Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[CH:19][C:18]=2[OH:29])=[O:16])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].Cl>CC(C)=O>[CH2:37]([O:36][C:34]([CH2:33][O:29][C:18]1[CH:19]=[C:20]([O:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][C:17]=1[C:15](=[O:16])[CH:14]=[CH:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=1)=[O:35])[CH3:38]
Reactant: CCCCCCc1ccc(C=CC(=O)c2ccc(OCC=C(C)C)cc2O)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCCCc1ccc(C=CC(=O)c2ccc(OCC=C(C)C)cc2OCC(=O)OCC)cc1
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
To a solution of 5.50 g of 4-n-hexyl-2'-hydroxy-4'-(3-methyl-2-butenyloxy)chalcone in 55 ml of dry acetone was added 1.4 g of crushed potassium hydroxide. After stirring for 5 minutes, 2.40 g of ethyl bromoacetate was added, and the mixture was stirred at room temperature for 40 minutes. After completion of the reaction, the reaction mixture was neutralized by adding dropwise dilute hydrochloric acid with ice cooling. The precipitated solid was collected by filtration, washed with water, dried and recrystallized from ethanol to give 5.73 g of 2'-ethoxycarbonylmethoxy-4-n-hexyl-4'-(3-methyl-2-butenyloxy)chalcone as pale yellow needles.
Reaction SMILES: [CH3:1][NH:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:10][N:11]([CH2:13][C:14]1[O:18][C:17]([CH2:19][S:20][CH2:21][CH2:22][NH2:23])=[CH:16][CH:15]=1)[CH3:12].CC(C)CC(=O)C>O>[CH3:12][N:11]([CH2:13][C:14]1[O:18][C:17]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:3]([NH:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:16][CH:15]=1)[CH3:10]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CNC(=C[N+](=O)[O-])SC
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1

Procedure:
N-Methyl-1-(methylthio)-2-nitroetheneamine (230 g) in water (400 ml) was stirred and heated at 45°-50°. 2-[[[5-(Dimethylamino) methyl-2-furanyl]methyl]thio]ethanamine (321 g) was added dropwise over 4 hr and the resultant solution stirred for a further 31/2 hr. The solution was then heated at reflux for 1/2 hr., cooled to 70° and 4-methylpentan-2-one (2 liters) added. The water was removed by azeotropic distillation under reduced pressure (260 torr) and the resultant solution treated with charcoal (10 g) at 50°. The solution was filtered and cooled to 10°. N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (380 g) was filtered off and dried m.p. 69°-70°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.Cl.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[S:6][CH:7]=2)[CH2:27][CH2:26]1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: COc1ccc(N2CCCNCC2)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCCN(Cc3csc(-c4ccccc4)n3)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
A mixture of 4-chloromethyl-2-phenylthiazole (80 mg, 0.38 mmol, 1 equiv), 1-(2,4-dimethoxyphenyl)-[1,4]diazepane HCl salt (117 mg, 0.38 mmol, 1 equiv) and Cs2CO3 (619 mg, 5 equiv) in 1 mL of DMF was stirred at room temperature overnight. The mixture was diluted with EtOAc 30 mL), washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) sequentially and then dried over magnesium sulfate. The residue was purified by flash column chromatograph using 30 to 100% EtOAc in hexane to afford the title compound as light tan solid (50 mg) after evaporation and drying in vacuo. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, 2H, J=8.0 Hz), 7.39 (m, 3H), 7.15 (s, 1H), 6.88 (d, 1H, J=8.8 Hz), 6.42 (s, 1H), 6.39 (d, 1H, J=8.8 Hz), 3.91 (s, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 3.25 (m, 4H), 2.92 (m, 4H), 1.98 (m, 2H). MS (ES) m/z 410.2 (M+H+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:33])[CH2:18][C:19]3[CH:20]=[C:21](Cl)[C:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=4)=[N:23][CH:24]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:34][N:35](C=O)C.O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:33])[CH2:18][C:19]3[CH:20]=[C:21]([C:34]#[N:35])[C:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=4)=[N:23][CH:24]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(C)c4)c(Cl)c3)nc2)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(C)c4)c(C#N)c3)nc2)CC1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
To a sealed tube were added N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-chloro-2′-methyl-2,4′-bipyridin-5-yl)acetamide 184 (46 mg, 0.10 mmol), zinc cyanide (14 mg, 0.12 mmol), Pd2(dba)3 (9 mg, 0.010 mmol), Q-phos (9 mg, 0.022 mmol) and 1 ml DMF/H2O (99/1, v/v). The reaction mixture was bubbled with nitrogen for 1 minute and stirred at 130° C. overnight. After cooling to room temperature, the solvents were evaporated and the crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-cyano-2′-methyl-2,4′-bipyridin-5-yl)acetamide 188. MS m/z 456.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.85 (d, 1H), 8.56 (d, 1H), 8.28 (d, 1H), 7.98 (s, 1 Hz), 7.88 (d, 1H), 7.78 (s, 1H), 7.73-7.70 (m, 1 Hz), 7.39 (dd, 1H), 3.89 (s, 2H), 3.69 (t, 2H), 3.65 (t, 2H), 3.16 (t, 2H), 3.11 (t, 2H), 2.61 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [CH:1]12[NH:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1.[OH:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH:26]=O>>[CH:14]1[C:15]2[C:10](=[C:9]([NH:8][CH:2]3[CH2:3][CH:4]4[N:7]([CH2:26][C:25]5[CH:28]=[CH:29][C:30]([CH3:31])=[C:23]([CH:24]=5)[O:22][CH2:21][CH2:20][OH:19])[CH:1]3[CH2:6][CH2:5]4)[CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: c1cc(NC2CC3CCC2N3)c2ccncc2c1
Reactant: Cc1ccc(C=O)cc1OCCO
Product: Cc1ccc(CN2C3CCC2C(Nc2cccc4cnccc24)C3)cc1OCCO

Procedure:
Reaction of Intermediate 29 with 3-(2-hydroxyethoxy)-4-methylbenzaldehyde affords the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:17])[C:14]([I:16])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:19][C:2]([F:1])([F:18])[C:3]([N:5]1[CH2:6][CH2:7][C:8]2[CH:15]=[C:14]([I:16])[C:13]([O:17][CH2:21][C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:12][C:9]=2[CH2:10][CH2:11]1)=[O:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(N1CCc2cc(O)c(I)cc2CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1cc2c(cc1I)CCN(C(=O)C(F)(F)F)CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
Dry acetone (6 ml) was added to a flask containing the product from step (a) (0.528 g, 1.3 mmol). To this was added 2-Bromo-1-phenyl-ethanone (0.327 g, 1.6 mmol, 1.2 eq) and potassium carbonate (0.378 g, 2.7 mmol, 2.0 eq). The reaction mixture was allowed to stir for 16 hours at room temperature. The acetone was removed under vacuum and the solid was dissolved in dichloromethane, washed with 4N HCl, and brine. Purification by silica-gel chromatography (gradient elution: 0-100% EtOAc in hexanes) gave the sub-title compound as a white solid (552 mg). MS: ESI (positive): 504 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]([NH:20][C:21](=[O:36])[C:22]3[CH:27]=[C:26]([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH:25]=[CH:24][C:23]=3[Cl:35])=[CH:18][C:17]([C:37](OCC)=[O:38])=[N:16]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[CH2:42]([CH2:44][NH2:45])[OH:43]>>[Cl:35][C:23]1[CH:24]=[CH:25][C:26]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:27][C:22]=1[C:21]([NH:20][C:19]1[N:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[N:16]=[C:17]([C:37]([NH:45][CH2:44][CH2:42][OH:43])=[O:38])[CH:18]=1)=[O:36]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2cccc(OCc3ccccc3)c2)n1
Reactant: NCCO
Product: O=C(NCCO)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2cccc(O)c2)n1

Procedure:
The title compound was prepared according to the method described for Example 85 using ethyl 1-(3-(benzyloxy)phenyl)-5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1H-pyrazole-3-carboxylate (Example 128) and ethanolamine. The residue was purified using reverse phase column chromatography eluting with 0-100% MeCN in water with 0.1% NH3.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([C:13]2[O:17][N:16]=[C:15]([CH2:18]OS(C)(=O)=O)[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[NH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35](=[O:46])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:45])([F:44])[F:43])[CH2:31][CH2:30]1)=[O:28].O>CN(C=O)C>[C:7]1([C:13]2[O:17][N:16]=[C:15]([CH2:18][NH:25][CH2:26][C:27]([N:29]3[CH2:30][CH2:31][N:32]([C:35](=[O:46])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]([F:45])([F:43])[F:44])[CH2:33][CH2:34]3)=[O:28])[CH:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)OCc1cc(-c2ccccc2)on1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNCc1cc(-c2ccccc2)on1)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 40 °C
Yield: 9.3 %

Procedure:
K2CO3 (201 mg, 1.46 mmol) was added to a stirred solution of methanesulfonic acid 5-phenyl-isoxazol-3-ylmethyl ester (200 mg, 0.73 mmol) and 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (257 mg, 0.73 mmol) in DMF (4 mL). The resulting mixture was heated at 40° C. for 1 hr. Cold water was then added and the resulting precipitate was isolated by filtration. The crude solid was purified by column chromatography using (silica gel of 60-120 mesh and 2% MeOH in CHCl3 as eluent) to afford 32 mg (9.2% yield) of 2-[(5-phenyl-isoxazol-3-ylmethyl)-amino]-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone. LCMS Purity: 96.53%. 1H NMR (DMSO-d6): δ 9.85 (s, 2H), 7.96-7.82 (m, 3H), 7.82-7.74 (t, 1H), 7.3 (d, 1H), 6.64-6.48 (d, 1H), 4.0-3.9 (d, 2H), 3.9-3.8 (m, 1H), 3.76-3.56 (m, 2H), 3.56-3.4 (m, 4H), 3.56-3.26 (bs, 1H), 3.2 (d, 2H), 2.49-2.29 (bs, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:25])([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(N(CC)CC)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:25])([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCO)cc1)Oc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccccc1

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 3-[4-(2-hydroxyethoxy)phenyl]-2-methyl-2-phenoxypropionate (1.10 g), which is the product of Reference example 8(d), triethylamine (0.49 ml) and methanesulfonyl chloride (0.25 ml) and the reaction mixture was treated to afford the desired compound (1.42 g) as a syrup.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:13]([O:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][CH2:24][CH2:25][O:26][CH2:27][CH3:28])[CH3:14]>ClCCl.CN(C=O)C.O.C(=O)(O)[O-].[Na+]>[CH2:13]([O:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]([C:4](=[O:5])[CH2:3][C:1]#[N:2])[CH2:24][CH2:25][O:26][CH2:27][CH3:28])[CH3:14]
Reactant: CCOCCNc1ccccc1C(=O)OCC
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCN(C(=O)CC#N)c1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of commercially available cyanoacetic acid (1.1 eq, 0.118 g, 1.39 mmole) in dichloromethane was added oxalylchloride (0.353 g, 2.78 mmole, 0.236 mL) and 2 drops N,N′-dimethylformamide). The reaction was stirred for 2 hours at RT until homogenous solution developed. 2-(2-Ethoxy-ethylamino)-benzoic acid ethyl ester (1 eq, 0.300 g, 1.26 mmole) was added and the resulting solution was allowed to stir at RT overnight. Reaction mixture was diluted with saturated sodium bicarbonate water (20 mL) and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively With water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 2-[(2-Cyano-acetyl)-(2-ethoxy-ethyl)-amino]-benzoic acid ethyl ester as clear liquid (0.292 g, 76%, LCMS calc M+H 305, obs M+H 305).
Reaction SMILES: [Si](O[CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][O:29]S(C)(=O)=O)[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(C(C)(C)C)(C)C.O.[F-].C([N+](CC)(CC)CC)C>C1COCC1.CCOC(C)=O>[CH3:17][C:14]1([CH3:18])[N:13]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:12]([CH2:11][C@H:10]2[CH2:26][CH2:27][CH2:28][O:29][CH2:9]2)[CH2:16][O:15]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CCCOC2)COC1(C)C
Yield: 54 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-(methylsulfonyloxy)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (37.7 g, 74.2 mmol) in THF (1000 mL) was added tetraethylammonium fluoride hydrate (41 g, 185.5 mmol) in portions. The reaction mixture was stirred under reflux overnight. The mixture was diluted with EtOAc (1000 mL), washed with water (300 mL) and brine (500 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography to afford (S)-tert-butyl 2,2-dimethyl-4-(((R)-tetrahydro-2H-pyran-3-yl)methyl)oxazolidine-3-carboxylate (12.0 g, 54%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][NH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)NNC(=O)CNC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
A solution of compound 7 (59 g, 200 mmol) and triethylamine (42 ml, 0.57 mol) in carbon tetrachloride (60 ml) is added to a stirred, room temperature of triphenylphosphine (63 g, 0.24 mol) in methylene chloride (900 ml). The reaction mixture is stirred for 30 minutes and then refluxed for 12 hours. After cooling to room temperature, the volatiles are removed in vacuo and the resulting residue is filtered through silica using methylene chloride:ethyl acetate (9:1) as the eluent. After removing the volatiles in vacuo, the crude product is purified by flash column chromatography over silica gel using methylene chloride:ethyl acetate (19:1) as the eluent. 24 g (44%) Of compound 8 is obtained as orange oil, which solidifies to a yellow solid on standing.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:25]([O:15][CH:12]1[CH2:11][CH2:10][N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(CN2CCC(O)CC2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1)c1ccccc1
Yield: 77.5 %

Procedure:
0.3 g (0.00127mol) of 1-(4-nitro-benzyl)-piperidin-4-ol and 0.356 ml (0.00254 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.177 ml (0.0015 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.335 g (78%) of 1-(4-nitro-benzyl)-piperidin-4-yl benzoate was obtained as yellow crystals. MS: me/e (% basic peak)=340 (C19H20O4+, 3.5), 235 (5), 218 (41), 105 (26), 82 (100).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.CN(P(N(C)C)(N(C)C)=O)C.[Li+].CC([N-]C(C)C)C.[C:34](=[O:36])=[O:35]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([S:8](=[O:10])(=[O:9])[NH2:11])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH2:14][C:34]([OH:36])=[O:35]
Reactant: O=C=O
Reactant: COc1cc(C)c(Br)cc1S(N)(=O)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COc1cc(CC(=O)O)c(Br)cc1S(N)(=O)=O
Temperature: -75 °C
Reaction time: 1.5 h
Yield: 3 %

Procedure:
A dry 25 mL 3-neck RBF, fitted with a magnetic stirring bar, a thermometer and septum with Ar inlet was charged with 5-bromo-2-methoxy-4-methylbenzene-sulfonamide 12e (0.586 g, 2.1 mmol), anhydrous THF (5 mL) and HMPA (0.37 mL, 2.1 mmol). The mixture was cooled to −75° C. and a 2.0 M solution of LDA (4.2 mL, 8.4 mmol) was added drop wise via a syringe. The reaction mixture was stirred at −75° C. for 1.5 hours and then cannulated into a flask containing 20 g of dry ice and 5 mL THF and left to warm up slowly to RT. The solvent was removed under reduced pressure and H2O (20 mL) was added to the residue. At this point, some of the unreacted starting material precipitated and was removed by filtration. The filtrate was acidified and the solution was extracted with EtOAc (3×20 mL). The combined organic layers were evaporated to dryness, the residue was treated with an aqueous solution of saturated NaHCO3 (10 mL) and the insoluble material was separated by filtration. The filtrate was acidified with concentrated HCl and the cloudy solution extracted again with EtOAc (3×5 mL). The combined organic layers were concentrated to ˜1 mL, causing crystallization of the product, which was collected by filtration to give pure (2-bromo-5-methoxy-4-sulfamoylphenyl)acetic acid (20 mg) 12f (˜3% yield).
Reaction SMILES: [CH2:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[Li]CCCC.[C:15]([N:19]=[C:20]=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[CH2:1]([C:5]1[S:6][C:7]([C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[CH:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)N=C=O
Reactant: CC(C)Cc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(=O)NC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
To 2-iso-butylthiophene (1 g, 7.143 mmol, see step (a) above) in THF (15 mL) was added n-BuLi (1.6 M in hexane, 5.3 mL, 8.48 mmol) at −78° C. and the reaction mixture was stirred at 0° C. for 2 hours. tert-Butylisocyanate (897 μL, 7.86 mmol) was then added to the mixture at −78° C. The stirred solution was kept at 0° C. for an additional 2 hours. The reaction mixture was then quenched with H2O (15 mL) and extracted with EtOAc (3×20 mL). The organic layer was dried over MgSO4, concentrated and purified using silica gel column chromatography (10:90 petroleum ether-EtOAc) to give the sub-title compound (1.2 g, 5.01 mmol) as white needles in 70% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[C:12]1([C:18]2[S:19][CH:20]=[C:21]([C:23]([N:25]3[CH2:30][C:29]4([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[O:28][CH2:27][CH2:26]3)=[O:24])[N:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CC#N>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]1[CH2:34][CH2:35][C:29]2([O:28][CH2:27][CH2:26][N:25]([C:23]([C:21]3[N:22]=[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[S:19][CH:20]=3)=[O:24])[CH2:30]2)[CH2:31][CH2:32]1
Reactant: OCCCCCCCCCBr
Reactant: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCN(CCCCCCCCCO)CC2)C1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 9-bromo-1-nonanol (0.346 g) in MeCN (3 mL) was added to solution of (2-phenylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 112, step b) (0.355 g) and triethylamine (0.288 mL) in MeCN (7 mL). The resulting mixture was stirred at 60° C. under argon for 17 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM, washed with brine (×2), dried over sodium sulphate, filtered and evaporated in vacuo. The yellow oil was purified by silica gel chromatography eluting with 0-7% MeOH in DCM to give the subtitled compound as a white solid. Yield 0.378 g.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[I-:16].[Na+].CNCCNC>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[I:16][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Brc1cncc(C#Cc2ccccc2)c1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Ic1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
Heat a mixture of 3-bromo-5-phenylethynylpyridine (5.71 g, 22.12 mmol), (prepared essentially as described in EXAMPLE 9), copper (I) iodide (211 mg, 1.1 mmol), sodium iodide (6.63 g, 44.24 mmol) and N,N′-dimethylethylenediamine (0.24 mL, 2.21 mmol) in 1,4-dioxane (20 mL) at 110° C. for 60 h. Cool to room temperature, dilute with ethyl acetate and wash with a saturated aqueous solution of sodium chloride, and dry (sodium sulfate). Purify the residue by silica gel chromatography, eluting with 15:1 hexanes:ethyl acetate, to give the title compound (5.45 g, 81%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]2[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]#[N:31])[CH:24]=3)[NH:19]2)[CH:15]=[CH:16][CH:17]=1.N1C=CC=CC=1>ClCCl>[C:30]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]([C:14]1[CH:13]=[C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:17]=[CH:16][CH:15]=1)[CH2:27][C:26]2([CH3:29])[CH3:28])#[N:31]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3)c2)Nc2ccc(C#N)cc21
Reaction time: 8 h
Yield: 46.6 %

Procedure:
To a round bottom flask, benzenesulfonyl chloride (83 mg, 0.54 mmol) was added dropwise a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (100 mg, 0.36 mmol) and pyridine (45 mg, 0.54 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. Filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford N-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide as off-white solid (70 mg, yield: 46.5%). MS (ESI+APCI) M+1=418.2.