Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([F:25])([F:24])[F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:34](=[N:36][OH:37])[NH2:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:38](N1C=CN=C1)(N1C=CN=C1)=[O:39].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([F:24])([F:23])[F:25])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]3[NH:35][C:38](=[O:39])[O:37][N:36]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (169 mg, 0.315 mmol) and 1,1′-carbonyldiimidazole (56.2 mg, 0.35 mmol) dissolved in acetonitrile (3.2 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.188 mL, 1.26 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was washed with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one. MS ESI calc'd. for C26H27ClF3N7O2 [M+H]+ 562. found 562. 1H NMR (500 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.95 (s, 1H), 8.80 (s, 1H), 8.49 (s, 1H), 7.94 (s, 1H), 5.40-5.31 (m, 1H), 3.95-3.85 (m, 1H), 3.80-3.72 (m, 2H), 3.59-3.51 (m, 1H), 2.44-2.33 (m, 1H), 2.11-1.95 (m, 2H), 1.95-1.83 (m, 1H), 1.42-1.32 (broad, 2H), 1.11-0.98 (broad, 2H), 0.89 (d, J=12.1, 1H), 0.67 (d, J=6.3, 3H), 0.65-0.53 (m, 2H), 0.53-0.34 (m, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C:3]([C:1]#[N:2])([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)(Cc1ccccc1)Cc1ccccc1
Yield: 80 %

Procedure:
Ethyl cyanoacetate (15.0 g, 0.133 mol) was dialkylated with benzyl bromide employing 1,8-diazabicyclo[5.4.0]undecene-7 as described by: Ono, N.; Yoshimura, T.; Tanikaga, R.; Kaji, A. Chem. Lett. 1977, 871-872. The obtained ethyl 2-benzyl-2-cyano-3-phenylpropionate (80% yield) was identical with the material described in Example 88. The ester was saponified to the corresponding carboxylic acid as previously described in Example 88. The title peptide was prepared under standard solid phase peptide conditions as examplified in Examples 1 and 2.
Reaction SMILES: [O:1]1[C@H:7]2[C@@H:2]1[CH2:3][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:6]2.[Cl-].[NH4+].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O>[N:15]([C@H:2]1[C@H:7]([OH:1])[CH2:6][CH2:5][C@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1)=[N+:16]=[N-:17]
Reactant: CCOC(=O)[C@H]1CC[C@H]2O[C@H]2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@@H](O)[C@H](N=[N+]=[N-])C1
Temperature: 75 °C
Reaction time: 13 h
Yield: 100.3 %

Procedure:
Ethyl (1S,3S,4R)-3,4-epoxycyclohexane-1-carboxylate (41 g) was dissolved in N,N-dimethylformamide (300 ml), ammonium chloride (19.3 g) and sodium azide (23.5 g) were successively added at room temperature, and the mixture was then stirred at 75° C. for 13 hours. The reaction mixture was filtered, the filtrate was concentrated to distill off 400 ml of the solvent, the product captured by the filter was put in the residue, and water was added to dissolve the collected product. The solution was extracted with ethyl acetate. The resultant organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (51.5 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:14])[O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([NH2:15])[N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:3]=1.[H-].[Na+].I[CH2:36][CH3:37]>>[NH2:1][C:2]1[C:7]([N:8]([CH2:36][CH3:37])[C:9](=[O:14])[O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([NH2:15])[N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:3]=1
Reactant: CCI
Reactant: CC(C)OC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: [H-]
Agent: [Na+]
Product: CCN(C(=O)OC(C)C)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N

Procedure:
Prepared in analogy to Example 6 with 60 mg (0.14 mmol) of isopropyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate from Example 3, 4.95 mg (0.21 mmol) of sodium hydride and 21.4 mg (0.17 mmol) of iodoethane. To complete the reaction, the same amount of sodium hydride and iodoethane are added once again. The residue is purified by preparative RP-HPLC.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C@@H:18]4[O:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20][CH2:19]4)=O)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.B.C1COCC1.O.[OH-].[Na+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C@@H:18]4[O:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20][CH2:19]4)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCCC(c2ccc3c(c2)OCO3)C1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)OC[C@H](CN1CCCC(c3ccc4c(c3)OCO4)C1)O2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 83.8 %

Procedure:
(3-Benzo[1,3]dioxol-5-ylpiperidin-1-yl-(R)-2,3-dihydrobenzo[1,4]dioxin-2-ylmethanone (285 mg, 0.77 mmol) was dissolved in dry DMF (2.5 ml) and 1 M BH3THF (3.10 ml, 3.10 mmol) was slowly added under a nitrogen atmosphere. The reaction mixture was stirred for 4.5 h at RT and then cooled to 0° C. Water was slowly added and the mixture basified with 2.5 M NaOH and extracted three times with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness. The crude product was dissolved in methanol (25 ml) and 5 M HCl (1.5 ml) was slowly added. The mixture was stirred for 1 h at RT and then at 60° C. for 2 h. The reaction mixture was evaporated to dryness, redissolved in EtOAc and washed twice with 1 M Na2CO3 and water. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness to give 228 mg of the title compound.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1/[C:15](=[N:33]/[O:34][CH3:35])/[C:16]([NH:18][C@@H:19]1[C:31](=[O:32])[N:21]2[C:22]([C:28]([OH:30])=[O:29])=[C:23]([CH2:26][OH:27])[CH2:24][S:25][C@H:20]12)=[O:17].C([O-])(=O)C.[Na+:40]>CO.C1COCC1.ClCCl>[CH3:35][O:34]/[N:33]=[C:15](\[C:16]([NH:18][C@@H:19]1[C:31](=[O:32])[N:21]2[C:22]([C:28]([O-:30])=[O:29])=[C:23]([CH2:26][O:27][C:3]([NH2:5])=[O:4])[CH2:24][S:25][C@H:20]12)=[O:17])/[C:11]1[O:10][CH:14]=[CH:13][CH:12]=1.[Na+:40]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.17 h

Procedure:
A mixture of THF (60 ml), dichloromethane (25 ml), and trichloroacetyl isocyanate (6.2 ml) was protected from moisture and cooled to -10°.To the stirred mixture was added (6R,7R)-7-[Z-2-(fur-2-yl)-2-methyoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (10 g) in one charge followed by THF (20 ml). The mixture was stirred for 10 minutes at 0° to +5° to give a clear solution. Methanol (6.6 ml) was added, followed by portionwise addition of anhydrous sodium acetate (0.3 g) to raise the pH to 3.5. Charcoal (1 g) and filter aid (0.5 g Hyflo Supercel) were added and the mixture stirred at 10° for 20 minutes. Further anhydrous sodium acetate (5 g) was then added and the mixture stirred at 10° to 15° for 5 minutes by which time the pH had risen to 7.2. The charcoal, undissolved sodium acetate, and filter aid were removed by filtration and the filter bed washed with methanol (23 ml ) containing dichloromethane (10 ml). The filtrate and washes were combined, warmed to 25°, and left undisturbed at that temperature. Crystallisation commenced after 12 minutes. After 1 hour the mixture was stirred briefly and then left undisturbed for a further 11/2 hours. The crystalline material was collected by filtration, washed with THF (2×50 ml) and dried in vacuo at 35° to give sodium cefuroxime in a yield of 78.5%theory corrected for THF and sodium acetate.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]([OH:36])([CH3:37])[CH3:35])=[O:4]
Reactant: CC(C)(O)CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(O)CNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 52.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), 1-amino-2-methylpropan-2-ol (9.30 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). This was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.9 min) to provide (R/S)-2-hydroxy-N-(2-hydroxy-2-methylpropyl)-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.037 mmol, 52.6% yield): LCMS=503.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.20 (2 H, m), 7.54-7.85 (7 H, m), 5.17 (1 H, s), 3.25 (2 H, s), 1.17 (3 H, s), 1.15 (3 H, s); HPLC peak RT=8.7 min (Method A).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[O:20].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(O)c(C=O)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (2.23 g), 2-hydroxy-5-methoxybenzaldehyde (6.08 g), and 4-dimethylaminopyridine (4.88 g) were suspended in monochlorobenzene (40 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, and water was then added thereto. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (2.72 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CN(C)C=O>[Cl:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C=Cc2ccccc2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1ccc(C=Cc2ccccc2)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 4-hydroxystilbene (2 g), potassium carbonate (7.04 g) and 1-bromo-3-chloropropane (5 mL) in N,N-dimethylformamide (10 mL) affords 2.06 g of 4-(3-chloropropoxy)stilbene as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=2)[CH3:13])=[O:10])=[CH:4][CH:3]=1.O[CH:27]1[CH2:31][CH2:30][O:29][CH2:28]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:29]1[CH2:30][CH2:31][CH:27]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:16][N:15]=3)[CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH2:28]1
Reactant: C[C@@H](NC(=O)Cc1ccc(O)cc1)c1ccc(NCC(F)(F)F)cn1
Reactant: OC1CCOC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)Cc1ccc(OC2CCOC2)cc1)c1ccc(NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of the starting 2-(4-hydroxyphenyl)-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}ethyl)acetamide (60 mg, 0.17 mmol) in 0.5 ml of dry THF was added the 3-Hydroxytetrahydrofuran (14.92 mg, 0.169 mmol), Di-tert-butyl azodicarboxylate (58.5 mg, 0.254 mmol) and triphenylphosphine (66.6 mg, 0.254 mmol). The mixture was stirred at room temperature for Overnight. The reaction mixture was washed with saturated sodium bicarbonate solution and brine. Organics were extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo. Purification by reverse phase chromatography gave 2-[4-(tetrahydrofuran-3-yloxy)phenyl]-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}ethyl)acetamide as a white solid (0.050 g, 70%). 1H NMR (CDCl3, 400 MHz) δ 8.212 (d, J=2.38 Hz, 1H); 7.189 (m, 4H); 6.830 (m, 2H); 6.624 (d, J=7.15 Hz, 1H); 5.103 (quintet, J=6.95 Hz, 1H); 4.924 (m, 1H); 4.379 (dd, J=8.06, 15.93 Hz, 2H); 3.999 (m, 3H); 3.905 (m, 1H); 3.519 (s, 2H); 2.187 (m, 2H); 1.387 (d, J=6.78 Hz, 3H); MS (ES): m/z 425.2 (M+H). FLIPR alpha1I IP=91 nM.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:7][C:5]1[O:4][N:3]=[C:2]([NH:1][S:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:16])=[O:15])[CH:6]=1
Reactant: Cc1cc(N)no1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)no1
Yield: 83.9 %

Procedure:
3-Amino-5-methylisoxazole (0.196 g, 2.0 mmol) was dissolved in dry pyridine (3 ml). Benzenesulfonyl chloride (0.352 g, 2.0 mmol) was added and the resultant solution stirred at room temperature for 16 h. Pyridine was removed under reduced pressure. The residue was dissolved in dichloromethane (75 ml) and washed with 1N HCl (2×50 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give N-(5-methy-3-isoxazolyl)benzene-sulfonamide (0.40 g, 84% yield). The product was purified by recrystallization using ethyl acetate/hexanes to give a white solid, m.p. 107°-8° C.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH:5]=[CH:6][CH2:7][NH:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1>>[CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4]/[CH:5]=[CH:6]\[CH2:7][N:8]([CH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1)[CH3:9]
Reactant: CNCC=CC#CC(C)(C)C
Reactant: CC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)c1cccc(CN(C)C/C=C\C#CC(C)(C)C)c1
Yield: 14.8 %

Procedure:
The procedure described in Example 1 was repeated, except that N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine (trans:cis=about 3:1) (17.7 g; 116.8 mmol), sodium carbonate (17.7 g; 166.8 mmol), and 3′-bromomethylacetophenone (23.7 g; 111.2 mmol) were used, to thereby yield 4.67 g of the target compound (yield: 14.8%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH:18]1[CH2:23][CH2:22][C:21]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1)(=[O:3])[CH3:2].[Si]([Cl:38])(C)(C)C>C(OCC)(=O)C>[ClH:38].[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH:18]1[CH2:19][CH2:20][C:21]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([N:24]([CH3:26])[CH3:25])[CH2:22][CH2:23]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Agent: CC(=O)OCCCCc1c(C2CCC(Cc3ccccc3)(N(C)C)CC2)[nH]c2ccccc12
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
4-(2-(4-Benzyl-4-(dimethylamino)cyclohexyl)-1H-indol-3-yl)butyl acetate (more polar diastereomer) (87 mg, 0.19 mmol) was dissolved in ethyl acetate (7 ml). Me3SiCl (49 μl, 0.39 mmol) was then added dropwise at RT and the mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl acetate (2×5 ml) and then dried. Example 175 (85 mg, m.p. 194-197° C., 90%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: N#Cc1cccc(CBr)c1
Product: N#Cc1cccc(COc2ccc(Cl)c([N+](=O)[O-])c2)c1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 3-bromomethyl-benzonitrile using the conditions described in Example 10C to provide 3-(4-chloro-3-nitro-phenoxymethyl)-benzonitrile which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:21]=1[CH:22]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:21]=1/[CH:22]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(C(F)(F)F)ccc1F)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0.404 mmol) in toluene 10 mL was added 2-fluoro-5-(trifluoromethyl)benzaldehyde 75 (77.7 mg, 0404 mmol). PTSA (153.8 mg, 0809 mmol) was added and the reaction mixture stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 76 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-2-(2-fluoro-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 76 was eluted at 34% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][N:2]([CH3:19])[CH2:3][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[CH2:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C(=O)[C@@H]1CCCCN1C(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C[C@@H]1CCCCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
(2S)—N,N-Dimethyl-1-(phenylcarbonyl)-2-piperidinecarboxamide (883 mg, 3.396 mmol) was dissolved in 20 mL of THF, cooled to 0° C., and then LiAlH4 (1.386 mg, 36.54 mmol) was added portion wise. The mixture was heated to 80° C. for 2 h, then allowed to cool to RT. The reaction was quenched in succession with H2O (1.0 mL), 15% aq. NaOH (1.0 mL) and H2O (3.0 mL), and was stirred at room temperature overnight. The contents were filtered, and the filtrate was concentrated in vacuo to provide N,N-dimethyl-1-[(2S)-1-(phenylmethyl)-2-piperidinyl]methanamine (590 mg, 75%). LCMS: (M+H)+: 233.1.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-])=O)=[CH:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:3]=1>CO.[Pd]>[NH2:7][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH:5]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1nn(C(=O)OC(C)(C)C)cc1N
Yield: 56.5 %

Procedure:
tert-Butyl 3-methyl-4-nitropyrazole-1-carboxylate (815 mg) was dissolved in MeOH (20 ml) and hydrogenated at room temperature for 40 hours with 10% Pd/C (0.2 g, 50% wet). The catalyst was filtered off and the solvent removed in vacuo. Column chromatography on silica (4 g), eluting with 1:1 EtOAc-heptane (500 ml) gave tert-butyl 4-amino-3-methylpyrazole-1-carboxylate (400 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[O:11][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(F)c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of 2-fluoro-6-nitrophenol (25.1 g, 157 mmol) in DMF (430 mL) were added K2CO3 (43.7 g, 313 mmol) and benzyl bromide (21 mL, 172 mmol). The reaction mixture was stirred at 80° C. overnight. After cooling to rt, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. Water (100 mL) and EA (100 mL) were added and the phases were separated. The aq. layer was extracted once with EA (100 mL) and the combined org. layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was dried under HV to give the title compound as a yellow oil (39.9 g).
Reaction SMILES: [Na].[O:2]=[C:3]1[C:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]=2[S:5](=[O:17])(=[O:16])[NH:4]1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Cl)[CH3:19]>C(O)C>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][N:4]1[C:3](=[O:2])[C:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]=2[S:5]1(=[O:17])=[O:16])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:19]
Reactant: CCOC(=O)CCl
Reactant: O=C1NS(=O)(=O)c2c1ccc1ccccc21
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CN1C(=O)c2ccc3ccccc3c2S1(=O)=O
Yield: 72 %

Procedure:
3-Oxo-naphth[2,1-d]isothiazoline-2-acetic acid ethyl ester -1,1-dioxide was prepared analogous to Example 1a from the sodium salt of 3-oxo-naphth[2,1-d]isothiazoline-1,1-dioxide and chloro-acetic acid ethyl ester. Yield: 72% of theory; m.p. 149- 150.5° C (from ethanol).