Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])N.[BrH:27].[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30]>O.[Cu]=O.CO.CC(C)=O>[Br:27][CH:29]([CH2:30][C:8]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[C:6]([F:5])[CH:7]=1)[C:28]([O:32][CH3:33])=[O:31]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(N)cc1F
Reactant: Br
Reactant: C=CC(=O)OC
Agent: O=[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)C(Br)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(F)c1
Reaction time: 0.42 h
Yield: 76.8 %

Procedure:
A solution of sodium nitrite (NaNO2) (3.1 g) in water (5 ml) was added dropwise, at temperature ranging from 0 to 5° C., to a mixture of 3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)aniline (12.3 g), aqueous HBr (47%, 28.4 g) and acetone (150 ml)-methanol (50 ml). The mixture was stirred for 25 minutes at the same temperature range, to which was added methyl acrylate (21.3 g). The mixture was heated at temperatures ranging from 30 to 35° C., to which was then added copper oxide (Cu2O) (0.05 g) at the same temperature range. The whole mixture was vigorously stirred. The reaction mixture was stirred for further 30 minutes, which was then concentrated under reduced pressure. To the concentrate was added aqueous ammonia, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, which was then dried (MgSO4), followed by distilling off the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:4), was obtained methyl 2-bromo-3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propionate (14.2 g) as an oily product.
Reaction SMILES: [Br-].[P:2]([C:6]1([P:22]([OH:25])([OH:24])=[O:23])[CH2:14][CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][N+:12]2([CH2:16][CH2:17][S:18]C(=O)C)[CH3:15])[CH2:7]1)([OH:5])([OH:4])=[O:3].C.[ClH:27]>>[Cl-:27].[P:22]([C:6]1([P:2]([OH:5])([OH:4])=[O:3])[CH2:14][CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][N+:12]2([CH2:16][CH2:17][SH:18])[CH3:15])[CH2:7]1)([OH:24])([OH:25])=[O:23]
Reactant: CC(=O)SCC[N+]1(C)CCCC2CC(P(=O)(O)O)(P(=O)(O)O)CC21
Reactant: Cl
Agent: [Br-]
Product: C[N+]1(CCS)CCCC2CC(P(=O)(O)O)(P(=O)(O)O)CC21
Product: [Cl-]

Procedure:
Octahydro-6,6-diphosphono-1-(2-acetylthioethyl)-1-methyl-1-pyrindinium bromide (0.05 mmol) is heated at reflux in 6N HCl (15 ml) under an atmosphere of nitrogen. The reaction mixture is cooled, treated with charcoal and filtered. The resulting filtrate is concentrated under reduced pressure. The resulting solid residue can be recrystallized from water and ethanol to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.N1C=CN=N1.OC1(C=CC=CC1)C(O)=O.[OH:27][CH2:28][C:29]([NH2:32])([CH3:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl.O>[OH:27][CH2:28][C:29]([NH:32][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[O:2][CH3:1])([CH3:31])[CH3:30]
Reactant: CC(C)(N)CO
Reactant: COc1ccccc1C(=O)O
Agent: O=C(O)C1(O)C=CC=CC1
Agent: c1c[nH]nn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccccc1C(=O)NC(C)(C)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
15.2 g (100 mmol) of 2-methoxy-benzoic acid are dissolved in 300 ml of methylene chloride and the solution is stirred with 14.2 g (105 mmol) of 1-hydroxy-benzoic acid triazole×1 H2O and 21.66 g (105 mmol) of N,N-dicyclohexylcarbodiimide at 0° C. The suspension thus obtained is stirred at room temperature for 0.5 hour, cooled to 0° C. again, and a solution of 9.89 g (111 mmol) of 1-hydroxy-2-methyl-2-propylamine and 12.65 g (125 mmol) of triethylamine in 300 ml of methylene chloride is added. The reaction is complete after 1 hour. The reaction mixture is washed with 1M of hydrochloric acid and saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated in vacuo. The crude product is stirred with petroleum ether, filtered off with suction, subsequently rinsed with the solvent and dried under a high vacuum.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:10][OH:11])=[O:4].[H-].[Na+].O>O1CCCC1>[CH2:10]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[C:3](=[O:4])[CH2:2][O:11]1
Reactant: O=C(CCl)N1CCC[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1COCC2CCCN12
Reaction time: 14 h

Procedure:
(S)-1-(Chloroacetyl)-2-pyrrolidinemethanol, 12 g (0.068 mol), is dissolved in 500 ml of tetrahydrofuran, the solution is cooled to 0°-5° C., and 3.96 g (0.099 mol) of 60% sodium hydride in mineral oil dispersion is slowly added. The mixture is allowed to reach room temperature and is stirred for 14 hours. Water, 20 ml, is added, the solvents evaporated in vacuo, and the residue suspended in 300 ml of chloroform and washed with 100 ml of water and then a saturated aqueous solution of sodium chloride, 2×200 ml. The chloroform layer is separated, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4-(3H)-one, 4.4 g; mp 63.5°-66°.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[C:26]([O:28]CC)=[O:27])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[C:26]([OH:28])=[O:27])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 55.9 %

Procedure:
A mixture of 1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethoxycarbonylpiperidine (trans isomer) (0.50 g) and 1N aqueous sodium hydroxide solution (5 ml) in methanol (5 ml) was refluxed for 3 hours. The reaction mixture was evaporated to remove methanol, neutralized with 10% hydrochloric acid and extracted with chloroform. The extract was washed with saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]piperidine-2-carboxylic acid (trans isomer) (0.26 g) as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1C=C[CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=O.[O-:16][CH2:17][CH3:18].[Na+].[O:20]1[CH:24]=[CH:23][N:22]=[C:21]1[SH:25]>C(O)C>[C:11]1(=[O:12])[N:10]([CH2:8][CH2:7][CH2:13][S:25][C:21]2[O:20][CH:24]=[CH:23][N:22]=2)[C:17](=[O:16])[C:18]2=[CH:2][CH:3]=[CH:4][CH:5]=[C:6]12
Reactant: CC[O-]
Reactant: Sc1ncco1
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCCSc1ncco1
Yield: 287.3 %

Procedure:
3-Bromopropylphthalimide (13.4g) was added to a stirred solution of sodium ethoxide (from 1.15 g sodium) and oxazole-2-thiol (5.1 g) in ethanol (100 ml). The resultant solution was heated under reflux for 2.5 hours and concentrated under reduced pressure. The residue was triturated with water (100 ml) to afford 2-(3-phthalimidopropylthio)oxazole (14 g), m.p. 101°. Recrystallisation from ethanol gave the pure oxazole, m.p. 102°-103°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH2:24]([O:26][C:27](=[O:51])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][C:39]=2C(F)(F)F)=[CH:32][C:31]=1[F:50])[CH3:25].C[CH2:53][OH:54]>>[F:50][C:31]1[CH:32]=[C:33]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]([CH2:44][N:1]3[CH2:6][CH2:5][C:4]4([C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH:8]=[CH:7]4)[CH2:3][CH2:2]3)=[C:42]([O:54][CH3:53])[CH:43]=2)[CH:34]=[CH:35][C:30]=1[CH2:29][CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:51]
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CBr)cc2C(F)(F)F)cc1F
Reactant: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCc1ccc(OCc2ccc(CN3CCC4(C=Cc5ccccc54)CC3)c(OC)c2)cc1F
Temperature: 80 °C
Reaction time: 16 h
Yield: 47.7 %

Procedure:
To a solution of spiro[indene-1,4′-piperidine] (0.515 g, 2.58 mmol) in EtOH (15 mL) is added N,N-diisopropylethylamine (1.4 mL, 2.589 mmol) and 3-[4-(4-bromomethyl-2-trifluoromethyl-benzyloxy)-2-fluoro-phenyl]-propionic acid ethyl ester (1.1 g, 2.58 mmol) at room temperature and the reaction mixture is stirred for 16 hours at 80° C. The mixture is concentrated, diluted with water, and extracted with EtOAc (2×50 mL). The combined extracts are washed with water (20 mL) and saturated brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude material is purified by silica gel column chromatography to give the title compound as a colorless gel (0.650 g, 47.7%). 1H NMR (400 MHz, CDCl3) δ 7.42-7.35 (m, 2H), 7.31-7.29 (d, J=8 Hz, 1H), 7.20-7.01 (m, 3H), 7.05 (s, 1H), 7.01-6.99 (d, J=8 Hz, 1H), 6.64-6.93 (d, J=4 Hz, 1H), 6.86-6.83 (d, J=12 Hz, 1H) 6.77 (s, 1H), 5.05 (s, 2H), 4.03-3.98 (m, 2H), 3.79 (s, 3H), 3.57 (s, 2H), 2.89-2.86 (d, J=12 Hz, 2H), 2.79-2.76 (t, J=8 Hz, 2H), 2.55-2.53 (d, J=8 Hz, 2H), 2.41-2.35 (t, J=12 Hz, 2H), 2.10-2.05 (t, J=8 Hz, 2H), 1.22-1.17 (t, J=8 Hz, 3H).
Reaction SMILES: O.[NH:2]1[C:6]([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][CH:16]3[CH:11]([CH2:12][CH:13]([C:19]([OH:21])=[O:20])[NH:14][CH2:15]3)[CH2:10]2)=[N:5][N:4]=[N:3]1.Cl.[CH2:23](O)[CH3:24]>>[CH2:23]([O:20][C:19]([CH:13]1[CH2:12][CH:11]2[CH:16]([CH2:17][CH2:18][CH:9]([CH2:8][CH2:7][C:6]3[N:5]=[N:4][NH:3][N:2]=3)[CH2:10]2)[CH2:15][NH:14]1)=[O:21])[CH3:24]
Reactant: CCO
Reactant: O=C(O)C1CC2CC(CCc3nnn[nH]3)CCC2CN1
Agent: Cl
Solvent: O
Product: CCOC(=O)C1CC2CC(CCc3nn[nH]n3)CCC2CN1
Yield: 100 %

Procedure:
A solution of 6.0 g (21.5 mmol) of 6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acid monohydrate in 70 mL of ethanol saturated with hydrogen chloride (g) is heated at reflux overnight. The mixture is concentrated in vacuo, suspended in diethyl ether, and again concentrated in vacuo. The residue is suspended in diethyl ether and heated at reflux for 3 hr. The solid is filtered and rinsed with diethyl ether to afford 7.4 g (100%) of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]([OH:15])[C:10]([CH3:17])([CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:15][CH:11]1[CH:12]([CH3:14])[CH2:13][NH:8][CH2:9][C:10]1([CH3:17])[CH3:16]
Reactant: [H][H]
Reactant: CC1CN(Cc2ccccc2)CC(C)(C)C1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CNCC(C)(C)C1O

Procedure:
A mixture of 1-benzyl-4-hydroxy-3,3,5-trimethylpiperidine (1.9 g, 8.15 mmole) and 20% palladium hydroxide (0.2 g) in methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) for 48 hr at 35° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 4-hydroxy-3,3,5-trimethylpiperidine as oil. Yield 1.0 g (87%), C9H17NO, m/z 144 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[Cl-:1].[CH:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][P+:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(CCl)cs1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)c1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Product: [Cl-]
Yield: 84.1 %

Procedure:
A mixture of 4-chloromethyl-2-isopropyl-1,3-thiazole (6.30 g), triphenylphosphine (9.42 g) and acetonitrile (200 mL) was heated under reflux for 15 hrs. After concentration of the reaction mixture, the precipitated crystals were washed with diethyl ether to give [(2-isopropyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride as colorless crystals (13.21 g, yield 84%). Recrystallization from acetonitrile-diethyl ether gave colorless prism crystals. melting point: 246-247° C.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:23][NH:24][CH3:25].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[CH2:11]([N:6]1[CH2:7][C@@H:8]([N:24]([CH2:23][C:22]2[CH:21]=[C:20]([C:19]([F:33])([F:34])[F:18])[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=2)[CH3:25])[CH2:9][C@H:5]1[C:3]([N:45]1[CH2:44][CH2:43][N:42]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[F:35])[CH2:47][CH2:46]1)=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C1CC(=O)CN1Cc1ccccc1
Reactant: Fc1ccccc1N1CCNCC1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3F)CC2)N(Cc2ccccc2)C1
Yield: 6 %

Procedure:
As described for Example 56b and 56d, 1-benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester (100 mg, 0.428 mmol) was converted, using (3,5-bis-trifluoromethyl-benzyl)-methyl-amine instead of 3,5-bis-trifluoromethyl-benzylamine, and using 1-(2-fluoro-phenyl)-piperazine instead of 1-(3-trifluoromethyl-phenyl)-piperazine, to the title compound (5.5 mg, 6.0%) as light yellow oil. MS m/e=623.4 [M+H]+.
Reaction SMILES: C([O:5][C:6]([C:8]1[NH:17][C:16]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:11](=[O:26])[C:10]=2[C:9]=1[CH3:27])=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC(OCC)OCC)C>>[CH3:27][C:9]1[C:10]2[C:11](=[O:26])[N:12]([CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH2:13][CH2:14][CH2:15][C:16]=2[NH:17][C:8]=1[CH:6]=[O:5]
Reactant: Cc1c(C(=O)OC(C)(C)C)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Solvent: CCOC(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Temperature: 25 °C
Yield: 40.9 %

Procedure:
3-Methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 10b (725 mg, 1.92 mmol) was dissolved in trifluoroacetic acid (2.6 ml, 34.2 mmol) in an ice-water bath under stirring. The reaction mixture was stirred at 40° C. in a water bath for 5 minutes, added with triethoxy methane (0.42 ml, 2.5 mmol) in one portion at −5° C. in an ice-water bath, and stirred for 2 minutes. Then the ice-salt bath was removed, and the reaction mixture was allowed to warm up to room temperature, became brown and stirred for another 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was quenched with a little water, adjusted to pH 8 with dilute sodium hydroxide solution (2 mol/L) and extracted with dichloromethane (50 ml×3). The combined organic extracts were concentrated under reduced pressure to obtain henna solid. The solid was purified by silica gel column chromatography to obtain the title compound 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c (240 mg, yield 40%) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][CH:12]([N:19]1[C:23]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:20]2[N:19]([CH:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:11][O:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=2)=[CH:31][CH:32]=1
Reactant: Oc1cccnc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CBr)C3CCCCC3)c2cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3cccnc3)C3CCCCC3)c2cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a solution of 46 mg (0.48 mmol) 3-hydroxypyridine in 3 mL N,N-dimethylformamide were added 21 mg (0.48 mmol, 55% dispersion in mineral oil) sodium hydride. The reaction mixture was stirred for 10 min. at room temperature. To this suspension 0.2 g (0.44 mmol) 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Ex. 34, int.) were added and the reaction mixture stirred for 4 days at room temperature. The reaction mixture was poured on 30 mL 1N hydrochloric acid and 30 mL ethyl acetate and the phases separated. The aqueous layer was extracted with 30 mL ethyl acetate. The combined organic layers were washed twice with 30 mL water and once with 30 mL brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40) to give the desired compound as white solid (65%). MS (Turbo Spray): m/z=468.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl.CO>C(O)(=O)C.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1CCC(N2Cc3c(NCc4cccc(Cl)c4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
3-(4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (1.04 g, 4 mmol) was dissolved in acetic acid (7 ml) with heat. The mixture was cooled slightly and methylene chloride (50 ml) was added slowly followed by 3-chlorobenzaldehyde (0.91 ml, 8 mmol) and sodium triacetoxyborohydride (2.54 g, 12 mmol). The reaction mixture was stirred at room temperature under a nitrogen atomosphere for 2 h, diluted with methylene chloride (100 ml), washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give a white solid. The solid was recystallized from methylene chloride/methanol to give 0.48 g (31%) of product as a white solid: mp 253-255° C.; 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 7.45 (s, 1H), 7.37-7.19 (m, 4H), 6.95 (d, J=7.4 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.45 (t, J=5.9 Hz, 1H), 5.14 (dd, J=5.1 and 13.1 Hz, 1H), 4.41 (d, J=5.8 Hz, 2H), 4.34 (d, J=17.3 Hz, 1H), 4.20 (d, J=17.2 Hz, 1H) 3.01-2.87 (m, 1H), 2.66-2.60 (m, 1H), 2.42-2.25 (m, 1H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.90, 171.24, 168.74, 143.03, 142.59, 133.08, 132.16, 130.19, 129.12, 126.80, 126.70, 125.73, 112.27, 110.55, 51.54, 45.73, 45.47, 31.25, 22.79; Anal. Calcd. For C20H18ClN3O3: C, 62.58, H, 4.73; N, 10.95. Found: C, 62.32; H, 4.61; N, 10.80.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:51][CH2:52][CH:53]1[CH2:57][O:56][C:55]([CH3:59])([CH3:58])[O:54]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:51][CH2:52][CH:53]4[CH2:57][O:56][C:55]([CH3:59])([CH3:58])[O:54]4)[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Reactant: CC1(C)OCC(CCOS(C)(=O)=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCC4COC(C)(C)O4)c4cc(F)ccc34)nc12
Temperature: 65 °C
Yield: 92.2 %

Procedure:
To a solution of N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (80 mg, 0.135 mmol) in DMF (5 mL) was added 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl methanesulfonate (36 mg, 0.162 mmol) followed by K2CO3 (56 mg, 0.405 mmol). The mixture was heated at 65° C. for 4 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(1-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (90 mg, 92%) The crude was used to the next step without purification. LCMS: (M+H)+=723.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)=[C:36]([O:48][CH2:49][C:50]([F:53])([F:52])[F:51])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:54]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:63])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:27])([F:29])[F:28])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:63])=[C:36]([O:48][CH2:49][C:50]([F:53])([F:51])[F:52])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:54]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(OCC(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OCC(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(pyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.5 g) was dissolved in dichloromethane (150 ml), and to the solution was added 3-chloroperbenzoic acid (0.75 g) under ice-cooling and the mixture, was stirred overnight at room temperature. An aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.5 g) as colorless crystals.