Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][C@@H:12]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)[N:5]=[C:4]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[N:3]=1.C(O)(C)C.Cl.C(OCC)(OCC)OCC.C([O-])(O)=O.[Na+].[CH:45]1([NH2:48])[CH2:47][CH2:46]1>>[CH:45]1([NH:48][C:2]2[N:3]=[C:4]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[N:5]=[C:6]3[C:7]=2[N:8]=[CH:9][N:11]3[C@@H:12]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)[CH2:47][CH2:46]1
Reactant: NC1CC1
Reactant: CC(C)C(=O)Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(OCC)OCC
Product: CC(C)C(=O)Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 41 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
Under nitrogen atmosphere, N-{4-chloro-5-formamido-6-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enylamino]pyrimidin-2-yl}isobutyramide (15 mg, 42.4 mmol) was dissolved in an anhydrous solution of isopropanol/HCl 1 N (254 ml, 254.4 mmol) and heated to 40-42° C. for 3.5 h. The solution was cooled to 5/10° C. and triethyl orthoformate (21 ml, 127.2 mmol) was added. The resulting mixture was stirred for 2 h at 5-10° C. NaHCO3 (21.37 g, 254.4 mmol) was added slowly, stirred 30 min and the salts were filtered off. To the resulting clear solution, NaHCO3 (3.56 g, 42.4 mmol) and cyclopropylamine (14.7 ml, 212 mmol) were added, the mixture was refluxed for 1 h and the salts were filtered off. The solution was evaporated and the syrup was dissolved in hot isopropanol (120 ml). This mixture was cooled to 0-2° C. and the resulting slurry filtered off. The solid was dried under vacuum at 30° C. There was obtained 10.97 g (73%) of (−)-N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide as a white powder. HPLC analysis: 95.0%+3.8% Abacavir.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:37]2[CH2:36][CH2:35][N:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=3)[CH2:39][CH2:38]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cccc(Cl)c3)CC2)c(Oc2ccccc2)nc1C
Yield: 85 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[NH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:21][CH:22]1[C:28]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:27]=2[CH2:26][CH2:25][CH2:24][NH:23]1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:21][CH:22]1[C:28]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:27]=2[CH2:26][CH2:25][CH2:24][N:23]1[CH2:2][C:3]([NH:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)=[O:4]
Reactant: COc1ccc(CC2NCCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: NC1CCc2ccccc21
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-bromoacetyl bromide with rac-1-aminoindane and 1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[N+:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:14][N:13]1[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:2][N:24]1[CH:25]=[N:26][C:22]([N+:19]([O-:21])=[O:20])=[N:23]1
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)Cn1c(Cn2cnc([N+](=O)[O-])n2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (3 mmol) and 3-nitro-[1,2,4]triazole (3 mmol) are dissolved in DMSO (20 ml). Potassium carbonate (6 mmol) is added to the solution. The mixture is allowed to stir at room temperature overnight. The reaction mixture is diluted with H2O and extracted with AcOEt. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:5) to give 7-(2,2-dimethyl-propyl)-6-(3-nitro-[1,2,4]triazol-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 41% yield.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([S:17]([N:20]2[CH:31]=[CH:30][C:29]3[C:21]2=[N:22][CH:23]=[C:24]2[C:28]=3[N:27]([CH:32]3[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]3)[N:26]=[N:25]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([S:17]([N:20]2[CH:31]=[CH:30][C:29]3[C:21]2=[N:22][CH:23]=[C:24]2[C:28]=3[N:27]([CH:32]3[CH2:33][CH2:34][C:35](=[O:38])[CH2:36][CH2:37]3)[N:26]=[N:25]2)(=[O:18])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c1ncc1nnn(C3CCC(O)CC3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCC(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CC1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
To a solution of oxalyl chloride (665.5 mg, 5.24 mmol) in anhydrous dichloromethane (40 mL) was added anhydrous dimethylsulfoxide (0.44 mL, 9.12 mmol) at −78° C. under nitrogen, followed by stirring for 15 minutes. Then the reaction temperature was warmed to −20° C. and a solution of 4-(6-Benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanol (750 mg, 1.94 mmol) in anhydrous dichloromethane (10 mL)was added dropwise. The mixture was stirred at −20° C. for 15 minutes and warmed to room temperature. Triethylamine (2.15 g, 19.4 mmol) was added and the mixture was stirred for 90 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. The extracts were dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was crystallized form ethanol to give 600 mg (78%) of 4-(6-Benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanone as a solid. 1H NMR (400 MHz, CDCl3) δ: 9.29 (s, 1H), 8.24-8.22 (m, 3H), 7.81-7.64 (m, 4H), 5.67-5.65 (m, 1H), 2.91-2.83 (m, 2H), 2.52-2.49 (m, 6H),
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](Cl)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:35])[CH2:25][C@H:26]([NH2:34])[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])([CH3:22])([CH3:21])[CH3:20].N1C=CC=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:19]([O:23][C:24](=[O:35])[CH2:25][C@H:26]([NH:34][S:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:17])=[O:16])[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])([CH3:21])([CH3:20])[CH3:22]
Reactant: CCOC(OCC)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.2 %

Procedure:
2-Benzyloxy-benzenesulfonyl chloride (see Example 23, step 1) (1.7 g, 6 mmol) and (S)-3-amino-4,4-diethoxy-butyric acid tert-butyl ester (see Example 93) (1.5 g, 6 mmol) and pyridine (1.9 g, 30 mmol) were dissolved in chloroform (150 mL) and stirred at room temperature for 3 days. The reaction was diluted with ethyl acetate (500 mL) and washed with 5% citric acid, sat. sodium bicarbonate, and sat. sodium chloride. The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash chromatography (SiO2, hexane:ethyl acetate, 8:1, then 4:1) gave the desired product (2.7 g, 91%) as a colorless oil. 1H NMR (400 MHz) CDCl3 δ 7.92 (m, 1H), 7.52 (d, 2H), 7.47 (t, 1H), 7.40 (t, 2H), 7.34 (d, 1H), 7.04 (t, 2H), 5.61 (d, 1H), 5.23 (q, 2H), 4.30 (d, 1H), 3.77 (m, 1H), 3.47 (m, 2H), 3.36 (m, 1H), 3.15 (m, 1H), 2.45 (t, 2H), 1.37 (s, 9H), 1.02 (t, 3H), 0.92 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=1)[CH3:2].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.CO>CS(C)=O>[CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:18]([C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[Cl:15])[NH:13][C:8]=2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1ccc(N)c(N)c1
Reactant: O=Cc1ccccc1Cl
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)Nc1ccc2nc(-c3ccccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A freshly prepared solution of (3,4-diamino-phenyl)-carbamic acid ethyl ester in DMSO (0.2 M, 0.10 mL) was placed in a vial. To it was added 2-chloro-benzaldehyde (0.2 M in toluene, 0.12 mL), followed by FeCl3 (0.02 M in THF, 0.050 mL). The mixture was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give [2-(2-chloro-phenyl)-3H-benzoimidazol-5-yl]-carbamic acid ethyl ester: MS (m/z) 315.97 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH3:17][N:18]1[CH2:23][CH:22]=[C:21](O[Si](C)(C)C)[CH2:20][CH2:19]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)=[O:4]
Reactant: CN1CC=C(O[Si](C)(C)C)CC1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(-c2ccccc2)cc1NC1CCN(C)CC1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a stirred solution of methyl-3-amino-5-phenylthiophene-carboxylate (233 mg, 1.0 mmol) and 1-methyl-4-trimethylsilanyloxy-1,2,3,6-tetrahydro-pyridine (370 mg, 2.0 mmol) in dichloroethane (3.0 mL) was added AcOH (0.114 mL, 2.0 eq) and followed addition of NaBH(OAc)3 (424 mg, 2.0 mmol) in one portion. The resultant reaction mixture was stirred at RT for weekend, aq. 10% NaOH (until basic) was added, after 30 min, reaction mixture was extracted with dichloromethane. The organic extract was washed with brine and dried. The crude product was purified on silica gel column using 20% EtOAc/hexane for unreacted starting material followed by CHCl3/MeOH/Et3N (180/16/1) furnished the 3-(1-methyl-piperidin-4-ylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (240 mg, 73%). NMR 1H (CDCl3, 400 MHz): 7.64-7.6 (m, 2H), 7.43-7.34 (m, 3H), 6.83 (brs, 2H), 3.83 (s, 3H), 3.46-3.4 (m, 1H), 2.82-2.74 (m, 1H), 2.3 (s, 3H), 2.26-2.2 (m, 4H), 1.72-1.62 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8](CO)[C:9](=[O:32])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C@H:13]([CH2:23][C:24]([OH:26])=[O:25])[C:12](=[O:27])[N:11]3[CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:5]2=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C@H:13]([CH2:23][C:24]([OH:26])=[O:25])[C:12](=[O:27])[N:11]3[CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C(O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@]2(C(=O)N(CO)c3cc(Cl)ccc32)N(CC2CC2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@]2(C(=O)Nc3cc(Cl)ccc32)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (rac) 2-((2′S,3′R,5′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-1-(hydroxymethyl)-2,6′-dioxospiro[indoline-3,2′-piperidine]-5′-yl)acetic acid (Example 62, Step L) (12.6 mg, 0.025 mmol) in MeOH (1 mL) at room temperature was added DIEA (8.74 μL, 0.050 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with 10% citric acid and concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA) to give the title compound.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Cl:7][CH2:8][CH2:9]O.OS(O)(=O)=O.O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:9][CH2:8][Cl:7])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)O
Reactant: OCCCl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)C(=O)OCCCl
Temperature: 25 °C
Yield: 60 %

Procedure:
Lactic acid (74 mL of an 85% aqueous solution, 0.84 mol) and freshly distilled 2-chloroethanol (670 mL, 10.0 mol) were refluxed with 400 mL of toluene and 0.4 mL of conc. H2SO4 until one equivalent of H2O was collected in a Dean-Stark trap. The reaction mixture was cooled to room temperature, diluted with ethyl ether, and washed with a NaHCO3 /NaCl solution. The organic phase was dried with MgSO4, solvent was removed under reduced pressure, and the residue was distilled at 10 mm Hg. A fraction recovered at 95°-100° C./10 mm Hg was redistilled to give 2-chloroethyl lactate as a clear colorless liquid (76.7 g, 60%): b.p. 95° C./10 mm Hg; 1H NMR δ 1.46 (d, 3 H, J=6.9 Hz), δ 2.95 (bs, 1 H), δ 3.72 (t, 2 H, J=5.6 Hz), δ 4.35 (q, 1 H, J=6.9 Hz), δ 4.44 (m, 2 H); 13C NMR20.4, 41.2, 64.8, 66.8, 175.2 ppm; HRMS calcd for C4H5ClO3Tms (M--CH3) 209.0401, obsd 209.0392.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[F:10][CH2:11][C:12]1([C:15]2[CH:16]=[C:17]([NH2:27])[N:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[N:19]=2)[CH2:14][CH2:13]1.N1C=CC=CC=1.CCOC(C)=O>C1COCC1>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2](=[O:3])[NH:27][C:17]1[N:18]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:19]=[C:15]([C:12]2([CH2:11][F:10])[CH2:13][CH2:14]2)[CH:16]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nc(C3(CF)CC3)cc2N)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C3(CF)CC3)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reaction time: 5 h
Yield: 36.8 %

Procedure:
Slowly add ClCO2CH2CCl3 (1.00 equiv; 717.49 μmoles; 152.01 mg) to a solution of 5-(1-fluoromethyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (176 mg, 0.71 mmoles) and pyridine in 4 mL of THF under nitrogen at 0° C. Stir the mixture from 0° C. to room temperature for 5 hours. Filter the insoluble and remove solvent from filtrate under reduced pressure give an oil. Subject oil to chromatorgraphy (hex/AcOEt 20-80%) to give 110 mg of title compound as a yellow oil. MS (ES+): m/z=420.0 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: Cc1ccc(O)c(C(=O)Nc2cc(Cl)cc(Cl)c2)c1
Yield: 71 %

Procedure:
Using 5-methylsalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[C:21](OCC)(=O)[CH3:22]>CN(C=O)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[C:6]([O:8][CH2:21][CH3:22])=[O:7])=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=C(O)c1ccc[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
0.9 g (7.2 mmol) of the methyl ester of pyrrole-2-carboxylic acid (prepared in a standard fashion by the esterification of commercial pyrrole-2-carboxylic acid) diluted with 10 ml of dry DMF is added dropwise at 0° C., under an inert atmosphere, to a suspension of 0.3 g (7.4 mmol) of NaH at 60% in 15 ml of dry DMF. After agitation for one hour at 23° C., a solution of 1.01 g (7.2 mmol) of 4-fluoronitrobenzene in 10 ml of dry DMF is added dropwise. The reaction mixture is then heated for 3 hours at 80° C. After the reaction medium has returned to 23° C., it is poured into 100 ml of an ice+water mixture and finally diluted with 200 ml of ethyl acetate. After decantation, the organic phase is washed with 3 times 100 ml of water followed by 100 ml of salt water. The organic solution is dried over magnesium sulphate, filtered and concentrated under vacuum. The evaporation residue is purified on a silica column (eluant: heptane/ethyl acetate: 9/1). The pure fractions are collected and evaporated under vacuum in order to produce a pale yellow powder with a yield of 49%.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=O.[OH-].[K+].C(O)(=O)C>CO.O>[OH:20][N:18]=[C:17]1[CH:16]=[CH:15][C:14](=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]#[N:9])[CH:13]=[C:12]1[O:11][CH3:10]
Reactant: N#CCc1ccccc1
Reactant: COc1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COC1=CC(=C(C#N)c2ccccc2)C=CC1=NO
Temperature: 55 °C
Reaction time: 6 h

Procedure:
21.0 g (0.18 mol) of phenylacetonitrile and 25 g (0.16 mol) of o-nitroanisole are added at 25° C. to a solution of 35.6 g KOH (0.54 mol, assay 85%) in 180 ml of methanol and the dark red reaction mixture is stirred at 55° C. for 6 hrs. After cooling, the mixture is diluted with 500 ml of water, and acidified by addition of 60 ml of acetic acid with cooling. The resulting orange precipitate is filtered, washed with water, methanol:water 1:1 (v/v), and dried at 80° C. under vacuum. The crude product (30.8 g, 75%) has a melting point of 180-182° C. (dec) (Lit: 187° C. dec; J. Org. Chem. 26, 4270, 1961) and is used in the next step without further purification. The 1H-NMR spectrum indicates the presence of two isomers in nearly 1:1 ratio.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:31]([F:34])([F:33])[F:32])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCCCCCC.C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:31]([F:32])([F:34])[F:33])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH:29]=[O:30])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C(NCCO)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-hydroxyethyl)-1-naphthamide (Preparation 8, 730 mg, 1.4 mmol) in EtOAc (100 mL) was added Dess-Martin reagent (725 mg, 1.7 mmol). The reaction was stirred at room temperature for 2 hours. TLC 65:35 EtOAc:heptane shows complete conversion to less polar spot. 50 mL NaHCO3 was added to reaction mixture and stirred for 15 minutes. Contents were diluted with water, extracted with EtOAc (2×75 mL), dried (Na2SO4), and concentrated under vacuum to afford the intermediate (713 mg, 98%) as a solid. m/z (Cl) 513 [M+H]+.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[I:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.O>CN(C)C=O>[I:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][Si:5]([CH3:7])([CH3:6])[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(I)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
387 mg of irdidazole and 411 mg of tertbutyldimethylsilyl chloride is added at ambient temperature and under an inert atmosphere to 500 mg of para-iodo-phenol in 4 ml of dimethylformamide and the mixture is maintained under agitation for 15 hours at ambient temperature then for 1 hour at 40° C. The reaction medium is poured into water, and the aqueous phase is extracted with dichloromethane. The organic phase is then dried and evaporated under reduced pressure. In this way 636 mg of expected product is obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=C[CH:17]=1.CO>CN(C)C1C=CN=CC=1.C(OCC)C>[C:9]([NH:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6](=[O:8])[CH3:17])(=[O:11])[CH3:10]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CO
Product: CC(=O)NC(C(C)=O)C(C)C
Temperature: 25 °C
Yield: 19.1 %

Procedure:
A mixture of L-valine (25.0 g, 0.21 mol), acetic anhydride (60.5 ml, 0.64 mol), pyridine (52 ml, 0.64 mol) and 4-dimethylaminopyridine (2.0 g, 16.6 mmol) was heated at reflux overnight. The reaction mixture was allowed to cool to room temperature and methanol added with rapid stirring. The mixture was concentrated under reduced pressure to give an oil which was dissolved in diethyl ether (250 ml), washed with 2M hydrochloric acid (150 ml), saturated aqueous sodium hydrogen carbonate (150 ml) and brine (150 ml) dried over anhydrous magnesium sulphate, filtered and evaporated. Distillation under reduced pressure gave N-acetyl-2-keto-3-amino-4-methylpentane (6.3 g, 19%) as a viscous straw coloured oil (76°-78° C. @1.5 mmHg).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([NH:10][C:11]1[S:12][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][N:15]=1)(=[O:9])[CH3:8].C(N(CC)CC)C>O1CCOCC1>[OH:4][CH2:3][C:2]([NH:1][S:16]([C:13]1[S:12][C:11]([NH:10][C:7](=[O:9])[CH3:8])=[N:15][CH:14]=1)(=[O:17])=[O:18])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: CC(=O)Nc1ncc(S(=O)(=O)Cl)s1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ncc(S(=O)(=O)NC(C)(C)CO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 59 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1-propanol (1.11 g, 12.5 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath) 2-acetamido-thiazole-5-sulfonyl chloride [CAS No. 69812-30-2; commercially available] (1.0 g, 4.15 mmol) and triethylamine (0.64 ml, 4.57 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate) to yield 2-acetamido-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.72 g, 59%) as a white solid. MS (ISP) 292.1 [(M−H)−]; mp 206° C.