Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)(=[O:3])[CH3:2].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].CO>C1(C)C=CC=CC=1.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.CCOCC>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(Br)n1
Reactant: OB(O)c1ccccc1
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: CO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a Schlenk tube charged with a solution of 200 mg (1.0 mmol) of 2-acetyl-6-bromopyridine and 23 mg (0.02 mmol) of (Ph3P)4Pd in 10 mL of degassed toluene was added a solution. of 150 mg (1.2 mmol) phenylboronic acid and 270 mg (2.5 mmol) Na2CO3 in 8 mL of degassed 4:1H2O/MeOH. The biphasic mixture was heated to 80° C. with rapid stirring for 1 h. On cooling to RT, Et2O (50 mL) was added and the layers were separated. The organic layer was dried over Na2SO4 and the volatiles were removed by rotary evaporation. The resulting oil was chromatographed on silica with 10-50% CH2Cl2/hexanes eluent to provide 176 mg (89%) of 2-acetyl-6-phenylpyridine as a white powder. 1H NMR (CDCl3); δ 2.84 (s, 3H); 7.43-7.62 (m, 3H); 7.91-8.08 (m, 3 H); 8.18 (d, J=6.6 Hz, 2H). Mass Spec.: m/e 197.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: O=C(O)CCc1ccccc1Br
Reactant: CO
Product: COC(=O)CCc1ccccc1Br

Procedure:
Prepared according to the procedure described in Example 34, Step 1, using 3-(2-bromo-phenyl)-propionic acid and methanol.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].C(N(CC)CC)C>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[S:28]([CH2:26][CH3:27])(=[O:30])=[O:29]
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of compound 7B (15 mg, 0.044 mmol), ethanesulfonyl chloride (5 μL, 1.5 eq), triethylamine (15 μL, 3.0 eq) and dichloromethane (1 mL) was stirred at room temperature overnight. The clear solution was directly loaded on silica gel column and eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (12.5 mg, 82% yield)
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[C:6](\[Cl:13])/[C:7](=[O:12])[O:8][CH2:9][CH2:10][CH3:11])[C@H:3]1[C:14]([OH:16])=[O:15].[C:18]([C@@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19]>C(Cl)(Cl)Cl>[CH3:17][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](\[Cl:13])/[C:7](=[O:12])[O:8][CH2:9][CH2:10][CH3:11])[C@H:3]1[C:14]([O:16][C@H:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:15]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCCOC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Solvent: ClC(Cl)Cl
Product: CCCOC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-propoxy-1-propenyl]-cyclopropane-1-carboxylic acid and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-propoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+22.5°±2° (c=0.7% in chloroform).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8](/[CH:10]=[CH:11]/[C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][CH:13]=2)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:5]1[O:9][C:8]([CH2:10][CH2:11][C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][CH:13]=2)=[N:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(=O)Nc1ncc(/C=C/c2ncc(C(C)(C)C)o2)s1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ncc(CCc2ncc(C(C)(C)C)o2)s1
Reaction time: 24 h

Procedure:
A solution N-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]acetamide (67 mg, 0.23 mmol) in ethyl acetate (10 mL) was added to a suspension of pre-reduced Pd/C (10%) in ethyl acetate (5 mL). The reaction flask was fitted with a hydrogen balloon and stirred for 24 hours. The reaction was filtered, and the mixture was resubmitted to hydrogenation using the same conditions as above. After an additional 24 hours, the reaction was filtered through a plug of celite, concentrated, and purified by chromatography (SiO2, 5% MeOH/CHCl3) to give N-[5-(2-(5-t-butyl-oxazol-2-yl)-ethyl)-thiazol-2-yl]-acetamide as a white solid (3.5 mg, 5%, C14H19N3O2S, MS m/e 294 (M+H)+). HPLC-HI 91% at 6.75 min (Zorbax SB C18 column 4.6×75 mm, 10-90% aqueous methanol over 8 minutes containing 0.1% TFA, 2.5 mL/min, monitoring at 220 nm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28]([O:30]C)=O)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH3:36]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28]([NH2:36])=[O:30])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: N
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(N)=O
Yield: 77 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.42 mmol) was reacted with ammonia to give the title compound as a solid (150 mg, 77%); NMR Spectrum 1.66 (d, 3H), 5.14 (q, 1H), 5.70 (s, 2H), 7.12-7.01 (m, 4H), 7.36 (m, 2H), 7.54 (s, 1H), 7.75 (m, 3H), 7.89 (s, 1H), 8.16 (s, 1H), 8.52 (s, 2H), 10.80 (s, 1H); Mass spectrum 457.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][NH:25][CH3:26])[C:18]4=[O:27])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[F:34][C:35]([F:47])([F:46])[C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][CH2:24][N:25]([CH3:26])[S:42]([C:39]5[CH:38]=[CH:37][C:36]([C:35]([F:34])([F:46])[F:47])=[CH:41][CH:40]=5)(=[O:44])=[O:43])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:31])([F:33])[F:32])[CH:3]=1
Reactant: CNCCN1C(=O)SC(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: CN(CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-N-methyl-4-(trifluoromethyl)benzenesulfonamide was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-3-(2-methylaminoethyl)thiazolidine-2,4-dione (from Example 394) and p-trifluoromethylbenzenesulfonyl chloride following General Procedure U.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:7]([CH:11]=1)[C:8]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:10])#[N:2]
Reactant: N#Cc1ccc(Oc2cccc(F)c2)c(C(=O)O)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(C#N)ccc2Oc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-cyano-2-(3-fluorophenoxy)benzoic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.54 (1H, s), 7.97 (2H, d, J=8.4 Hz), 7.77–7.65 (2H, m), 7.47–7.34 (3H, m), 7.04–6.80 (4H, m), 5.35 (1H, m), 3.90 (3H, s), 1.54 (3H, d, J=7.8 Hz).
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH2:16][CH2:17][NH2:18])=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>C(Cl)Cl>[C:30]([O:29][C:27]([NH:18][CH2:17][CH2:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH2:6][C:5]3[NH:1][N:2]=[N:3][N:4]=3)[CH:8]=2)[NH:12][CH:11]=1)=[O:26])([CH3:33])([CH3:32])[CH3:31]
Reactant: NCCc1c[nH]c2ccc(Cc3nnn[nH]3)cc12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(Cc3nnn[nH]3)cc12
Reaction time: 16 h
Yield: 64.3 %

Procedure:
To a stirred suspension of 2-(5-tetrazol-5-ylmethyl-1H-indol-3-yl)ethylamine (1.76 g, 7.27 mmol) in dry CH2Cl2 (40 ml) was added triethylamine (1.5 g, 14.9 mmol) and (BOC)2O (1.9 g, 7.3 mmol) and the mixture stirred for 16 h. The solvent was removed under vacuum and the residue chromatographed on silica-gel eluting with EtOH/Et2O/H2O/NH3 (20:60:8:1) to give the title product (1.6 g, 64%); δ (360 MHz, CD3OD) 1.41 (9H, s, 3 of CH3); 2.87 (2H, t, J=7.4 Hz, CH2); 3.30 (2H, t, J=7.4 Hz, CH2); 4.32 (2H, s, CH2); 6.99 (1H, d, J=8.3 Hz, Ar-H); 7.04 (1H, s, Ar-H); 7.26 (1H, d, J=8.3 Hz, Ar-H); 7.49 (1H, s, Ar-H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Reactant: Cc1ccccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ccccc1COc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 2-Methylbenzyl bromide (38 mg, 0.27 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(2-methyl-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (20.9 mg, 28%). HRMS Calcd. for C18H17N2O3 (M+H)+, 309.1234. Found: 309.1233.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17](O)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH3:51])[C:46]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:16]=[C:17]([C:46]2[C:47]([CH3:51])=[CH:48][CH:49]=[CH:50][C:45]=2[CH3:44])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(OCc2ccccc2)cc(-c2c(C)cccc2C)c1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of methyl 3-(benzyloxy)-5-hydroxybenzoate (3.10 g, 12.0 mmol) and N-ethyldiisopropylamine (2.51 mL, 14.4 mmol) in dichloromethane (30 mL) was added dropwise trifluoromethanesulfonic anhydride (2.22 mL, 13.2 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 1,2-dimethoxyethane (40 mL), and 2,6-dimethylphenylboronic acid (2.25 g, 15.0 mmol), tripotassium phosphate (3.82 g, 18.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.693 g, 0.600 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 80° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-20% ethyl acetate/hexane) to give the title compound (3.60 g, yield 87%) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:13][CH3:14])([O:11][CH3:12])[O:9][CH3:10].[CH2:15]([N:33]=[C:34]=[O:35])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:15]([NH:33][C:34]([NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:13][CH3:14])([O:9][CH3:10])[O:11][CH3:12])=[O:35])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CO[Si](CCCNCCN)(OC)OC
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCNCCC[Si](OC)(OC)OC
Temperature: 25 °C

Procedure:
To 22.2 g (0.10 mole) of 3-(2-aminoethylamino)propyltrimethoxysilane under nitrogen was added 29.5 g (0.10 mole) of octadecylisocyanate over a 45 min. period. The reaction temperature rose to ca. 70° C. Upon cooling to ambient temperature, the product solidified to a white wax. IR (neat film) 3300, 2900, 1620, 1570, 1470, 1090 cm-1. NMR (CDCl3) 0.4-1.0 (m; 5H), 1.1-2.0 (m; 34H), 2.4-2.8 (m; 2H), 2.9-3.4 (m; 7H), 3.55 (s; 9H), 5.5 (br s; 2H) ppm.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]#[N:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[F:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[CH:14]=[N+:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.FC1C=CC=CC=1C=O.N1CCCCC1>>[F:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[CH:14]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:2]1[N:1]([CH2:6][CH2:7][C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccccc1C=[N+]1CCCCC1
Reactant: N#CCCn1cccc1
Agent: O=Cc1ccccc1F
Agent: [Cl-]
Solvent: C1CCNCC1
Product: N#CCCn1cccc1C(c1ccccc1F)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 3-pyrrol-1-yl-propionitrile and 1-(2-fluoro-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 3 from 2-fluorobenzaldehyde and piperidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[N:9]([CH2:12][CH3:13])=[C:10]=[O:11]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:10]([NH:9][CH2:12][CH3:13])=[O:11])[CH:3]=1
Reactant: CCN=C=O
Reactant: Nc1cc(Br)ccn1
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1cc(Br)ccn1
Temperature: 110 °C
Yield: 76.2 %

Procedure:
To a mixture of 4-bromopyridin-2-amine (2 g, 11.56 mmol) in chloroform (10 mL), isocyanatoethane (0.913 mL, 11.56 mmol) was added, and the resulting reaction mixture was heated at 110° C. for 2 h. The reaction mixture was concentrated under reduced pressure and triturated with acetonitrile, then collected by filtered to give the title compound as a white solid (2.15 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[CH:26]=[C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=5)[S:28][C:21]=34)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[CH:26]=[C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH2:33][N:1]6[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]6)=[CH:31][CH:30]=5)[S:28][C:21]=34)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: NC(=O)C1CCNCC1
Reactant: O=Cc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: NC(=O)C1CCN(Cc2ccc(-c3cc4nccc(Nc5ccc6[nH]ccc6c5)c4s3)cc2)CC1

Procedure:
The title compound was prepared from piperidine-4-carboxylic acid amide and 4-[7-(1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-benzaldehyde by a procedure analogous to example 17. LC-MS: 482 (MH+); HPLC RT: 3.56 minutes.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:36])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:35])[C:24]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:35][N+:23]1[C:24]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:36])[CH3:16])[N:22]=1
Reactant: CN(C)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCNc1n[n+]([O-])c2c3c(ccc2[n+]1[O-])CCCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.6 %

Procedure:
H2O2 (70%, 0.12 mL, ca. 2.4 mmol) was added dropwise to a stirred solution of TFAA (0.34 mL, 2.4 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 172 (70 mg, 0.2 mmol) and TFA (95 μL, 1.2 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 173 (38 mg, 52%) as a red solid: mp (MeOH/EtOAc) 139-142° C.; 1H NMR δ 8.06 (d, J=8.9 Hz, 1H, H-5), 7.51 (d, J=8.9 Hz, 1H, H-6), 7.38 (br s, 1H, NH), 3.59-3.66 (m, 2H, CH2N), 3.49-3.55 (m, 2H, CH2), 2.83-2.92 (m, 2H, CH2), 2.61-2.65 (m, 2H, CH2N), 2.32 [s, 6H, N(CH3)2], 1.80-1.88 (m, 4H, 2×CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]3=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]3[CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)Oc1ccc(-c2cccnc2N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(3-chloro-4-isopropoxyphenyl)pyridin-2-amine (770 mg) in THF (dry) (10 mL) was added to a suspension of NaH (60%, 586 mg) and 2-chloroethanesulfonyl chloride (0.919 mL) in THF (dry) (10 mL) at 0° C. The mixture was stirred at room temperature overnight. Water and hexane were added to give a white precipitate. The precipitate was collected by filtration, washed with water and EtOAc and crystallized from THF-IPE to give the title compound (600 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[NH:9][C:5]=2[CH:4]=1.[H-].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([N:7]1[C:6]2[CH:26]=[CH:27][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][C:5]=2[N:9]=[C:8]1[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12][CH2:11]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: FC(F)(F)c1ccc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2c(c1)nc(N1CCN(c3ncccc3C(F)(F)F)CC1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(trifluoromethyl)-2-{4-[3-(trifluoromethyl)(2-pyridyl)]piperazinyl}benzoimidazole (415 mg, 1.0 mmol, Example 53) in anhydrous DMF (5 mL, Aldrich) was added sodium hydride (72 mg, 50% in mineral oil, 1.5 mmol, Aldrich) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. After the mixture was cooled to 0° C., it was treated with benzyl bromide (171 mg, 1.0 mmol, Aldrich) and stirred at room temperature for 16 h. The reaction was then quenched with saturated aqueous solution of NaHCO3 (30 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (25% EtOAc/hexane) to give the title compound as white solid. MS (ESI, pos. ion) m/z: 506.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.C([O:16][C:17]([C:19]1([CH2:26][CH2:27]OC)[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=O)C.[Cl-].C[Al+]C>C1(C)C=CC=CC=1>[OH:25][CH:22]1[CH2:23][CH2:24][C:19]2([C:17](=[O:16])[N:11]([C:8]3[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:12])[F:13])=[CH:6][CH:7]=3)[CH2:27][CH2:26]2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Reactant: Nc1ccc(OCC(F)(F)F)nc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(c2ccc(OCC(F)(F)F)nc2)CCC12CCC(O)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-(2,2,2-Trifluoro-ethoxy)-pyridin-3-ylamine (5.11 g, obtained in example 108, step 2) was added to a solution of 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (5.10 g, obtained in example 2, step 3) in toluene (160 mL). The mixture was stirred for 10 minutes at RT. Then, dimethylaluminiumchloride (1M in hexane, 66.4 mL) was added dropwise over a period of 30 minutes. The reaction mixture was heated to reflux for 2 hours and then at 95° C. for 16 hours. The mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The title compound was obtained as an inseparable mixture of cis and trans diastereomeres as a brown oil (9.56 g, 100%). This mixture was used without further purification. MS (m/e): 345.1 [MH+].
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13]C[NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[C:15]1([S:21]([N:24]2[C:29]3[CH:30]=[C:31]([Cl:35])[CH:32]=[C:33](Br)[C:28]=3[O:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.BrC1C2OCCN(S(C3C=CC=C(Cl)C=3)(=O)=O)C=2C=CC=1>>[C:15]1([S:21]([N:24]2[C:29]3[CH:30]=[C:31]([Cl:35])[CH:32]=[C:33]([N:8]4[CH2:9][CH2:10][NH:11][CH2:13][CH2:14]4)[C:28]=3[O:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)N1CCOc2c(Br)cc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=S(=O)(c1cccc(Cl)c1)N1CCOc2c(Br)cccc21
Product: O=S(=O)(c1ccccc1)N1CCOc2c(N3CCNCC3)cc(Cl)cc21

Procedure:
Similarly, but replacing piperazine-1-carboxylic acid tert-butyl ester with [1,4]diazepane-1-carboxylic acid tert-butyl ester and 4-benzenesulfonyl-8-bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine with 8-bromo-4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine the following compound was prepared: