Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]12[CH2:11][CH2:10][C@:9]1([CH2:12][O:13]CC1C=CC=CC=1)[CH2:8][N:7]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:6]2=[O:29])=[O:4].O1CCCC1.[H][H]>[C].[Pd].C(O)C>[CH3:1][O:2][C:3]([C@@:5]12[CH2:11][CH2:10][C@:9]1([CH2:12][OH:13])[CH2:8][N:7]([C@@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22])[C:6]2=[O:29])=[O:4]
Reactant: COC(=O)[C@@]12CC[C@]1(COCc1ccccc1)CN([C@H](C)c1ccccc1)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)[C@@]12CC[C@]1(CO)CN([C@H](C)c1ccccc1)C2=O

Procedure:
A 10% palladium-carbon catalyst (50% wet, 200 mg) was added to a solution of (1S,5R)-5-benzyloxymethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane-1-carboxylic acid methyl ester (1.82 g, 4.62 mmol) in ethanol (20 mL)-tetrahydrofuran (20 mL), and the mixture was stirred in a hydrogen atmosphere at 40° C. for 2.5 hours. After removing the catalyst by filtration, the filtrate was concentrated to give the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:12][CH2:13][CH:14]=[CH2:15])[C:6]([O:8]CC=C)=[O:7])[CH:2]=[CH2:3].[OH-].[Na+:17]>C1(C)C=CC=CC=1.O>[CH2:13]([O:12][CH:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:6]([O-:8])=[O:7])[CH:14]=[CH2:15].[Na+:17]
Reactant: C=CCOC(=O)C(OCC=C)OCC=C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC(OCC=C)C(=O)[O-]
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
21.2 g (0.1 mole) of allyl diallyloxyacetate is dissolved in 42 g of toluene then 3.92 g (98 mmoles) of sodium hydroxide dissolved in 50 g of water is introduced into this solution. This bipbase reaction medium is agitated vigorously for 30 minutes at 30° C., then decanted and the aqueous phase is collected and subjected to a vacuum distillation to eliminate the freed allyl alcohol by azeotropic distillation. The aqueous phase is then poured into acetone to precipitate the expected sodium diallyloxyacetate.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:51])([CH3:50])[CH2:38][CH2:39][O:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([O:40][CH2:39][CH2:38][C:37]([CH3:51])([CH3:50])[CH3:36])[CH:46]=3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: CC(C)(C)CCOc1cccc(B(O)O)c1
Product: CC(C)(C)CCOc1cccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3cccc(N4CC(=O)NS4(=O)=O)c3)cc2)c1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 3-(3,3-dimethyl-butoxy)phenylboronic acid (45 mg, 0.2 mmol, prepared according to general procedure H) to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[3′-(3,3-dimethyl-butoxy)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: OC1[C:9]([O:10][CH2:11]CC)=[CH:8]C(C=O)=CC=1[N+]([O-])=O.[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=[O:22]>>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=1[O:17][CH2:8][CH2:9][O:10][CH3:11]
Reactant: CCCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: COc1ccc(C=O)cc1O
Product: COCCOc1cc(C=O)ccc1OC
Yield: 89 %

Procedure:
Followed the procedure described in Step 2 of Intermediate 65 starting from 3-hydroxy-4-methoxybenzaldehyde, isolated 2.4 g, yield 89%.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]([C:11]1[CH:12]=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:16]=1)=[O:10].O>O1CCCC1>[OH:10][CH:9]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]1[CH:12]=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:16]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)c1cc(C=O)cc(-c2ccc(C)cc2)c1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(C)cc2)cc(C(O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phenylmagnesium bromide (850 mg, 4.7 mmol) was added to a solution of ethyl 5-formyl-4′-methylbiphenyl-3-carboxylate (360 mg, 1.3 mmol) in tetrahydrofuran (8 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 h, and then water (10 mL) was added. The mixture was extracted with EtOAc (20 mL×2). The combined organic layers were dried over anhydrous MgSO4 and concentrated. The residue was purified by silica gel column chromatography to afford the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]=[C:8]1[CH:16]([CH2:17][CH2:18][C:19](OC)=[O:20])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1>O1CCCC1>[OH:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:7]
Reactant: COC(=O)CCC1C(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1CCCO
Temperature: 25 °C
Yield: 85.6 %

Procedure:
Lithium aluminum hydride (0.5M solution in diglyme, 13.8 mL, 6.9 mmol) was added dropwise at 0° C. to methyl 3-(2-oxoindolin-3-yl)propanoate (1.51 g, 6.90 mmol) in tetrahydrofuran (30 mL). The mixture was allowed to warm to room temperature and then quenched with 2N aqueous hydrochloric acid. The reaction was extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (50% ethyl acetate/hexanes) to give product as a white solid (1.13 g, 86%); 1H NMR (DMSO-d6); δ1.38 (m, 2H); 1.85 (m, 2H); 3.32-3.38 (t, J=6.4 Hz, 1H); 4.38 (t, J=5.2 Hz, 1H); 6.80 (d, J=8 Hz, 1H); 6.94 (m, 1H); 7.16 (m, 1H); 7.22 (d, J=7.2 Hz, 1H); 10.3 (s, 2H)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C=O)C.O>[CH2:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCCN2CCC(Cc3ccccc3)CC2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCCN1CCC(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Sodium azide was added to a solution of 4-benzyl-1-(3-p-toluenesulfonyloxypropyl)piperidine (0.216 g, 0.56 mmol) in DMF (5 mL). The resulting solution was stirred at 80° C. for 3 h then cooled at 25° C., diluted with water (50 mL) and extracted with diethyl ether (2×50 mL). The collected organic phase was washed with water (2×50 mL), dried and concentrated in vacuum to afford crude title compound as an oil (0.15 g). 1H-NMR (CDCl3): 1.2-1.4 (m, 2H), 1.4-1.6 (m, 1H) 1.628 (dd, J=13.2 Hz, 2H), 1. 761 (t, J=7.2 Hz, 2H), 1.857 (t, J=11.4 Hz, 2H), 2.367 (t, J=7.2 Hz, 2H), 2.53 (d, J=7.2 Hz, 2H), 2.86 (bd, J=11.4, 2H), 3.314 (t, J=6.9 Hz, 2H), 7.14 (d, J=7.5 Hz, 2H), 7.19 (d, J=6.9, 1H), 7.275 (t, J=7.2 Hz, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:2]1.[Li]CCCC.CN([CH:21]=[O:22])C>C1COCC1>[CH:21]([C:2]1[S:1][CH:5]=[CH:4][C:3]=1[NH:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:11])[CH3:10])=[O:22]
Reactant: CC(C)(C)C(=O)Nc1ccsc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccsc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To an oven dried flask was charged with N-(thiophen-3-yl)pivalamide (2.0 g, 10.91 mmol) and THF (50 mL) at rt, then the light tan solution was cooled down to −78° C., followed by dropwise addition of n-BuLi (2.4M in hexanes, 9.60 mL, 24.01 mmol) over 5 min under N2. The resulting off-white suspension was stirred for 1 hr, followed by addition of DMF (3.21 mL, 41.5 mmol) through a syringe over 2 min. In 20 min, the suspension became tan solution and the reaction mixture was warmed to rt and continued stirring for 30 min. The conversion was completed as determined by TLC, thus the reaction was quenched with sat. NH4Cl, partitioned between Et2O/H2O (150 mL/50 mL), after separation, the organic solution was washed with brine, dried (Na2SO4), concentrated and purified on Biotage Fresh Collector eluting with 10˜40% EtOAc/Hexanes to afford the expected product, N-(2-formylthiophen-3-yl)pivalamide (1.85 g, 80%) as a tan oil. 1H-NMR (500 MHz, CHLOROFORM-D) δ ppm 1.32 (s, 9 H) 7.68 (d, J=5.19 Hz, 1 H) 8.19 (d, J=5.19 Hz, 1 H) 9.71 (s, 1 H) 10.97 (s, 1 H); Mass spec. 212.09 (MH+) calc. for C10H13NO2S 211.07.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1([CH3:23])[O:9][N:8]=[C:7]([S:10][CH2:11][C:12]2[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][N:15]([CH3:18])[C:16]=2F)[CH2:6]1.O>CN(C)C=O>[C:1]([C:16]1[N:15]([CH3:18])[N:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[C:12]=1[CH2:11][S:10][C:7]1[CH2:6][C:5]([CH3:23])([CH3:4])[O:9][N:8]=1)#[N:2]
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1C#N
Temperature: 40 °C
Reaction time: 1 h
Yield: 176.7 %

Procedure:
0.2 g (4.0 mmoles) of sodium cyanide was added to a solution of 0.5 g (1.6 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred at 40° C. for 1 hour to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.9 g of crude 3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O[NH:38][C:39](=[NH:48])[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=1>CN(C=O)C>[CH3:13][CH:2]([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:10][N:48]=[C:39]([C:40]3[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=3)[N:38]=2)=[CH:11][CH:12]=1
Reactant: N=C(NO)c1ccc(CO)cc1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of 10.0 g (56.2 mmol) of 4-(2-methylpropyl)benzoic acid, 10.8 g (56.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 7.6 g (56.2 mmol) of 1-hydroxybenzotriazole hydrate in 70 mL of DMF was stirred at rt for 30 min. N-Hydroxy-4-(hydroxymethyl)benzamidine (9.3 g, 56.2 mmol, from Step A) was added to the reaction mixture at rt and the resulting slurry was stirred at 140° C. for additional 2 h. The reaction was cooled to rt and quenched with 50 mL of water. The aqueous layer was extracted with 200 mL of ethyl acetate. The organic layer was washed with 0.5 N HCl solution, saturated NaHCO3 solution and water and then was concentrated to dryness to afford 16.5 g of the title compound: 1H NMR (400 Mhz, CD3OD) δ 0.95 (d, J=6.7, 6H), 1.96 (m, 1H), 2.61 (d, J=7.3, 2H), 7.42 (d, J=8.0, 2H), 7.54 (d, J=8.2, 2H), 8.13 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:17]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: CO
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(N)ccc1O
Temperature: 25 °C
Yield: 89 %

Procedure:
5-Amino-2-hydroxybenzoic acid (10 g, 65.3 mmol) was suspended in MeOH (150 ml), and aqueous 96% sulfuric acid (12 ml, 225 mmol) was added drop wise. The mixture was heated to reflux for 96 hours. After cooling to RT, the solvent was partially removed under vacuum; the remaining solution was basified with NaHCO3 5% and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated under vacuum affording methyl 5-amino-2-hydroxybenzoate as a solid (9.68 g, 57.9 mmol, 89% yield, MS/EST+168.0 [MH]+).
Reaction SMILES: [C:1]([NH:5][S:6]([CH:9]1[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:15][CH2:14]C1.C([Li])CCC.CN(C)C=O>CCOC(C)=O>[C:1]([NH:5][S:6]([C:9]1([CH:14]=[O:15])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)C1CC1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)C1(C=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a round-bottom flask equipped with a stir bar was added N-(tert-butyl)cyclopropanesulfonamide (10.0 g, 56.4 mmol) and THF (220 mL). The flask was placed under a nitrogen atmosphere and the solution was then cooled to −78° C. To the stirred solution was added dropwise over 10 minutes n-butyllithium (46.3 mL, 2.5M in hexanes). The resulting solution was stirred at −78° C. for 30 mins and then the cold bath was removed and the solution was allowed to warm to room temperature temperature with stirring for 30 mins. The solution was cooled to −78° C. To the solution was added N,N-dimethylformamide (13.1 mL, 169 mmol). The solution was allowed to slowly warm to room temperature with stirring for 17 h. The mixture was concentrated and the resulting yellow residue was dissolved in EtOAc (100 mL). The solution was transferred to a separatory funnel and was washed with aq. 1N HCl (150 mL). The aqueous phase was extracted with EtOAc (2×100 mL) and the combined organics were washed with sat. aq. NaCl (50 mL); dried over Na2SO4; and filtered. The filtrate concentrated in vacuo to afford a yellow viscous oil which solidified upon standing at room tempearture. This material was dissolved in EtOAc (10 mL); diluted with hexanes (50 mL); and the resulting solution was then stored at −78° C. for 2 h upon which crystals formed. The crystals were collected via filtration; were washed with cold hexanes; and residual solvent was removed in vacuo to afford N-(tert-butyl)-1-formylcyclopropane-1-sulfonamide as a colorless, crystalline solid (8.89 g, 77%). 1H NMR (500 MHz, CDCl3) δ 9.52 (s, 1H), 4.72 (br. s., 1H), 1.90-1.85 (m, 2H), 1.66-1.62 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [O:1]1[CH2:10][CH:2]1[CH2:3][C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1.[N:11]1([C:22](=[O:23])[C:21]2[NH:20][CH:19]=[N:18][C:17]=2[N:15]([CH3:16])[C:13]1=[O:14])[CH3:12]>C(O)(C)C.N1C=CC=CC=1>[OH:1][CH:2]([CH2:3][C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH2:10][N:20]1[C:21]2[C:22](=[O:23])[N:11]([CH3:12])[C:13](=[O:14])[N:15]([CH3:16])[C:17]=2[N:18]=[CH:19]1
Reactant: Cc1nc(CC2CO2)no1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Cc1nc(CC(O)Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 86 %

Procedure:
1.4 g. 3-(2,3-epoxy-propyl)-5-methyl-1,2,4-oxadiazole and 1.8 g. of theophylline are boiled under stirring in a mixture of 20 cm3 isopropyl alcohol and 0.1 cm3 of pyridine for 8 hours. 2.75 g. (86% yield) of 7-[2-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)-propan-1-yl]-theophylline are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:33])([CH3:32])[C:13](=[O:31])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=4)=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[F:40][C:41]([F:45])([F:44])[CH2:42]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:33])([CH3:32])[C:13](=[O:31])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:42][C:41]([F:45])([F:44])[F:40])[CH:25]=4)=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(O)c4)CC3)C(=O)C2(C)C)cc1OC
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(OCC(F)(F)F)c4)CC3)C(=O)C2(C)C)cc1OC
Temperature: 100 °C

Procedure:
0.8 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(3-hydroxyphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 76) and 0.75 g potassium carbonate are suspended in 10 ml of DMF. 0.4 g of 1,1,1-trifluoro-2-iodoethane are added and the reaction mixture is heated to 100° C. for 8 h until the reaction is completed according to TLC analysis. The solvent is evaporated under reduced pressure, and the remaining residue is taken up in DCM. The organic phase is washed with water, dried over MgSO4, and the solvent is removed under reduced pressure. Purification of the resulting crude product by column chromatography (silica gel and EA/PE/TEA=10:10:1) and by crystallization from diethyl ether yields the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CCO.[Pd]>[F:11][C:5]1[CH:4]=[C:3]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:2]([F:1])=[CH:7][C:6]=1[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCOCC2)cc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)c(N2CCOCC2)cc1F
Reaction time: 5 h
Yield: 91.2 %

Procedure:
A mixture of 4-(2,5-difluoro-4-nitrophenyl)morpholine (11 g, 44 mmol) and 10% Pd—C (50% wet, 1.1 g) in EtOH (150 mL) was hydrogenated for 5 h at room temperature. The reaction mixture was filtered by celite, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from iPr2O/AcOEt to give the title compound (8.6 g, 91% yield) as a pale red powder: 1H NMR (300 MHz, DMSO-d6): δ ppm 2.66-2.95 (4H, m), 3.56-3.83 (4H, m), 5.00 (2H, s), 6.55 (1H, dd, J=13.8, 8.5 Hz), 6.77 (1H, dd, J=12.8, 8.3 Hz). LC-MS (ESI) m/z 215 [M+H]+.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].[H-]>C1COCC1.C1(C)C=CC=CC=1>[NH2:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([C:3]([CH3:5])([CH3:4])[C:1]#[N:2])=[CH:7][CH:8]=1
Reactant: CC(C)(C#N)c1ccc(C#N)cc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(CN)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
4-(1-cyano-1-methylethyl)benzonitrile (2.28 g, 13.41 mmol) is dissolved in dry THF and the solution cooled to 0° C. Red-A1 (85% soln in toluene, 2.62 ml, 13.41 mmol of hydride) is added and the reaction stirred at 0° C. for 4 hours. The mixture is quenched with methanol and concentrated under vacuo. The residue is dissolved in CH2Cl2, washed with 2 portions of water, dried over magnesium sulfate, filtered and evaporated to dryness. The crude is purified by normal phase MPLC (SiO2, DCM to DCM/MeOH 3:1), giving 2-[4-(aminomethyl)phenyl]-2-methylpropanenitrile (900 mg, 5.17 mmol, 39%) as a colorless oil. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.68 (s, 6H) 4.00-4.05 (m, 2H) 7.55 (q, J=8.59 Hz, 4H) 8.35 (broad s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].F[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: Nc1ccccc1S
Reactant: N#Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccccc1Sc1ccccc1N
Temperature: 0 °C

Procedure:
2-Aminothiophenol (6.26 g, 50 mmol) was dissolved in dry THF (50 ml) and sodium hydride (2 g of 60% dispersion, 1 eq) added with stirring at 0° C. under nitrogen. After stirring for 0.5 hr this mixture was added portionwise to a stirred solution of 2-fluorobenzonitrile (1 eq) in THF (30 ml). The mixture was allowed to warm to room temperature overnight and then evaporated in vacuo and the residue purified by chromatography on silica, eluting with dichloromethane. The title compound was obtained as an off-white solid (5.27 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[N:26]=[CH:27][C:28]([NH:31][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[O:9][C:10]=2[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:29][CH:30]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2Br)oc1C(F)(F)F
Product: COCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3Br)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H18BrF3N4O3 (m/e) 499, obsd 500 (M+H).
Reaction SMILES: C(O[C:4](=[O:22])[CH:5]=[C:6]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[F:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>O>[Cl:20][C:16]1[C:15]([F:21])=[C:14]2[C:19]([C:4](=[O:22])[CH:5]=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:13]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C=C(Nc1cccc(Cl)c1F)c1ccccc1
Solvent: O
Product: O=c1cc(-c2ccccc2)[nH]c2c(F)c(Cl)ccc12
Temperature: 175 °C
Reaction time: 0.67 h

Procedure:
3-(3-Chloro-2-fluoro-phenylamino)-3-phenyl-acrylic acid ethyl ester (9.2 g, 0.029 mole) and polyphosphoric acid (160 mL, 3.0 mole) were combined and mechanically stirred under nitrogen at 175° C. external temperature for 40 minutes. While still hot, the reaction was poured over 800 mL of stirring ice-water rinsing with water. The mixture was a fine suspension, and was allowed to stir overnight. After stirring overnight, the mixture was filtered to collect the solid. The solid was washed with 4×150 mL water, and then with 4×150 mL of 4:1 ether/methanol. The solid was placed in the vacuum oven at 45° C. for 4 h and afforded the title compound as an off white product; 1H NMR (DMSO-d6, 400 MHz) δ 6.58 (bs, 1H), 7.50-7.54 (d of d, 1H, J=6.6 Hz & J=8.9 Hz), 7.60-7.64 (m, 3H), 7.82-7.84 (m, 2H), 8.07-8.09 (d of d, 1H, J=1.5 Hz & J=8.7 Hz); MS(ES+): 274.03 (100) [MH+], 275.99 (30) [(M+2)H+]. LCMS tR=2.97 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19]>O1CCCC1>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:18](=[O:19])[O:20][C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[CH:10]=2)[CH:6]=[N:7]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cn[nH]c2c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 59.6 %

Procedure:
A mixture of 6-amino-1H-indazole (2.00 g) and pyridine (2.67 ml) in tetrahydrofuran was stirred at 0° C. and then p-nitrophenyl chloroformate (3.18 g) was added and stirred at the same temperature for 2 hours. The reaction mixture was evaporated and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated in vacuo. The pale yellow powder was washed with isopropyl ether and diethyl ether, and vacuumed to afford 4-nitrophenyl N-(lH-indazol-6-yl)carbamate (2.67 g).