Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:24][CH:23]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: O=C(Cc1ccccc1)Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(NC(=O)Cc3ccccc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with N-(4-Hydroxy-phenyl)-2-phenyl-acetamide from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C27H29NO6 [M+H]+: 484.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH:25]3[CH2:27][CH2:26]3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:28][O:29][CH2:30][CH2:31]Cl>CN(C)C=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:31][CH2:30][O:29][CH3:28])[C:19](=[O:24])[N:18]([CH:25]3[CH2:26][CH2:27]3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COCCCl
Reactant: O=c1[nH]c(=O)n(C2CC2)c2ncn(Cc3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C2CC2)c1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.2 g (15.9 mmol) of potassium carbonate were added to a hot solution of 3 g (11.0 mmol) of 7-benzyl-3-cyclopropylxanthine from stage a) in dimethylformamide at 60° C. and the mixture was stirred at 60° C. for one hour. 1.51 g (15.9 mmol) of 2-methoxyethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 6 hours. It was then allowed to cool to room temperature and concentrated under reduced pressure. The oily residue was taken up in dichloromethane and extracted using 1 N sodium hydroxide solution, washed with water until neutral, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was employed in stage c) without further purification.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][O:46][CH2:47][CH2:48][OH:49])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][CH2:45][O:46][CH2:47][CH2:48][OH:49])[CH2:43][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OCCOCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCOCCO)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-(2-piperazin-1-yl-ethoxy)-ethanol (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H48Cl2N5O4 [(M+H)+] 696.3078, observed 696.3076.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br)[CH3:20].O>CN(C)C=O>[C:2]([C:4]1[CH:12]=[CH:11][C:9]([O:10][CH2:25][CH2:24][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:27])=[C:6]([O:7][CH3:8])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc(C(C)=O)cc1OC
Reaction time: 17.5 h
Yield: 98.1 %

Procedure:
Acetovanillone (16.6 g, 0.10 mol), potassium carbonate (30.0 g, 0.22 mol) and ethyl-4-bromobutyrate (17 mL, 0.12 mol) were combined in dimethylformamide (50 mL) and stirred under Argon for 17.5 h. The reaction was poured into water (800 mL) and stirred for 24 h. The product was isolated by filtration to yield ethyl 4-(4-ethanoyl-2-methoxyphenoxy)butanoate (27.5 g, 98%) as a white powder. 1H NMR (δ, ppm): 1.28 (t, CO2CH2CH3), 2.21 (p, ArOCH2CH2CH2), 2.56 (t, ArOCH2CH2CH2), 2.60 (s, ArCOCH3), 3.92 (s, ArOCH3), 4.13 (t, ArOCH2), 4.18 (q, CO2CH2), 6.92 (d, aromatic H ortho to ArOCH2), 7.54 (s, aromatic H ortho to ArOCH3), 7.58 (d, aromatic H ortho to ArCOCH3).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]2[CH:12]=[C:13]([C:16]([NH:18][CH:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:20]([F:23])([F:22])[F:21])=[O:17])[S:14][CH:15]=2)[CH:7]=1.[N:30]1[C:39]2[C:34](=[CH:35][C:36](B(O)O)=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[N:30]1[C:39]2[C:34](=[CH:35][C:36]([N:4]3[CH:3]=[CH:2][C:7]4=[C:10]([C:11]5[CH:12]=[C:13]([C:16]([NH:18][CH:19]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=6)[C:20]([F:23])([F:21])[F:22])=[O:17])[S:14][CH:15]=5)[CH:9]=[N:8][N:6]4[CH2:5]3)=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(NC(c1ccccn1)C(F)(F)F)c1cc(-c2cnn3cc(Br)cnc23)cs1
Reactant: OB(O)c1ccc2ncccc2c1
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: C1COCCO1
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1cc(-c2cnn3c2C=CN(c2ccc4ncccc4c2)C3)cs1

Procedure:
4-(6-bromopyrazolo[1,5-a]pyrimidin-3-yl)-N-(2,2,2-trifluoro-1-pyridin-2-ylethyl)thiophene-2-carboxamide (1 eq) was mixed with quinolin-6-ylboronic acid (1.3 eq). Dioxane (10 mL) and 1M Na2CO3 (2 eq) were added. The mixture was evacuated and flushed with nitrogen under stirring, then a solution Pd(Ph3P)4 (0.05 eq) in dioxane was added under inert gas. The temperature was brought to 100° C. The reaction mixture was stirred at this temperature overnight. The reaction mixtures were filtered through Celite, and the latter was washed with methanol. Purification by reverse phase LC gave 4-(6-quinolin-6-ylpyrazolo[1,5-c]pyrimidin-3-yl)-N-(2,2,2-trifluoro-1-pyridin-2-ylethyl)thiophene-2-carboxamide. 1H NMR (400 MHz, DMSO-d6): 6.11-6.22 (1H, m), 7.47-7.52 (1H, m), 7.67 (1H, dd, J=8.3 Hz, J=4.4 Hz), 7.81 (1H, d, J=7.8 Hz), 7.93-7.98 (1H, m), 8.19 (1H, d, J=8.8 Hz), 8.32 (1H, d, J=1.2 Hz), 8.34 (1H, dd, J=8.8 Hz, J=1.95 Hz), 8.48-8.53 (1H, m), 8.59 (1H, d, J=1.95 Hz), 8.67-8.70 (1H, m), 8.72 (1H, s), 8.76 (1H, d, J=1.2 Hz), 9.00 (1H, dd, J=4.4 Hz, J=1.7 Hz), 9.26 (1H, d, J=2.2 Hz), 9.54 (1H, d, J=9.3 Hz), 9.71 (1H, d, J=2.2 Hz). LC-MS APCI: m/z 531.0 [M+H]+.
Reaction SMILES: OC1C=C[C:5]([N:8]2[C:16]3C(=CC(OC)=C[CH:15]=3)[CH:10]=[C:9]2C2C=CC=CC=2)=[CH:4]C=1.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:40]3[C:35](=[CH:36][C:37]([O:41][C:42](=[O:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:38][CH:39]=3)[CH:34]=[C:33]2[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:28][CH:27]=1>>[CH2:5]([N:8]([CH2:16][CH3:15])[CH2:9][CH2:10][O:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[C:40]3[C:35](=[CH:36][C:37]([O:41][C:42](=[O:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:38][CH:39]=3)[CH:34]=[C:33]2[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[CH:30][CH:31]=1)[CH3:4]
Reactant: O=C(Oc1ccc2c(c1)cc(-c1ccccc1)n2-c1ccc(O)cc1)c1ccccc1
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2-c1ccc(O)cc1
Product: CCN(CC)CCOc1ccc(-n2c(-c3ccccc3)cc3cc(OC(=O)c4ccccc4)ccc32)cc1

Procedure:
Following a procedure similar to that described in Example 1E but substituting for 1-(4-hydroxyphenyl)-5-methoxy-2-phenylindole an equivalent amount of 1-(4-hydroxyphenyl)-5-benzoyloxy-2-phenylindole there can be obtained 1-{4-[2-(diethylamino)ethoxy]phenyl}-5-benzoyloxy-2-phenylindole.
Reaction SMILES: N[C:2]1[CH:6]=[CH:5][NH:4]N=1.CC(O[C:12]([C:14]1[CH:19](C(C)C)[N:18]2[N:23]=[CH:24][CH:25]=[C:17]2[NH:16][C:15]=1[CH3:26])=[O:13])(C)C>>[CH3:26][C:15]1[NH:16][C:17]2[N:18]([N:23]=[CH:24][CH:25]=2)[CH2:19][C:14]=1[C:12]([N:16]1[CH2:17][CH2:25][N:4]([C:5]2[CH:6]=[CH:2][CH:19]=[CH:14][CH:12]=2)[CH2:26][CH2:15]1)=[O:13]
Reactant: Nc1cc[nH]n1
Reactant: CC1=C(C(=O)OC(C)(C)C)C(C(C)C)n2nccc2N1
Product: CC1=C(C(=O)N2CCN(c3ccccc3)CC2)Cn2nccc2N1

Procedure:
Condensation of compound 3 and compound 4 as described in Example 18, Method 2 Step C provided the title compound. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, UV detection at 220λ, 4 min. gradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H2O with 0.1% TFA, Solvent B: 90% MeOH/H2O with 0.1% TFA), 4 mL/min. Rt=1.96 min, (87% pure). (M+H: 323).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][F:14])(=O)=O)=CC=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](=[O:33])[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][NH:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[F:14][CH2:13][CH2:12][N:26]1[CH:27]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[C:23](=[O:33])[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25]1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCF)cc(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
2-Fluoroethyl 4-methylbenzenesulfonate (1.00 g) was added to a suspension of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (1.00 g) and cesium carbonate (2.49 g) in DMF (9 ml) at room temperature. The reaction mixture was stirred at 80° C. for two hours. The reaction mixture was returned to room temperature and diluted by adding ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography [ethyl acetate:hexane:methanol=1:1:0->7:3:0->1:0:0->19:0:1 (v/v)] to give 0.35 g of the title compound as an oily substance.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[O:30]=[C:21]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[CH:15][CH:16]=2)[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of (S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 58, step 1, 0.92 g) in dry methylene chloride (8.8 mL) at 0° C. under N2 is treated with trifluoroacetic acid (2.2 mL) over one minute, and the resulting mixture is stirred at 0° C. for four hours and added slowly to saturated aqueous potassium carbonate (30 mL) at 0° C. to neutralize excess trifluoroacetic acid. The mixture is then diluted with water (50 mL) and saline (50 mL), extracted with methanol/methylene chloride (3×150 mL, 25/75), and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, mp 164-166° C. (decomp.).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)=[CH2:2].[CH3:10][SiH:11]([CH3:13])[Cl:12]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH:7]12[CH2:9][CH:4]([CH:3]([CH2:1][CH2:2][Si:11]([CH3:13])([CH3:10])[Cl:12])[CH2:8]1)[CH:5]=[CH:6]2
Reactant: C[SiH](C)Cl
Reactant: C=CC1CC2C=CC1C2
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C[Si](C)(Cl)CCC1CC2C=CC1C2
Temperature: 70 °C

Procedure:
To a flask equipped with a dropping funnel were charged 150 parts of 2-vinyl-5-norbornene and 0.1 part of a solution of chloroplatinic acid in isopropanol (containing 2% as a platinum atom) were charged. While heating to 70° C., 136 parts of dimethylchlorosilane were added dropwise to the mixture and reacted at 70° C. for an hour. Distillation was performed under reduced pressure to give 195 parts of 2-(5-norbornenyl)ethyldimethylchlorosilane.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1>CN(C)C=O.CCOCC>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([O:4][CH:1]([CH3:3])[CH3:2])=[N:9][CH:10]=1
Reactant: CC(C)O
Reactant: Fc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Oc1ccc(Br)cn1
Temperature: 130 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To isopropanol (11 mL, 143 mmol) under nitrogen at 25° C. was added sodium hydride (95%, 1.94 g, 76.7 mmol) portion wise over 5 minutes. The reaction was stirred for 16 hours and a solution of 2-fluoro-5-bromopyridine (9 g, 51 mmol) in N,N-dimethyl formamide (250 mL) was added over 10 minutes. The resulting mixture was heated at 130° C. for 4 hours and cooled to 25° C. The mixture was diluted with ether (500 mL) and washed with water (600 mL) and brine (300 mL). The organic layer was dried (MgSO4), filtered, and concentrated to provide 10.1 g of the title compound (92%) as light yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.25 Hz, 6H) 5.08-5.28 (m, 1H) 6.75 (d, J=8.82 Hz, 1H) 7.86 (dd, J=8.82, 2.57 Hz, 1H) 8.26 (d, J=2.57 Hz, 1H); MS (ESI) m/z 217.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=O)=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([CH3:16])[CH:10]=2)=[N:6][CH:7]=1.C1C=C[C:30]2[N:35]([OH:36])N=NC=2C=1.C(Cl)CCl.CNO.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([N:35]([OH:36])[CH3:30])=[O:22])=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([CH3:16])[CH:10]=2)=[N:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CCn1nc(C)cc1Nc1cc(Nc2ccccc2C(=O)O)c(Cl)cn1
Agent: CNO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCn1nc(C)cc1Nc1cc(Nc2ccccc2C(=O)N(C)O)c(Cl)cn1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
A solution of 2-({5-chloro-2-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)amino]-4-pyridinyl}amino)benzoic acid (55 mg, 0.148 mmol), HOBT (22.65 mg, 0.148 mmol) and EDC (28.4 mg, 0.148 mmol) in N,N-dimethylformamide (DMF) (5 mL) was stirred under nitrogen at room temp for 30 minutes. To this solution was added N-methylhydroxylamine (12.35 mg, 0.148 mmol) and the solution was stirred for another 15 minutes. The reaction mixture was cooled to 5° C. and DIEA (0.052 mL, 0.296 mmol) was added dropwise. After addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified using preparative HPLC (0.1% formic acid, 5 to 95% water: acetonitrile). Fractions were combined and evaporated. 2-({5-Chloro-2-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)amino]-4-pyridinyl}amino)-N-hydroxy-N-methylbenzamide (16 mg, 0.034 mmol, 23.05% yield) isolated as a white solid. LCMS (M+H)+=401.0 (M+H); 1H NMR (400 MHz, MeOD) ppm 1.30 (t, J=7.20 Hz, 3 H) 2.19 (s, 3 H) 3.37 (d, J=1.52 Hz, 3 H) 3.96 (q, J=7.07 Hz, 2 H) 5.95 (s, 1 H) 6.32 (s, 1 H) 7.21-7.33 (m, 1 H) 7.42-7.53 (m, 2 H) 7.56 (d, J=7.33 Hz, 1 H) 7.86 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[CH:7][C:8]=1[S:14]([Cl:13])(=[O:16])=[O:15]
Reactant: COc1ccc(OC)c(OC)c1
Reactant: O=S(=O)(O)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(S(=O)(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
To a solution of 10.0 g of 1,3,4-trimethoxy benzene in CHCl3 (100 ml) was added dropwise 6.90 g of chlorosulfonic acid over 10 minutes under ice cooling. After stirring at room temperature for two hours, the solution was poured into ice water and the resulting mixture was extracted with CHCl3. The aqueous layer was filtered with celite, the filtrate was neutralized with an aqueous solution of 2 mol/L KOH (pH=9), and the solvent was evaporated under reduced pressure to obtain 7.81 g. Phosphorus oxychloride (30 ml) was added to the obtained residue and the reaction mixture was stirred at an external temperature of 100° C. for one hour. The solution was poured into ice water and the resulting mixture was extracted with Et2O; the organic layer was washed with water and with saturated brine and then dried over MgSO4; the drying agent was separated by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: EtOAc/n-hexane=1/10 to 1/2; v/v) to obtain 1.80 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[C:26]([CH:30]=1)[C:27](O)=[O:28])(=[O:21])=[O:20]>>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:27]([C:26]3[CH:30]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:23]=[CH:24][C:25]=3[C:31]3[S:32][CH:33]=[CH:34][N:35]=3)=[O:28])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: Fc1cc(N2CCNCC2)ccc1C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)c(F)c3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 1-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine (Example P) and 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid (Example O). MS (ISP): 514.5 MH+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]([CH2:15][OH:16])[CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.Br[CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:29]([O:28][CH2:27][CH2:26][CH2:25][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH:6]([CH2:15][OH:16])[CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(O)cc2)C(CO)C1
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(CO)C1

Procedure:
In an analogous manner to that described in Example 44(e), by alkylating tert-butyl (3RS,4RS,5SR)-3-hydroxy-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate with benzyl 3-bromopropyl ether in the presence of potassium carbonate in butan-2-one there was obtained tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-5-hydroxymethyl-piperidine-1-carboxylate as a colourless oil; MS: 472 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH3:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].Cl>CN(C)C=O>[C:19]([O:23][C:24](=[O:27])[CH2:25][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]([CH3:12])[CH2:10][OH:11])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(CO)NCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(CO)N(CC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 19.5 h

Procedure:
To a mixture of an optically-active compound of 2-benzylaminopropan-1-ol (111.2 g), potassium carbonate (111.6 g) and N,N-dimethylformamide (556 ml) cooled to 0° C. was added dropwise bromoacetic acid tert-butyl ester (109 ml) over 20 minutes, and the mixture was stirred at room temperature for 19.5 hours. The mixture was acidified by the addition of 2M aqueous hydrochloric acid solution and 6M aqueous hydrochloric acid solution to pH 2, and washed with toluene (1000 ml). The separated organic layer was extracted with 0.1M aqueous hydrochloric acid solution (300 ml). The combined aqueous layer was adjusted to pH 10 by 4M aqueous sodium hydroxide solution, and extracted with ethyl acetate (700 ml). The organic layer was sequentially washed with water (900 ml) and saturated aqueous sodium chloride solution (500 ml). The separated aqueous layer was extracted with ethyl acetate (400 ml) again. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the titled compound (160.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:18]=[CH:19][C:20]([N+:25]([O-:27])=[O:26])=[C:21]([CH:24]=1)[NH:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:23][NH:22][C:21]1[CH:24]=[C:17]([CH:18]=[CH:19][C:20]=1[N+:25]([O-:27])=[O:26])[O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1cc(Oc2cccc(NC(=O)OC(C)(C)C)c2)ccc1[N+](=O)[O-]
Yield: 120.4 %

Procedure:
Using tert-butyl (3-hydroxyphenyl)carbamate (11.0 g, 52.3 mmol) produced in Example C1(i), 5-fluoro-N-methyl-2-nitroaniline (8.58 g, 50.4 mmol), N,N-dimethylformamide (200 ml) and potassium carbonate (28.6 g, 207 mmol) as starting materials, and in the same manner as in Example C1(ii) except that the reaction temperature was set to 80° C., the title compound (21.8 g) was obtained as an orange syrup.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CN(C)P(=O)(N(C)C)N(C)C.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=1.[C:29](=O)([O:32]C)[O:30][CH3:31]>C1COCC1>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([CH2:28][C:29]([O:30][CH3:31])=[O:32])[CH:25]=[CH:24][N:23]=1
Reactant: COC(=O)OC
Reactant: COc1cc(C)ccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)Cc1ccnc(OC)c1
Reaction time: 0.5 h

Procedure:
To the solution of lithium diisopropylamide (Aldrich, 2.0M, 122 mL, 244 mmol), THF (90 mL) and hexamethylphosphoric triamide (Aldrich, 16 mL, 89 mmol) at −78° C. under nitrogen was added, in 10 min, a solution of 2-methoxy-4-methylpyridine (10.0 g, 81 mmol) in THF (30 mL). After 30 min, a solution of dimethyl carbonate (Aldrich, 7.5 mL, 90 mmol) in THF (30 mL) was added over 15 min. The stirring was continued for 2 h at −78° C. before the reaction was quenched with MeOH (30 mL). The mixture was filtered through Celite and the cake was washed with EtOAc. The filtrate was concentrated in vacuo, and the crude product was purified by silica gel chromatography. MS: 182 (M+1).