Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19]([OH:21])=O.[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>CN(C=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=1)=[O:21]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (1.054 g, 6.50 mmol) was added to a solution of 5-bromo-2-fluorobenzoic acid (1.129 g, 5.0 mmol) in DMF (10 mL) and the RM was stirred for 2 h at 0° C. 4-(trifluoromethoxy)aniline (1.129 g, 5.0 mmol) was added and the RM was allowed to warm up RT and stirred for 2 days. The solvent was evaporated off under reduced pressure and the residue was treated with aq. NaHCO3, stirred and filtered. The filtered material was washed with water, dissolved in EtOAc, washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 100 g, n-hexane/EtOAc 2:1) to afford the title compound as a white crystalline solid. UPLC-MS (Condition 2) tR=1.27 min, m/z=378.0/380.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10][C:9]2=[O:15])=[N:4][N:5]([CH3:7])[CH:6]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])[CH2:10][C:9]2=[O:15])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cn1cc(Br)c(N2CC(CO)CC2=O)n1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(Br)c(N2CC(CO[Si](C)(C)C(C)(C)C)CC2=O)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37 %

Procedure:
To a solution of 1-(4-bromo-1-methyl-1H-pyrazol-3-yl)-4-(hydroxymethyl)pyrrolidin-2-one (84 mg) and 1H-imidazole (27 mg) in DMF (3.0 mL) was added tert-butyldimethylchlorosilane (54 mg). The reaction mixture was stirred at room temperature for 20 hr, and diluted with ethyl acetate. The diluted solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (44 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH2:8][C@@H:9]2[C@@H:25]([C@:26]3([CH3:33])[C:31]=1[CH2:30][C@@H:29]([OH:32])[CH2:28][CH2:27]3)[CH2:24][CH2:23][C@@:22]1([CH3:34])[C@H:10]2[CH2:11][CH2:12][C@@H:13]1[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:4][CH3:5])[CH3:2].N1C=CC=CC=1.[C:41](Cl)(=[O:44])[CH2:42][CH3:43].C(=O)(O)[O-].[K+]>O>[CH2:4]([N:3]([CH2:6][C:7]1[CH2:8][C@@H:9]2[C@@H:25]([C@:26]3([CH3:33])[C:31]=1[CH2:30][C@@H:29]([O:32][C:41](=[O:44])[CH2:42][CH3:43])[CH2:28][CH2:27]3)[CH2:24][CH2:23][C@@:22]1([CH3:34])[C@H:10]2[CH2:11][CH2:12][C@@H:13]1[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:1][CH3:2])[CH3:5]
Reactant: CCC(=O)Cl
Reactant: CCN(CC)CC1=C2C[C@@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]2C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)O[C@H]1CC[C@@]2(C)C(=C(CN(CC)CC)C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 2 h

Procedure:
To a solution of 10 parts of 6-(diethylaminomethyl)cholest-5-en-3β-ol in 40 parts of pyridine at 0° is added, slowly and with stirring, 5 parts of propionyl chloride. When the addition is complete, stirring is continued for 2 hours while the reaction mixture warms to room temperature, whereupon 100 parts of water and 100 parts of aqueous 5% potassium bicarbonate are consecutively mixed in. The oil which separates is extracted with hexane. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation, affording 6-(diethylaminomethyl)-3β-(propionyloxy)cholest-5-ene as the residue.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O1CCCC1.C(Cl)Cl>[N:16]1([CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=2[F:1])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: Fc1ccc(Br)cc1COCCCCBr
Solvent: C1CCOC1
Solvent: ClCCl
Product: Fc1ccc(Br)cc1COCCCCN1CCOCC1
Reaction time: 72 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (550 mg, 1.62 mmol) in tetrahydrofuran (8 ml) was treated with morpholine (1.4 ml, 16.2 mmol). The resulting reaction mixture was stirred for about 72 hours. The reaction mixture was then diluted with methylene chloride and washed with saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]3[CH:15]([CH2:16][N:17]([C:19](OC(C)(C)C)=O)C)[CH2:14][CH2:13][S:12][C:8]=3[NH:9]2)=[CH:5][CH:4]=1.Br[CH2:29][CH2:30][CH2:31][Cl:32]>>[Cl:32][CH2:31][CH2:30][CH2:29][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:26])([F:27])[F:1])[CH:11]=2)[C:7]2[CH:15]([CH2:16][NH:17][CH3:19])[CH2:14][CH2:13][S:12][C:8]1=2
Reactant: ClCCCBr
Reactant: CN(CC1CCSc2[nH]c3cc(C(F)(F)F)ccc3c21)C(=O)OC(C)(C)C
Product: CNCC1CCSc2c1c1ccc(C(F)(F)F)cc1n2CCCCl

Procedure:
By the same procedure as in Example 39(2), 7-trifluoromethyl-4-(N-t-butoxycarbonyl-N-methylaminomethyl)-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (1.5 g) is made to react with 3-bromopropyl chloride followed by the reaction to remove the butoxycarbonyl group to give 9-(3-chloropropyl)-7-trifluoromethyl-4-methylaminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole. Ethanol (15 ml) and a 50% aqueous solution of dimethylamine are added to the product. The solution is heated at 90°-95° C. in a sealed-tube for 8 hours and evaporated to remove the solvent. The residue is dissolved in chloroform and extracted with dilute hydrochloric acid. The extract is adjusted to pH 8 with an aqueous solution of sodium hydroxide and extracted with chloroform. The extract is washed with water, dried and condensed to give the title compound (1.28 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=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>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:15]2[CH:14]=[C:13]([Cl:12])[CH:18]=[C:17]([Cl:19])[CH:16]=2)=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N)ccc(Br)c1Cl
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1c(N)ccc(-c2cc(Cl)cc(Cl)c2)c1Cl
Yield: 63.9 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 1, using 2.3 grams (0.010 mole) of 2-amino-5-bromo-6-chlorobenzonitrile (prepared as in Step A of Example 2), 2.9 grams (0.015 mole) of 3,5-dichlorophenylboronic acid, 0.1 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0), and 30 mL of aqueous 2M sodium carbonate in 75 mL of toluene. The solid product was recrystallized from toluene, yielding 1.9 grams of 2-amino-6-chloro-5-(3,5-dichlorophenyl)benzonitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH3:13]
Reactant: O=C1Nc2cccc(Br)c2C1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(=O)c2c(Br)cccc21
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a stirred solution of 4-bromoisatin (90.4 g, 400 mmol) in N,N-dimethylformamide (400 mL) was added cesium carbonate (196.0 g, 600 mol) at ambient temperature. The reaction mixture was stirred for 30 min, iodomethane (37.4 mL, 600 mmol) was added and the mixture was stirred at ambient temperature for 18 h. The solid was removed by filtration, the filtrate was concentrated in vacuo, and the residue was triturated in water and washed with diethyl ether to afford 4-bromo-1-methyl-1H-indole-2,3-dione (82.0 g, 85%): 1H NMR (300 MHz, DMSO-d6) δ 7.95-7.89 (m, 1H), 7.68-7.64 (m, 1H), 7.53-7.49 (m, 1H), 3.50 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][NH2:32])[CH:29]=2)[CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:32][CH2:31][C:28]4[CH:29]=[C:30]5[C:25]([CH:24]=[CH:23][CH:22]=[N:21]5)=[CH:26][CH:27]=4)[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: NCc1ccc2cccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5cccnc5c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (480 mg, 1.69 mmol) and quinolin-7-ylmethanamine (400 mg, 2.53 mmol) in acetonitrile (5 mL) and N,N-diisopropylethylamine (1.5 mL, 8.6 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-prep HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM diethylamine]) to yield an off white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:58]([O:60][CH2:61][CH3:62])=[CH2:59])CCC>O1CCOCC1>[CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[C:9]=1[C:58]([O:60][CH2:61][CH3:62])=[CH2:59]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: C=C(OCC)c1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a pressure flask were charged compound tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (13.66 g, 16.86 mmol), tributyl(1-ethoxyvinyl)tin (11.4 mL, 33.74 mmols) and dioxane (150 ml). The flask was degassed with Ar briefly, capped and heated at 100° C. with stirring overnight. After cooling, the reaction mixture was concentrated. The residue was taken into ether (200 ml), washed with 0.5 M KF (50 ml), brine and dried (MgSO4). After solvent was removed under reduced pressure, the residue was purified on silica. Elution with DOM in hexanes (0-30%) gave compound tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (11.55 g, 85%).
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[CH:10][C:4]=2[S:3]1.[CH3:13]CN(CC)CC.CI>CCO>[CH3:13][S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc2sc(=S)[nH]c2c1
Solvent: CCO
Solvent: CI
Product: CSc1nc2cc(C#N)ccc2s1
Yield: 97.3 %

Procedure:
To a solution of 2-thioxo-2,3-dihydrobenzothiazole-5-carbonitrile (260 mg, 1.35 mmol) in EtOH (10.8 mL) was added Et3N (137 mg, 1.35 mmol) and methyliodide (192 mg, 1.35 mmol). The mixture was heated at reflux for 1 h. The volatiles were evaporated and the residue was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give 2-methylsulfanylbenzothiazole-5-carbonitrile 271 mg (97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH3:11])[C:6]=1[C:7](Cl)=[O:8].[C:12]1([S:18]([N:21]2[C:29]3[CH:28]=[C:27]([Sn:30]([CH3:33])([CH3:32])[CH3:31])[CH:26]=[C:25]([NH2:34])[C:24]=3[CH:23]=[N:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH3:11])[C:6]=1[C:7]([NH:34][C:25]1[CH:26]=[C:27]([Sn:30]([CH3:33])([CH3:32])[CH3:31])[CH:28]=[C:29]2[C:24]=1[CH:23]=[N:22][N:21]2[S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19])=[O:8]
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: CCn1ncc(Cl)c1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCn1ncc(Cl)c1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Chloro-1-ethyl-1H-pyrazole-5-carbonyl chloride (122 mg) in DCM (5 ml) was added over 5 min to 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (250 mg) in DCM (10 ml) and pyridine (0.05 ml). The reaction was stirred at room temperature for 1.5 h. Saturated sodium bicarbonate (aq) (20 ml) was added and the reaction stirred vigorously before the DCM was passed through a hydrophobic frit and evaporated to dryness. The residue was passed through a silica cartridge, preconditioned with cyclohexane. The silica cartridge was washed with cyclohexane:diethyl ether (1:1, v/v), then diethyl ether. The product containing ether fraction was evaporated to dryness to give title compound, 303 mg.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23](OS(C)(=O)=O)[CH2:22][C@H:21]1[C:30](=[O:33])[NH:31][CH3:32])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>O1CCCC1.CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:22][C@H:21]1[C:30](=[O:33])[NH:31][CH3:32])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(CS)cc1
Reactant: CNC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
1.80 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added, whilst ice-cooling, to a solution of 5.70 ml of 4-methoxybenzyl mercaptan dissolved in 100 ml of dry tetrahydrofuran, and the mixture was then stirred at 0° to 5° C. for 30 minutes. At the end of this time, a solution of 11.00 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-methanesulfonyloxy-2-methylcarbamoylpyrrolidine [prepared as described in step (2) above] in 80 ml of dry dimethylformamide was added to the mixture, and the mixture was stirred at 34° C. for 4.5 hours. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 5:1 by volume mixture of ethyl acetate and hexane) to afford 4.35 g of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[O:13]([NH2:15])[CH3:14].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:14][O:13][N:15]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a solution of 5-bromo-indanone (100 g, 0.474 mol) in ethanol (650 ml) under argon was added methoxylamine hydrochloride (198 g, 2.38 mol) and pyridine (125 ml). The mixture was refluxed for 2.5 hours, cooled to room temperature and poured into saturated aqueous sodium hydrogen carbonate solution. The mixture was then extracted with ethyl acetate and the organic phase dried (Na2SO4) and then concentrated in vacuo. The crude material was recrystallised from isopropanol to furnish the title compound, (110 g, 97%), as a brown solid; 1H NMR (CDCl3) 7.52 (1H, d, J 8.3 Hz), 7.43 (1H, d, J 1 Hz), 7.35 (1H, dd, J 8.3, 1 Hz), 3.97 (3H, s), 2.99 (2H, m), 2.85 (2H, m).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][Cl:35]>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][Cl:35])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: ClCCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCl)c2n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (4.7 g, 13.38 mmol) and potassium carbonate (4.62 g, 33.4 mmol) in dry DMF (50 ml) were stirred and heated at 50° C., under nitrogen, for 75 mins. The mixture was allowed to cool to room temperature and then cooled to 0° C. and 1-bromo-3-chloropropane (2.106 g, 13.38 mmol) was added. The mixture was stirred at 0 to 10° C. for approximately 5 hours then allowed to warm to room temperature and stirred for approximately a further 40 hours when LCMS indicated approximately 70% of the desired product. The mixture was allowed to settle and the supernatant was pipetted off and the solvent evaporated on a rotary evaporator using a high vacuum pump at about 23° C. Chloroform and water was added to the combined residues which were stirred and the phases separated using a hydrophobic frit. The aqueous layer was re-extracted with further portions of chloroform and the combined chloroform extracts were evaporated under high vacuum at 23° C. to give a yellow solid (2.798 g). This crude material was combined with similar material obtained from two similar preparations (0.56 g and 0.995 g) and purified by flash column chromatography on silica using 2:1 ethyl acetate/chloroform as eluant to give the title compound as an off-white solid. (3.011 g).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][C:16]=2[CH3:24])[CH2:7][CH2:6]1.[CH3:28][N:29]1[C:38]2[NH:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][CH2:33][C:32]=2[CH:31]=[N:30]1.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:34]3[CH2:33][C:32]4[CH:31]=[N:30][N:29]([CH3:28])[C:38]=4[NH:37][C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]3=4)=[O:20])=[CH:17][C:16]=2[CH3:24])[CH2:7][CH2:6]1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: Cc1cc(C(=O)O)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Yield: 5 %

Procedure:
4-{4-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid from Example E43 (139 mg, 0.37 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (75 mg, 0.37 mmol) were dissolved in dichloromethane (5 ml) and DIEA (0.195 ml, 1.11 mmol). WSCD (93 mg, 0.48 mmol) and DMAP (9 mg, 0.07 mmol) were added and the mixture was heated at reflux for 3 days, then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (11 mg, 5%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=1)=[C:5]2[CH3:20].[Cu](C#N)[C:22]#[N:23].CN1CCCC1=O>C(OCC)(=O)C>[C:22]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=1)=[C:5]2[CH3:20])#[N:23]
Reactant: Cc1cc(-c2[nH]c3ccc(Br)cc3c2C)cc(C)c1O
Reactant: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2[nH]c3ccc(C#N)cc3c2C)cc(C)c1O

Procedure:
1.32 g of 5-bromo-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole and 0.54 g of copper cyanide were added to 10 ml of N-methylpyrrolidone, and the mixture was refluxed for 4 hours. To the reaction mixture was added ethyl acetate, and the mixture was washed with 20% aqueous ammonia solution and water, and dried. The solvent was evaporated, and the residue was purified by silica gel column chromatography. Recrystallization of the crude product from ether-petroleum ether gave 5-cyano-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][C:4](=[O:13])[N:3]3[CH2:2]1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([CH2:1][CH2:2][N:3]3[C:4](=[O:13])[CH2:5][CH2:6]2)[CH:10]=1)=[O:21]
Reactant: O=C1CCc2cccc3c2N1CC3
Reactant: O=C(Cl)CCCCCBr
Product: O=C(CCCCCBr)c1cc2c3c(c1)CCN3C(=O)CC2

Procedure:
Using 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (3.00 g) and 6-bromohexanoyl chloride (2,91 ml) according to the same method as that of Reference Example 1, the title compound (3.94 g) was obtained as white crystals having a melting point of 97 to 98° C.
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>>[C:15]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1
Reactant: O=C(O)c1cccnc1
Reactant: CCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCOC(=O)c1cccnc1

Procedure:
Tridecyl nicotinate was prepared using the method of Example 1 from commercial tridecanol (an isomeric mixture) and nicotinic acid. The product had a boiling point of 136° to 140° C. under 0.05 mm pressure and an estimated purity of 100% based on a molecular weight of 305.5.