Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][C:11]1[CH:12]=[C:13]([C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=2)=[CH:20][C:21]#[N:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH2:32]([O:31][C:25]1[CH:24]=[C:23]([C:19]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([N:10]3[CH:3]=[CH:7][CH:6]=[CH:5]3)[CH:12]=2)=[CH:20][C:21]#[N:22])[CH:28]=[CH:27][C:26]=1[O:29][CH3:30])[CH3:33]
Reactant: CCOc1cc(C(=CC#N)c2ccc(OC)c(N)c2)ccc1OC
Reactant: COC1CCC(OC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(-n3cccc3)c2)ccc1OC
Temperature: 25 °C

Procedure:
2,5-Dimethoxytetrahydrofuran (0.2 g, 1.7 mmol) was added to a stirred solution of 3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile (0.5 g, 1.5 mmol) in acetic acid (10 mL). The reaction mixture was heated to reflux under nitrogen for one hour. The mixture was cooled down to room temperature. The mixture was stirred with EtOAc (100 mL) and saturated NaHCO3 (40 mL) was added slowly. The EtOAc solution was washed with water (60 mL), brine (60 mL) and dried (MgSO4). Solvent was removed and the residue was purified by flash chromatography (silica gel, Hexane:EtOAc 6:4) to afford mixture of isomers of 3-(3-ethoxy-4-methoxy-phenyl)-3-(4-methoxy-3-pyrrol-1-yl-phenyl)-acronitrile (0.4 g, 60%) as a white solid: mp 109-111° C.; 1H NMR (CDCl3) δ 7.00 (m, 2H), 7.47-6.81 (m, 6H), 6.30 (m, 2H), 5.59 (5.57) (s, 1H), 4.05 (m, 2H), 3.91 (m, 6H), 1.45 (m, 3H); 13C NMR (CDCl3) δ 161.67(161.61), 153.93(154.35), 151.56(151.00), 148.27(148.00), 131.40(132.10), 129.83(130.06), 129.03(127.16), 125.93(127.93), 123.07, 122.21, 122.05(121.93), 118.52(118.43), 114.00, 112.01(112.06), 111.09(112.70), 109.15(109.28), 92.45, 64.56, 56.05(56.00), 14.69; Anal. Calcd for C23H22N2O3. Theoretical: C, 73.78; H, 5.92, N, 7.48. Found: C, 73.46; H, 5.71; N, 7.35.
Reaction SMILES: C(O)CCC.[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2.[Cl:24][C:25]1[O:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1>C(OCC)(=O)C>[ClH:24].[O:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11][CH2:10]2
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cl
Product: c1ccc2oc(Nc3ccc4c(c3)CCNC4)nc2c1
Temperature: 25 °C
Yield: 65 %

Procedure:
A 1-butanol (10 mL) solution of 6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (1.00 g) and 2-chlorobenzoxazole (0.50 mL) was heated to reflux for 11 hours, then cooled to room temperature, and then diluted with ethyl acetate. The precipitate was collected by filtration, then washed with ethyl acetate, and dried under reduced pressure to obtain the title compound (791 mg, 65%) as a beige solid.
Reaction SMILES: C([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#N.[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1.S(C)C.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].[NH4+].[Cl-]>CCOCC.[Cu]I.C1COCC1>[O:24]([C:22]([N:5]1[CH:4]=[CH:3][CH:8]([C:12]2[CH:13]=[CH:14][C:9]([CH3:17])=[CH:10][CH:11]=2)[CH:7]=[CH:6]1)=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#Cc1cccnc1
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C2C=CN(C(=O)Oc3ccccc3)C=C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 3-cyanopyridine (10 g, 96 mmol), CuI (914 mg, 4.8 mmol), p-tolylmagnesium bromide (100 mL of a 1M solution in Et2O, 100 mmol), THF (200 mL), and Me2S (100 mL) under N2 at 23° C. was added phenyl chloroformate (12.6 mL, 100 mmol) over a 30 min. period. After 2 h, aqueous NH4Cl (20%, 100 mL) and Et2O (100 mL) were added and the mixture was warmed to room temperature. The organic layer was washed sequentially with 1N HCl (50 mL), H2O (50 mL), a 1:1 mixture of 20% aqueous NH4Cl and conc. NH4OH (3×50 mL), and brine (50 mL) then dried (MgSO4). Concentration gave the crude 1-phenoxycarbonyl-4-(p-tolyl)-1,4-dihydropyridine as a tan solid. A portion (8 g) of this crude dihydropyridine was treated with S8 (810 mg) in decalin (25 mL) at reflux for 6 h. This reaction was cooled to rt, EtOAc (100 mL) and H2O (50 mL) were added and the resulting mixture was filtered through celite®. The organic layer was washed sequentially with 1N NaOH (30 mL), water and brine then dried over (K2CO3). Purification (flash chromatography, 20% EtOAc/hexanes) gave the titled compound as a tan solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:8][CH:7]=1.C(N(CC)CC)C.Br[CH2:44][CH2:45][O:46][C:47](Cl)=[O:48].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.CN(C=O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:22]([C@H:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:1]4[CH2:44][CH2:45][O:46][C:47]4=[O:48])=[CH:35][CH:34]=3)[C@@H:13]([CH3:33])[CH2:14]2)[C:23](=[O:25])[CH3:24])=[CH:27][CH:28]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN)cc2)c2ccccc21
Reactant: O=C(Cl)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN3CCOC3=O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S,4R)-N-{1-[4-(3-Amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide (50 mg, 0.102 mmol) was dissolved in methylene chloride (3 mL) and triethylamine (0.150 mL, 1.08 mmol) and cooled to −40° C. 2-Bromoethylchloroformate (0.016 mL, 0.153 mmol) was added and the reaction was allowed to warm to room temperature. After 1 hour at room temperature, DMF (2 mL) and Cs2CO3 (100 mg, 0.307 mmol) were added and the mixture was stirred over night. The mixture was partitioned between methylene chloride and water; the methylene chloride layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (1/1 hexanes/ethyl acetate-ethyl acetate gradient) to afford the product.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[C:15]1([S:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:20][CH2:19][CH:18]([CH2:21][S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:17][CH2:16]1.[OH2:42]>C(OCC)(=O)C.[Ru](=O)=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[C:15]1([S:29]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH2:20][CH2:19][CH:18]([CH2:21][S:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=[O:2])=[O:42])[CH2:17][CH2:16]1
Reactant: O
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)C1(c2cc(F)ccc2F)CCC(CSc2ccccn2)CC1
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=S(=O)(CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)c1ccccn1

Procedure:
To a solution of sodium periodate (223 mg, 1 mmol) in ethyl acetate (2 mL) and water (4 mL) was added ruthenium dioxide (5 mg), followed by the product from Example 78 (250 mg, 0.47 mmol) in ethyl acetate (2 mL). After 30 mins the reaction was diluted with ethyl acetate, filtered through Celite® and the water layer from the filtrate removed. The organic layer was dried (MgSO4), evaporated, and the residue purified by flash chromatography on silica eluting with iso-hexane/ethyl acetate (1:1) to give a white solid (220 mg).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][C@@H:14]([OH:31])[CH2:15][O:16][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27]([O:29]C)=[O:28])[CH3:18].O1CCCC1>CO>[F:3][C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][C@@H:14]([OH:31])[CH2:15][O:16][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])[CH3:18]
Reactant: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C[C@@H]2CCCN2C[C@@H](O)CO[C@H](C)c2ccccc2/C=C/C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
2 N aqueous sodium hydroxide solution (0.36 mL, 0.72 mmol) was added to a solution of methyl (2E)-3-{2-[(1R)-1-({(2R)-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]-2-hydroxypropyl}oxy)ethyl]phenyl}prop-2-enoate (111 mg, 0.24 mmol), which had been obtained in Example 1 (1f), in mixture of tetrahydrofuran (0.72 mL) and methanol (0.72 mL), and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was added with water (10 mL), subsequently with 1N aqueous hydrogen chloride solution (0.72 mL), and extracted with ethyl acetate (10 mL×2). After that, the organic layers were combined, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound as a white amorphous substance (71 mg, yield 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[CH:8]=[N:9][O:10][C:11]=2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19]C(C)(C)C)=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:35]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1)=C=O>Cl.O1CCOCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[N:9][O:10][C:11]=2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([NH:35][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=2)=[O:19])=[CH:24][CH:25]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1oncc1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCC[C@@H]1c1oncc1Cc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A solution of (R)-tert-butyl 2-(4-(4-chlorobenzyl)isoxazol-5-yl)pyrrolidine-1-carboxylate (32 mg, 0.9 mmol) was dissolved in 4M HCl in 1,4-dioxane (2 mL), stirred for 2 h and then concentrated in vacuo. The resulting reaction residue was suspended in dicloromethane (2 mL) and DIEA (31 μL, 0.18 mmol) before 1-isocyanato-4-(trifluoromethyl)benzene (25 mg, 0.13 mmol) was added. After 16 h of stirring, the reaction mixture was concentrated in vacuo. Purification of the resulting residue by silica gel column chromatography (hexanes/ethyl acetate gradient, 10-100% EtOAc) afforded (R)-2-(4-(4-chlorobenzyl)isoxazol-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxamide (19 mg, 47%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([NH:7][N:8]([C:12](=[O:31])/[CH:13]=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:16]=1)[CH:9]([CH3:11])[CH3:10])=[O:6].[C:35]([O-:38])([O-])=O.[K+].[K+].BrCCBr.BrCCOC1C=C(C=CC=1)C(NN(C(=O)/C=C/[C:62]1C2[C:65](=[CH:66]C=CC=2)[N:64]([C:71](OC(C)(C)C)=O)[CH:63]=1)C(C)C)=O>C(#N)C>[CH:9]([N:8]([C:12](=[O:31])/[CH:13]=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:16]=1)[NH:7][C:5](=[O:6])[C:4]1[CH:32]=[CH:33][CH:34]=[C:2]([O:1][CH2:62][CH2:63][N:64]2[CH2:71][CH2:35][O:38][CH2:66][CH2:65]2)[CH:3]=1)([CH3:11])[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CC(C)N(NC(=O)c1cccc(OCCBr)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: CC(C)N(NC(=O)c1cccc(O)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: [K+]
Solvent: CC#N
Solvent: BrCCBr
Product: CC(C)N(NC(=O)c1cccc(OCCN2CCOCC2)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 80 °C

Procedure:
To solution containing (E)-tert-butyl 3-(3-(2-(3-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (67.3 mg, 0.15 mmol) and K2CO3 (40.13 mg, 0.29 mmol) dissolved in anhydrous acetonitrile (10.0 ml), 1,2-dibromoethane (0.0313 ml, 0.36 mmol) was added drop-by-drop. The reaction mixture was refluxed at 80° C. for 48 hr. After concentration under reduced pressure, the solution was separated through silica gel chromatography (n-hexane:EtOAc:methanol=10:3:1) so that ivory solid form of (E)-tert-butyl 3-(3-(2-(3-(2-bromoethoxy)benzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (15 mg, 18.1%). The resultant (E)-tert-butyl 3-(3-(2-(3-(2-bromoethoxy)benzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (15.0 mg, 0.026 mmol) and K2CO3 (7.27 mg, 0.053 mmol) were dissolved in anhydrous acetonitrile (10.0 ml) and the solution was drop-wise added with morpoline (0.01 ml, 0.053 mmol). The reaction mixture was refluxed at 85° C. for 12 hr. After concentration under reduced pressure, the solution was separated through silica gel chromatography (MC:methanol=24:1) so that ivory solid form of (E)-tert-butyl 3-(3-(1-isopropyl-2-(3-(2-morpholinoethoxy)benzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (10.6 mg, 69.9%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[CH2:15]([CH:17]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][SH:23])[CH3:16].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:15]([CH:17]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][S:23][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2)[CH3:16]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: Ic1ccc2c(ccc3nccn32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3nccn32)c1
Temperature: 80 °C

Procedure:
1g (120 mg, 0.5 mmol) and 3-mercaptopropionic acid 2-ethylhexyl ester (110 mg, 0.5 mmol) were dissolved in 1,4-dioxane (5 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.15 mL, 0.84 mmol), Pd2dba3 (10 mg, 0.01 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.02 mmol) were added, and the mixture was degassed with N2 for an additional 10 minutes. The reaction was heated to 80° C. overnight, then cooled to room temperature, concentrated, and purified by silica gel chromatography to give the desired product, 1i.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[OH:6].[H][H].[ClH:16]>O>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:6])[OH:7].[ClH:16]
Reactant: NCCCP(=O)(O)c1ccccc1
Reactant: [H][H]
Agent: Cl
Solvent: O
Product: NCCCP(=O)(O)C1CCCCC1

Procedure:
A mixture of 1.5 g of 3-aminopropyl(phenyl)phosphinic acid in 10 ml of water and 7.9 ml of 1N hydrochloric acid is treated with hydrogen at 25° in the presence of 0.2 g of Nishimura-catalyst (Rh/PtO2). After 1.2 hours hydrogen up-take stops. The reaction mixture is filtered and the filtrate evaporated to dryness. The residue is recrystallized frommethanol/propylenoxide to give 1.2 g of 3-aminopropyl(cyclohexyl)phosphinicacid ×0,4 mol hydrochloric acid as a white solid, m.p. 202°-203°.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[NH:3]1.[H-].[Na+].[CH3:18]O.IC>C1COCC1.O>[CH3:18][N:3]1[C:2]([CH3:15])([CH3:1])[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:14]
Reactant: CC1(C)NC(=O)c2c([N+](=O)[O-])cccc21
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CN1C(=O)c2c([N+](=O)[O-])cccc2C1(C)C
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
A solution of 3,3-dimethyl-7-nitroisoindolin-1-one (Compound 148C, 100 mg, 0.48 mmol) in THF (5 mL), was treated with 60% NaH (58 mg, 1.44 mmol) and stirred for 15 minutes. Methanol (0.078 mL, 1.92 mmol) and iodomethane (0.12 mL, 1.92 mmol) were added to this solution and stirred at 50° C. overnight. Cold water (3 mL) was added, the reaction mixture was concentrated to remove THF and extracted with EtOAc (3×5 mL). The combined organic layer washed with brine, dried (Na2SO4) and concentrated to provide 70 mg of the title compound (66%). 1H NMR (CDCl3, 600 MHz): δ 1.45 (s, 6H), 3.56 (s, 3H), 7.13 (dd, J=7.8, 84 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[N:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[O:27][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])=[N:25][CH:24]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1ccccc1-c1ncc(CBr)o1
Product: O=c1n(Cc2cnc(-c3ccccc3Cl)o2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
113 mg (0.37 mmol) of the compound from Example 5A were reacted with 100 mg (0.37 mmol) of the compound from Example 54A analogously to the preparation of the compound in Example 77. This gave 23 mg (12% of theory) of the title compound.
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>CCOCC>[C:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][CH:10]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: CC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A one-necked, 25-mL, round-bottomed flask equipped with an argon inlet adapter was charged with 5 mL pyridine, 4-bromophenol (1.00 g, 5.78 mmol), and acetic anhydride (2.80 g, 27.4 mmol). The resulting mixture was stirred for 12 h at room temperature. A mixture of water (20 mL) and ether (50 mL) was added and the resulting organic phase was washed with a second 20-mL portion of water. The organic phase was dried over MgSO4, filtered, and concentrated to provide a colorless oil:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:35]([O:38][CH2:39]C)(=[O:37])[CH3:36]>C(#N)C>[CH3:39][O:38][C:35](=[O:37])[CH2:36][N:23]1[C:24]2[C:20](=[CH:19][C:18]([S:15]([N:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:1])[F:28])=[CH:4][CH:5]=4)[CH2:14][CH2:13]3)(=[O:17])=[O:16])=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: O=S(=O)(c1ccc2[nH]ccc2c1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)Cn1ccc2cc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)ccc21
Yield: 99 %

Procedure:
5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-1H-indole (60 mg, 0.15 mmol), methyl bromo acetate (16 μL, 0.18 mmol) and cesium carbonate (95 mg, 0.29 mmol) were stirred in acetonitrile (10 ml) overnight at 70° C. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated to provide {5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid methyl ester (99%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.11(d, 1H) 7.60 (dd, 1H), 7.43 (d, 2H), 7.36 (d, 1H), 7.24 (d, 1H), 6.83 (d, 2H), 6.90 (d, 1H), 4.91 (s, 2H), 3.76 (s, 3H), 3.32-3.30 (m, 4H), 3.15-3.13 (m, 4H).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]I.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[I-:1].[I-:1].[CH2:2]([N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccncc1
Reactant: ICCCCCCCCCCI
Product: [I-]
Product: c1cc[n+](CCCCCCCCCC[n+]2ccccc2)cc1
Temperature: 65 °C
Yield: 90 %

Procedure:
1,10-Diiododecane (mmol) was added to a solution (30 mL) of dry pyridine, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting yellow solid was isolated in a 90% yield. 1H NMR (300 MHz, DMSO-D6) δ 9.10 (2H, d, C2&C6-H), 8.63 (1H, t, C4-H), 8.19 (2H, t, C3&C5-H), 4.60 (2H, t, C′1-CH2), 1.89 (2H, m, C′2-CH2), 1.24 (6H, m, C′3-5-CH2); 13C NMR (75 MHz, DMSO-D6) δ 145.3, 144.5, 127.9, 60.6, 30.6, 28.8, 28.1, 25.2.
Reaction SMILES: [F:1][C:2]1[C:7]([Li])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[CH:10]1[CH:11]=C[NH+]=[CH:14][CH:15]=1.[O-][Cr](Cl)(=O)=O.[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>CCOCC.C(Cl)Cl>[CH:21]1([C:25]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:24])[CH2:22][CH2:23][CH2:14][CH2:15][CH2:10][CH2:11]1
Reactant: c1cc[nH+]cc1
Reactant: [Li]c1cccnc1F
Reactant: C1CCOC1
Agent: O=[Cr](=O)([O-])Cl
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1cccnc1F)C1CCCCCC1
Temperature: -70 °C
Reaction time: 16 h

Procedure:
A solution of cycloheptylcarboxaldehyde (1.89 g, 15 mmol) in dry THF (10 mL) was added dropwise at −70° C. to a solution of 2-fluoro-3-lithiopyridine (prepared from 2-fluoropyridine (1.3 ml, 15 mmol) and LDA (16.5 mmol); Guengoer T., Marsais F., Queguiner G., J. Organomet. Chem. (1981), 215 (2), 139-150) in THF (30 ml). After 2 h30 at −70° C., the reaction was stirred at room temperature during 16 hours. Hydrolysis was performed by addition of water, the mixture was then diluted with ether. After separation of the two layers, the ether solution was washed with brine, dried over Na2SO4 and evaporated in vacuum to yield a viscous oil. The alcohol was dissolved in CH2Cl2 (50 ml) at room temperature and PCC (6.46 g, 30 mmol) was added. After 16 hours, the mixture was filtered on a pad of Celite and concentrated. The residual oil was chromatographied on silica gel (CH2Cl2/hexane 75/25) and the cycloheptyl(2-fluoro-3-pyridinyl)methanone 40 was isolated as a colorless oil (780 mg, 24%).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:21].C([O-])(O)=O.[Na+]>C(O)(CC)(C)C.CCO>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:21])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: [O-][n+]1ccccc1Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)(C)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCNc1cccc[n+]1[O-]
Reaction time: 48 h

Procedure:
A mixture of N-Boc-1,3-diaminopropane (3.48 g, 20 mmol), 2-chloropyridine N-oxide hydrochloride (3.98 g, 24 mmol), and NaHCO3 (8.40 g, 100 mmol) in tert-amyl alcohol (50 mL) is heated at reflux under argon. After 48 h, the reaction is cooled, diluted with EtOH, filtered, and concentrated. The residue is reconcentrated from toluene and chromatographed (silica gel) to give the title compound.