Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1.[CH3:43][C:44]([CH3:51])([CH2:49]O)[C:45]([O:47][CH3:48])=[O:46]>C1(C)C=CC=CC=1>[CH3:48][O:47][C:45](=[O:46])[C:44]([CH3:51])([CH3:49])[CH2:43][O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: COC(=O)C(C)(C)CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)COc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2.65 g (10.1 mmol) of triphenylphosphine and 20 ml of toluene is prepared and 2 ml (10.2 mmol) of DIAD (diisopropyl azodicarboxylate) are added at 0° C. The solution obtained is added to a solution of 1 g (8.4 mmol) of 4-hydroxybenzonitrile and 1.30 ml (10.2 mmol) of methyl 2,2-dimethyl-3--hydroxy-propanoate in 10 ml of toluene at 0° C. The reaction mixture is subsequently stirred for 30 min at 80° C. and then concentrated under reduced pressure. The crude product is purified by chromatography on silica gel using toluene as the eluent to give the expected compound in the form of a colorless oil (yield=89%).
Reaction SMILES: NCCC[OH:5].C1C(=O)N(OC(CC[S:18][S:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)C(=O)C1.OP(O)(O)=O>C(Cl)Cl.CC(O)C>[N:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:19][S:18][OH:5]
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Reactant: NCCCO
Agent: O=P(O)(O)O
Solvent: CC(C)O
Solvent: ClCCl
Product: OSSc1ccccn1
Reaction time: 1.25 h

Procedure:
3-Aminopropanol (0.76 ml, 10 mmol) was dissolved in a mixture of CH2Cl2 (5 ml) and 2-propanol (3 ml) and cooled in an ice bath. A solution of SPDP (1.23 g, 3.9 mmol) in CH2Cl2 (2 ml) was added dropwise in ca. 1 min. The mixture was stirred in the cooling bath for 1.25 h, and a 13% aqueous solution of NaH2PO4 (15 ml) and 85% H3PO4 (0.5 ml) were added. The products were extracted with ethyl acetate (2×30 ml), the organic layers were washed with 13% NaH2PO4, 15% KHCO3 and dried in vacuo. The crude compound 3 (1.14 g) was purified by flash-chromatography on silica-gel, elution with mixtures of CHCl3 and 2-propanol (100:0 to 100:7 by volume). Yield of pure compound 3 was 1.01 g (94%). TLC of compound 3 (CHCl3-2-propanol, 9:1): one spot, Rf ca. 0.3. 1H NMR of compound 3 (CDCl3), δ, ppm: 1.68 (quint., 6 Hz, 2H), 2.60 (t, 7 Hz, 2H), 3.05 (t, 7 Hz, 2H), 3.4 (br., 1H), 3.42 (q, 6 Hz, 2H), 3.62 (br., 2H), 6.99 (br., 1H), 7.10 (m, 1H), 7.58-7.65 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][O:9][C:10]2[N:11]=[C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][N:15]=[C:14]([CH3:24])[N:13]3[CH:25]=2)=[N:6][CH:5]=[N:4]1)[CH3:2].[Br:26]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:26][C:25]1[N:13]2[C:14]([CH3:24])=[N:15][N:16]=[C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]2=[N:11][C:10]=1[O:9][CH2:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][N:6]=1
Reactant: CCn1ncnc1COc1cn2c(C)nnc(-c3ccccc3)c2n1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCn1ncnc1COc1nc2c(-c3ccccc3)nnc(C)n2c1Br
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a solution of 2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-methyl-8-phenylimidazo[1,2-d][1,2,4]triazine (205 mg, 0.61 mmol) in a mixture of carbon tetrachloride (100 ml) and chloroform (50 ml) was added bromine (34.2 μl, 0.67 mmol) dropwise. The mixture was stirred for 1 h, the solvent removed in vacuo and the residue recrystallised from a mixture of diethyl ether and methanol to give the title compound (160 mg). δH (400 MHz; d6-DMSO) 1.35 (3H, t, J 7.2), 3.15 (3H, d, J 6.6), 4.31 (2H, q, J 7.2), 5.72 (2H, s), 7.58 (3H, m), 7.98 (1H, s), 8.42 (2H, m); m/z (ES+) 414/416 (M++H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[CH2:13](O)[CH3:14]>>[CH2:13]([O:11][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:12])[CH3:14]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CCO
Product: CCOC(=O)c1c[nH]c2ccccc12

Procedure:
The title compound is prepared starting from indole-3-carboxylic acid (commercially available from Aldrich) by esterification with ethanol using standard methods of organic synthesis (e.g. J. March, Advanced Organic Chemistry, Reactions, Mechanisms and Structure (1992, 4th edition) 393–394 (Wiley interscience, New York).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[C:14][C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Brc1cncnc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C#Cc1cncnc1
Temperature: 110 °C
Yield: 36.9 %

Procedure:
Triethylamine (10 mL) was degassed by bubbling argon over a period of 30 min. (S)-N-tert-Butoxycarbonyl-2-ethynylpyrrolidine (0.300 g, 5.12 mmol), tetrakis(triphenylphosphine)palladium (0.180 g, 0.1 mmol), palladium(II) acetate (0.0346 g, 0.10 mmol), copper (I) iodide (6.25 mg, 0.033 mmol) and 5-bromo-pyrimidine (0.4867 g, 3.07 mmol) were added. The mixture was heated at 110° C. for 9 h, then cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in chloroform (50 mL) and the organic phase washed with water (25 mL), saturated aqueous NaHCO3 solution (3×20 mL) and water (25 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography, eluting with ethyl acetate/hexane (1/1, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 0.310 g (74%) of a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([O:7][CH3:8])=[N:4][S:5][CH:6]=1.[CH3:9][N:10](C)C=O.[C-]#N.[Na+]>O>[C:9]([C:2]1[C:3]([O:7][CH3:8])=[N:4][S:5][CH:6]=1)#[N:10]
Reactant: CN(C)C=O
Reactant: COc1nscc1Br
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COc1nscc1C#N
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 38.8 g. (0.2 mole) of 4-bromo-3-methoxyisothiazole prepared as in Example 15 in 80 ml. of dimethylformamide was added 54 g. (0.6 mole) of cuprous cyanide. The mixture was stirred and heated at reflux for 1 hour. Then the reaction mixture was cooled to 25° C., and 40 g. (0.81 mole) of sodium cyanide in 120 ml. of water was added in portions. The mixture exothermed to 60°-70° C. and was allowed again to cool to 25° C. The reaction solution was then extracted thoroughly with ether. The ether extracts were washed with 10% sodium cyanide solution and then water. After drying over anhydrous magnesium sulfate and evaporation 23.4 g. (83%) of 4-cyano-3-methoxyisothiazole was obtained as a white solid, m.p. 60°-62° C. after crystallization from ligroin (90°-120°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1.Cl[CH2:46][C:47](=[O:49])[CH3:48].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:46][C:47]([CH3:48])=[O:49])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1
Reactant: CCc1cc(NC(CC)c2ccc(O)cc2)nc(Cl)n1
Reactant: CC(=O)CCl
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(NC(CC)c2ccc(OCC(C)=O)cc2)nc(Cl)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of 3.0 g of dl-5-chloro-6-ethyl-4-(α-ethyl-4-hydroxybenzyl)aminopyrimidine dissolved in 30 ml of N,N-dimethylformamide were added 1.2 g of chloroacetone and 1.7 g of anhydrous potassium carbonate, and the mixture was stirred at 80° C. for 8 hours. After completion of the reaction, the reaction mixture was charged into water and the separated oily product was extracted with ethyl acetate. The extract was washed with water, dried with anhydrous sodium sulfate, and then ethyl acetate was distilled off under reduced pressure. The oily product obtained was isolated by column chromatography (Wako Gel C-200, trade name, eluted with toluene: ethyl acetate=7:1) to give 1.3 g of the desired product as pale yellow liquid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[N:12]([CH2:25][O:26][CH3:27])[C:13](Br)=[N:14][C:15]=3[N:16]([CH2:21][CH2:22][CH3:23])[C:17]2=[O:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH3:29][SH:30].O>CN(C)C=O>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[N:12]([CH2:25][O:26][CH3:27])[C:13]([S:30][CH3:29])=[N:14][C:15]=3[N:16]([CH2:21][CH2:22][CH3:23])[C:17]2=[O:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(Br)n2COC
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(SC)n2COC
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.3 %

Procedure:
6-Methylthio-3-(n-propyl)-7H-purin-2(3H)-one (Compound B8, 11.8 g, 52.5 mmol), which was obtained by the method described in Journal of Heterocyclic Chemistry (J. Heterocycl. Chem.), 30, p. 241, 1993, was dissolved in N,N-dimethylformamide (200 mL). To the solution was added sodium hydride (1.51 g, 63.0 mmol, 1.2 equivalents) and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added chloromethyl methyl ether (4.85 mL, 63.9 mmol, 1.2 equivalents) and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous ammonium chloride, the mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was evaporated, and to the resulting residue was added diethyl ether. The deposited crystals were collected by filtration to obtain a methoxymethyl adduct. (R)-8-Benzyl-2-bromo-7,8-dihydro-1-methoxymethyl-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 36a, 2.81 g, 6.52 mmol), which was obtained from the methoxymethyl adduct in a manner similar to that in Example 35, was dissolved in N,N-dimethylformamide (26 mL), to the solution was added an about 15% aqueous solution of methylmercaptan sodium salt (6.10 mL, 13.1 mmol, 2.0 equivalents), and the mixture was stirred at room temperature for three days. To the reaction solution was added water, the mixture was extracted with chloroform, then the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated. The reaction residue was purified by silica gel column chromatography (chloroform:methanol=98:2) and the eluent was concentrated. To the residue was added acetonitrile, and the deposited crystals were collected by filtration to obtain the title compound (2.17 g, 84%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][CH2:17][O:18][CH2:19][CH3:20].[I-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][O:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
In DMF (80 ml) was dissolved 4-bromophenol (10 g). To the mixture was added at room temperature potassium carbonate (16.0 g) and then were added 2-chloroethylethyl ether (8.3 ml) and sodium iodide (9.53 g), and the mixture was stirred at 90° C. for 5 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with 1N sodium hydroxide and saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 1-bromo-4-(2-ethoxyethoxy)benzene (10.7 g). In THF (100 ml) was dissolved 1-bromo-4-(2-ethoxyethoxy)benzene (10.3 g). To the mixture was added dropwise at −78° C. 1.6M n-butyllithium/hexane (29.1 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (13.2 g) in THF (13 ml) and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added 10% sulfuric acid (50 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(2-ethoxyethoxy)phenyl borate (2.52 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8]1>O1CCCC1>[O:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][OH:15])[CH2:9][CH2:8]1
Reactant: CCOC(=O)CC1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 15 mL of tetrahydrofuran (THF) at 0° C. was added LiAlH4 (0.28 g, 7.3 mmol). This mixture was stirred for 10 min then the ethyl tetrahydropyran-4-yl-acetate (Combi-Blocks Inc., 0.50 g, 2.9 mmol) was added. The reaction was stirred for 5 min at 0° C. then was allowed to warm to ambient temperature and was stirred for 90 min. The reaction was quenched with excess NaHSO4.10H2O and was stirred for 60 min. The mixture was filtered through Celite. The filtrate was concentrated to give the title compound which was carried on without further purification. MS (DCI/NH3) m/z 131 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[OH:23][CH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:29]3[CH:30]=[C:25]([CH2:24][OH:23])[CH:26]=[CH:27][CH:28]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Agent: OBO
Product: OCc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)c1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 3-(hydroxymethyl)phenylboronic acid as a boronic acid, the desired compound was obtained.
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][N:18]=2)[CH3:16])=[O:13])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[CH:19][N:18]=2)[CH3:16])=[O:13])=[CH:9][CH:10]=1)([CH3:4])=[CH2:3]
Reactant: C[C@@H](NC(=O)Cc1ccc(C(C)(C)O)cc1)c1ccc(OCC(F)(F)F)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C(C)c1ccc(CC(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Temperature: 100 °C
Yield: 82.7 %

Procedure:
A mixture of 2-[4-(1-hydroxy-1-methylethyl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (400 mg, 1.01 mmol) and p-toluenesulfonic acid monohydrate (38.4 mg, 0.202 mmol) in toluene (4.5 mL) was heated at 100° C. in a sealed tube for 6 h. The mixture was cooled to room temperature, diluted with CH2Cl2 (40 mL) and washed with water (2×50 mL). The organic layer was dried over MgSO4, concentrated and purified by normal phase chromatography (20-100% EtOAc/Hexanes) to give 316 mg (83%) of 2-(4-isopropenylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.21 (d, J=2.35 Hz, 1H), 7.45 (m, 2H), 7.20 (m, 4H), 6.64 (d, J=7.32 Hz, 1H), 5.38 (s, 1H), 5.11 (m, 1H), 5.09 (s, 1H), 4.37 (q, J=7.94 Hz, 2H), 3.58 (s, 2H), 2.15 (s, 3H), 1-39 (d, J=6.77 Hz, 3H); MS (Electrospray): m/z 379.5 (M+H).
Reaction SMILES: [Br:1][C:2]1[O:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:9][N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[C:11]1=[O:17]>C(O)(=O)C>[Br:1][C:2]1[O:8][C:5]([CH:6]=[N:9][N:10]2[CH2:15][CH2:14][NH:13][C:12](=[O:16])[C:11]2=[O:17])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: NN1CCNC(=O)C1=O
Solvent: CC(=O)O
Product: O=C1NCCN(N=Cc2ccc(Br)o2)C1=O
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
1.9 pts. by wt. of 5-bromofurfural, 1.3 pts. by wt. of 1-amino-2,3-dioxo-piperazine and 7 pts. by vol. of glacial acetic acid were warmed to 90° for 10 minutes and then left for 30 minutes at RT. The precipitate is filtered off, washed with 3 pts. by vol. of glacial acetic acid and recrystallised from dimethylformamide, with the addition of animal charcoal. 1.1 pts. by wt. (38.5%) of 1-(5-bromofurfurylideneamino)-2,3-dioxo-piperazine are obtained as yellowish crystals of decomp. pt. 220°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12]C(=O)C(C)(C)C)[C:6]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[C:5]2[CH3:25].CC(C[AlH]CC(C)C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][OH:12])[C:6]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[C:5]2[CH3:25]
Reactant: Cc1c(-c2cccnc2)n(COC(=O)C(C)(C)C)c2ccc(Cl)cc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1c(-c2cccnc2)n(CO)c2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flask is charged with 2,2-dimethyl-propionic acid 5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl ester (Example 65, 0.607 g, 1.684 mmol) and dichloromethane (10 mL) and cooled to −78° C. DIBAL-H (1M in hexane, 4.21 mL, 4.21 mmol) is added and the mixture is stirred at −78° C. for 1 h. The reaction is quenched with MeOH (1 mL) and then washed with saturated aqueous sodium potassium tartrate and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo, to give a residue which is purified by silica gel flash chromatography (heptane-ethyl acetate, 3:7) to afford (5-chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-methanol as a white color solid. 1H NMR (400 MHz, MeOD) δ ppm 2.27 (s, 3H), 5.46 (s, 2H), 7.25 (dd, J=8.6, 2.0 Hz, 1H), 7.55 (s, 1H), 7.58 (s, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.62-7.67 (m, 1H), 8.08 (dt, J=8.1, 2.0, 1.8 Hz, 1H), 8.66 (dd, J=4.9, 1.6 Hz, 1H), 8.75 (d, J=1.3 Hz, 1H). HRMS (ESI) m/z 273.0807 [(M+H)+ Calcd for C15H14ClN2O: 273.0795].
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:19])[CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC.C(OCCOCC)C>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[F:18][C:13]1[CH:12]=[C:11]([C:8]2[O:9][C:10]3[C:2]([CH:20]=[CH2:21])=[CH:3][C:4]([OH:19])=[CH:5][C:6]=3[N:7]=2)[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Oc1cc(Br)c2oc(-c3ccc(O)c(F)c3)nc2c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CCOCCOCC
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 115 °C
Reaction time: 48 h
Yield: 72.6 %

Procedure:
Dichlorobis(tri-o-tolylphosphine)palladium (II) (0.87 g, 1.1 mmol) was added into a mixture of 7-bromo-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol (7.16 g, 22.1 mmol), tributyl(vinyl)tin (10.5 g, 33.25 mmol) and ethylene glycol diethyl ether (65 mL). The reaction mixture was stirred at 115° C. for 48 h, cooled to room temperature and treated with activated carbon. The mixture was filtered through MgSO4 and concentrated. Purification by flash chromatography, on acidic silica gel (hexanes/EtOAc/CH2Cl2 1/1/1), gave a white solid (4.35 g, 72% yield, m.p. 250-252° C.); MS m/e 272 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:28][O:29][CH2:30][CH3:31])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([Br:32])=[CH:6][C:5]=2[N:4]=1.[OH-].[Na+].C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)(Cl)Cl.O>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:11]2[C:10]3[CH:9]=[CH:8][C:7]([Br:32])=[CH:6][C:5]=3[N:4]=[C:3]([NH2:2])[C:12]=2[N:13]=[C:14]1[CH2:28][O:29][CH2:30][CH3:31]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Hydrogen chloride (100 mL of a 4 M solution in 1,4-dioxane) was added to tert-butyl [4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (10.0 g, 20.3 mmol), and the reaction was stirred for one hour. The reaction was adjusted to pH 11 with the addition of sodium hydroxide pellets in a small amount of water. Chloroform (300 mL) was added followed by saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried overnight in a drying oven to provide 5.60 g of 1-(4-aminobutyl)-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(N(CC)CC)C.[CH3:24][OH:25].C1(N=C=NC2CCCCC2)CCCCC1>C(=S)=S>[CH2:15]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([N:1]=[C:24]=[O:25])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:16]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: S=C=S
Solvent: CCN(CC)CC
Product: CCn1c2ccccc2c2cc(N=C=O)ccc21
Reaction time: 4 h

Procedure:
38.6 g of 3-amino-9-ethylcarbazole and 27.9 ml of triethylamine were added to 300 ml of methanol, and, while cooling with ice, 15.2 g of carbon disulfide was added dropwise thereto. After conducting reaction at room temperature for 3 hours, 41.3 g of dicyclohexylcarbodiimide was added thereto, followed by reacting at room temperature for 4 hours. Crystals thus precipitated were collected by filtration, heat-refluxed in 500 ml of ethyl acetate, and cooled to precipitate and then filter off solids. The filtrate was concentrated to obtain the desired product (29 g).