Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[N+]([O-])=O)[CH:2]([CH3:4])[CH3:3].N([O-])=O.[Na+].[ClH:20]>O>[Cl:20][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:5]=1[CH2:1][CH:2]([CH3:4])[CH3:3])[CH:9]=[O:10]
Reactant: Cl
Reactant: CC(C)Cc1ccc(C=O)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)Cc1ccc(C=O)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
4-Isobutyl-3-nitrobenzaldehyde (3.3 g, 0.0159 mol) is added to a solution of stannous chloride (8.37 g, 0.0441 mol) in concentrated hydrochloric acid (23 mL) at 0-5° C. The reaction mixture is slowly brought to 60-65° C. and is stirred at this temperature for 30 minutes. The reaction mixture is again cooled to 0-5° C. During cooling formation of solid is observed which is broken before proceeding further. Solution of sodium nitrite (1.36 g, 0.0188 mol) in demineralized water (3 mL) is added to the above reaction mixture at 0-5° C., allowed to stir for 10 minutes at this temperature. It is then poured into a slurry of cuprous chloride (3.6 g, 0.0346 mol) in demineralized water (5 mL) at 60-65° C. & stirred for 20 minutes. The reaction mixture is extracted in ethyl acetate (2×30 mL). Combined organic layer is dried over sodium sulfate and concentrated to get the crude, which is purified using column chromatography (230-400 mesh; toluene:n-hexane, 3:7) to yield 3-chloro-4-isobutylbenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Cl.[Mg].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([Cl:20])[N:14]=1>BrCCBr>[Cl:12][C:13]1[N:14]=[C:15]([Cl:20])[CH:16]=[C:17]([CH2:4][C:3]2[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:10])[N:18]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: ClCc1c(Cl)cccc1Cl
Agent: [Mg]
Solvent: BrCCBr
Product: Clc1cc(Cc2c(Cl)cccc2Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A solution of 2,6-dichlorobenzylchloride (0.102 mol) in 1,1-diethylether (10 ml) was added dropwise to magnesium (0.102 mol) in 1,1-diethylether (60 ml). The reaction was initiated by adding 2 drops of 1,2-dibromoethane. After most of magnesium disappeared, 2,4,6-trichloropyrimidine (0.051 mol) in 1,1-diethylether (30 ml) was added. The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2/hexane 1/2). The desired fractions were collected and the solvent was evaporated, yielding 3.3 g of (21%) 2,4-dichloro-6-[(2,6-dichloro-phenyl)methyl]pyrimidine (interm. 1; melting point (mp.): 106–107° C.). b) Intermediate (1) (0.0081 mol) in 2-propanol (100 ml) was heated until complete dissolution. The solution was then transferred into a pressure tube and NH3 gas was bubbled into it for 20 minutes. Then the mixture was heated to 80° C. for 16 hours. The solvent was evaporated, yielding a residue of two compounds: 2-chloro-6-[(2,6-di-chloro-phenyl)methyl]-4-pyrimidinamine (interm. 2) and 4-chloro-6-[(2,6-dichloro-phenyl)methyl]-2-pyrimidinamine (interm. 3).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][OH:13])[C:8]=2[C:14]([F:17])([F:16])[F:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-]>ClCCl>[C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]=[O:13])[C:8]=2[C:14]([F:16])([F:17])[F:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1noc(-c2ccccc2)c1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=Cc1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 105.3 %

Procedure:
To a mixture of (5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)methanol (step A, 1.79 g, 7.36 mmol) in dichloromethane (23 mL) at 0° C. was added Dess-Martin Periodinane (3.43 g, 8.10 mmol). The reaction mixture was stirred at 0° C. for 10 min. and then at room temperature for 30 min. An additional 1.0 g of the Dess-Martin Periodinane was added, and the reaction mixture was stirred for an additional 30 min. A 1:1 mixture of saturated aqueous sodium thiosulfate and saturated aqueous bicarbonate (50 mL) was added slowly. The organic layer was collected, and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduce pressure to give 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbaldehyde (1.87 g, 7.75 mmol, quantitative yield) as a pale yellow oil. The compound had an HPLC ret. time=2.09 min. (condition A).
Reaction SMILES: C(OC([NH:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([OH:18])=O)=O)(C)(C)C.[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH:44]([NH2:46])[CH3:45]>>[NH2:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:21]=1)[C:16]([NH:46][CH:44]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[Cl:37])[CH3:45])=[O:18]
Reactant: CC(COCc1cc(C(=O)O)cc(C2(C#N)CCCC2)c1)(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(N)c1ccccc1Cl
Product: CC(NC(=O)c1cc(COCC(C)(N)Cc2ccccc2)cc(C2(C#N)CCCC2)c1)c1ccccc1Cl

Procedure:
Prepared from 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoic acid and 1-(2-chlorophenyl)ethanamine using a similar procedure as described for the preparation of Example 20. HRMS ES calculated for C32H36ClN3O2: 530.2569, found: 530.2561.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:20][C:21]1[C:26]2[O:27][CH2:28][C:29]3([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:32]3[CH2:33][CH2:34][C:29]4([C:25]5[CH:24]=[CH:23][CH:22]=[C:21]([F:20])[C:26]=5[O:27][CH2:28]4)[CH2:30][CH2:31]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Reactant: Fc1cccc2c1OCC21CCNCC1
Agent: Cl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Yield: 78 %

Procedure:
In the same manner as in Example 19, step 3 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.416 g, 1.66 mmol) obtained in Example 19, step 2 and 7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.500 g, 1.99 mmol) obtained in Reference Example 5, the title compound (0.570 g, 79%) was obtained.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13]3([C:32](=S)[C:17]4([CH2:22][CH2:21][CH:20]([C@H:23]5[CH2:28][CH2:27][C@H:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]5)[CH2:19][CH2:18]4)[C:16]3=S)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>[Ni].C1COCC1>[CH2:29]([C@H:26]1[CH2:25][CH2:24][C@H:23]([CH:20]2[CH2:21][CH2:22][C:17]3([CH2:32][C:13]4([CH2:12][CH2:11][CH:10]([C@H:7]5[CH2:6][CH2:5][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]5)[CH2:15][CH2:14]4)[CH2:16]3)[CH2:18][CH2:19]2)[CH2:28][CH2:27]1)[CH2:30][CH3:31]
Reactant: CCC[C@H]1CC[C@H](C2CCC3(CC2)C(=S)C2(CCC([C@H]4CC[C@H](CCC)CC4)CC2)C3=S)CC1
Agent: [Ni]
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](C2CCC3(CC2)CC2(CCC([C@H]4CC[C@H](CCC)CC4)CC2)C3)CC1

Procedure:
A mixture of 1 mmol of 3,11-bis(trans-4-propylcyclohexyl)dispiro[5.1.5.1]tetradecane-7,14-dithione (preparable by reaction of the corresponding diketone with P4S10) and 25 ml of tetrahydrofuran is added at room temperature to a well stirred suspension of fresh Raney nickel in THF and stirred for 24 h at room temperature. The usual working up yields 3,11-bis(trans-4-propylcyclohexyl)dispiro[5.1.5.1]tetradecane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:21])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:23][O:24][C:25](=[O:37])[C@H:26]([CH2:28][NH:29][C:30]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:31])[NH2:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:21])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C@H:26]([C:25]([O:24][CH3:23])=[O:37])[CH2:28][NH:29][C:30]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:31])=[O:6]
Reactant: COC(=O)[C@@H](N)CNC(=O)c1cccs1
Reactant: O=C(CCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Yield: 96.7 %

Procedure:
A solution of 2-chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]benzoic acid (Example 41; 75.8 mg, 0.25 mmol), 3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester hydrochloride (Example 301; 73 mg, 0.28 mmol), HBTU (113 mg, 0.30 mmol), HOBT (41 mg, 0.27 mmol) and diisopropylethylamine (0.22 mL, 1.26 mmol) in N,N-dimethylformamide (6 mL) was stirred overnight at room temperature. The solvent was evaporated. Ethyl acetate (30 mL) was added and the solution was washed with sodium hydrogen carbonate solution and 0.5 M HCl. Each of the aqueous layers was extracted with ethyl acetate (10 mL) and the combined organic layers were dried (Na2SO4), filtered, evaporated, and chromatographed (10-100% ethyl acetate/hexanes) to give N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (125 mg, 98%).
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1[C:19]2[C:10](=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:9]=[CH:8][CH:7]=1.[N+:20]([O-])([OH:22])=[O:21].[OH-].[Na+]>O>[N+:20]([C:11]1[CH:12]=[C:13]2[C:18]([N:17]=[CH:16][CH:15]=[CH:14]2)=[C:19]2[C:10]=1[CH:9]=[CH:8][CH:7]=[N:6]2)([O-:22])=[O:21]
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cc2cccnc2c2ncccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Referring to Scheme 5, 237 ml sulfuric acid (concentrate) was first added to a 1 L three-necked flask. 35 g 1,10-phenanthroline was then added into the flask, and the temperature of mixture was kept lower than 100° C. Next, 2436 ml (67%) HNO3 was added drop by drop, and the temperature of mixture was kept lower than 110° C. The mixture was subsequently heated to 100° C. and stirred overnight. After completion of reaction, the reaction mixture was cooled to room temperature and placed into 2 L water, and then NaOH(aq) was added to adjust pH value to a range from 6 to 7, so as to give solids. The solids were washed by water, and dried to obtain solids 5-nitro-1,10-phenanthroline 30 g (0.13 mol, yield 68%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]([CH3:21])[C:12]1[CH:13]=[CH:14][C:15]([I:18])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(Nc1ccc(I)cc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A stirred solution of N-benzyloxycarbonyl-4-iodoaniline (11.5 g, Reference Example 27) in dimethylformamide (70 ml) was treated portionwise with sodium hydride (⅙ g of a 60% dispersion in oil), under nitrogen and at room temperature. When effervescence had ceased methyl iodide (6.3 g) was added and the mixture was stirred at room temperature for 2 hours, after which it was partitioned between ethyl acetate and water. The organic phase was separated, then dried over magnesium sulphate and then evaporated to give the title compound (11.5 g) as a pink oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:17]2[CH2:20][CH:19]([NH2:21])[CH2:18]2)=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[CH2:1]([NH:21][CH:19]1[CH2:20][N:17]([CH:16]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1ccc(C(c2ccc(Cl)cc2)N2CC(NCc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
0.134 cm3 of benzaldehyde is added, at room temperature under an argon atmosphere, to a solution of 369 mg of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine in 15 cm3 of dichloromethane. The mixture is cooled to around 0° C., before gradually adding thereto 382 mg of sodium triacetoxyborohydride, and then 70 mm3 of acetic acid. After stirring for 16 hours at room temperature, the mixture is poured over 50 cm3 of a saturated aqueous sodium hydrogen carbonate solution and then extracted with twice 25 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethane/methanol (95/5 by volume)]. 0.29 g of N-benzyl-N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}amine is obtained in the form of a colorless oil [1H NMR spectrum (300 MHz, CDCl3, δ ppm):2.71 (broad t, J=7 Hz,:2 H); 3.42 (mt:2 H); 3.49 (mt:1 H); 3.70 (s:2 H); 4.25 (s:1 H); from 7.20 to 7.40 (mt:13 H)].
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][C@H:2]12.CS(O[CH:16]1[CH2:19][N:18]([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17]1)(=O)=O.C(N(CC)CC)C>C(#N)C>[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]2[CH2:19][CH:16]([N:6]3[CH2:5][CH2:4][N:3]4[C:7](=[O:10])[CH2:8][CH2:9][C@@H:2]4[CH2:1]3)[CH2:17]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CC[C@@H]2CNCCN12
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CC[C@@H]2CN(C3CN(C(c4ccccc4)c4ccccc4)C3)CCN12
Temperature: 150 °C
Yield: 53 %

Procedure:
(8aR)-Hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (see WO 03/066635; 0.17 g, 1.2 mmol), 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (see J. Org. Chem.; 56; 1991; 6729; 0.40 g, 1.3 mmol) and triethylamine (0.20 mL, 1.4 mmol) were dissolved in acetonitrile. The mixture was heated for 15 min at 150° C. using microwave single node heating and then the solvent was removed by evaporation. The residue was partitioned between ethyl acetate and aqueous NaHCO3 and the aqueous phase extracted further with ethyl acetate. The organic phase was dried and then the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol-methylene chloride 5:95). There was obtained 0.23 g (54%) of (8aR)-2-[1-(diphenylmethyl)azetidin-3-yl]hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one as a pale yellow oil. 1H NMR (500 MHz, CDCl3): 1.5-1.6 (m, 2H), 1.7-1.8 (m, 1H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 2H), 2.6-2.7 (d, 1H), 2.8 (m, 1H), 2.8-2.9 (m, 3H), 3.0 (qn, 1H), 3.4 (t, 2H), 3.6 (m, 1H), 4.0 (d, 1H), 4.4 (s, 1H), 7.2 (m, 2H), 7.2-7.3 (m, 4H), 7.4 (m, 4H); LCMS: m/z 362 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]([CH3:15])[CH2:7][C:6]2=[O:16].N1C=CC=CC=1.Cl[C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:24]([O:26][CH3:27])=[O:25])[CH:8]([CH3:15])[CH2:7][C:6]2=[O:16]
Reactant: COC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(=O)CC(C)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1.2 g. (5.45 mmol) of the quinoline product of Example 4, 792 mg. (10.7 mmol) of dry pyridine and 5.5 ml. of methylene chloride was stirred and cooled by an ice-water bath while 758 mg. (8.02 mmol) of methyl chloroformate in 1 ml. of methylene chloride was added over a 10 min. period at a rate to maintain a 10°-15° C. temperature. The ice bath was removed and the reaction allowed to stir at room temperature for 45 min. then poured onto 25 ml. of saturated sodium bicarbonate solution. The methylene chloride layer was separated and washed with 25 ml. saturated sodium bicarbonate solution and saturated sodium chloride solution, then dried over magnesium sulfate, and gravity filtered and evaporated to a yellow solid. The solid was triturated with 5 ml. anhydrous ether, filtered, and washed with minimum ether, then air dried to 1.1 g. of a yellow solid, m.p. 156°-158°. This material was dissolved in 10 ml. of hot ethyl acetate, treated with 50 mg. Darco G60, filtered and crystallized by the addition of hexane to give 727 mg. of an off-white solid, m.p. 159°-160° after drying in vacuum at 100° C (1 mm) for 24 hrs.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][NH:11][C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]=4[CH:16]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:39]([O:41][C:42](Cl)=[O:43])[CH3:40]>C1C=CC=CC=1>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([C:42]([O:41][CH2:39][CH3:40])=[O:43])[C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]=4[CH:16]=3)[CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cl
Reactant: CC1(Cc2ccc3c(c2)OCCO3)CN(C(c2ccccc2)c2ccccc2)CCN1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1(C)Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Yield: 90 %

Procedure:
12.4 g of 1-diphenylmethyl-3-methyl-3-(3,4-ethylenedioxybenzyl)-piperazine (3a) are dissolved in 100 ml of dry benzene and combined with 3.3 g of triethylamine. 3.6 g of chloroformic acid ethyl ester in 20 ml of benzene are added dropwise with stirring at room temperature. After 12 hours the solution is washed free of halogen with water and evaporated to dryness in vacuum. 13.1 g (90%) of 1-diphenylmethyl-3-methyl-3-(3,4-ethylenedioxybenzyl)-4-carbethoxypiperazine are obtained (m.p. = 153° - 155° C., diisopropylether), which are dissolved in 100 ml of dry tetrahydrofuran and added dropwise with stirring over 30 minutes to a boiling suspension of 3.8 g of lithium aluminum hydride in 200 ml of tetrahydrofuran. After three hours, the mixture is combined with water and filtered. The filtrate is evaporated to dryness in vacuum. 10.7 g (93%) of 1-diphenylmethyl-3-methyl-3-(3,4-ethylenedioxybenzyl)-4-methylpiperazine are obtained.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[OH:24][C@@H:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27]>>[CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH:22][C:26](=[O:27])[CH:25]([OH:24])[CH:29]([CH3:31])[CH3:30])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1
Reactant: CC(C)[C@H](O)C(=O)O
Product: CCCC(NC(=O)C(O)C(C)C)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (S)-2-hydroxy-3-methyl-butyric acid to afford the title compound: 13C NMR (100 MHz, CDCl3) 13.9, 16.1, 19.1, 19.4, 25.9, 32.3, 35.4, 52.8, 55.5, 59.2, 67.4, 68.8, 105.3, 131.3, 137.2, 169.4, 174.1; MS m/z 424.4 (M+1).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:20][C:19]3[C:18]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O>C(O)C>[C:1]1([S:7]([NH:10][CH:11]2[CH2:20][C:19]3[C:18]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc2c1CC(NS(=O)(=O)c1ccccc1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1cccc2c1CC(NS(=O)(=O)c1ccccc1)CC2

Procedure:
3.89 g (10 mmol) of ethyl 7-benzenesulphonylamino-5,6,7,8-tetrahydronaphth-1-yl-oxyacetate and 840 mg (15 mmol) of KOH are stirred in 50 ml of C2H5OH and 20 ml of H2O at room temperature for 20 hours. The solvent is stripped off, the residue is partitioned between H2O and CH2Cl2, the mixture is brought to pH 4.5 with 10% strength HCl and extracted twice with CH2Cl2, the organic phases are dried over MgSO4 and concentrated in vacuo, the residue is triturated with ether and the crystals are filtered off with suction and dried.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:20]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:21]=4[S:22][C:23]=3[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:43]([Si:47](Cl)([CH3:49])[CH3:48])([CH3:46])([CH3:45])[CH3:44]>C1COCC1.CN(C=O)C.C1(C)C=CC=CC=1>[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:20]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:21]=4[S:22][C:23]=3[C:24]3[CH:29]=[CH:28][C:27]([O:30][Si:47]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:49])[CH3:48])=[CH:26][CH:25]=3)=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2sc3cc(O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 60 °C
Yield: 19.6 %

Procedure:
To a solution of 30 g (58.8 mmol) of 6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl 4-[2-(1-piperidinyl)ethoxy]phenyl ketone hydrochloride in 120 mL of anhydrous THF and 60 mL of anhydrous DMF was added 20 mL (144 mmol) of anhydrous triethylamine and 9.75 g (64.7 mmol) of tertbutyldimethylsilyl chloride under a nitrogen atmosphere. The reaction mixture was heated at 60° C. in an oil bath for 4 h and then cooled to room temperature. The solution was diluted with 225 mL of toluene, filtered through a medium glass frit, and concentrated at reduced pressure. The residue was purified by PrepLC (0 to 4% MeOH in CH2Cl2) to give 6.77 g (11.5 mmol, 20%) of a yellow foam.