2:15][N:14]=[CH:18][C:40]1[CH:41]=[CH:42][C:37]([C:36]([OH:35])=[O:59])=[CH:38][CH:39]=1
Reactant: [OH-]
Reactant: Cc1cc(C)c2cccc(OCc3c(Cl)ccc(S(=O)(=O)N4CCC[C@H]4C(=O)NCCN)c3Cl)c2n1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NN=Cc1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.15 g (7.25.10-4 mol) of 4-(aminoiminomethyl)benzoic acid hydrochloride in 10 ml of dimethylformamide (DMF) is prepared and 0.15 g (7.98.10-4 mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 0.11 g (7.25.10-4 mol) of 1-hydroxy-7-azabenzotriazole (HOAT) are added. The resulting mixture is stirred for 30 minutes at room temperature (about 20° C.) and a solution of 0.4 g (7.25.10-4 mol) of 1-[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-aminoethyl]-2(S)-pyrrolidine-carboxamide in 10 ml of DMF is then added dropwise. The reaction medium is stirred for 5 hours at room temperature and then poured into iced water. 1 N sodium hydroxide solution is then added slowly until the pH is 8, after which the mixture is extracted with dichloromethane. The organic phase is washed with water, dried over sodium sulfate and then concentrated under reduced pressure. The crude product is purified by chromatography on NH2 -grafted silica gel (LICHROPREP® NH2) using a dichloromethane/methanol mixture (95/5; v/v) as the eluent to give 0.2 g of the expected product (yield=40%). The product is used directly to obtain the salt.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH:16]([CH3:21])[CH2:17][C:18](O)=[O:19])=[C:11]([NH2:23])[C:10]=1[C:24]([NH2:26])=[O:25].O.[NH2:28][NH2:29].CN(C)C=O>C(O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:21])[CH2:17][C:18](=[O:19])[NH:28][N:29]=2)=[C:11]([NH2:23])[C:10]=1[C:24]([NH2:26])=[O:25]
Reactant: CC(CC(=O)O)C(=O)c1ccc(CCN2CCCC2=O)c(C(N)=O)c1N
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(CCN2CCCC2=O)c(C(N)=O)c1N

Procedure:
7.2 g (0.02 mole) of 4-(4-(2-(2-oxo-pyrrolidin-1-yl)ethyl)-amino-carbonyl-amino-phenyl)-4-oxo-3-methyl-butyric acid and 1 ml (0.02 mole) of hydrazine hydrate are heated under reflux in 80 ml of ethanol and 10 ml of dimethylformamide for 2 hours. The crude product (6.3 g) which precipitates out on cooling is filtered off with suction and recrystallised from 90% strength ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH2:6]O)=[C:4]([F:14])[CH:3]=1.S(Cl)([Cl:17])=O>O1CCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH2:6][Cl:17])=[C:4]([F:14])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)Oc1cc(CO)c(F)cc1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)Oc1cc(CCl)c(F)cc1Cl
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
Then, 6.7 g of 4-chloro-2-fluoro-5-isopropoxybenzylalcohol was dissolved in 70 ml of tetrahydrofuran, to which 1 ml of pyridine was added, and the mixture was cooled to 5° C.. Then, 5 ml of thionyl chloride was slowly added dropwise at 5° to 10° C., and the mixture was stirred at 5° C. for 1.5 hours. After completion of the reaction, the reaction mixture was filtered to separate the precipitated crystals, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, which afforded 7.3 g of 4-chloro-2-fluoro-5-isopropoxybenzyl chloride.