Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](Cl)(CCCC)CCCC)CCC.[N-:15]=[N+:16]=[N-:17].[Na+].[C:19]([C:21]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][C:22]=1[NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33])#[N:20].Cl>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[NH:15]1[C:19]([C:21]2[C:30]3[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=3[CH:24]=[CH:23][C:22]=2[NH:31][S:32]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])=[N:20][N:17]=[N:16]1
Reactant: N#Cc1c(NS(=O)(=O)c2ccccc2)ccc2c1CCCC2
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1ccc2c(c1-c1nnn[nH]1)CCCC2)c1ccccc1
Temperature: 220 °C
Reaction time: 0.08 h
Yield: 5 %

Procedure:
Tri-n-butyl tin chloride (0.16 mL) was added to a solution of sodium azide (0.039 g) in DMF (0.6 mL) and the mixture was stirred for 5 minutes. Tetra-butyl ammonium bromide (0.0065 g) was then added, followed by N-(1-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)benzenesulfonamide (Intermediate 1, 0.177 g). The mixture was heated by microwave irradiation at 220° C. for 1 hour. The solution was then acidified with 1N hydrochloric acid and the products were extracted into DCM, dried with magnesium sulfate and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18). The fractions containing the desired product were combined, and the solvent was removed by evaporation to give the title compound as a beige solid (0.01 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.ClCCl.C([O-])(=O)C.[K+].[C:39]([O:43][C@H:44]([C:50]1[C:65]([CH3:66])=[CH:64][C:53]2[N:54]=[C:55]([C:57]3[CH:62]=[CH:61][N:60]=[C:59](Cl)[CH:58]=3)[S:56][C:52]=2[C:51]=1[C:67]1[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=1)[C:45]([O:47][CH2:48][CH3:49])=[O:46])([CH3:42])([CH3:41])[CH3:40].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:39]([O:43][C@@H:44]([C:50]1[C:65]([CH3:66])=[CH:64][C:53]2[N:54]=[C:55]([C:57]3[CH:62]=[CH:61][N:60]=[C:59]([C:3]4[CH:4]=[C:5]5[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:6]5=[N:7][CH:2]=4)[CH:58]=3)[S:56][C:52]=2[C:51]=1[C:67]1[CH:68]=[CH:69][C:70]([Cl:73])=[CH:71][CH:72]=1)[C:45]([O:47][CH2:48][CH3:49])=[O:46])([CH3:40])([CH3:41])[CH3:42]
Reactant: CCOC(=O)[C@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1cn(C)c2nc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(c4)c(C)cn5C)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of 6-bromo-1,3-dimethyl-1H-pyrrolo[2,3-b]pyridine (15 mg, 0.067 mmol) in dioxane (1 mL) was added bis(pinacolato)diboron (20 mg, 0.080 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (5.5 mg, 0.0067 mmol), potassium acetate (20 mg, 0.201 mmol). The mixture was degassed and heated at 100° C. for 2 h. The mixture was cooled, and then added (R)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (24 mg, 0.045 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.0045 mmol), K2CO3 (31 mg, 0.227 mmol) and water (0.3 mL, degassed). The reaction mixture was heated at 110° C. for 1 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4 and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C36H35ClN4O3S: 639.3 (M+H+); Found: 639.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].Br[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CC(C)CCBr
Reactant: CCOC(=O)CSc1ccc(O)cc1
Solvent: CC(C)=O
Product: CCOC(=O)CSc1ccc(OCCC(C)C)cc1
Temperature: 25 °C

Procedure:
To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol), k2CO3 (anhydrous, 10 g) and 1-bromo-3-methyl butane (3 g, excess) was added in boiling acetone. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. The reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform; washed well with water and concentrated. The crude product obtained was taken to next step with out purification. Yield 2.7 g (94%); (M+H)+ 283.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][C:3]=1[O:25][CH2:26][C:27](OCC)=[O:28].CC(C[AlH]CC(C)C)C.O>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][OH:28]
Reactant: CCOC(=O)COc1cc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)ccc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1OCCO
Temperature: 0 °C
Yield: 98.5 %

Procedure:
Compound 42 (93 mg, 0.22 mmol) was dissolved in THF (5 mL) and cooled to 0° C. under nitrogen. DIBAL-H (1M in hexane, 370 μL, 0.55 mmol) was added drop-wise over several minutes. The ice bath was removed and the stirring reaction allowed to warm to ambient temperature. The reaction was re-cooled to 0° C. and water (10 mL) added dropwise over several minutes. The ice bath was removed and the reaction stirred until solids began to form. The solids were filtered and the filtrate washed several time with dichloromethane to ensure all product was removed from the aluminate solids. The filtrate was concentrated in vacuuo to give 82 mg (98%) of compound 44 as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.88 (s, 6H), 0.91 (s, 6H), 1.25 (s, 2H), 1.77 (s, 2H), 1.90 (s, 2H), 2.20 (s, 3H), 3.91-3.98 (m, 2H), 4.02-4.15 (m, 2H), 6.68 (d, J=8.1 Hz, 1H) 6.75-7.05 (m, 2H), 7.09-7.15 (m, 3H) 7.25-7.36 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:11]1)=[O:4].Cl[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[C:26]([CH3:34])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:17][CH:16]=2)[CH2:11]1)=[O:4]
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1C1CC(c2ccc(O)cc2)=NO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: COC(=O)[C@@H]1CCC[C@@H]1C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Temperature: 50 °C
Yield: 42.7 %

Procedure:
The product from step 28a (0.31 g, 1.1 mmol) was combined with 4-chloromethyl-2-methylquinoline (0.20 g, 1.0 mmol), potassium carbonate (0.22 g, 1.6 mmol) and potassium iodide (0.05 g, 0.3 mmol) in acetontrile (5 mL) under a nitrogen atmosphere and heated to 50° C. for 18 h. The reaction was filtered, concentrated, and purified by FCC on silica gel eluting ethyl an acetate:hexanes gradient to give cis-2-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-cyclopentanecarboxylic acid methyl ester (0.19 g, 47%) as an oil. MS found: (M+H)+=445.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[O:24]=[C:25]1[CH2:29][S:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]([NH:38][S:39]([N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)(=[O:41])=[O:40])=[O:37])[CH2:32][CH2:31]2)=[N:26]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:29]4[S:28][C:27]([N:30]5[CH2:31][CH2:32][CH:33]([C:36]([NH:38][S:39]([N:42]6[CH2:46][CH2:45][CH2:44][CH2:43]6)(=[O:41])=[O:40])=[O:37])[CH2:34][CH2:35]5)=[N:26][C:25]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:21])([F:23])[F:22])[CH:3]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: O=C1CSC(N2CCC(C(=O)NS(=O)(=O)N3CCCC3)CC2)=N1
Product: O=C1N=C(N2CCC(C(=O)NS(=O)(=O)N3CCCC3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
Pyrrolidine-1-sulfonic acid (1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carbonyl)-amide was prepared from 1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and Pyrrolidine-1-sulfonic acid [1-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperidine-4-carbonyl]-amide following General Procedure E.
Reaction SMILES: [H-].[Na+].C([NH:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([CH3:14])[C:8]=1[Cl:15])(=O)C.[CH3:16][C:17]1[N:21]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:20]=[C:19]([S:28](Cl)(=[O:30])=[O:29])[N:18]=1>O1CCCC1>[Cl:15][C:8]1[C:9]([CH3:14])=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[NH:6][S:28]([C:19]1[N:18]=[C:17]([CH3:16])[N:21]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:20]=1)(=[O:30])=[O:29]
Reactant: Cc1nc(S(=O)(=O)Cl)nn1-c1ncccn1
Reactant: CC(=O)Nc1c(Cl)ccc(C)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2nc(C)n(-c3ncccn3)n2)c1Cl
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A suspension of sodium hydride (8.7 g) in dry tetrahydrofuran (400 ml) was stirred at 25° C., and N-acetyl-2,6-dichloro-3-methylaniline (50.4 g) was added portionwise. After stirring for 15 minutes, 5-methyl-1-(2-pyrimidinyl)-1,2,4-triazole-3-sulphonyl chloride (30 g), prepared by a method analogous to that of Example A was added over 5 minutes. The mixture was stirred at 25° C. for 18 hours and the solvent was removed in vacuo. The residue was treated with 1M sodium hydroxide solution (500 ml) for 5 minutes with stirring, and was then extracted with ethyl acetate (500 ml). The ethyl acetate layer was re-extracted with 1M sodium hydroxide solution (300 ml). The combined aqueous phases were acidified with concentrated hydrochloric acid and the solid was filtered off. Recrystallisation from acetonitrile gave 38 g of the desired product, mp 214°-216° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].ClCCCl.[CH:36](OCC)=[O:37]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([CH:36]=[O:37])[CH2:13][CH2:12]1)[C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])=[O:4]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Reactant: CCOC=O
Solvent: ClCCCl
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C=O)CC1
Temperature: 95 °C

Procedure:
A solution of 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]thiophene-2-carboxylic acid methyl ester (100 mg, 0.22 mmol) in ethyl formate (1.5 mL) under nitrogen, was placed in a bath at 65° C. for 20 h after which was added 1,2-dichloroethane (2.5 mL) and another portion of ethyl formate (2 mL). The bath temperature was raised to 95° C. and the reaction refluxed for a further 21 h. Tlc showed ca 80% conversion. The reaction was stripped off solvent and the residue purified by column chromatography using methylene chloride: acetonitrile:methanol=9:1:0.1 as eluent to give 5-Cyclohex-1-enyl-3-[(1-formyl-piperidin-4-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (42 mg, 41%)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CO>[C:10]1([C:8]2[O:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:9]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCNCC1
Reactant: BrCCOc1cc(-c2ccccc2)on1
Solvent: CO
Product: c1ccc(-c2cc(OCCN3CCCCC3)no2)cc1
Temperature: 0 °C
Yield: 92.2 %

Procedure:
3-(2-Bromoethoxy)-5-phenylisoxazole (268 mg) was dissolved in methanol (1.0 ml), and piperidine (426 mg) was added thereto, followed by reflux of the resulting mixture for 3 hours. After the reaction mixture was added to ice-cold water (20 ml) and extracted with ether (20 ml×2), the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound (251 mg, 92%) as colorless crystals.
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(NC4C=CC=CC=4)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:33]([CH2:36][CH:37]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[C:45]([NH:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:39]=2[O:38]1)=[N+]=[N-].[N-]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[NH2:33][CH2:36][CH:37]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[C:45]([NH:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:39]=2[O:38]1
Reactant: [N-]=[N+]=NCC1Cc2cccc(Nc3ccccc3)c2O1
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Nc4ccccc4)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: NCC1Cc2cccc(Nc3ccccc3)c2O1
Yield: 46 %

Procedure:
To a solution of (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.5 mmol) in toluene (20 mL) was added bromobenzene (0.23 g, 1.5 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.061 g, 0.075 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.125 g, 0.225 mmol), and sodium tert-butoxide (0.18 g, 1.875 mmol) and the reaction mixture was allowed to reflux 3 h. The solvent was removed in vacuo. The residue was washed with water (100 mL) and ethyl acetate (50 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:10) afforded (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatement of (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate with sodium azide (0.18 g, 2.78 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-N-phenyl-2,3-dihydro-1-benzofuran-7-amine. Treatment of the azide with polymer-supported triphenylphosphine (1.09 g, 4.17 mmol) generally according to the procedure described for Example 21 provided 0.042 g, (46%) of (±)-2-(aminomethyl)-N-phenyl-2,3-dihydro-1-benzofuran-7-amine as a white solid, fumarate salt. mp 216-218° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.O>CN(C=O)C>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(OCc3ccc4ccccc4n3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 6-hydroxytetralone, prepared as in step 1, (2.43 g, 15 mmol) and potassium carbonate (2.76 g, 20 mmol) in DMF (65 mL) was added chloromethylquinoline hydrochloride (3.42 g, 16 mmol), and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (100 mL). The extract was dried with MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5:1 methylene chloride-ethyl acetate to provide 2.3 g 3,4-Dihydro-6-(2-quinolylmethoxy)-1(2H)-naphthalenone.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][N:13]=[C:14]([CH:32]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1)[CH2:33][CH2:34][OH:35])[CH2:15][O:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:11][O:12][N:13]=[C:14]([CH:32]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1)[CH2:33][CH:34]=[O:35])[CH2:15][O:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:21]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:19]=1
Reactant: CON=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCO)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC=O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Dissolve oxalyl chloride (2.01 g, 15.82 mmol) in dry CH2Cl2 (30 mL) and cool to -78° C. under N2, add DMSO (2.47 g, 31.64 mmol) in dry CH2Cl2 (12 mL) dropwise and stir at -78° C. for 15 mins. Add the product of Step 7 (6.56 g, 12.66 mmol) in dry CH2Cl2 (20 mL) dropwise and stir at -78° C. for 3 h. Add diisopropylethylamine (4.91 g, 37.97 mmol) and stir at -78° C. for 1 h. Warm slowly to 0° C. and stir at 0° C. for 30 mins. Add water (150 mL) and extract with CH2Cl2. Wash combined organic extracts with saturated aqueous NaCl, dry (MgSO4), filter, and concentrate to give 6.53 g (12.66 mmol, 100%) of a yellow oil. MS (FAB): m/e 516 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[OH:17])([CH3:9])[CH3:8].[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23]C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:17][C:11]1[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]([O:2][CH2:1][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18]
Reactant: CCCCCCO
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCOC(=O)CCCC(C)(C)c1ccc(O)cc1O

Procedure:
5.5 Parts of methyl-5-(2',4'-dihydroxyphenyl)-5-methyl-hexanoate, 50 parts of n-hexanol, and 0.5 parts of p-toluene sulphonic acid are heated on a steam-bath for 6 hours. The excess hexanol is then removed under reduced pressure and the residual oil taken up in ether, washed with sodium bicarbonate solution, water, and evaporated. Short path distillation of the residual oil at 0,7 mbar yields 5.8 parts of n-hexyl 5-(2',4'-dihydroxyphenyl)-5-methyl-hexanoate of the formula ##STR16## with the following percentage composition by weight:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:23]=[C:24]4[NH:33][C:32](=[O:34])[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]4[CH:35]=3)=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(OCC)(=O)C.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1.O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][C:22]3[CH:23]=[C:24]4[NH:33][C:32](=[O:34])[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]4[CH:35]=3)[CH2:18][CH2:19]2)=[CH:12][CH:13]=1
Reactant: O=C(c1cc2[nH]c(=O)c3ccccc3n2c1)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(CN3CCN(c4ccc(F)cc4)CC3)cn2c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Under cooling on ice, lithium aluminum hydride (657 mg, 17.3 mmol) was added to a solution of 2-[4-(4-fluorophenyl)piperazine-1-carbonyl]pyrrolo[1,2-a]quinazolin-5(4H)-one (the above Compound 1-1, 3.38 g, 8.66 mmol) in anhydrous tetrahydrofuran (75 mL). This reaction solution was stirred at room temperature for 2 hours. A small amount of ethyl acetate was added dropwise to the reaction solution, and then a saturated aqueous solution of sodium potassium tartrate tetrahydrate (100 mL), and water (100 mL) were added sequentially. The mixture was extracted twice with chloroform (100 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was collected by filtration with ethanol, to obtain the title compound (2.85 g, yield: 87%) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([CH2:14][O:15]CC1C=CC=CC=1)([OH:13])[CH2:4][O:5]CC1C=CC=CC=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.[H][H]>C(O)C.[Pd]>[F:1][C:2]([F:24])([F:23])[C:3]([OH:13])([CH2:14][OH:15])[CH2:4][OH:5]
Reactant: [H][H]
Reactant: OC(COCc1ccccc1)(COCc1ccccc1)C(F)(F)F
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Product: OCC(O)(CO)C(F)(F)F
Reaction time: 8 h
Yield: 104.3 %

Procedure:
A solution of 1,1,1-trifluoro-3-[(benzyl)oxy]-2-{[(benzyl)oxy]methyl}-2-propanol (98.9 g, 290.9 mmol) in ethanol (1750 ml) was added to 5% palladium on carbon (9.73 g, wet, Degussa, E101 No/W) under nitrogen. The mixture was then stirred under an atmosphere of hydrogen using a Wright valve in a 5 liter hydrogenation vessel. After approximately 3 hours most of the theoretical volume of hydrogen had been taken up. After stirring under hydrogen overnight (approximately a further 1 liter of hydrogen had been taken up overnight), the catalyst was filtered off through a pad of celite and the pad washed with ethanol. The filtrate and washings were then concentrated under reduced pressure and the residue azeotroped (×2) with dichloromethane whereupon the residue became solid. This material was left on the vacuum pump to give the title compound (48.56 g) as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([C:16]([NH:18][C@@H:19]([CH2:24][OH:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(OCC)(=O)C>CS(C)=O.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([C:16]([NH:18][C@@H:19]([CH:24]=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](CO)NC(=O)[C@H](NS(=O)(=O)c1ccc(F)cc1)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](C=O)NC(=O)[C@H](NS(=O)(=O)c1ccc(F)cc1)C(C)C
Temperature: 25 °C
Yield: 67 %

Procedure:
N-(4-Fluorophenylsulfonyl)-D-valyl-D-leucinol (1.5 g) was dissolved in dimethyl sulfoxide (20 ml) and dichloromethane (10 ml), and triethylamine (2.4 g) was added. The solution was stirred at room temperature while adding a solution (20 ml) of sulfur trioxide-pyridine complex (2.6 g) in dimethyl sulfoxide, which was followed by stirring for 1 hr. After the completion of the reaction, ethyl acetate was added. The mixture was washed with dilute hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative TLC plate (developing solvent: hexane-ethyl acetate, 1:1, v/v) to give 1.0 g of N-(4-fluorophenylsulfonyl)-D-valyl-D-leucinal (Compound 55) as white crystals. [Step 1]