Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CN(C)C=O.[C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])[CH3:11].[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>Cl>[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=1)(=[O:12])[CH3:11]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)Nc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Reaction time: 1.25 h
Yield: 42.6 %

Procedure:
To a flask charged with anhydrous aluminum chloride (128.1 g, 0.961 mol) was added dropwise neat dimethylformamide (21 mL, 0.27 mol) at a rate such that the internal temperature remained below 70° C. The resulting mixture was thoroughly mixed. To the stirred thick mixture was added in ten portions a mixture of acetanilide (13.53 g, 0.100 mol) and succinic anhydride (10.01 g, 0.100 mol) that had been preground together with a mortar and pestle. The addition rate was controlled to keep the internal temperature at less than or equal to 72° C. The resulting mixture was stirred at 65° C. to 70° C. for 1.25 hours, then poured hot onto ice (1.0 kg). The mixture was acidified with concentrated hydrochloric acid (60 mL), and the resulting solids were filtered. The filtercake was washed with 0.05 M hydrocloric acid and allowed to air dry overnight. The filtercake was suspended in hot water (93 mL), methanol (120 mL) was added, and the hot cloudy solution was gravity filtered. The filtrate was boiled down to 100 mL volume and allowed to cool. The solids were filtered, washed with water-methanol, and dried in vacuo to give 10.03 g of 4-(4-acetylamino-phenyl)-4-oxo-butyric acid as a tan solid.
Reaction SMILES: CN(C=O)C.[Na+].[CH3:7][C:8]1[CH:17]=[C:16]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([O-:29])(=O)=[O:27])=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:32])=O>C(Cl)Cl>[CH3:7][C:8]1[CH:17]=[C:16]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([Cl:32])(=[O:29])=[O:27])=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(COc2ccc(S(=O)(=O)[O-])cc2)c2ccccc2n1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 97.5 %

Procedure:
A catalytic amount of DMF was added to a solution of the 4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonic acid sodium salt (1.0 g, 2.8 mmol) from step (2a) in thionyl chloride (3.0 ml, 41.0 mmol). The reaction was heated to 60° C. for 2 h, allowed to cool to room temperature, diluted with methylene chloride, concentrated in vacuo, diluted with THF, concentrated in vacuo to give 4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonyl chloride (0.95 g, 97%) as a light yellow solid.
Reaction SMILES: CO.Cl[C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[N:8][CH:9]=1.[CH3:13][S-:14].[Na+]>O>[CH3:13][S:14][C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSc1ccc([N+](=O)[O-])nc1
Reaction time: 13 h
Yield: 45.3 %

Procedure:
A methanol (40 mml) solution of 5-chloro-2-nitropyridine (2.0 g, 12.6 mmol) was added dropwise to a methanol (20 ml) solution of sodium thiomethoxide (1.02 g, 13.9 mmol) while being cooled with ice, and after the mixture was stirred for 13 hours while raising its temperature to the room temperature, water added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was recrystalized with ethyl acetate-hexane to obtain 972 mg (yield 45%) of 5-methylthio-2-nitropyridine.
Reaction SMILES: Cl.S1C2C=CC=CC=2N=C1[C@H]1CCC[C@H]1N.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2Cl)(=O)C.C([O:49][C@@H:50]1[C@H:54]([O:55]C(=O)C)[C@@H:53]([CH2:59][O:60]C(=O)C)[O:52][C@H:51]1[N:64]1[C:88]2[N:87]=[C:86]([Cl:89])[N:85]=[C:68]([NH:69][C@@H:70]3[CH2:74][CH2:73][CH2:72][C@@H:71]3[S:75][C:76]3[S:77][C:78]4[CH:84]=[CH:83][CH:82]=[CH:81][C:79]=4[N:80]=3)[C:67]=2[N:66]=[CH:65]1)(=O)C.C[O-].[Na+]>CO.C(N(CC)CC)C>[S:77]1[C:78]2[CH:84]=[CH:83][CH:82]=[CH:81][C:79]=2[N:80]=[C:76]1[S:75][C@H:71]1[CH2:72][CH2:73][CH2:74][C@H:70]1[NH:69][C:68]1[C:67]2[N:66]=[CH:65][N:64]([C:88]=2[N:87]=[C:86]([Cl:89])[N:85]=1)[C@@H:51]1[O:52][C@H:53]([CH2:59][OH:60])[C@@H:54]([OH:55])[C@H:50]1[OH:49]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCC[C@@H]4Sc4nc5ccccc5s4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCC[C@@H]4Sc4nc5ccccc5s4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 38 %

Procedure:
The above cis-2-(2-benzothiazolyl)cyclopentylamine hydrochloride (1.5 g, 4.6 mmol) was combined with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.0 g, 4.5 mmol) and triethylamine (2.49 ml) and reacted by the method described in Example 1. Deacylation of the purified cis-2',3',5'-tri-O-acetyl-N-[2-[(2-benzothiazolyl)thio]cyclopentyl]-2-chloroadenosine using sodium methoxide in methanol provided the title cis-N-[2-[(2-benzothiazolyl)thio]cyclopentyl]-2-chloroadenosine (0.89 g, 38%) as a foam (following column chromatography) (a ca. 2:1 mixture of diastereoisomers), 1H NMR (DMSO-d6) δ1.62-2.45 (6H, 5m, --CH2CH2CH2 --), 3.52-3.60 (1H, m, H-5'a), 3.64-3.70 (1H, m, H-5'b), 3.94 (1H, br q, H-4'), 4.11 (1H, br q, H-3'), 4.62 (1H, q, H-2'), 5.75-5.83 (1H, 2m, H-1'), 7.26-7.94 (4H, 4m, Ar--H).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N+]([O-])=O)=[N:7][CH:8]=1.[CH3:12][O:13][CH2:14][CH2:15][OH:16]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([O:16][CH2:15][CH2:14][O:13][CH3:12])=[N:7][CH:8]=1
Reactant: COCCO
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [Na]
Product: COCCOc1ccc(Br)cn1
Yield: 86 %

Procedure:
To a stirred solution of sodium (591 mg, 24.6 mmol) in 2-methoxyethanol (20 mL) was added a solution of 5-bromo-2-nitropyridine (17-1, 5.00 g, 24.6 mmol) in 2-methoxyethanol (10 mL) at room temperature. The reaction mixture was stirred at reflux for 2.5 h. The solution was concentrated and the residue was diluted with CH2Cl2 and H2O. The organic layer was dried and evaporated under reduced pressure to give 5-bromo-2-(2-methoxyethoxy)pyridine (17-2, 4.9 g) in 86% yield: 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=2.6 Hz, 1 H), 7.64 (dd, J=8.7, 2.6 Hz, 1 H), 6.72 (d, J=8.7 Hz, 1 H), 4.43 (t, J=6.6 Hz, 2 H), 3.73 (t, 2H), 3.41 (s, 3 H). ESI-MS: m/z 232.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[C:5](O)=[O:6].[CH3:16][N:17](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:18].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[C:5]([N:17]([CH3:18])[CH3:16])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CS(=O)(=O)Nc1cc(Br)cc(C(=O)O)c1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(Br)cc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a mixture of 3-bromo-5-(methylsulfonamido)benzoic acid (360 mg, 1.22 mmol), HATU (490 mg, 1.29 mmol) and DIEA (260 μl, 1.49 mmol) in DMF (5 ml) was added dimethylamine (3.10 ml, 6.20 mmol, 2N in THF) and the resulting mixture was stirred at room temperature overnight. 30 ml of dichloromethane were added and washed with sodium bicarbonate 4%. The aqueous phase was further extracted with ethyl acetate. The organics were washed with water and brine, dried over magnesium sulphate and the solvent was removed to give a residue which purified by reverse phase chromatography using SP1® Purification System (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give 325 mg (83% yield) of the title compound. Purity 99%.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12].C([O-])(O)=[O:14].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([NH2:12])=[O:14]
Reactant: N#Cc1c(N)sc2ccccc12
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1c(N)sc2ccccc12
Temperature: 0 °C
Yield: 41 %

Procedure:
A solution of 2-amino-benzo[b]thiophene-3-carbonitrile (50 mg, 0.29 mmol) in concentrated H2SO4 (1.5 mL) was heated at 60° C. for 2 h. The solution was poured into ice-water (5 mL), mixed with saturated NaHCO3 solution (30 mL), and extracted with ethyl acetate (30 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 1:1) then provided the title compound (23 mg, 41%) as a white solid: MS (ES) m/z 193 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Li+].C[Si]([N-:17][Si](C)(C)C)(C)C.[OH-].[Na+].CO>C1(C)C=CC=CC=1>[F:1][CH:2]([F:11])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:17]
Reactant: O=C(c1ccccc1)C(F)F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: NC(c1ccccc1)C(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a solution of 2,2-difluoro-1-phenylethanone (1 g, 6.4 mmol) in toluene (32 mL) at room temperature was added LiHMDS (1M in THF) (7.05 mL, 7.05 mmol). The reaction mixture was stirred for 30 min, followed by addition of BH3-DMS (1.216 mL, 12.81 mmol). The reaction mixture was stirred for 1 h. After cooling at 0° C., aqueous 2 N NaOH solution was carefully added over 5 min (Caution! gas evolution). The reaction was stirred for 1 h. The layer was separated and washed with water and brine. After dried over sodium sulfate, HCl in MeOH (7.17 mL, 8.97 mmol) was added to form a white precipitate. The precipitate was filtered off, washed with ether, and dried in vacuo yielding 2,2-difluoro-1-phenylethanamine (21%). 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (s, 5H), 6.52-6.07 (m, 1H), 4.78-4.69 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH2:9][CH3:10])[CH:7]=1.O.[NH2:14][NH2:15].O>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:15][N:14]=[C:8]2[CH2:9][CH3:10]
Reactant: NN
Reactant: CCC(=O)c1cc(Br)ccc1F
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1n[nH]c2ccc(Br)cc12

Procedure:
A solution of 7.50 g (32.5 mmol) 1-(5-bromo-2-fluorophenyl)-1-propanone (Example 8A) in 1-methyl-2-pyrrolidinone (NMP; 100 ml) was treated with 3.25 g (3.16 ml, 64.9 mmol) hydrazine hydrate and stirred at reflux temperature for 16 h. Upon cooling, the mixture was poured into a mixture of ice and water. The precipitate was collected by filtration and washed thoroughly with water to yield 4.56 g (62% of th.) of the title compound as a beige-coloured solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[CH3:8][CH2:9][C:10](=O)[CH2:11][CH3:12]>>[CH2:9]([C:10]1([CH2:11][CH3:12])[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1)[CH3:8]
Reactant: CCC(=O)CC
Reactant: OCC(CO)CO
Product: CCC1(CC)OCC(CO)CO1
Yield: 46 %

Procedure:
The same procedure as in the step (7a) of Example 7 was repeated using 2-(hydroxymethyl)-1,3-propanediol, and 3-pentanone to obtain the title compound (1.5 g, yield: 46%) as a light yellow oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(OC(C)(C)C)=O)=[C:18]([F:30])[CH:17]=2)[CH2:11]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]([NH:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:30])[CH:17]=2)[CH2:11]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2C[C@H](CN)OC2=O)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Acetic anhydride (0.15 mL) was added to a solution of 5-(S)-aminomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one (0.325 g, 1.0 mmol) and pyridine (0.25 mL) in DCM (4.0 mL). The mixture was stirred at r.t. for 4 h, and solvent was removed under vacuum. The resulted 5-(S)-acetamidomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]oxazoli-dine-2-one was washed with water (2×3 mL), diethyl ether (3 mL), and dried under vacuum. 50% TFA in DCM (3 ′mL) was added, and the mixture was kept at r.t. for 1 h. Solvents were removed under vacuum, and the residue distributed between ethyl acetate (40 mL) and saturated aq. sodium bicarbonate (20 mL). Organic layer was washed with aq. sodium bicarbonate, water, brine, dried (MgSO4). Solvent was removed under vacuum to afford the product as a white solid. Yield 0.25 g (95%). MS (m/z): [M+H]+=268.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:17](/[CH:20]([CH2:23]O)[CH2:21][OH:22])=[CH:18]\[CH3:19].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH:17](/[C@@H:20]1[CH2:21][O:22][C@@H:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[CH2:14][CH2:13]2)[O:16][CH2:23]1)=[CH:18]\[CH3:19]
Reactant: O=C[C@H]1CC[C@H](c2ccc(F)c(F)c2)CC1
Reactant: C/C=C/C(CO)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C/C=C/[C@H]1CO[C@H]([C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)OC1
Reaction time: 1.25 h

Procedure:
A solution of 3.0 g of trans-4-(3,4-difluorophenyl)cyclohexanecarboxaldehyde (prepared in accordance with Example 2) and 2.4 g of 2-(1E-propenyl)-1,3-propanediol in 75 ml of toluene was treated with 3 drops of 10 percent (v/v) sulphuric acid and the reaction mixture was heated to boiling for 1.25 hours, whereby moist toluene was distilled off and replaced by fresh toluene. Then, the reaction mixture was neutralized with triethylamine and, after cooling, washed three times with water, dried over sodium sulphate and concentrated. Chromatographic purification of the residue on 100 g of silica gel with hexane/ethyl acetate (vol. 49:1) and repeated recrystallization of the trans/cis mixture from hexane gave 0.8 g of pure trans-5-(1E-propenyl)-2-[trans-4-(3,4-difluoro-phenyl)cyclohexyl]-1,3-dioxane; m.p. (C-N) 96.0° C., cl.p. (N-I) 125.5° C., Δε (115° C.)=12.4.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].CS(O)(=O)=O.[NH2:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.N1C=CC=CC=1.C(C1C=CC(CNS(C=C)(=O)=O)=CC=1)#N>ClCCl>[C:14]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][S:4]([CH2:3][CH2:2][Cl:1])(=[O:6])=[O:5])=[CH:17][CH:16]=1)#[N:13]
Reactant: O=S(=O)(Cl)CCCl
Reactant: N#Cc1ccc(CN)cc1
Agent: C=CS(=O)(=O)NCc1ccc(C#N)cc1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(CNS(=O)(=O)CCCl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Chloroethane sulfonyl chloride (4.8 g, 0.029 mol) was added drop by drop to solution of 4-aminomethyl benzonitrile methan sulphonic acid salt acid (7 g, 0.029 mol) and pyridine (24 ml) in dry dichloromethane (25 ml) at −5° C. under nitrogen atmosphere. The reaction mixture was stirred at RT for 2 days and then partitioned between water and dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel using 1% methanol in chloroform as eluent to give mixture of the sub-title compound and ethenesulfonic acid 4-cyano-benzylamide (3.4 g) as a solid. This was directly taken for next step without further purification.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:29]#[N:30])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:29]#[N:30])=[O:8])[CH:2]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: Cc1cccc(C(=O)C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
m-Toluoyl cyanide was prepared according to the general procedure reported by G. A. Olah et al. [supra]. Under dry conditions, 2.4170 g of m-toluoyl chloride (99%, Aldrich) (15.63 mmol), 40 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 2.4 mL of trimethylsilyl cyanide (18 mmol) were added to a 100-mL round bottom flask. To this solution 0.39 mL of tin (IV) chloride (3.3 mmol) was added. On addition of the tin (IV) chloride the color of the solution changed from clear to yellow. The reaction mixture was stirred for 2 hr at room temperature. After 2 hr of stirring, the color of the solution was dark brown. The reaction was quenched with 120 mL of ice-cold water and then extracted with two 120 mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 120-mL portions of ice-cold water, dried with MgSo4, and filtered. The methylene chloride was removed by rotary evaporation to yield 2.125 g of a dark brown oil. This oil was distilled at 45°-48° C. (0.2 mm) to yield 1.410 g (62%) of m-toluoyl cyanide as a white solid: IR (CCl4) (partial) 2220, 1685, 1600, 1580 cm-1.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]=[C:7]2[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br>C(Cl)Cl>[F:13][C:12]([F:14])([F:15])[C:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:3]([OH:2])[C:4]=2[CH2:5][CH:6]=1
Reactant: COc1cccc2c1CC=C2C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc2c1CC=C2C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a suspension of 4-methoxy-1-trifluoromethyl-indan-1-ol (170 mg, 0.73 mmol) in benzene (4 mL) was added p-toluenesulfonic acid (139 mg, 0.73 mmol). The mixture was stirred overnight at 80° C., and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 4-methoxy-1-trifluoromethyl-3H-inden. The 4-methoxy-1-trifluoromethyl-3H-inden was dissolved in CH2Cl2 (2 ml) and 1M-BBr3 (in CH2Cl2, 1.46 mL, 1.46 mmol) was added dropwise. The mixture was stirred for 1 hour at room temperature, and then washed with saturated ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 1-trifluoromethyl-3H-inden-4-ol (70 g, 48%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH2:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH2:32](Br)[CH2:33][CH2:34][CH3:35]>C(#N)C>[CH2:32]([NH:15][CH:13]1[CH2:14][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[O:10])[CH2:12]1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCBr
Reactant: NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCNC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (0.09 M in acetonitrile, 500 mL, 0.045 mmol), prepared using procedures similar to those described in Example 2, was added triethylamine (20 μL, 0.135 mmol) and n-butylbromide (6.14 μL, 0.054 mmol) followed by additional acetonitrile (1.0 mL). The reaction mixture was stirred at room temperature for 16 h, at which time it was purified directly by reverse phase HPLC to afford the title compound (8.4 mg). 1H NMR (400 MHz, CDCl3): 8.50 (s, 1H), 7.39 (dd, 1H), 7.32 (dd, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.35 (br s, 2H), 4.00 (br s, 1H), 3.87 (br s, 1H), 3.74-3.68 (m, 1H), 3.20 (br s, 3.5H), 2.56 (t, 2H), 2.03 (s, 2H), 1.50-1.42 (m, 2H), 1.39-1.29 (m, 2H), 0.91 (t, 3H). MS (EI) for C20H21F3IN3O: 504 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:26](=[O:28])[CH3:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 41 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminoindoline (1.0 g) and acetic anhydride (1 ml) were treated as in Example 133 to give the title compound (450 mg) as a pale yellow powder (yield: 41%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23].[I-].[Li+].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH3:11][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: CC(C(=O)OCc1ccccc1)c1ccccc1
Reactant: CC(C)=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)=CCC(C)(C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.8 %

Procedure:
A solution of 2-phenyl-propionic acid benzyl ester (2.0 g, 8.32 mmol), 4-bromo-2-methyl-2-butene (1.21 mL, 9.99 mmol), and lithium iodide (1 g) in tetrahydrofuran (15 mL) at 0° C. was treated dropwise with the lithium hexamethyldisilazide (9.99 mL, IM in tetrahydrofuran, 9.99 mmol). The reaction was allowed to warm to 25° C. and stirred for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.51 g, 98%). 1H NMR (300 MHz, CDCl3): δ ppm 1.53 (m, 6 H) 1.63 (m, 3 H) 2.60 (m, 1 H) 2.80 (m, 1 H) 4.94 (m, 1 H) 5.11 (m, 2 H) 7.26 (m, 10 H). MS (ESI+) m/z 326 (M+NH4)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[S:8])SC.[N-:9]=[N+:10]=[N-:11].[Na+].O>O1CCOCC1>[OH:1][CH2:2][CH2:3][N:4]1[C:5]([SH:8])=[N:11][N:10]=[N:9]1
Reactant: CSC(=S)NCCO
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCCn1nnnc1S
Yield: 4.8 %

Procedure:
A mixture of methyl N-(2-hydroxyethyl)dithiocarbamate (3.7 g.), sodium azide (2.4 g.), water (20 ml.) and dioxane (20 ml.) was heated under reflux for four hours. After the dioxane was removed from the mixture under reduced pressure, the aqueous solution was washed with ether. The solution was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was concentrated under reduced pressure to give oily product (0.47 g.). The oily product was purified by column chromatography on silica gel to give 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol (0.17 g.). m.p. 135° to 137° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]=2[CH:17]=1)([O-])=O>CCO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]=2[CH:17]=1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2o1
Reaction time: 4 h

Procedure:
Ethyl 5-nitrobenzofuran-2-carboxylate (Aldrich, 8.0 g) was dissolved in a mixture of EtOH and THF, treated with 10% Pd/C (wet, Degussa type E101, Aldrich) and hydrogenated on a Parr apparatus at 35 psi for 4 h. The reaction mixture was filtered over Celite, washed with THF and EtOH and concentrated under vacuum to give crude solid product, 6.3 g which was used without purification. 1H NMR (CDCl3) 7.34-7.37 (m, 2H), 6.87 (d, 1H), 6.81 (dd, 1H), 4.41 (q, 2H, OCH2), 3.60 (broad s, 2H, NH2), 1.40 (t, 3H, OCH2CH3); m/z 206.39 [M+H]+