Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[C:23]([CH3:29])[CH:22]=1)(=[O:20])=[O:19])[CH3:2].B(Cl)(Cl)Cl.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:29])[CH:22]=1)(=[O:20])=[O:19])[CH3:2]
Reactant: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(C)c1
Yield: 48.4 %

Procedure:
The title compound was prepared from 6-ethyl-8-fluoro-5-[(4-methoxy-3-methylphenyl)sulfonyl]-5,6-dihydrophenanthridine (0.53 g, 1.3 mmol), tetrabutylammonium iodide (1.2 g, 3.2 mmol), and 1 M boron trichloride in dichloromethane (8.9 mL, 8.9 mmol) according to the procedure and in the same manner as described in Example 35, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:1 gradient), followed by re-crystallization from a mixture of dichloromethane-hexane to yield 4-[(6-ethyl-8-fluorophenanthridin-5(6H)-yl)sulfonyl]-2-methylphenol as a homogeneous solid (0.25 g, 50%), m.p. 181° C.;
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH3:2]>[Pd].C(O)C>[CH2:31]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH3:32]
Reactant: CCN(CC)CCOc1ccc(N(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CCOc1ccc(N(C(=O)c2ccc(N)cc2)c2ccccc2)cc1

Procedure:
A solution of 4.69 g. of 4'-(2diethylaminoethoxy)-4-nitro-N-phenylbenzanilide (Example 20) in 300 ml. of ethanol was hydrogenated in the presence of 1 g. of palladium-on-carbon catalyst. The catalyst was removed by filtration, the filtrate evaporated to remove the solvent, and the residue recrystallized from isopropyl alcohol-ether and ethanol-ether to give 4'-(2-diethylaminoethoxy)-4-amino-N-phenylbenzanilide, yellow solid, m.p. 174.5°-178.5°C.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[C:11]([O:15][C:16](=[O:26])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1)([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O.C(OCC)(=O)C>[C:11]([O:15][C:16](=[O:26])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH:19]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc([N+](=O)[O-])n2)c1
Temperature: 0 °C
Yield: 46.7 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 595 mg, 5.26 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL) and a 60% dispersion of sodium hydride in mineral oil (211 mg, 5.28 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 25 min, the reaction was chilled to 0° C. and (3-bromomethyl-phenyl)-carbamic acid tert-butyl ester (1.50 g, 5.26 mmol) was added. The reaction continued to stir under nitrogen at 0° C. for 20 min. The reaction was diluted with ethyl acetate (200 mL), washed with water (2×50 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Purification by flash column (Merck silica gel 60, 40-63 μm; 15% ethyl acetate/hexanes) followed by recrystallization from methylene chloride afforded [3-(3-nitro-pyrazol-1-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (782 mg, 47%) as a beige solid: H1-NMR (400 MHz, DMSO-d6) δ 1.45 (9H, s), 5.39 (2H, s), 6.88 (1H, d, J=7.6 Hz), 7.06 (1H, d, J=2.4 Hz), 7.22 (1H, t, J=8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 7.40 (1H, s), 8.11 (1H, d, J=2.8 Hz), 9.36 (1H, s).
Reaction SMILES: [CH2:1]([N:8]([C:15]([C:17]1([CH2:20][NH:21][C:22]([O:24]C(C)(C)C)=O)[CH2:19][CH2:18]1)=[O:16])[C@H:9](C(OC)=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C@@H:9]([CH3:10])[C:22](=[O:24])[NH:21][CH2:20][C:17]2([CH2:19][CH2:18]2)[C:15]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](C)N(Cc1ccccc1)C(=O)C1(CNC(=O)OC(C)(C)C)CC1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C[C@H]1C(=O)NCC2(CC2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.8 g (7.2 mmol) 2-1 in 75 mL CH2Cl2 and 5 mL TFA was allowed to stir at room temperature overnight. The solvents were removed by rotary evaporation, the residue was basified with saturated aqueous Na2CO3, and extracted with three portions of 2:1 CHCl3/EtOH. The organic extracts were concentrated, redissolved in CH2Cl2, filtered and concentrated to provide a brown oil. This material was dissolved in 75 mL of toluene, cooled to 0° C. and 8.4 mL (16.9 mmol) of a 2 M solution of AlMe3 in toluene was added dropwise. The reaction was allowed to slowly warm to room temperature overnight with stirring. An additional 2 mL of AlMe3 was added and stirring was continued for an additional 24 h. The reaction was cooled to 0° C., carefully quenched with 100 mL of 1M HCl, and extracted with 3 portions of EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to provide 2-2 as a white taffy. Data for 2-2: LC/MS: rt=1.38 min; m/z (M+H)=258.1. found; 258.1 required.
Reaction SMILES: [Na+:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].Br[CH2:16][C:17]#[C:18][CH3:19]>C(O)(C)C>[Na+:1].[CH2:16]([O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:10])=[O:11])=[CH:5][CH:4]=1)[C:17]#[C:18][CH3:19]
Reactant: CC#CCBr
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC#CCOc1ccc(S(=O)(=O)[O-])cc1
Yield: 81 %

Procedure:
To a solution of 4-hydroxybenzenesulfonate sodium salt (52.35 g, 0.225) in 1L of isopropanol and 225 mL of a 1.0N solution of sodium hydroxide was added 59.96 g (0.45 mol) of 1 bromo-2-butyne. The resulting mixture was heated to 70° for 15 h and then the isopropanol was removed by evaporation in vacuo. The resulting white precipitate was collected by filtrtation, washed with isopropanol and ether and dried in vacuo to give 45.08 g (81%) of the desired product as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:7]=2)[CH:3]=[N:2]1.Cl[CH2:44][CH2:45][CH2:46][N:47]([CH3:49])[CH3:48].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:48][N:47]([CH3:49])[CH2:46][CH2:45][CH2:44][N:1]1[CH:5]=[C:4]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[CH:7]=2)[CH:3]=[N:2]1
Reactant: CN(C)CCCCl
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cn[nH]c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnn(CCCN(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 107.1 %

Procedure:
(S)-2-(1-((5-(1H-Pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (43 mg, 0.07 mmol) and 3-chloro-N,N-dimethylpropan-1-amine (47 mg, 0.39 mmol) were dissolved in DMF (3 ml) and cesium carbonate (240 mg, 0.74 mmol) was added. After stirring the mixture at 75° C. for 3.5 h, the solvent was evaporated under reduced pressure and the residue was suspended in water and extracted with dichloromethane (×3). The organic phase was successively washed with water and brine, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure, to obtain 50 mg (70% yield) of the title compound as a brown solid. Purity 69%.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]1>CCCCO>[C:12]([NH:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[C:3]=2[N:25]2[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:26]2)[NH:8][CH:9]=1)(=[O:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 135 °C
Yield: 78.4 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.190 g, 0.698 mmol), DIEA (0.365 mL, 2.10 mmol), and (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.390 g, 2.10 mmol) were placed in n-BuOH (2 mL) and heated to 135° C. for 8 hours. The reaction was then cooled to room temperature and concentrated to dryness. The residue was purified by silica gel chromatography (500:18 DCM:MeOH) to give (S)-tert-butyl 1-(3-acetamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.240 g, 78% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:12][C@H:11]([O:13][CH:14]([O:16][CH2:17][CH3:18])[CH3:15])[CH2:10][CH:9]([O:19][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]1[CH3:37])[CH3:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>C1COCC1>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:12][C@H:11]([O:13][CH:14]([O:16][CH2:17][CH3:18])[CH3:15])[CH2:10][CH:9]([OH:19])[CH:8]1[CH3:37])[CH3:5])[CH3:2]
Reactant: CCOC(C)O[C@@H]1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(C)[C@@H](OC(C)OCC)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(C)O[C@@H]1CC(O)C(C)[C@@H](OC(C)OCC)C1
Yield: 68.4 %

Procedure:
6.48 g (12.14 mmol) of 18 and 6.31 g (20 mmol) of tetrabutylammonium fluoride (hydrate) in 150 ml of THF is stirred overnight at room temperature. Then, it is hydrolyzed with sodium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution and dried on sodium sulfate. After concentration by evaporation, the residue is chromatographed on silica gel (mobile solvent: EE:H=8:2), whereby 2.41 g (8.3 mmol) of title compound 19 is obtained.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=4)[CH2:17][CH2:16]3)=[N:11][NH:10][C:9]2=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[NH2:27][C:23]1[CH:22]=[C:21]([N:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][C:12]3[N:8]([CH2:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:9](=[O:30])[NH:10][N:11]=3)[CH2:20][CH2:19]2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=c1[nH]nc(CCN2CCN(c3cccc([N+](=O)[O-])c3)CC2)n1CC1CCCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(N2CCN(CCc3n[nH]c(=O)n3CC3CCCCC3)CC2)c1
Reaction time: 72 h
Yield: 93.9 %

Procedure:
To a solution of 4-(cyclohexylmethyl)-5-{2-[4-(3-nitrophenyl)piperazin-1-yl]ethyl}-2,4-dihydro-3H-1,2,4-triazol-3-one D9 (0.30 g, 0.72 mmol) in methanol (20 mL), a catalytic amount of 10% Pd/C was added and the slurry was pressurized to 20-30 bar in an autoclave for 3 days. The catalyst was filtered through a Celite pad and the filtrate was evaporated to afford 0.26 g (93%) 5-{2-[4-(3-aminophenyl)piperazin-1-yl]ethyl}-4-(cyclohexylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one D10 as an orange semi-solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][C@H:16]([C:18]([OH:20])=[O:19])[NH2:17].[CH3:21]O>>[CH3:21][O:19][C:18](=[O:20])[C@@H:16]([CH2:15][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1)[NH2:17]
Reactant: CO
Reactant: N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](N)Cc1ccc2ccccc2c1
Temperature: 60 °C

Procedure:
Thionyl chloride (5 ml) was added dropwise over 15 min. to a suspension of (R)-3-(2-naphthyl)alanine (5.0 g) in methanol (50 ml) at 35° C. After addition the mixture was heated at 60° C. for 1 h, cooled and the solvent removed in vacuo. Water (75 ml) and ethyl acetate (125 ml) were added and pH was adjusted to 8.5 with sodium carbonate. The organic phase was separated and dried (magnesium sulfate) to afford 4.86 g of (R)-3-(2-naphthyl)alanine methyl ester.
Reaction SMILES: Cl.C1COCC1.[CH3:7][O:8][C:9]1[C:18]2[O:17]C(C)(C)[O:15][CH2:14][C:13]=2[CH:12]=[C:11]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])[CH:10]=1>O>[OH:17][C:18]1[C:9]([O:8][CH3:7])=[CH:10][C:11]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])=[CH:12][C:13]=1[CH2:14][OH:15]
Reactant: COc1cc(N2CCCC2=O)cc2c1OC(C)(C)OC2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N2CCCC2=O)cc(CO)c1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.5 %

Procedure:
10% hydrochloric acid (4 ml) was added to a THF solution (7 ml) of 1-(8-methoxy-2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)pyrrolidin-2-one (0.36 g, 1.3 mmol) and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, which was then extracted with dichloromethane. The extracted material was dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol:=300:1→30:1). The purified product was concentrated to dryness under reduced pressure to obtain 1-(4-hydroxy-3-hydroxymethyl-5-methoxyphenyl)pyrrolidin-2-one (0.31 g) as light brown powder.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]([C:19]1[N:20]([CH3:29])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH2:28])=[CH:23][CH:22]=2)=[O:18]>>[CH3:15][O:16][C:17]([C:19]1[N:20]([CH3:29])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH:28][C:12]([C:10]1[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=1)=[O:14])=[CH:23][CH:22]=2)=[O:18]
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: COC(=O)c1cc2cc(N)ccc2n1C
Product: COC(=O)c1cc2cc(NC(=O)c3ccc(-c4ccccc4)o3)ccc2n1C

Procedure:
Carboxylic acid (56) (23 mg, 0.12 mmol) was coupled to 5-amino-1-methyl-1H-indole-2-carboxylic acid methyl ester (25 mg, 0.12 mmol) using Method D to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[CH3:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:3]1[C:2](=[O:1])[CH2:6][CH2:5][CH:4]1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: CCCCCC1=C(CC(=O)OC)CCC1=O
Solvent: ClCCl
Product: CCCCCC1C(=O)CCC1CC(=O)OC
Reaction time: 6 h
Yield: 99 %

Procedure:
In a glovebox, into a 10 ml glass vial were placed 15.0 mg (0.0250 mmole) of [((R,R)-Me-Duphos)Ru(H)(cyclooctatriene)]BF4, 5.62 ml of CH2Cl2 and 11.23 g (50.0 mmole) of methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate. The resulting yellow solution was placed in a 75 ml autoclave, purged with hydrogen and pressurized to 90 bar of hydrogen. After 6 hours, the solution was exposed to air and passed through a column of silica gel to separate the catalyst. This gave a 99% yield of the desired Hedione® product with the following ratios of isomers: cis/trans=98/2; (+)-cis/(−)-cis=82.3/17.7, 64.6% ee.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([Cl:16])=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([S:17][CH3:18])=[CH:11][CH:10]=3)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([Cl:16])=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([S:17]([CH3:18])=[O:24])=[CH:11][CH:10]=3)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCn1ncc2c(Cl)c3cc(SC)ccc3nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCn1ncc2c(Cl)c3cc(S(C)=O)ccc3nc21
Temperature: 0 °C
Yield: 93.9 %

Procedure:
To a solution of 1-ethyl-4-chloro-6-(methylthio)-1H-pyrazolo[3,4-b]quinoline (2.4 g, 8.7 mmol) in CHCl3 (50 ml) at -40° C. is added m-chloroperoxybenzoic acid (2.75 g, 8.7 mmol). The reaction mixture is slowly warmed to 0° C. and then saturated NaHCO3 (10 ml) is added. The reaction mixture is partitioned between water (20 ml) and CH2Cl2 (20 ml), the layers are separated and then the aqueous layer is extracted with CH2Cl2 (20 ml). The CH2Cl2 extracts are combined, dried over MgSO4 and evaporated. The residue is purified by column chromatography on silica gel eluting with 50% ether/hexane, then 25% ethyl acetate/25% hexane/50% ether and finally ethyl acetate (100%) to afford 2.4 g of 1-ethyl-4-chloro-6-(methylsulfinyl)-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl.[C:15]1([B-:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+]>>[C:34]1([B-:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1.[CH2:10]([PH+:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCP(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Agent: c1ccc([B-](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCC[PH+](CCCC)CCCC

Procedure:
Tri-n-butylphosphine is reacted with hydrochloric acid in the presence of sodium tetraphenylborate to produce tri-n-butylphosphonium tetraphenylborate (53% yield) (see Nonpatent Document 6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:57]=[CH:56][CH:55]=[CH:54][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[C:40]3[N:39]=[C:38]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[N:37](COCC[Si](C)(C)C)[C:36]=3[CH:35]=[CH:34][CH:33]=2)=[CH:13][CH:12]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:1][O:2][C:3]1[CH:57]=[CH:56][CH:55]=[CH:54][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[C:40]3[N:39]=[C:38]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[NH:37][C:36]=3[CH:35]=[CH:34][CH:33]=2)=[CH:13][CH:12]=1
Reactant: COCCCc1nc2c(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COCCCc1nc2c(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc2[nH]1

Procedure:
Analogously to Example 228a, 0.5 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(3-methoxypropyl)-1-(2-trimethylsilanylethoxymethyl)-1H-benzoimidazol-4-ylmethoxy]piperidine-1-carboxylate and 5.44 ml of tetrabutylammonium fluoride solution (1M in tetrahydrofuran) are reacted. The title compound is obtained as a yellowish oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=4.99.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH:35]([OH:39])[CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:39][CH:35]1[CH2:36][CH2:37][CH2:38][CH:33]([NH:32][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=2)=[O:23])[CH2:34]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: NC1CCCC(O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCCC(O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.10 g, 0.22 mmol), 3-aminocyclohexanol (mixture of cis and trans) (45 mg, 0.39 mmol), HBTU (0.10 g, 0.26 mmol), and HOBT (0.03 g, 0.26 mmol). Then added DMF (1.0 mL) followed by N,N-diisopropylethylamine (0.07 ml, 0.26 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-100% EtOAc) to afford 106 mg of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-cyclohexyl)amide as an off-white foam. MS: [M+H]+=556.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH2:12])=O.[NH4+:13].[OH-].O>>[NH2:12][C@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:5]1[C:3]([NH2:13])=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1N
Agent: [OH-]
Solvent: O
Product: NC(=O)[C@@H]1CCCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
cis-2-Aminocycloheptanecarboxylic acid methyl ester (1.65 g, 9.64 mmol) was treated with 20 mL of NH4OH/H2O and stirred at room temperature for 24 h. The solution was concentrated in vacuo and azeotroped once with toluene. The reaction afforded 2.20 g of cis-2-aminocycloheptanecarboxylic acid amide as a white solid: 1H NMR (DMSO-d6) δ 7.81 (m, 3 H), 7.20 (s, 1 H), 2.76 (m, 1 H), 1.68–1.40 (m, 11 H); MS m/e 157.28 (M+H)+.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.II.[N:13]1[CH:14]=[C:15]([CH:25]=[O:26])[N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:17]=12>C1COCC1>[C:5]1([CH2:4][CH2:3][CH:25]([C:15]2[N:16]3[C:17]([S:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=43)=[N:13][CH:14]=2)[OH:26])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCCc1ccccc1
Reactant: O=Cc1cnc2sc3ccccc3n12
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(CCc1ccccc1)c1cnc2sc3ccccc3n12

Procedure:
Magnesium metal (0.29 g), 12 g atom) in dry THF (70 mL) was treated with (2-bromoethyl) benzene (0.44 mL) and an Iodine crystal. When the Iodine color had discharged additional (2-bromoethyl)benzene (1.2 mL) was added and the suspension was reacted for 24 hours. Solid imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula J-3) (0.606 g, 3.0 mmol) was added and the mixture was reacted for 1.25 hours. The solution was decanted into 5% NH4Cl solution (250 mL) and the mixture was extracted with ethyl acetate. Drying and evaporation of the extract gave pure α-(2-phenylethyl)-imidazo[2,1-b]benzothiazole-3-methanol (Formula J-4) (0.81 g) after trituration of residue with acetonitrile. An aliquot of the triturated product was crystallized from acetonitrile solution to provide an analytical sample of α-(2-phenylethyl)-imidazo[2,1-b]benzothiazole-3-methanol (Formula J-4) (m.p. 174-175°).