Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[NH:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26](Cl)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>C(C(C)=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:4]2[CH2:5][CH2:6][NH:7][C:2]([CH3:1])([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=3)[CH2:3]2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Reactant: COc1ccc(CC2(C)CNCCN2)cc1OC
Solvent: CCC(C)=O
Product: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccc(Cl)cc3)CCN2)cc1OC
Yield: 80 %

Procedure:
If 3-methyl-3-(3,4-dimethoxybenzyl)-piperazine is reacted with p-chlorophenyl-phenylmethyl chloride in methyl ethyl ketone according to Example 2, 1-(p-chlorophenyl-phenylmethyl)-3-methyl-3-(3,4-dimethoxybenzyl)-piperazine is obtained in 80 percent yield after a 12-hour reaction period. The hydrochloride has a melting point of 235°-237° C. (isopropanol).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15](Cl)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:26]1)=[O:24])[CH3:21].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[CH2:20]([O:22][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH:31]2[CH2:32][CH2:33][N:34]([C:15]([C:13]3[C:14]4[C:5]([CH:6]=[C:7]5[C:12]=3[CH:11]=[CH:10][CH:9]=[CH:8]5)=[CH:4][CH:3]=[CH:2][CH:1]=4)=[O:16])[CH2:35][CH2:36]2)[CH2:26]1)=[O:24])[CH3:21]
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Reactant: CCOC(=O)C1CCCN(C2CCNCC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCCN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anthracene-9-carbonyl chloride (62.2 mmol) was suspended in anhydrous dichloromethane (30 mL) and added slowly by pipette to a solution of [1,4′]bipiperidinyl-3-Carboxylic acid ethyl ester bishydrochloride (62.2 mmol) and triethylamine (4 eq., 35 mL) in anhydrous dichloromethane (50 mL) at such a rate that a gentle reflux was maintained. The resulting suspension was stirred overnight at ambient temperature then shaken with ice-cold water containing sodium hydroxide (0.19 mol, 7.6 g). The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane. The combined dichloromethane solution was washed with water, dried with anhydrous sodium sulfate, diluted with a little xylene and evaporated to dryness to give the title compound (containing a small amount of the corresponding isopropyl ester) as a pale yellow gummy foam (30.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13](C1NC=CN=1)(C1NC=CN=1)=[O:14]>C1COCC1>[O:14]=[C:13]1[NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12]1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]c(=O)oc2c1
Yield: 56 %

Procedure:
To a solution of methyl 4-amino-3-hydroxybenzoate (Intermediate 75, 1.06 g, 6.34 mmol) in THF (13.5 mL) was added carbonyl diimidazole (1.88 g, 11.6 mmol) and the reaction mixture was heated to reflux temperature for 1 day. After that time, the solvent was removed and the residue was partitioned between CH2Cl2 and 1N aqueous HCl solution. The organic phase was washed with 1N aqueous HCl solution (2×) and water, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to provide the title compound as white solid (870 mg of a 79% purity, 56% yield). The crude was used in the next step without any further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2C(OC(C)(C)C)=O)=[O:8])=[CH:3][CH:2]=1.Cl.CCN(C(C)C)C(C)C.[CH3:32][N:33]1[CH:37]=[C:36]([S:38](Cl)(=[O:40])=[O:39])[N:35]=[CH:34]1>O1CCOCC1>[CH3:32][N:33]1[CH:37]=[C:36]([S:38]([N:12]2[CH2:13][CH2:14][CH:9]([C:7]([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][N:5]=3)=[O:8])[CH2:10][CH2:11]2)(=[O:40])=[O:39])[N:35]=[CH:34]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1ccncc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(S(=O)(=O)N2CCC(C(=O)c3ccccn3)CC2)c1
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 6 (950 mg, 3.27 mmol) in 1,4-dioxane (5 mL) was added 4 N HCl in dioxane (10 mL) and stirred for 1 h. The solvent was removed under vacuum. The residue was dissolved in CH2Cl2 (10 mL), added DIPEA (1.94 mL, 10.8 mmol) and 1-methylimidazole-4-sulfonyl chloride (589 mg, 3.27 mmol). The reaction was stirred for 18 h at room temperature. The reaction mixture was washed with 2 N NaOH (10 mL), dried over MgSO4 and concentrated under vacuum to afford 7 as a light orange oil (920 mg, 84%); 1H-nmr (400 MHz, CDCl3) δ 8.63 (d, J=5.0 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.85 (td, J=8.0, 1.5 Hz, 1H), 7.50 (s, 1H), 7.48 (dd, J=8.0, 1.5 Hz, 1H), 7.44 (s, 1H), 4.00-3.82 (m, 3H), 3.77 (s, 3H), 2.86 (t, J=11.0 Hz, 2H), 2.04-1.96 (m, 2H), 1.91-1.78 (m, 2H); m/z 335.1 [M+H].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[CH:13]3)=[O:9])[CH2:3][CH2:2]1.[CH:19](=O)[CH2:20][CH3:21].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:19]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[CH:13]3)=[O:9])[CH2:3][CH2:2]1)[CH2:20][CH3:21]
Reactant: O=C(NC1CCNCC1)c1ccc2[nH]ncc2c1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN1CCC(NC(=O)c2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
Acetic acid (0.048 ml) was added to a solution of the N-(4-piperidinyl)-1H-indazole-5-carboxamide (40.0 mg, 0.164 mmol) obtained in Example 58 in methanol (1.2 ml), and the resulting solution was maintained at room temperature for 30 minutes. Propionaldehyde (48.0 mg, 0.826 mmol) was added to the solution and the resulting mixture was maintained at room temperature for another 2 hours. Then, a solution of sodium cyanoborohydride (51.5 mg, 0.820 mmol) in methanol (3.0 ml) was added dropwise thereto, and the resulting mixture was stirred for 18 hours while being maintained at room temperature. A 1N-aqueous sodium hydroxide solution (0.8 ml) was added to the reaction solution, and the resulting mixture was stirred while being maintained at room temperature, and then was concentrated to dryness. The resulting crude product residue was purified by a silica gel column chromatography (eluent: chloroform/methanol/aqueous ammonia=20/1/0.1) to obtain N-(1-propylpiperidin-4-yl)-1H-indazole-5-carboxamide (31 mg, 46%).
Reaction SMILES: O.[OH-].[Li+].[N:4]1([C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>CO.O>[N:4]1([C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)Cc1ccc(N2CCCC2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc(N2CCCC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (36 mg, 0.85 mmol) was added to a solution of ethyl (6-pyrrolidin-1-ylpyridin-3-yl)acetate (100 mg, 0.4 mmol) in methanol (3.0 mL) and water (1.0 mL). The reaction mixture was stirred at r.t. overnight. The mixture was adjusted to pH=4 with aqueous HCl, and concentrated to afford the crude product which was directly used for next step without further purification. Analytic LCMS (M+H)+: m/z=207.1.
Reaction SMILES: [OH:1][C:2]1([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH3:29][O:30][C@:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:35]([F:38])([F:37])[F:36])[C:32](Cl)=[O:33]>ClCCl.CN(C1C=CN=CC=1)C>[C:10]1([CH2:9][O:8][C:6]([N:4]2[CH2:3][C:2]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([O:1][C:32](=[O:33])[C@:31]([O:30][CH3:29])([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:35]([F:37])([F:38])[F:36])[CH2:5]2)=[O:7])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C1(O)CN(C(=O)OCc2ccccc2)C1
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CO[C@@](C(=O)OC1([C@H]2CCCCN2C(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1)(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 8.1 %

Procedure:
To a solution of 1,1-dimethylethyl 2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (368 mg, 0.94 mmol), prepared using procedures similar to those described in Reference 5, in dichloromethane (5 mL) was added DMAP (115 mg, 0.94 mmol) and the resulting solution was cooled to 0° C. (R)-(−)-α-Methoxy-α-trifluoromethylphenylacetyl chloride (105 μL, 0.56 mmol) was added to the solution by syringe and the mixture was allowed to warm to room temperature then stirred an additional 12 hours. The solution was then partitioned with saturated aqueous sodium bicarbonate and the organic phase dried over anhydrous magnesium sulfate then filtered and concentrated to an oily residue. Silica gel flash chromatography using hexanes:ethyl acetate 3:1 as eluent afforded the less polar 1,1-dimethylethyl (2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (27.5 mg, 5% yield), the more polar 1,1-dimethylethyl (2S)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (105 mg, 19% yield) and starting material (253 mg, 69% recovery).
Reaction SMILES: Cl.[Cl-].[N:3]1[CH:8]=[CH:7][CH2+:6]=[CH:5][CH:4]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:6]2[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=2)=[CH:13][CH:12]=1
Reactant: C1=CN=CC=[CH2+]1
Reactant: COc1ccc(N)cc1
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Product: COc1ccc(Nc2ccncc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1-(4-pyridinium chloride hydrochloride (10.0 g, 0.04 mol) and p-anisidine (4.9 g, 0.04 mol) is heated at 150° C. until the pyridine stops distilling. The resulting black oil is allowed to cool to room temperature during which time it solidifies. The solid is broken into a powder and repeatedly washed with acetone until the color is light brown. Recrystallization from isopropanol gives the product as a yellow powder, mp 129°-134° C.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:13]=1[F:26].B.O>C1COCC1>[F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:13]=2[F:26])=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1cc(C(=O)Nc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CNc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-2-fluoro-3-(3-fluorophenyl)-5-methyl-benzamide (130 mg, 0.30 mmol, 1.0 eq) in THF (25 mL) was added dropwise a solution of borane (1M in THF, 1.2 mL, 1.2 mmol, 4 eq) under N2. The reaction was heated at 60° C. overnight. TLC showed the reaction was not complete so further borane (1 M in THF, 1.0 mL, 1 mmol) was added and heating continued at 60° C. for 2 h. The mixture was poured into water and extracted with EtOAc and the combined organic extracts washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound as an oil (100 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:5][NH2:6].C1CCC(N=C=NC2CCCCC2)CC1.[C:31](=S)=[S:32]>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]([F:13])([F:14])[F:15])[CH2:5][N:6]=[C:31]=[S:32]
Reactant: S=C=S
Reactant: NCc1ccc(OCC(F)(F)F)c(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: Fc1cc(CN=C=S)ccc1OCC(F)(F)F
Temperature: -10 °C
Reaction time: 3 h

Procedure:
The crude 3-fluoro-4-(2,2,2-trifluoroethoxy)benzylamine (7.54 g) was added dropwise to a mixture of 7.45 g of DCC, 15 ml of carbon disulfide and 30 ml of diethyl ether with stirring at -10° C. The temperature of the mixture was returned to room temperature, and it was left to stand for 3 hours. The reaction mixture was filtered, and the residue was washed with ethyl ether and combined with the filtrate. The solvent was evaporated under reduced pressure. The resulting oily product was purified by column chromatography (silica gel; developing
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([N:14]3[CH2:19][CH2:18][CH2:17][C@@H:16]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=5[CH2:26][C@H:15]34)=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Nc1nc2ccc(C(=O)O)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1nc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)cc2s1
Yield: 63 %

Procedure:
The title compound is prepared from 2-amino-benzothiazole-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 63% of theory; LC (method 4): tR=1.76 min; Mass spectrum (ESI+): m/z=350 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:13](=[O:33])[NH:12]2)=[CH:7][CH:6]=1)#[N:4].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41]Br)[CH:36]=1>CCCCC.O1CCCC1>[Br:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[CH2:41][N:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=2)[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[N:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[CH:24]=2)[C:13]1=[O:33]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(Br)c2)C1c1ccc(C#N)cc1
Reaction time: 0.08 h

Procedure:
Sodium hydride (55.9 mg 1.397 mmol; 60% dispersion in mineral oil) is washed with pentane (2×10 ml) and suspended in tetrahydrofuran (10 ml). A solution of ethyl 4-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 4A) (500 mg, 1.164 mmol) in tetrahydrofuran (5 ml) is added with stirring. After 5 minutes at room temperature, a solution of 1-bromo-3-(bromomethyl)benzene (320 mg, 1.23 mmol) in tetrahydrofuran (5 ml) is added, and the reaction is stirred at room temperature for 16 h. The solution is quenched with water (50 ml) and extracted with ethyl acetate (3×150 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The yellow residue (approximately 1.05 g) is purified by flash chromatography over silica gel 60 (50 g) with cyclohexane/ethyl acetate (5:1) as eluent. The product is isolated as an amorphous foam.
Reaction SMILES: [ClH:1].[O:2]([C:9]1[CH:24]=[CH:23][C:12]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1(C)C=CC=CC=1>[ClH:1].[O:2]([C:9]1[CH:24]=[CH:23][C:12]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][NH+:18]=2)=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(Oc2ccc(OCCOc3ccccn3)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ccc(OCCOc3cccc[nH+]3)cc2)cc1

Procedure:
Excess of gaseous hydrogen chloride was gradually introduced into a solution of 2-[2-(4-phenoxyphenoxy)ethoxy]pyridine (1.54 mg, 5.0 mmol) in toluene (50 ml) with stirring. THe produced white precipitate was collected by filtration, washed with toluene several times and dried to give 2-[2-(4-phenoxyphenoxy)ethoxy]pyridinium hydrochloride (1.65 g) as white crystals. M.P., 138.1° C.
Reaction SMILES: [CH2:1]([NH:3]Cl)[CH3:2].N1C=CC=CC=1.[CH3:11][C@@H:12]1[C@:17]([CH2:19][C:20]2[C:26](=[O:27])[CH:25]=[CH:24][C:22](=[O:23])[CH:21]=2)([CH3:18])[C@@H:16]2[CH2:28][CH2:29][CH:30]=[C:31]([CH3:32])[C@@:15]2([CH3:33])[CH2:14][CH2:13]1>C(O)C>[CH3:2][CH2:1][NH:3][C:24]1[C:22](=[O:23])[CH:21]=[C:20]([CH2:19][C@@:17]2([CH3:18])[C@@H:16]3[CH2:28][CH2:29][CH:30]=[C:31]([CH3:32])[C@@:15]3([CH3:33])[CH2:14][CH2:13][C@@H:12]2[CH3:11])[C:26](=[O:27])[CH:25]=1
Reactant: CCNCl
Reactant: CC1=CCC[C@H]2[C@](C)(CC3=CC(=O)C=CC3=O)[C@@H](C)CC[C@]12C
Solvent: CCO
Solvent: c1ccncc1
Product: CCNC1=CC(=O)C(C[C@]2(C)[C@@H](C)CC[C@]3(C)C(C)=CCC[C@@H]23)=CC1=O

Procedure:
Add 2.5 g of ethylamino hydrochloride and 5 ml of pyridine to a solution of 500 mg avarone in 1000 ml of 50% ethanol, and distill off the ethanol under water-jet vacuum after 20 hours. Extract the aqueous residue with dichloromethane and chromatograph the reduced dichloromethane extract using a silica gel column and dichloromethane as extraction agent. In the course of this process 3'-ethylamino and 4'-ethylamino avarone is obtained.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18](=[O:28])[CH2:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[C:22](O)[CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:28])[CH2:19][C:20]1[CH:25]=[C:24]([O:26][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:6])[CH:23]=[C:22]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:21]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Trifluoromethanesulphonic anhydride (7.05 g, 25.0 mmol) was added dropwise to a solution of 3,5-dihydroxyphenyl acetic acid methyl ester (1.80 g, 10.0 mmol) and pyridine (4.9 mL, 60.0 mmol) in DCM (20 mL) at 0° C. The temperature was maintained at 0° C. for 15 mins before warming to room temperature and the mixture stirred for 18 hrs. The reaction was diluted with DCM washed with H2O, Na2CO3, dil. HCl, brine, dried (MgSO4) and evaporated under reduced pressure to give a yellow oil. The residue was purified by flash column chromatography (EtOAc:petroleum ether), yield 4.0 g (89%), 1H NMR (CDCl3) δ 7.31 (d, 2H), 7.17 (t, 1H), 3.74 (s, 3H), 7.73 (s, 2H).
Reaction SMILES: [NH2:1][CH:2]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][CH2:5][CH:6]([NH2:16])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[CH2:34][O:35][CH2:36][C:37](Cl)=[O:38]>ClCCl>[CH2:19]([O:18][CH2:17][CH:2]1[CH2:3][NH:4][CH2:5][CH:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:16][C:37](=[O:38])[CH2:36][O:35][CH2:34][C:33](=[O:40])[NH:1]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(CNCC(N)COCc1ccccc1)COCc1ccccc1
Reactant: O=C(Cl)COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1COCC(=O)NC(COCc2ccccc2)CNCC(COCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,5-diamino-1,5-dibenzyloxymethyl-3-aza-pentane (0.57 g, 1.7 mmol) (Example 6(d)) and triethylamine (0.34 g, 3.4 mmol) in dichloromethane (10 ml) and a solution of diglycolic acid dichloride (0.29 g, 1.7 mmol) in dichloromethane (10 ml) were added simultaneously over 2.5 hours to vigorously stirred dichloromethane (10 ml) at 0° C. The solution was stirred at ambient temperature overnight, washed with water (2×30 ml), dried with sodium sulphate and evaporated. Yield 0.59 g (78%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:25][C:13]([F:12])([F:24])[C:14]1[CH:15]=[CH:16][C:17]([S:20]([O:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(OC1CCC2(CC1)OCCO2)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (82 mmol, 13.0 g) in CH2Cl2 (80 mL) at 0° C. was added 4-(trifluoromethyl)benzenesulfonyl chloride (90 mmol, 20.0 g), Et3N (123 mmol, 12.4 g) and DMAP (8.19 mmol, 1.0 g). The reaction mixture was stirred at 0° C. and then gradually warmed up to room temperature. After stirring overnight, the reaction mixture was washed with sat. NH4Cl (300 mL). The aq layer was separated and extracted with CH2Cl2 (3×300 mL). The organic layers were combined, dried over MgSO4 and concentrated. Chromatography on silica gel, eluting with EtOAc and hexane, provided the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[CH2:25][SH:26]>>[CH2:1]([N:5]1[C:9]2=[C:10]([S:26][CH2:25][C:19]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=3[F:17])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: Fc1ccc(CS)c(F)c1
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(SCc3ccc(F)cc3F)c21
Yield: 39 %

Procedure:
The title compound (cis/trans=16:84) was prepared as pale brown crystals in 39.0% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=22/78) and 2,4-difluorophenylmethanethiol.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[CH:8][C:7]([O:15]C)=[CH:6][CH:5]=2.B(Br)(Br)Br.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[CH:8][C:7]([OH:15])=[CH:6][CH:5]=2
Reactant: COc1ccc2c(c1)c(CC(N)=O)c(Br)n2Cc1ccccc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)Cc1c(Br)n(Cc2ccccc2)c2ccc(O)cc12
Temperature: 0 °C
Yield: 34.2 %

Procedure:
A solution of 4 g (11 mmol) of 2-bromo-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide and 35 mL of BBr3/methylene chloride in 200 mL of methylene chloride was stirred for 1 hour, poured into ice-water, made basic with sodium bicarbonate and extracted with methylene chloride. This solution was washed with brine, dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel and eluted with ethyl acetate to give 1.35 g (33% yield) of 2-bromo-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide.