Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4]>C(OCC)(=O)C.CCCCCC>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:4])=[O:1])=[CH:7][CH:8]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 73.6 %

Procedure:
Using N-Boc-L-tHyp(Tosyloxy)-OMe (5g, 10.5 mmol), powdered KOH (1.75 g, 26.5 mmol) and 4-nitrophenol (3.66 g, 26.3 mmol) after 4 days at reflux, 2.52 g (65%) of the corresponding 4-nitrophenyl ether was obtained by column chromatography (silica ge, ethyl acetate/hexane mixtures) and crystallization of the appropriate fractions from ethyl acetate/hexane (1:1). An alternate method is to triturate the oily crude and pentane several times [hexane doesn't work] and then add a very, small amount of ethyl acetate to solidify the product. The filtered, solid product may than be crystallized as above. Elemental analysis for C17H22N2O7 (366.324 g/mmol): Calculated C, 55.74; H, 6.05; N, 7.65. Found C, 55.71; H, 6.05; N, 7.65.
Reaction SMILES: C1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH2:30]C)[C:25](=[C:32]([S:35][CH2:36][CH:37]([OH:45])[CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[C:33]#[N:34])[NH:24][CH2:23][CH2:22]2)C>C(N(CC)CC)C>[CH3:16][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[C:25](=[C:32]([S:35][CH2:36][CH:37]([O:45][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:38][N:39]1[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1)[C:33]#[N:34])[NH:24][CH2:23][CH2:22]2
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOc1cc2c(cc1OCC)C(=C(C#N)SCC(O)CN1CCOCC1)NCC2
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(=C(C#N)SCC(CN1CCOCC1)OC(=O)c1ccccc1)NCC2

Procedure:
After adding 40 ml of benzene, 1.0 g of triethylamine and 1.5 g of benzoyl chloride to 4.06 g of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile, the reaction mixture is refluxed for 45 minutes, then cooled down and filtered. After evaporating the filtrate, the residue crystallizes out on adding ethyl acetate to obtain the named product in a yield of 3.25 g, m.p.: 144° C. (from isopropanol).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:33]1(=[O:39])[NH:37][C:36](=[O:38])[CH:35]=[CH:34]1>>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:13]2[CH2:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH:35]3[C:36](=[O:38])[NH:37][C:33](=[O:39])[CH:34]3[C:14]=2[C:15]2[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][C:20]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C1C=CC(=O)N1
Reactant: COc1ccc2c(c1)cc(C=Cc1ccccc1OC)n2CCCO[Si](C)(C)C(C)(C)C
Product: COc1ccc2c(c1)c1c(n2CCCO[Si](C)(C)C(C)(C)C)CC(c2ccccc2OC)C2C(=O)NC(=O)C12
Yield: 89 %

Procedure:
The reaction of 1-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)-5-methoxy-2-[2-(2-methoxyphenyl)ethenyl]-1H-indole (III; Ar=2-methoxyphenyl, R10═CH2CH2CH2OSiMe2t-Bu) (98) prepared as described in example 51 with maleimide using the procedure described in example 68 gave 6-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)-9-methoxy-4-(2-methoxyphenyl)-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H, 3aH)-dione (IV; Ar=2-methoxyphenyl; R10═CH2CH2CH2OSiMe2t-Bu) (99) in a 89% yield as a tan powder, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH3:28])=[N:13][C:14]=1[CH2:15][CH3:16].Cl[C:32]1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.ICC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:32])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1O
Solvent: CCI
Product: CCO[C@H]1Cc2ccccc2[C@@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting (1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and iodoethane and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.81, 1.17-1.21, 1.30-1.34, 1.51-1.59, 1.98, 3.90-3.96, 4.02-4.08, 6.71-6.73, 7.04-7.07, 7.19; MS (ESI+) for C25H27Cl2N3O m/z 457 (M+H)+.
Reaction SMILES: [Br-].[C:2]([CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[OH-].[Na+].[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH:30]=O>C(Cl)Cl.O>[Br:26][C:27]1[CH:28]=[C:29](/[CH:30]=[CH:4]/[C:2]#[N:3])[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N#C/C=C/c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 125.9 %

Procedure:
To a mixture of (cyanomethyl)triphenylphosphonium bromide (70.6 g, 185 mmol) and sodium hydroxide (7.39 g, 185 mmol) in DCM (100 mL) and water (300.00 mL) at 0° C. was added 3-bromo-4-fluorobenzaldehyde (25.0 g, 123 mmol). It was allowed to warm to room temperature and stirred for 2 h. The organic layer was separated, and the water layer was extracted with DCM twice. The combined organic phases were dried over Na2SO4 and concentrated to give a crude product, which was washed with diethyl ether. The residue was purified to give the title compound as a white solid (35 g, 88% yield). LCMS: rt=1.50 min, [M+H+]=226
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CC[O-].[Na+].[C:14]1(=[O:19])[O:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][CH2:16][CH2:15][C:14]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: O=C1CCCO1
Reactant: COc1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(OCCCC(=O)O)cc1
Temperature: 155 °C
Reaction time: 0.08 h

Procedure:
4-Methoxyphenol was added to a solution of NaOC2H5 made by dissolving 2.3 g of Ka in 50 ml ethanol. After 5 minutes, gamma-butyrolactone was added and the mixture heated at reflux overnight. Ethanol was distilled off and the residue heated at 155° C. overnight, then cooled, diluted with water and acidified to pH 3 with dilute hydrochloric acid. The product was collected by filtration, 19.5 g, m.p. 103-104° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([CH3:26])[CH2:10][O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])=[CH:14][CH:13]=1.[Si:27]([O:34][C@H:35]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=1)[CH:36]=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C([BH3-])#N.[Na+]>CO>[Cl:44][C:40]1[CH:39]=[C:38]([C@@H:35]([O:34][Si:27]([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:29])[CH3:28])[CH2:36][NH:8][C@H:9]([CH3:26])[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)[CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1cccc(Cl)c1
Reactant: C[C@@H](N)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](COc1ccc(CC2SC(=O)NC2=O)cc1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.5 %

Procedure:
A mixture of 36.5 g of 5-{4-[2(R)-aminopropoxy]benzyl}thiazolidine-2,4-dione trifluoroacetate [prepared as described in Preparation 2], 98.4 g of (R)-α-(t-butyldimethylsilyloxy)-α-(3-chlorophenyl)acetaldehyde [prepared as described in Preparation 12] and 400 ml of absolute methanol was stirred at room temperature for 2.5 hours, after which the mixture was cooled using a salted ice-bath. 29.0 g of sodium cyanoborohydride were then added to the mixture in small portions, and the mixture was allowed to stand overnight at room temperature. At the end of this time, the methanol was distilled off under reduced pressure, the residue was mixed with water and ethyl acetate, and the ethyl acetate layer was separated from the mixture. The ethyl acetate layer was then washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 46.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[N:13](C3CCCCO3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1OC
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1OC
Yield: 92.5 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (550 mg, 1.51 mmol) in methanol (30 mL) was added 6 N HCl (30 mL). The solution was stirred at room temperature for 3 hours when water (80 mL) was added and the suspension filtered to give after drying, the title compound (390 mg, 93% yield). ES-MS (m/z) 280 [M+1]+.
Reaction SMILES: [Br:1]Br.[C:3]1(=[O:10])[NH:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1.Br>C(Cl)(Cl)Cl>[Br:1][CH:4]1[CH2:5][CH2:6][C:7](=[O:9])[NH:8][C:3]1=[O:10]
Reactant: BrBr
Reactant: O=C1CCCC(=O)N1
Agent: Br
Solvent: ClC(Cl)Cl
Product: O=C1CCC(Br)C(=O)N1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
4.5 ml bromine were added to 10.2 g glutarimide suspended in 20 ml chloroform and the mixture was stirred in a closed vessel for 90 minutes at a bath temperature of 110° C. After cooling, the vessel was opened and stirring was continued until no more hydrogen bromide escaped. The reaction mixture was evaporated in vacuo, the residue dissolved in ethanol and evaporated again. 17.1 g (99% of theoretical) of the title compound remained in the form of practically white crystals, which melted at 76 to 83° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)([Cl:18])=O.CN(C)C=O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([Cl:18])=[O:15])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (100 mg, 0.50 mmol) in thionyl chloride (110 μL, 1.5 mmol) was added N,N-dimethylformamide (20 μL, 0.26 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Excess thionyl chloride and N,N-dimethylformamide were removed in vacuo and the resulting acid chloride was used directly in next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH:19]=[CH2:20].CCN(C(C)C)C(C)C>>[O:14]1[CH2:15][CH2:16][N:11]([CH2:10][C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2](/[CH:20]=[CH:19]/[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:3][CH:4]=2)=[O:17])[CH2:12][CH2:13]1
Reactant: O=C(CN1CCOCC1)Nc1ccc(Br)cn1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1ccc(NC(=O)CN2CCOCC2)nc1
Temperature: 105 °C
Reaction time: 16 h
Yield: 75.3 %

Procedure:
A solution of 58b (640 mg, 2.14 mmol), tert-butyl acrylate (1.37 g, 10.7 mmol), DIPEA (0.74 ml, 4.28 mmol), Pd-(OAc)2 (47 mg, 0.21 mmol) and P (o-tol)3 (129 mg, 0.42 mmol) in propionitrile (8 ml) and DMF (2 ml) was purged with nitrogen for 10 minutes, and then was heated at 100-110° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the reaction mixture was cooled to 20-35° C., filtered through celite, and then concentrated. The resultant residue was diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combine organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 60% ethyl acetate/pet ether as an eluent to get the desired compound as an off-white solid (560 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.20 (dd, J=8.8, 2.5 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.53 (d, J=16.1 Hz, 1H), 6.56 (d, J=16.2 Hz, 1H), 3.62 (t, J=4.4 Hz, 4H), 3.21 (s, 2H), 2.55-2.51 (m, 4H), 1.48 (s, 9H); MS (ES) m/e 348.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[CH3:8].[Li]CCCC.C(NCC)C.[CH3:19][N:20]([CH:22]=O)[CH3:21]>C1COCC1>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[C:2]([CH3:8])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccnc(C)c1
Agent: [Li]CCCC
Solvent: CCNCC
Solvent: C1CCOC1
Product: Cc1cc(C=CN(C)C)ccn1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
11.05 g 2,4-Lutidine (0.1 mol) were dissolved in 50 ml THF. The solution was cooled and stirred, maintaining the temperature at between −70 to −50° C. 81.25 ml nBuLi (0.13 mol) was added over 0.25 hour. The dark red solution was stirred for a further 0.5 hour, then 15.14 ml diethylamine (0.145 mol) was added in one portion producing an orange suspension. After a 0.5 hour, 15.5 ml DMF (0.2 mol) was added. The brown-red solution was stirred for 1 hour then quenched with 50 ml 50% saturated aqueous ammonium chloride solution. Upon warming to ambient temperature, the reaction mixture was extracted with tert. butyl methyl ether (TBME) (3×100 ml), and the combined organic phases were washed with 50 ml H2O, dried over Na2SO4, filtered and concentrated under reduced pressure (45° C./450-20 mbar) providing an orange-red oil (14.8 g, 91%) which was sufficiently pure (Gas Liquid Chromatography (GLC) 98 area %) to be used directly in the next step.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21]O)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:25])=O>ClCCl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][Cl:25])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCCO)ccc3o2)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1csc(-c2cc3cc(CCCCl)ccc3o2)n1
Temperature: 25 °C

Procedure:
A mixture of 3-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]propanol (0.40 g) and thionyl chloride (0.4 ml) in dichloromethane (5 ml) was stirred under reflux for 5 hours. After being cooled to room temperature, the solution was concentrated under reduced pressure. The resulting residue -was partitioned between aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a 4-tert-butyl-2-[5-(3-chloropropyl)benzofuran-2-yl]thiazole (0.28 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:13][N:12]([C:14]([C:16]3[O:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)=[O:15])[CH2:11]2)=[CH:5][CH:4]=1.S(Cl)([Cl:29])=O>ClCCl>[Cl:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:13][N:12]([C:14]([C:16]3[O:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)=[O:15])[CH2:11]2)=[CH:5][CH:4]=1
Reactant: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CO)cc2)C1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CCl)cc2)C1
Yield: 80.2 %

Procedure:
5A (3.48 g, 9.47 mmol) was dissolved in dichloromethane (150 mL) and the mixture was cooled in an ice bath. While stirring, thionyl chloride (0.76 mL, 10.4 mmol) was added dropwise. The cooling bath was removed after 30 min. The mixture was stirred for 2.5 h and then evaporated to dryness. The residue was purified by column chromatography eluting with dichloromethane. There was obtained 2.93 g (80%) of 5B as a solid. 1H NMR (500 MHz, CDCl3): δ 4.22 (m, 2H), 4.57 (s, 2H), 4.65 (m, 2H), 5.14 (m, 1H), 7.29 (d, 2H), 7.36 (d, 2H), 7.53 (t, 2H), 7.59 (t, 1H), 8.16 (d, 2H), MS (APCI+) m/z 386 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:1][C:2]1[C:14]2[N:13]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:6][CH:7]4[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]4)[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2c1[nH]c1cc(O)ccc12
Reactant: BrCC1CCCCC1
Product: Cc1nccc2c3ccc(OCC4CCCCC4)cc3n(CC3CCCCC3)c12
Yield: 75 %

Procedure:
The title compound was synthesized from 1-methyl-7-hydroxy-β-carboline (0.5 g, 1.587 mmol) in presence of 1-bromomethylcyclohexane (1.240 g, 3.173 mmol) as described here above.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([C:32]1[S:36][CH:35]=[N:34][CH:33]=1)=[CH2:31].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:31]=[CH:30][C:32]2[S:36][CH:35]=[N:34][CH:33]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1cncs1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=Cc3cncs3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 80 °C

Procedure:
A pressure vessel is charged with 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (828 mg, 1.52 mmol), 5-vinyl thiazole (186 mg, 1.68 mmol), triethylamine (0.32 mL, 2.28 mmol) and tri-o-tolylphosphine (37 mg, 0.12 mmol) in CH3CN (1.5 mL). The vessel is degassed and palladium(II) acetate (6.80 mg, 0.03 mmol) is added. The vessel is sealed and heated at 80° C. for 20 h. The reaction mixture is concentrated and dissolved in EtOAc, washed with 1N HCl , dried over MgSO4 and concentrated. The residue is purified by column chromatography to afford the title compound as a yellow solid; (M+H)+=528.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N:11]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:20]([O:19][C:17]([N:11]1[CH2:16][CH2:15][N:14]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:13][CH2:12]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Clc1nc2ccccc2o1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(c2nc3ccccc3o2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A mixture of 2-chlorobenzoxazole (1.00 g, 6.51 mmol), benzyl 1-piperazinecarboxylate (1.43 g, 6.51 mmol), and K2CO3 (1.80 g, 13.0 mmol) in DMF (13 mL) was stirred at 100° C. overnight, cooled, diluted with water, and extracted with EtOAc. The extracts were combined, washed with water and brine, dried over Na2SO4 and concentrated in vacuo to provide the title compound (1.70 g, 77%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([OH:13])[CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][CH2:26][CH2:27]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([O:13][CH2:27][CH2:26][O:25][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][O:19]3)[CH:12]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: OCCOC1CCCCO1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(O)c2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(OCCOC3CCCCO3)c2)n1
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a solution of 5-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-chloro-phenol (WO2011/154734A1, which is incorporated herein by reference, 340 mg, 1.28 mmol), 2-(tetrahydro-pyran-2-yloxy)-ethanol (0.26 mL, 1.92 mmol) and Ph3P (671 mg, 2.56 mmol) in dry THF (10 mL) was added diethylazodicarboxylate (0.41 mL, 2.56 mmol) and the mixture stirred for 10 min. Water (4 drops) was added and the mixture concentrated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (450 mg, 89%). LCMS (Method 3): Rt 3.73 min, m/z 394 [MH+].