Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1.C(OCC)(=O)C>ClC1C=CC=CC=1>[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]2=3)=[O:3])[CH2:23][CH2:22]1
Reactant: CN1CCC(O)CC1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: CN1CCC(OC(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1

Procedure:
A quantity of 4.1 gm (0.015 mol) of 5-chlorocarbonyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one was refluxed with 3.45 gm (0.03 mol) of 1-methyl-4-piperidinol in 50 ml of chlorobenzene for two hours. After cooling, the reaction solution was diluted by the addition of 200 ml of ethyl acetate and then extracted exhaustively with 15% hydrochloric acid. The combined extracts were neutralized with potassium carbonate and extracted several times with chloroform, and the combined chloroform extracts were evaporated to dryness in vacuo. By recrystallization from ethyl acetate, colorless crystals were obtained, m.p.: 203°-204° C. Yield: 1.2 gm (23% of theory).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:19])[CH2:17][CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br:20]Br>C(O)(=O)C>[Br:20][CH:17]([CH3:18])[C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)=[O:19]
Reactant: BrBr
Reactant: CCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
This compound is obtained simply by reacting 1-(3,5-ditert-butyl-4-hydroxyphenyl)propan-1-one (prepared from 2,6-ditertbutylphenol according to Russ. J. Org. Chem. (1997), 33, 1409-1416) with bromine in acetic acid or also according to a protocol described in one of the following references: Biorg. Med. Chem. Lett. (1996), 6(3), 253-258; J. Med. Chem. (1988), 31(10), 1910-1918; J. Am. Chem. Soc. (1999), 121, 24.
Reaction SMILES: [CH3:1][N:2]1[C:7](SC)=[N:6][C:5](=[O:10])[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[N:3]1.[CH3:18][O-:19].[Na+]>CO>[CH3:1][N:2]1[C:7]([O:19][CH3:18])=[N:6][C:5](=[O:10])[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[N:3]1
Reactant: C[O-]
Reactant: CSc1nc(=O)c(-c2cccc(Cl)c2)nn1C
Agent: [Na+]
Solvent: CO
Product: COc1nc(=O)c(-c2cccc(Cl)c2)nn1C
Yield: 59.6 %

Procedure:
To a solution of 2-methyl-3-methylthio-6-(m-chlorophenyl)-5-oxo-2,5-dihydro-1,2,4-triazine (0.5 g) in methanol (10 ml), sodium methoxide (0.23 g) was added, and the resultant mixture was stirred at room temperature for 2 hours. After stirring, the resulting mixture was evaporated to dryness to give a crude product. Recrystallization of the crude product from ethanol gave 0.28 g of 2-methyl-3-methoxy-6-(m-chlorophenyl)-5-oxo-2,5-dihydro-1,2,4-triazine in 60% yield. M.P., 119° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])[CH:5]=[CH:4][C:3]=1[N+:31]([O-])=O>CO.[C].[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:16]([F:17])([F:18])[F:19])[C:20]([F:21])([F:22])[F:23])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])[CH:5]=[CH:4][C:3]=1[NH2:31]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(N)c(C)c1
Yield: 99.7 %

Procedure:
To a solution of 2-methyl-4-[2-propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoromethyl-ethyl)-phenoxy]-1-nitrobenzene (293 mg, 0.609 mmol) in methanol (3.0 mL), palladium carbon (29 mg) was added and the resultant mixture was stirred for 3 hours under a hydrogen atmosphere. The reaction solution was filtered using celite, concentrated in vacuo, and 2-methyl-4-[2-propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoromethyl-ethyl)-phenoxy]-phenylamine (274 mg, yield >100%) was obtained as a red-purple oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH2:17][O:18][CH2:19][C:20]#[CH:21])[C:4]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1.I[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][C:2]1[N:3]([CH2:16][CH2:17][O:18][CH2:19][C:20]#[C:21][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: Ic1ccccc1
Reactant: C#CCOCCn1c(C)nc2c(N)nc3c(c21)CCCC3
Product: Cc1nc2c(N)nc3c(c2n1CCOCC#Cc1ccccc1)CCCC3
Temperature: 50 °C
Reaction time: 18 h
Yield: 21.7 %

Procedure:
Using the general method of Example 12 Part A, 2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (0.396 g, 1.392 mmol) was reacted with iodobenzene (0.17 mL, 1.532 mmol) at ambient temperature. After 18 hours the reaction was incomplete. The solution was heated to 50° C. for 3 hours to complete the reaction. The volatiles were removed under reduced pressure. The resulting oil was partitioned between dichloromethane and 4% aqueous sodium carbonate and the organic layer removed. The aqueous layer was extracted with dichloromethane (3×). The organic fractions were combined, dried with anhydrous sodium sulfate and the volatiles were removed under reduced pressure. The resulting oil was purified by chromatography over silica gel (95/5 dichloromethane/methanol). The resulting white solid was dissolved in dichloromethane (2 mL) and reacted with 1M HCl in ether (2 mL). The volatiles were removed under reduced pressure and the resulting solids recrystallized from methanol to provide 0.1089 g of 2-methyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (hydrochloride),.g as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:24])[CH2:10][O:11][C:12]1[CH:13]=[C:14]([F:23])[C:15]([C:18]([O:20]CC)=[O:19])=[N:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+].Cl>C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:24])[CH2:10][O:11][C:12]1[CH:13]=[C:14]([F:23])[C:15]([C:18]([OH:20])=[O:19])=[N:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ncc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](COc1cnc(C(=O)O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
A mixture of ethyl 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-3-fluoropyridine-2-carboxylate (402 mg), THF (4 mL), ethanol (4 mL) and 1M aqueous lithium hydroxide solution (4 mL) was stirred at 0° C. for 3 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (357 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][NH2:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]=1.[NH2:15][C:16](=[O:29])[CH2:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][CH:24]2[O:26][CH2:25]2)=[CH:20][CH:19]=1>CO>[NH2:15][C:16](=[O:29])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH:24]([OH:26])[CH2:25][NH:10][CH2:9][CH2:8][CH2:7][N:6]2[C:5]3[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=3[N:3]=[C:2]2[CH3:1])=[CH:27][CH:28]=1
Reactant: Cc1nc2ccccc2n1CCCN
Reactant: NC(=O)Cc1ccc(OCC2CO2)cc1
Solvent: CO
Product: Cc1nc2ccccc2n1CCCNCC(O)COc1ccc(CC(N)=O)cc1

Procedure:
A mixture of 4.16 grams of 2-methyl-1H-benzimidazole-1-propanamine and 4.56 grams of 1-[4-(2-amino-2-oxoethyl)phenoxy]-2,3-epoxypropane in 50 ml of 90% methanol was refluxed for 22 hours. The solvent was then evaporated to leave a thick oil which was chromatographed on a silica gel column using methanol. The fractions containing the desired product were determined by thin-layer chromatography and combined. The solvent was evaporated to leave a thick oily residue which solidified partially on standing. This was recrystallized from ethanol to give N-{3-[4-(2-amino-2-oxoethyl)phenoxy]-2-hydroxypropyl}-2-methyl-1H-benzimidazole-1-propanamine melting at about 146°-149° C. This compound has the following structural formula: ##STR14##
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]3[CH2:14][CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[N:3]=1.Cl[C:23]1N=C2C(N=C(I)N2CC)=C(N2CCOC[C@@H]2C)N=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]3[CH2:13][CH2:14]3)[N:8]2[CH2:11][CH3:23])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[N:3]=1
Reactant: CCn1c(I)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1CC1)n2C
Product: CCn1c(C2CC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21

Procedure:
The compound (f-1) was prepared in an analogous fashion to (S)-4-(2-chloro-8-cyclopropyl-9-methyl-9H-purin-6-yl)-3-methylmorpholine, using (S)-4-(2-chloro-9-ethyl-8-iodo-9H-purin-6-yl)-3-methylmorpholine as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 5.31 (broad s, 1H), 5.00 (broad s, 1H), 4.26 (q, J=7.2 Hz, 2H), 3.97 (dd, J=11.3, 3.4 Hz, 1H), 3.74 (m, 2H), 3.58 (td, J=12.2, 2.7, 1H), 3.43 (broad t, 1H), 1.92 (m, 1H), 1.41 (t, J=7.2 Hz, 3H), 1.34 (d, J=6.2 Hz, 3H), 1.12 (m, 2H), 1.06 (m, 2H); LC-MS m/z (method A)=322 [M+H]+, RT=2.81 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:19]([CH:21]1[CH2:23][CH2:22]1)#[CH:20]>>[CH:21]1([C:19]#[C:20][C:2]2[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=2)[CH2:23][CH2:22]1
Reactant: C#CC1CC1
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: O=C(NCCC(O)c1cccc(C#CC2CC2)c1)C(F)(F)F

Procedure:
Sonogashira reaction of 25 with ethynylcyclopropane yielded N-(3-(3-(2-cyclopropylethynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as dark brown oil. Yield (0.8 g, 83%). This used without further purification in the next transformation.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.[OH:18][CH2:19][C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.[H-].[Na+]>CN(C)C=O.O>[Cl:9][C:7]1[CH:8]=[C:3]([CH2:2][O:18][CH2:19][C:20]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH:6]=1
Reactant: N#Cc1ccc(-c2cc(Cl)cc(CBr)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Cl)cc(-c3ccc(C#N)cc3)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3′-(Bromomethyl)-5′-chlorobiphenyl-4-carbonitrile (38.3 mg, 0.12 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (30.3 mg, 0.1 mmol) were combined in dimethylformamide (2 mL) and cooled to 0° C. The reaction was treated with sodium hydride (5 mg, 0.2 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (25% ethyl acetate/hexanes) gave 35 mg (56%). 1H-NMR (CDCl3, 300 MHz) δ 7.71 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.28-7.35 (m, 4H), 7.19-7.21 (m, 1H), 7.10-7.13 (m, 2H), 4.36 (s, 2H), 3.69-3.76 (m, 2H), 3.41 (s, 2H), 2.97-3.06 (m, 2H), 2.15-2.19 (m, 2H), 1.80-1.90 (m, 2H), 1.40 (s, 9H). Mass spec.: 517.21 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([O:15][CH3:16])[CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[N:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH:13]([O:15][CH3:16])[CH2:12][N:11]([C:23]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:24])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CNCC(OC)C2)cc1
Reactant: O=C(Cl)N1CCOCC1
Product: CCc1ccc(C2CC(OC)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
880 mg (4.0 mmol) of 3-(4-ethylphenyl)-5-methoxypiperidine and 780 mg (5.2 mmol, 1.3 eq.) of morpholine-4-carbonyl chloride were reacted according to General Method 3A. Yield: 896 mg (58% of theory)
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:25])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH:3]=[O:4].C(Br)(C)C.[Mg].[C:31]([O:34][C:35](C)(C)[CH3:36])(=[O:33])[CH3:32].[Cl-].[NH4+]>CCOCC>[CH3:1][CH:2]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:25])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH:3]([OH:4])[CH2:32][C:31]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)C=O
Reactant: CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC(C)Br
Product: CCOC(=O)CC(O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Yield: 66 %

Procedure:
To a mixture of ether (344 ml) and 2,6,10,14,18-pentamethyl-5,9,13,17-nonadecatetraenal (34.4 g), Grignard reagent (prepared by adding portionwise isopropyl bromide (18.5 g) to a mixture of ether (100 ml) and metallic magnesium (3.7 g), adding further t-butyl acetate (17.4 g) thereto while cooling with ice and then stirring the resultant mixture for 1 hour) is dropwise added while cooling with ice. The resultant mixture is stirred at room temperature for 3 hours, and the reaction mixture is poured into an aqueous saturated solution of ammonium chloride. The ether layer is separated, washed with water, dried and evaporated. The residual material is chromatographed on silica gel (500 g) using a mixture of benzene and ethyl acetate (9.5:0.5 by weight) to give ethyl 3,7,11,15,19-pentamethyl-6,10,14,18-eicosatetraen-2-ol-1-carboxylate (28.5 g) as a pale yellow oil. IR: 3480, 1030 cm-1 (OH); 1720, 1180 cm-1 (COO).
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[S:8][C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH2:19])(=[O:18])=[O:17])=[N:6][N:5]=1.[CH3:20]I>CO>[CH3:20][S:3][C:4]1[S:8][C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH2:19])(=[O:18])=[O:17])=[N:6][N:5]=1
Reactant: CI
Reactant: NS(=O)(=O)c1ccccc1Cc1nnc(S)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(Cc2ccccc2S(N)(=O)=O)s1
Reaction time: 0.08 h
Yield: 15.3 %

Procedure:
To a solution containing 1.0 g of potassium hydroxide in 50 ml of methanol was added 5 g of the crude oxadiazole prepared in Example 2. After stirring about five minutes, 3.5 g of methyl iodide was added. The solution was refluxed one hour, cooled to 30°, an extra 10 ml of methyl iodide was added, and the solution was refluxed an additional two hours, then concentrated in vacuo. After water (about 150 ml) was added to the residue, the suspension was extracted with methylene chloride. The methylene chloride solution was dried (MgSO4), concentrated in vacuo, and the residue was recrystallized from acetonitrile to give 0.8 g of the subject compound; m.p. 175°-178° C. NMR(CDCl3, DMSO-d6): δ 2.8(s, SCH3); 4.9(s, CH2); 7.3(s, NH2); 7.4-8.3 (m, ar) ppm. Mass spectrum by direct probe using electron impact ionization showed highest significant m/e 301.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[C:4]([Cl:26])[CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[Cl:26][C:4]1[CH:3]=[C:2]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][O:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=S(=O)(Nc1cccc(CCOCc2ccc(Br)cc2Cl)c1)C(F)(F)F
Product: O=S(=O)(Nc1cccc(CCOCc2ccc(-c3ccc(Cl)cc3)cc2Cl)c1)C(F)(F)F

Procedure:
N-{3-[2-(3-Chloro-4′-chloro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfonamide was prepared from the product of Example 21 and 4-chloro benzene boronic acid according to the procedure of Example 2 and isolated as a white solid (65%), 97-99° C. NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 7.75 (m, 3H, ArH), 7.61 (d, J=8 Hz, 1H, ArH), 7.54 (d, J=8 Hz, 2H, ArH), 7.42 (d, J=8 Hz, 1H, ArH), 7.31 (t, J=8 Hz, 1H, Ar5), 7.19 (d, J=8 Hz, 1H, H4) 7.11 (s, 1H, H2), 7.09 (d, J=8 Hz, 1H, H6), 4.57 (s, 2H, OCH2), 3.65 (t, J=7 Hz, 2H, OCH2), 2.85 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C22H18Cl2F3N1O3S1: C, 52.39; H, 3.60; N, 2.78. Found: C, 52.07; H, 3.47; N, 2.70.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:16]([CH2:21][C:22](=N)O)([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([CH2:21][C:22]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)CC(=N)O
Reactant: Nc1ccccc1Nc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1nc2ccccc2n1-c1ccccc1

Procedure:
N-phenyl-o-phenylenediamine (55.27g; 0.3 mole) and carboethoxyacetimidate hydrochloride [Ber., 28, 478 (1895)](58.70g; 0.3 mole) are refluxed in ethanol (200ml) for 4 hours. The separated ammonium chloride is filtered from the hot solution. The filtrate is evaporated to a syrup which is taken up in chloroform and washed twice with water. After drying (MgSO4), the chloroform is evaporated, ligroin is added, and crystallization slowly occurs. The solid is filtered and recrystallized from ligroine to give 50.3g (59.8%); m.p. 87°-89°; Lit. m.p. 89°-91° [J. Hetero. Chem., 3(3), 280 (1966)].
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:17]1[CH:19]2[CH2:20][CH2:21][CH2:22][CH:18]12>>[OH:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: C1CC2OC2C1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Product: O=C(OCc1ccccc1)N1CCN([C@@H]2CCC[C@H]2O)CC1
Temperature: 80 °C
Yield: 44.2 %

Procedure:
A solution of 0.524 g of benzyl piperazine-1-carboxylate is cooled to 0° C., 0.2 g of 1,2-epoxycyclopentane is added and it is heated at 80° C. for four days. The reaction mixture is concentrated under vacuum and the residue is purified by silica gel chromatography, eluting with EtOAc/MeOH mixture. 0.32 g of the expected compound is obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:12][OH:13])([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14]=O>Cl>[C:9]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:12][O:13][CH2:14][O:1][CH2:2]1)(=[O:11])[CH3:10]
Reactant: C=O
Reactant: CCOC(=O)C(CO)(CO)C(C)=O
Agent: Cl
Product: CCOC(=O)C1(C(C)=O)COCOC1
Temperature: 25 °C
Yield: 14 %

Procedure:
A solution of ethyl 2,2-bis(hydroxymethyl)-3-oxobutanoate (75 g, 0.39 mol) and 40% formaldehyde (360 mL) in concentrated hydrochloric acid (360 mL) was heated at 50° C. for 17 h. The two-phase solution was cooled to room temperature and extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with water, dried over magnesium sulfate, and evaporated to give a residue, which was purified by flash column chromatography eluting with a continuous gradient of petroleum ether/ethyl acetate 15:1 to 9:1 to afford the title compound (33 g, 14%, 2 steps) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.25 (m, 3H), 2.31 (s, 3H), 4.25-4.19 (m, 4H), 4.35 (d, J=12.0 Hz, 2H), 4.77 (d, J=6.0 Hz, 1H), 4.82 (d, J=6.0 Hz, 1H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[OH:14]>ClCCl>[Cl:6][C:7]1[C:8]([OH:14])=[CH:9][C:10]([CH3:13])=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=1
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1cc(O)c(Cl)cc1S(=O)(=O)Cl
Reaction time: 0.17 h
Yield: 7.1 %

Procedure:
To a solution of chlorosulfonic acid (1.22 g, 10.5 mmol) dissolved in 10 mL of dichloromethane was added 2-chloro-5-methylphenol (1.0 g, 7.0 mmol) dropwise. After 10 minutes, the reaction was quenched by pouring it into ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO4, filtered, and concentrated to give 120 mg (7.1%) of the title compound.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[H][H]>C(O)C.O.[Pd]>[C:1]([O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(=O)OC1CCNCC1
Yield: 92 %

Procedure:
10% Pd/C (500 mg) was added to a solution of 1-benzylpiperidin-4-yl acetate [(11 g, 47 mmol), J. Org. Chem. 68(2), 613-616; 2003] in a mixture of ethanol and water (90:10, 110 mL), and the mixture was stirred at 60° C., under 60 psi of hydrogen gas for 18 hours. The reaction mixture was then filtered through Arbocel®, washing through with ethanol, and the filtrate was concentrated in vacuo to afford the title product in 92% yield, 7.2 g. 1H NMR (CDCl3, 400 MHz) δ: 1.60 (m, 2H), 1.81-2.18 (m, 5H), 2.78 (m, 2H), 2.95-3.18 (m, 2H), 4.82 (m, 1H); LRMS APCI+ m/z 145 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH2:22])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl[C:24]([O:26][CH3:27])=[O:25]>N1C=CC=CC=1.CCOCC>[CH3:27][O:26][C:24](=[O:25])[NH:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[NH:15][CH:14]=[C:13]2[C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)Cl
Reactant: CCC1(c2c[nH]c3c(N)cccc23)CCc2cc(F)ccc21
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC1(c2c[nH]c3c(NC(=O)OC)cccc23)CCc2cc(F)ccc21
Yield: 35.8 %

Procedure:
Dissolve 3-(1-ethyl-5-fluoro-indan-1-yl)-1H-indol-7-ylamine (0.35 g, 1.19 mmol) in pyridine (3 ml). Add methyl chloroformate (0.10 ml, 1.31 mmol, 1.1 equivalents) and stir at room temperature under nitrogen overnight. Dilute with ether, wash with 1N aqueous hydrochloric acid (2×), dry over anhydrous sodium sulfate, filter, and concentrate solution in vacuo. Purify the residue on silica eluting with 0 to 75% ethyl acetate/hexanes over 30 minutes to provide the title compound as a white solid (0.15 g, 36%). LC-MS m/z 353.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=3)[CH:14]=[CH:13]2)[CH2:8][CH2:7]1.Cl.[NH2:28][OH:29].C([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=[N:28][OH:29])[CH:19]=3)[CH:14]=[CH:13]2)[CH2:8][CH2:7]1
Reactant: NO
Reactant: O=Cc1ccc2ccn(C3CCN(CCc4ccccc4F)CC3)c2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=Cc1ccc2ccn(C3CCN(CCc4ccccc4F)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A mixture of 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-formylindole (1.94 g) obtained in Example 348-4), hydroxylamine hydrochloride (0.5 g) and anhydrous sodium acetate (0.55 g) in methanol (60 ml) was stirred at room temperature for 1 hr. Then the reaction mixtures were concentrated and the residue was partitioned between ethyl acetate (150 ml) and a 1 N aqueous solution (30 ml) of sodium hydroxide. The ethyl acetate layer was washed successively with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindole (1.96 g) as an ivory powder (yield: 96.8%).