Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[CH:13]=1)=[O:6].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.[NH4+].[Cl-]>C1COCC1.CC(=O)OCC>[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:13]=1)=[O:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ncoc1-c1cccc(CCO)c1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1-c1cccc(CCO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 5-[3-(2-hydroxy-ethyl)-phenyl]-oxazole-4-carboxylic acid methyl ester (200 mg, 0.81 mmol) was dissolved in dry THF (5.0 mL). tert-Butyldimethylsilyl chloride (124 mg, 0.83 mmol) was added at 0° C. followed by imidazole (61 mg, 0.89 mmol). The reaction mixture was stirred at rt for 2 days. Sat. aq. NH4Cl (10 mL) and EA (10 mL) were added, the layers separated and the aq. layer extracted with EA (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (20:80 hept-EA) gave the title compound as a colorless oil. TLC: rf (20:80 hept-EA)=0.21. LC-MS-conditions 02: tR=1.19 min, [M+H]+=362.50.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10](O)[C:9]=2[N:8]=[CH:7][C:6]=1[CH3:16])[CH:2]=[CH2:3].P(Br)(Br)[Br:18].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([Br:18])[C:9]=2[N:8]=[CH:7][C:6]=1[CH3:16])[CH:2]=[CH2:3]
Reactant: BrP(Br)Br
Reactant: C=CCOc1c(C)cnc2c1CCCC2O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=CCOc1c(C)cnc2c1CCCC2Br

Procedure:
3.5 Grams of 4-allyloxy-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline was dissolved in 40 ml of chloroform, to this solution was added dropwise a solution consisting of 2.8 g of phosphorus tribromide and 5 ml of chloroform under ice-cooled condition. The reaction mixture was stirred under ice-cooled condition for 2 hours, further stirred at room temperature for 2 hours. The reaction mixture was poured into a cold sodium hydroxide aqueous solution, then extracted with chloroform. The chloroform layer was washed with an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate. Chloroform was removed by evaporation, then the residue thus obtained was purified by a silica gel column chromatography (eluent: methylene chloride/methanol=100/1) to obtain 1.3 g of 4-allyloxy-8-bromo-3-methyl-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[C:15]([F:25])[CH:14]=3)[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2].C(O)(=O)C.Cl.ClCCl>CO>[CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[C:15]([F:25])[CH:14]=3)[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1F
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)c(F)c1)C2
Temperature: 0 °C
Yield: 87.1 %

Procedure:
A suspension of ethyl {-4-[4,9-bis(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetate (200.0 g, 443 mmol) in a mixture of glacial acetic acid (2080 mL) and hydrochloric acid (2 M, 700 mL) was heated to reflux under a nitrogen atmosphere, with the reaction progress monitored by TLC analysis (silica, dichloromethane:methanol, 99:1). After 60 minutes the reaction mixture was cooled to 0° C. The precipitated solid was isolated by filtration, washed with water (1400 mL), and freeze-dried to give the desired product as an off-white solid (163.4 g, 87% yield).
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:18])[C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[CH:10]=1)([CH3:6])([CH3:5])[CH3:4].O.C(=O)([O-])[O-].[K+].O.O.[K+].[K+].[K+].C(=O)([O-])[O-].[N+:34]([CH2:36][C:37]([O:39][CH3:40])=[O:38])#[C-:35].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.CC(=O)OCC.C1(C)C=CC=CC=1>[CH3:40][O:39][C:37]([C:36]1[N:34]=[CH:35][O:14][C:12]=1[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:18])[CH:10]=1)=[O:38]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CC(C)(C)OC(=O)c1cccc(C(=O)O)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ncoc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of isophthalic acid mono-tert-butyl ester (4.00 g, 18.00 mmol) and potassium carbonate sesquihydrate (6.03 g, 43.20 mmol) in DMF (36.0 mL) was treated with a solution of methyl isocyanoacetate (3.45 mL, 36.00 mmol) in DMF (6.0 mL). After 5 min, the reaction mixture was cooled to 0° C. and a solution of DPPA (4.01 mL, 18.00 mmol) in DMF (6 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 2 h and then overnight at rt. A 1:1 mixture of toluene:EA (400 mL) was added and the organic layer was washed with water (150 mL), 10% aq. citric acid solution (150 mL) and sat. aq. NaHCO3 (150 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound as a white solid. TLC: rf (60:40 hept-EA)=0.27. LC-MS-conditions 02: tR=1.04 min, [M+H]+=304.32.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[C:11]([I:13])[CH:10]=[N:9]2)[CH2:4][O:3]1.[CH2:15]1COCC1.[Li+].CC([N-]C(C)C)C.C1CCCCC1.CI.[NH4+].[Cl-]>>[CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][N:8]2[C:12]([CH3:15])=[C:11]([I:13])[CH:10]=[N:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](Cn2cc(I)cn2)O1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CI
Solvent: C1CCCCC1
Product: Cc1c(I)cnn1C[C@@H]1COC(C)(C)O1
Reaction time: 1 h

Procedure:
To a solution of 1-{[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}-4-iodo-1H-pyrazole (500 mg, 1.62 mmol) in THF (4 mL, 50 mmol), cooled to −78° C., was added 1.5 M of LDA in cyclohexane (3.25 mL, 4.87 mmol). After stirring for 1 h, methyliodide (1.01 mL, 16.2 mmol) was added slowly, and the mixture was stirred at −78° C. for 1 h. Sat. NH4Cl was added to quench, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo. The material was purified via column chromatography, eluting with 5-10% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=323.06 (100) [MH+]. HPLC: tR=1.20 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [CH2:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[OH:21])=[CH:11][CH:10]=2)[C:7](=[O:22])[C:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][C:39](=[O:41])[O:38][N:37]=3)=[CH:26][CH:25]=2)=[C:5]([CH2:42][CH2:43][CH3:44])[N:4]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O>[CH2:1]([C:3]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])=[CH:13][CH:14]=2)[C:7](=[O:22])[C:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][C:39](=[O:41])[O:38][N:37]=3)=[CH:26][CH:25]=2)=[C:5]([CH2:42][CH2:43][CH3:44])[N:4]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OC3CCC[C@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCCC3=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution of 2-ethyl-3-(4-{[(2R)-2-hydroxycyclopentyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.2 g) in dichloromethane (4 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.22 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.13 g, 65%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12](O)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(OCC)(=O)C>O1CCCC1.CCCCCC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)C1(c2ccccn2)CCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OCC1(c2ccccn2)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-pyridin-2-yl-cyclopentanecarboxylic acid (431) (5 g, 26.178 mmol) in tetrahydrofuran was added BH3.tetrahydrofuran (1M) (52.36 mL) at 0° C. and stirring was continued for 1 h, then this reaction mixture was allowed to stir at room temperature for 5 h while silica thin layer chromatography was performed (50% ethyl acetate in Hexane; Rf=0.5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:14])[CH2:9][NH:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:22](Br)[CH:23]=[CH2:24]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([OH:14])[CH2:9][N:10]([CH2:11][CH2:12][OH:13])[CH2:24][CH:23]=[CH2:22])=[CH:6][CH:7]=1
Reactant: OCCNC[C@H](O)c1ccc(Cl)cc1
Reactant: C=CCBr
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: C=CCN(CCO)C[C@H](O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To (R)-1-(4-chlorophenyl)-2-[(2-hydroxyethyl)amino]-1-ethanol (755 mg, 3.5 mmol) produced in Example 12, dimethylacetamide (5 mL), triethylamine (532 mg, 1.5 equivalents) and allyl bromide (508 mg, 1.2 equivalents) were added. The mixture was stirred at 25° C. for 16 hours. Toluene (5 mL) and distilled water (5 mL) were added to the mixture, and the organic layer and aqueous layer were separated. The organic layer was washed twice with distilled water (5 mL), then concentrated and dried under vacuum, to obtain 817 mg of the title compound as colorless oil (yield: 79%, chemical purity: 92.2 area %). The retention time in the chemical purity analysis method was 2.0 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([NH:7]C(OC(C)(C)C)=O)[CH2:3]1.[ClH:15].O1CCOCC1>>[ClH:15].[ClH:15].[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3]1
Reactant: CN1CCC(NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCC(N)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The prepared N-methyl-3-t-butoxycarbonylaminopyrrolidine (1.8 g, 8.9 mmoles) is dissolved in HCl/dioxane (4N, 44 mL, 256 mmoles) and allowed to stir at RT for 45 min. The dioxane is removed by concentration and N-methyl-3-aminopyrrolidine dihydrochloride salt is dried under high vacuum (1.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[OH-].C([P+](CCCC)(CCCC)CCCC)CCC.Br[CH2:31][CH2:32][O:33][CH3:34].Cl>C1COCC1>[CH3:34][O:33][CH2:32][CH2:31][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1O
Reactant: COCCBr
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOc1ccc(C(=O)O)cc1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 6.6 %

Procedure:
To a solution of 4-hydroxy-3-methyl-benzoic acid (2.0 g, 13 mmol) in THF (24 mL) was added tetrabutylphosphonium hydroxide (18 mL of 40% w/v, 26 mmol). The reaction mixture was cooled to 0° C. in an ice water bath and then 1-bromo-2-methoxy-ethane (1.8 g, 1.2 mL, 13 mmol) was added. The reaction mixture was then allowed to warm to room temperature and stir overnight. The reaction mixture was made acidic by addition of 1M HCl and the reaction was extracted with ethyl acetate. The organics were dried over sodium sulfate and evaporated to yield 180 mg of 4-(2-methoxyethoxy)-3-methylbenzoic acid (yield: 6%). ESI-MS m/z calc. 210.2. found 209.2 (M-H)−. Retention time: 0.96 minutes (3 min run). The following compounds were synthesized using the procedures described above: 3-methyl-4-propoxybenzoic acid, 4-(2-isopropoxyethoxy)-3-methylbenzoic acid, and 4-(3-methoxypropoxy)-3-methylbenzoic acid.
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:25][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:26])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 50 %

Procedure:
As described for example 125, 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (120 mg, 50%) which was obtained as a white solid. MS: m/e=430.3 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:9][CH3:10])O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19]C(=O)C)C.[N-]=C=O.N1C=CC=CC=1>CCOCC>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:10][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: [N-]=C=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: OCCC(c1ccccc1)c1ccccc1

Procedure:
3.2 G of diphenyl-ethyl-carbinol, 1.9 g of isocyanate acetic acid ethyl ester and 1.6 ml of pyridine are heated at 50° C for 72 hours. The solution is diluted with 50 ml of ether, washed several times at 0° C with 0.1-molar citric acid solution and water, dried over sodium sulfate, and completely evaporated under reduced pressure. After elimination of 2.3 g of diphenylethylcarbinol by means of petroleum ether, 1,1-diphenyl-propyloxycarbonyl-glycine-ethyl ester is obtained in the form of an oil; Rf = 0.2 in the thin-layer chromatogram in chloroform.
Reaction SMILES: C([Li])(CC)C.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH3:17][S:18]SC>O1CCCC1>[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([S:18][CH3:17])[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CSSC
Reactant: COc1ccccc1C(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cccc(SC)c1C(=O)O
Reaction time: 2 h
Yield: 29.6 %

Procedure:
N,N,N′N′-Tetramethylethylendiamine (16 g, 138 mmol) was added drop-wise at −70° C. to a solution of sec-butyllithium (92 mL, 1.3 M in cyclohexane, 120 mmol) in 80 mL tetrahydrofuran. 2-Methoxybenzoic acid (7.0 g, 46 mmol) in 40 mL tetrahydrofuran was added drop-wise at −70° C. over 2 hours. After complete addition stirring was continued at −70° C. for another 2 hours. Dimethyl disulfide (15.2 g, 161 mmol) was added at −70° C. within 10 min. Stirring was continued at −70° C. for another hour and the reaction was allowed to slowly warm up over night. The reaction mixture was quenched with 40 mL water and extracted with 200 mL ethyl acetate. The aqueous phase was adjusted to pH1 by addition of 25% HCl and extracted twice with dichloromethane. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude product was crystallized with cyclohexane and yielded the title compound as an off-white solid (2.7 g, 30%), MS: m/e=197.4 [(M−H)−].
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[C:7]([O:19][CH3:20])[C:6]2=3)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:52])[CH:25]([C:27]1[CH:32]=[CH:31][C:30](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:29][CH:28]=1)[CH3:26].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[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>[CH3:22][O:23][C:24](=[O:52])[CH:25]([C:27]1[CH:28]=[CH:29][C:30]([C:18]#[C:17][C:9]2[CH:8]=[C:7]([O:19][CH3:20])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:31][CH:32]=1)[CH3:26]
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Reactant: C#Cc1cc(OC)c2c(c1)C(C)(C)CCC2N(C)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.085 g, 0.30 mmol), methyl-2-(4-iodophenyl)propionate (Reagent 1, 0.087 g, 0.3 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow solid (0.115 g, 86%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH2:12][CH2:13][NH:14][C:15](=O)OC(C)(C)C.FC(F)(F)C(O)=O.[F:29][C:30]([F:46])([F:45])[C@@H:31]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:32]1[CH:37]=[CH:36][C:35](C=O)=[CH:34][CH:33]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:65]>C(Cl)Cl.CO>[ClH:65].[F:46][C:30]([F:29])([F:45])[C@@H:31]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:32]1[CH:33]=[CH:34][C:35]([CH2:15][NH:14][CH2:13][CH2:12][N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]2=[O:1])=[CH:36][CH:37]=1
Reactant: CS(=O)(=O)N[C@@H](c1ccc(C=O)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCN1CCc2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N[C@@H](c1ccc(CNCCN2CCc3ccccc3C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.1 %

Procedure:
Dissolve tert-butyl 2-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)ethylcarbamate (220 mg, 0.76 mmol) in DCM (3 mL) and add trifluoroacetic acid (1 mL, 13.23 mmol). Stir at ambient temperature for 30 minutes. Concentrate the mixture under reduced pressure, then dissolve in 1,2-dichloroethane (20 mL). Add N-[(1S)-2,2,2-trifluoro-1-(4-formylphenyl)-ethyl]-methanesulfonamide (150 mg, 0.53 mmol), acetic acid (0.05 mL, 0.87 mmol), and sodium triacetoxyborohydride (642.3 mg, 3.03 mmol). Stir the mixture at ambient temperature overnight. Concentrate under reduced pressure to give a residue and dilute the residue with MeOH (2 mL). Purify the residue via preparatory TLC using 10% MeOH in DCM to give a colorless oil. Dissolve the oil in MeOH (3 mL) and add HCl (1M in diethyl ether; 0.5 mL, 0.5 mmol) and stir for 30 minutes. Concentrate under reduced pressure to give the title compound as a white solid (10 mg, 3.7%). MS (m/z): 456 (M-Cl).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[O:13][C:12](=[O:14])[CH:11]=[CH:10]1)[C:2]1C=CC=CC=1.[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][C:10]1[CH:9]([O:8][CH2:1][CH3:2])[O:13][C:12](=[O:14])[CH:11]=1
Reactant: O=C1C=CC(OCc2ccccc2)O1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC1OC(=O)C=C1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
This procedure was carried out in a manner similar to that described by C. Escobar, et al., Ann. Quim. (1971), 67, 43-57.). To a solution of 5-ethoxy-5H-furan-2-one (II, R1=Et) (10.0 g, 78.0 mmol) in carbon tetrachloride (50 mL) at 0° C. was added over 0.5 h a solution of bromine (4.05 mL, 78.2 mmol) in carbon tetrachloride (25 mL). The reaction was stirred 1 h at 0° C., then 2 h at room temperature. The solvents were removed under reduced pressure and the residue was short-path distilled at pump vacuum (about 0.5 mm). The fraction collected at 100° C.-120° C. provided 4-bromo-5-ethoxy-5H-furan-2-one (13.2 g, 82% yield) as a yellow oil. 1H-NMR (500 MHz, CDCl3) δ 6.24 (s, 1H), 5.63 (s, 1H), 3.71 (m, 1H), 3.63 (m, 1H), 1.14 (t, J=7.1 Hz, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20]C)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].I[Si](C)(C)C.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][OH:20])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: C[Si](C)(C)I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: CO
Solvent: CC#N
Product: C[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To a solution of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (10.0 g) in acetonitrile (200 mL), under an atmosphere of argon, was added iodotrimethylsilane (23.8 mL) and the resultant mixture stirred for 16 hours. Methanol (30 mL) was then added and the mixture stirred for 15 minutes, saturated potassium carbonate (30 mL) and sodium thiosulphate (0.5 g) were then added and the mixture stirred for 2 hours. The acetonitrile was removed in vacuo, the residue dissolved in water (150 mL) and continuously extracted with ethyl acetate for 16 hours. The ethyl acetate was removed in vacuo and the residue chromatographed on silica (eluting with 0-5% methanol in ethyl acetate) to give the desired compound (7.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].C(N(CC)CC)C.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1F)([O-:27])=[O:26]>>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N+:25]([O-:27])=[O:26])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Solvent: CCN(CC)CC
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ccccc3[N+](=O)[O-])cc12
Yield: 48 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and o-nitrofluorobenzene were used. Triethylamine was used as base, o-nitrofluorobenzene was used as solvent, and the reaction was heated at reflux for 24 hours. Column chromatography afforded the title compound (48%) as a red amorphous solid: 1H NMR (CDCl3) δ 9.62 (br s, NH), 8.77 (br s, NH), 8.19 (dd, J=8.7 and 1.5 Hz,1H), 7.47 (d, J=1.6 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.29-7.23 (m, 1H), 7.09-7.00 (m, 3H), 6.69-6.64 (m, 1H), 3.20-3.12 (m, 2H), 2.63 (dd, J=14.0 and 9.5 Hz, 1H), 2.54-2.45 (m, 1H), 2.45 (s, 3H), 2.25 (dd, J=17.1 and 9.2 Hz, 1H), 1.91-1.54 (m, 4H); 13C NMR (CDCl3) δ 145.4, 135.7, 134.8, 132.1, 130.1, 128.6, 126.5, 123.6, 120.7, 116.4, 116.4, 116.1, 114.1, 112.2, 66.7, 57.5, 40.8, 31.5, 29.8, 21.9; FAB HRMS calculated for [C20H22N4O2.H] 351.1823, found 351.1797.