Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[N:9]2)[CH:3]=1.CN([CH:20]=[C:21]([C:29](=O)C)[C:22](OC(C)(C)C)=O)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16][C:21]([CH3:29])([CH3:22])[CH3:20])=[O:15])[CH:10]=[N:9]2)[CH:3]=1
Reactant: CC(=O)C(=CN(C)C)C(=O)OC(C)(C)C
Reactant: Cc1c(C(=O)O)cnn1-c1cc(Cl)ccn1
Solvent: CC#N
Product: Cc1c(C(=O)OC(C)(C)C)cnn1-c1cc(Cl)ccn1
Temperature: 85 °C
Yield: 27 %

Procedure:
1-(4-Chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid: To a solution of tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.032 g, 0.148 mmol) in acetonitrile (2 mL) was added TEA (0.021 mL, 0.148 mmol) and Intermediate 42A (0.024 g, 0.133 mmol). The dark brown solution was heated to 85° C. for 1 h. The reaction mixture was concentrated, and water (1 mL) and CH2Cl2 (1 mL) were added. The organic layer was concentrated and purified by silica gel chromatography to give tert-butyl 1-(4-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate (12 mg, 27%) as yellow oil. MS(ESI) m/z: 294.2 (M+H)+. To the oil was added 4 N HCl in dioxane (2 mL). The reaction was stirred at rt for 4 h, and the clear orange solution was evaporated to dryness followed by coevaporation with toluene (2×) to give the desired product as sticky pink solid. MS(ESI) m/z: 238.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[OH:11][S:12](O)(=[O:14])=[O:13]>CC(C)=O>[NH2:1][C:2]1[S:3][N:4]=[C:5]2[C:10]([S:12]([OH:14])(=[O:13])=[O:11])=[CH:9][CH:8]=[CH:7][C:6]=12
Reactant: O=S(=O)(O)O
Reactant: Nc1snc2ccccc12
Solvent: CC(C)=O
Product: Nc1snc2c(S(=O)(=O)O)cccc12

Procedure:
A solution of 10.0 g. of 3-amino-2,1-benzisothiazole in 100 g. of concentrated H2SO4 was heated at 50°-55° C. for one-half hour, then cooled and added to 500 ml. of cold acetone. The product was removed by filtration and then reprecipitated from bicarbonate solution by addition of sufficient acetic acid to give a pH of 4.75-4.80. 8.5 Grams of purified 3-amino-2,1-benzisothiazole-7-sulfonic acid product was obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C@H:15]1[C:20](O)=[O:21])=O)(C)(C)C.O.[OH-].[Na+]>O1CCCC1>[CH3:12][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C@H:15]1[CH2:20][OH:21]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCNC[C@H]1CO
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of lithium aluminium hydride in tetrahydrofuran (1M, 22.0 ml, 22.0 mmol) was added dropwise to a solution of (2S)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (see U.S. Pat. No. 5,348,955, 1.007 g, 4.38 mmol) in tetrahydrofuran (20 ml) cooled to −15° C. The mixture was allowed to warm to 15° C. over 1.5 hours and then heated at reflux for 3 hours. The mixture was cooled in an ice bath and then water (0.4 ml) was added dropwise followed by a dilute solution of sodium hydroxide (1M, 0.4 ml) and a further portion of water (1.2 ml). The mixture was stirred at room temperature for 0.5 hours and then allowed to stand overnight. The resultant precipitate was filtered and the residue was washed with diethyl ether. The filtrate was evaporated and the residue purified by silica gel chromatography eluting with a 10% mixture of methanol (containing 10% 7M ammonia in methanol) in dichloromethane to give [(2S)-1-methylpiperazin-2-yl]methanol (0.3802 g, 67% yield):
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:3].[C:13]([OH:18])([CH2:16][CH3:17])([CH3:15])[CH3:14].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)[O:18][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14]
Reactant: CCC(C)(C)O
Reactant: CSc1ccc(OC(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)OC(=O)Oc1ccc(SC)cc1
Reaction time: 2 h

Procedure:
One hundred ml of dichloromethane and 20.27 g (0.1 mol) of p-methylthiophenyl chloroformate prepared in the same manner as in Example 1 were placed in a flask, and 50 ml of a dichloromethane solution containing 8.15 g (0.1 mol) of tert-amyl alcohol and 8.70 g (0.11 mol) of pyridine was dropped thereto at room temperature. The resulting mixture was then stirred for two hours. The reaction solution was washed with water to remove pyridine hydrochlorate, and the organic layer was concentrated under reduced pressure. Finally excessive pyridine was removed in vacuum whereupon 5.09 g of the desired product, tert-amyl p-methylthiophenyl carbonate was obtained as an oily material (yield 100%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=2)[CH:9]=1)=[N+]=[N-]>CCO.CC(O)=O.[Fe]>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:8]2[CH:9]=[C:5]([CH2:4][NH2:1])[N:6]=[CH:7]2)=[N:11][CH:12]=1
Reactant: [N-]=[N+]=NCc1cn(-c2ccc(Br)cn2)cn1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: NCc1cn(-c2ccc(Br)cn2)cn1
Yield: 55.8 %

Procedure:
A mixture of 2-(4-(azidomethyl)-1H-imidazol-1-yl)-5-bromopyridine (500 mg, 1.79 mmol) and iron powder (767 mg, 13.7 mmol) in EtOH (8 mL) and HOAc (6 mL) was heated at reflux for 2 h. It was filtered through celite. The filtrate was concentrated in vacuo. The residue was partitioned between 5% NaHCO3 and EtOAc. The biphasic solution was filtered. The EtOAc phase was separated, dried over Na2SO4, and concentrated in vacuo to give (1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methanamine (253 mg).
Reaction SMILES: C([C@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)[CH2:5]1)(=O)C.[O-:19]CC.[Na+].Cl>C(O)C.O1CCOCC1>[CH2:17]([O:16][C:14]([C:12]1[N:13]=[C:9]([N:6]2[CH2:7][CH2:8][C@H:4]([OH:19])[CH2:5]2)[S:10][CH:11]=1)=[O:15])[CH3:18]
Reactant: CC[O-]
Reactant: CCOC(=O)c1csc(N2CC[C@H](C(C)=O)C2)n1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(N2CC[C@H](O)C2)n1
Reaction time: 8 h
Yield: 1953.3 %

Procedure:
To a solution of (3S)-3-acetyl-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)pyrrolidine (5.0 g, 17.6 mmol) (obtained as described in Reference Example 20(2)) in ethanol (150 ml) was added sodium ethoxide (60 mg, 0.879 mmol) at room temperature, and the mixture was stirred overnight under the same conditions. After checking the completion of the reaction, a solution of 4N hydrogen chloride in 1,4-dioxane (0.22 ml) was added thereto to neutralize the reaction mixture. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using toluene:acetonitrile (1:1→1:2) as the eluant to afford (3S)-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (4.16 g, yield 98%) as a white solid.
Reaction SMILES: [C@H:1]1([NH2:8])[CH2:6][CH2:5][C@H:4]([NH2:7])[CH2:3][CH2:2]1.[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH:15]=O)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH2:15][NH:7][C@H:4]1[CH2:5][CH2:6][C@H:1]([NH:8][CH2:15][C:14]2[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH3:22])=[C:12]([O:11][CH2:9][CH3:10])[CH:13]=2)[CH2:2][CH2:3]1)[CH3:10]
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: N[C@H]1CC[C@H](N)CC1
Product: CCOc1ccc(CN[C@H]2CC[C@H](NCc3ccc(OCC)c(OCC)c3)CC2)cc1OCC

Procedure:
The title compound was prepared by a similar way as in Preparation Example 1, except that trans-1,4-cyclohexane diamine was used instead of trans-1,2-cyclohexane diamine and 3,4-diethoxybenzaldehyde was used instead of veratraldehyde.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>ClCCl>[C:18]([O:1][CH:2]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCCCCCC(O)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(CCCCCCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
8-Hydroxy-8-phenyloctanoic acid (25 g) was dissolved in dichloromethane (100 ml), and acetic anhydride (12 ml), pyridine (25 ml) and dimethylaminopyridine (0.1 g) were added to the solution, followed by stirring at room temperature for 3 hours. The reaction solution was washed with water and then twice with 2N hydrochloric acid, and the organic layer was washed with water, dried and concentrated under reduced pressure to give 8-acetoxy-8-phenyloctanoic acid (21 g). Its typical physical properties and nuclear magnetic resonance spectrum are shown in Table 13.
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:23]([NH:25][C@H:26]([P:28](=[O:31])([OH:30])[OH:29])[CH3:27])=[O:24])[CH2:21][OH:22])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:23]([NH:25][C@H:26]([P:28](=[O:29])([OH:31])[OH:30])[CH3:27])=[O:24])[CH2:21][OH:22]
Reactant: C[C@H](NC(=O)[C@H](CO)NC(=O)OCc1ccccc1)P(=O)(O)O
Solvent: NCc1ccccc1
Product: C[C@H](NC(=O)[C@@H](N)CO)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 3(ii), from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-seryl)amino]-ethylphosphonic acid there was obtained (1R)-1-(L-serylamino)-ethylphosphonic acid of melting point 250°-251° C. (decomposition); [α]D20 =-41.7° (c=0.5% in water).
Reaction SMILES: Cl.[CH2:2]([C:4]1([CH2:10][CH3:11])[O:9][CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:3].C(C1(CC)CO1)C.[OH:19][C@@H:20]1[C@@H:39](N2CCOC(C)(C)C2)[CH2:38][C@@:37]2([CH3:48])[C@@H:22]([CH2:23][CH2:24][C@@H:25]3[C@@H:36]2[C:35](=[O:49])[CH2:34][C@@:33]2([CH3:50])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C:30](=[O:32])[CH3:31])[CH2:21]1.[OH-].[Na+]>C(O)CO.O>[CH2:2]([C:4]1([CH2:10][CH3:11])[O:9][CH2:8][CH2:7][N:6]([C@H:39]2[CH2:38][C@@:37]3([CH3:48])[C@@H:22]([CH2:23][CH2:24][C@@H:25]4[C@@H:36]3[C:35](=[O:49])[CH2:34][C@@:33]3([CH3:50])[C@H:26]4[CH2:27][CH2:28][C@@H:29]3[C:30](=[O:32])[CH3:31])[CH2:21][C@@H:20]2[OH:19])[CH2:5]1)[CH3:3]
Reactant: CCC1(CC)CNCCO1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: CCC1(CC)CO1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: CCC1(CC)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(C)=O)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
2,2-Diethylmorpholine hydrochloride (9.6 g) [prepared from the known 2,2-diethyloxirane (B. Rickborn et al, J. Am. Chem. Soc., 1971, 93, 1693) in a similar manner as for the preparation of 2,2-dimethylmorpholine of Example 1] was added to a stirred mixture (3.5:1) of (2α,3α,5α)-2,3-epoxypregnane-11,20-dione 20-cyclic 1,2-ethanediyl acetal and its 3α,4α-epoxy isomer (5.0 g) (prepared as described in British patent 1,039,441) in 1,2-ethanediol (50 ml). Powdered sodium hydroxide (2.14 g) was then added and the mixture was heated at 110° C. for 22 h and then poured into water (500 ml). The precipitated solid was filtered off, washed with water and suspended in a mixture of methanol (45 ml) and water (10 ml). Methanesulfonic acid (1.4 ml) was added and the resulting solution was stirred at room temperature for 45 min and then poured into water (500 ml). After extraction with ethyl acetate, aqueous sodium hydroxide (4M) was added to the aqueous phase until the pH exceeded 9. The precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After washing the solution with water and drying over sodium sulfate, the solvent was removed under reduced pressure to afford an amorphous solid which was crystallised from diethyl ether to give (2β,3α,5α)-2-(2,2-diethyl-4-morpholinyl)-3-hydroxypregnane-11,20-dione (2.04 g). m.p. 177°-179° C.; [α]D +126.0° (c 0.7).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:5]=1[C:6]1[C:7]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:8][C:9]([CH2:24][O:25][CH2:26][CH:27]=[CH2:28])=[CH:10][C:11]=1[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:3])[NH2:2].[CH2:34]1COCC1>[Pt]=O>[C:1]([C:4]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:5]=1[C:6]1[C:7]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:8][C:9]([CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:10][C:11]=1[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:3])[NH2:2]
Reactant: C1CCOC1
Reactant: C=CCOCc1cc(OCC(=O)O)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Agent: O=[Pt]
Product: CCCOCc1cc(OCC(=O)OC)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Platinum oxide (30 mg) was added to a stirred THF (30 mL) solution containing the compound of Example 58 (120 mg, 0.262 mmol) under a nitrogen atmosphere. The mixture was then stirred under a hydrogen atmosphere for 30 minutes. After filtration and concentration, the residue was chromatographed on silica (gradient 0-6% methanol in methylene chloride) to afford the subtitled compound (117 mg, 97%) as a white solid. IR (KBr) 3364, 3166, 1758, 1742, 1642 cm−1; 1H-NMR (CDCl3): δ 0.91 (t, J=7.4 Hz, 3H, —CH3), 1.57-1.65 (m, 2H), 3.40 (t, J=6.6 Hz, 2H, —OCH2—), 3.83 (s, 3H, —OCH3), 4.60 (s, 2H, —OCH2—), 4.91 (s, 2H, —OCH2—), 5.52 (s, 2H, —NCH2—), 5.95 (br s, 1H, —NH), 6.06 (br s, 1H, —NH), 6.58 (s, 1H), 7.04 (s, 1H), 7.07-7.10 (m, 2H), 7.20-7.41 (m, 6H); ESIMS m/e 461 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([CH3:11])[N:3]=1>C(O)(=O)C.[Zn]>[CH3:11][C:4]1[N:3]=[CH:2][C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=1
Reactant: Cc1cc2occc2c(Cl)n1
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1cc2occc2cn1
Temperature: 110 °C
Yield: 91.9 %

Procedure:
To a solution of 4-chloro-6-methylfuro[3,2-c]pyridine (12.98 g, 0.0776 mol) in glacial acetic acid (160 ml) under a nitrogen atmosphere was added zinc powder (7.0 g, 0.107 mol.). This mixture was heated at 110° C. for 2.5 hours and then filtered hot to remove zinc. The acetic acid solution was evaporated and the residue dissolved in water and made strongly basic by addition of sodium hydroxide. The zinc salts were filtered and washed thoroughly with methylene chloride. The aqueous filtrate was extracted with methylene chloride and the combined washings were dried over anhydrous sodium sulfate, filtered through a charcoal pad and the solvent evaporated to give 9.5 g (87% yield) of pure product, mp: 55°-56° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[F:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>O>[F:18][C:19]1[CH:20]=[C:21]([C:25](=[CH:14][C:13]2[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=2)[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: O=C(O)Cc1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CSc1ccc(C=C(C(=O)O)c2cccc(F)c2)cc1
Temperature: 120 °C
Yield: 39.1 %

Procedure:
A mixture of acetic anhydride (60 mL), 4-(methylthio)benzaldehyde (4.99 g, 33 mmol), 3-fluorophenylacetic acid (5.08 g, 33 mmol), and triethylamine (3.98 g, 39 mmol) was heated to reflux for 4 hours. The reaction was cooled to 120° C., and water (120 mL) was added through an addition funnel. A yellow precipitate formed and, after further cooling to room temperature, was collected by filtration, washed with water, and recrystallized from toluene to give the desired intermediate as a yellow solid (3.72 g, 39%): mp 184°-187° C. 1H NMR (CDCl3) 300 MHz 7.92 (s,1H), 7.35 (m, 1H), 7.26 (d, J=6.3 Hz, 1H), 7.19 (d, J=7.7 Hz, 1H) 7.00 (m, 5H), 2.44 and 2.36 (s, 3H); 19F NMR (CDCl3) -112.61 (m). Mass spectrum M+H=289.
Reaction SMILES: [C:1]1([NH:11][S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]([OH:25])=O)[CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:26]CCl>CN(C)C=O>[C:1]1([NH:11][S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]([Cl:26])=[O:25])[CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a suspension of 3-[3-(naphthalen-1-ylsulfamoyl)-phenyl]-acrylic acid (15d) (0.22 g, 0.62 mmol) in dichloromethane (2.5 ml) oxalyl chloride (0.16 ml, 1.86 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.23 g, 99%).
Reaction SMILES: N([O-])=O.[Na+].O.N[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].NC(N)=[O:18].[N+]([O-])(O)=O>S(=O)(=O)(O)O>[NH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([OH:18])[C:13]([OH:15])=[O:14]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: NC(N)=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: NCCCCC(O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An aqueous solution (100 ml) of sodium nitrite (25.9 g, 0.36 mole) was gradually added to a stirred solution of L-lysine hydrate (19.0 g, 0.097 mole) in 10% sulfuric acid (250 mL) at 45-50° C. over a 2 hr period. After addition was complete, the solution was stirred at 25° C. for 3 hr. Urea was added to the solution in order to decompose nitric acid formed in the reaction process and the aqueous solution was poured on to an ion exchange column (Amberlite IR-120, H+ form, 200 ml). After the column was thoroughly washed with water, it was eluted with aqueous ammonium hydroxide until the eluant became negative to ninhydrin test. Combined fractions were evaporated in vacuo, which gave a yellow oil, 7.5 grams.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]3[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=3[N:12]=2)[CH3:10])[N:5]=[C:4]([NH2:27])[N:3]=1>CCOC(C)=O.[Pd]>[F:26][C:23]1[CH:24]=[CH:25][C:13]2[N:12]=[C:11]([C@@H:9]([NH:8][C:6]3[N:5]=[C:4]([NH2:27])[N:3]=[CH:2][N:7]=3)[CH3:10])[N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14]=2[CH:22]=1
Reactant: C[C@H](Nc1nc(N)nc(Cl)n1)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncnc(N)n1)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-chloro-N—[(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[1,3,5]triazine-2,4-diamine (100 mg, 0.26 mmol) in EtOAc (10 mL) was added a slurry of 10% Pd/C (40 mg) in IMS (5 mL) and the reaction mixture stirred at RT under a hydrogen atmosphere for 18 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (C18, gradient 20-55% MeOH in 0.5% TFA/H2O) then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH affording 267 as a colourless foam (42.3 g, 46%). LCMS (Method K): RT 3.14 min [M+H]+ 350.0. 1H NMR (DMSO-d6, 400 MHz, 80° C.): δ 7.87 (1H, s), 7.66 (1H, dd, J=8.8, 4.9 Hz), 7.60-7.56 (2H, m), 7.54-7.49 (3H, m), 7.08 (1H, bs), 7.04 (1H, ddd, J=9.8, 8.7, 2.5 Hz), 6.77 (1H, dd, J=9.0, 2.5 Hz), 6.28 (2H, bs), 5.23 (1H, quintet, J=7.1 Hz), 1.45 (3H, d, J=6.9 Hz)
Reaction SMILES: FC1C=C(C(C)C(=O)C[OH:11])C=CC=1C1C=CC=CC=1.[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)(Cl)Cl>[C:33]1([P:26](=[O:11])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C(=O)CO)c1ccc(-c2ccccc2)c(F)c1
Solvent: ClC(Cl)(Cl)Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To 3-(2-fluoro-4-biphenylyl)-2-oxo-1-butanol (2.00 g, 7.74 mmol) in carbon tetrachloride (5 ml) was added triphenylphosphine (2.15 g, 8.20 mmol) at room temperature. After the addition, the mixture was stirred over night at room temperature, then concentrated to give triphenylphosphine oxide as precipitates. After filtration of the precipitates, the filtrates were evaporated under reduced pressure to a residue, which was chromatographed to afford 1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (1.01 g, 47% yield) as crystalline materials: mp 57°-59° C.; NMR(CDCl3)δ 1.48(d, 3H), 4.07(m, 3H), 6.93-7.63(m, 8H); IR(neat) 1740, 1620, 1480, 1420, 1270 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2I)=[O:5])[CH3:2].[CH3:22][CH:23]([CH3:26])[C:24]#[CH:25]>[Cu]I>[Cl:16][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([C:25]#[C:24][CH:23]([CH3:26])[CH3:22])[CH:11]=1)[O:8][CH:7]([C:18]([F:21])([F:20])[F:19])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15]2
Reactant: C#CC(C)C
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Agent: [Cu]I
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#CC(C)C)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To 2.000 g (4.624 mmole) of ethyl-6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 267 mg (0.231 mmole) tetrakis(triphenylphospine)palladium(0), 88 mg (0.462 mmole) copper (I) iodide, 40 mL degassed toluene, 1.930 mL (13.87 mmole) degassed TEA, and 0.473 g (6.94 mmole) 3-methyl-1-butyne. The mixtures was stirred overnight at room temperature. The mixture was concd and the resulting oil was purified using reverse phase chromatography to afford 1.573 g (91%) of a yellow crystalline solid: 1H NMR (CDCl3/400 MHz) 1.26 (d, 6H, J=6.8 Hz), 1.34 (t, 3H, J=7.2 Hz), 2.80 (septet, 1H, J=6.8 Hz), 4.27-4.35 (m, 2H), 5.78 (q, 1H, J=6.8 Hz), 7.09 (d, J=2.4 Hz), 7.31 (d, 1H, J=2.4 Hz), 7.59 (s, 1H); MS (ES+) 373 (M+1, 100): MS (EI) 372 (M+, 22), 303 (100), 275 (35).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([N:31]3[CH2:35][CH2:34][O:33][C:32]3=[O:36])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([N:31]5[CH2:35][CH2:34][O:33][C:32]5=[O:36])=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: O=C1OCCN1c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(N5CCOC5=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-06) and 3-(1H-indol-5-yl)oxazolidin-2-one (intermediate-59) (0.390 g, 63%).
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][OH:4].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)([O:4][CH2:3][C:2]([F:9])([F:1])[C:5]([F:8])([F:7])[F:6])(=[O:18])=[O:17]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 2,2,3,3,3-pentafluoropropan-1-ol (9.7 ml) and pyridine. Cool to between 0° C. and 10° C. and add portion-wise the p-toluenesulfonylchloride (6.2 g) and stir with warming to room temperature. After 3 hours at room temperature, pour the reaction mixture into ice water and stir for 30 min to give a solid. Filter the solid, wash with water, and dry to give of the title compound.