Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:12]([C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[CH3:31])[CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)[CH:15]=2)=[CH:7][CH:6]=1)C.[CH3:48][Mg]Br.C([O:54][CH2:55][CH3:56])(=O)C>C1COCC1.[Cl-].[NH4+]>[CH3:36][S:33]([C:30]([C:22]1[CH:23]=[C:24]2[C:29](=[C:20]([C:16]3[CH:15]=[C:14]([CH2:13][CH:12]([S:11][C:8]4[CH:7]=[CH:6][C:5]([C:55]([OH:54])([CH3:56])[CH3:48])=[CH:10][CH:9]=4)[C:37]4[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:44])=[O:45])=[CH:41][CH:42]=4)[CH:19]=[CH:18][CH:17]=3)[CH:21]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)([CH3:32])[CH3:31])(=[O:34])=[O:35]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1ccc(SC(Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c2ccc(S(C)(=O)=O)cc2)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(SC(Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: -78 °C

Procedure:
A solution of Example 40 (280 mg, 0.4 mmol) and anhydrous CeCl3 (150 mg, 0,5 mmol) in THF (5 mL) was stirred at 21° C. for 1 h, then cooled at −78° C. Methylmagnesium bromide (3M, Ether, 0.6 mL, 2.1 mmol) was added and the resulting reaction mixture warmed slowly to 0° C., then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 1:1 to 2:8) provided the title compound as a solid.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].CN1[C:18]([CH3:19])=[CH:17][C:15](=[O:16])N(C)C1=O>O>[CH3:19][C:18]1[NH:2][C:3]([NH2:5])=[N:4][C:15](=[O:16])[CH:17]=1
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Reactant: N=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(=O)nc(N)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Guanidine hydrochloride (IIIc) (10 g, 0.1 mol) was added to 1 M ethanolic sodium ethoxide (100 ml) and the mixture was stirred for 10 minutes at room temperature. Sodium chloride was removed from the mixture by filtration, and the filtrate was condensed to a syrup in vacuo below 35°. To the residue was added 1,3,6-trimethyluracil (800 mg, 0.005 mol) and the mixture was heated at ~90° for 6 hours under nitrogen. The reaction mixture was dissolved in water (20 ml) and the solution added to a column of Amberlite IRC-50 (H+) (30×3 cm diameter) and the column was washed with water. The uv absorbing fractions were collected and evaporated to dryness in vacuo. The solid residue was recrystallized from water to give 6-methylisocytosine (IIb, R1 =H, R2 =methyl) (320 mg, mp 290°-292° dec.). The uv and ir characteristics were identical with those of an authentic sample of 6 -methylisocytosine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.CN(C)[C:13](=[O:17])[CH2:14][CH2:15][CH3:16].O=P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:3]1
Reactant: Cn1ccc2ccccc21
Reactant: CCCC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCC(=O)c1cn(C)c2ccccc12
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 1-methyl-1H-indole (5.9 g, 45.0 mmol) in CHCl3 (150 mL) was added N,N-dimethylbutyramide (5.8 g, 50.4 mmol, 1.1 eq) followed by POCl3 (5.0 mL, 53.5 mmol, 1.2 eq) at 0° C. Then mixture was heated to reflux and stirred for 2 h. The reaction was quenched with saturated aqueous NaHCO3 then stirred for 30 min at room temperature. The mixture was extracted by CH2Cl2 (3×40 mL) and combined organic layers were dried over Na2SO4. The crude product was purified by flash column chromatography (0-50% EtOAc in hexanes) to afford 1-(1-methyl-1H-indol-3-yl)butan-1-one (6.53 g, 32.4 mmol, 72%).
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[C:13]3[CH2:20][CH:21]([N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:22][CH:11]([C:12]=23)[CH2:10]1)(=O)C1C=CC=CC=1.C([Li])CCC>C1COCC1.CCCCCC.Cl>[C:18]([C:14]1[CH:15]=[CH:16][C:17]2[NH:9][CH2:10][C@@H:11]3[CH2:22][C@H:21]([N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:20][C:13]=1[C:12]=23)#[N:19]
Reactant: CCCN(CCC)C1Cc2c(C#N)ccc3c2C(C1)CN3C(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCN(CCC)[C@@H]1Cc2c(C#N)ccc3c2[C@H](CN3)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 113.8 %

Procedure:
To a stirred solution of 4.8 g (0.0124 mol) of 1-benzoyl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole prepared as in Example 1 in 200 mL of THF cooled to -78° C. under N2 atmosphere, was added 16 mL (0.025 mol) of 1.6M solution of n-butyllithium in hexane. The reaction mixture was stirred at -78° C. for 30 minutes and then allowed to warm to -20° C. To the reaction mixture was added 100 mL in 1N HCl. The mixture was extracted once with ethyl ether. The acidic solution was made alkaline with the addition of cold 5N NaOH. The basic mixture was extracted twice with CH2Cl2. The combined organic solution was washed with saturated aqueous NaCl solution. The CH2Cl2 solution was dried over MgSO4 and evaporated to give 4 g of an oil. Chromatography of this oil over silica gel with ethyl acetate as eluent gave 3 g (85%) of product as an oil, which upon standing solidified.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(O)C>[CH3:14][C:4]1[CH:3]=[C:2]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=2)[N:7]2[N:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:6]2[N:5]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Cl)n2nc(C(C)C)nc2n1
Solvent: CCO
Product: Cc1cc(Nc2ccc(C(F)(F)F)cc2)n2nc(C(C)C)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of Intermediate 18 (0.042 g, 0.199 mmol) in ethanol (5 mL), 4-(trifluoromethyl)aniline (ALDRICH, 0.025 mL, 0.199 mmol) was added and the mixture was stirred at room temperature overnight. Solvent was removed in vacuo and the crude mixture was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures from 75:25 to 25:75%) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[C:7]([Li])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:2]([CH:3]([C:7]([CH3:10])([CH3:9])[CH3:8])[OH:4])([CH3:6])([CH3:5])[CH3:1]
Reactant: CC(C)(C)C=O
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(O)C(C)(C)C

Procedure:
To a solution of trimethylacetaldehyde (5.12 g, 59.4 mmol) in anhydrous tetrahydrofuran (15 ml) at -78° C. under an argon atmosphere is added 40.9 ml of a solution of t-butyllithium in hexanes (1.6M, 65.4 mmol). The mixture is allowed to warm from -78° to room temperature over 2 hours. The reaction is quenched with 25 ml of 1M hydrochloric acid and the resulting mixture extracted with two 25 ml portions of ether. The combined ethereal extracts were washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate, and the solvent evaporated to yield a yellow oil (9.3 g) which is purified by vacuum distillation to yield a colorless oil.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[Cl:27][C:28]1[C:29]2[C:36](I)=[CH:35][N:34]([CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:30]=2[N:31]=[CH:32][N:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[Cl:27][C:28]1[C:29]2[C:36]([C:8]3[CH:7]=[CH:6][C:5]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[C:4]([O:3][CH3:2])[CH:9]=3)=[CH:35][N:34]([CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:30]=2[N:31]=[CH:32][N:33]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: Clc1ncnc2c1c(I)cn2C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)ccc1NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 81.3 %

Procedure:
A mixture of water (25 ml) and tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (65% pure) (4.25 g, 7.92 mmol) was frozen and subjected to vacuum followed by filling with nitrogen while defreezing. 4-Chloro-7-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.83 g, 5.28 mmol), tetrakis (triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol), sodium carbonate (1.40 g, 13.20 mmol) and ethylene glycol dimethyl ether (50 ml) were added and the resulting mixture was heated at 80° C. under an atmosphere of nitrogen overnight. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure to give a residue which was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate twice. The combined ethyl acetate extracts were dried over magnesium sulfate and evaporated to give a dark oil which was purified by flash column chromatography on silica using n-heptane/ethyl acetate (3:1) with 2% triethylamine as the mobile phase. Appropriate fractions were collected, combined and concentrated to give tert-butyl N-[4-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate as white solids (1.90 g, 4.29 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.65 (s, 1H), 7.94 (s, 2H), 7.74 (d, 1H), 7.19 (d, 1H), 7.07 (dd, 1H), 5.22 (m, 1H), 3.87 (s, 3H), 2.19 (m, 2H), 1.99 (m, 2H), 1.91 (m, 2H), 1.73 (m, 2H), 1.48 (s, 9H); TLC (n-heptane/ethyl acetate=1:1) Rf 0.58.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:32]5[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: COc1ccc(B(O)O)cc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(OC)cc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-methoxy-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.78 min; Mass spectrum (ESI+): m/z=487 [M+Na]+.
Reaction SMILES: [CH:1]([C@H:14]1[NH:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH2:30][CH:22]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:1]([C@H:14]1[NH:19][CH2:18][C@@H:17]([NH:20][CH2:30][C@@H:22]([OH:21])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC2CO2)cc1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)NC1
Product: O[C@H](CN[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)NC1)Cc1ccccc1
Yield: 32.9 %

Procedure:
Compound 3 (0.075 g, 0.281 mmol) was reacted with S-(−)-2,3-epoxypropyl benzene (0.056 g, 0.422 mmol) (Procedure A) and was purified by flash column chromatography over silica gel using diethyl ether/MeOH/Et3N (90:10:0.2) to yield 4d (0.037 g, 33%). 1H NMR (400 MHz, CDCl3): δ 1.23-1.35 (2H, m, H-5), 1.41-1.49 (1H, m, H-4ax), 1.75-1.78 (1H, m, H-4eq), 2.36-2.41 (1H, dd, J=3.2 Hz, J=8.8 Hz, NHCH2), 2.66-2.84 (5H, m, H-2, NHCH2, Ph-CH2), 2.89-2.92 (1H, m, H-3eq), 3.23 (1H, dt, J=2.4 Hz, J=10.0 Hz, H-6ax), 3.75 (1H, d, J=10.0 Hz, (Ph)2CH) 3.78-3.85 (1H, m, and CH—OH), 7.12-7.31 (13H, m, ArH), 7.35-7.36 (2H, m, ArH). Optical rotation, [α]25D=(−) 49.3° (c 0.96, MeOH). Free base was converted into oxalate salt 206-209° C.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[C:7]([C:9]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:13]([C:9]2([C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][N:8]=3)[CH2:10][CH2:11][CH2:12]2)=[O:15])=[CH:20][CH:19]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(O)C1(c2cccc(Cl)n2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C2(c3ccccn3)CCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(6-Chloropyridin-2-yl)cyclobutanecarboxylic acid hydrochloride (2.6 g, 10.48 mmol) was suspended in dichloromethane (30 ml). 2-(4-Methoxyphenyl)ethanamine (1.743 g, 11.53 mmol) and 4-dimethylaminopyridine (2.56 g, 20.96 mmol) were added and stirring at room temperature was continued for 30 min. The reaction mixture was cooled to 0° C. and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.21 g, 11.53 mmol) was added in small portions. The reaction mixture was allowed to warm to room temperature and stirring was continued over night. The reaction mixture was poured on water. The aqueous layer was extracted with dichloromethane (3×). The combined organic layers were washed with 5% aqueous citric acid and dried (MgSO4). The solvent was evaporated in vacuo and the crude product purified by flash chromatography (silica, heptane, ethyl acetate). Yield: 709 mg (2.056 mmol, 19.6%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]1)=[O:11].[OH-].[Li+]>C1COCC1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: CCOC(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
ethyl 1-(1H-indole-2-carbonyl)piperidine-4-carboxylate (3.0 g, 9.99 mmol) and lithium hydroxide, H2O (4.19 g, 100 mmol)) were dissolved in THF (Ratio: 1, Volume: 20 ml) and Water (Ratio: 2, Volume: 40.0 ml) and allowed to stir overnight at room temperature. The reaction was diluted with water, and extracted with diethyl ether. The aqueous layer was acidified using 2N HCl to pH ˜2. A fine, white suspension resulted. The aqueous layer was extracted with ethyl acetate twice. The combined ethyl acetate layers were dried over magnesium sulfate, filtered and concentrated to afford the product as a white solid. (Yield: 678 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 12.33, 11.53, 7.60, 7.41, 7.21-6.94, 6.76, 4.40-4.21, 3.17, 2.66-2.53, 1.97-1.82, 1.63-1.47
Reaction SMILES: [ClH:1].[CH:2]1[C:15]2[C:6](=[N:7][C:8]([NH:16][NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:5]=[CH:4][CH:3]=1.[CH:24](OCC)(OCC)OCC>>[Cl-:1].[C:18]1([N+:17]2[N:16]=[CH:8][N:7]3[C:24]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]3=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(NNc2nc3ccccc3c3ccccc23)cc1
Reactant: CCOC(OCC)OCC
Reactant: Cl
Product: [Cl-]
Product: c1ccc(-[n+]2ncn3c4ccccc4c4ccccc4c32)cc1
Temperature: 25 °C

Procedure:
A suspension of N-phenanthridin-6-yl-N′-phenylhydrazine hydrochloride (2.0 g, 6.2 mmol) in triethyl orthoformate (100 ml) is stirred under reflux under argon for 17 h. After cooling to room temperature, the mixture is concentrated and the precipitate is filtered off and washed with petroleum ether, methyl tert-butyl ether and acetone. Yield: 1.2 g (57%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25].CC([O-])(C)C.[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC/C=C\CBr
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CC/C=C\CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 38.4 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.47 g) is alkylated using (Z)-1-bromo-2-pentene (1 g; 6.71 mmol) and KOtBu (0.75 g; 6.71 mmol) at RT for 20 h. After aqueous work-up and flash chromatography on silica gel eluting with light petroleum/EtOAc (2.5:1) the pure alkylated acetamide (0.85 g; 2.56 mmol) is de-acetylated under reflux conditions using DBU (0.7 ml) in MeOH (60 ml). (Z)-5-amino-3,3-dimethyl-6-nitro-1-(pent-2-enyl)-1,3-dihydro-indol-2-one (0.62 g) is obtained after aqueous work-up.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([O:14][Na])([CH3:13])[CH3:12]>CC(O)C>[O:14]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)O[Na]
Solvent: CC(C)O
Product: CC(C)Oc1ccc([N+](=O)[O-])cn1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A freshly oven dried 500 mL round-bottom flask was charged with 2-chloro-5-nitropyridine (5.0 g, 31.6 mmol) and anhydrous iPrOH (50 mL). The resultant solution was cooled in an ice bath and iPrONa (50 mmol) in iPrOH (250 mL) added slowly, followed by stirring at the same temperature for 30 min and then at room temperature for 14 h. The reaction was quenched with H2O (5 mL), filtered through celite, and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified through automated normal-phase chromatography to afford 2-isopropoxyl-5-nitropyridine (4.6 g, 79%) which was used directly for the next step: 1H NMR (400 MHz, CDCl3) δ 9.02 (d, 1 H), 8.30 (dt, 1 H), 6.75 (d, 1 H), 5.40 (sep, 1 H), 1.38 (d, 6H); MS (ES) (M++H) expect 183.1, found 183.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2O.[Cl:20][C:21]1[CH:22]=[C:23]([C:27]([C:29]2[CH:30]=[N:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[O:28])[CH:24]=[CH:25][CH:26]=1.[Cl:36]C1C=C(C(C2C=NC=CC=2)=O)C=CC=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C:27]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]3[Cl:36])([C:29]2[CH:30]=[N:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[OH:28])[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(c1ccc(Cl)nc1)c1cccc(Cl)c1
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1
Reactant: O=C(c1cccnc1)c1cccc(Cl)c1
Product: OC(c1ccc(Cl)nc1)(c1cccc(Cl)c1)c1ccc2ncc(-c3ccccc3)c(Cl)c2c1

Procedure:
The title compound was prepared using 6-bromo-4-chloro-3-phenylquinoline (Intermediate 3, step c) and (3-chlorophenyl)(6-chloropyridin-3-yl)methanone in place of 6-bromo-2,4-dichloro-3-phenylquinoline and (3-chlorophenyl)(pyridin-3-yl)methanone, respectively, according to the procedure described in Example 25. 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.40 (d, J=2.69 Hz, 1H), 8.29 (d, J=2.20 Hz, 1H), 8.10 (d, J=9.05 Hz, 1H), 7.70 (dd, J=2.69, 8.31 Hz, 1H), 7.65 (dd, J=2.08, 8.93 Hz, 1H), 7.47-7.54 (m, 5H), 7.37 (d, J=1.47 Hz, 1H), 7.31-7.35 (m, 3H), 7.18 (dt, J=1.80, 7.15 Hz, 1H); MS m/e 490.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=[O:20].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]([NH2:5])=[O:20]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1Cl
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1Cl
Reaction time: 12 h
Yield: 99 %

Procedure:
A solution of 2-chloro-4-(4-formylphenoxy)benzonitrile (1.0 equiv) in DMSO (0.2 M solution) was treated with K2CO3 (0.5 equiv) and 33% H2O2. After 12 h, the reaction mixture was poured into H2O and extracted with ethyl acetate. The combined organic layers were washed twice with water and brine. After drying the extracts over magnesium sulfate and evaporation under vacuum, the crude product was purified by silica gel chromatography using the aprropriate eluent (typically mixtures of hexanes/ethyl acetate) to afford the title compound as a solid.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)(=O)=O)=CC=1.[CH3:31][O:32][CH:33]1[CH2:37][O:36][CH2:35][CH:34]1O>>[CH3:31][O:32][C@H:33]1[CH2:37][O:36][CH2:35][C@H:34]1[O:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: COC1COCC1O
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Product: CO[C@H]1COC[C@H]1OCCOC1CCNCC1
Yield: 84.8 %

Procedure:
Using benzyl 4-(2-{[(4-methylphenyl)sulfony]oxy}ethoxy)piperidine-1-carboxylate (2.50 g, 5.77 mmol) produced in Reference Example 1 (1c) and 4-methoxytetrahydrofuran-3-ol (820 mg, 6.94 mmol), the desired title compound (1.20 g, yield 85%) was obtained by the same method as in Reference Examples 1 (1d) and 1 (1e).
Reaction SMILES: [I:1][C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:14]([OH:16])=O)[CH:11]=3)[C:4]=2[NH:5][N:6]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:14]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[O:16])[CH:11]=3)[C:4]=2[NH:5][N:6]=1
Reactant: O=C(O)c1ccc2c(c1)Cc1c(I)n[nH]c1-2
Reactant: C1COCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2c(c1)Cc1c(I)n[nH]c1-2)N1CCOCC1
Yield: 47.9 %

Procedure:
A mixture of Example 84A (0.210 g, 0.644 mmol), PyBOP (0.503 g, 0.966 mmol), morpholine (0.084 mL, 0.966 mmol), and diisopropylethylamine (0.39 mL, 2.25 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water and NaHCO3. The organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with EtOAc to give 0.122 g (48%) of the desired product as red solid. MS (DCI/NH3) m/z: 396.0 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 3.46-3.67 (m, 10H) 7.41 (m, 1H) 7.59 (s, brd, 1.5H) 7.67 (d, J=7.46 Hz, 0.5H).