Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH3-]C#N.[Na+].[NH2:5][CH2:6][C@@H:7]([C:16]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:27])[NH:21]2)[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH2:28]([N:30]1[C:34]2=[N:35][C:36]([CH2:62][CH3:63])=[C:37]([CH2:46][NH:47][C:48](=[O:61])[C:49]3[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][CH2:57][CH2:58][CH:59]=O)=[CH:51][CH:50]=3)[C:38]([NH:39][CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[C:33]2[CH:32]=[N:31]1)[CH3:29].C(O)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.O>[Si:9]([O:8][C@H:7]([C:16]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:27])[NH:21]2)[CH2:6][NH:5][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][C:52]1[CH:51]=[CH:50][C:49]([C:48]([NH:47][CH2:46][C:37]2[C:38]([NH:39][CH:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[C:33]3[CH:32]=[N:31][N:30]([CH2:28][CH3:29])[C:34]3=[N:35][C:36]=2[CH2:62][CH3:63])=[O:61])=[CH:54][CH:53]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCC=O)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c3[nH]c(=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
NaCNBH3 (160 mg, 2.55 mmol) was added to a solution of Intermediate 2 (240 mg, 0.61 mmol), Intermediate 36 (250 mg, 0.51 mmol), and acetic acid (0.032 mL, 0.561 mmol) in THF (5 mL). The reaction mixture was stirred at rt for 1 h. H2O (2 mL) was added followed by satd. NaHCO3 solution (20 mL) and EtOAc (100 mL). The organic layer was separated, dried over MgSO4 (s), filtered, and concentrated in vacuo. Purification by column chromatography on silica gel eluting with a gradient of 0-100% DCM-DCM/MeOH/Ammonia (80/20/1) afforded the title compound as a yellow solid (200 mg). ES/MS calcd. for C45H64N7O5Si+ 810.5. found m/z=810.5 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][NH:10]C(=O)OC(C)(C)C)=[C:7]([CH3:18])[CH:6]=[C:5]([CH3:19])[N:4]=1>Cl>[NH2:10][CH2:9][C:8]1[C:3](=[O:2])[NH:4][C:5]([CH3:19])=[CH:6][C:7]=1[CH3:18]
Reactant: COc1nc(C)cc(C)c1CNC(=O)OC(C)(C)C
Agent: Cl
Product: Cc1cc(C)c(CN)c(=O)[nH]1
Reaction time: 6 h
Yield: 97.3 %

Procedure:
A solution of tert-butyl [(2-methoxy-4,6-dimethylpyridin-3-yl)methyl]carbamate (Cpd U, 140 g, 0.52 mol) in 6N HCl (500 mL) was heated at 100° C. and stirred for six hours. The reaction mixture was concentrated and the residue was re-crystallized with EtOH to afford the title compound (Cpd V, 77 g, 55%) as hydrochloride salts. 1H NMR (400 MHz, D2O) δ 6.31 (s, 1H), 4.11 (s, 2H), 2.31-2.30 (s, 6H); MS 175.1 [M+Na].
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+]>CCO>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH:25]=[C:26]([CH3:27])[CH3:28])([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2ccc(Cl)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccc(Cl)cc2C1
Temperature: 25 °C

Procedure:
5-Chloro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (394) (120 mg, 0.3 mmol) is dissolved in EtOH (20 mL) and set to stir at RT. To this solution is added 5M KOH (2 mL). The reaction mixture is stirred at RT overnight. After concentration in vacuo, the resulting residue is dissolved in water (20 mL) and washed with EtOAc (20 mL). The phases are separated and the aqueous phase is acidified with concentrated HCl to pH 2. The aqueous phase is washed with 100 mL EtOAc. The organic phases are collected, concentrated to dryness, and then the resulting residue is purified on an HPLC. The desired product (395) is obtained as white solid (73 mg, 63%).
Reaction SMILES: [OH-].[Na+].F[CH:4](F)[O:5][C:6]1[CH:7]=[C:8](/[C:16](/[CH3:23])=[CH:17]/[C:18]([O:20]CC)=[O:19])[CH:9]=[CH:10][C:11]=1[O:12][CH:13](F)F>CCO>[CH3:4][O:5][C:6]1[CH:7]=[C:8](/[C:16](/[CH3:23])=[CH:17]/[C:18]([OH:20])=[O:19])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: CCOC(=O)/C=C(\C)c1ccc(OC(F)F)c(OC(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(/C(C)=C/C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 114.5 %

Procedure:
Aqueous 1.0 M NaOH (20 mL) was added to a solution of (E)-ethyl 3-(3,4-bis(difluoromethoxy)phenyl)-2-butenoate (0.36 g, 1.1 mmol) in EtOH (20 mL). The solution was stirred at rt for 16 h and then concentrated under reduced pressure to remove the EtOH. The aqueous phase was acidified with 1 M HCl and extracted with EtOAc, washed with water, brine, dried and concentrated. The crude product was recrystallised from EtOH/water to afford (E)-3-(3,4-dimethoxyphenyl)-2-butenoic acid (0.28 g, 85%) as a colourless crystalline solid; mp 73-74° C.; δH (500 MHz, CDCl3) 2.60 (d, J=1.5 Hz, 3H, CH3), 6.15 (q, J=1.5 Hz, 1H, C═CH), 6.55 (t, J=73 Hz, 2H, OCHF2), 7.28 (d, J5,6=8.0 Hz, 1H, H5), 7.36-7.38 (m, 2H, H2, H6); δC (125 MHz, CDCl3) 18.2, 115.6 (t, J=262 Hz), 115.7 (t, J=262 Hz), 117.2, 120.9, 122.1, 124.7, 140.6, 142.1, 143.1, 155.7, 170.1; νmax 1042, 1254, 1621, 1692, 2926 cm−1.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC2NC=C3C(=O)N(C4C=CC([Cl:47])=CC=4)N=C3C=2C=1>>[Cl:47][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]5)=[CH:17][C:18]=4[C:9]3=[N:8]2)=[CH:2][CH:3]=1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)cc3c-2nn1-c1ccccc1
Reactant: Nc1ccc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2c1
Product: O=c1c2c[nH]c3ccc(N4CCNCC4)cc3c-2nn1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared following the procedure described for 7a using 6b. 1H-NMR (DMSO-d6) δ (ppm): 3.25 (4H, br), 3.50 (4H, br), 3.75 (3H, s), 7.00 (1H, d, J=9.06 Hz), 7.40 (1H, m), 7.48 (1H, br), 7.68 (1H, d, J=9.06 Hz), 7.92 (1H, d, J=8.79 Hz), 8.05 (2H, d, J=8.79 Hz), 8.56 (1H, br), 9.12 (1H, br). m/z 380.9 (MH+).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1/[CH:10]=[CH:11]/[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1.[C:18](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CI.C(N(CC)CC)C>[CH3:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[C:4]=1/[CH:10]=[CH:11]/[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[CH3:18]
Reactant: Cc1cccc(C)c1/C=C/C1CCCCN1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1/C=C/C1CCCCN1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.2 %

Procedure:
To a solution of 520 mg of 2-[(E)-2-(2,6-dimethylphenyl)vinyl]piperidine monohydrochloride in 7 ml of dimethylformamide, 0.13 ml of methyl iodide, 0.58 ml of triethylamine and 572 mg of potassium carbonate were added, followed by stirring at ambient temperature for 12 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give 470 mg of 2-[(E)-2-(2,6-dimethylphenyl)vinyl]-1-methylpiperidine. The product was dissolved in 5 ml of ethanol, and 2.5 ml of 35% hydrogen chloride-ethanol was added to the solution, followed by stirring at ambient temperature for 1 hour. The reaction mixture was evaporated under reduced pressure and the residue was azeotropically distilled with 5 ml of toluene 3 times to give crystals. The collected crystals were recrystallized from ethanol-ethyl acetate to give 395 mg of 2-[(E)-2-(2,6-dimethylphenyl)vinyl]-1-methylpiperidine monohydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.[C:19]1(C)C=CC=CC=1.C[Mg]Br.[Cl-].[NH4+]>O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH2:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: Cc1ccccc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: C=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 258 g 4,4'-dimethoxybenzophenone in 3000 ml warm toluene was added to 1600 ml 1.4M methylmagnesium bromide under nitrogen with stirring, over a one-hour period. The reaction temperature was kept below 40° C. After addition was complete, stirring was continued for one hour at 30°-40° C. and two hours at 50° C. The mixture was cooled to room temperature and poured into a stirred mixture of 400 ml acetic acid and 624 g ammonium chloride in 7200 ml deionized water. After gas evolution and exotherm had subsided, the organic (toluene) phase was separated and the aqueous phase was washed with 2×600 ml toluene. The combined toluene phases were washed with 1×2400 ml water, then placed in a flask and treated with a solution of 1470 ml deionized water and 1470 ml acetic acid at 50° C. for three hours to effect dehydration of the intermediate hydroxy compound. On cooling, the phases were separated and the toluene phase was washed with 2×1000 ml deionized water, then dried over magnesium sulfate. Filtration and removal of toluene gave a slightly wet cake which was triturated with 1400 ml diethyl ether, filtered and dried to give 222 g 1,1-di(p-methoxyphenyl)-ethene, m.p. 141°-143° C. whose structure was also confirmed by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:23])([CH3:22])[N:10](CC3C=CC(OC)=CC=3)[C:11](=[O:12])[C:6]2=[CH:5][CH:4]=1.[N+]([O-])([O-])=O.[NH4+].O.[CH3:30]COC(C)=O>CC#N>[CH2:1]([O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:23])([CH3:22])[NH:10][C:11](=[O:12])[C:6]2=[CH:5][CH:4]=1)[CH3:30]
Reactant: COc1ccc(CN2C(=O)c3ccc(OC)nc3C2(C)C)cc1
Reactant: CCOC(C)=O
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc2c(n1)C(C)(C)NC2=O
Yield: 72 %

Procedure:
To solution of 2-methoxy-6-(4-methoxy-benzyl)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one (0.33 g, 1.0 mmol) in CH3CN (5 mL) was added eerie ammonium nitrate (1.64 g, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours before water and EtOAc were added into the mixture. The organic layer was separated, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel column chromatography to give the title compound (0.15 g, 72%) as a solid. MS: 207.1 (M+H+).
Reaction SMILES: [CH:1]1([C:5]2[C:13](I)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[O:16]1CCC[CH2:17]1.C([Li])CCC.CN(C)C=O>CCOCC>[CH:1]1([C:5]2[C:13]([CH:17]=[O:16])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C2CCC2)c(I)cc1C(=O)O
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(C2CCC2)c(C=O)cc1C(=O)O
Temperature: -78 °C
Yield: 41 %

Procedure:
Into a three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 230.1, 5.00 g, 12.7 mmol, 1.00 equiv, 80%) in a solvent mixture of tetrahydrofuran and Et2O (50/50 mL). This was followed by the addition of butyllithium (15 mL, 2.50 equiv, 95%) dropwise with stirring at −78° C. To this was added N,N-dimethylformamide (2.50 g, 32.5 mmol, 2.00 equiv). The resulting solution was stirred for 1 h at −78° C. and then carefully quenched by slow addition of 50 mL of NH4Cl (aq.). The pH was adjusted to 1-2 with hydrogen chloride (6 M). The resulting solution was diluted with 100 mL of ethyl acetate, then washed with 4×50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:1) as eluent to furnish 1.62 g (41%) of 4-cyclobutyl-5-formyl-2-methylbenzoic acid as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C(N(CC)C(C)C)(C)C.[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[C:23]#[C:24][CH3:25]>C(Cl)Cl.C(#N)C>[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:12][C:6]2([C:4]([O:3][CH3:2])=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[C:23]#[C:24][CH3:25]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)OC)CCCCC2)cc1
Reaction time: 16 h

Procedure:
To a stirred suspension of methyl-1-amino-1-cyclohexane carboxylate hydrochloride (10 g, 51.7 mmol) and N,N-diisopropylethylamine in methylene chloride (200 mL) and acetonitrile (50 mL), 4-but-2-ynyloxy-benzenesulfonyl chloride (14.0 g, 56.8 mmol) was slowly added at room temperature. The reaction mixture was stirred for 16 hrs and evaporated to dryness. It was extracted with chloroform, washed well with water and dried over anhydrous MgSO4. The chloroform layer was filtered and concentrated. The product was crystallized from a mixture acetone:hexane 1:10 to give methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclohexanecarboxylate as white crystals, 12.5 g.(66%), mp 118-2° C. Electrospray Mass Spec 366 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([CH2:23][CH2:24][CH2:25][NH:26][C:27]([NH:29][NH:30]C(OC(C)(C)C)=O)=[O:28])[S:21][CH:22]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([CH2:23][CH2:24][CH2:25][NH:26][C:27]([NH:29][NH2:30])=[O:28])[S:21][CH:22]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(CCc3csc(CCCNC(=O)NNC(=O)OC(C)(C)C)c3)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(c2ccc(CCc3csc(CCCNC(=O)NN)c3)nc2)CC1
Yield: 23.3 %

Procedure:
By a method similar to Production Example 116, step 10, tert-butyl 2-{[3-(4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}thiophen-2-yl)propyl]carbamoyl}hydrazinecarboxylate (255.0 mg, 0.481 mmol) was deprotected with trifluoroacetic acid, and purified by aminopropylated silica gel column chromatography (2%-methanol-dichloromethane mixture) to give the title compound (48.3mg, yield 23.3%) as an off-white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:7]1.[C:21](=O)([O-])[O-:22].[K+].[K+]>CN(C)C=O>[CH:21]([C:7]1[O:6][CH:10]=[CH:9][C:8]=1[C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:22]
Reactant: COC(=O)c1cccc(-c2ccoc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2ccoc2C=O)c1
Reaction time: 0.5 h

Procedure:
N,N-dimethylformamide (1.7 ml) was stirred at 0° C. and to this was added dropwise phosphorus oxychloride (0.51 ml). The mixture was stirred for 30 minutes and was added a solution of methyl 3-(furan-3-yl)benzoate (1 g) in N,N-dimethylformamide (0.6 ml), and then was stirred at room temperature overnight. The reaction mixture was poured onto ice/water and then adjusted to pH 8 with an aqueous potassium carbonate solution. The product was extracted with ethyl acetate-tetrahydrofuran (1:1, 2×100 ml) and the extracts were combined, washed successively with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane:ethyl acetate (5:1) to afford methyl 3-(2-formylfuran-3-yl)benzoate (0.75 g).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CON(C)[C:35](=[O:48])[C:36]1[CH:41]=[CH:40][N:39]=[C:38]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:37]=1>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35]([C:36]3[CH:41]=[CH:40][N:39]=[C:38]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH:37]=3)=[O:48])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1ccnc(N2CCOCC2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccnc(N2CCOCC2)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (590 mg, 1.2 mmol) in THF (2 mL) was added isopropylmagnesium chloride (1.3 mL, 2.6 mmol) slowly at 0° C. One hour later, N-methoxy-N-methyl-2-morpholin-4-yl-isonicotinamide (300 mg, 1.2 mmol) was added and warmed up to RT while stirring overnight, quenched with water, extracted with ethyl acetate, concentrated and purified by flash column to give 4-chloro-N-[5-chloro-2-(2-morpholin-4-yl-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:27].[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([O:19][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:31]3[CH2:30][CH2:29][O:28][CH2:33][CH2:32]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-[4-(morpholino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-morpholinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[S:22][C:21]([C:23]#[N:24])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]2[S:22][C:21]([C:23]#[N:24])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: N#Cc1ccc(C#Cc2ccc(O)cc2)s1
Reactant: CCC/C=C/C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/COc1ccc(C#Cc2ccc(C#N)s2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A solution of N,N-dicyclohexylcarbodiimide (0.22 g) in dichloromethane (10 cm3) is added to a solution of (E)-hex-2-enoic acid (0.10 g), 1-(4-hydroxyphenyl)-2-(2-cyanothiophen-5-yl)acetylene (0.32 g), 4-(dimethylamino)pyridine (0.04 g) in dichloromethane (20 cm3), cooled in an ice bath (0° C.) under an atmosphere of nitrogen. The reaction mixture is stirred overnight, filtered to remove precipitated material and the filtrate is evaporated down under reduced pressure. The crude product is purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C.)/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield 1-(4-[(E)-hex-2-enyloxy]phenyl)-2-(2-cyanothiophen-5-yl)acetylene (0.26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21]CC4C=CC=CC=4)=[CH:18][CH:19]=3)[CH:14]=[C:13]2[C:29]([O:31][CH3:32])=[O:30])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[CH:14]=[C:13]2[C:29]([O:31][CH3:32])=[O:30])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cc(O)ccc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 48 h
Yield: 16.5 %

Procedure:
A suspension of 5% palladium on carbon in ethyl acetate (450 ml) and methyl N-(3,4-dichlorophenylsulphonyl)-5-benzyloxyindole-2-carboxylate(2.01 g) was stirred at 60° c under hydrogen at atmospheric pressure for 48 hours. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by column chromatography using 20%ethyl acetate/isohexane as eluent to give the desired product as a gum (270 mg,16%). NMR: δ 3.85(s, 31H), 7.0 (m, 2H), 7.35 (s, 1H), 7.9 (m, 3H), 8.1 (s, 1H), 9.6 (s, 1H); m/z 401.9 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH:17][C:18]([C:20]2[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[C:22]([O:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[CH:21]=2)=[O:19])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>ClCCl>[F:47][C:46]([F:49])([F:48])[C:44]([OH:50])=[O:45].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH:17][C:18]([C:20]2[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:22]([O:35][CH2:36][C:37]([OH:39])=[O:38])[CH:21]=2)=[O:19])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)NNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc(C(=O)NNC(=O)C2CCNCC2)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of t-butyl 4-[3-(1-t-butoxycarbonylpiperidin-4-ylcarbonyl)carbazoyl]-2-(t-butoxycarbonylmethoxy)phenoxyacetate (360 mg) and TFA (4 ml) in dichloromethane (8 ml) was stirred at ambient temperature for 5 hours. The solvent was removed by evaporation and the residue was triturated with ether to give the title compound as a solid; NMR Spectrum (d6 -DMSO) 1.68-2.02 (m, 4H), 2.55-2.68 (m, 1H), 2.85-3.05 (dt, 2H), 3.2-3.4 (br d, 2H), 4.74 (s, 2H), 4.78 (s, 2H), 6.97 (d, 1H), 7.4 (s, 1H), 7.47 (dd, 1H), 8.5 (br s, 2H), 9.9 (s, 1H), 10.2 (s, 1H); Mass Spectrum (+ve FAB, MeOH/NBA): 396 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:28]=[CH:27][C:22]4[NH:23][C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH2:30](Cl)Cl>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]([CH3:30])[C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:28]=[CH:27][C:22]4[NH:23][C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: ClCCl
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)c(F)c4)CC3)cc2o1
Agent: Cl
Product: CN(CCCc1ccc(F)c(F)c1)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1

Procedure:
Condensation of 6-(trans-4-[3-(3,4-difluorophenyl)propylamino]-cyclohexyl}-3H-benzoxazol-2-one (400 mg, 1.0 mmol) with p-formaldehyde (740 mg, 24.7 mmol) following the procedure described in Example 17, except CH2Cl2 (15 mL) was also added, followed by formation of the HCl salt, gave 6-(trans-4-{[3-(3,4-difluorophenyl)propyl]methylamino}cyclohexyl)-3H-benzoxazol-2-one (226 mg, 52%), as a white solid: mp 224-227° C.; IR (KBr): 2945, 1764 cm−1; 1H NMR (500 MHz, DMSO-d6):, δ 11.50 (s, 1H), 9.94 (s, 1H), 7.40-7.34 (m, 2H), 7.16 (s, 1H), 7.12-7.09 (m, 1H), 7.00 (s, 2H), 3.33-3.29 (m, 1H), 3.18-3.11 (m, 1H), 3.03-2.97 (m, 1H), 2.71 (d, J=5 Hz, 3H), 2.68-2.63 (m, 2H), 2.59-2.50 (m, 1H), 2.14-1.98 (m, 4H), 1.94-1.88 (m, 2H), 1.66-1.51 (m, 4H); ESI-MS (m/z): 401 [M+H]+; HPLC: method A, 5.97 minutes (97.1%); Anal. Calcd for C23H26F2N2O2.HCl: C, 63.23; H, 6.23; N, 6.41. Found: C, 62.94; H, 6.56; N, 6.32.