Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:33]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][N:27]([CH2:29][C:30]([OH:32])=O)[CH:28]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:64]([NH2:69])[C:65]([CH3:68])([CH3:67])[CH3:66]>CN(C)C=O>[CH3:66][C:65]([CH3:68])([CH3:67])[CH2:64][NH:69][C:30](=[O:32])[CH2:29][N:27]1[CH:28]=[C:24]([C:23]2[N:18]3[N:17]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[CH:10][CH:11]=4)[N:33]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH:25]=[N:26]1
Reactant: CC(C)(C)CN
Reactant: O=C(O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CNC(=O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-pyrazol-1-yl)-acetic acid (0.60 g, 0.128 mmol) in dimethylformamide (1 ml) was added EDCI (50 mg, 0.256 mmol), diisopropylethylamine (112 μl, 0.640 mmol), HOBT (35 mg, 0.256 mmol) and finally neopentylamine (30 μl, 0.256 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The title compound was purified by preparatory HPLC to yield the desired product. LCMS method: 2, RT: 2.51 min, MI: 517 [M+1]; 1H NMR (300 MHz, DMSO) 9.40 (s, 1H), 8.85 (s, 1H), 8.42 (s, 1H), 8.16 (s, 2H), 7.61 (d, 2H), 7.54 (d, 1H), 7.40 (dd, 2H), 6.92 (d, 2H), 4.98 (s, 2H), 4.02 (t, 2H), 2.93 (d, 2H), 2.87 (t, 2H), 2.63 (s, 4H), 1.69 (s, 4H), 0.83 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1Br
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1Br

Procedure:
3-Bromo-4-methoxybenzaldehyde (50 g, 232 mmol), malonic acid (36.3 g, 348 mmol) and 250 ml of anhydrous pyridine are introduced into a 500 ml round-bottomed flask. Piperidine (11.4 ml, 116 mmol) is added and the medium is brought to reflux for 3 h. The pyridine is removed under vacuum and the medium is run on to 500 ml of a 1M aqueous hydrochloric acid solution. The solid is filtered off, washed with water and dried over P2O5.
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[Na+].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1CCN(c2ccc(C(=O)OCC)cc2)CC1
Reaction time: 0.25 h

Procedure:
A 0° C. solution of methyltriphenylphosphonium bromide (500 mg, 1.4 mmol) in THF (1.5 mL) was treated dropwise with 1M sodium hexamethyldisilazide in THF (1.4 mL), stirred for 15 minutes, and added dropwise to a 0° C. solution of Example 158B (0.25 g, 1.0 mmol) in THF (2.1 mL). After stirring for 15 minutes, the reaction was quenched with water and was extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated The concentrate was purified by flash column chromatography on silica gel with 9:1 hexanes/ethyl acetate to provide the desired product. MS (DCI) m/e 246 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[NH:20][S:19]2(=[O:25])=[O:24])=[C:14]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:13]=1.[Li+].[BH4-].Cl>C1COCC1>[CH2:27]([O:26][C:14]1[CH:13]=[C:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][OH:2])[CH:17]=[CH:16][C:15]=1[N:18]1[S:19](=[O:25])(=[O:24])[NH:20][C:21](=[O:23])[CH2:22]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CN(c2ccc(Cc3ccccc3CCO)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {2-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-phenyl}-acetic acid methyl ester (32 mg, 0.067 mmol) in THF (4 mL) is added LiBH4 (25 mg, 0.115 mmol) and the mixture is stirred at RT for 2 h. The mixture is cooled in an ice bath and is acidified with 1N HCl. The mixture is extracted with EtOAc and the organic phase is washed with 1N HCl and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound as a gum.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)(Cl)=[O:5])[CH3:2].[CH2:18]([OH:21])[CH:19]=[CH2:20].C(N(CC)CC)C>C(Cl)Cl.O>[F:17][C:14]([F:15])([F:16])[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:21][CH2:18][CH:19]=[CH2:20]
Reactant: CCOP(=O)(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: C=CCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCC
Reaction time: 5 h

Procedure:
The 3-trifluoromethylbenzylphosphonochloridic acid ethyl ester of Example 4 (0.2 g, 0.7 mmol) was dissolved in 20 mL of CH2Cl2 and added slowly at 0° C. to a mixture of 1.0 mmol of allyl alcohol and 1.0 of mmol triethylamine in 20 mL of CH2Cl2. The reaction mixture was stirred for 5 hours and then diluted with H2O. The aqueous phase was further extracted 3 times with CH2Cl2. The organic extracts were combined and, after drying with anhydrous Na2SO4, were evaporated to give the crude product as an oil. Purification by column chromatography on silica gel using ethyl acetate/hexane (2.5:1) yielded 0.14 g (63%) of analytically pure product as a colorless oil. D.C.I.M.S.[MH+ 309].
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[OH:18])[CH2:7][CH2:6]2)[O:4]CC1.O.[NH+]1C=CC=CC=1>CC(C)=O>[OH:18][C:12]1[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=1[CH:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1
Reactant: Oc1ccc(C2CCC3(CC2)OCCO3)c(O)c1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(c2ccc(O)cc2O)CC1
Yield: 99.9 %

Procedure:
A round bottomed flask was charged with 4-(1,4-dioxaspiro[4.5]dec8-yl)-1,3-benzenediol (11.3 g), acetone (250 ml) and water (50 ml). To the stirred solution was added pyridinium ptoluenesulfonate (1.14 g) in one portion and the reaction mixture was then heated to reflux temperature for 8 hr. After allowing the reaction mixture to cool to room temperature, most of the acetone was removed in vacuo and the remaining mixture was partitioned between ethyl acetate (200 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford an off white powder. After washing the powder with dichloromethane (100 ml) and removing excess solvent under reduced pressure, the title compound (9.30 g, 100%) was obtained as an off-white powder. m/z (ES+) 207 (M+H+).
Reaction SMILES: C([O:8][C:9](=[O:47])[C@H:10]([N:16]1[CH2:20][C@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[C@H:18]([CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][C:37]([F:46])([F:45])[C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:31][CH2:30]2)[CH2:17]1)[CH2:11][CH:12]1[CH2:15][CH2:14][CH2:13]1)C1C=CC=CC=1.C(OC(=O)[C@H](N1C[C@H](C2C=CC=C(F)C=2)[C@@H](CN2CCC(CCC(F)(F)C3C=CC(F)=CC=3)CC2)C1)CC1CCC1)C1C=CC=CC=1>>[F:46][C:37]([F:45])([C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1)[CH2:36][CH2:35][CH:32]1[CH2:33][CH2:34][N:29]([CH2:28][C@H:18]2[C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH2:20][N:16]([C@H:10]([CH2:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)[C:9]([OH:47])=[O:8])[CH2:17]2)[CH2:30][CH2:31]1
Reactant: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@@H](CN2CCC(CCC(F)(F)c3ccc(F)cc3)CC2)[C@@H](c2cccc(F)c2)C1
Agent: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCC(F)(F)c3ccc(F)cc3)CC2)[C@@H](c2cccc(F)c2)C1
Product: O=C(O)[C@@H](CC1CCC1)N1C[C@@H](CN2CCC(CCC(F)(F)c3ccc(F)cc3)CC2)[C@@H](c2cccc(F)c2)C1

Procedure:
The title compound was prepared using procedures analogous to those described in EXAMPLE 155, Step J, substituting 2-(R)-(3-(R)-((4-(3,3-difluoro-3-(4-fluorophenyl)propyl)piperidin-1-yl methyl)-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid benzyl ester (from EXAMPLE 198, Step A) for 2-(R)-(3-(S)-((4-(3,3-difluoro-3-(4-fluorophenyl)propyl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid benzyl ester. For the title compound: 1H NMR (500 MHz, CD3OD) δ 7.49 (dd, J=9, 6, 2H), 7.35 (td, J=8, 6, 1H), 7.16 (t, J=9,22H), 7.11-7.06 (m, 2H), 7.00 (td, J=9,2, 1H), 3.76 (q, J=8, 1H), 3.72-3.62 (m, 2H), 3.44 (t, J=10, 1H), 3.36 (dd, J=9, 6, 11H), 3.21 (dd, J=11, 7, 1H), 2.92-2.73 (m, 3H), 2.50 (septet, J=8, 1H), 2.22-2.06 (m, 5H), 2.02-1.67 (m, 9H), 1.60 (bd, J=12, 2H), 1.31-1.01 (m, 5H); ESI-MS 561 (M+H); HPLC A: 2.64 min.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:16]([O:28][CH2:29][CH:30]1[O:32][CH2:31]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:31][CH:30]([OH:32])[CH2:29][O:28][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC(C)CCCCCCCCCOCC1CO1
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC(C)CCCCCCCCCOCC(O)COc1ccc(N2CCS(=O)(=O)CC2)cc1
Yield: 29.8 %

Procedure:
4-(1,1-dioxo-thiomorpholin-4-yl)phenol (2.3 g, 10 mmol), isododecylglycidyl ether (2.4 g, 10 mmol) and ethyltriphenylphosphonium bromide (0.2 g) are reacted and purified as described for compound 102 to afford a light yellow liquid 1.4 g (30%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][O:18][CH2:19][CH2:20][OH:21])=[O:6])[CH:2]=[CH2:3].[C:22]([SH:25])(=[O:24])[CH3:23].[OH-].[Ca+2].[OH-]>CC(C)CC(=O)C>[C:22]([S:25][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:9]1)(=[O:24])[CH3:23]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COCCO
Reactant: CC(=O)S
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1COCCO

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (28.0 g) and thioacetic S-acid (12.47 ml) in 4-methyl-2-pentanone (168 ml) was added calcium hydroxide (6.41 g) below 45° C. Under reduced pressure (50-60 mmHg), the solvent (60 ml) was removed at 40°-50° C. The resulting suspension was heated at 80°-85° C. for 15 hours. After cooling, insoluble material was filtered off and washed with ethyl acetate (50 ml). The filtrate and washing were combined, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (280 g) and eluted with a mixture of methanol and dichloromethane (1:99 V/V) to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-hydroxyethyloxymethyl)pyrrolidine (10.74 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=O)[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1.CCOC(C)=O>C1(C)C=CC=CC=1.C1CCCCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[S:45])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=O)cc2)CCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=S)cc2)CCC1
Yield: 185.6 %

Procedure:
To a solution of {1-[4-(4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (30 mg, 0.0642 mmol) in toluene (3 mL) was added Lawesson's reagent (2,4-bis-(4-methoxy-phenyl)-[1,3,2,4]dithiadiphosphetane 2,4-disulfide) (15.6 mg, 0.039 mmol). The reaction mixture was heated at reflux for 3 hours. The cooled mixture was subjected to flash chromatography (SiO2, 20% EtOAc in cyclohexane). A second chromatography (SiO2, 3% EtOAc in toluene) afforded the title compound (35 mg). LCMS (Method A): RT=5.08 min, [M+H]+=484.
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C@H:7]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C:9](=[CH:21][CH2:22]P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH3:44][Si:45]([CH3:68])([CH3:67])[O:46][C:47]([CH3:66])([CH3:65])[C:48]#[C:49][CH2:50][C@H:51]([C:53]1[C@:54]2([CH3:64])[C@@H:59]([CH2:60][CH2:61][CH:62]=1)[C:58](=O)[CH2:57][CH2:56][CH2:55]2)[CH3:52]>C1COCC1>[C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C@H:7]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:10][C:9](=[CH:21]/[CH:22]=[C:58]2\[CH2:57][CH2:56][CH2:55][C@@:54]3([CH3:64])[C@H:59]\2[CH2:60][CH2:61][CH:62]=[C:53]3[C@H:51]([CH3:52])[CH2:50][C:49]#[C:48][C:47]([CH3:66])([O:46][Si:45]([CH3:44])([CH3:68])[CH3:67])[CH3:65])[CH2:8]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=CCP(=O)(c2ccccc2)c2ccccc2)C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: C[C@H](CC#CC(C)(C)O[Si](C)(C)C)C1=CCC[C@H]2C(=O)CCC[C@]12C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](CC#CC(C)(C)O[Si](C)(C)C)C1=CCC[C@H]2/C(=C/C=C3C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C3)CCC[C@]12C
Reaction time: 0.75 h

Procedure:
511 mg (0.893 mmol) of carefully dried (3R,5R)-[2-[3,5-bis-(t-butyl-dimethyl-silanyloxy)-cyclohexylidene]-ethyl]-diphenyl-phosphine oxide (Tetrahedron Lett. 32, 7663 (1991)) was dissolved in 5 ml of abs. THF and treated at -78° with 0.65 ml of nBuLi (1.55M, hexane). 15 Minutes later, 179 mg (0.496 mmol) of (4aS,8aR)-5-[(R)-5-trimethylsilanyloxy-1,5-dimethyl-hex-3-ynyl]-4a-methyl-1,2,3,4,4a,7,8,8a-octahydro-naphthalen-1-one, dissolved in 0.5 ml of abs. THF, was added to the deep red solution and kept for 1 h at -78° and for 0.75 h at 0°. The reaction mixture was then poured onto crushed ice/KH2PO4, extracted twice with ether, washed with water and brine, dried over sodium sulfate, and the solvents carefully removed i.V. Flash chromatography (SiO2, hexane/AcOEt=9/1) afforded 108 mg of the title compound as colorless oil, besides 122 mg of recovered ketone in the more polar fractions.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16]C)[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:18][CH3:19])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:20])[CH:5]=1.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([OH:16])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:18][CH3:19])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:20])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2

Procedure:
5,6-Dichloro-9a-ethyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (15 gm., 0.048 mole) is mixed with pyridine hydrochloride (120 gm.) in a reaction vessel and heated in a metal bath at 195°-200° C. for 30 minutes. The mixture is cooled somewhat and poured with stirring into cold water (800 ml.). The solid that separates is removed by filtration and washed with water. After drying, the product is triturated with acetonitrile (80 ml.) at 60°, cooled, filtered and dried. The yield of crude 5,6-dichloro-9a-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one is 12.2 gm., m.p. 260°-265° C. This material is pure enough for use in the next step.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>O1CCOCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:14]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: Nc1ccc(O)cc1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: O=C(CCCCCCCCCCBr)Nc1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 94.7 g (0.357 mol) of 11-bromoundecanoic acid and 70 ml of thionyl chloride was heated with a 90° oil bath until gas evolution had essentially stopped. Excess thionyl chloride was distilled from the reaction mixture under aspirator vacuum. Toluene (50 ml) was added and this was also distilled under aspirator vacuum. The cooled reaction mixture was then added to a slurry of 78.0 g (0.715 mol) of 4-aminophenol in 500 ml of dioxane. After stirring for 30 min the mixture was filtered and the solid was washed with hot dioxane. The combined filtrates were concentrated and the residue was recrystallized from chloroform to give the end product as colorless crystals, mp 116°-117°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:23][N:24]=[C:25]=[S:26]>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:25](=[S:26])[NH:24][CH3:23])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CN=C=S
Reactant: Nc1nc2ccccc2c2c1ncn2CCC1CCNCC1
Solvent: ClCCl
Product: CNC(=S)N1CCC(CCn2cnc3c(N)nc4ccccc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A suspension of 0.50 g of 4-amino-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]-quinoline and 0.37 g of methylisothiocyanate in 10 ml of methylene chloride was stirred at room temperature for 1 hour, and then the precipitated crystals were collected by filtration to give 0.56 g of colorless crystals. Recrystallization from a mixture of methylene chloride and methanol gave colorless crystals having the melting point of from 216 to 218° C.
Reaction SMILES: Cl[Si:2]([CH3:23])([CH3:22])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]1[CH3:21].CCN(CC)CC.C[SiH]([N:34](C1C2C(=C(C)C=C(C)C=2)C(C)=C1C)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)C>CCCCCC>[CH:35]1([NH:34][Si:2]([CH3:23])([CH3:22])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[CH3:21])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC1=C(C)C(N(C2CCCCC2)[SiH](C)C)c2cc(C)cc(C)c21
Reactant: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)NC1CCCCC1)CCC3
Reaction time: 24 h
Yield: 89.9 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-3-phenyl-s-indacen-1-yl) silane (9c)) (5.6340 g, 0.01633 moles) was stirred in hexane (100 mL) as NEt3 (2.9673 g, 0.02932 moles) and cyclohexylamine (1.6373 g, 0.01651 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (5.8969 g, 89.9 percent).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[NH:8][C:7](=[O:14])[C:6]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4].[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[O:37][CH:38]([CH3:40])[CH3:39].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C:33]2[CH:34]=[CH:35][C:36]([O:37][CH:38]([CH3:39])[CH3:40])=[C:31]([F:30])[CH:32]=2)[C:7](=[O:14])[C:6]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)Oc1ccc(B(O)O)cc1F
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)C)c(F)c2)c2ncnn12
Reaction time: 16 h
Yield: 97.4 %

Procedure:
To a suspension (15 mL) of 4′-[(7-butyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), [3-fluoro-4-(1-methylethoxy)phenyl]boronic acid (0.51 g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.47 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.68 g, 98%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[N:3]=1.ClC1N=C(O[CH:33]2[CH2:50][CH:49]3[N:35]([C:36](=[O:56])[N:37]([CH3:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH:43][CH:44]4[C:46]([C:52]([OH:54])=[O:53])([NH:47][C:48]3=[O:51])[CH2:45]4)[CH2:34]2)C2C(C=1)=CC(OC)=CC=2>>[N:14]1([C:4]2[N:3]=[C:2]([O:1][CH:33]3[CH2:50][CH:49]4[N:35]([C:36](=[O:56])[N:37]([CH3:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH:43][CH:44]5[C:46]([C:52]([OH:54])=[O:53])([NH:47][C:48]4=[O:51])[CH2:45]5)[CH2:34]3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Reactant: COc1ccc2c(O)nc(-n3cccn3)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-n3cccn3)cc2c1

Procedure:
The title product 67 was prepared from 1-hydroxy-6-methoxy-3-(pyrazol-1-yl)isoquinoline following the same procedures described for the preparation of 17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42, Example 10): m/z=575 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:25])[CH2:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[CH:20][NH:21]3)=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.CN(C)C1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=C(OC)C=2)=CC=1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:25])[CH2:11][C:12](=[O:24])[CH2:13][CH2:14][C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[CH:20][NH:21]3)=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(O)cc1)CC(=O)/C=C/c1ccc2cc[nH]c2c1
Agent: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(N(C)C)cc2)ccc1O
Product: O=C(CCc1ccc(O)cc1)CC(=O)CCc1ccc2cc[nH]c2c1

Procedure:
The title compound was synthesized using the same procedure employed for Example 372, but with (1E,6E)-1-(4-hydroxyphenyl)-7-(1H-indol-6-yl)hepta-1,6-diene-3,5-dione (28 mg, 85 μmol, synthesized in Example 149) as the starting material instead of (1E,6E)-1-(4-dimethylaminophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel column chromatography eluting with hexane/ethyl acetate=75/25 to 65/35. The product was obtained as a gum (18.4 mg, 66%) having the following characteristics.