Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].CCN(C(C)C)C(C)C.[CH2:30](Cl)[O:31][CH2:32][CH2:33][O:34][CH3:35]>CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:20])=[N:4][O:5][C:6]=1[N:7]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:9])=[O:10]
Reactant: COCCOCCl
Reactant: Cc1noc(NS(=O)(=O)c2csc3ncccc23)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)thieno[2,3-b]-pyridine-3-sulfonamide (0.76 g, 2.3 mmoles) (see Example 3), DIEA (0.6 ml, 35 mmoles) and EtOAc (100 ml) was added MEM-Cl (0.3 ml, 2.5 mmoles). The orange-brown solution was stirred 3 hours at ambient temperature, then washed with saturated NaHCO3 (200 ml). The organic layer was dried (MgSO4), filtered and concentrated to collect 0.92 g (95%) of the title compound as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[C:16]([C:23]2[N:24]=[C:25]([NH2:28])[S:26][CH:27]=2)=[CH:15]1.C(N(CC)CC)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:28][C:25]2[S:26][CH:27]=[C:23]([C:16]3[C:17]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:14][CH:15]=3)[N:24]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: Nc1nc(-c2c[nH]c3ncccc23)cs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc([N+](=O)[O-])c1)Nc1nc(-c2c[nH]c3ncccc23)cs1
Yield: 66 %

Procedure:
Prepared from 3-nitrophenyl acetic acid (1 g, 5.52 mmol), N-(1-methanesulfonyl)-benzotriazole (1.5 eq, 1.6 g), 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine and triethylamine (3eq, 2.3 ml) in THF (20 mL) by microwave irradiation at 170° C. for 10 mins as described above. The reaction mixture was concentrated to dryness and CH3CN added. The desired final product was filtered and washed with ether to give clean 2-(3-nitrophenyl)-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-acetamide (1.4 g, 66% yield.)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[O:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25]>>[CH3:17][C:16]1[CH:15]=[CH:14][O:13][C:12]=1[C:10]([NH:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=2)[C:24]([OH:26])=[O:25])[CH:8]=[CH:7][CH:6]=1)=[O:11]
Reactant: C#Cc1cccc(NC(=O)c2occc2C)c1
Reactant: O=C(O)c1cncc(Br)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)O)c2)c1

Procedure:
In a manner similar to that described for Example 480 (step 1), 3-methyl-furan-2-carboxylic acid (3-ethynyl-phenyl)-amide and 5-bromo nicotinic acid were reacted to provide the title compound.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>ClCCl>[F:1][C@H:2]1[C@H:6]([O:7][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1C[C@@H](O)[C@H](F)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Temperature: 0 °C

Procedure:
(trans)-Benzyl 3-fluoro-4-hydroxypyrrolidine-1-carboxylate (2.0 g, 8.36 mmol) was added to dichloromethane and cooled to 0° C. Methanesulfonyl chloride (1.30 mL, 16.7 mmol) and triethylamine (2.3 mL, 16.7 mmol) were sequentially added, and the reaction was allowed to warm to ambient temperature overnight under vigorous stirring. The following day, additional dichloromethane was added, and the reaction mixture was washed with a saturated solution of NaHCO3. The combined organic layers were dried over MgSO4, filtered and evaporated. The crude oil was purified on silica gel using ethyl acetate and hexane to produce 2.0 g (70% isolated yield) of the desired product as an oil.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH2:44][O:45][CH3:46])[N:20]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH2:44][O:45][CH3:46])[N:20]([CH2:39][C:40]([CH3:41])([CH3:43])[CH3:42])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(COC)n(CC(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(COC)n(CC(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
A mixture of hydroxylammonium chloride (4.01 g), sodium hydrogen carbonate (6.50 g) and dimethyl sulfoxide (30 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2,2-dimethylpropyl)-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.76 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (0.75 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.63 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.78 g, 39%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.7 %

Procedure:
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (24.4 g, 0.14 mol) in 200 mL DMF was added morpholine (25.7 mL, 0.28 mol), followed by the addition of K2CO3 (23.6 g, 0.17 mol). The mixture was stirred at room temperature for 48 h. The mixture was poured into 0.7 L H2O and the precipitate was collected by filtration. The precipitate was further rinsed with 0.5 L H2O. The resulting solid was air dried by purging with a flow of air for 24 h, thus affording 29.3 g of 4-(3-methoxy-4-nitrophenyl)morpholine (0.12 mol, 86%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)#[CH:2].Br[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].C(N(CC)CC)C.O>CN(C)C=O>[CH3:9][C:5]1[N:4]=[C:3]([C:1]#[C:2][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[CH:8]=[CH:7][CH:6]=1
Reactant: C#Cc1cccc(C)n1
Reactant: N#Cc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C#Cc2cccc(C#N)c2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 28.4 %

Procedure:
A mixture of 1 g (8.54 mMol) 2-ethynyl-6-methyl-pyridine (prepared in analogy to D. E. Ames et al., Synthesis, 1981, p. 364-5), 2.3 g (12.8 mMol) 3-bromo-benzonitrile, 0.47 g (0.7 mMol) bis-(triphenylphosphine)-palladium-II-chloride, 80 mg (0.41 mMol) cuprous iodide and 1.53 ml (15 mMol) triethylamine in 10 ml dimethylformamide is stirred for 3 hours at 90° C. The reaction mixture is cooled to ambient temperature, poured into water and extracted with dichloromethane. The organic layer is dried over sodium sulfate, filtered, evaporated to dryness and the residue is purified by chromatography on silica gel with hexane/ethyl acetate (4:1) as eluant. Crystallization from hexane of the obtained product affords 0.53 g (28.4%) of the title compound as brown crystals, melting point 120-3° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[CH:10]([Mg]Br)([CH3:12])[CH3:11]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]([OH:9])[CH:10]([CH3:12])[CH3:11]
Reactant: O=Cc1cnccc1Br
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(C)C(O)c1cnccc1Br
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromo-pyridine-3-carbaldehyde (400 mg, 2.15 mmol) in THF (10 mL) at −78° C. was added dropwise 1.0 M isopropyl-magnesium bromide solution in THF (3.23 mL). After 15 min, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, then purification by flash chromatography eluted with 50% ethyl acetate in hexane to yield 1-(4-bromo-pyridin-3-yl)-2-methyl-propan-1-ol as slight yellow crystals.
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:20]=[CH:19][C:18]2[C:9](=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:13][CH:12]=3)[CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:10]1[C:11]2[C:16]([CH:17]=[C:18]3[C:9]=1[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:20]=[CH:19]3)=[CH:15][C:14]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:13][CH:12]=2
Reactant: CC(C)(C)c1ccc2cc3cc(C(C)(C)C)ccc3cc2c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc2c(Br)c3cc(C(C)(C)C)ccc3cc2c1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Bromine (3.02 g, 18.9 mmol) is added at 0° C. to a solution of 2,6-di-tert-butylanthracene (5.0 g, 17.2 mol) in carbontetrachloride (200 ml). The mixture is then stirred at 0° C. for 15 hours. After allowing to heat up to room temperature, half the amount of solvent is evaporated and the resulting mixture is poured into methanol. The precipitate is collected by filtration, recrystallized from n-hexane/methanol and the desired product is obtained as a white solid (1.13 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[K+].[Br-].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1>C(#N)C>[Br-:10].[CH2:11]([C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH3:21])[C:31]=1[N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[NH:5][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCCCCCCBr
Reactant: Clc1nc[nH]c1Cl
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCc1c(-[n+]2c[nH]c(Cl)c2Cl)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) was dissolved into 27 mL of acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) was added and the mixture was allowed to stir for 0.5 h. 1-bromoheptane (1.41 mL, 9 mmol) was added and the solution was allowed to reflux overnight. The solution was filtered hot to remove a white precipitate (presumed to be KBr) and 2-bromomethylnaphthalene (1.98 g, 9 mmol) was added and the mixture was returned to reflux overnight. The mixture was then allowed to cool to room temperature, resulting in a yellow/white precipitate (2.73, 67% yield). 1H NMR (500 MHz, DMSO-d6) 9.70 (1H, s, NCHN), 7.99 (4H, m, Ar), 7.57 (3H, m, Ar), 5.68 (2H, s, NCH2), 4.23 (2H, t, NCH2), 1.82 (2H, tt, CH2), 1.30 (8H, m, CH2), 0.93 (3H, t, CH3). MS: m/z=374.8 (theor for C21H25Cl2N2Br1=456.25).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:15]1(C)[C:19]2(CS(O)(=O)=O)[C:20](C[CH:16]1[CH2:17]C2)=[O:21].O1C=CCCC1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH:20]2[CH2:19][CH2:15][CH2:16][CH2:17][O:21]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C1=COCCC1
Solvent: ClCCl
Product: c1ccc(CN2CC[C@@H](OC3CCCCO3)C2)cc1
Reaction time: 14 h
Yield: 120 %

Procedure:
To a stirred solution of (R)-(+)-1-benzyl-3-pyrrolidinol (5.00 g, 28 mmol) and D-camphor-10-sulfonic acid (6.97 g, 30 mmol) in CH2Cl2 (10 ml) was added 3,4-dihydro-2H-pyran (20 ml) at rt and the reaction mixture was stirred for 14 h (in most cases, the reaction was completed after exothermic reaction subsided). The reaction mixture was diluted with CH2Cl2 (100 ml), washed with saturated NaHCO3 aqueous solution, dried (Na2SO4), and concentrated to give brown oil. This tas purified by column chromatography (silica gel:200 g, CH2Cl2 /MeOH:40/1 as eluent) to give 8.78 g (97.6%) of desired compound as brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:43]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][O:14][CH3:43])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2COC)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of (±)-trans-3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 6, 1.0 mmol, 547 mg) in THF (4.0 mL) at 0° C., NaH (60% dispersion in mineral oil, 1.5 mmol, 60 mg) was added and stirring continued for 10 min at room temperature, then methyl iodide (1.5 mmol, 94 μL) was added. The resulting mixture was stirred at room temperature for 2 hour, poured into water, and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 50% ethyl acetate in hexanes to give (±)-trans-3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-4-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (1.0 mL), added 4.0 M HCl in dioxane (1.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated to give (±)-trans-4-(4-benzyloxy-phenyl)-3-butyl-6-(4-methoxymethyl-pyrrolidin-3-ylmethoxy)-pyridazine di hydrochloride.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(NCC)C.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
The crude crystals (942 mg) of Fmoc-Leu-OBzl (2-MeO-4-OC12OC22) were dissolved in chloroform (9 mL), and diethylamine (1.99 mL, 19.2 mmol) was added dropwise under ice-cooling. The mixture was warmed to room temperature, acetonitrile (4.5 mL) was added, and the mixture was stirred for 3.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was precipitated with acetonitrile (10 mL) to give Leu-OBzl (2-MeO-4-OC12OC22) as wet crystals.
Reaction SMILES: Cl[Si:2]([CH3:17])([CH3:16])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:5]=[C:4]1[CH3:15].CCN(CC)CC.C[SiH]([N:28](C1C2C(=C(C)C=C(C)C=2)C(C)=C1C)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)C>CCCCCC>[CH:29]1([NH:28][Si:2]([CH3:17])([CH3:16])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[CH:5]=[C:4]2[CH3:15])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC1=Cc2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Reactant: CC1=C(C)C(N(C2CCCCC2)[SiH](C)C)c2cc(C)cc(C)c21
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1=Cc2cc3c(cc2C1[Si](C)(C)NC1CCCCC1)CCC3
Reaction time: 16 h
Yield: 94.1 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-s-indacen-1-yl) silane (5.67 g, 0.0216 moles) was stirred in hexane (50 mL) as NEt3 (2.18 g, 0.0216 moles) and cyclohexylamine (2.13 g, 0.0216 moles) were added. This mixture was allowed to stir 16 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (6.62 g, 94.3 percent).
Reaction SMILES: [CH2:1]([C@H:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][C@H:6]([C:17]([OH:19])=[O:18])[NH:5]1)[CH2:2][CH3:3].C(N(CC)CC)C.[C:27](=[S:29])=[S:28].[CH3:30]I>C(O)C.CO>[CH2:1]([C@H:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][C@H:6]([C:17]([OH:19])=[O:18])[N:5]1[C:27]([S:29][CH3:30])=[S:28])[CH2:2][CH3:3]
Reactant: S=C=S
Reactant: CCC[C@@H]1N[C@@H](C(=O)O)Cc2c1[nH]c1ccccc21
Reactant: CI
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCO
Product: CCC[C@H]1c2[nH]c3ccccc3c2C[C@H](C(=O)O)N1C(=S)SC
Yield: 38.7 %

Procedure:
In the same manner as described in Example 73, (1RS,3SR)-trans-1-n-propyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (0.9 g), triethylamine (0.4 g), carbon disulfide (0.3 g), methyl iodide (0.56 g) and 80% methanol (14 ml) are reacted and treated. The product is treated with aqueous ethanol to give the title compound (0.47 g) as pale yellow powder.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:19]([O:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[C:25](F)[C:24]=1[N+:32]([O-:34])=[O:33])[CH:20]=[CH2:21]>C1COCC1>[CH2:19]([O:22][C:23]1[C:24]([N+:32]([O-:34])=[O:33])=[C:25]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[C:26]([F:30])=[C:27]([F:29])[CH:28]=1)[CH:20]=[CH2:21]
Reactant: C=CCOc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Reactant: Nc1ccc(I)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a solution of 4-iodophenylamine (0.940 g, 4.3 mmol) in THF (50 mL) was dropwise added LHMDS solution (5.6 mL, 5.6 mmol, 1 M in THF) at −78° C. After stirring for 1 h at −78° C., a solution of 1-allyloxy-3,4,5-trifluoro-2-nitro-benzene (1.1 g, 4.7 mmol) in THF (10 mL) was added dropwise into the reaction mixture, which was stirred at −78° C. for 1 h and at room temperature for 16 h. The progress of reaction was monitored by 1H NMR. After completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue obtained was triturated with hexane to yield (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(4-iodo-phenyl)-amine as an orange solid (1.1 g). 1H-NMR (400 MHz, CDCl3): δ 4.54 (2H, d, J=4.8), 5.24 (1H, s), 5.32 (1H, d, J=10.8), 5.42 (1H, d, J=17.2), 6.06-6.02 (1H, m), 6.45 (2H, d, J=8.4), 6.57-6.62 (1H, m), 7.47 (2H, d, J=8.4).
Reaction SMILES: [C:1]1([S:7]([O:10][CH2:11][C:12]([N:14]2[CH2:18][C@@H:17]([F:19])[CH2:16][C@H:15]2[C:20]([NH2:22])=O)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C>[C:1]1([S:7]([O:10][CH2:11][C:12]([N:14]2[CH2:18][C@@H:17]([F:19])[CH2:16][C@H:15]2[C:20]#[N:22])=[O:13])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
(2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolid ine-2-carboxamide (516 mg) was dissolved in acetonitrile (10 mL) and triethylamine (0.52 mL) was added to the solution. While this mixture was cooled in an ice bath, trifluoroacetic anhydride (0.27 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture was concentrated under reduced pressure. Water (5 mL) was added to the residue and the resulting crystal was collected by filtration. The filtered solid was washed with water and was dried under reduced pressure to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carbonitrile as a white crystal (339 mg, 70% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[S:9]1[CH:10]=[CH:11][C:7]2[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:13]=[CH:12][C:8]1=2
Reactant: C1COCCN1
Reactant: ClCCOc1ccc2sccc2c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc2cc(OCCN3CCOCC3)ccc2s1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
5-(2-Chloroethoxy)benzo[b]thiophene (0.25 g, 1.17 mmol) was dissolved in DMF (3 mL) and treated with morpholine (0.205 mL, 2.35 mmol) and sodium iodide (0.035 g, 0.235 mmol). The mixture was heated to 70° C. and stirred overnight. The reaction was cooled down to room temperature and poured into a saturated aqueous solution of sodium bicarbonate (20 mL), which was extracted several times with ethyl acetate. All the organic extracts were combined and washed with a saturated aqueous solution of sodium bicarbonate, water and brine. The ethyl acetate layer was then dried with sodium sulfate and purified by flash chromatography using a gradient of 0 to 8% methanol in dichloromethane to obtain a clear oil. Yield=0.237 g. MS (M+H)+ 264.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[C:13]([O:17][C:18](=[O:21])[CH2:19][NH2:20])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C=O)C.O>[C:13]([O:17][C:18](=[O:21])[CH2:19][NH:20][C:2](=[O:4])[C:1]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)c1ccccc1N
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of isatoic anhydride (25 g, 0.15 mol) in DMF (250 ml), glycine tert butyl ester (30.64 g, 0.18 mol) is added, followed by the dropwise addition of triethylamine (52 ml, 0.37 mol) over a period of 30 minutes. The resulting suspension is heated at 50° C. for 3 hours, 60° C. for 30 minutes, then at 70° C. for 30 minutes. The reaction mixture is then allowed to cool to RT and treated with water (300 ml). The resulting solution is stirred at RT for 30 minutes, diluted further with water (200 ml), and the product extracted with EtOAc (2×500 ml). The organic extracts are combined, washed with water (2×300 ml), brine (1×300 ml), dried (MgSO4), filtered, concentrated in vacuo, and dried under vacuum to give the title compound as a peachy white solid.