Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][NH:6][N:7]=[C:8]([C:10]1[C:19]2[C:18]([C:20]([OH:22])=[O:21])=[CH:17][C:16](Cl)=[C:15]([C:24]([OH:26])=[O:25])[C:14]=2[C:13]([C:27](=[N:29][NH:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[OH:28])=[CH:12][C:11]=1Cl)[OH:9].[NH2:39][CH2:40][CH2:41][CH2:42][OH:43]>>[CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][NH:6][N:7]=[C:8]([C:10]1[C:19]2[C:18]([C:20]([OH:22])=[O:21])=[CH:17][C:16]([NH:39][CH2:40][CH2:41][CH2:42][OH:43])=[C:15]([C:24]([OH:26])=[O:25])[C:14]=2[C:13]([C:27](=[N:29][NH:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[OH:28])=[CH:12][C:11]=1[NH:39][CH2:40][CH2:41][CH2:42][OH:43])[OH:9]
Reactant: CN(C)CCCNN=C(O)c1cc(Cl)c(C(O)=NNCCCN(C)C)c2c(C(=O)O)cc(Cl)c(C(=O)O)c12
Reactant: NCCCO
Product: CN(C)CCCNN=C(O)c1cc(NCCCO)c(C(O)=NNCCCN(C)C)c2c(C(=O)O)cc(NCCCO)c(C(=O)O)c12

Procedure:
Compound 7 (45 mg, 0.089 mmol) was suspended in 3-amino-propanol (0.5 ml) in a microwave reaction vessel. The tube was flushed with nitrogen, sealed and treated at 150° C. for 10 min in the microwave. The mixture was then diluted down with water (25 ml), basified with 2M sodium carbonate and extracted with chloroform (5×5 ml). The organics were treated in the usual manner to afford a blue solid. The crude product was purified by HPLC to obtain 9 as a blue solid. Yield 9 (4.13 mg, 0.0071 mmol, 7.9%): 1H NMR (MeOD) δ: 1.98-2.07(m, 8H), 2.61(s, 12H), 2.84(m, 4H), 3.53(t, 4H, J=6.9 Hz), 3.84(t, 4H, J=6.0 Hz), 4.09(t, 4H, J=7.1 Hz), 7.68(s, 2H); 13C NMR (MeOD) δ: 25.98(2×CH2), 33.15(2×CH2), 39.15(2×CH2), 41.29(2×CH2), 44.71(4×CH3), 57.66(2×CH2), 60.63(2×CH2), 102.06(2×C), 118.41(2×CH), 121.52(2×C), 126.06(2×C), 146.49(2×C), 163.80(2×C═O), 166.72(2×C═O); HRMS (ES+) calcd C30H42N6O6 [M+H]+ 583.3239. Found: 583.3260.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:45]=[CH:44][C:24]([C:25]([NH:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][CH:41]4[CH2:43][CH2:42]4)[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[O:26])=[CH:23][C:22]=1[O:46][CH3:47].C(O)(C(F)(F)F)=O>>[CH:14]1([N:7]2[CH2:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:45]=[CH:44][C:24]([C:25]([NH:27][C@H:28]5[CH2:29][CH2:30][C@H:31]([N:34]6[CH2:39][CH2:38][N:37]([CH2:40][CH:41]7[CH2:43][CH2:42]7)[CH2:36][CH2:35]6)[CH2:32][CH2:33]5)=[O:26])=[CH:23][C:22]=4[O:46][CH3:47])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C

Procedure:
2-Chloro-9-cyclopentyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (Intermediate 1) (0.13 g, 0.43 mmol, 1 eq), 4-amino-N-(trans-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (Intermediate 11) (0.26 g, 0.67 mmol, 1.5 eq) and TFA (0.17 mL, 2.2 mmol, 5 eq) in TFE (3 mL) were heated together at 80° C. for 18 hours. Further quantity of Intermediate 1 (0.10 g) was added and the reaction further heated for 48 hours. RM was concentrated in vacuo and the residue was purified by flash column chromatography on silica eluting with 0→420% ammonia/MeOH in DCM gradient followed by preparative HPLC (Preparative—4) then finally preparative RP-HPLC-MS (Preparative—1) to give 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((trans)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (0.11 g, 26%).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][O:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]1([C:7]2[CH2:8][O:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:36])=[O:35])=[O:26])=[CH:21][CH:22]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1
Reactant: NS(=O)(=O)c1ccccc1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1)NS(=O)(=O)c1ccccc1

Procedure:
Prepared by coupling 3d and benzene sulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (46%); ESI m/z: 492 (M−H−, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](Cl)=[O:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.[CH3:34][NH:35][O:36][CH3:37].C(N(CC)CC)C>C(Cl)Cl>[CH3:37][O:36][N:35]([CH3:34])[C:24]([C:6]1[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)=[O:25]
Reactant: CNOC
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)Cl)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
To a solution of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride (200 mg) in methylene chloride (4 ml) were added N,O-dimethylhydroxylamin e hydrochloride (70 mg) and triethylamine (0.2 ml) and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and crystallized from diisopropyl ether to give the title compound (180 mg).
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([OH:24])([CH3:23])[CH2:19][CH:20]([CH3:22])[CH3:21])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[O:24][C:18]([CH2:19][CH:20]([CH3:21])[CH3:22])([CH3:23])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1C(C)(O)CC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nn(C)c(F)c1C1=Nc2ccccc2C(C)(CC(C)C)O1
Reaction time: 2 h
Yield: 63 %

Procedure:
The above product from step 2 is boiled in 150 ml of toluene with 0.2 g of p-toluenesulphonic acid on a water separator for 2 h. The mixture is washed with aqueous sodium bicarbonate solution and the organic phase is concentrated under reduced pressure. By stirring with heptane, it is possible to precipitate and remove by filtration the N-(2-acetylphenyl)-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide still present from the previous step. Chromatography gives 7.2 g (purity 85.1%; 63% of theory) of 2-(5-fluoro-1,3-dimethyl-1H-pyrazol-4-yl)-4-isobutyl-4-methyl-4H-3,1-benzoxazine.
Reaction SMILES: O[N:2]=[C:3]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].[H][H]>C(O)(=O)C.[Pd]>[NH2:2][CH:3]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[OH:5]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)C(CC(C)C)=NO)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(C(O)C(N)CC(C)C)cc1
Yield: 82.1 %

Procedure:
2-Hydroxyimino-1-(4-methoxyphenyl)-4-methyl-pentane-1-one (8.72 g; 37.1 mmol) was dissolved in acetic acid (88 ml). The solution was added with 5% palladium-charcoal (0.87 g) and the reactant was catalytically hydrogenated at normal pressure and at 80° C. until hydrogen was absorbed in a molar amount of three times that of the reactant. After removal of the catalyst by filtration, the acetic acid was removed under reduced pressure. The residue was dissolved in 1N hydrochloric acid (80 ml). The solution was washed twice with ether (30 ml) and the aqueous layer was basified with a 20% aqueous solution of sodium hydroxide. The aqueous layer thus treated was extracted three times with chloroform and the extracts were combined together and then washed once with brine. The resulting extract was dried over sodium sulfate and the solvent was removed by distillation under reduced pressure to give light-yellowish crystals (6.80 g). The crystals were recrystallized from benzene and hexane to obtain 5.24 g of the intended compound as white crystals (yield: 63%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([NH:17][C:18]([C:20]3[N:24]4[CH:25]=[CH:26][C:27]([CH:29]=[CH2:30])=[CH:28][C:23]4=[N:22][CH:21]=3)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1.[OH2:39].CC(C)=O.[OH2:44]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([NH:17][C:18]([C:20]3[N:24]4[CH:25]=[CH:26][C:27]([CH:29]([OH:44])[CH2:30][OH:39])=[CH:28][C:23]4=[N:22][CH:21]=3)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: C=Cc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2cc(C(O)CO)ccn12
Temperature: 25 °C

Procedure:
To a solution of N-(1-benzyl-1H-indazol-4-yl)-7-vinylimidazo[1,2-a]pyridine-3-carboxamide (27 mg; 0.069 mmol) in acetone/water (3:2; 1 mL) were added osmium tetroxide (0.1 equivalents as a 2% solution in t-butanol) and N-methylmorpholine N-oxide (1.2 equivalents as a 50% solution on water). The mixture was stirred at ambient temperature for several days. Further aliquots of osmium tetroxide and N-methyl morpholine N-oxide were added at intervals until the reaction was complete by LC. The mixture added to water and extracted into ethyl acetate. Some insoluble material was isolated by filtration. The extracts were combined, concentrated under vacuum and combined with the solids isolated by filtration. The combined material was purified by preparative thin layer chromatography on silica, eluting with dichloromethane/ethanol/ammonium hydroxide (100:20:0.5) to give the desired product (2.6 mg). MS (APCI), m/z=428.2 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([CH2:8][N:9]2[C:15](=[O:16])[C@@H:14]([NH:17][C:18]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[NH:28][C:27]4=[O:37])[CH2:22][CH2:21]3)=[O:19])[CH2:13][NH:12][C@H:11]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:10]2)[CH2:7][CH2:6]1.C(N(CC)CC)C>ClCCl>[C:1]([N:12]1[CH2:13][C@@H:14]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:28][C:27]3=[O:37])[CH2:24][CH2:25]2)=[O:19])[C:15](=[O:16])[N:9]([CH2:8][CH:5]2[CH2:6][CH2:7]2)[CH2:10][C@@H:11]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(N[C@H]1CN[C@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C[C@@H](NC(=O)N2CCC(n3cc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N(CC2CC2)C[C@@H]1c1ccccc1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Acetyl chloride (2.1 □L, 0.03 mmol) was added to a solution of N-[(3R,6S)-1-(cyclopropylmethyl)-7-oxo-3-phenyl-1,4-diazepan-6-yl]-4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxamide (16.9 mg, 0.03 mmol) and triethylamine (9 □L, 0.06 mmol) in dichloromethane (0.5 mL). After 30 min, the mixture was concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) gave the title compound (17 mg). MS 571.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[CH:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C:17](=[O:19])[NH:1][C:2]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:15][CH:14]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1NCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 81 %

Procedure:
[N-(2-Aminophenyl)]-benzylamine (15.1 mmol, 3.0 g) in dichloromethane (80 ml) is charged with triphosgene (5.3 mmol, 1.57 g) in dichloromethane (40 ml) and is stirred at room temperature over the weekend. The suspension is poured into water (100 g) and is extracted with dichloromethane (2×50 ml). The organic layer is a suspension The colorless solid is filtered off, is dried in vacuo and is recrystallized from ethyl acetate to give the title product (81%)(R1=H, R2=benzyl, n=0).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3].[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28].C1CCC(N=C=NC2CCCCC2)CC1.II>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([O:10][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[F:17])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOCc1c(OC)cccc1C(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: II
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCOCc1c(OC)cccc1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Yield: 110 %

Procedure:
Into a 200 mL round bottom flask was added 6.6 g (0.0297 mol) of 2-allyloxymethyl-3-methoxy benzoic acid and 40 mL of ethyl acetate. 24.05 g of a 25% pentafluorophenol (6.01 g, 0.0327 mol) solution in ethyl acetate was added while stirring. The reaction flask was placed into a water bath and while stirring small portions of DCC (6.2 g, 0.030 mol) were added. The stirring continued overnight at room temperature. The reaction was filtered through two Whatman #541 filters to remove the DCU precipitate. The ethyl acetate solution was concentrated to yield 12.8 g (110% yield), indicating presence of DCC and DCU. This was confirmed by TLC (1:1 ethyl acetate:hexane), which indicated a Rf of 0.72 plus other less polar compounds (I2 stain indicates about 85% purity). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.7 (d, 1H), 7.45 (t, 1H), 7.15 (d, 1H), 6.0-5.9 (m, 1H), 5.3-5.1 (2d, 2H), 4.88-4.83 (d, 21-H), 4.06 (d, 2H), 3.90 (s, 3H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].C(=O)=O.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O-:20].[K+]>>[OH:20][C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:1]([OH:2])=[O:4])[CH:15]=2)[CH:10]=1
Reactant: [O-]c1ccc2ccccc2c1
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc2cc(O)ccc2c1
Temperature: 280 °C
Yield: 76 %

Procedure:
A stainless steel pressure autoclave is charged with 50 parts of kerosene and 38 parts of potassium carbonate and heated to 280° C. It is then pressurized with 10 bar of carbon dioxide. Over the course of 5 hours, a mixture of 50 parts of potassium β-naphtholate and 38 parts of potassium carbonate are metered in as a suspension in kerosene via a metering pump, part of the kerosene being distilled off, condensed and transferred out of the reaction vessel at reduced pressure. After the usual workup, the 2-hydroxynaphthalene-6-carboxylic acid is obtained in a yield of 76% based on potassium naphtholate used. In addition, 14% of unreacted β-naphthol and small amounts of 2-hydroxynaphthalene-3-carboxylic acid and 2-hydroxynaphthalene-3,6-dicarboxylic acid are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]=[CH:5]2.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl.C(OCC)C>[C:11]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH:6]=[CH:5]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc2c(c1)C=CC2
Reactant: Br[Mg]c1ccccc1
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: C1=Cc2cc(-c3ccccc3)ccc2C1
Temperature: 10 °C

Procedure:
A dry 100 mL three-neck round bottom flask equipped with a condenser, magnetic stir bar, thermometer, and a nitrogen inlet was charged with 5-bromoindene (99+% purity, 9.65 g, 50 mmol), diethyl ether (anhydrous, 60 mL), and phenylmagnesium bromide (18.0 mL 3M in diethyl ether, 54 mmol). The mixture was chilled to 10° C. and [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride (0.1 g, 0.2 mmol) was added. The reaction mixture was warmed gradually to reflux. As the reaction progressed the clear solution became turbid from the precipitation of magnesium bromide by-product. After 4 hours at reflux the reaction mixture was quenched in chilled 5% aqueous HCl (200 mL). Additional diethyl ether (100 mL) was added and the organic phase was separated, water washed, and dried over anhydrous magnesium sulfate. Evaporation of diethyl ether followed by vacuum distillation (90° C./0.5 mm Hg) gave 5-phenylinene (8.4 g, 97% purity by GC) as pale yellow crysta1s. 1HNMR (CD2Cl2, 500 MHz) 50:50 mixture of isomers; δ7.72 (s, 1H); 7.62 (m, 5H); 7.52 (t, J=8 Hz, 2H); 7.43 (m, 6H); 7.32 (m, 2H); 6.93 (m, 2H); 6.61 (m, 2H); 3.47 (s, 2H); 3.44 (s, 2H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[SiH3]Cl.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].Cl.C(N(CC)CC)C>C(N(CC)CC)C.C1CCCCC1>[Si:1]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Cl:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCCCCCCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: [SiH3]Cl
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCl
Temperature: 25 °C

Procedure:
A 250 ml, three-necked flask was fitted with a large magnetic, egg-shaped stir bar, a thermocouple, a small, pressure-equalizing addition funnel, a reflux condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 16.20 grams (0.108 mole, 1.00 equivalents) of t-butyldimethylsilyl chloride, and 100 grams of cyclohexane. The silyl chloride rapidly dissolved, endothermically. 6-Chloro-1-hexanol, 15.06 grams (0.108 mole, 1.00 equivalent) was then added dropwise in five minutes. Triethylamine, 10.93 grams (0.108 mole, 1.00 equivalent) was then added dropwise to the reaction mixture. An exotherm was noted, and fumes of triethylamine hydrochloride were observed. A fine, white precipitate rapidly developed. The reaction mixture was stirred at room temperature, and monitored by GC analysis. An aliquot of the clear supernatant was injected into the GC. After one and a half hours, both starting materials were still present, and the conversion to the desired product was only 27.8%. The reaction mixture was stirred overnight at room temperature, under a blanket of argon. The sample after 21 hours indicated only a 53.3% conversion to the desired product. After 161.5 hours stirring, the conversion was still only 88.0%.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:24])=O>C(Cl)(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: ClCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 200 g. of m-phenoxy-benzyl alcohol in 1 liter of dry chloroform 2 ml. of pyridine are added and a solution of 142.8 g. thionyl-chloride in 150 ml. of chloroform is added dropwise under cooling with ice water. When the addition is completed the cooling is terminated and the solution is allowed to warm up to room temperature under stirring and the temperature is maintained under stirring until the vigorous gas evolution ceases. The mixture is then boiling under stirring until the gas evolution ceases completely. The solution is then poured into 2 liters of cold water, the chloroform layer is separated and the aqueous layer is shaken out in 400 ml. of chloroform. The combined chloroform solutions are washed once with water and dried above sodium sulphate. The drying agent is filtered off and chloroform is distilled off; thus 210 g. (96%) of m-phenoxy-benzyl chloride are obtained, which can be distilled at 128° to 130° C. at a pressure of 0.3 mmHg. Substantially no forerun and residue are obtained.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=3[C@:5]3([C@@H:10]2[CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:4][CH2:3]1.[CH:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:35]=[C:34](Cl)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[C:23]1([C:26]2[N:35]=[C:34]([O:19][C:16]3[CH:17]=[CH:18][C:13]4[CH2:12][C@H:11]5[N:2]([CH3:1])[CH2:3][CH2:4][C@@:5]6([C:14]=4[CH:15]=3)[C@H:10]5[CH2:9][CH2:8][CH2:7][CH2:6]6)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=1
Reactant: CN1CC[C@@]23CCCC[C@@H]2[C@@H]1Cc1ccc(O)cc13
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2nc(-c4ccccc4)nc4ccccc24)cc13
Yield: 95.7 %

Procedure:
The O-demethylation procedure described in Steroids 11:151 [1968] was modified for this synthesis. First, 16.1 g (62.3 mmol) of dextrorphan, 2, were dissolved in 500 mL hot acetone, to which 15.5 g (64.4 mmol) AM-ex-OL (Aldrich) and 17.13 g (123.9 mmol) potassium carbonate were added. The reaction mixture was stirred at reflux overnight under an atmosphere of argon. After cooling, the reaction mixture was poured into a separatory funnel to which 500 mL water were added. Extraction with 1×500 and 2×250 mL benzene was followed by washing the combined organics with 1×250 mL water and removing the solvent in vacuo to give 27.51 g (96%) product as a white glass which was homogeneous by TLC. Recrystallization in ethyl acetate gave pure 3 as white crystals, mp 138°-139° C. EIMS m/z 461. Anal. (C31H31N3) C, H, N.
Reaction SMILES: COC(=O)N(CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)CC1C=C2C(C)=NN(C)C2=NC=1N(CC1CCCC1)CC.[C:42]([O:46][C:47](=[O:81])[CH2:48][N:49]([CH2:66][C:67]1[CH:72]=[C:71]([C:73]([F:76])([F:75])[F:74])[CH:70]=[C:69]([C:77]([F:80])([F:79])[F:78])[CH:68]=1)[CH2:50][C:51]1[C:52]([C:61]#[C:62][CH2:63][CH2:64][CH3:65])=[N:53][C:54]2[C:59]([CH:60]=1)=[CH:58][CH:57]=[CH:56][CH:55]=2)([CH3:45])([CH3:44])[CH3:43]>C(O)C.[Pd]>[C:42]([O:46][C:47](=[O:81])[CH2:48][N:49]([CH2:66][C:67]1[CH:72]=[C:71]([C:73]([F:76])([F:75])[F:74])[CH:70]=[C:69]([C:77]([F:78])([F:79])[F:80])[CH:68]=1)[CH2:50][C:51]1[C:52]([CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])=[N:53][C:54]2[C:59]([CH:60]=1)=[CH:58][CH:57]=[CH:56][CH:55]=2)([CH3:43])([CH3:44])[CH3:45]
Reactant: CCCC#Cc1nc2ccccc2cc1CN(CC(=O)OC(C)(C)C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC)c(C)nn2C
Solvent: CCO
Product: CCCCCc1nc2ccccc2cc1CN(CC(=O)OC(C)(C)C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 44 %

Procedure:
The compound obtained in Example 16, [(3,5-bis-trifluoromethyl-benzyl)-(2-pent-1-ynyl-quinolin-3-ylmethyl)-amino]-acetic acid tert-butyl ester (163 mg, 0.3 mmol) was dissolved in ethanol (3 mL), and palladium [10% on carbon powder (50 mg)] was added. The resulting mixture was stirred under H2 (using a balloon) for 3 h. The sample was diluted in ethanol and filtered through Celite™. The Celite™ was washed with ethanol, the filtrate was concentrated by rotary evaporation, and the resulting sample was dried overnight under vacuum and the crude was purified (Biotage Horizon HPFC chromatography system, SiO2, 80:20 hexanes: ethyl acetate) to give the titled product as a colorless oil (0.075 g, yield: 45%).