Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:10][C:11]1[CH:12]=[N:13][C:14]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27][CH3:28])[CH:22]=2)=[C:15]([CH:19]=1)[C:16](O)=[O:17].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[F:10][C:11]1[CH:12]=[N:13][C:14]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27][CH3:28])[CH:22]=2)=[C:15]([CH:19]=1)[C:16]([NH:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:17]
Reactant: NC1(CO)CCCCC1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)NC2(CO)CCCCC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 62.7 %

Procedure:
A solution of (1-aminocyclohexyl)-methanol (R. J. W. Cremlyn et al J. Chem. Soc Perkins I, 1972, 1727) (130 mg, 0.78 mmol) and triethylamine (300 μl) in dimethylformamide (5 ml) was added to a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (218 mg, 0.78 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol) and 1-hydroxybenzotriazole (116 mg, 0.86 mmol) in dimethylformamide (4 ml) and the reaction was stirred under nitrogen at room temperature for 64 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was removed and washed with sat. sodium bicarbonate solution (25 ml) followed by 1M citric acid (25 ml) and brine (25 ml). The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate:pentane (20:80 changing to 30:70 then 50:50, by volume) to give 5-fluoro-N-(1-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (191 mg) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]#[CH:20].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:20]#[C:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:13])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12]
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: C#CCOCCOC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COCCOCC#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.6 %

Procedure:
5-Chloro-7-iodo-1,3-benzodioxol-4-amine (1.0 g, 3.36 mmol) and 3-(2-methoxyethoxy)prop-1-yne (766 mg, 6.72 mmol) in ethyl acetate (12 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, and then treated with bis(triphenylphosphine) palladium(II) dichloride (236 mg, 10 mol %) followed by copper(I) iodide (64 mg, 10 mol %) and diisopropylamine (681 mg, 6.74 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours and then filtered through Celite. The filtrate was purified by column chromatography on silica using a 1:1 mixture of methyl tert-butyl ether and iso-hexane as eluent to give 5-chloro-7-[3-(2-methoxyethoxy)prop-1-yn-1-yl]-1,3-benzodioxol-4-amine (816 mg, 86%) as a dark orange oil; solidified on standing; NMR Spectrum: (CDCl3) 3.40 (s, 3H), 3.58 (m, 2H), 3.74 (m, 2H), 4.06 (s, 2H), 4.42 (s, 2H), 6.01 (s, 2H), 6.88 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][CH:9]2[C:4](=[C:5]([N+:13]([O-])=O)[CH:6]=[CH:7][CH:8]2[Br:12])[CH2:3]1.C1C[O:19][CH2:18][CH2:17]1>>[Br:12][C:8]1[CH:7]=[CH:6][C:5]([NH:13][C:18](=[O:19])[CH3:17])=[C:4]2[C:9]=1[CH2:10][CH2:11][N:2]([CH3:1])[CH2:3]2
Reactant: C1CCOC1
Reactant: CN1CCC2C(=C([N+](=O)[O-])C=CC2Br)C1
Product: CC(=O)Nc1ccc(Br)c2c1CN(C)CC2
Reaction time: 3 h
Yield: 80 %

Procedure:
A solution of the product of Example 30 (6 g, 22.1 mmol) was dissolved in 100 mL THF. Raney nickel washed with acetone (2×5 mL) and THF (3×5 mL) was added and the reaction vessel purged with hydrogen. The reaction was stirred for 3 hours and freshly rinsed catalyst added. After 90 minutes, the reaction was complete. The catalyst was removed by filtration, washed with THF, and the filtrate evaporated. The residue was dissolved in 100 mL acetic anhydride and stirred for 72 hours. Excess acetic anhydride was removed in vacuo and the solid residue washed with ether. The solid was dissolved in chloroform and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The solid was washed with ether and dried to give 5.03 g (80%) of the desired product, mp 192-194° C. (dec).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:21]#[N:22])[CH:10]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[NH:9]1)=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([C:21]#[N:22])[CH:10]([CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC2CCCCC2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)cc2)C(CC2CCCCC2)NC(C(=O)O)C1c1cccc(Cl)c1F
Yield: 99 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 59b (1.9 g, 3.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 99%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:39])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:38])[CH2:9]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:39][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:38][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Reaction time: 1.5 h

Procedure:
A solution of acryloyl chloride (53.4 mg, 0.59 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred mixture of 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 103, 270 mg, 0.59 mmol) and DIPEA (0.112 mL, 0.65 mmol) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and was then diluted with CH2Cl2 (25 mL) and washed with sat. NaHCO3 (50 mL). The aqueous washes were extracted with CH2Cl2 (2×25 mL). The combined organic solutions were then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 provided the title compound mixed together with diacylated material. This material was dissolved in CH2Cl2 and triturated with diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether (10 mL) and air dried to give impure product (120 mg) as a yellow solid. This solid was purified by crystallisation from CH3CN to give the title compound (47 mg, 0.092 mmol, 16%) as a yellow solid. All the residues were combined, concentrated in vacuo and crystallised from CH3CN to give a second crop of the title compound (26 mg, 0.051 mmol, 9%) as a yellow solid. Total yield of title compound=73 mg, 24%; 1H NMR: (CDCl3) 1.87-1.99 (1H, m), 2.11-2.24 (1H, m), 2.30 (6H, s), 2.83-2.95 (1H, m), 3-3.19 (4H, m), 3.88 (3H, s), 3.99 (3H, s), 5.75 (1H, dd), 6.34 (1H, dd), 6.44 (1H, dd), 6.79 (1H, s), 7.20 (1H, d), 7.23-7.32 (2H, m) partially obscured by CDCl3 peak, 7.37-7.42 (1H, m), 7.67 (1H, s), 8.08 (1H, d), 8.38 (1H, d), 8.46 (1H, s), 9.00 (1H, s), 9.71 (1H, s); m/z: ES+ MH+ 512.26.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12](O)=[O:13]>O.[Zn]>[Cl:8][C:7]1[C:2]2[NH:1][C:12](=[O:13])[CH2:11][S:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1c(S)cccc1Cl
Reactant: O=C(O)CBr
Agent: [Zn]
Solvent: O
Product: O=C1CSc2cccc(Cl)c2N1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The zinc salt (2.0 g) of 2-amino-3-chlorothiophenol was suspended in water (30 ml), and bromoacetic acid (1.6 g) was added thereto, followed by stirring at 70° C. for 3 hours. The precipitated crystals were filtered, washed with water and dried to obtain 1.8 g of the objective 5-chloro-2,3-dihydro-1,4-benzothiazine-3-one (m.p. 160°-161° C.).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]2[C:27](=[O:28])[NH:26][N:25]=[CH:24][C:13]3=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][C:16]([CH:17]=1)=[C:12]23.[CH3:29][CH:30]1[CH2:32][CH:31]1[C:33](O)=[O:34].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:28]=[C:27]1[C:11]2[C:12]3[C:13](=[C:14]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:15][C:16]=3[CH:17]=[C:9]([NH:8][C:33]([CH:31]3[CH2:32][CH:30]3[CH3:29])=[O:34])[CH:10]=2)[CH:24]=[N:25][NH:26]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC1CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CC1C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reaction time: 8 h
Yield: 37 %

Procedure:
Triethylamine (0.030 mL, 0.22 mmol), the title compound of Example 7 (15 mg, 0.054 mmol) and 2-methyl-cyclopropanecarboxylic acid (6 mg, 0.062 mmol) were stirred in N,N-dimethylformamide (1.0 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) was added and the reaction was stirred overnight at which point the volatile components were removed under vacuum. The resulting mixture was purified on silica gel, eluting with 3:2 hexane:ethyl acetate. The purest fractions were combined and after solvent removal, the resulting solids were triturated with diethyl ether to give the title compound (7 mg, 0.020 mmol) as yellow powder in 36% yield.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]([O:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]2[CH3:27])=[O:13])([CH3:10])([CH3:9])[CH3:8]>N1C=CC=CC=1>[C:7]([O:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]2[CH3:27])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC1=CC(C)(C)Nc2ccc(NC(=O)OC(C)(C)C)cc21
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)N1c2ccc(NC(=O)OC(C)(C)C)cc2C(C)=CC1(C)C
Reaction time: 18 h

Procedure:
Butyryl chloride (185 μl) was added dropwise to a solution of 6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (50 mg) and a catalytic amount of N,N-dimethylaminopyridine in pyridine (4 ml). After stirring for 18 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>7/3 (v/v) as eluent.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH:13]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(O)=O>CCO>[CH2:21]([N:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(CN(Cc1ccccc1)Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 79.3 %

Procedure:
To a suspension of D-glucose (36.0 g, 200.0 mmol) and Bn2NH (39.5 g, 200.0 mmol) in absolute EtOH (200 mL) was added AcOH (12.0 g, 200.0 mmol). Upon refluxing for 3 h, the reaction mixture was cooled and filtered with suction. The resulting filter cake was washed with EtOH to colorless and dried in a desiccator over calcium chloride to give 1-dibenzylamino-1-deoxy-D-fructose as a white solid (57.0 g, 79%).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[N:6]#[O+].[Cl:8][C:9]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:10]=1[NH2:11]>C(#N)C.C(OCC)C>[F:1][B-:2]([F:5])([F:4])[F:3].[Cl:8][C:9]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:10]=1[N+:11]#[N:6]
Reactant: N#[O+]
Reactant: Nc1cc(F)ccc1Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOCC
Product: N#[N+]c1cc(F)ccc1Cl
Reaction time: 1 h

Procedure:
Nitrosonium tetrafluoroborate (802 mg, 6.87 mmol) was added to a solution of 2-chloro-5-fluoroaniline (1.00 g, 6.87 mmol) in acetonitrile (50 mL) at 0° C. The resulting mixture was stirred for 1 h, then diluted with ethyl ether (150 mL). The precipitate was filtered and air-dried to give 2-chloro-5-fluorobenzenediazonium tetrafluoroborate (1-1) as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 8.66 (ddd, 1H, J=6.7, 2.1, 1.0 Hz), 8.16 (m1, 2H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)=[O:15].[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>ClCCl>[O:24]=[C:23]([O:25][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(=O)OC2CCCCO2)cc1
Yield: 170.8 %

Procedure:
To a saturated solution of anhydrous p-toluenesulphonic acid in dry dichloromethane (35 ml) successively 2-[4-(methoxycarbonyl)phenyl]acetic acid (E11) (0.671 g, 3.45 mmol) and 3,4-dihydro-2H-pyran (3 ml, 32.9 mmol) were added, and the resultant solution was stirred for 45 minutes at room temperature. To the reaction mixture triethylamine (1 ml, 7.2 mmol) was added and the volatiles were evaporated. The obtained crude title product (1.64 g) was immediately utilized in the next step of the synthesis.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:35][CH2:36][CH3:37])=[C:18]([CH:24]4[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[C:19]([F:23])=[C:20]([Cl:22])[CH:21]=3)[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12.[ClH:38].O1CCOCC1>ClCCl>[ClH:22].[ClH:38].[NH:26]1[CH2:27][CH:24]([C:18]2[C:17]([O:35][CH2:36][CH3:37])=[C:16]([CH:14]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH:11]([F:13])[F:12])=[N:9]3)[CH3:15])[CH:21]=[C:20]([Cl:22])[C:19]=2[F:23])[CH2:25]1
Reactant: CCOc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-fluorophenyl)azetidine-1-carboxylate (0.64 g, 1.2 mmol) in dichloromethane (5 mL) was added 4.0 M hydrogen chloride in dioxane (2.4 mL, 9.5 mmol). The reaction solution was stirred at room temperature for 6 h. The solvent was removed to give the desired product as a white solid (0.61 g, 100%). LCMS calculated for C19H21ClF3N6O (M+H)+: m/z=441.1; Found:441.1.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:35]I>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][I:35])=[CH:6][N:7]=1
Reactant: II
Reactant: OCCc1ccc(Br)nc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Brc1ccc(CCI)cn1
Reaction time: 6 h
Yield: 91.6 %

Procedure:
A solution of 2-(6-bromopyridin-3-yl)ethanol (2.0 g, 9.9 mmol, 1.0 equiv) in dichloromethane (31 mL) was added dropwise to a solution of imidazole (0.91 g, 13.4 mmol, 1.4 equiv), triphenylphosphine (3.3 g, 12.4 mmol, 1.3 equiv), and iodine (3.1 g, 12.4 mmol, 1.3 equiv) in dichloromethane (31 mL) at room temperature. After stirring for 6 h, the reaction was filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (15% ethyl acetate in heptane) to provide the title compound as a white solid (2.83 g, 92%). MS (LCMS) m/z 312.0 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.15 (t, J=7.03 Hz, 2H) 3.43 (t, J=7.03 Hz, 2H) 7.54 (d, J=7.81 Hz, 1H) 7.61 (dd, J=8.20, 2.73 Hz, 1H) 8.22 (d, J=2.34 Hz, 1H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10]([NH2:12])=[S:11].C(O)(=O)C>CCOCC>[OH:4][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:3])=[O:20])[C:10]([NH2:12])=[S:11]
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(N)=S
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCC(O)CCCN(CCCCCCC(=O)OC)C(N)=S
Reaction time: 4 h

Procedure:
A solution of diazomethane (approx. 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 7-[1-(4-hydroxynonyl)thioureido]heptanoic acid (10.3 g., 0.03 mole) (Example 3) in ether (50 ml.). The resulting solution is allowed to stand at room temperature for 4 hours. Then acetic acid is added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution, brine, then dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 7-[1-(4-hydroxynonyl)thioureido]heptanoate as a viscous oil.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:37])[C:26]=2[CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([Mg]Br)=[CH:41][CH:40]=1.Cl>C1COCC1>[CH2:1]([O:23][C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([C:42]3[CH:43]=[CH:44][C:39]([Cl:38])=[CH:40][CH:41]=3)([OH:37])[C:26]=2[CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc2c(c1)C(=O)c1ccccc1-2
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc2c(c1)C(O)(c1ccc(Cl)cc1)c1ccccc1-2
Temperature: 25 °C
Yield: 88 %

Procedure:
Under a nitrogen atmosphere, 2-docosyloxy-9-fluorenone (250 mg, 0.50 mmol) prepared in the above-mentioned 1-1 was suspended in THF (2.5 ml), and dissolved at 50° C. 4-Chlorophenylmagnesium bromide solution was added dropwise, and the mixture was stirred. After completion of the reaction, the reaction mixture was cooled to room temperature, 1N hydrochloric acid was added dropwise thereto in a water bath until foaming stopped to quench the reaction. The mixture was extracted with chloroform (15 ml), and washed 3 times with 1N hydrochloric acid (5 ml), 3 times with 5% NaHCO3 solution (5 ml), and once with 20% NaCl solution (5 ml). The organic layer was dried over Na2SO4, and the solvent of the filtrate was evaporated. The obtained residue was isolated and purified by silica gel column chromatography, and precipitated with methanol (3 ml) to give 2-docosyloxy-9-(4-chlorophenyl)-9-fluorenol (270 mg, 0.44 mmol, 88%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CN1CCC(c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1

Procedure:
(23.9 mg, 67%) from 3-(1-methyl-4-piperidinyl)-1H-indole (Example 5d, 21.5 mg, 0.1 mmol) and phenylsulfonyl chloride (26.4 mg, 0.15 mmol), HRMS-FAB+ for C20H22N2O2S, calculated MH+ : 355.14807; found: 355.15074.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][O:16][C:17]([C:19]1[N:20]([CH3:26])[CH:21]=[C:22]([S:24][CH3:25])[CH:23]=1)=[O:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:21]2[N:20]([CH3:26])[C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:23][C:22]=2[S:24][CH3:25])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(SC)cn1C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cc(SC)c(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
p-Chlorobenzoyl chloride (2.75 ml, 20 mmol), dissolved 20 ml of methylene chloride and 2.6 g (20 mmol) of aluminum chloride are mixed well at room temperature. After about 5 minutes 1.87 g (10 mmole) of 2-methoxycarbonyl-4-methylthio-1-methylpyrrole is added dropwise. The reaction mixture turns immediately into a dark red colored solution. The reaction is stirred for one hour before it is diluted with 75 ml of methylene chloride and extracted with water. The methylene chloride layer is separated, washed sucessively with 25 ml sodium bicarbonate solution and 50 ml of saturated brine, dried over anhydrous sodium sulfate and concentrated to an oil. The oil is crystallized from ethanol to give 1.0 g of 5-(p-chlorobenzoyl)-2-methoxycarbonyl-4-methylthio-1-methylpyrrole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(O)(=O)C.C(=O)(O)[O-].[Na+]>O>[C:12]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1)(=[O:14])[CH3:13]
Reactant: COc1c(C)cc(N)cc1C
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(C)cc(NC(C)=O)cc1C
Temperature: 50 °C
Yield: 82.6 %

Procedure:
4-Amino-2,6-dimethylanisole (4, 5 g, 33.2 mmol) was placed in a round-bottom flask fitted with a reflux condenser, and acetic anhydride (3.4 mL, 35.4 mmol) and acetic acid (3 mL, 53.1 mmol) were added sequentially. The mixture was heated to 50° C. for 4 h, cooled, poured into water and basified with saturated aq. sodium bicarbonate. The solution was extracted with methylene chloride, and the combined extracts were washed with brine and dried (MgSO4). Removing the solvent and recrystallizing the resulting solid from hexane-methylene chloride yielded 4-acetamido-2,6-dimethylanisole (7, 5.3 g, 83% yield). Spectral data: 1H NMR: δ 2.1 (s, 3H), 2.2 (s, 6H), 3.65 (s, 3H), 7.10 (s, 2H), 8.10 (s, 1H); 13C NMR: δ 16.1, 24.2, 60.0, 121.5, 131.8, 134.3, 154.3, 169.8; CI-HRMS: calcd. for C11H16NO2 (M+H+) 194.1181, fnd. 194.1181.