Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C[O:4]CC1.[CH2:6]1[CH2:11][CH2:10][CH:9]([N:12]=[C:13]=[N:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:8][CH2:7]1.C(N)CCCCCCCCCCC>N1C=CC=CC=1>[C:13]([NH:12][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:11][CH2:10]1)([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:4]
Reactant: C1CCOC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCCCCCCCN
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
If desacylsaponins are soluble in anhydrous pyridine alone or mixed with anhydrous THF, the reaction can be carried out with DCC. 100 mg of (4) (60 μmoles) are dissolved in pyridine and/or THF, using no less than 1 ml but no more than 5 ml of solvent. 0.4 ml of a 0.3M dodecylamine solution (120 μmoles) in pyridine and/or THF is added to the desacylsaponin solution, followed by 120 μmoles of dry DCC and 120 μmoles of dry NHS. The mixture is allowed to react with mixing overnight at 0° C. to 10° C. Insoluble dicyclohexylurea is formed, which is removed by centrifugation. The supernatant containing the conjugated desacylsaponins (5) is diluted with 10 volumes of EtOAc to precipitate (5) and to remove the free alkyl amine, residual DCC, and NHS. The precipitate is dissolved in water and extracted with EtOAc before concentration with a roto-evaporator and lyophilization. Modification is confirmed by mass spectra.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][Cl:12])=[O:6]
Reactant: O=C(O)c1cc(O)cc(O)c1
Reactant: OCCCCCCCl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=C(OCCCCCCCl)c1cc(O)cc(O)c1
Yield: 84.3 %

Procedure:
1.541 g (10.0 mmol) 3,5-dihyroxybenzoic acid, 2.732 g (20.0 mmol) 6-chlor-1-hexanol were dissolved in 20 ml toluene, and 0.2 ml of concentrated sulfuric acid was added thereto. The reaction mixture was then heated at reflux temperature for 20 hours, and was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 120 g silica gel using cyclohexane:ethyl acetate (7:3) as eluant yielded 2.3 g (84%) of 6-chlorohexyl 3,5-dihydroxybenzoate as orange oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][Si:17]([CH3:19])([CH3:18])[C:20]#[C:21][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc2c(c1)CC1(CC2)OCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)CC1(CC2)OCCO1

Procedure:
A solution of 7'-bromo-3', 4'-dihydrospiro[1,3-dioxolane-2,2'(1H)-naphthalene](3.40 g, 12.6 mmol), trimethylsilylacetylene (7.0 ml), 50 mmol) (Aidrich), triphenyephosphine (0.66 g, 2.50 mmol), and palladium acetate (0.28 g, 1.2 mmol) in triethylamine (18 ml) was stirred at 70° C. for 18 hours and then concentrated in vacuo. The residue was absorbed onto silica gel from a diethyl ether solution and partially purified by elution through silica gel (15 g) with diethyl ether: hexane (1:9). Further purification by chromatography on silica gel eluting with ethyl acetate:hexane (1:19) gave 3', 4'-dihydro-7'[2-(trimethylsilyl)-ethynyl]spiro[1,3-dioxolane-2,2'(1'H)-naphthalene] (1.45 g). 1H NMR (CDCl3 200 MHz) δ: 0.23 (s, 9H, SiMe3) 1.93 (t, J=7 Hz, 2 CH2), 2.95 (t, J=7 Hz, 2H, CH2) 4.02 (s, 4H, OCH2CH2O), 7.03 (d, J=8 Hz, 1H, Ar), 7.17 (s, 1H, Ar), 7.21 (d, J=8 Hz, 1H, Ar).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[N:23]1([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C1CNCCNC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCCNCC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 1,4-diazepane to give 261. MS: (ESI+)=382.1
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[C:23]([F:43])=[CH:24][C:25]([Cl:42])=[C:26]([CH:41]=1)[O:27][C:28]1[N:33]=[C:32]2[S:34][C:35]([NH:37][C:38](=[O:40])[CH3:39])=[N:36][C:31]2=[CH:30][CH:29]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[C:38]([NH:37][C:35]1[S:34][C:32]2[C:31]([N:36]=1)=[CH:30][CH:29]=[C:28]([O:27][C:26]1[C:25]([Cl:42])=[CH:24][C:23]([F:43])=[C:22]([NH:21][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=3[Cl:1])[CH:41]=1)[N:33]=2)(=[O:40])[CH3:39]
Reactant: CC(=O)Nc1nc2ccc(Oc3cc(N)c(F)cc3Cl)nc2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (0.11 g, 0.5 mmol) produced in Example C61(v) in oxalyl chloride (0.5 mL) was added N,N-dimethylformamide (40 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1 mL) and tetrahydrofuran (1 mL), and the solution was added dropwise to a solution of N-[5-(5-amino-2-chloro-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (0.12 g, 0.33 mmol) in N,N-dimethylacetamide (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50), and recrystallized from methanol to give the title compound (40 mg, 22%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1.CC(C)([O-])C.[K+].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[N:13]([S:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=2)(=[O:30])=[O:29])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2cnccc12
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)n2cc(CCNC(=O)OC(C)(C)C)c3ccncc32)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Boc-6-azatryptamine (1.1 eq.) and 3-methoxybenzenesulfonyl chloride (1.0 eq.) in THF at room temperature is treated portionwise with solid potassium t-butoxide (1.2 eq), stirred at room temperature for 16 h, poured into saturated NaHCO3 and extracted with EtOAc. The combined extracts are dried over MgSO4 and concentrated in vacuo. Chromatographic purification of this concentrate using silica gel and EtOAc/Hexanes as eluent gives the title sulfonated compound.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[C:16]([C:18]1[CH:23]=[CH:22][C:21](OB(O)O)=[CH:20][CH:19]=1)#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[N:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7]([C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Br)c(-c2ccco2)nc1N
Reactant: N#Cc1ccc(OB(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(-c2cc(C#N)c(N)nc2-c2ccco2)cc1
Yield: 15.4 %

Procedure:
2-Amino-5-bromo-6-(2-furyl)nicotinonitrile (20 mg, 75.7 μmol), 4-cyanophenylboric acid (30 mg, 204 μmol), dichlorobis(acetonitrile) palladium (II) (2 mg, 7.71 μmol), and a solution of 2 M aqueous potassium carbonate (150 μL, 300 μmol) in N,N-dimethylformamide (0.6 mL) was stirred at 80° C. for 14 hours. After cooling as it was, the reaction solution was diluted with ethyl acetate and water. After filtering off the insoluble matters, the organic layer in the filtrate was concentrated. A half of the residue was purified by HPLC on a reverse phase column and using a water-acetonitrile-trifluoroacetic acid system as the elution solvent, to give the title compound (3.33 mg).
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10]C(C)(C)C)=O)#[N:2].FC(F)(F)C(O)=O.[CH2:22]([C:34]1[CH:42]=[CH:41][C:37](C(O)=O)=[CH:36][CH:35]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:22]([C:34]1[CH:35]=[CH:36][C:37]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:3]2[C:1]#[N:2])=[O:10])=[CH:41][CH:42]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C#N
Reactant: CCCCCCCCCCCCc1ccc(C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCc1ccc(C(=O)N2CCC[C@@H]2C#N)cc1
Yield: 39.3 %

Procedure:
General procedure D was used to deprotect 1.4 mmols of 41 using 14 mL of dichloromethane and trifluoroacetic acid. After previously described recrystallization techniques, the TFA salt of 41 was coupled to 0.4 grams (1.4 mmols) of 4-dodecylbenzoic acid using 0.73 grams (1.4 mmols) of PyBOP and 0.72 grams (5.6 mmols) of N,N-diisopropylethylamine in 14 mL of dichloromethane according to general procedure E. Using previously described work-up and purification techniques (column chromatography, 25% EtOAc in hexanes), yielded 0.2 grams (0.55 mmols, 39%) of the title product as an off-white solid. 1H and 13C NMR data were identical to that of 29.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH:21]([N:32]1[C@H:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:36](=[O:42])[NH:35][C@H:34]([CH:43]2[CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)[C:33]1=[O:52])[C:22]([NH:24][C:25]1C=CC=CC=1O)=[O:23].CNC.O1CCCC1>ClCCl>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@@H:21]([N:32]1[C@H:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:36](=[O:42])[NH:35][C@H:34]([CH:43]2[CH2:44][C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:51]2)[C:33]1=[O:52])[C:22]([N:24]([CH3:1])[CH3:25])=[O:23]
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc(F)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N(C)C)c1ccc(F)cc1F
Reaction time: 0.25 h
Yield: 62 %

Procedure:
Carbonyldiimidazole (4.80 g, 1.54 equiv.) was suspended in anhydrous dichloromethane (40 mL) and the suspension was left at room temperature for 15 minutes. (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide (10.50 g, pre-dried in vacuo over P4O10 for 24 hours) was then added with stirring and the resultant solution was stirred at room temperature for 6 hours. The resulting yellow solution was then treated with a 2.0M solution of dimethylamine in tetrahydrofuran (54 mL, 5.6 equiv.) and the resulting mixture was stirred at room temperature for 16 hours. The solvents plus residual dimethylamine were removed under reduced pressure and the reaction mixture was taken up in dichloromethane (200 mL) and washed with 1M hydrochloric acid (200 mL). The organic phase was separated using a hydrophobic frit and was evaporated under reduced pressure to ca. 50 mL. The crude product was applied to 4×90 g silica Biotage™ columns on a Quad 3 system; each column being eluted with (i) 2:1 v/v ethyl acetate:cyclohexane (12×50 mL fractions), (ii) ethyl acetate (12×50 mL fractions), (iii) 9:1 v/v ethyl acetate:methanol to give (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide (5.753 g, 62%) as a colourless solid.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:24])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14](=[O:23])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:25]([C:28]([CH3:30])=[CH2:29])[CH2:26][CH2:27][C@:5]1([CH:31]=[O:32])[CH2:4][CH2:3]2.CC(=CC)C.Cl([O-])=[O:39].[Na+].O.OP([O-])(O)=O.[Na+]>CC(O)(C)C.O.[Cl-].[NH4+]>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:24])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14](=[O:23])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:25]([C:28]([CH3:30])=[CH2:29])[CH2:26][CH2:27][C@:5]1([C:31]([OH:39])=[O:32])[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: O
Solvent: CC(C)(C)O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbaldehyde (17.6 g, 36.1 mmol) in t-BuOH (100 mL) was added 2-methyl-2-butene (40 mL, 476 mmol). A solution of sodium chlorite (15 g, 133 mmol) and sodium phosphate monobasic monohydrate (25 g, 181 mmol) in water (200 mL) was added drop wise over 1.25 h and the mixture was stirred at rt for an additional 45 minutes. The mixture was diluted with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×125 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by using a 300 g Thomson silica gel column and a 10-50% ethyl acetate in hexanes gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid as a white foam (16.4 g, 36.1 mmol, 100%). LCMS: m/e 453.2 (M−H)−, 2.61 min (method 3). 1H NMR (400 MHz, chloroform-d) δ=10.02 (br. s., 1H), 4.75 (d, J=1.8 Hz, 1H), 4.64-4.61 (m, 1H), 3.02 (td, J=10.8, 4.8 Hz, 1H), 2.55-2.36 (m, 3H), 2.33-2.19 (m, 2H), 2.08-1.86 (m, 4H), 1.70 (s, 3H), 1.08 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 1.82-0.90 (m, 15H).
Reaction SMILES: [S:1]([CH2:5][CH2:6][C:7]#[CH:8])([CH3:4])(=[O:3])=[O:2].I[C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:1]([CH2:5][CH2:6][C:7]#[C:8][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)([CH3:4])(=[O:3])=[O:2]
Reactant: Cc1cccc(I)c1
Reactant: C#CCCS(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cccc(C#CCCS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.8 %

Procedure:
A mixture of 1-mesylbut-3-yne (758 mg, 5.10 mmol), 3-iodotoluene (1.31 g, 6.00 mmol), copper (I) iodide (40 mg), PdCl2(PPh3)2 (70 mg) in 12 mL of Et3N is stirred at room temperature under N2 for 20 hr. The mixture is filtered and washed with Et3N (3×15 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a pale yellow oil (565 mg, 47%): 1H NMR (CDCl3) 2.31 (s, 3 H), 2.88 (t, J=6.9 Hz, 2 H), 3.07 (s, 3 H), 4.38 (t, J=6.9 Hz, 2 H), 7.20 (m, 4 H).
Reaction SMILES: C[O:2]/[C:3](=[N:13]/[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)[CH:25]=[N:24][CH:23]=2)[OH:21])=[CH:16][CH:15]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.C(Cl)Cl.CO.C([O-])([O-])=O.[K+].[K+]>Cl>[Cl:12][C:8]1[CH:7]=[C:6]([C:5]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:20]([OH:21])[C:22]4[N:26]([CH2:27][C:28]5[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[CH:32][CH:33]=5)[CH:25]=[N:24][CH:23]=4)[CH:18]=3)[NH:13][C:3](=[O:2])[CH:4]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COC(/C=C/c1cccc(Cl)c1)=N/c1ccc(C(O)c2cncn2Cc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2C(O)c2ccc3[nH]c(=O)cc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A mixture of intermediate 7 (0.94 mol) in HCl 3N (5 ml) was stirred at reflux overnight, cooled at room temperature and poured out into ice water. DCM and methanol (little quantity) were added. The organic layer was basified by K2CO3, separated, dried over MgSO4, filtered, and the solvent was evaporated, yielding 0.44 g of 4-[[5-[[4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-quinolinyl]hydroxymethyl]-1H-imidazol-1-yl]methyl]-benzonitrile (compound 1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([O:19][C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:23]=[CH:24][CH:25]=2)[N:3]=1.[CH3:31][N:32]1[CH2:36][CH2:35][CH:34]([N:37]2[CH:41]=[C:40]([NH2:42])[CH:39]=[N:38]2)[CH2:33]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:31][N:32]1[CH2:36][CH2:35][CH:34]([N:37]2[CH:41]=[C:40]([NH:42][C:2]3[N:10]=[C:9]4[C:5]([N:6]=[CH:7][N:8]4[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([O:19][C:20]4[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:23]=[CH:24][CH:25]=4)[N:3]=3)[CH:39]=[N:38]2)[CH2:33]1
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Cl)nc3c2ncn3COCC[Si](C)(C)C)c1
Reactant: CN1CCC(n2cc(N)cn2)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3cnn(C4CCN(C)C4)c3)nc3c2ncn3COCC[Si](C)(C)C)c1
Temperature: 25 °C

Procedure:
To a mixture of N-{3-[(2-chloro-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-6-yl)oxy]phenyl}prop-2-enamide (210 mg, 0.471 mmol) and 1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-amine (93.9 mg, 0.565 mmol) in 1,4-dioxane (7.85 mL) were added Pd2(dba)3 (43.0 mg, 10 mol %), Xantphos (27.2 mg, 10 mol %), and cesium carbonate (460 mg, 1.41 mmol). The reaction vial was sealed, then evacuated and back-filled with nitrogen three times. The mixture was subjected to microwave irradiation at 140° C. for 1 hr at normal absorption. After cooling to rt the reaction was diluted with EtOAc and filtered through a glass fiber filter set. The filtrate was concentrated and dried to give the title compound, which was carried forward without further purification, assuming quantitative yield. m/z (APCI+) for C28H37N9O3Si 576.20 (M+H)+.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][CH2:13][N:6]3[C:7]=2[C:2]=1[C@H:3]1[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:4]1[CH2:5]3.[ClH:24].Cl.[CH:26]1[CH:35]=[CH:34][C:33]2CCCN3[C:32]=2[C:27]=1[C@H]1CNC[C@H]1C3>>[ClH:24].[ClH:24].[C:26]1([C:10]2[CH:1]=[C:2]3[C:7]4=[C:8]([CH2:11][CH2:12][CH2:13][N:6]4[CH2:5][C@@H:4]4[CH2:14][NH:15][CH2:16][C@H:3]34)[CH:9]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:27]=1
Reactant: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CCC2
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCc4cccc(c43)[C@H]2C1
Agent: Cl
Product: c1ccc(-c2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CCC3)cc1

Procedure:
Following the procedure described in EXAMPLE 7, Part A, (±)-cis-tert-butyl 5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate, an intermediate from EXAMPLE 11, was converted into the title compound as an oil. 1H NMR (CDCl3): δ 6.90 (s, 2H), 3.90-3.77 (m, 1H), 3.61-3.52 (m, 1H), 3.35-3.25 (m, 2H), 3.20-3.12 (m, 2H), 3.08-2.95 (m, 2H), 2.85-2.68 (m, 3H), 2.57-2.47 (m, 1H), 1.98-1.88 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:11][N:12]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH:15]([O:20][CH2:21][CH:22]2[O:24][CH2:23]2)[CH2:14][C:13]1([CH3:26])[CH3:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:27][CH:28]1[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:30]([CH3:46])([CH3:45])[CH2:29]1>O1CCOCC1.C(OCC)C>[CH2:37]([O:36][N:31]1[C:32]([CH3:34])([CH3:35])[CH2:33][CH:28]([O:27][CH2:23][CH:22]([OH:24])[CH2:21][O:20][CH:15]2[CH2:14][C:13]([CH3:25])([CH3:26])[N:12]([O:11][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:17]([CH3:18])([CH3:19])[CH2:16]2)[CH2:29][C:30]1([CH3:45])[CH3:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Reactant: CCCCCCCCON1C(C)(C)CC(OCC2CO2)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCCCCCCCON1C(C)(C)CC(OCC(O)COC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Yield: 45.7 %

Procedure:
Sodium hydride (0.7 g. 5.9 mmol) is added to a solution of 17.0 g (59.5 mmol) of 1-(1-octyloxy--2,2,6,6-tetramethylpiperidin-4-yloxy)-2,3-epoxypropane (prepared in Example 11) in 75 ml of dioxane. The reaction mixture is heated at reflux for 10 minutes and then cooled to 60° C., whereupon a solution of 10.0 g (29.3 mmol) of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine (prepared in Example 5) in 25 ml of dioxane is rapidly added. The reaction mixture is heated at reflux for 4 hours, treated with an additional 0.6 g of sodium hydride, and heated at reflux for 7 hours. The reaction mixture is diluted with diethyl ether (500 ml), and the organic solution is washed with 1N hydrochloric acid (2×100 ml) and saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated to an oil. Purification by flash chromatography on silica gel (9:1 heptane: ethyl acetate) affords 8.4 g (46% yield) of the title compound, a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].ClC1C([O:15][C:16](=O)[CH2:17][N:18]2[CH2:22][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:20][C:19]2=[O:30])=C(Cl)C(Cl)=C(Cl)C=1Cl>CN(C)C=O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH:21]2[CH2:22][N:18]([CH2:17][C:16]([N:4]3[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]3)=[O:15])[C:19](=[O:30])[CH2:20]2)=[CH:28][CH:27]=1
Reactant: O=C(CN1CC(c2ccc(Cl)cc2)CC1=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=C1CNCCN1
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)CN2CC(c3ccc(Cl)cc3)CC2=O)CCN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4.46 g (44.6 mmol) of piperazin-2-one (ketopiperazine) and 300 ml of dimethylformamide are added to 22.4 g (44.6 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid pentachlorophenyl ester and the whole is stirred for 5 hours at room temperature. The whole is concentrated to dryness by evaporation under reduced pressure at 70°, stirred with 150 ml of ethyl acetate for 1 hour and then 150 ml of diethyl ether are added; the whole is filtered with suction, washed with 50 ml of diethyl ether and allowed to dry. 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-3-oxopiperazine having a melting point of 205°-207° is obtained and can be purified further by recrystallisation from 300 ml of butanol, washing with 50 ml of diethyl ether and drying, and then melts at 208°-210°.