Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCCOC1C=CC(C2(C#[N:19])CCCCC2)=CC=1.Cl[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([C:37]#[N:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C.[CH3:48][C:49]1([CH3:54])[CH2:53][CH2:52][CH2:51][NH:50]1>CN1C(=O)CCC1>[NH3:19].[CH3:48][C:49]1([CH3:54])[CH2:53][CH2:52][CH2:51][N:50]1[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([C:37]#[N:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1
Reactant: CC1(C)CCCN1
Reactant: N#CC1(c2ccc(OCCCBr)cc2)CCCCC1
Reactant: N#CC1(c2ccc(OCCCCl)cc2)CCCCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCCN1CCCOc1ccc(C2(C#N)CCCCC2)cc1
Product: N
Temperature: 180 °C
Yield: 17 %

Procedure:
A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (150 mg, 0.54 mmol), N,N-diisopropylethylamine (188 μL, 1.08 mmol) and 2,2-dimethyl-pyrrolidine (131 mg, 1.08 mmol) in NMP (0.5 mL) was heated at 180° C. in the microwave (Smith Personal Synthesiser) for 600 seconds. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (2×15 mL), dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 98:2:0.2 to 95:5:0.5 to give the title compound as a brown oil (31 mg, 17%). 1H NMR (400 MHz, CDCl3) δ7.38 (d, 2H), 6.90 (d, 2H), 4.04 (t, 2H), 2.78 (t, 2H), 2.54 (t, 2H), 2.16-2.12 (m, 2H), 1.94 (pentet, 2H), 1.90-1.64 (m, 11H), 1.20-1.34 (m, 1H), 0.98 (s, 6H); HRMS (ESI+) 341.2588 (M+H)+.
Reaction SMILES: [N:1]1([C:10]2[CH:51]=[CH:50][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]3[S:22][C:21]([C:23]4[CH:32]=[C:31]5[C:26]([CH2:27][CH2:28][CH2:29][N:30]5[C:33](=[O:44])[NH:34][C:35]5[S:36][C:37]6[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=6[N:39]=5)=[CH:25][CH:24]=4)=[N:20][C:19]=3[C:45]([O:47]CC)=[O:46])=[CH:12][CH:11]=2)[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:4]2[CH:3]=[N:2]1.CO.C1COCC1.[Li+].[OH-]>O>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]3[S:22][C:21]([C:23]4[CH:32]=[C:31]5[C:26]([CH2:27][CH2:28][CH2:29][N:30]5[C:33](=[O:44])[NH:34][C:35]5[S:36][C:37]6[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=6[N:39]=5)=[CH:25][CH:24]=4)=[N:20][C:19]=3[C:45]([OH:47])=[O:46])=[CH:50][CH:51]=2)[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:4]2[CH:3]=[N:2]1
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)sc1CCCOc1ccc(-n2ncc3cncnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)sc1CCCOc1ccc(-n2ncc3cncnc32)cc1
Temperature: 60 °C
Yield: 58.9 %

Procedure:
The title compound 5-(3-(4-(1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy)propyl)-2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiazole-4-carboxylic acid (23) was prepared by the following procedure: To ethyl 5-(3-(4-(1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy)propyl)-2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiazole-4-carboxylate (23I) (120 mg, 0.17 mmol) was added MeOH and THF. LiOH (20 mg, 0.85 mmol) was dissolved in water and added to the reaction mixture. The reaction mixture was stirred and heated at 60° C. for two hours. The reaction was cooled and put in refrigerator overnight. The precipitate was transferred to a centrifuge tube and centrifuged down at 17,000 RPM. The precipitate was washed water. Then the precipitate was added to acetonitrile and water and lyophilized to give 69 mg (59%) of the desired product 5-(3-(4-(1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy)propyl)-2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiazole-4-carboxylic acid (23): 1H NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 9.10 (s, 1H), 8.61 (s, 1H), 8.04 (d, J=8.7, 2H), 7.66 (s, 1H), 7.45 (d, J=34.2, 2H), 7.20 (t, J=18.3, 5H), 4.12 (s, 3H), 3.95 (s, 3H), 2.79 (s, 2H), 2.16 (s, 3H), 1.89 (s, 2H), −0.00 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:14][C:13](=[O:15])[C:12]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[CH:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CO
Reactant: COc1cc(C=C(C(=O)O)c2ccc(O)cc2)cc(OC)c1
Agent: O=S(=O)(O)O
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1

Procedure:
Methanol (3.0 L) was added to a thoroughly dried 7 (427.5 g, 1.42 mol) under argon. To this stirred suspension concentrated sulfuric acid (100 mL) was added and heated at reflux for 20 h under nitrogen. Methanol was evaporated under reduced pressure at 30° C. The residue was taken up in ethyl acetate (3.0 L) and washed with water (2×1.0 L), saturated aqueous Na HCO3 (2×1.0 L), brine (2×1.0 L). The organic layer was dried on anhydrous magnesium sulfate, filtered and the solvent was evaporated. The residue obtained was dried thoroughly under high vacuum as white solid, (433.6 g 97%): mp 106-108° C.; 1HNMR(360 MHz, CDCl3): δ 7.72 (s, 1H), 7.06 (d, J=7.9 Hz, 2H), 6.77 (d, J=7.9 Hz, 2H), 6.33 (t, J=2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 2H), 5.74 (s, 1H), 3.81 (s, 3H), 3.60 (s, 6H); MS (EI) m/z 315[M]+; Anal. (C18H18O5) C, H.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](I)[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=1)[CH2:5]2.[C-:27]#[N:28].[Na+].CCCCCC.CCOC(C)=O>C(#N)C.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.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:27]#[N:28])[C:8]2[C:7](=[O:12])[N:6]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:18][CH:19]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: [C-]#N
Reactant: O=C1c2c(I)cc(Cl)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCCCC
Product: N#Cc1cc(Cl)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
A mixture of 5-chloro-7-iodo-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.675 g, 1.42 mmol), Pd(PPh3)4 (0.162 g, 0.14 mmol), sodium cyanide (0.089 g, 1.85 mmol), and CuI (0.027 g, 0.14 mmol) in acetonitrile (5 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate (typically 2:1 hexane-EtOAc) afforded 6-chloro-3-oxo-2-(4-phenoxy-benzyl)-2,3-dihydro-1H-isoindole-4-carbonitrile (0.307 g, 58%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.32 (s, 2H), 4.77 (s, 2H), 6.95-7.38 (m, 9H), 7.63 (s, 1H), 7.75 (s, 1H). GC-MS: m/z 374 (M)+, 297 (M−77)+, 281 (M-93)+.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH2:14][O:15]C)[CH:11]=[C:10]([CH:17]2[CH2:19][CH2:18]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(NC(N)=N)=CC=1.C1(C(=O)CC(=O)COC)CC1.B(Br)(Br)Br>ClCCl>[NH:1]([C:8]1[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]([CH:17]2[CH2:18][CH2:19]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCc1cc(C2CC2)nc(Nc2ccccc2)n1
Agent: BrB(Br)Br
Agent: COCC(=O)CC(=O)C1CC1
Agent: N=C(N)Nc1ccccc1
Solvent: ClCCl
Product: OCc1cc(C2CC2)nc(Nc2ccccc2)n1
Temperature: -68 °C
Reaction time: 2 h

Procedure:
5.9 g (23 mmol) of 2-anilino-4-methoxymethyl-6-cyclopropylpyrimidine, prepared from phenylguanidine and 1-cyclopropyl-4-methoxy-1,3-butanedione, are dissolved in 200 ml of dichloromethane and the solution is cooled to -68° C. 6.8 g (27 mmol) of boron tribromide are slowly added dropwise to the salmon-coloured solution within a period of half an hour, with vigorous stirring, and the cooling bath is then removed and stirring is continued for a further 2 hours at room temperature. After the addition of 150 g of ice-water, the precipitated crude product is filtered off and recrystallised from methanol using active carbon. The light-yellow crystals melt at 124°-126° C. Yield: 4.7 g (19.5 mmol; 84.7% of the theoretical yield).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][CH:18]([F:20])[F:19])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:21](=[O:24])([O-])[O-].[Na+].[Na+].O.[CH2:28]([OH:30])[CH3:29]>C1(C)C=CC=CC=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>[C:28]([C:21]1[O:24][C:2]2[C:1]([C:4]3[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:6]([CH3:7])[CH3:5])[C:5]=3[O:16][CH2:17][CH:18]([F:20])[F:19])=[CH:3][CH:9]=[CH:4][C:1]=2[CH:2]=1)(=[O:30])[CH3:29]
Reactant: CCO
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cc(B(O)O)c(OCC(F)F)c(C(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1

Procedure:
A mixture of 1.08 mmol of 3,5-diisopropyl-2-(2,2-difluoroethoxy) phenylboronic acid, 498 mg (1.62 mmol) of 2-acetyl-7-trifluoromethanesulfonate benzo[b]furan (see Example 4, step A) and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-acetyl-7-[3,5-diisopropyl-2-(2,2-difluoroethoxy)phenyl]-benzo[b]furan as a clear yellow pasty solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].[OH-].[Li+].O1CCOCC1.Cl>O>[Br:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1c(Br)ccc(NS(=O)(=O)c2ccccc2F)c1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(Br)ccc(NS(=O)(=O)c2ccccc2F)c1C(=O)O

Procedure:
A mixture of Example 318C (150 mg, 0.3 mmol), lithium hydroxide (127 mg, 3.0 mmol), dioxane (3 mL), and water (1.5 mL) was sealed in a vial and microwaved at 160° C. for 15 minutes. The mixture was acidified to pH 1 with 1M HCl and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried (Na2SO4), filtered, and concentrated to an oil which was triturated with 1:1 hexanes/diethyl ether to provide the desired product. MS (ESI(+)) m/e 404, 406 (M+H)+, 421, 423 (M+NH4)+, 426, 428 (M+Na)+; (ESI(−)) m/e 402, 404 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.48 (br s, 1H), 10.34 (br s, 1H), 7.72 (m, 2H), 7.63 (d, 1H), 7.41 (m, 1H), 7.34 (m, 1H), 6.89 (d, 1H), 3.75 (s, 3H).
Reaction SMILES: CN(C)C=O.[C:6]([O:17][CH3:18])(=[O:16])[C:7]1[CH:15]=[C:13]([OH:14])[C:11]([OH:12])=[C:9]([OH:10])[CH:8]=1.Br[CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>O>[OH:14][C:13]1[C:11]2[O:12][CH2:20][CH2:21][O:10][C:9]=2[CH:8]=[C:7]([C:6]([O:17][CH3:18])=[O:16])[CH:15]=1
Reactant: BrCCBr
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)c2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To 20 mL of an N,N-dimethylformamide solution containing 2.25 g of methyl gallate, 1.3 mL of 1,2-dibromoethane and 4.05 g of potassium carbonate were added, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, then fed into water, and the resultant solution was extracted with a mixed solvent of ethyl acetate:toluene of 5:1. The organic layer was washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 1.66 g of a brown oily substance, methyl 8-hydroxy-2,3-dihydro-1,4-benzodioxin-6-carboxylate.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([O-:13])([O-])[O:9][CH2:10][CH3:11].[CH3:14][O:15][C:16]1[C:17]([F:32])=[C:18]([CH:27]=[C:28]([F:31])[C:29]=1[F:30])[C:19]([CH2:21][C:22](OCC)=O)=[O:20].[CH:33]1([NH2:36])[CH2:35][CH2:34]1>C(Cl)Cl>[CH:33]1([NH:36][CH:22]=[C:21]([C:19](=[O:20])[C:18]2[CH:27]=[C:28]([F:31])[C:29]([F:30])=[C:16]([O:15][CH3:14])[C:17]=2[F:32])[C:8]([O:9][CH2:10][CH3:11])=[O:13])[CH2:35][CH2:34]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC)c1F
Reactant: NC1CC1
Reactant: CCOC([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(OC)c1F
Reaction time: 0.5 h

Procedure:
3.5 ml of acetic anhydride and 1.1 ml of ethyl orthoformate were added to 1.40 g (0.005 mole) of ethyl 3-methoxy-2,4,5-trifluorobenzoylacetate (XXIX) [prepared as described in Step (E9) above], and the mixture was heated under reflux for 1 hour and then concentrated by evaporation under reduced pressure. 0.38 g (0.006 mole) of cyclopropylamine was added dropwise, whilst ice-cooling and stirring, to a solution of the residue in 10 ml of methylene chloride, and the mixture was stirred for a further 30 minutes. The solvent was then removed by evaporation under reduced pressure from the reaction mixture, and the residue was subjected to silica gel column chromatography eluted with a 9:1 by volume mixture of toluene and ethyl acetate, to afford 1.23 g of ethyl 3-cyclopropylamino-2-(3-methoxy-2,4,5-trifluorobenzoyl)acrylate (XXXI) as a pale brown oily substance.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([CH:15]([CH3:17])[CH3:16])CC)(C)C.Cl[Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20](C)[CH3:21].[C-]#[C-].[Li+].[Li+].C(N)CN>C1COCC1.O>[CH2:1]([O:8][Si:19]([C:20]#[CH:21])([CH:15]([CH3:16])[CH3:17])[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(Cl)C(C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: OCc1ccccc1
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: O
Solvent: NCCN
Solvent: C1CCOC1
Product: C#C[Si](OCc1ccccc1)(C(C)C)C(C)C
Temperature: -20 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A solution of benzyl alcohol (0.1 mL, 1.0 mmol) in THF (0.5 mL) was added dropwise to a cooled (−78° C.) solution of diisopropylethylamine (1 mL), dichlorodiisopropylsilane (0.3 mL, 1.62 mmol) in THF (4 mL). The solution was stirred for 3 h (−78→−20° C.). The mixture was cooled down to −78° C. and lithiumacetylid-ethylendiamin-complex (250 mg, 2.71 mmol) was added. The reaction mixture was stirred for 5 h (−78→20° C.). Water (4 mL) was added. The mixture was extracted with dichloromethane (20 mL). The organic phase was dried (Na2SO4) and concentrated. Compound 14a (100 mg, 41%) was obtained after flash chromatography. 1H-NMR (CDCl3): δ 7.4 (5H, 5×HC═), 5.0 (2H, CH2), 2.6 (1H, CH), 1.0 (14H, 2×CH, 2×CH3).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9](S(C)(=O)=O)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[CH2:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH3:29]>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9]([NH:33][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2c(c1=O)CCCC2
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)Nc1ncc(OCC2CC2)c(-c2cn(C)c(=O)c3c2CCCC3)n1

Procedure:
The title compound of Example 163, step 4 was treated with treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 8.32 (s, 1H), 7.64 (s, 1H), 3.83 (d, J=6.8 Hz, 2H), 3.44 (s, 3H), 3.30-3.20 (m, 2H), 2.47-2.41 (m, 4H), 1.67-1.57 (m, 4H), 1.19-1.13 (m, 4H), 0.51-0.49 (m, 2H), 0.24-0.22 (m, 2H). LCMS: 419.1 (M+H)+
Reaction SMILES: CO.[C:3]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:22]([O:26][C:27]([NH:29][S:30]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:32])=[O:31])=[O:28])[CH2:23][CH2:24][CH3:25].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:22]([O:26][C:27]([N:29]([CH3:3])[S:30]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:31])=[O:32])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOC(=O)NS(=O)(=O)NCC(=O)OCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOC(=O)N(C)S(=O)(=O)NCC(=O)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methanol (8.5 mmol) and triphenylphosphine (2.6 g, 8.5 mol) in dry THF is added a solution of ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate from the previous step (2.4 g, 8.5 mol) and DIAD (2.0 g, 8.5 mmol) in dry THF dropwise at 0° C. under N2 atmosphere. The mixture is stirred at 0° C. for 2 h, warmed to RT and is stirred overnight. After the solvent is removed in vacuo, the residue is purified by column chromatography to afford ethyl 2-((N-(butyloxycarbonyl)-N-methylsulfamoyl)amino)acetate.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>C1COCC1.CN(C=O)C>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH3:31])[CH:34]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: COc1cccc(N=C=O)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 31.9 mg (0.21 mmol) of 3-methoxyphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of methanol and 1 N hydrochloric acid (2:1), again concentrated and dried under high vacuum. 17 mg (32.7% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([CH:23]([CH2:26][CH3:27])[CH2:24][NH2:25])[CH3:22]>>[CH2:21]([CH:23]([CH2:26][CH3:27])[CH2:24][NH:25][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:22]
Reactant: CCC(CC)CN
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: CCC(CC)CNCc1ccc(Oc2ccc(C(N)=O)cn2)c(OC)c1
Yield: 68.4 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-ethylbutylamine (0.0186 g, 0.184 mmol) gives the title compound (0.0450 g, 68.6%): TOF MS ES+ 358.2 (M+H)+. HRMS calcd for C20H28N3O3 358.2131 (M+H)+, found 358.2127, time 0.41 ml; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.6 min, 98.8% purity.
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)#[N:8].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2](=[CH2:6])[C:3]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=1)=[O:4]
Reactant: C=C(F)C(=O)Cl
Reactant: N#Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)Oc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
10 g (0.092 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were added dropwise, at a temperature of 5° C., with stirring and in the course of 20 minutes, to a solution of 10.7 g (0.09 mol) of 4-cyanophenol and 9.1 g (0.09 mol) of triethylamine in 150 ml of anhydrous methylene dichloride, and the reaction mixture was then stirred for a further 30 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of anhydrous methylene dichloride. After 0.005 g of hydroquinone monomethyl ether had been added, the volatile constituents in the mixture of filtrate and wash solution were removed by distillation, and the residue was recrystallized from boiling n-hexane. 11.2 g (65% of theory) of 4-cyanophenyl α-fluoroacrylate were obtained, melting point 78° to 79° C.
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:15][CH2:16][CH2:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9]1[O:13][CH:12]([CH3:14])[CH2:11][O:10]1)[CH2:2][CH3:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:31][CH2:32][C:33](Cl)=[O:34]>O>[CH2:16]([O:15][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:6][N:7]([CH2:8][CH:9]1[O:13][CH:12]([CH3:14])[CH2:11][O:10]1)[C:33](=[O:34])[CH2:32][Cl:31])[CH2:17][CH3:18]
Reactant: O=C(Cl)CCl
Reactant: CCCOC(CNCC1OCC(C)O1)OCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCOC(CN(CC1OCC(C)O1)C(=O)CCl)OCCC

Procedure:
N-(2,2-Dipropoxyethyl)-N-(4-methyl-1,3-dioxolan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-dipropoxyethyl)-N-(4-methyl-1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [CH2:1]([C:9]1[CH:40]=[CH:39][C:12]([C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=CC(CCCCCCCCCC)=[CH:24][CH:23]=3)[CH:19]=[CH:18][C:17]=2[OH:38])=O)=[CH:11][CH:10]=1)[CH2:2]CCCCCC.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44](S(O)(=O)=O)=[CH:43][CH:42]=1>ClC1C=CC=CC=1Cl>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:38][C:17]3[CH:18]=[CH:19][C:20]([C:22]4[CH:27]=[CH:2][C:1]([CH2:9][CH2:10][CH2:11][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH3:51])=[CH:24][CH:23]=4)=[CH:21][C:16]=3[N:15]=2)=[CH:39][CH:40]=1)[CH2:2][CH2:19][CH2:18][CH2:17][CH2:16][CH2:21][CH3:20]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCCCCCc1ccc(-c2ccc(O)c(NC(=O)c3ccc(CCCCCCCC)cc3)c2)cc1
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCCCc1ccc(-c2ccc3oc(-c4ccc(CCCCCCCC)cc4)nc3c2)cc1
Reaction time: 0.67 h
Yield: 156.8 %

Procedure:
Step iv) In a 50 ml-round-bottomed flask, 1.30 g (2.40 mM) of 2-(4-octylbenzoylamino)-4-(4-decylphenyl)phenol, 0.13 g (0.68 mM) of p-toluenesulfonic acid and 20 ml of o-dichlorobenzene were placed, followed by stirring for 40 min. at 189°-192° C. After the reaction, o-dichlorobenzene was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 0.62 g of 2-(4-octylphenyl)-5-(4-decylphenyl)benzoxazole (yield: 49.3%). ##STR19##