Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([S:22][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[CH:13]=[N:14][NH:15][C:3]=23)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Cl
Product: CCOC(=O)c1cnc2cn[nH]c2c1Sc1ccccc1

Procedure:
The above compound was prepared from ethyl 7-chloro-1H-pyrazolo[4,3-b]pyridine-6-carboxylate and thiophenol in an analogous manner to the preparation of Example 1 giving a white solid, m.p. 130°-131° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([C@@H:18]1[CH2:20][O:19]1)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1([CH3:40])[N:27]([C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[C@H:26]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[CH2:39][C@H:25]2[O:24]1.[Li]CCCC>C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[C@@H:18]([OH:19])[CH2:20][C@H:29]([C:28]([N:27]1[C@H:26]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[CH2:39][C@H:25]2[O:24][C:23]1([CH3:22])[CH3:40])=[O:32])[CH2:30][CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@H](C[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)C(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Temperature: -78 °C

Procedure:
(1S, 2S)-[2-(3,5-Difluorophenyl)-1-oxiranylethyl]-carbamic acid tert-butyl ester (VI, 113 mg) and 1-((3aS, 8aR)-2,2-Dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-3-yl)-butan-1-one (VII, 94 mg) were combined in dry THF (3 mL), and cooled to −78° C. To this solution was added BuLi (2.5 M in hexanes, 0.32 mL) over 5 min., whereupon the solution was allowed to warm to 0° C. for 1.5 h. The reaction mixture was partitioned between 0.5 N HCl (4 mL) and 1:1 EtOAc/hexanes (2×4 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (20-30% EtOAc/hexanes) to give an oil: MH+559.1.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][N:2]2[C:9](=[O:27])[C:10]([C:13]1[N:18]=[CH:17][C:16]([NH:19]C(=O)C(C)(C)C)=[C:15]([I:26])[CH:14]=1)([CH3:12])[CH3:11].[OH-].[Na+]>OS(O)(=O)=O>[NH2:19][C:16]1[C:15]([I:26])=[CH:14][C:13]([C:10]([CH3:11])([CH3:12])[C:9]([N:2]2[CH2:3][CH:4]3[CH2:7][CH2:8][CH:1]2[CH2:6][CH2:5]3)=[O:27])=[N:18][CH:17]=1
Reactant: CC(C)(C)C(=O)Nc1cnc(C(C)(C)C(=O)N2CC3CCC2CC3)cc1I
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C(=O)N1CC2CCC1CC2)c1cc(I)c(N)cn1
Temperature: 100 °C
Yield: 78.5 %

Procedure:
A vigorously stirred mixture of N-{6-[2-(2-azabicyclo[2.2.2] oct-2-yl)-1,1-dimethyl-2-oxoethyl]-4-iodopyridin-3-yl}-2,2-dimethyl-propionamide (4.66 g, 9.64 mmol.) in 24% H2SO4 (48 mL) was heated at 100° C. for approximately 3.5h. After cooling to room temperature, the reaction mixture was basified to pH=10 with 2.5N NaOH and then extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by recrystallization from dichloromethane/diethyl ether to give the title compound as prisms (3.02 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)C2)c([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 43.5 %

Procedure:
The trans-(3-amino-cyclopentyl)-carbamic acid tert-butyl ester (420 mg, 2.09 mmol) was mixed with 4-fluoro-3-nitrotoluene (342 mg, 2.2 mmol) and potassium carbonate (915 mg, 6.6 mmol) in DMF (20 mL). The stirring mixture was heated at 85° C. for 16.5 hours. The reaction mixture was evaporated under reduced pressure. The residue was partitioned with 50 mL of dichloromethane and 50 mL of brine. The aqueous phase was extracted again with 50 mL of dichloromethane and each organic extract was washed with a portion of brine. After drying, filtering and evaporation of solvents, the crude mixture was purified on silica gel eluting with ethyl acetate and hexanes to give trans-[3-(4-methyl-2-nitro-phenylamino)-cyclopentyl]-carbamic acid tert-butyl ester as a orange oil (305 mg). 1H-NMR is consistent with the assigned structure. LC-MS showed a single peak, C17H25N3O4 (m/e) calcd 335.1845, obsd 336.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]([NH2:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[NH2:23][C:24]1[S:28][N:27]=[C:26]([CH3:29])[CH:25]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@H:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]([NH2:14])=[O:13])=[CH:3][C:2]=1[NH:23][C:24]1[S:28][N:27]=[C:26]([CH3:29])[CH:25]=1)#[N:9]
Reactant: Cc1cc(N)sn1
Reactant: N#Cc1ccc(N[C@H](CC2CCCCC2)C(N)=O)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N[C@H](CC3CCCCC3)C(N)=O)ccc2C#N)sn1
Reaction time: 18 h
Yield: 99.1 %

Procedure:
A mixture of (R)-2-(3-bromo-4-cyanophenylamino)-3-cyclohexylpropanamide (222 mg, 0.634 mmol), 5-amino-3-methylisothiazole hydrochloride (126 mg, 0.840 mmol), BINAP (60 mg, 0.096 mmol), Pd(OAc)2 (45 mg, 0.200 mmol) and K2CO3 (360 mg, 2.60 mmol) in dioxane (4 mL) was degassed with Ar, then was stirred at 120 C for 18 h. Water and EtOAc were added. After being filtered, the organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-cyclohexylpropanamide as a solid (241 mg).
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:8][C:9]([CH:11]([C:14]2[C:23]([F:24])=[C:22]([F:25])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:26])[C:15]=2[F:27])[CH2:12]O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.Cl>C(Cl)Cl.O>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]([C:11]([C:14]2[C:15]([F:27])=[C:16]([F:26])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:22]([F:25])[C:23]=2[F:24])=[CH2:12])=[O:10])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1c(F)c(F)c(C(CO)C(=O)OC(c2ccccc2)c2ccccc2)c(F)c1F
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)c(F)c(C(=O)OC)c(F)c1F
Reaction time: 1 h
Yield: 98.1 %

Procedure:
In 175 ml of methylene chloride was dissolved 35.0 g of methyl 4-(1-diphenylmethoxycarbonyl-2-hydroxyethyl)-2,3,5,6-tetrafluorobenzoate. To the solution was added 7.9 g of methanesulfonyl chloride with ice-cooling. Into the mixture was dropped 16.8 g of triethylamine in 10 minutes. The resulting mixture was stirred at the same temperature for 1 hour, and 200 ml of water was added to the reaction mixture. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 33.0 g (yield: 97.9%) of methyl 4-(1-diphenylmethoxycarbonylvinyl)-2,3,5,6-tetrafluorobenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[NH2:18][OH:19].[OH-].[K+]>C(O)C>[CH3:1][O:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[N:18][OH:19])[CH2:5][CH2:4]1
Reactant: COC1(c2ccc(C)cc2)CCC(=O)CC1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC1(c2ccc(C)cc2)CCC(=NO)CC1

Procedure:
A mixture of 3.73 g. (0.17 mole) of 4-methoxy-4-(p-methylphenyl)cyclohexanone (prepared as in Example 28), 3.75 g. of hydroxylamine hydrochloride and 7.5 ml. of aqueous 50% potassium hydroxide solution in 70 ml. of ethanol is heated at reflux for about 4 hours. The solvent is removed under vacuum and the residue dissolved in water and ether. The organic layer is washed with water and brine and evaporated to dryness to give 4.04 g. (99%) of product. A sample recrystallized from aqueous methanol gives pure 4-methoxy-4-(p-methylphenyl)cyclohexanone oxime, having a melting point of 114° to 115.5° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].Cl[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1.O>CN(C=O)C>[OH:6][CH2:5][CH2:4][CH2:3][O:7][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCO)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
Sodium hydride (0.42 g, 60% suspension in mineral oil, 10.61 mmol) was added to a solution of 1,3-propanediol (2.30 mL, 31.83 mmol) in DMF (22 mL) at 0° C., and the mixture was stirred at rt for 20 minutes. To the resultant pale yellow slurry was added 6-chloronicotinonitrile (1.50 g, 10.61 mmol) in one portion. The mixture was stirred at rt for 18 h. It was then poured into water. The precipitates were filtered and the filtrate was extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.56 g, 83%) as a white solid. 1H NMR (300 MHz, CD2Cl2) δ 8.47 (d, 1H), 7.82-7.79 (m, 1H), 6.84-6.82 (m, 1H), 4.53 (t, 2H), 3.75 (t, 2H), 2.06-1.99 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:16][CH3:17])[C:5](=O)[C:4]=2[CH:3]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:16][CH3:17])[CH2:5][C:4]=2[CH:3]=1
Reactant: COc1cccc2c(=O)c3cc(Cl)ccc3sc12
Agent: CC(C)[O-]
Agent: Cl
Agent: [Al+3]
Product: COc1cccc2c1Sc1ccc(Cl)cc1C2
Temperature: 190 °C
Reaction time: 2 h

Procedure:
An intimate mixture of 2-chloro-5-methoxythioxanth-9-one (8 g.) and aluminium isopropoxide (32 g.) is heated and stirred in an atmosphere of nitrogen for 31/2 hours at 190° C. The mixture is cooled, 2N-hydrochloric acid (210 ml.) is added and the mixture extracted three times with ether. The combined ether extracts are washed with brine, dried over MgSO4 and the solvent evaporated in vacuo to give 2-chloro-5-methoxythioxanthene, m.p. 95°-96° C. on recrystallisation from methanol.
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:18])([F:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1.[CH2:19]([S:21]SCC)[CH3:20].Cl>C1COCC1>[CH2:19]([S:21][C:15]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=[C:8]([C:7]([F:6])([F:17])[F:18])[CH:16]=1)[CH3:20]
Reactant: CCSSCC
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCSc1cc(C(F)(F)F)ncc1C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
7.1 ml of n-butyl lithium (1.6 M hexane solution) was added dropwise to a mixture of 1.62 g of 2,2,6,6-tetrahydropiperidine and 15 ml of THF at −78° C., and the mixture was heated to 0° C., then stirred at 0° C. for 10 minutes. 7 ml of a THF solution of 1.0 g of 6-trifluoromethylnicotinic acid was added to the reaction mixture at −78° C., and the mixture was stirred at −78° C. for 1 hour. Next, 1.42 ml of diethyl disulfide was added to the reaction mixture at −78° C., and heated to room temperature, then stirred at room temperature for 30 minutes. 10 ml of 1 N hydrochloric acid was poured to the reaction mixture, and the reaction mixture was separated into the organic layer and the aqueous layer. 1 N hydrochloric acid was added to the aqueous layer, and the precipitated solid was filtered. The resulting solid was washed with 1 N hydrochloric acid and n-hexane to obtain 0.52 g of 4-ethylsulfanyl-6-trifluoromethylnicotinic acid. The separated organic layer was allowed to stand overnight, and the precipitated solid was filtered, then washed with n-hexane to further obtain 0.68 g of 4-ethylsulfanyl-6-trifluoromethylnicotinic acid. 4-Ethylsulfanyl-6-trifluoromethylnicotinic acid
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.CN(C)C=O.FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>C(Cl)Cl.O>[N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH2:41][C:42]([F:45])([F:44])[F:43])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: N[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](NCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of trans-N-(6-nitrothieno[3,2-b]pyridin-7-yl)cyclohexane-1,4-diamine (120 mg, 0.41 mmol) and N,N-diisopropylethylamine (0.36 mL, 2.0 mmol) in methylene chloride (2 mL)/N,N-dimethylformamide (2 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.18 mL, 1.2 mmol). The reaction was stirred at room temperature for 4 h. The resulting mixture was diluted with water, extracted with dichloromethane. The organic layers were concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (34 mg, 22%). LCMS calculated for C15H18F3N4O2S (M+H)+: m/z=375.1. Found: 375.0.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][NH2:8].C(N(CC)CC)C.S=[C:17]1[CH2:21][S:20][C:19](=[O:22])[NH:18]1>C(O)C>[O:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][NH:8][C:17]1[CH2:21][S:20][C:19](=[O:22])[N:18]=1
Reactant: O=C1NC(=S)CS1
Reactant: NCc1ncco1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1N=C(NCc2ncco2)CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of 1-(1,3-oxazol-2-yl)methanamine hydrochloride (500 mg) in ethanol (10 mL) were added triethylamine (0.99 mL) and 4-thioxothiazolidin-2-one (495 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (357 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.[CH3:11][C:12]1([CH2:33]C(=C2C(=O)OC(C)(C)OC2=O)O)[CH2:17][CH2:16][C:15]2[C:18]([CH3:32])=[C:19]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]([CH3:23])=[C:21]([CH3:22])[C:14]=2[O:13]1>C1(C)C=CC=CC=1>[CH3:10][CH:2]([O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[CH2:33][C:12]1([CH3:11])[CH2:17][CH2:16][C:15]2[C:18]([CH3:32])=[C:19]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]([CH3:23])=[C:21]([CH3:22])[C:14]=2[O:13]1)/[CH:1]=[CH:20]/[CH2:19][C@H:18]([CH3:32])[CH2:15][CH2:16][CH2:17][CH:12]([CH3:33])[CH3:11]
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC(O)=C1C(=O)OC(C)(C)OC1=O)O2
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: Cc1ccccc1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC(=O)CC(=O)OC(C)/C=C/C[C@H](C)CCCC(C)C)O2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.40 g (5.0 mmol) of Meldrum's acid adduct i.e. rac.-5-[2-[3,4-dihydro-2,5,7,8-tetramethyl-6-phenylmethoxy-2H-1-benzopyran-2-yl]-1-hydroxyethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione and 1.19 g (6.0 mmol) of alcohol (2RS,3E,6R)-6,10-dimethyl-3-undecen-2-ol in 4 ml of dry toluene was degassed by 3 cycles of evacuating/purging with argon and then heated under argon to 100° C. CO2 evolution started at ca 90° C. and ceased after ca. 30 minutes. The light yellow solution was stirred for another 2 hours at 100° C. The cooled solution was diluted with hexane, washed with water, sat. NaHCO3 solution and brine, dried over Na2SO4, filtered and evaporated to leave 3.6 g of a brown oil. Chromatography on 250 g of silica gel (hexane/ethyl acetate 5% --6%) afforded 2.33 g (81%) of [2R,S)-3-oxo-4-[3,4-dihydro-2,5,7,8-tetramethylβ-oxo-6-(ohenylmethoxy)-2H-1-benzopyran-2-yl-butanoic acid-1,5,9-trimethyl-2-decenyl ester as a colorless very viscous oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([C:22]([NH2:24])=[O:23])[CH:21]=2)[NH:18][CH:17]=[C:16]3[CH:25]2[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH2:27][CH2:26]2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].Br[C:37]1[CH:42]=[CH:41]C(CCNC(=O)C)=[CH:39][CH:38]=1>>[CH:2]1([C:1]([NH:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]4[C:19](=[C:20]([C:22]([NH2:24])=[O:23])[CH:21]=3)[NH:18][CH:17]=[C:16]4[CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:32])=[O:33])[CH2:27][CH2:26]3)=[CH:9][CH:8]=2)=[O:3])[CH2:41][CH2:42][CH2:37][CH2:38][CH2:39]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CCNC(C)=O)cc4)cc23)CC1
Reactant: CC(=O)NCCc1ccc(Br)cc1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CCNC(=O)C5CCCCC5)cc4)cc23)CC1
Yield: 52.5 %

Procedure:
The title compound was prepared according to the general procedure of 5-{4-[2-(acetylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, substituting N-[2-(4-bromophenyl)ethyl]cyclohexanecarboxamide (100 mg, 0.324 mmol) for N-[2-(4-bromophenyl)ethyl]acetamide. Purified by flash chromatography to afford 32 mg of the title compound (52.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[N:11]2)=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][NH2:32])[CH:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][NH:32][C:21]([C:17]2[S:16][C:15]([C:12]3[CH:13]=[CH:14][N:10]([CH2:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])[CH:25]=1
Reactant: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)O
Reactant: NCCc1cccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)NCCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
To a solution of 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (0.1 g, 0.30 mmol) in methylene chloride (5 mL) was added 2-pyridin-3-yl-ethylamine (0.04 g, 0.33 mmol), benzotriazol-1-yloxytris(dimethylamino)-hexafluorophosphate (0.146 g, 0.33 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.60 mmol) and the mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (50 mL), washed with water (50 mL) and brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel eluting with 50% ethyl acetate, 50% hexane to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (2-pyridin-3-yl-ethyl)-amide as a white solid (0.095 g, 73%). 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=2 Hz, 2H), 7.58 (d, J=4 Hz, 1H), 7.25-7.28 (m, 1H), 7.14 (d, J=2 Hz, 1H), 6.90-7.03 (m, 4H), 6.70 (d, J=2 Hz, 1H), 5.96-6.03 (m, 1H), 4.34 (t, J=7 Hz, 2H), 3.65-3.73 (m, 2H), 3.17 (t, J=7 Hz, 2H), 2.95 (t, J=7 Hz, 2H), 2.68 (s, 3H). MS (M+H)+=436.2; Rt=1.28 min; HRMS (M+H)+=436.16.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([CH2:14][CH3:15])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:22][C:19]2[CH:20]=[CH:21][C:16]([C:11]([CH2:14][CH3:15])([CH3:12])[CH3:13])=[CH:17][CH:18]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCC(C)(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 96.9 %

Procedure:
Following procedure A, 2-chloro-5-nitropyridine (303 mg, 1.91 mmol, 1.00 eq) and 4-tert-pentylphenol (397 mg, 2.42 mmol, 1.27 eq) were dissolved in DMSO (6 mL). Anhydrous K2CO3 (403 mg, 2.92 mmol, 1.53 eq) was added and the reaction mixture was stirred at room temperature for 7 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100) to afford the title compound as colourless solid (530 mg, 1.85 mmol, 97% yield). Rf=0.31 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C16H19N2O3+ [M+H]+ 287.1390. found: 287.1381. 1H NMR (400 MHz, CDCl3) δ 9.07-9.05 (m, 1H, aromatic H), 8.45 (dd, J=9.4, 2.4 Hz, 1H, aromatic H), 7.40 (d, J=8.6 Hz, 2H, aromatic H), 7.09 (d, J=8.6 Hz, 2H, aromatic H), 6.99 (d, J=9.2 Hz, 1H, aromatic H), 1.67 (q, J=7.4 Hz, 2H, Ar—C(CH3)2CH2CH3), 1.31 (s, 6H, Ar—C(CH3)2CH2CH3), 0.73 (t, J=7.4 Hz, 3H, Ar—C(CH3)2CH2CH3). 13C NMR (101 MHz, CDCl3) δ 167.17, 150.46, 147.34, 145.20, 140.27, 134.90, 127.56, 120.72, 111.28, 37.89, 37.06, 28.55, 9.26.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4]=[C:5]([O:21][C:22](=[O:36])[N:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:6]2[N:7]=[CH:8][N:9]([C:19]=2[N:20]=1)[C@@H:10]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:11]1[OH:12].[CH3:37][O:38][C:39]1[CH:60]=[CH:59][C:42]([C:43](Cl)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)=[CH:41][CH:40]=1.C1(C)C=CC=CC=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([C:43]([O:17][CH2:16][C@H:15]2[O:18][C@@H:10]([N:9]3[C:19]4[N:20]=[C:3]([NH:2][CH3:1])[N:4]=[C:5]([O:21][C:22](=[O:36])[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:6]=4[N:7]=[CH:8]3)[C@H:11]([OH:12])[C@@H:13]2[OH:14])([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:42]2[CH:59]=[CH:60][C:39]([O:38][CH3:37])=[CH:40][CH:41]=2)=[CH:49][CH:48]=1
Reactant: CNc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CNc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
Compound 5 (0.51 g, 1.05 mmol, 1.0 eq) and 4,4′-dimethoxytritylchloride (0.39 g, 1.14 mmol, 1.09 eq) were azeotroped three times with toluene for ˜15 h. To the dried compound 5, anhydrous pyridine (5 mL) was added. The mixture was stirred at room temperature under Ar atmosphere for 4 h. 4-Dimethylaminopyridine (0.09 g, 0.7 mmol, 0.7 eq) was subsequently added and stirring was continued for 17 h. The reaction was quenched with methanol (1 mL) and evaporated to dryness. The crude residue was dissolved in 50 mL of dichloromethane and washed with 5% sodium bicarbonate followed by saturated sodium chloride. The organic layer was dried over sodium sulfate and filtered. The product was then purified via silica gel chromatography using a solvent mixture of 90% dichloromethane, 9% methanol, 1% triethylamine to give 11 as a light yellow crystalline solid (0.56 g, 67%). TLC (CH2Cl2:MeOH, 9:1 v/v): Rf=0.4; 1H NMR (CD3OD, 400 MHz) 2.71 (br.s, 1H), 2.98-3.03 (q, 1H), 3.21 (d, J=3.2 Hz, 3H), 3.25-3.27 (m, 1H), 3.29-3.32 (m, 1H), 3.60 (d, J=4.8 Hz, 6H), 3.66 (m, 1H), 4.07-4.10 (m, 1H), 4.45 (m, 1H), 4.83 (m, 1H), 5.87 (d, J=4.8 Hz, 1H), 6.64-6.69 (m, 5H), 7.05-7.38 (m, 18H), 8.0 (s, 1H); 13C NMR ((CD3)2SO, 500 MHz) 28.8, 55.6, 72.2, 74.9, 82.3, 85.3, 87.7, 113.8, 114.0, 126.3, 127.8, 128.5, 128.7, 129.1, 129.2, 129.3, 129.9, 130.2, 130.4, 131.2, 141.2, 149.2, 159.9; ESI-MS (ES+) calculated for C45H42N6O8 794.3064, found 795.7 (M+H+), 303.4 ([(MeO)2Tr]+).