Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[OH-].[Na+].[Cl-].[C:16]([NH3+])(C)(C)C.S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:4][CH3:16]
Reactant: CC(C)(C)[NH3+]
Reactant: Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Product: CNc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,3-dichloro-6-nitroaniline (1.026 g, 5 mmole), was suspended in toluene (10 ml). To this vigorously stirred suspension was added 50% aqueous sodium hydroxide solution (1.7 g), tertiary-butyl ammonium chloride (0.07 g, 0.25 mmole) and dimethyl sulfate (0.51 ml, 5.4 mmole). After 4 hr stirring at room temperature the intense red solution was washed with water, brine, dried with magnesium sulfate, filtered, evaporated in vacuo. Weight=1.03 g, m.p.=82° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CS(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:43][C:44]([F:47])([F:46])[F:45])[C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)cc3c2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)N4CCCCC4)CC2)n3CC(F)(F)F)CC1
Yield: 86 %

Procedure:
The title compound was synthesized in analogy to example 3, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 2) and 2,2,2-trifluoroethyl methanesulfonate, to afford the desired product as a colorless foam (86%). MS (ISP): 613.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][CH2:34][CH2:35]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:35][CH2:34][O:33][CH3:32])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCCO
Reactant: Oc1ccc2ncnc(Cl)c2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a solution of 4-chloroquinazolin-6-ol (1.00 g, 5.54 mmol), triphenyl phosphine (1.45 g, 5.54 mmol) and 2-methoxyethanol (0.421 g, 5.54 mmol) in dichloromethane (83 mL) was added diisopropyl azodicarboxylate (1.18 g, 5.54 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure. The residue was chromatographed (30% ethyl acetate in hexanes) to provide the product (1.15 g, 87%) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].Br[C:15]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([C:15]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:7]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)c(C(=O)O)c1

Procedure:
This compound is obtained according to the procedure described in 1.1. by reacting 3,4-dimethoxybenzoyl chloride and 2-bromo-5-methoxybenzoic acid after halogen-lithium exchange. It is used in crude form in the following reaction.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[O-:12][CH2:13][CH3:14].[Na+].C(OCC)C.[Cl-].[NH4+]>C(O)C>[CH:1]1([C:4]2[N:9]=[C:8]([C:10](=[NH:11])[O:12][CH2:13][CH3:14])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: CC[O-]
Reactant: N#Cc1ccnc(C2CC2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=N)c1ccnc(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-cyclopropylpyrimidine-4-carbonitrile (20.97 g, 144.5 mmol) in ethanol (100 mL) was added sodium ethoxide (1.8 g, 78.9 mmol of sodium metal in 30 mL of ethanol). The reaction mixture was stirred at room temperature for 30 minutes. Diethyl ether (300 mL) was added to the reaction mixture followed by a saturated aqueous solution of ammonium chloride (50 mL). The mixture was extracted with diethyl ether (100 mL×3). The combined organics were washed with brine (50 mL×2), dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried under high vacuum to afford the title compound. The material was used without further purification. 1H NMR (500 MHz, CDCl3) δ 1.10-1.15 (m, 2H), 1.16-1.22 (m, 2H), 1.43 (t, 3H), 2.32 (tt, 1H), 4.44 (q, 2H), 7.50 (d, 1H), 8.72 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][OH:14])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1.N1CCCC1>CO>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19](/[C:20](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][CH2:12][CH2:13][OH:14])/[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1
Reactant: O=Cc1cc(Cl)ccc1OCCCO
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)ccc1OCCCO
Temperature: 70 °C
Yield: 87.6 %

Procedure:
5-Chloro-2-(3-hydroxy-1-propoxy)-benzaldehyde (8 g, 37 mmol) and 6-chlorooxindole (6.2 g, 37 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (3 mL, 37 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as a yellow solid (Yield: 11.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([NH:8][C:9]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])[CH:7]=1.Br[C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:16][N:15]1[C:11]([C:9]([NH:8][C:6]2[CH:7]=[C:2]([O:1][C:20]3[CH:25]=[N:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:3]=[CH:4][C:5]=2[CH3:18])=[O:10])=[CH:12][C:13]([CH3:17])=[N:14]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Cc1cc(C(=O)Nc2cc(O)ccc2C)n(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.8 %

Procedure:
A mixture of N-(5-hydroxy-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (4.67 g, 19.0 mmol), 5-bromo-2-nitropyridine (3.68 g, 18.1 mmol), cesium carbonate (9.29 g, 28.5 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=80/20→0/100) and then column chromatography (NH silica gel, hexane/ethyl acetate=80/20→0/100) to give the title compound (3.38 g, 44%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:13])[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].O.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(#N)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH2:12][CH:3]([CH2:2][OH:1])[CH2:4]2)[CH3:27]
Reactant: OCC1CCc2c(O)cccc2C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1cccc2c1CCC(CO)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 2-hydroxymethyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene (2.72 g,) and potassium carbonate (3.17 g) in acetonitrile, ethyl bromoacetate (2 ml) was added at room temperature. After stirring overnight at room temperature, the reaction mixture was poured into water and extracted with ether. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=6:4) to give the title compound (4.10 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(N(CC)CC)C.[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C1COCC1>[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](=[O:6])[NH2:7])[CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: NC(=O)c1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(NC(=O)c2ccccc2Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 3-aminobenzamide (310 mg, 2.3 mmol) in 7.6 mL of THF at 0° C. was added triethyl amine (0.63 mL, 4.6 mmol) followed by 2-bromobenzoylchloride (500 mg, 2.3 mmol). The reaction was stirred at 0° C. for 15 minutes and partitioned between water and dichloromethane. The layers were separated, the organics dried and solvent removed to give 2-bromo-N-(3-carbamoylphenyl)benzamide which was used for coupling without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[OH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:15][CH2:14]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of benzyl chloroformate (35 ml, 247 mmol) in tetrahydrofuran (70 ml) was added to an ice-cold solution of 4-hydroxypiperidine (25 g, 247 mmol) and triethylamine (45 ml, 321 mmol) in tetrahydrofuran (350 ml). The mixture was stirred overnight at room temperature and the solvent removed under reduced pressure. The residue was partitioned between 5% hydrochloric acid and ethyl acetate, and the organic layer washed with brine, dried over magnesium sulfate, and the solvent removed under reduced pressure to give 4-hydroxy-N-CBZ-piperidine as a pale yellow oil.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][C:7](=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>P(=O)(O)(O)O>[CH2:9]([C:8]([C:7](=[O:19])[CH3:6])=[CH:2][C:1]([OH:5])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCC(C)=O
Reactant: O=CC(=O)O
Agent: O=P(O)(O)O
Product: CCCCCCCCCCC(=CC(=O)O)C(C)=O

Procedure:
Prepared from glyoxylic acid (4.94 g, 6.5 mmol), 2-tridecanone (12.9 g, 6.5 mmol) and orthophosphoric acid (20 ml). 1H n.m.r. δ (CDCl3) 0.87, t J 7.2 Hz, 3H, CH3; 1.30, m, 16H, CH2; 2.39, s, 3H, CH3; 2.77, t J 7.0 Hz, 2H, CH2; 6.50, s, CH.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].C(=O)([O-])[OH:16].[Na+].O>CS(C)=O>[CH:2]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])=[O:16]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C=O)c(OC)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 38.6 %

Procedure:
To a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (3.00 g, 11.6 mmol) in dimethyl sulfoxide (16 ml) was added sodium hydrogen carbonate (1.00 g, 13.6 mmol), and the mixture was stirred at 50° C. for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:0-7:3, v/v) to give the title compound (870 mg, 39%) as a colorless oil.
Reaction SMILES: O[C:2]1[CH:7]=[C:6](O)[CH:5]=[C:4](O)[C:3]=1[C:10](=[O:12])[CH3:11].C(N(CC)C(C)C)(C)C.[CH3:22][O:23]CCl>O1CCCC1>[CH3:22][O:23][CH2:11][C:10]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:12]
Reactant: CC(=O)c1c(O)cc(O)cc1O
Reactant: COCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 200 ml of anhydrous tetrahydrofuran were dissolved 30 g of 2',4',6'-trihydroxyacetophenone and 115.0 g of N,N-diisopropylethylamine, and 50.2 g of chloromethyl methyl ether was gradually added to the solution under ice cooling over a period of 20 minutes and the reaction mixture was stirred under ice cooling for 1 hour and at room temperature for 4 hours to effect reaction. After the reaction, the reaction mixture was extracted with 3 l of ether, and the ether layer was washed with water (500 ml×3 times), shaken with a saturated aqueous solution of sodium chloride (300 ml×2 times), dried with anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by distillation and the obtained residue was recrystallized from a mixed solvent of methanol and water to obtain 18.9 g (yield=41.4%) of 2'-hydroxy-4',6'-bis(methoxyacetophenone in the form of a colorless prism.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:18]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCC1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C2CCCC2)cc1

Procedure:
In analogy to the procedure of Example I, the title compound is prepared from 31 g (0.287 mol) of anisole, 46 g (0.345 mol) of aluminium chloride and 40 g (0.302 mol) of cyclopentanecarbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:6][CH:7]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:14]1([S:20]([NH:1][C:2]2[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:6][CH:7]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N)cnc1CCCC#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(NS(=O)(=O)c2ccccc2)cnc1CCCC#N

Procedure:
A solution of 5-amino-2-(3-cyanopropyl)-3-methylpyridine* (5 g) in chloroform (50 ml) was treated with benzenesulphonyl chloride (7.35 ml) and triethylamine (3 ml) for 96 hours. The chloroform layer was extracted with dilute sodium hydroxide solution (2×50 ml). The chloroform layer was discarded and the combined aqueous extracts were adjusted to pH=5 and extracted with chloroform (3×50 ml). The combined extracts were dried over magnesium sulphate, the solvent was removed and the residue was chromatographed on silica gel eluted with 2% v/v methanol in chloroform to give the title compound (3.28 g) as white prisms. m.p. 119°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCCCO)ccc21
Yield: 44.1 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (4-hydroxy-butyl)-amide (37 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (70 mg), 4-amino-butan-1-ol (20 mg), HBTU (80 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 429.6.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[CH2:31][CH2:30]3)=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:30][CH2:31][N:32]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[CH2:33][CH2:34]3)=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CCN(c2ccncc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
TFA (0.5 mL, 6.90 mmol) was added to a solution of N-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1-(pyridin-4-yl)piperidine-4-carboxamide (12 mg, 0.023 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (7 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 8.50 (s, 1H), 8.10 (m, 2H), 7.73 (d, 1H, J=8.8 Hz), 7.65 (m, 2H), 7.57 (d, 1H, J=9.2 Hz), 7.27 (m, 2H), 6.94 (m, 2H), 4.17 (m, 2H), 3.11 (m, 2H), 2.77 (m, 1H), 2.03 (m, 2H), 1.89 (m, 2H); ESI-MS [M+2H/2]+: 219.61.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][N:24]=[C:23]2[O:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][N:24]=[C:23]2[O:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[O:4])[CH2:34][CH2:33]1
Reactant: O=C(CBr)Nc1ccccn1
Reactant: COc1ccc2ncnc(OCC3CCC(N)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2ncnc(OCC3CCC(NCC(=O)Nc4ccccn4)CC3)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Bromo-N-pyridin-2-yl-acetamide (0.075 g, 0.35 mmol) and potassium carbonate (0.054 g, 0.39 mmol) were added to a solution of 4-(6-methoxy-quinazolin-4-yloxymethyl)-cyclohexylamine (0.1 g, 0.35 mmol) in DMF (3.5 ml). The reaction mixture was stirred at room temperature for 2 days and then concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane/MeOH 19/1 1% NH4OH).
Reaction SMILES: [N:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:11]([CH3:15])[C:12](=O)[CH3:13].C(=O)([O-])O.[Na+]>CC(O)C>[CH3:15][C:11]1[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[S:9][C:12]=1[CH3:13]
Reactant: CC(=O)C(C)Cl
Reactant: NC(=S)N1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nc(N2CCCCC2)sc1C
Yield: 99.2 %

Procedure:
A mixture of piperidine-1-carbothioamide (3.00 g), 3-chloro-2-butanone (4.43 g) and 2-propanol (30 mL) was heated under reflux for 15 hrs. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-(4,5-dimethyl-1,3-thiazol-2-yl)piperidine as a colorless oil (4.05 g, yield 99%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([O:36][CH3:37])=[CH:31][CH:30]=2>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:28]3[C:29]4[C:34](=[CH:33][C:32]([O:36][CH3:37])=[CH:31][CH:30]=4)[CH:35]=[C:27]3[CH3:26])=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Reactant: COc1ccc2[nH]c(C)cc2c1
Product: COc1ccc2c(c1)cc(C)n2Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1
Yield: 72 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro) benzenesulfonamide (Intermediate 8), and 2-methyl-5-methoxyindole, the title compound was isolated as a yellow solid in 72% yield (98% purity by HPLC).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH2:13][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:5]([CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc(CC(C)C)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(CC(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
1-(2,4-Dihydroxy-5-isobutyl-phenyl)-ethanone (1 eq) was dissolved in DMF and potassium carbonate (4.4 eq) then benzyl bromide (4.4 eq) was added. The suspension was heated, with stirring to 150° C., under nitrogen, for 16 hrs. The solution was cooled to room temperature, filtered and concentrated to dryness. This solid was purified column chromatography (silica, hexanes:ethyl acetate 4:1) then re-crystallised from ethyl acetate:hexanes to give 1-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-ethanone as colourless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(F)cc3)CC2)cc1

Procedure:
1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4-fluoro-benzyl)4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (17.4 g, 40 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 10.8 g (66%); colorless solid; mp 154° C.; MS: 408 (M+H)+.