Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH:16]=[CH2:17])[NH:10][C:9](=[O:18])[CH2:8][CH2:7]2)[CH:2]=[CH2:3].[H-].[Na+].[CH2:21](Br)[CH:22]=[C:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH:16]=[CH2:17])[N:10]([CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C:9](=[O:18])[CH2:8][CH2:7]2)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc2c(cc1CC=C)CCC(=O)N2
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc2c(cc1CC=C)CCC(=O)N2CC=C(C)C
Yield: 64.6 %

Procedure:
81 Grams of 6-allyl-7-allyloxy-3,4-dihydro-2(1H)-quinolinone obtained in Example 15 was dissolved in 500 ml of dimethylformamide, then 13 g of 60% oily sodium hydride and 50 g of prenyl bromide were added thereto and reacted similarly as in Example 17, after the reaction was finished, the reaction mixture was treated similarly, there was obtained yellow oily product. This oily product was subjected to treatment by means of a silica gel flush column chromatography by using a mixed solvent of methylene chloride-methanol (100:1) as the eluent. The secondary eluted portion was collected and concentrated, there was obtained 67 g (64.6%) of 6-allyl-7-allyloxy-3,4-dihydro-1-prenyl-2(1H)-quinolinone as pale yellow oily product. This oily product become a solid matter then it was allowed to stand at below 20° C., the solid matter was washed with ice-cooled petroleum ether to change white solid, dried in a desiccator and pulverized, there was isolated white powdery product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](=O)[CH3:13])=[CH:10][N:11]=2)[CH:2]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](=[N:16][OH:17])[CH3:13])=[CH:10][N:11]=2)[CH:2]=1
Reactant: NO
Reactant: CC(=O)c1cnc(-c2cccnc2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=NO)c1cnc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1-[2-(3-pyridyl)thiazol-5-yl]ethanone (0.8 g, 3.76 mmol) in 50 ml EtOH was treated with hydroxylamine hydrochloride (0.277 g, 3.95 mmol) and potassium carbonate (0.551 g, 3.95 mmol), and stirred at ambient temperature, monitored by LCMS and TLC, which indicated a ca. 1:1 mixture of isomer formation. After 3 hours, the mixture was concentrated in vacuo to approximately 10 ml. Addition of saturated ammonium chloride gave Isomer A of the title product as a beige precipitate which was filtered, and washed successively with water, isopropanol, and tertiary-butyl methyl ether (yield 156 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@@H:24]3[C@H:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH:27]=[CH:26][CH2:25]3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:37](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:37][N:23]([S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:19][CH:18]=1)(=[O:22])=[O:21])[C@@H:24]1[C@H:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH:27]=[CH:26][CH2:25]1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CC=CC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CC=CC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a stirred solution of 325.5 mg (0.64 mmol) of tert-butyl cis-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxylate in 4 mL of N,N-dimethylformamide was added 353.8 mg of potassium carbonate, followed by 184.9 mg (1.28 mmol) of iodomethane. The suspension was stirred at room temperature overnight. After removal of the volatile material, 80 mL of ethyl acetate was added. The organic phase was washed with water and saturated sodium chloride solution, and dried over magnesium sulfate. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane (3:7) to give 292.1 mg of tert-butyl cis-6-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxylate in 87% yield. MS: 523.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:25][S:26]([N:7]1[C:6]2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:28])=[O:27]
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Reactant: CS(=O)(=O)Cl
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(S(C)(=O)=O)c12
Yield: 95 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and methylsulfonyl chloride as starting materials, the title compound was obtained in a yield of 95% as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([Cl:21])[CH:15]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:16]1[CH:15]=[C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:20]=[CH:19][C:17]=1[NH2:18]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Nc1ccc(-c2cccc([N+](=O)[O-])c2)cc1Cl

Procedure:
This compound was prepared by General Method 14 (EXAMPLE 191) from 3-nitrobenzeneboronic acid (0.25 g, 1.5 mmol), 4-bromo-2-chloroaniline (0.21 g, 1.0 mmol), and (PPh3)4Pd (35 mg, 0.030 mmol) to afford a crude material which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.C(O)(=O)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>CC1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:10][C:4]1[N:5]=[C:6]([CH3:9])[C:7]([NH:8][C:17](=[O:18])[CH2:16][Cl:15])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(N)nc(C)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(N)nc(C)c1NC(=O)CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a stirred solution of 3.3 parts of 4,6-dimethyl-2,5-pyridinediamine in 30 parts of acetic acid were added 4.7 parts of 2-chloroacetyl chloride at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with methylbenzene and neutralised with sodium carbonate. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated, yielding 2.6 parts (50.7%) of N-(6-amino-2,4-dimethyl-3-pyridinyl)-2-chloroacetamide as a residue (int. 97).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:27])([CH3:26])[C:8]3[C:13]([O:14][C:15]=2[C:16]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:12]([CH:22]=O)[C:11]([O:24][CH3:25])=[CH:10][CH:9]=3.C([O-])(=O)C.[Na+].Cl.[NH2:34][OH:35]>CO.C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:27])([CH3:26])[C:8]3[C:13]([O:14][C:15]=2[C:16]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:12]([CH:22]=[N:34][OH:35])[C:11]([O:24][CH3:25])=[CH:10][CH:9]=3
Reactant: NO
Reactant: COC(=O)Cc1c(OC)ccc2c1Oc1c(ccc(OC)c1C=O)C2(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cc1c(OC)ccc2c1Oc1c(ccc(OC)c1C=NO)C2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
5 g (13.5 mmol) of methyl 3,6-dimethoxy-9,9-dimethyl-5-formylxanthene-4-acetate were dissolved in a mixture of 75 ml of methanol, 75 ml of THF and 20 ml of water. After the addition of 1.66 g of sodium acetate and 1.4 g of hydroxylamine hydrochloride the mixture was stirred at room temperature overnight and then diluted with 200 ml of water. The precipitated solid was filtered off, washed with water and dried, whereby 4.95 g of methyl 3,6-dimethoxy-9,9-dimethyl-5-[(hydroximino)methyl]xanthene-4-acetate were obtained as a white powder of m.p. 234°-236°; IR 1743, 1629, 1604, 1582, 1498 cm-1.
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[O:3][Si:4]([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])([O:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8].N1C=CC=CC=1.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29].O>C(OCC)C>[CH3:11][Si:10]([CH3:13])([CH3:12])[O:9][Si:4]([CH2:5][CH2:6][CH2:7][NH:8][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])([O:3][Si:2]([CH3:19])([CH3:1])[CH3:20])[O:14][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)O[Si](CCCN)(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: C=C(C)C(=O)Cl
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)C(=O)NCCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
In 200 ml of ethyl ether was dissolved 36.6 g of the 3-[tris(trimethylsiloxy)silyl]propylamine obtained above, and the solution was added with 9.5 g of pyridine. The mixture was cooled in ice bath to 0°-5° C. Separately, 12.6 g of methacryloyl chloride was dissolved in 30 ml of ethyl ether. The methacryloyl chloride solution was placed in a separating funnel and dropped therefrom to the above mixture over about one hour. The mixture was continuously stirred for 16 hours. After the stirring, 200 ml of water was added to the reaction mixture, and the resulting mixture was stirred and the supernatant was separated. The supernatant was combined with the extract from the bottom layer with ethyl ether, and then ethyl ether was removed by heating. The residue was distilled in vacuo to give 36.6 g of a distillate at 165° C./2 mmHg.
Reaction SMILES: [F:1][C:2]([F:29])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].Cl.C(N=C=NCCCN(C)C)C.ON1C(=O)CCC1=O.[CH2:50]([CH2:52][NH2:53])[OH:51]>CN(C=O)C.C(OCC)(=O)C>[F:29][C:2]([F:1])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26]([NH:53][CH2:52][CH2:50][OH:51])=[O:27])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: NCCO
Reactant: O=C(O)c1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCO)c1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
100 mg (0.2 mmol) of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, 73 mg (0.38 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 44 mg (0.38 mmol) of N-hydroxysuccinimide are dissolved in 3 ml of dimethyflormamide and stirred for 2.5 h at RT. The reaction mixture is then added dropwise at 0° over a period of 30 minutes to a solution of 0.75 ml (12.3 mmol) of ethanolamine in 2 ml of DMF. After stirring for 14 h at RT, the reaction mixture is poured into 50 ml of ethyl acetate and extracted with aqueous sodium chloride solution (30 ml) and pH 7 buffer (30 ml), and the organic phase is dried (sodium sulfate) and concentrated. Crystallisation from THF/diethyl ether gives N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-hydroxy-ethyl-aminocarbonyl)-4-pyridyl]-2-pyrimidineamine; m.p. 159°, FAB-MS: 452 (M+ +H).
Reaction SMILES: [CH:1]1([C:7]#[CH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([O:13][C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>CN(C=O)C.O.CCCCCC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:9]([O:13][C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:8]#[C:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:20][CH:19]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reactant: C#CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCc1ccc(C#CC2CCCCC2)cc1
Temperature: 25 °C
Yield: 34.7 %

Procedure:
Add cyclohexylacetylene (1.1 mL, 8.4 mmol) to a slurry of N-(tert-butoxycarbonyl)-4-bromo-benzylamine (2 g, 6.9 mmol), dichlorobis(triphenylphosphine)palladium (147 mg, 0.2 mmol), copper(I) iodide (67 mg, 0.4 mmol) and triethylamine (1.4 mL, 9.7 mmol) in DMF (7 mL). Stir the reaction in a sealed flask at 110° C. for 16 h. Cool to room temperature, dilute with water (10 mL) and hexane/EtOAc (1:1, 100 mL). Filter the bi-phasic mixture through Celite®, collect the organic phase and wash with 5% aqueous NaCl (3×30 mL). Concentrate the organic phase in vacuo and purify by chromatography on silica gel (120 g) eluting with hexane/EtOAc (20:1 to 3:2 gradient) to obtain the desired intermediate (0.75 g, 34%). MS (ES+) m/z: 258 [M-(t-Bu)+H]+.
Reaction SMILES: [CH2:1]([CH:4]1[NH:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([CH:4]1[N:8]([C:18](=[O:21])[CH:19]=[CH2:20])[C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1CCC(C)(C)N1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1CCC(C)(C)N1C(=O)C=C
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 5-allyl-2,2-dimethylpyrrolidine (1.5 g, 10.5 mmol) in 50 ml of anhydrous CH2Cl2, triethylamine (3 ml, 21 mmol) and acryloyl chloride (0.94 ml, 11.6 mmol) were added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature and stirred for overnight. Analysis of the reaction mixture by LCMS indicated the completion of the reaction. Saturated aqueous NaHCO3 was added to the reaction mixture and the layers were separated. Aqueous layer was worked up twice with CH2Cl2 and the combined organic layers were dried over Na2SO4. Removal of the volatiles and purification of the crude by column chromatography gave the product in 80% yield (1.60 g) as colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@@:4]1([CH3:17])[OH:16].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CN(C=O)C>[CH3:25][S:26]([O:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@:4]1([OH:16])[CH3:17])(=[O:28])=[O:27]
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CCC[C@]2(C)[C@@H](COS(C)(=O)=O)[C@](C)(O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
A solution of (1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (12 g, 50 mmol) in anhydrous DMF (100 mL) was cooled with an ice bath under N2. To this mixture, triethylamine (15 mL, 110 mmol) and methanesulfonyl chloride (5.0 mL, 60 mmol) was added. The ice bath was removed and the mixture stirred at room temperature for 3 h. The reaction was diluted with diethyl ether and washed with 1 M HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was concentrated to dryness to yield [(1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-1-yl]-methyl methanesulfonate (12) (15 g, 97% yield) as an orange solid.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([C:29]1[N:33]=[C:32]([C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=2)[O:31][N:30]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[NH:39][CH2:38][C:37]2[CH:36]=[CH:35][C:34]([C:32]3[O:31][N:30]=[C:29]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:33]=3)=[CH:41][CH:40]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C1CCCC1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(CN)cc2)n1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNC(c3ccc(C(F)(F)F)cc3)C3CCCC3)cc2)n1
Yield: 55 %

Procedure:
The same procedure as employed in the preparation of Example 223 (step b) but using cyclopentyl[4-(trifluoromethyl)phenyl]methanone and 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzylamine gave the title compound as a colorless oil (55%). 1H NMR (DMSO-d6, 300 MHz) δ 8.00 (d, 2H), 7.64 (m, 2H), 7.50 (m, 4H), 3.62-3.34 (m, 2H), 2.74 (m, 2H), 2.12-1.85 (m, 2H), 1.70 (m, 2H), 1.60-0.92 (m, 25H), 0.83 (m, 3H). HPLC (Condition A), Rt: 5.42 min (HPLC purity: 98.3%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:22][CH2:23][CH2:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:29]=1)(=[O:21])[CH3:20]>C1COCC1>[C:19]([O:22][CH2:23][CH2:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][CH2:31][OH:32])[CH:29]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OCCc1cc(CCO[Si](C)(C)C(C)(C)C)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)OCCc1cc(CCO)cs1
Reaction time: 1 h

Procedure:
TBAF (1M in THF, 3.65 mL) was added dropwise to a solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)ethyl acetate [Aromatic Intermediate 21, step a] (1.2 g) in dry THF (30 mL). This solution was allowed to stand at 20° C. for 1 hour, then the solvents were evaporated under reduced pressure and the residue was purified by flash silica chromatography, using 40% ethyl acetate in isohexane as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.63 g.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[S:16][C:15]([C:18]([NH:20][C@@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)=[O:19])=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH:29]1([C:33]([Cl:35])=[O:34])[CH2:32][CH2:31][CH2:30]1>>[ClH:35].[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([NH:20][C:18]([C:15]1[S:16][C:17]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:33]([CH:29]5[CH2:32][CH2:31][CH2:30]5)=[O:34])[CH:4]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=1)=[O:19])[CH2:22]2
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(NC(=O)C4CCC4)c3)c2s1

Procedure:
50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 28.6 mg (0.24 mmol) of cyclobutanecarbonyl chloride are reacted together by general method F. 38 mg (61.3% of theory) of the title compound are obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([C:16]([F:19])([F:18])[F:17])[CH2:15][O:14]2)(=O)=O)=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([NH2:36])[C:30]=3[CH:29]=[N:28]2)=[CH:23][CH:22]=1.[Bi](Cl)(Cl)Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-]>ClCCl.C(Cl)(Cl)Cl.O1CCCC1.[Bi](Cl)(Cl)Cl.CN(C=O)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([NH:36][CH2:12][C:13]4([C:16]([F:17])([F:18])[F:19])[CH2:15][O:14]4)[C:30]=3[CH:29]=[N:28]2)=[CH:25][CH:26]=1
Reactant: Nc1cccc2c1cnn2-c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CO2)cc1
Agent: Cl[Bi](Cl)Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-n2ncc3c(NCC4(C(F)(F)F)CO4)cccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
[2-(trifluoromethyl)-2-oxiranyl]methyl 4-methylbenzenesulfonate (6.14 g, 20.75 mmol) and 1-(4-fluorophenyl)-1H-indazol-4-amine (4.73 g, 20.75 mmol) in dry dichloromethane (5 ml) were stirred for 5 min. Bismuth chloride (654 mg, 2.07 mmol) was added and the mixture stirred at room temperature over the weekend. More bismuth chloride (0.33 g, 1.05 mmol) was then added and the mixture stirred overnight. The reaction was finally stirred overnight under nitrogen (to reduce the volume of DMF). There was no further progress on leaving for a further night. The reaction mixture was then diluted with chloroform (200 ml) and tetrahydrofuran (50 ml). N,N-Diisopropylethylamine (0.54 ml, 3.11 mmol) was added followed by polymer supported carbonate resin (Fluka, ca. 3.5 mmoles carbonate/g resin, 11.91 g) and the mixture stirred overnight. More THF (30 ml) was then added followed after 2 hours by some 4 A molecular sieves. After a further 3 hours LCMS indicated the reaction to be complete and the mixture was filtered. The filtrate was washed with water, the aqueous phase was back-extracted with dichloromethane and the combined organic phases were dried and evaporated to give crude product which was purified by silica gel chromatography using the Flashmaster II (2×100 g cartridges) eluting with a 0 to 50% dichloromethane:ethyl acetate gradient to give the title compound (4.31 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-ethoxy-phenyl)-carbamic acid tert-butyl ester (Example J25) (215 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (280 mg, 71%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11](CC2C=CC(OC)=CC=2OC)[CH2:10][C:9]2[N:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[S:25][C:8]=2[C:7]1=[O:36])=[O:5])[CH3:2].S(Cl)(Cl)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:23]=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:30][CH:31]=3)[S:25][C:8]=2[C:7]=1[OH:36])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)c2sc(-c3ccc(C(C)(C)C)cc3)nc2CN1Cc1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ncc2nc(-c3ccc(C(C)(C)C)cc3)sc2c1O
Reaction time: 5 h
Yield: 60.1 %

Procedure:
2-(4-tert-Butyl-phenyl)-5-(2,4-dimethoxy-benzyl)-7-oxo-4,5,6,7-tetrahydro-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (0.5 g, 0.98 mmol) was dissolved in 6.7 mL of anhydrous dichloromethane. To the solution was added 108 μL of thionyl chloride, and the reaction was stirred for 5 h. The solution was filtered on a fine glass frit filter to collect a white solid precipitate. The solid was washed twice with cold dichloromethane and then partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated to produce 0.21 g of a yellow solid. MS: (+) m/z 357.0 (M+1).