Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9](=O)[CH3:10])[C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3].C([O-])(=O)C.[Na+].Cl.[CH3:18][NH:19][OH:20]>O1CCOCC1.O>[C:5]([N:4]1[CH2:1][C:2]2([CH3:3])[CH:9]([CH2:10][O:20][N:19]2[CH3:18])[CH2:8]1)(=[O:7])[CH3:6]
Reactant: CNO
Reactant: C=CCN(CC(C)=O)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CC2CON(C)C2(C)C1

Procedure:
15.5 g (0.1 mol) of N-allyl-N-(2-oxopropyl)-acetamide are dissolved in 100 ml of dioxane, and 9 g of anhydrous sodium acetate and 9 g (0.108 mol) of N-methylhydroxylamine hydrochloride in 10 ml of water are added. The mixture is heated under reflux overnight and cooled and the salts are filtered off with suction and washed with dioxane. The filtrate is concentrated, the residue is taken up in 100 ml of water and K2CO3 is added. The mixture is extracted with CHCl3, the extract is dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])[CH:19]([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6]1)=[O:26])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3ccccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1(b) from 2-piperazin-1-yl-quinoline hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(N(CC)CC)C>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1)([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 67.5 °C
Reaction time: 20 h

Procedure:
A stirred mixture of 3.05 g (14.31 mmol) of 4-tert-butyl-bromobenzene (Compound 20), 1.41 g (14.39 mmol) of trimethylsilylacetylene (Compound 16), 139 mg (0.13 mmol) of cuprous iodide, 293 mg (0.42 mmol) of bis(triphenyophosphine)palladium (II) chloride and 3 ml of triethylamine was flushed with nitrogen and then heated under nitrogen at 65-70 degrees C. for 20 hours. The reaction mixture was stirred at room temperature for a further 4 hours and the triethylamine then removed under vacuum. The residue was purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDCl3): & 0.26 (9H, s), 1.31 (9H, s), 7.32 (2H, d, J-8.2 Hz), 7.42 (2H, d, J-8.2 Hz).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:19])[CH2:13][O:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH3:10].[C:20]1([S:26]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([CH:38]=[O:39])=[CH:35][CH:36]=3)[CH:31]=[CH:30]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:9]([O:11][C:12](=[O:19])[CH:13]([O:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH:38]([C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([S:26]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:28])=[O:27])[CH:30]=[CH:31]2)[OH:39])[CH3:10]
Reactant: C=CCCOCC(=O)OCC
Reactant: O=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCOC(C(=O)OCC)C(O)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 17.7 ml lithium diisopropylamide (2 molar in tetrahydrofuran) in 40 ml tetrahydrofuran was added a solution of 5.61 g but-3-enyloxy-acetic acid ethyl ester [Tetrahedron (1982), 38(17), 2733-9] in 30 ml tetrahydrofuran at −78° C. After stirring for 30 min., a solution of 4.05 g 1-benzenesulfonyl-1H-indole-5-carbaldehyde in 30 ml tetrahydrofuran was added and stirring at −78° C. continued for additional 30 min. Then, the reaction mixture was quenched with 50 ml of saturated of ammonium chloride solution in water and warmed to ambient temperature. It was then extracted with ethyl acetate and the combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give a crude product which was purified by chromatography (silicagel, eluent: gradient of n-heptane/ethyl acetate) to give 4.37 g of 3-(1-benzenesulfonyl-1H-indol-5-yl)-2-but-3-enyloxy-3-hydroxy-propionic acid ethyl ester (mixture of diasteromers) as colorless oil.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.[CH:27]([N-]C(C)C)(C)C.[Li+].CI.NCCC(CN)O.S(=O)(=O)(O)O>C1COCC1>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:11](=[O:19])[C:10]([CH3:27])([CH3:20])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Reactant: CC(C)[N-]C(C)C
Agent: NCCC(O)CN
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1C(=O)C(C)(C)C[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
10 g (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one (2-a, R1=Piv) is added to THF (100 ml). The mixture is cooled to −30° C. Lithium diisopropylamide (17.16 ml, 2 M) is added and the mixture is stirred for 1 h. Methyl iodide (5.4 ml) is added and the mixture is stirred for 3 h. Aminoethylethanolamine (6.1 ml) is added and the mixture is warmed to 40° C. and stirred for 15 min. Sulphuric acid (12 g) is then added. The mixture is concentrated in vacuo and the residue taken up in toluene. The phases are separated. The organic phase is concentrated in vacuo and taken up in methanol (300 ml) at reflux. On cooling, the precipitate is colledted by filtration to give (R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3,3-dimethyl-pyrrolidin-2-one. 1H NMR (DMSO): 1.04 (3H), 1.15 (3H), 1.28 (9H), 1.72 (1H), 1.38 (1H), 2.59 (1H), 3.14 (1H), 4.37 (1H), 7.31 (3H), 7.45 (2H), 7.62 (4H).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1([C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[CH:35][N:36]=2)[CH:33]=1)[C:15]([S:18]CC1C=CC(OC)=CC=1)=[N:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1([C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[CH:35][N:36]=2)[CH:33]=1)[C:15](=[S:18])[NH:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C(SCc1ccc(OC)cc1)C1(c2ccc3nccn3c2)CCCCC1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=S)C1(c2ccc3nccn3c2)CCCCC1OCc1ccccc1
Reaction time: 1 h
Yield: 79 %

Procedure:
500 mg of the 2-benzyloxy-1-(imidazo[1,2-a]-pyridin-6-yl)-1-((4-methoxybenzylthio)(methylimino)methyl)cyclohexane prepared in the Preparative Example 4 was dissolved in 5 ml of dichloromethane, followed by the addition of 1 ml of anisole. The obtained mixture was cooled with ice, followed by the gradual addition of 5 ml of trifluoroacetic acid. The obtained mixture was stirred for one hour, followed by the addition of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (50:1)]. The obtained oil was crystallized from ether and the obtained crystal was recovered by filtration. Thus, 300 mg of the title compound was obtained as a white powder (yield 79%).
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>C(O)C>[ClH:1].[CH2:24]1[O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][C@H:10]3[C@H:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:4][CH:5]=4)[CH2:14][CH2:13][N:12]([CH2:5][CH2:4][CH2:3][CH2:8][CH3:7])[CH2:11]3)=[CH:18][C:19]=2[O:25]1
Reactant: Oc1ccc(C2CCNCC2COc2ccc3c(c2)OCO3)cc1
Reactant: CCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCOc1ccc([C@@H]2CCN(CCCCC)C[C@H]2COc2ccc3c(c2)OCO3)cc1

Procedure:
(+-)-trans-3-(3,4-methylenedioxyphenoxymethyl)-1-pentyl-4-(4-pentyloxyphenyl)piperidine hydrochloride was prepared by refluxing 4-(4-hydroxyphenyl)-3-(3,4-methylenedioxyphenoxymethyl)piperidine hydrochloride (0.35 g) with 1-bromopentane (1.8 ml) and K2CO3 (1 g) in abs. ethanol (25 ml) for 2 h. The rinse-up procedure described in example 1 gave the title compound. M.p. 148.2° C.
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[CH:20][C:19]=2[Cl:28])[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:28][C:19]1[CH:20]=[C:21]([O:24][CH:25]([F:27])[F:26])[CH:22]=[CH:23][C:18]=1[C:13]1[CH:14]([N+:15]([O-:17])=[O:16])[C:9](=[O:8])[N:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1c(-c2ccc(OC(F)F)cc2Cl)ccnc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1N=CC=C(c2ccc(OC(F)F)cc2Cl)C1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.6 %

Procedure:
2-Benzyloxy-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridine(6.90 g, 17.0 mmol) was dissolved in TFA (25 mL) and stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo. Purification using flash chromatography (15% MeOH/DCM) gave 1.00 g (19%) of 4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-3H-pyridin-2-one as an orange solid: MS(AP) m/z 316.9 [(M+H)+, 98], 359.8 [(M+H+CH3CN)+, 100].
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[OH:11].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][C:16]=1[Cl:22]>>[ClH:14].[NH2:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([Cl:22])[CH:17]=1
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: N[C@H]1Cc2ccccc2[C@H]1O
Agent: [H-]
Agent: [Na+]
Product: Cl
Product: N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared in a similar manner to Example 26 from (±) cis 2-amino-1-indanol (2.24 g, 15.0 mmol), sodium hydride (0.54 g of an 80% dispersion in oil; 18.0 mmol) and 1,2-dichloro-4-fluorobenzene (2.97 g, 18.0 mmol). The crude product was purified by chromatography on silica eluting with 0-4% ethanol in diethyl ether. The resulting light brown oil (3.89 g) was extracted into a mixture of hexane and diethyl ether and treated with ethereal HCl to give the hydrochloride salt. Recrystallisation afforded the title compound as a colourless solid, m.p. 214°-215° C. (dec) (from methanol/ethyl acetate/diethyl ether).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>N1C=CC=CC=1>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:18])=[CH:3][C:2]=1[NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(CC(=O)Nc2cccc(C3CCCCC3)c2)ccc1OCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cc(CC(=O)Nc2cccc(C3CCCCC3)c2)ccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
3-Amino-4-benzyloxy-N-(3-cyclohexylphenyl)phenylacetamide (the compound of Example 33) (200 mg) is dissolved in pyridine (5 ml), and thereto is added dropwise methanesulfonyl chloride (111 mg), and the mixture is stirred for 0.5 hour. Water is added to the mixture, and the mixture is extracted with ethyl acetate. The organic layer is dried under sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give 4-benzyloxy-N-(3-cyclohexylphenyl)-3-methanesulfonylaminophenyl-acetamide (200 mg). This product is dissolved in ethanol (10 ml), and thereto is added 10% palladium on carbon (20 mg). The mixture is subjected to catalytic hydrogenation at 25° C. The catalyst is removed by filtration, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 10% chloroform/methanol) to give the desired compound (120 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13](NC2C=CN(CC(O)=O)N=2)=[O:14])[CH:5]=CC=1S(C)(=O)=O.[C:31]([Cl:36])(=O)[C:32]([Cl:34])=O.C(Cl)[Cl:38]>CN(C)C=O>[CH:26]1([CH2:25][C@H:12]([C:4]2[CH:3]=[CH:2][C:32]([Cl:34])=[C:31]([Cl:36])[CH:5]=2)[C:13]([Cl:38])=[O:14])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: ClCCl
Reactant: O=C(Cl)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Solvent: CN(C)C=O
Product: O=C(Cl)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as in PCT WO 2002/046173 A1, Example 3, 375 mg, 1.31 mmol) was dissolved in methylene chloride (20 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 753 μL, 1.76 mmol) which produced gas evolution and it was then warmed to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to about 5 mL and then another portion of methylene chloride (˜3 mL) was added to produce a roughly 0.16 M solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride which was used.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[NH2:21]>CCOC(C)=O.C1CCCCC1>[CH3:28][O:27][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3)[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:24]=1[O:25][CH3:26]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Clc1cccc(Oc2cncc(Cl)n2)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COc1cc(Nc2cncc(Oc3cccc(Cl)c3)n2)cc(OC)c1OC
Yield: 43 %

Procedure:
Using Method EE with 2-chloro-6-(3-chlorophenyloxy)-pyrazine (200 mg, 0.83 mmol) and 3,4,5-trimethoxyaniline (183 mg, 1.00 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (165 mg). Yield: 43%. 1H NMR (250 MHz, DMSO-d6) δ 3.43 (s, 6H, [CH3O]3+5), 3.54 (s, 3H, [CH3O]4), 6.76 (s, 2H, Harom2′+6′), 7.18 (d, 1H, Harom 4, J=6.5 Hz), 7.28 (d, 1H, Harom 6, J=6.7 Hz), 7.36 (s, 1H, Harom 2), 7.43 (t, 1H, Harom 5, J=8.1 Hz), 7.79 (s, 1H, HPz 5), 7.98 (s, 1H, HPz 3), 9.62 (s, 1H, NH).
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:35][CH3:36])=[C:10]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][S:23]([C:26]2[S:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH:27]=2)(=[O:25])=[O:24])(=[O:14])=[O:13])[CH:11]=1)(=[O:5])=[O:4])=[CH2:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1.C(Cl)Cl>[CH3:36][O:35][C:9]1[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH2:2][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)(=[O:4])=[O:5])=[CH:11][C:10]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[CH:27]=1)(=[O:25])=[O:24])(=[O:13])=[O:14]
Reactant: C=CS(=O)(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)CCN2CCCC2)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid [2-(5-ethenesulfonyl-2-methoxybenzenesulfonylamino)phenyl]-amide (0.2 mmol, prepared as in Example 19) in dry THF (2 mL) was added 0.2 mL of pyrrolidine. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (10 mL) and was washed with saturated sodium chloride aqueous solution (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc then DCM/methanol/AcOH (100:2:1 to 100:10:2) to furnish 121 mg of benzo[b]thiophene-2-sulfonic acid {2-[2-methoxy-5-(2-pyrrolidin-1-yl-ethanesulfonyl)-benzenesulfonylamino]phenyl} amide. LC: Tr 0.94 min; MS: 636.8 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 1.68 (m, 4H), 2.38 (m, 4H), 2.78(t, 2H), 3.28 (t, 2H), 4.20 (s, 3H), 6.76 (d, 1H), 6.96 (d, 1H), 7.14 (t, 1H), 7.21 (d, 1H), 7.36 (d, 1H), 7.41 (t, 1H), 7.49(t, 1H), 7.60 (s, 1H), 7.79 (d, 1H), 7.83 (d, 1H), 8.07 (d, 1H), 8.26 (d, 1H) ppm.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([Cl:31])=[CH:26][N:25]=1>>[CH:1]1([NH:7][C:26]2[C:27]([Cl:31])=[CH:28][N:29]=[C:24]([Cl:23])[N:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc(Cl)c(NC2CCCCC2)n1
Temperature: 100 °C
Yield: 87.3 %

Procedure:
Into a round bottom flask was added cyclohexanamine (1.0 mL, 8.7 mmol) and 1,4-dioxane (30 mL, 380 mmol). N,N-Diisopropylethylamine (1.83 mL, 10.5 mmol) was added followed by 2,4,5-trichloro-pyrimidine (1.20 mL, 10.5 mmol) and the mixture was heated at 100° C. overnight and then concentrated under reduced pressure. The residue was taken up in DCM (100 mL) and washed with water (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-20% EtOAc/hex as the eluting solvent to obtain cyclohexyl-(2,5-dichloro-pyrimidin-4-yl)-amine as a white solid (1.87 g, 87%). m.p.=93-94° C.; LCMS (m/e) 246 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 5.45-5.30 (m, 1H), 4.13-4.00 (m, 1H), 2.10-1.99 (m, 2H), 1.85-1.74 (m, 2H), 1.74-1.63 (m, 1H), 1.55-1.39 (m, 2H), 1.36-1.18 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH:16]([OH:27])[C:17]3[N:21]([CH3:22])[C:20]4[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=4[N:18]=3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[C:3]=1[C:32]#[N:33].CN(C=O)C.[SH:39][CH2:40][C:41]([NH2:43])=[O:42].C[O-].[Na+]>CO>[NH2:33][C:32]1[C:3]2[C:2](=[N:7][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH:16]([OH:27])[C:17]4[N:21]([CH3:22])[C:20]5[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=5[N:18]=4)[CH2:10][CH2:9]3)=[CH:5][C:4]=2[C:28]([F:31])([F:30])[F:29])[S:39][C:40]=1[C:41]([NH2:43])=[O:42]
Reactant: NC(=O)CS
Reactant: Cn1c(C(O)CNC2CCN(c3cc(C(F)(F)F)c(C#N)c(Cl)n3)CC2)nc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(C(O)CNC2CCN(c3cc(C(F)(F)F)c4c(N)c(C(N)=O)sc4n3)CC2)nc2ccccc21
Temperature: 60 °C

Procedure:
6′-Chloro-4-[2-hydroxy-2-(1-methyl-1H-benzoimidazol-2-yl)-ethylamino]-4′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (344.0 mg, 0.718) mmol was dissolved into 2 mL of dry DMF. To this was added a 1.09 M MeOHic solution of mercaptoacetamide (1.00 mL, 1.09 mmol) and a 1 M solution of MeOHic NaOMe (2.87 mL, 2.87 mmol). The reaction mixture was heated at 60° C. for 2 h. LC-MS indicated complete conversion to the mercaptoacetamide adduct. The reaction was then heated at 80° C. overnight. The reaction mixture was concentrated on a rotary evaporator with heating to 70° C. to give a dark orange oil. The oil was dissolved into a minimal amount of MeOH, applied to a SIO2 column and eluted with 0–10% MeOH/CH2Cl2 and 0–10% MeOH/CH2Cl2-1% NH3) to give 213.7 mg, 55.8%, of the title compound. ES+ 534.3 m/z (MH+)
Reaction SMILES: [N:1]([CH:4]([CH3:28])[CH2:5][O:6][CH:7]1[CH2:27][CH2:26][C:10]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]4[CH2:24][CH2:23]4)=[C:16]([Cl:25])[CH:15]=3)[O:13][C:9]=2[CH2:8]1)=[N+]=[N-].C1(P([C:42]2[CH:47]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH2:48]>C1COCC1>[Cl:25][C:16]1[CH:15]=[C:14]([C:12]2[O:13][C:9]3[CH2:8][CH:7]([O:6][CH2:5][CH:4]([NH:1][C:47](=[O:48])[CH3:42])[CH3:28])[CH2:27][CH2:26][C:10]=3[N:11]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][CH:22]1[CH2:24][CH2:23]1
Reactant: CC(COC1CCc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2C1)N=[N+]=[N-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O
Solvent: C1CCOC1
Product: CC(=O)NC(C)COC1CCc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(2-azidopropoxy)-2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydro-1,3-benzoxazole (6.08 g) in THF (30 mL) were added triphenylphosphine (4.75 g) and water (5 mL), and the mixture was stirred overnight at 60° C. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate). To the obtained oil were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound (3.02 g).
Reaction SMILES: FC1C=C(OC)C=C(F)C=1C[NH2:5].C(N(CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[F:41][C:42]1[CH:71]=[C:70]([O:72][CH3:73])[CH:69]=[C:68]([F:74])[C:43]=1[CH2:44][N:45]1[C:50]2[N:51]=[CH:52][CH:53]=[CH:54][C:49]=2[S:48](=[O:56])(=[O:55])[N:47]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])C=2)[C:46]1=[O:67]>CN(C=O)C>[F:74][C:68]1[CH:69]=[C:70]([O:72][CH3:73])[CH:71]=[C:42]([F:41])[C:43]=1[CH2:44][N:45]1[C:50]2[N:51]=[CH:52][CH:53]=[CH:54][C:49]=2[S:48](=[O:55])(=[O:56])[N:47]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[N:5]=2)[C:46]1=[O:67]
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Reactant: COc1cc(F)c(CN)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)n3)S(=O)(=O)c3cccnc32)c(F)c1

Procedure:
The title compound (112 mg, 0.23 mmol) was prepared in two steps from (IntC3) (165 mg, 0.5 mmol), 2,6-difluoro-4-methoxybenzylamine (90 uL, 0.6 mmol) and N,N-diisopropylethylamine (180 uL, 1.0 mmol); followed by 1,1′-carbonyldiimidazole (253 mg, 1.56 mmol), triethylamine (0.11 mL, 0.79 mmol) in DMF (1.5 mL) using the methods of (95).