Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:25][CH2:26][CH3:27])[CH2:5][CH2:6][NH:7][C:8]([NH:19][C:20]1[CH:24]=[CH:23][S:22][CH:21]=1)=[C:9]1[C:14](=[O:15])OC(C)(C)[O:11][C:10]1=[O:18])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.CO>C(OCC)C>[CH2:26]([O:25][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][NH:7][C:8]1[NH:19][C:20]2[CH:24]=[CH:23][S:22][C:21]=2[C:14](=[O:15])[C:9]=1[C:10]([OH:11])=[O:18])[CH3:27]
Reactant: CCOC(CCNC(Nc1ccsc1)=C1C(=O)OC(C)(C)OC1=O)OCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCOCC
Solvent: CO
Product: CCOC(CCNc1[nH]c2ccsc2c(=O)c1C(=O)O)OCC
Temperature: 25 °C
Yield: 78.4 %

Procedure:
5-((3,3-Diethoxypropylamino)(thiophene-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.62 mol) was suspended in a solution of hexamethyldisilazane (1.08 L, 5.18 mol) in xylenes (2.4 L) and was heated at reflux for 24 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to afford a dark oil. The dark oil was carefully treated with methanol (0.5 L) to form brown solids, followed by addition of ethyl ether (1.6 L). The resultant solids were filtered and washed with MeOH/Ether (1:3) (0.8 L). The solids were dried under vacuum to afford 432.2 g (78%) of the desired intermediate 5-(3,3-Diethoxypropylamino)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylic acid as a beige solid. 1H NMR (400 MHz, DMSO d6) δ 1.09 (m, 6H), 1.91 (m, 2H), 3.40 (m, 2H), 3.58 (m, 2H), 4.06 (s, 1H), 4.60 (t, 1H, J=5.2 Hz), 7.28 (d, 1H, J=4.8 Hz), 8.05 (d, 1H, J=4.8 Hz), 9.94 (m, 1H), 11.8 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH3:18][N:19]1[C:23]([CH3:24])=[C:22](B2OC(C)(C)C(C)(C)O2)[C:21]([CH3:34])=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:22]2[C:21]([CH3:34])=[N:20][N:19]([CH3:18])[C:23]=2[CH3:24])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
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: CC#N
Product: Cc1nn(C)c(C)c1-c1cncc(Cl)c1N1CCC(C(N)=O)CC1

Procedure:
General procedure E was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (75 mg, 0.27 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic pinacol ester (65 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium(0) (16 mg, 5 mol %), acetonitrile (3 mL) and 0.5 M sodium carbonate (0.77 mL, 0.38 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, EtOH, 94:6-80:20, biotage 25+S) to furnish the title compound as a very pale yellow solid (34 mg, 35%), along with recovered 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (52 mg, 57% RSM), LC-MS (ESI, 4 min) Rt 1.55 min, m/z 348 (100%, [M+H]+); m/z (ESI) C17H22N5OCl requires 347.1513, found [M+H]+ 347.1508.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:9][C:8]1[N:7]=[C:5]([C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]=2[O:2][CH3:1])[N:15]2[C:10]=1[CH:11]=[N:12][C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[N:14]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccccc3OC)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccccc4OC)n3n2)cc1
Yield: 15.3 %

Procedure:
Applying the Cyclization Procedure 1, 2-(methyloxy)-N[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 51) (145 mg, 0.38 mmol), 1,2-dichloroethane (4.5 mL) and phosphorus oxychloride (0.285+0.178 mL, 4.97 mmol), to afford 5-methyl-7-[2-(methyloxy)phenyl]-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (21 mg) as a yellow solid. MS m/z 362 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]1[CH2:11][S:8](=[O:10])(=[O:9])[O:7][CH2:6]1>O.CC(C)=O>[N:1]([CH2:6][CH2:5][CH2:11][S:8]([OH:10])(=[O:9])=[O:7])=[N+:2]=[N-:3]
Reactant: O=S1(=O)CCCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a stirred solution of sodium azide (3.5 g, 50 mmol) in water (25 mL) was added a solution of 1,3-propane sultone (6.1 g, 50 mmol) in acetone (25 mL). The reaction mixture was stirred at room temperature for 24 h then concentrated to dryness. The resulting solid was suspended in diethyl ether (100 mL) and stirred at reflux for 1 h. The suspension was cooled to room temperature and the solid was collected by filtration, washed with acetone and diethyl ether, and dried under vacuum, affording of 3-azido-1-propanesulfonic acid (7.6 g, 80%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH:19]=[CH:20][CH:21]=O)=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][CH3:28].[O:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][CH2:20][CH2:21][CH:33]2[O:29][C:30](=[O:35])[NH:31][C:32]2=[O:34])=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C1COC(=O)N1
Reactant: CCCOc1cc(C=CC=O)ccc1OCc1nc(-c2ccccc2)oc1C
Product: CCCOc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 11, 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-propoxycinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-propoxyphenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-ether to give colorless needles, m.p.119-120° C.
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([O:13]C)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O>[CH2:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@@H](C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC[C@H]1CC[C@@H](C(=O)O)CC1
Yield: 75.3 %

Procedure:
The cis methyl ester (14, 500 mg) was dissolved in methanol (5 ml) and stirred in a nitrogen atmosphere. A solution of NaOH in aqueous methanol (5 ml; 2.4 g NaOH in 30 ml water which was then diluted to 100 ml with methanol) was added and the mixture stirred for 24 hr at room temperature. The methanol was evaporated, water added, and then extracted with heptane (3×). The aqueous fraction was acidified to approximately pH 4 with dilute HCl, saturated with NaCl, and extracted with EtOAC (3×). The EtOAC extract was washed with water and dried over Na2O4, then evaporated in vacuo to give the cis-carboxylic acid (9, 0.35 g). A small aliquot was esterfied with diazomethane and analyzed by HPLC. Less than 1% of the trans isomer was present. The reaction was repeated on the remaining 400 mg. A total of 626 mg of the cis acid was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][CH:13]=O)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=1.Cl.[N:16]1([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:29])=[CH:23][CH:22]=2)[CH:20]=[N:19][N:18]=[N:17]1.C([BH3-])#N.[Na+].CO>C(O)(=O)C>[CH3:1][C:2]1[C:3]([CH2:12][CH2:13][N:33]2[CH2:32][CH2:31][N:30]([C:28](=[O:29])[CH2:27][C:24]3[CH:23]=[CH:22][C:21]([N:16]4[CH:20]=[N:19][N:18]=[N:17]4)=[CH:26][CH:25]=3)[CH2:35][CH2:34]2)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: Cc1cc2c(cc1CC=O)COC2=O
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc2c(cc1CCN1CCN(C(=O)Cc3ccc(-n4cnnn4)cc3)CC1)COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with (6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (100 mg, 0.53 mmol) was added 1-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazine hydrochloride (162 mg, 0.53 mmol), sodium cyanoborohydride (165 mg, 2.6 mmol), methanol (10 mL), and a drop of acetic acid. The mixture was allowed to stir at RT for 16 hours. LC showed formation of the desired product. The solvent was removed under reduced pressure. The residue was redissolved in DMSO-water, and purified by mass-directed HPLC. LC/MS: (1E, m/z) (M+1)+=447.3;
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])[CH3:14].CI>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1([CH3:1])[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1CCCCN1C(=O)c1ccccc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCCN1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
To a solution of diisopropyl amine (2.11 g, 25.86 mmol) in THF (50 mL) at 0° C. was added nBuLi (9.4 mL, 23.51 mmol, 2.5M in hexanes). This solution was stirred for 15 min at 0° C. and then cooled to -78° C. Ethyl-1-benzoyl-piperidine-2-carboxylate (6.16 g, 23.5 mmol) was added and the reaction was allowed to stir for 45 min at which time methyl iodide (3.34 g, 23.51 mmol) was added. The reaction was warmed to room temperature and gently warmed (~40° C.) for 2 h. The reaction was quenched with NaHCO3, extracted with ether, dried over Na2SO4 and concentrated to give ethyl-1-benzoyl-2-methyl-piperidine-2-carboxylate (6.49 g, 100% yield). 1H NMR (300 MHz, CDCl3) δ1.10 (m, 3H), 1.45 (s, 3H), 1.4-1.7 (comp m, 4H), 2.90 (m, 2H), 3.5 (m, 2H), 4.14 (m, 2H), 7.24 (m, 5H).
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:2]([Cl:1])=[O:4]
Reactant: CNC1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CN(C(=O)Cl)C1CCCCC1
Yield: 295.9 %

Procedure:
To a solution of triphosgene (4.35 g) in toluene (70 ml) is added dropwise N-methylcyclohexylamine (5 g). To the mixture is added dropwise pyridine (3.5 g), and the mixture is refluxed for 4 hours. The mixture is allowed to cool, and the organic layer is separated, washed with 0.1 N hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent to give N-methyl-N-cyclohexylaminocarbonyl chloride (7.62 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][C@@H:42]([CH2:47][OH:48])[CH2:43][CH:44]([CH3:46])[CH3:45]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:41][C@@H:42]([CH2:47][OH:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:16])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](N)CO
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)C[C@H](CO)NC(=O)[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and D-leucinol (37 uL) according to Method A to give the title compound (51 mg). 1H-NMR (400 MHz, CD3OD) d 7.79 (s, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.29-7.18 (m, 5H), 7.04 (d, J=8.5 Hz, 1H), 4.80 (s, 2H), 4.55 (t, J=7.0 Hz, 1H), 4.25 (dd, J=4.8 Hz, J=9.5 Hz, 1H), 3.86 (m, 1H), 2.75 (dd, J=9.5 Hz, J=13.5 Hz, 1H), 1.35 (s, 9H), 0.82 (m, 6H); IR (KBr) 3312, 2958, 1639 cm−1; HRMS m/z 629.2926 (calc. of monoisotopic mass for C32H43N3O10 gives 629.2948).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1>C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH2:15])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 22 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl(4-methyl-3-nitrophenyl)carbamate (10.1 g, 39.8 mmol) in ethanol (60 mL)/tetrahydrofuran (20 mL) was added 10% palladium-carbon (2.12 g), and the mixture was stirred at room temperature under a hydrogen atmosphere (3 atm) for 22 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (8.82 g, 99%) as a colorless solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][C:14]2[CH:15]=[C:16]([C:21]3([O:32][CH3:33])[C@H:26]([OH:27])[C@@H:25]([OH:28])[C@H:24]([OH:29])[C@@H:23]([CH2:30][OH:31])[O:22]3)[CH:17]=[CH:18][C:19]=2[Cl:20])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:20][C:19]1[CH:18]=[CH:17][C:16]([C:21]2([O:32][CH3:33])[C@H:26]([OH:27])[C@@H:25]([OH:28])[C@H:24]([OH:29])[C@@H:23]([CH2:30][OH:31])[O:22]2)=[CH:15][C:14]=1[CH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:35][CH:34]=1
Reactant: COC1(c2ccc(Cl)c(Cc3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC1(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
The crude (3R,4S,5S,6R)-2-(3-(4-((tert-butyldimethylsilyl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (9.0 g) was dissolved in tetrahydrofuran (70 mL). To the resulting solution was added tetrabutyl ammonium fluoride trihydrate (22.1 g, 70 mmol). The resulting mixture was stirred at room temperature for 2 hr, and concentrated under a reduced pressure. To the mixture were added ethyl acetate (400 mL) and water (200 mL). The resulting mixture was separated into an aqueous phase and an organic phase. The organic phase was successively washed with water (200 mL×3) and a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under a reduced pressure to produce 6.5 g of a crude product, which was directly used in the next reaction without purification.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C@H:14]([OH:17])[CH2:15][OH:16])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:20](OC)([CH3:22])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:21][C:20]1([CH3:22])[O:17][C@@H:14]([CH2:13][CH2:12][C:10]2[NH:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[CH2:15][O:16]1
Reactant: OC[C@@H](O)CCc1cc(-c2ccccc2)n[nH]1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OC[C@H](CCc2cc(-c3ccccc3)n[nH]2)O1
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of (S)-4-(3-phenyl-1H-pyrazol-5-yl)butane-1,2-diol (2.5 g, 10.76 mmol) in acetone (50 mL) were added 2,2-dimethoxypropane (11.21 g, 108 mmol) and p-toluenesulfonic acid (0.185 g, 1.076 mmol) at room temperature. After stirring for 3 h, the reaction was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure to give the title compound (2.70 g) without further purification. LCMS m/z=273.0 [M+H]+.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>>[Cl:11][C:12]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][CH:5]=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(F)c1Cl
Solvent: O=CO
Product: O=CNc1cccc(F)c1Cl
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
A solution of acetic anhydride (10 mL, 106 mmol) and formic acid (30 mL, 795 mmol) was stirred at room temperature for 10 mins. 2-Chloro-3-fluoroaniline (2.9 g, 20 mmol) was added and the reaction mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, the solvents were removed in vacuo and the residue was redissolved in DCM (100 mL) and was washed with sat aq. NaHCO3 until the aqueous phase had a measured pH of 8. The organic layer was further washed with water (2×100 mL), separated and dried over MgSO4. Filtration and concentration in vacuo gave N-(2-chloro-3-fluoro-phenyl)-formamide (3.3 g, 95%) as a colorless solid which did not require further purification. MS (M+H)+: 173.9, tR=2.04 min (method 1).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=1.[Cl-].[Na+]>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([Cl:1])[C:13]([NH2:16])=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)c1cc(Br)ccc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Br)cc(Cl)c1N
Temperature: 70 °C
Yield: 98.7 %

Procedure:
6.4 g (48 mmol) of N-chlorosuccinimide are added to a solution of 10 g (44 mmol) of 4-bromo-2-tert-butylphenylamine (example 1a) in 150 ml of DMF. The medium is heated at 70° C. for 2 hours. It is then poured into a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic phases are combined and washed with water and then dried over sodium sulphate. The residue is chromatographed on silica gel (90/10 heptane/ethyl acetate). 11.4 g of 4-bromo-2-tert-butyl-6-chlorophenylamine are obtained in the form of an orange oil (yield=99%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][N:7]=1.B>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:13][CH:14]=1
Reactant: COCCOc1ccc(C(=O)O)cn1
Agent: B
Solvent: C1CCOC1
Product: COCCOc1ccc(CO)cn1
Temperature: 0 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
6-(2-methoxyethoxy)nicotinic acid (3.94 g 20.0 mmol) was dissolved in anhydrous THF (80 ml) and cooled to 0° C., and stirred under argon while a solution of 1M borane in THF (80 ml) was added over a period of 1 hour. The mixture was allowed to warm to room temperature and left to stir for 4 hours to complete the reaction. The reaction was cooled to 0° C., and quenched by the careful addition of methanol (20 ml total) in small aliquots. The mixture was allowed to stir overnight to complete the quench, then concentrated to dryness in vacuo. The solids were partitioned between ethyl acetate (100 ml) and saturated Na2CO3 (50 ml), and separated, then the aqueous extracted again with ethyl acetate (100 ml). The combined organics were washed with brine (50 ml), then dried (MgSO4) and concentrated in vacuo to give the crude product as clear oil (2.86 g).
Reaction SMILES: O[CH2:2][C@H:3]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCN(S(F)(F)[F:28])CC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:28][CH2:2][C@H:3]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1[C@@H](CO)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1[C@@H](CF)Cc1ccccc1
Temperature: 25 °C
Yield: 4.3 %

Procedure:
(R)-2-(1-hydroxymethyl-2-phenylethyl)isoindole-1,3-dione (1.20 g) was added to a methylene chloride (20 mL) solution of DAST (825 mg) at −78° C. and the reaction solution was agitated at room temperature. DAST (500 mg) was added to the reaction solution after 2 hours, and the reaction solution was agitated at 50° C. for 3 hours. Saturated sodium bicarbonate solution was added for reaction solution to the reaction solution after allowing the reaction solution to be cooled to room temperature, and the organic layer was partitioned. The organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system), and 52 mg of the title compound was obtained.
Reaction SMILES: C[O-].[Na+].ClC1C=CC=CC=1.CO[C:13](=[O:18])[C:14]([O:16][CH3:17])=[O:15].[CH3:19][C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21]>CO>[CH3:17][O:16][C:14](=[O:15])[C:13]([CH2:19][C:20](=[O:21])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Clc1ccccc1
Product: COC(=O)C(=O)CC(=O)C(C)(C)C
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
198 g of methanolic sodium methyate solution (30% strength by weight) are added to 400 g of chlorobenzene. The methanol is distilled off at 65° C. in the course of 1 hour. The mixture is cooled to 10° C. and 118 g (1 mol) of molten oxalic acid dimethyl ester are introduced in the course of 1 hour. Thereafter, 100 g (1 mol) of pinacolin are allowed to run in and the mixture is subsequently stirred at room temperature for 15 minutes. It is heated, and the methanol formed in the reaction is distilled off in the course of 2 hours. Neutralisation with sulphuric acid, separation of the phases and distillation of the organic phase gives 165 g of pivaloylpyruvic acid methyl ester (87.8% of the theoretical yield). Purity: 99.0%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:24][C:25]([CH3:29])([CH3:28])[CH2:26][NH2:27]>>[OH:24][C:25]([CH3:29])([CH3:28])[CH2:26][NH:27][C:20]([C:17]1[NH:18][N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22]
Reactant: CC(C)(O)CN
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NCC(C)(C)O)[nH]n1
Yield: 26 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-2-methyl-propylamine instead of morpholine, to the title compound (9.1 mg, 26%) which was obtained as a brown solid. MS: m/e=385.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([B:8](O)O)[CH:5]=[CH:6][CH:7]=1.[C:11]1([NH2:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[NH2:21])[CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([B:8]2[NH:22][C:11]3[C:20]4[C:15]([CH:14]=[CH:13][CH:12]=3)=[CH:16][CH:17]=[CH:18][C:19]=4[NH:21]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Nc1cccc2cccc(N)c12
Solvent: Cc1ccccc1
Product: Brc1cccc(B2Nc3cccc4cccc(c34)N2)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of 3-bromobenzene boronic acid (20 g, 0.1 mol) and naphthalene-1,8-diamine (17.3 g, 0.11 mol) in anhydrous toluene (600 mL) was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether:EtOAc 5:1 to afford the title compound as a grey solid in 54% yield, 23 g.