Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:33])[C:5]([C:3]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:31])([F:32])[F:30])[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 53 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(2-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (27 mg, 0.059 mmol), β-alanine (530 mg, 5.9 mmol) and NaOMe solution (9.6 mL, 4.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 16 mg of the title compound. MS: (+) m/z 512.27 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[O:17]=[C:15]([NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Reactant: Nc1nccs1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2nccs2)CC1
Reaction time: 20 h

Procedure:
To a round-bottomed flask containing 2-(1-tert-butoxycarbonyl-piperazin-4-yl)-acetic acid×2HCl (0.150 g, 0.54 mmol) was added 2-aminothiazole (0.059 g, 0.59 mmol) and anhydrous dichloromethane (7 ml). The reaction mixture was cooled into an ice-bath under argon, and then diisopropylethylamine (0.29 ml, 1.66 mmol) was added followed by PyBOP (0.280 g, 0.54 mmol). The ice-bath was removed, and the reaction mixture was allowed to stir for 20 h under argon. The solvent was removed in vacuo, the residue was absorbed on silica gel and the free running powder was placed on a 20 g isolute silica column which was eluted with 30 to 50% ethyl acetate in dichloromethane. The title compound was obtained as a colourless oil that solidified on standing at room temperature (0.123 g, 70%); 1H-NMR (500 MHz, DMSO-d6) 1.40 (s, 9H, C(CH3)3), 2.47 (br t obscured by solvent peak, piperazine NCH2), 3.31 (s, 2H, NCH2CO), 3.34 (br t, 4H, piperazine N(CH2)2), 7.22 (d, J=3.5 Hz, 1H, thiazole H), 7.47 (d, J=3.5 Hz, 1H, thiazole H), 11.84 (s, 1H, CONH);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13](=[O:15])[CH3:14])=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: CC(=O)c1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, pale brown solid, m.p. 148° C. and MS: m/e=348 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-acetyl-benzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N+:3]=1[O-].O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:4]1[C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(C(F)(F)F)ccc1Cl
Product: FC(F)(F)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Heat a mixture of 2-chloro-5-trifluoromethylpyridine-N-oxide (40 g, 202.5 mmol) and POCl3 (200 mL) to 80° C. and stir for 16 hours. After cooling to room temperature, remove the excess POCl3 under vacuum. Pour the residue into ice water, and neutralize the mixture to pH=7 with solid NaHCO3. Extract the resulting mixture with diethyl ether (3×80 mL), dry the combined ether extracts (Na2SO4), filter, and evaporate to give a brown oil. Purification by column chromatography affords the title product as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 1H), 7.41 (d, 1H).
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.C(Br)C.[Br:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:28])[C:16]=2[CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[Br:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:3]3[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]3)([OH:28])[C:16]=2[CH:15]=1
Reactant: O=c1c2ccccc2sc2ccc(Br)cc12
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CN1CCC(C2(O)c3ccccc3Sc3ccc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 1.2 l g. (0.05 mol) of magnesium turnings covered by tetrahydrofuran in an Argon atmosphere is added about 0.5 g. of 4-chloro-N-methylpiperidine (from 8.5 g., 0.025 mol of the hydrochloride salt) and a small amount of ethyl bromide. The mixture is heated until the reaction is initiated, the remainder of the chloro compound in about 20 ml. of tetrahydrofuran is added and the mixture is refluxed for four hours. 2-Bromothioxanthone (7.3 g., 0.025 mol) is added and the mixture is refluxed for five hours, and then stirred at room temperature 3 days. The reaction mixture is poured into aqueous ammonium chloride and filtered to give 2-bromo-9(1-methyl-4-piperidyl)thioxanthene-9-ol, m.p. 225.5°-226° C.
Reaction SMILES: [NH2:1][C:2]1([CH2:19][OH:20])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:18])=[C:6]([F:17])[CH:7]=2.Br[CH2:22][C:23]#[N:24].CC(C)([O-])C.[Li+]>C1COCC1>[NH2:1][C:2]1([CH2:19][O:20][CH2:22][C:23]#[N:24])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:18])=[C:6]([F:17])[CH:7]=2
Reactant: NC1(CO)c2cc(Br)c(F)cc2Oc2ncc(Cl)cc21
Reactant: N#CCBr
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCOCC1(N)c2cc(Br)c(F)cc2Oc2ncc(Cl)cc21
Yield: 43.5 %

Procedure:
A solution of (5-amino-7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-b]pyridin-5-yl)methanol (2.83 g, 7.87 mmol) and bromoacetonitrile (5.48 mL, 79 mmol) in 16 mL THF was heated to 40° C. and treated drop wise with lithium tert-butoxide [1N in THF (79 mL, 79 mmol)] over a time period of 4 hours. After completed addition the reaction mixture was concentrated under reduced pressure. Purification of the crude residue by column chromatography [0-40% (95:5 EtOAc/MeOH)/DCM] gave 2-((5-amino-7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-b]pyridin-5-yl)methoxy)acetonitrile (1.362 g, 3.42 mmol, 43.4% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:43]=[CH:42][C:5]([C:6]([N:8]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][CH:22]=4)[N:17]=3)=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:47]=1[CH2:54][C:55](O)=[O:56].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:47]=1[CH2:54][C:55]([NH:1][C:2]1[CH:43]=[CH:42][C:5]([C:6]([N:8]([CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][CH:22]=4)[N:17]=3)=[CH:14][CH:15]=2)=[O:7])=[CH:4][CH:3]=1)=[O:56]
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Reactant: Cc1ccc(-c2ccc(-c3noc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc(N)cc5)cc4)n3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(OC)c(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Prepared using General Procedure 6. To a suspension of tert-butyl 2-(4-amino-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-64 (60 mg, 0.104 mmol) and 2-(2,5-dimethoxyphenyl)acetic acid (20.48 mg, 0.104 mmol) stirring in DMF (2 mL) were added HATU (43.7 mg, 0.115 mmol) and TEA (36.4 μL, 0.261 mmol). After stirring at room temperature for 2 h the reaction mixture was diluted with EA (25 mL) and washed with NaHCO3 (2×25 mL), 1 M HCl (2×25 mL) and brine (25 mL). The organics were dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (EA/hexanes) to afford 56 mg (71%) of tert-butyl 2-(4-(2-(2,5-dimethoxyphenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-65. LCMS-ESI (m/z) calculated for C45H44N4O7: 752; found 753 [M+H]+, tR=2.76 min (Method 10).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH2:7]([OH:14])[C@@H:8]([C@@H:10](CO)[OH:11])[OH:9]>S(=O)(=O)(O)O>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:14])[OH:6])[OH:4]
Reactant: OC[C@@H](O)[C@@H](O)CO
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Separately, the polyol-type ganoderan was kept at 90°-100° C. for 1-2 hours in 0.05-0.1M sulfuric acid to obtain, as well as glycerol and erythritol, an insoluble substance. Hydrolysis of the insoluble substance gave D-glucose as sole product, while hydrolysis of a methylated polyol-type ganoderan gave a substantial amount of 2,4,6-tri-O-methyl-D-glucose. By exposure to the action of exo-beta-1,3 glucanase, only D-glucose was obtained. These facts confirm that the backbone of ganoderan consists of beta-1,3-linked D-glucopyranose residues.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].C(OCC)(=O)C>C(O)C>[CH:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
1-Indanone (2.5 g, 19 mmol) was dissolved in ethanol (25 ml), and the solution was mixed with sodium borohydride (790 mg, 21 mmol) and stirred at room temperature for 3 hours. The reaction solution was mixed with ethyl acetate, washed with hydrochloric acid (1 N) and saturated brine and dried with anhydrous sodium sulfate, the solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 2.4 g (18 mmol, 93%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[C:44]([F:48])=[CH:45][CH:46]=[CH:47][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc(Oc3c(F)cccc3F)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4c(F)cccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 90 °C
Reaction time: 15 h
Yield: 84.7 %

Procedure:
Into a 250 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2-[4-(2,6-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 15 h at 90° C. in an oil bath and then concentrated under vacuum. The residue was diluted with water and extracted with dichloromethane and the organic layers combined. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (10/1) to give 500 mg (85%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[O:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.[Cl-].[NH4+]>C(OCC)C.C1COCC1>[OH:21][C:18]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: N#Cc1ccc(I)cc1
Reactant: O=C1CCOCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)CCOCC2)cc1
Reaction time: 1.5 h

Procedure:
Under inert conditions, 109 ml (218 mmol) of a 2 M solution of isopropylmagnesium chloride in diethyl ether were added dropwise at −40° C. to a solution of 50.0 g (218 mmol) of 4-iodobenzonitrile in 1000 ml of anhydrous THF. After the mixture had been stirred at the same temperature for 1.5 h, a solution of 32.8 g (327 mmol) of tetrahydro-4H-pyran-4-one in 250 ml of anhydrous THF was added. After the addition had ended, the reaction mixture was stirred first at −40° C. for 10 min, then at 0° C. for 30 min and finally at RT for 60 min. Then approx. 20 ml of saturated aqueous ammonium chloride solution were added at −20° C. Subsequently, the solvent was substantially removed on a rotary evaporator. 1000 ml of water were added to the remaining residue, which was extracted three times with approx. 500 ml each time of dichloromethane. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the solvent was removed on a rotary evaporator. The resulting crude product was purified by stirring with 10:1 cyclohexane/ethyl acetate. 19.3 g (43% of theory) of the title compound were obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:7](O)=[O:8]>>[CH3:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:7]([Cl:3])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCC(C)C(=O)O
Product: CCCCCCC(C)C(=O)Cl
Yield: 100 %

Procedure:
Then, 2.38 g (19.0 mmol) of thionyl chloride was maintained at a temperature of 36°~38° C. in a flask, to which was added dropwise 2.51 g (15.9 mmol) of the above (+)-2-methyl octanoic acid over 7 minutes with stirring. After the reaction with stirring at room temperature for 40 minutes, the reaction was further continued by stirring at a temperature of 80° C. for 30 minutes. Then, the reaction product was distilled to obtain 2.81 g (15.9 mmol, yield: 100%) of a colorless and transparent (+)-2-methyl octanoyl chloride.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH2:20])=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[O:9])[CH2:4][CH2:3]1.[F:21][C:22]([F:33])([F:32])[CH:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1>>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH2:20])=[CH:17][CH:18]=3)[N:13]([C:29]([N:26]3[CH2:25][CH2:24][CH:23]([C:22]([F:32])([F:21])[F:33])[CH2:28][CH2:27]3)=[O:30])[N:12]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC1CCN(C(=O)Oc2n[nH]c3cc(N)ccc23)CC1
Reactant: O=C(Cl)N1CCC(C(F)(F)F)CC1
Product: CC1CCN(C(=O)Oc2nn(C(=O)N3CCC(C(F)(F)F)CC3)c3cc(N)ccc23)CC1

Procedure:
In analogy to example 12, 35.66 mg (0.13 mmol) of 6-amino-1H-indazol-3-yl 4-methylpiperidine-1-carboxylate were reacted with 33.63 mg (0.16 mmol) of 4-trifluoromethylpiperidine-1-carbonyl chloride. Yield: 10 mg (17%), M+H+: 454.13.
Reaction SMILES: [CH3:1]C1CCCCC1=O.C(I)C.[CH3:12][C:13]1([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19]>>[CH2:12]([C:13]1([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[CH3:1]
Reactant: CC1(C)CCCCC1=O
Reactant: CC1CCCCC1=O
Solvent: CCI
Product: CCC1(C)CCCCC1=O

Procedure:
The alkylation of 2-methylcyclohexanone with ethyl iodide takes place in a manner similar to that described above for the preparation of 2,2-dimethyl-cyclohexanone.
Reaction SMILES: [CH2:1]([N:5]([C:19]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:28][CH2:29][C@@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[OH:31]>>[CH2:1]([N:5]([C:19]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])[C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH2:14][CH:15]([NH:28][CH2:29][C@H:30]([OH:31])[C:32]3[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=3)[CH2:16][CH2:17]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(=O)NCC(=O)OCC)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCCCN(C(=O)NCC(=O)OCC)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from ethyl ({[butyl-4-(4-oxo-1-piperidinyl)anilino]carbonyl}amino)acetate (which was obtained in Example 367) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.1 Hz, 3 H), 1.17 (t, J=7.1 Hz, 3 H), 1.15–1.40 (m, 6 H), 1.80–1.95 (m, 2 H), 2.50–2.80 (m, 5 H), 2.90 (s, 3 H), 3.49 (t, J=6.9 Hz, 2 H), 3.55–3.60 (m, 2 H), 3.65 (d, J=5.9 Hz, 2 H), 4.04 (q, J=7.1 Hz, 2 H), 4.48 (dd, J=7.9, 4.4 Hz, 1 H), 5.60 (t, J=5.9 Hz, 1 H), 6.80 (d, J=8.2 Hz, 1 H), 6.90–7.10 (m, 5 H), 7.17 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 606.3 (MH+); HRMS Calcd. for C29H44N5O7S (MH+): 606.2956. Found: 606.2955.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 101 %

Procedure:
To a solution of (2R,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (9.81 g: 40 mmole) in dichloromethane (49 ml) in a nitrogen atmosphere under ice cooling, triethylamine (6.67 ml: 48 mmole) and methanesulfonyl chloride (3.70 ml: 48 mmole) are added. The mixture is stirred for 20 minutes to give (2R,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as a crude oil (13.05 g). Yield: 101%. NMR δ(CDCl3) ppm: 1.46(d, J=9.6 Hz, 9H), 2.5(m, 2H), 3.02(s, 3H), 3.76(s, 3H), 3.8(m, 2H), 4.3 to 4.6(m, 1H), 5.2 to 5.3(m, 1H).
Reaction SMILES: [C:1](/[N:3]=[C:4](\SC)/[NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)#[N:2].C[Si](C)(C)[NH:18][O:19][Si](C)(C)C>C(Cl)(Cl)(Cl)Cl>[Cl:12][C:10]1[CH:11]=[C:6]([NH:5][C:4]2[O:19][N:18]=[C:1]([NH2:2])[N:3]=2)[CH:7]=[C:8]([Cl:13])[CH:9]=1
Reactant: CS/C(=N\C#N)Nc1cc(Cl)cc(Cl)c1
Reactant: C[Si](C)(C)NO[Si](C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1noc(Nc2cc(Cl)cc(Cl)c2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 21.8 %

Procedure:
In a 5 mL microwave vial, (Z)-methyl N′-cyano-N-(3,5-dichlorophenyl)carbamimidothioate (156 mg, 0.6 mmol, Eq: 1.00) and N,O-bis(trimethylsilyl)hydroxylamine (160 mg, 900 μmol, Eq: 1.5) were combined with CCl4 (1 ml) to give a colorless suspension which was capped and heated in a 80° C. oil bath for 2.5 hr. The mixture was concentrated in vacuo and MeOH added. The mixture was stirred at RT for 18 hours. The reaction mixture was concentrated in vacuo and the crude material was purified by preparative TLC (silica gel, 1.0 mm, 9:1 DCM/MeOH) to give product which was recrystallized from MeOH and dried in vacuo (89° C., 2 torr, overnight) to give 32 mg (22%) of desired product as a light brown solid.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][CH2:20][S:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26]>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][CH2:20][S:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccccc1Cl
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Cl
Solvent: Cc1ccccc1
Product: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1Cl
Temperature: 55 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(3-methylthiopropoxy)quinoline (0.95 g, 2.8 mmol) and 2-chloroaniline (1.51 g, 11.8 mmol) in toluene was heated to 55° C. and stirred overnight. The solvent was evaporated and the residue was partioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4 and evaporated. The residue was chromatographed (SiO2 ; CH2Cl2 :MeOH 95:5) yielding 0.95 g (74%) of the desired product.
Reaction SMILES: C([C:3]1[CH:18]=[CH:17][C:6]([O:7][CH:8]([CH3:16])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:5][CH:4]=1)=O.C1(C)C=CC=CC=1.C(OO)(=[O:28])C>O>[OH:28][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH:8]([CH3:16])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:5][CH:4]=1
Reactant: CC(=O)OO
Reactant: CCCCOC(=O)C(C)Oc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)C(C)Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
While stirring a mixture of 25 g of butyl 2-(4-formylphenoxy)propionate and 75 g of toluene at room temperature, 22.8 g of 40% peracetic acid was dropwise added. After stirring at 20° to 30° C. for 2 hours and at 50° C. for 2 hours, 2.0 g of water was added, and the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature and subjected to the same after-treatment as in Example 1, whereby 19.5 g of butyl 2-(4-hydroxyphenoxy)propionate was obtained as a colorless transparent liquid by the distillation under reduced pressure. The boiling point was 160° C./1 mmHg.