Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1(P([Pd-4](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)C=CC=CC=1>[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)OC1(C)C
Reactant: OC[C@@H]1CC(c2ccc(Br)cn2)=NO1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Temperature: 75 °C
Yield: 48.9 %

Procedure:
[(5S)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (Intermediate 11, 0.277 g, 1.08 mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(1H -1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 7, 0.35 g, 0.9 mmol), potassium carbonate (0.622 g, 4.5 mmol), and tetrakis(triphenylphosphino)palladium(0) (0.1 g, 0.09 mmol) were combined and suspended in DMF (7 ml) and water (1 ml). The mixture was heated at 75° C. for 2 hours, then was poured into cold water (30 ml). The solids formed were collected, rinsed with water and washed with dichloromethane (2×10 ml), the solids were then dissolved in warm trifluoroethanol (2 ml), and further purified by column chromatography, eluting with 8% methanol in dichloromethane to give the title compound as a white solid (0.193 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]2[CH:9]=[C:10]([CH2:12]Cl)[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:2][C:3]1[N:8]2[CH:9]=[C:10]([CH2:12][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1cn2c(Cl)cccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2cn3c(Cl)cccc3n2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
A mixture of 5-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine hydrochloride (3.00 g), 4-hydroxybenzaldehyde (1.81 g), potassium carbonate (6.14 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 15 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with an queous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzaldehyde (3.55 g, yield 98%) as colorless crystals. m.p. 126-130° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([OH:16])=[S:15])=[CH:3]1.[C:23](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14]([O:16][CH3:23])=[S:15])=[CH:3]1
Reactant: O=C([O-])[O-]
Reactant: O=C1CC(O)C=C1CCCCCC(C(O)=S)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=S)C(CCCCCC1=CC(O)CC1=O)c1ccccc1

Procedure:
A stirred mixture of 4.38 g. of 7-(4-hydroxycyclopent-2-en-1-on-2-yl)-2-phenylthioheptanoic acid, 1.99 g. of potassium carbonate, 1.63 ml. of iodomethane and 26 ml. of acetone is refluxed for 3.5 hours. The acetone is evaporated and the residue is partitioned between water and ether. The ether layer is washed with brine, dried and concentrated, giving the product as an oily liquid, identified by PMRδ 3.67 (3, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.[I:20]N1C(=O)CCC1=O>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1[I:20])[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: Nc1cc2c(cc1I)C[C@]1(C2)C(=O)Nc2ncccc21
Reaction time: 18 h

Procedure:
To a solution of (2R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (4.00 g, 15.9 mmol, described in Intermediate 6) in THF (64 mL) at ambient temperature was added N-iodosuccinimide (3.58 g, 15.92 mmol). The reaction mixture was stirred for 18 h, then purified by silica gel chromatography, eluting with EtOAc:hexanes—70:30, to give the title compound. MS: m/z=378 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[CH:4][CH:3]=1.[OH:25]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:25])=[CH:4][CH:3]=1
Reactant: O=C1CCc2cc(OCCCCSc3ccc(Cl)cc3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCS(=O)c3ccc(Cl)cc3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[4-(4-chlorophenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][C:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18](Cl)=[O:19])[C:10]=2[O:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O.CC(C)=O>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]([C:17]1[C:10]2[O:9][C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:6])[C:12](=[O:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)Cl)cccc2c1=O
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)NCCCO)cccc2c1=O
Reaction time: 3 h

Procedure:
A solution of 7.6 ml of 3-aminopropanol in 50 ml of water was added dropwise over a period of 30 minutes to a suspension of 30 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride and 15.2 g of potassium carbonate in 400 ml of acetone. The thick suspension was stirred for 3 hours at 20°-25° C. The solvents were removed in vacuo and the residue was taken up in 300 ml of water. After stirring for 1 hour, the precipitate was collected by suction filtration and washed with water. The crude product was purified by crystallization from 95% ethanol and 23.8 g of the title compound were obtained, m.p. 191°-193° C. An additional 4.7 g of the title compound was obtained by concentration in vacuo of the crystallization filtrate.
Reaction SMILES: [C:1]1([S:11](Cl)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(OCC)(=O)C>[C:1]1([S:11]([NH:15][C:16]2[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=2[O:31][CH3:32])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:20])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cccc2ccccc12
Yield: 61.7 %

Procedure:
Prepared according to the procedure described for Example 127 using 1-naphthalenesulfonyl chloride (0.68 g, 3.0 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (0.73 g, 3.0 mmol), and ethyl acetate instead of dichloromethane to afford the product (0.8 g); m.p. 212-213° C.
Reaction SMILES: [CH2:1]1[N:8]([CH2:9][CH2:10][NH+:11]([CH2:22][C:23]([O-:25])=[O:24])[CH2:12][CH2:13][N:14]2[CH2:21][C:19](=[O:20])[O:18][C:16](=[O:17])[CH2:15]2)[CH2:7][C:5](=[O:6])[O:4][C:2]1=[O:3].C1CN2C(=NCCC2)C1.[NH2:35][NH2:36]>CS(C)=O>[C:16]([CH2:15][N:14]1[CH2:21][C:19](=[O:20])[NH:36][NH:35][C:5](=[O:6])[CH2:7][N:8]([CH2:1][C:2]([OH:4])=[O:3])[CH2:9][CH2:10][N:11]([CH2:22][C:23]([OH:25])=[O:24])[CH2:12][CH2:13]1)([OH:18])=[O:17]
Reactant: O=C([O-])C[NH+](CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Reactant: NN
Agent: C1CN=C2CCCN2C1
Solvent: CS(C)=O
Product: O=C(O)CN1CCN(CC(=O)O)CC(=O)NNC(=O)CN(CC(=O)O)CC1
Reaction time: 48 h

Procedure:
A 500 mL three-neck flask is charged with 150 mL of dry DMSO and flushed with nitrogen. Two syringes are charged separately with solutions of diethylenetriaminepentaacetic acid dianhydride (2.82 g, 7.89 mmol) and DBN (2.94 g, 2.92 mL, 23.67 mmol) in 122 mL of DMSO and anhydrous hydrazine (0.25 g, 0.25 mL, 7.89 mmol) in 125 mL DMSO. The two solutions are added simultaneously at the rate of 40 mL/hour to the flask at ambient temperature, employing a syringe pump. After the completion of addition the reaction mixture is stirred for 48 hours, concentrated under vacuum to 10 mL, and water (10 mL) is added. The solution at pH 10.5 is applied to AGIX-8 (100-200 mesh, acetate form) resin and the column is eluted with 1N acetic acid. The product is obtained by removal of acetic acid, followed by lyophilization.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[O:13][C:14](C)(C)[CH3:15].CSCC(OCC)=O>[Ni].C(N(CC)CC)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][CH:4]=1)[NH:7][C:14](=[O:13])[CH2:15]2
Reactant: CC(C)(C)OCl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: [Ni]
Agent: CCOC(=O)CSC
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(C(F)(F)F)ccc2N1

Procedure:
In analogous fashion, 4-trifluoromethylaniline was reacted with t-butyl hypochlorite, ethyl 2-(methylthio)acetate and triethylamine followed by reduction of the 3-thiomethyl-5-trifluoromethyl-2-oxindole thus obtained with Raney nickel, to give 5-trifluoromethyl-2-oxindole, m.p. 189.5°-190.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH3:13][N:14]([CH3:26])[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[N:14]([CH3:13])[CH3:26])=[CH:18][CH:19]=2)=[CH:6][N:7]=1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1nc(Br)cnc1N
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: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2ccc(C(=O)N(C)C)cc2)cnc1N
Temperature: 110 °C

Procedure:
Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (6.012 g, 25.91 mmol), [4-(dimethylcarbamoyl)phenyl]boronic acid (5 g, 25.91 mmol), sodium carbonate (5.492 g, 51.82 mmol) and Pd(PPh3)4 (2.994 g, 2.591 mmol) in a mixture of acetonitrile (28.85 mL) and water (28.85 mL) was heated at 110° C. The reaction mixture was allowed to cool and the residual solid filtered off. The filtrate was diluted with EtOAc and water and the layers separated. The aqueous layer was acidified to pH4 (by addition of 1M HCl) and then extracted with dichloromethane (3×), dried (MgSO4), filtered and concentrated in vacuo to leave the product as a yellow solid. The ethyl acetate extracts were concentrated in vacuo and combined with the filtered solid. Preabsorbed onto silica and purified by column chromatography on silica using the companion eluting with ethyl acetate/petroleum ether (0-100% EtOAc). Product eluted with 100% EtOAc. Product fractions combined and conc in vacuo to leave a yellow solid (1.95 g, 50% Yield). 1H NMR (400.0 MHz, DMSO) d 3.02 (3H, s), 3.15 (3H, s), 4.04 (3H, s), 7.54 (2H, m), 7.97 (2H, m), 8.71 (1H, s) ppm; MS (ES+) 301.13
Reaction SMILES: [CH3:1][C:2]([CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][CH3:5].[H-].[Na+].[CH2:15](Br)[CH2:16][CH2:17][CH3:18].O>C1(C)C=CC=CC=1>[CH2:15]([O:12][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:2]([CH3:1])=[CH:3][CH2:4][CH3:5])[CH2:16][CH2:17][CH3:18]
Reactant: CCC=C(C)C(O)CCCCC
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC=C(C)C(CCCCC)OCCCC
Temperature: 80 °C
Reaction time: 12 h
Yield: 77.9 %

Procedure:
20 g of 4-methyl-3-decen-5-ol dissolved in 100 ml of toluene are added dropwise at 80° C. over a period of 30 minutes to 6.2 g of a 55-60% sodium hydride dispersion in 100 ml of toluene. The mixture is stirred at 80° C. for 12 hours, then cooled to 50° C. and treated dropwise with a solution of 24.1 g of n-butyl bromide in 50 ml of toluene. The mixture is subsequently held at reflux temperature for 6 hours. For the working-up, the mixture is treated at room temperature with water, the organic layer is separated and washed neutral with water, dried and, after the addition of 0.2 g of potassium carbonate, fractionally distilled There are obtained 20.7 g of 5-butoxy-4 methyl-3-decene of boiling point 60° C./0.03 Torr, nD20 =1.4378. Odour: caramel-like, delicate, fatty-fruity.
Reaction SMILES: [C:1]1([N:7]=[N+:8]=[N-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=1)#[C:11][CH3:12]>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:11]([CH3:12])=[C:10]([C:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=3)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: CC#CC1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Product: Cc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)nnn1-c1ccccc1
Temperature: 120 °C
Yield: 3.1 %

Procedure:
The above-prepared phenyl azide (214 mg) and 200 mg of tert-butyl 4-(1-propynyl)-1,2,3,6-tetrahydropyridine-1-carboxylate prepared in 3) were dissolved in 3 ml of toluene and the solution was stirred at 120° C. for one night. The resulting solution was cooled down to room temperature, the solvent was evaporated in vacuo and the resulting residue was purified by a preparative thin-layer silica gel chromatography (hexane:ethyl acetate=2:1) to give 9.4 mg of the title compound as a white solid.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(N(S(F)(F)[F:29])CC)C.[ClH:32]>>[ClH:32].[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:2]2([F:29])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1cccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Product: COc1cccc(C2(F)CCNCC2)c1
Yield: 76 %

Procedure:
This material was prepared from the reaction of tert-Butyl 4-hydroxy-4-(3-methoxyphenyl)piperidine-1-carboxylate with diethylaminosulfur trifluoride and deprotection of the crude product using methanolic hydrogen chloride as described in Step 2 of Example 1 to afford 4-(3-methoxyphenyl)-4-fluoropiperidine hydrochloride in 76% yield.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]1[CH:42]=[CH:41][C:30]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=[CH:29][C:28]=1[OH:43])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CN=C1.O>ClCCl>[Si:1]([O:43][C:28]1[CH:29]=[C:30]([CH:41]=[CH:42][C:27]=1[O:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)c(O)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](Oc1cc(C(=O)OCc2ccccc2)ccc1OCc1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 116.3 %

Procedure:
A solution of tert-butyldiphenylsilyl chloride (850 mg, 3.09 mmol) in dichloromethane (10 cm3+5 cm3 rinse) was added to a stirred solution of benzyl 4-benzyloxy-3-hydroxybenzoate (827 mg, 2.47 mmol) and imidazole (421 mg, 6.18 mmol) in dichloromethane (15 cm3). After a few minutes a precipitate formed. The mixture was stirred overnight under an atmosphere of nitrogen, then was poured into water (50 cm3) The layers were shaken and separated, then the aqueous phase was further extracted with dichloromethane (2×50 cm3). The combined extracts were washed with brine (50 cm3) and evaporated to a pale yellow oil. This was filtered through a short silica column and eluted with 20% ethyl acetate in petroleum ether. Evaporation of the filtrate gave benzyl 3-(tert-butyldiphenylsilyloxy)-4-benzyloxybenzoate (1.646 g) as a very pale yellow oil, containing some tert-butyldiphenyl-silanol, which was used directly for the next step.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([S:37]([N:40]1[CH2:45][CH2:44][N:43]3[CH:46]=[CH:47][CH:48]=[C:42]3[CH:41]1[CH2:49][C:50]([OH:52])=O)(=[O:39])=[O:38])[CH:31]=[CH:30]2.[NH:53]1[CH2:57][CH2:56][N:55]=[C:54]1[C:58]1[CH:63]=[CH:62][C:61]([CH2:64][CH2:65][NH2:66])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>C1COCC1>[NH:55]1[CH2:56][CH2:57][N:53]=[C:54]1[C:58]1[CH:59]=[CH:60][C:61]([CH2:64][CH2:65][NH:66][C:50](=[O:52])[CH2:49][CH:41]2[N:40]([S:37]([C:32]3[CH:31]=[CH:30][C:29]4[C:34](=[CH:35][CH:36]=[C:27]([O:26][CH3:25])[CH:28]=4)[CH:33]=3)(=[O:38])=[O:39])[CH2:45][CH2:44][N:43]3[CH:46]=[CH:47][CH:48]=[C:42]23)=[CH:62][CH:63]=1
Reactant: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)O)ccc2c1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)NCCc3ccc(C4=NCCN4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 35 %

Procedure:
HATU (563 mg, 1.48 mmol, 2.0 eq.) was added to a mixture of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S-2) (297 mg, 0.74 mmol, 1.0 eq.), 2-(4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl)ethanamine (A49) (140 mg, 0.74 mmol, 1.0 eq.), and DIPEA (0.39 ml, 2.22 mmol, 3.0 eq.) in THF (10 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 14 h. The solvent was evaporated under reduced pressure, the residue dissolved in DCM (30 ml) and washed with saturated ammonium chloride solution (15 ml), saturated sodium bicarbonate solution (15 ml), water (15 ml) and brine (15 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield the crude product which was purified by column chromatography (neutral alumina; 1% MeOH/DCM) to afford the desired product as an off-white solid. Yield: 35% (140 mg, 0.245 mmol); MS, Rt=3.3 min; m/z=572.5 [MH]+
Reaction SMILES: [S:1]1(=O)(=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.[CH2:8]([NH2:11])[CH2:9][NH2:10]>O>[CH2:8]([NH:11][CH:3]1[CH2:4][CH2:5][S:1][CH2:2]1)[CH2:9][NH:10][CH:3]1[CH2:4][CH2:5][S:1][CH2:2]1
Reactant: NCCN
Reactant: O=S1(=O)CC=CC1
Solvent: O
Product: C(CNC1CCSC1)NC1CCSC1
Yield: 63 %

Procedure:
A mixture of 2,5-dihydrothiophene 1,1-dioxide (236.4 parts, 2.0 moles); ethylenediamine (480.8 parts, 8 moles); and water (600 ml.) was heated at 70°-80° C. for 4 hours. The water and unreacted ethylenediamine were distilled under reduced pressure. Benzene (750 ml.) was added to the residue and the residual water was removed by azeotropic distillation. After removing the benzene, a reddish colored viscous oil in the amount of 375 g. (63 percent yield) that solidified on cooling was obtained.
Reaction SMILES: [C:1]12([C:7]3=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=[C:6]3[O:5][CH2:4]1)[CH2:3][CH2:2]2.CN(C)C=O.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([O:12][C:8]2[C:7]3[C:1]4([CH2:4][O:5][C:6]=3[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]4)=[N:20][CH:21]=1)([O-:27])=[O:26]
Reactant: Oc1cccc2c1C1(CC1)CO2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a solution of spiro[1-benzofuran-3,1′-cyclopropan]-4-ol (Intermediate 85, 70 mg) in dry N,N-dimethylformamide (2 ml) potassium carbonate (89 mg, 0.647 mmol) and then 2-chloro-5-nitropyridine (75 mg, 0.475 mmol) were added and the reaction mixture was stirred for 3 hours at 100° C. The reaction was quenched with brine (1 ml), diluted with water (2 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 9:1 as eluents affording the title compound as a white solid (100 mg).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[I:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21].[CH2:23]1[CH2:28][CH2:27][CH:26]([CH:29]=[O:30])[CH2:25][CH2:24]1>C1COCC1>[CH:26]1([CH:29]([OH:30])[CH2:21][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[I:13])=[O:22])[CH2:27][CH2:28][CH2:23][CH2:24][CH2:25]1
Reactant: CC(=O)c1ccccc1I
Reactant: O=CC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(CC(O)C1CCCCC1)c1ccccc1I
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 77.4 %

Procedure:
To a solution of diisopropylamine (1.6 mL, 11.1 mmol) in THF (38 mL) at 0° C. was added n-BuLi (4.1 mL, 10.2 mmol) under an atmosphere of N2. After 30 min the solution was cooled to −30° C. and a solution of 1-(2-iodophenyl)ethanone (2.27 g, 9.23 mmol) in THF (6 mL) was added dropwise to the mixture and was stirred for 45 min at −30° C. The mixture was cooled to −78° C. and cyclohexylcarboxaldehyde (1.2 mL, 9.69 mmol) was added dropwise and the mixture was allowed to warm to −40° C. over 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography to afford the title compound as yellow oil (2.56 g, 78%). 1H NMR: 1.02-1.27 (m, 4H), 1.41-1.49 (m, 1H), 1.66-1.76 (m, 4H), 1.89 (d, 1H, J=12.4 Hz), 2.88 (d, 1H, J=3.2 Hz), 2.98 (dd, 1H, J=9.2 Hz, 17.2 Hz), 3.13 (dd, 1H, J=2.0 Hz, 17.2 Hz), 3.99-4.01 (m, 1H), 7.11-7.15 (m, 1H), 7.42 (d, 2H, J=4.4 Hz), 7.93 (d, 1H, J=8.0 Hz).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[N:16][CH:15]=[CH:14]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].O>C(O)(=O)C.[Pt]=O>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][NH:16][CH2:15][CH2:14]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=S(=O)(Nc1ccc2cnccc2c1)c1ccccc1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(Nc1ccc2c(c1)CCNC2)c1ccccc1
Yield: 76.2 %

Procedure:
A solution of 6-phenylsulphonamidoisoquinoline (2.11 g, 0.0074M) in acetic acid (50 ml) was hydrogenated over a platinum oxide catayst (0.5 g) at approximately 345 kilopascals pressure and room temperature for 3 hours (the theoretical uptake of hydrogen was observed). A small volume of H2O was added to dissolve the product and the catalyst was then filtered off. The filtrate was evaporated to dryness to yield an oil which crystallised under ether to yield 6-phenylsulphonamido-1,2,3,4-tetrahydroisoquinoline (1.63 g, 76%).