Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:23])[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:1]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][N:14]([CH3:23])[CH3:13])[CH2:18][CH2:19]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN(C)CCN1CCNCC1
Product: CCCCCCC/C=C/C(=O)N1CCN(CCN(C)C)CC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and 1-[2-(dimethylamino)ethyl]piperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.B(O)(O)[C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3ccc4ccccc4c3)C2=O)cc1
Yield: 68 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and naphthalen-2-yl-2-boronic acid instead of phenyl boronic acid, to obtain the title compound (68%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8](OCC)[O:9]CC)(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[O:9]=[CH:8][CH2:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC(OCC)OCC
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)OCC=O

Procedure:
As a nonlimiting example using method C in FIG. 2, (5-oxo-1,3-oxathiolan-2-yl) methyl butanoate or the 5-acetyloxy derivative thereof may be obtained from process which includes reacting 2,2-diethoxyethyl butanoate in DCM and treating with TFA and water. This reaction yields 2-oxoethylbutanoate, which may be reacted with mercaptoacetic acid in CSA and DCM to produce the desired (5-oxo-1,3-oxathiolan-2-yl) methyl butanoate., or with 1,4-dithiane-2,5-diol in THF to obtain the 5-acetyloxy derivative.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]2[CH:8]=[N:7][C:6]([CH3:13])=[CH:5][C:4]=2[C:3]=1[NH2:14].[F:15][C:16]([F:28])([F:27])[C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]=[C:23]=[O:24])=[CH:19][CH:18]=1>>[F:1][C:2]1[C:3]([NH:14][C:23]([NH:22][CH2:21][C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:28])[F:27])=[CH:26][CH:25]=2)=[O:24])=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH:8]=[N:7][C:6]([CH3:13])=[CH:5]2
Reactant: Cc1cc2c(N)c(F)cc(F)c2cn1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)c(F)cc(F)c2cn1

Procedure:
Prepared from 6,8-difluoro-3-methylisoquinolin-5-amine (Description 73) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 396 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClCCl>[N:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:22])[CH3:21])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (0.33 g) in a mixture of dichloromethane (20 ml) and acetic anhydride (1.5 ml) was allowed to stand overnight and then evaporated. The residue was triturated with 50 ml of 10% sodium carbonate solution, and then the mixture was diluted to 100 ml with water and extracted several times with chloroform. The combined extracts were dried over sodium sulphate, evaporated and the residue crystallised from ethanol to give the title compound (0.15 g), m.p. 244°-247° C. Found: C,68.82; H,6.67; N,18.69. C17H20N4O requires: C,68.89; H,6.80; N,18.91%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:24]=[CH:25][C:26]([C:49](=[O:71])[NH:50][S:51]([C:54]4[CH:59]=[CH:58][C:57]([NH:60][CH2:61][CH:62]5[CH2:67][CH2:66][O:65][CH2:64][CH2:63]5)=[C:56]([N+:68]([O-:70])=[O:69])[CH:55]=4)(=[O:53])=[O:52])=[C:27]([CH:48]=3)[O:28][C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[NH:34][CH:33]=[C:32]4[CH2:38][CH2:39][NH:40]C(=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:40][CH2:39][CH2:38][C:32]1[C:31]2[C:35](=[CH:36][CH:37]=[C:29]([O:28][C:27]3[CH:48]=[C:23]([N:20]4[CH2:21][CH2:22][N:17]([CH2:16][C:9]5[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:8]=5[C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)[CH2:18][CH2:19]4)[CH:24]=[CH:25][C:26]=3[C:49]([NH:50][S:51]([C:54]3[CH:59]=[CH:58][C:57]([NH:60][CH2:61][CH:62]4[CH2:63][CH2:64][O:65][CH2:66][CH2:67]4)=[C:56]([N+:68]([O-:70])=[O:69])[CH:55]=3)(=[O:53])=[O:52])=[O:71])[CH:30]=2)[NH:34][CH:33]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]cc(CCNC(=O)OC(C)(C)C)c5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]cc(CCN)c5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 0.25 h

Procedure:
A solution of EXAMPLE 299E (146.6 mg) in dichloromethane (10 mL) was cooled in an ice bath and 2,2,2-trifluoroacetic acid (5 mL) was added dropwise over 5 minutes. The reaction mixture was stirred 15 minutes under nitrogen, the ice bath was removed and the reaction was allowed to come to ambient temperature. The reaction was stirred 1.5 hours and then concentrated. The crude material was purified by reverse phase chromatography with ammonium acetate buffer in acetonitrile to give the title compound. 1H NMR (300 MHz, dimethyosulfoxide-d6) δ 10.86 (d, 1H), 8.39 (d, 1H), 8.33 (t, 1H), 8.06 (br s, 1H), 7.71 (dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H), 7.26 (d, 1H), 7.19 (d, 1H), 7.05 (m, 3H), 6.89 (d, 1H), 6.70 (dd, 1H), 6.52 (dd, 1H), 6.15 (d, 1H), 3.83 (dd, 2H), 3.22 (m, 3H), 2.82-3.00 (m, 8H), 2.72 (s, 2H), 2.16 (m, 6H), 1.96 (s, 2H), 1.88 (m, 4H), 1.60 (d, 2H), 1.38 (m, 2H), 1.24 (m, 2H), 0.93 (s, 6H).
Reaction SMILES: Cl.[CH:2]1([C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[NH2:11])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].CO.C(Cl)Cl>C(Cl)Cl>[CH:2]1([C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]([S:20]([CH3:19])(=[O:22])=[O:21])[S:20]([CH3:19])(=[O:22])=[O:21])[CH2:4][CH2:3]1
Reactant: Nc1cnccc1C1CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)N(c1cnccc1C1CC1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A suspension of 4-cyclopropylpyridin-3-amine hydrochloride (297 mg, 1.741 mmol) in anhydrous CH2Cl2 (8.5 mL) was cooled to 0° C. and treated with triethylamine (0.849 mL, 6.09 mmol) and methanesulfonyl chloride (0.298 mL, 3.83 mmol). The mixture was stirred at 0° C. for 1 hour, then at room temperature for 1 hour. TLC (SiO2, 5% methanol/CH2Cl2; used sample of free base 10036010-0967 as starting material reference) showed the reaction was complete. The mixture was diluted with CH2Cl2 (50 mL), washed with saturated aqueous NaHCO3 (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to give a tan solid. The solid was purified by SiO2 flash chromatography (3.8 cm×10 cm) eluting with 3% methanol/CH2Cl2 to afford the product as a white solid (403 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[N+:21]([O-])=O.[Sn](Cl)Cl.[OH-].[NH4+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:19])([F:20])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[NH2:21]
Reactant: O=[N+]([O-])c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F
Agent: Cl[Sn]Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-(4-fluoro-3-nitrophenyl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.819 g, 2.51 mmol) in ethanol (10 ml) was added anhydrous tin(II) chloride (2.0 g). After stirring at ambient temperature for 2 h the resulting solution was treated with 30% ammonium hydroxide (40 ml). This mixture was stirred for 10 min then concentrated at reduced pressure. The residue was then treated with ethanol and evaporated at reduced pressure to remove residual water. This residue was then boiled with 10% methanol in dichloromethane and insoluble material removed by filtration. The filtrate was evaporated in vacuo, the residue treated with a hot solution of 50% toluene in ethyl acetate and insoluble material removed by filtration. The filtrate was evaporated at reduced pressure and the residue crystallised from hot toluene to furnish 2-fluoro-5-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)phenylamine: δH (400 MHz, DMSO) 5.42 (2H, br), 6.87 (1H, m), 7.07 (1H, dd, J 9 and 2), 7.20 (1H, dd, J 12 and 8), 7.50 (1H, d, J 7), 8.13 (1H, s), 9.18 (1H, d, J 7); m/z (ES+) 297 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:39]([F:42])([F:41])[F:40])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH2:29][S:30]([CH3:38])=[N:31]C(=O)C(F)(F)F)=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:39]([F:40])([F:42])[F:41])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH2:29][S:30]([CH3:38])=[NH:31])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CS(CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12)=NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=N)CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-[4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-[S-methyl-N-(2,2,2-trifluoroacetyl)sulfinimidoyl]ethyl]-1-naphthalene-carboxamide (70 mg) (i.e. the title compound of Step A) in methanol (2 mL) was added potassium carbonate (300 mg) at room temperature. After stirring overnight at room temperature, the reaction mixture was filtered through a short pad of silica gel and rinsed with ethyl acetate. After concentration, the residue was purified by column chromatography on silica gel using dichloromethane/methanol (98:2 to 92:8) as eluent to afford the title compound, a compound of the present invention, as a semisolid (9 mg, 15% yield).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]([CH3:36])[CH2:15][O:16]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@H:10]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[Si:38]([O:37][C@H:10]1[C@H:11]([CH:14]([CH3:36])[CH2:15][OH:16])[CH2:12][CH2:13][NH:8][CH2:9]1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]
Reactant: CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(CO)[C@@H]1CCNC[C@H]1O[Si](C)(C)C(C)(C)C

Procedure:
Trans-1-benzyl-3-t-butyldimethylsilyloxy-4-(1-triphenylmethoxyprop-2-yl)piperidine (4.5 g; diastereomer A) was hydrogenated in ethanol (60 cm3) at 60° and 60 p.s.i. pressure over 10% palladium on carbon (0.9 g) for 5 hours. The solution was cooled, filtered through "Avicel" to remove the catalyst and evaporated in vacuo to afford trans-3-t-butyldimethylsilyloxy-4-(1-hydroxyprop-2-yl)piperidine as a crude oil (diastereomer A).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[C:3]=1[CH:4]=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[C:3]=1[CH2:4][OH:5]
Reactant: C=CC[C@H](C)Oc1cc(F)cc(F)c1C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cc(F)cc(F)c1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
To a solution of (S)-2,4-difluoro-6-(pent-4-en-2-yloxy)benzaldehyde (0.3394 g, 1.500 mmol) in THF (4 ml) at 0° C. was added dropwise, lithium aluminum hydride (0.900 ml, 1.800 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was cooled to 0° C. and quenched dropwise with brine then diluted with EtOAc and water. The organic phase was washed with brine, dried (Na2SO4) and concentrated. The oil was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane; 10 CV) to give (S)-(2,4-difluoro-6-(pent-4-en-2-yloxy)phenyl)methanol (0.1344 g, 0.589 mmol, 39.2% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 6.59-6.28 (m, 2H), 6.07-5.71 (m, 1H), 5.30-5.02 (m, 2H), 4.69 (d, J=5.6 Hz, 2H), 4.49 (sxt, J=6.0 Hz, 1H), 2.61-2.39 (m, 2H), 2.32 (t, J=6.8 Hz, 1H), 1.40 (d, J=6.1 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH2:39][CH:40]([CH2:45][CH3:46])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:37])=[CH:30][CH:29]=1>CN(C)C=O>[OH:6][C:5]1[C@@H:7]([C@H:9]([OH:10])[CH2:11][O:12][C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH2:39][CH:40]([CH2:45][CH3:46])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:37])=[CH:30][CH:29]=2)[O:8][C:2](=[O:1])[C:3]=1[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CCCCC(CC)COC(=O)/C=C/c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CCCCC(CC)COC(=O)/C=C/c1ccc(OC[C@@H](O)[C@H]2OC(=O)C(O)=C2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 g of ascorbic acid (113.5 mmol; 1 eq.) are dissolved in 100 ml of di-methylformamide in an argon-flushed 3-necked flask, 32.76 g of triphenyl-phosphine are added, and 25.3 g of diisopropyl azodicarboxylate (124.9 mmol; 1.1 eq) are slowly added dropwise at 0° C. After 30 min, the 2-ethylhexyl(E)-3-(4-hydroxyphenyl)acrylate (32.95 g; 1.05 eq; 119.2 mmol) dissolved in 45 ml of dimethylformamide is added dropwise. After 30 min at 0° C., the mixture is stirred at room temperature for a further 6 hrs. The reaction solution is evaporated to dryness, suspended in 100 ml of ethyl acetate/hexane 1:2, filtered, and the product is precipitated as a white solid by addition of 100 ml of hexane.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17](N(OC)C)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CON(C)C(=O)CC1c2ccccc2CCc2ccccc21
Reactant: Ic1ccncc1
Product: O=C(CC1c2ccccc2CCc2ccccc21)c1ccncc1

Procedure:
In analogy to example 55, step 2, from 2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-N-methoxy-N-methyl-acetamide and 4-iodopyridine was prepared the title compound as a white solid, MS (ESI+): m/z=314.1 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].N.[CH3:25][N:26]1CCCC1=O>>[O:23]=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:13]1[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:25]#[N:26])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN1CCCC1=O
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(Br)cc12
Agent: N
Product: N#Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reaction time: 0.75 h

Procedure:
A mixture of 2-[2-(5-bromo-1H-indol-3-yl) ethyl]-1H-isoindole-1,3(2H)-dione (4.0 g), cuprous cyanide (1.1 g) and N-methyl-2-pyrrolidinone (10 ml) was heated at reflux for 1 hour. The reaction mixture was poured onto ice (30 g) and concentrated ammonia (15 ml) was added and the suspension was stirred for 0.75 hour. The solid was filtered off, washed with water and methanol and was crystallised from aqueous acetone to give the title compound (2.7 g) as a fawn solid m.p. 217°-221° C. T.L.C. Silica ether Rf 0.44.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[CH:8][C:7]=1[CH:17]([CH3:19])[CH3:18].[CH3:20][O:21][C:22]1[C:29]([CH3:30])=[C:28]([CH3:31])[C:27]([O:32][CH3:33])=[C:26]([CH3:34])[C:23]=1[CH2:24]Cl.C(N(CC)CC)C>CN(C)C=O>[CH3:20][O:21][C:22]1[C:29]([CH3:30])=[C:28]([CH3:31])[C:27]([O:32][CH3:33])=[C:26]([CH3:34])[C:23]=1[CH2:24][N:2]([CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[CH:8][C:7]=1[CH:17]([CH3:19])[CH3:18])[CH3:1]
Reactant: COc1c(C)c(C)c(OC)c(CCl)c1C
Reactant: CNCCOc1cc(C)c(NC(C)=O)cc1C(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C)c(C)c(OC)c(CN(C)CCOc2cc(C)c(NC(C)=O)cc2C(C)C)c1C
Temperature: 25 °C
Yield: 75 %

Procedure:
N-Methyl-2-(4-acetylamino-2-isopropyl-5-methylphenoxy)ethylamine (4.94 g) and 2,5-dimethoxy-3,4,6-trimethylbenzyl chloride (4.29 g) were dissolved in N,N-dimethylformamide (70 ml), and triethylamine (1.89 g) was added dropwise while stirring the mixture at room temperature. The mixture was stirred at room temperature for 16.5 hours. After the reaction, the solvent was distilled off, and water was added. The mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (eluent; ethyl acetate/benzene=1/1) to give 6.40 g of a pale-yellow solid. A portion (1.0 g) was taken therefrom and recrystallized from diisopropyl ether to give 0.62 g of the title compound (colorless crystals).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]([OH:25])=O)[S:22][C:15]=12)=[O:8].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.Cl.[NH2:73][CH2:74][CH2:75][CH2:76][NH:77][CH2:78][C:79]([O:81][CH3:82])=[O:80]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]([NH:73][CH2:74][CH2:75][CH2:76][NH:77][CH2:78][C:79]([O:81][CH3:82])=[O:80])=[O:25])[S:22][C:15]=12)=[O:8]
Reactant: COC(=O)CNCCCN
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc3cc(C(=O)O)sc23)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CNCCCNC(=O)c1cc2nccc(Oc3cccc(NC(=O)c4occc4C)c3)c2s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cooled (0° C.) solution of 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid (150 mg, 0.38 mmol) in anhydrous DMF (10 ml) were added PyBOP (218 mg, 0.42 mmol) and N,N-diisopropylethylamine (245 mg, 1.9 mmol). The mixture was stirred at 0° C. for 10 minutes, followed by addition of methyl [(3-aminopropyl)amino]acetate dihydrochloride (100 mg, 0.46 mmol). Stirring was continued at 0° C. for another 40 minutes. The mixture was diluted with ethyl acetate (100 ml), washed with brine (4×100 ml), dried over Na2SO4, and concentrated to give the crude, which was purified by silica gel chromatography eluting with 5-8% methanol in chloroform to give methyl [(3-{[(7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridin-2-yl)carbonyl]amino}propyl)amino]acetate as light beige solid. Yield: 98 mg, 49%.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][O:5][C:6]([CH3:25])([CH3:24])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:23])[CH2:11][CH:12]([OH:22])[CH2:13][C:14]([CH:16]1[CH2:21][O:20][C:18](=[O:19])[CH2:17]1)=[O:15]>CCOCC>[OH:22]/[C:12](/[CH2:11][CH:10]([CH3:23])[CH2:9][CH2:8][CH2:7][C:6]([O:5][CH3:4])([CH3:24])[CH3:25])=[CH:13]/[C:14](=[C:16]1[CH2:21][O:20][C:18](=[O:19])[CH2:17]1)[O:15][CH3:3]
Reactant: C=[N+]=[N-]
Reactant: COC(C)(C)CCCC(C)CC(O)CC(=O)C1COC(=O)C1
Solvent: CCOCC
Product: COC(/C=C(/O)CC(C)CCCC(C)(C)OC)=C1COC(=O)C1
Reaction time: 4 h
Yield: 61.3 %

Procedure:
An etherealdiazomethane solution containing 0.04 moles of diazomethane is added to a solution of 2.0 g (0.006 moles) of 3-(9-methoxy-3-hydroxy-5,9-dimethyl-decanoyl)-4-butyrolactone in 5 ml of dry ether, and the reaction mixture is allowed to stand at room temperature for 4 hours. The solvent is distilled off in vacuo, the residue is taken up with ether, and the solution is filtered through a short column filled with Kieselgel 60 adsorbent. Ether is removed from the effluent to obtain 1.2 g (63.2%) of the aimed compound as a pale yellow oil; Rf =0.62 (developed with a 10:0.4 mixture of benzene and methanol).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH:21]([CH3:23])[N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:12].C(O)(C(F)(F)F)=O>ClCCl.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH:21]([CH3:23])[NH:20][CH2:19][CH2:18]2)=[O:12]
Reactant: CC1c2c(cccc2C(=O)Nc2nc3ccccc3s2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC1NCCc2cccc(C(=O)Nc3nc4ccccc4s3)c21
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A solution of EXAMPLE 163B (150 mg) in dichloromethane (10 mL) was treated with TFA (1 mL). The reaction mixture was stirred for 2 hours at 30° C. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromotography (silica gel, dichloromethane/methanol=10/1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16](=[O:17])[CH:15]3[CH:10]([CH:11]4[O:18][CH:14]3[CH2:13][CH2:12]4)[C:9]2=[O:19])=[C:4]([CH2:20][CH3:21])[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[F-].[Cs+].ClCCl>COCCOC>[CH2:20]([C:4]1[C:5]([CH:8]2[C:16](=[O:17])[CH:15]3[CH:10]([CH:11]4[O:18][CH:14]3[CH2:13][CH2:12]4)[C:9]2=[O:19])=[CH:6][CH:7]=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:3]=1)[CH3:21]
Reactant: CCc1cc(Br)ccc1C1C(=O)C2C3CCC(O3)C2C1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: COCCOC
Product: CCc1cc(-c2ccc(F)cc2)ccc1C1C(=O)C2C3CCC(O3)C2C1=O
Temperature: 80 °C

Procedure:
A mixture of (1RS,2SR,6RS,7SR)-4-(4-bromo-2-ethylphenyl)-10-oxatricyclo-[5.2.1.02,6]decane-3,5-dione (200 mg, 0.57 mmol), 4-fluorophenylboronic acid (112 mg, 0.80 mmol) and cesium fluoride (260 mg, 1.71 mmol) are stirred together in degassed 1,2-dimethoxyethane (5 ml) at room temperature under an atmosphere of nitrogen for 40 minutes at room temperature. [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (74 mg, 0.09 mmol) is added, and the reaction mixture is heated to 80° C. for 20 hours. The mixture is cooled to room temperature, filtered through a plug of diatomaceous earth, washing with 2M aqueous hydrochloric acid and dichloromethane. The organic phase is collected, and the aqueous phase is extracted with dichloromethane. The organic solutions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column choramtography on silica gel to give (1RS,2SR,6RS,7SR)-4-(3-ethyl-4′-fluorobiphen-4-yl)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione.