Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH:29]1([CH2:35][CH2:36]C=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([CH2:35][CH2:36][C:21]2[C:20]3[CH:19]=[CH:18][C:17]([F:22])=[CH:16][C:15]=3[N:14]=[C:13]3[C:23]4[N:10]([CH2:11][C:12]=23)[C:9](=[O:26])[C:8]2[CH2:7][O:6][C:5](=[O:27])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:28])[C:25]=2[CH:24]=4)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Reactant: O=CCCC1CCCCC1
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)ccc1c2CCC1CCCCC1

Procedure:
The product of Example 84 is treated with 3-cyclohexylpropanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:17][OH:18])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1.C(N(CC)C(C)C)(C)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>ClCCl>[NH2:1][C:2]1[C:3]([C:7](=[N:17][O:18][C:28](=[O:31])[CH2:29][CH3:30])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)ON=C(Nc1ccc(F)c(Cl)c1)c1nonc1N
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (0.1 g, 0.37 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.92 mmol) in dichloromethane (4 mL) was treated with propanoyl chloride (38 μL, 0.44 mmol) and stirred for 1 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (57 mg, 47%). LCMS for C12H12ClFN5O3 (M+H)+: m/z=328.0.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:42])([CH3:41])[CH2:29][C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][C:33]=1[F:40])=[O:31].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH2:36][C:35]1[CH:38]=[CH:39][C:32]([C:30](=[O:31])[CH2:29][C:28]([CH3:27])([CH3:41])[CH3:42])=[C:33]([F:40])[CH:34]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)CC(=O)c1ccc(CN)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1F
Yield: 48.1 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (96 mg, 0.225 mmol) with 4-(3,3-dimethyl-butyryl)-3-fluoro-benzylamine (105 mg, 0.45 mmol) by using tris(dibenzylideneacetone)dipalladium(0) (41 mg, 0.045 mmol), BINAP (56 mg, 0.09 mmol) and cesium carbonate (103 mg, 0.315 mmol) in anhydrous toluene (15 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 7-chloro-6-[4-(3,3-dimethyl-butyryl)-3-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (54 mg, 49%). MS (ES+) m/z: 499 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=O)[CH:4]=1.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>S(Cl)(Cl)=O>[NH:14]1[C:13]([NH:12][C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: Nc1nnn[nH]1
Reactant: COc1ccnc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COc1ccnc(C(=O)Nc2nnn[nH]2)c1
Yield: 11.7 %

Procedure:
1.67 g of 4-methoxy-2-pyridinecarboxylic acid, 20 ml of thionyl chloride and 1.2 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from ethanol, whereby 0.28 g of N-(5-tetrazolyl)-4-methoxy-2-pyridinecarboxamide is obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([O:24][Si](C)(C)C)C#N)=[CH:17][CH:16]=1)[CH3:14].[CH:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>COCCOC>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH:29]([OH:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:17][CH:16]=1)[CH3:14]
Reactant: O=Cc1ccccc1
Reactant: CCc1ccc(C(C#N)O[Si](C)(C)C)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COCCOC
Solvent: CC(C)NC(C)C
Product: CCc1ccc(C(=O)C(O)c2ccccc2)cc1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
Dissolve 290 ml (2.069 mol) diisopropylamine in 3.6 liters DME and precool to −78° C. Add 820 ml (2.05 mol) n-butyllithium (2.5 M solution in hexane) dropwise in the space of approx. 20 min (temperature<−60° C.). After 15 min at −60° C., add a solution of 435 g (1.864 mol) (4-ethylphenyl)[(trimethylsilyl)oxy]acetonitrile in 1.4 liters DME dropwise (temperature<−60° C.). Stir the mixture for a further 30 min at −60° C., before adding a solution of 189.5 ml (1.864 mol) benzaldehyde in 1.4 liters DME (time approx. 20 min, temperature −60° C.). Heat the mixture over a period of 4 h to RT, before adding 7 liter satd. ammonium chloride solution. Extract the reaction mixture with ethyl acetate. After phase separation, wash the organic phase with satd. ammonium chloride solution, dry, and concentrate by vacuum evaporation. Dissolve the residue in 7 liters dioxan and 5 liters methanol, and add 6 liters 1 N hydrochloric acid. Stir the mixture overnight at RT, then, after adding 11 liters satd. sodium chloride solution, extract with 6.5 liters ethyl acetate. Wash the organic phase with water and with satd. sodium chloride solution, dry, and concentrate by vacuum evaporation. Dissolve the residue in 2 liters diisopropyl ether, add seed crystals and stir for 2 h. The precipitated solid is filtered with suction, washed with 300 ml diisopropyl ether and petroleum ether and dried under vacuum. Concentrate the mother liquor, and after storing for 2 days at 4° C., again filter off the precipitated solid with suction, wash with approx. 100 ml diisopropyl ether and petroleum ether and dry under vacuum. On combining the two solids, 154.9 g (34% of theor.) of the target product is obtained.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[CH3:13])(=O)=O.O[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[C:27]([CH3:38])[C:26]=1[CH3:39]>>[F:14][C:12]([C:11]1[S:10][N:9]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:6][O:5][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:38])[C:26]=1[CH3:39])([F:15])[CH3:13]
Reactant: CCc1ccc(-c2nsc(C(C)(F)F)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: CCc1ccc(-c2nsc(C(C)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Step 5 and 6 by coupling [5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazol-4-yl]methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H-NMR (300 MHz, CD3OD) δ 7.58 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 5.02 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.68 (q, J1=15.2 Hz, J2=7.5 Hz, 2H), 2.52 (t, J=8.1 Hz, 2H), 2.24 (s, 3H), 2.13 (t, J=18.6 Hz, 3H), 2.09 (s, 3H), 1.24 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C25H27F2NO3S, 460.2 (M+H). found 460.2.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:15][CH:14]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33]C)=[O:31])[CH2:13][CH2:12]3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:36]>CN(C=O)C>[CH3:36][N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:17]=2)[CH2:12][CH2:13][CH:14]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: CI
Reactant: CCOC(=O)CCCCCC1CCc2cc(-c3ccccc3)c(-c3ccccc3)nc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCC1CCc2cc(-c3ccccc3)c(-c3ccccc3)nc2N1C
Reaction time: 5 h

Procedure:
A suspension of sodium hydride (61.1 mg of a 60% mixture in mineral oil, 1.528 mmol) in dry DMF (5 ml) under N2 was treated with a solution of rac-ethyl 6-(6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexanoate (step 3) (131 mg, 0.306 mmol) in DMF (5 ml). After 30 mins at room temperature iodomethane (0.096 ml, 1.528 mmol) was added and stirring continued for 5 h. The mixture was partitioned between DCM (50 ml) and water (50 ml) and the aqueous portion was separated and extracted with DCM (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-30% EtOAc in iso-hexane afforded a mixture of the title products as a colourless oil;
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C@@:22]1([CH3:55])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[N:24]([CH:42]([CH2:52][CH3:53])[C:43]([O:45][N:46]=[C:47]([CH:49]2[CH2:51][CH2:50]2)[NH2:48])=O)[C:23]1=[O:54])[CH:20]=[CH2:21]>C1COCC1>[CH2:19]([C@@:22]1([CH3:55])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[N:24]([C@H:42]([C:43]2[O:45][N:46]=[C:47]([CH:49]3[CH2:51][CH2:50]3)[N:48]=2)[CH2:52][CH3:53])[C:23]1=[O:54])[CH:20]=[CH2:21]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)C(=O)ON=C(N)C2CC2)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)c2nc(C3CC3)no2)C1=O

Procedure:
A solution of tetrabutylammonium fluoride (1.0M in THF, 1.880 mL, 1.880 mmol) was added to a solution of N′-(2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoyloxy)cyclopropanecarboximidamide (Example 89, Step B) (0.204 g, 0.376 mmol) in THF (3.76 mL) at rt. After 2 hours the reaction mixture was concentrated in vacuo and purified using a 24 g SiO2 column eluting with 25% Et2O/hexames to provide (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methylpiperidin-2-one.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:22]12([NH2:32])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:22]12([NH:32][C:17](=[O:18])[CH2:16][O:15][C:14]3[CH:13]=[CH:12][C:11]([C:1]45[CH2:10][CH:5]6[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]6)[CH2:8]4)[CH2:2]5)=[CH:21][CH:20]=3)[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)NC12CC3CC(CC(C3)C1)C2
Yield: 93.3 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and adamantan-1-amine (0.105 g, 0.69 mmol) according to the example 1, which was given N-(adamantan-1-yl)-2-(4-(adamantan-1-yl)phenoxy)acetamide as a white solid (0.27 g, 92.1% yield).
Reaction SMILES: C(OC([N:6]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=2)[C:8]2([CH:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][C:11](=[O:19])[NH:10][CH:9]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C:7]1=[O:34])=O)C.[OH-].[Na+]>CO>[Cl:33][C:30]1[CH:31]=[C:32]2[NH:6][C:7](=[O:34])[C:8]3([CH:13]([CH:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:12][C:11](=[O:19])[NH:10][CH:9]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:27]2=[CH:28][CH:29]=1
Reactant: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)NC(=O)CC2C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(C2CCCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(Cl)c2)N1
Yield: 58.2 %

Procedure:
In a manner similar to the method described in example 4d, racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclopentyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.26 g, 0.52 mmol) was reacted with NaOH (37 mg, 0.93 mmol) in methanol to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclopentylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.13 g, 59%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:5]=1[CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)=[NH:9].[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>C1COCC1>[C:27]([N:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([NH:7][CH2:6][C:5]2[C:4]([O:3][CH3:2])=[CH:24][CH:23]=[CH:22][C:21]=2[O:25][CH3:26])=[NH:9])[S:12][CH:13]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2)cs1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2C(C)=O)cs1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of 100 mg (0.25 mmol) N-(2,6-dimethoxybenzyl)-N′-(4-pyrrolidine-2-yl-1,3-thiazole-2-yl)guanidine hydrochloride, Example 147, 0.021 ml acetyl chloride and 0.04 ml pyridine in 10 ml THF were stirred for 1 hour at 5° C. and then 4 hours at room temperature. Chromatography of the crude product on RP-silica gel (Chromabond column, acetonitrile/water+0.1% glacial acetic acid; 0-100%) yielded 33 mg of the desired product; ESI-MS [M+H+]=404.15.
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.N1C=CC=CC=1C1C=CC=CN=1.C([Li])CCC.[F:25][C:26]([F:46])([F:45])[C:27]1[CH:44]=[CH:43][C:30]([O:31][C:32]2[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38](Cl)=[O:39])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1>CCCCCC.O.CCOCC.C1COCC1>[F:25][C:26]([F:45])([F:46])[C:27]1[CH:44]=[CH:43][C:30]([O:31][C:32]2[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38]([CH:2]3[C:3](=[O:6])[CH2:4][CH2:5][C:1]3=[O:7])=[O:39])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1
Reactant: O=C(Cl)COc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C1CCC(=O)C1
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C1CCC(=O)C1C(=O)COc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 1 h

Procedure:
To THF (250 ml) under N2 with stirring is added cyclopentane-1,3-dione (0.10 mol) and 2,2'-bipyridyl (~3-5 mg) as an indicator. After cooling to -70°, n-butyllithium in hexane is added slowly while the temperature is allowed to rise to -5° near the end of the addition (~130 ml of 1.6 M solution, 0.20 mol). After the pink indicator persists at -5°, the mixture is recooled to -65° and 4-(4-trifluoromethylphenoxy)phenoxyacetyl chloride is added dropwise over 5 min. After 1 hour, the reaction mixture is diluted with water and ether is added. The organic layer is washed with water, dried over sodium sulfate and concentrated in vacuo to give 2-[4-(4-trifluoromethylphenoxy)phenoxyacetyl]cyclopentane-1,3-dione (V; Y is H, Z is CF3, R1 is H and n is one).
Reaction SMILES: [Mg].[CH3:2][SiH:3]([CH3:5])Cl.Br[C:7]1[CH:16]=[CH:15][C:10]([O:11][SiH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=1>O1CCCC1>[CH3:2][SiH:3]([CH3:5])[C:7]1[CH:16]=[CH:15][C:10]([O:11][SiH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=1
Reactant: C[SiH](C)Oc1ccc(Br)cc1
Reactant: C[SiH](C)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C[SiH](C)Oc1ccc([SiH](C)C)cc1

Procedure:
To a three-necked 2-l flask containing 37.0 g (1.52 mol) of magnesium, 94.0 g (1 mol) of dimethylchlorosilane and 100 ml of freshly-distilled tetrahydrofuran was added slowly and under nitrogen a solution of 328.0 g (1.42 mol) of 4-bromophenoxydimethylsilane and 94.0 g (1 mol) of dimethylchlorosilane. During the addition, the reaction temperature was kept at 40°-50° C. After the addition was complete, the reaction mixture was refluxed and part of the tetrahydrofuran was removed by distillation. After cooling, the inorganic salt was precipitated by petroleum ether (b.p. 30°-60° C.) and filtered. The filtrate was concentrated on a rotary evaporator and then vacuum distilled. The expected compound (234.0 g, 78.5%) distilled at 85°-95° C./3.5 mm.
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([C:28]3[S:29][C:30](I)=[CH:31][CH:32]=3)=[C:10]([P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])[C:11]=2[P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:39]1[S:43][C:42]([C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)=[C:41]([P:49]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])=[O:50])[C:40]=1[P:57]([O:62][CH2:63][CH3:64])([O:59][CH2:60][CH3:61])=[O:58])CCC.[F-].[K+]>C1COCC1.[Cu]Cl>[CH2:15]([O:14][P:12]([C:11]1[C:10]([P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([C:28]2[S:29][C:30]([C:9]3[S:8][C:7]([C:5]4[S:6][C:2]([C:39]5[S:43][C:42]([C:44]6[S:45][CH:46]=[CH:47][CH:48]=6)=[C:41]([P:49]([O:51][CH2:52][CH3:53])([O:54][CH2:55][CH3:56])=[O:50])[C:40]=5[P:57]([O:59][CH2:60][CH3:61])([O:62][CH2:63][CH3:64])=[O:58])=[CH:3][CH:4]=4)=[C:11]([P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])[C:10]=3[P:20]([O:22][CH2:23][CH3:24])([O:25][CH2:26][CH3:27])=[O:21])=[CH:31][CH:32]=2)[S:8][C:7]=1[C:5]1[S:6][CH:2]=[CH:3][CH:4]=1)([O:17][CH2:18][CH3:19])=[O:13])[CH3:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1sc(-c2cccs2)c(P(=O)(OCC)OCC)c1P(=O)(OCC)OCC
Reactant: CCOP(=O)(OCC)c1c(-c2ccc(I)s2)sc(-c2ccc(I)s2)c1P(=O)(OCC)OCC
Agent: Cl[Cu]
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1c(-c2cccs2)sc(-c2ccc(-c3sc(-c4ccc(-c5sc(-c6cccs6)c(P(=O)(OCC)OCC)c5P(=O)(OCC)OCC)s4)c(P(=O)(OCC)OCC)c3P(=O)(OCC)OCC)s2)c1P(=O)(OCC)OCC
Yield: 77 %

Procedure:
In THF, 0.155 g (0.201 mmols) of the 5,5″-diiodo-3′,4′-bis(diethoxyphosphoryl)-[2,2′;5′,2″]-terthiophene obtained in Example 7(4) and 0.307 g (0.422 mmols) of 5-tributylstannyl-3,4-bis(diethoxyphosphoryl)-[2,2′]-bithiophene obtained in Example 6(5) were dissolved, to which 0.0438 g (0.442 mmols) of commercially available copper(I) chloride was added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 18 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 1 hour. Subsequently, the solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column to obtain the specified substance in the form of a yellow oil at a yield of 0.216 g (yield: 77%).
Reaction SMILES: N1C=CC=CC=1.S(Cl)(Cl)=O.C1C=C2C([N:19]([CH2:22][C:23](O)=[O:24])C(=O)C2=CC=1)=O.[NH:26]1[CH2:33][CH2:32][CH2:31][C@@H:27]1[C:28]([OH:30])=O>ClCCl.O>[C:28]1(=[O:30])[NH:19][CH2:22][C:23](=[O:24])[N:26]2[CH2:33][CH2:32][CH2:31][C@H:27]12
Reactant: O=C(O)[C@H]1CCCN1
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C1NCC(=O)N2CCC[C@H]12
Temperature: 25 °C

Procedure:
Pyridine (2.5 ml ), and thionyl chloride (22.5 ml) were added to a solution of N-phthaloylglycine (57.5 g) in dichloromethane and the reaction stirred under reflux for 18 hours. The mixture was allowed to cool to room temperature, (R)-proline (30.5 g) added and the reaction again stirred under reflux for 18 hours. On cooling, water was added and the resulting precipitate filtered, washed with further water and dried. This material was suspended in ethanol (330 ml) and dichloromethane (250 ml), and hydrazine hydrate (26.5 ml) added. The reaction mixture was stirred at room temperature for 18 hours, filtered and the filtrate evaporated to dryness in vacuo. This material was crystallised from ethanol, to afford the title compound, 26.05 g.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=1[O:35][CH2:36][CH3:37]>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:22][CH2:23][N:24]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[O:35][CH2:36][CH3:37])[CH2:25][CH2:26]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: CCOc1c(N)ncnc1Cl
Product: CCOc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(C)C)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-isopropyl-pyridine and 6-chloro-5-ethoxy-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=491, obsd=491).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7]([OH:9])=[O:8].[C:15]([OH:24])(=[O:23])[C:16]1C(=CC=[CH:21][CH:22]=1)N>>[C:7]([C:6]1[CH:10]=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH:14][CH:16]1[CH2:22][CH2:21][O:24][C:15]1=[O:23])([OH:9])=[O:8]
Reactant: Nc1ccccc1C(=O)O
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Product: COc1cc(NC2CCOC2=O)c(C(=O)O)cc1OC

Procedure:
In the method of the Reference Example 1, 4,5-dimethoxyanthranilic acid was reacted in the place of anthranilic acid to obtain α-[(2-carboxy-4,5-dimethoxyphenyl)-amino]-γ-butyrolactone, melting point: 214° C.(decomp.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>CO>[ClH:23].[ClH:23].[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=1)[CH3:22]
Reactant: CCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CO
Product: CCOc1ccc(N2CCNCC2)cc1
Reaction time: 5 h

Procedure:
A mixture of 1-(tert-butyloxycarbonyl)-4-(4-hydroxyphenyl)piperazine (XXII, 0.602 g, 2.2 mmol) in dry THF (4 ml) is added to an ice-cooled slurry of sodium hydride (0.1013 g, 2.5 mmol--60% in oil) in THF (1 ml). DMF (15.3 ml) is added to solubilize the solids that had precipitated, after which ethyl iodide (0.34 ml, 4.3 mmol) is added. The ice/water bath is removed and the mixture stirred for five hr. Another portion of ethyl iodide (0.35 ml, 4.4 mmol) is added and the mixture is allowed ti stir over the weekend at 20-25°, at which time it is concentrated and the resulting solids are partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The combined organic phases are dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel eluting with methanol/dichloromethane (1/99) containing ammonium hydroxide (0.5%), followed by methanol/dichloromethane (2/98) containing ammonium hydroxide (0.5%). The appropriate fractions are pooled and concentrated to give 1-(tert-butyloxycarbonyl)-4-(4-ethoxyphenyl)piperazine (XXIII). 1-(Tert-butyloxycarbonyl)-4-(4-ethoxyphenyl)-piperazine (XXIII, 0.43 g) is dissolved in methanol and methanol saturated with hydrochloric acid gas is added. After stirring at 20-25° for 5 hours the slurry is concentrated and ether is added. The solids are collected, washed with ether, and dried to give 1-(4-ethoxyphenyl)piperazine dihydrochloride (XXIV), MS (m/z) 206; IR (mineral oil) 1253, 1511, 2542, 2432, 1475 and 2622 cm-1.