Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC(/C=C/C[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.Br[CH2:33][C:34]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:38][CH2:37][CH2:36][O:35]1>>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[CH2:15][CH2:16][N:11]([CH2:33][C:34]3([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:38][CH2:37][CH2:36][O:35]3)[CH2:12][CH2:13]2)=[CH:18][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Reactant: BrCC1(c2ccccc2)OCCO1
Product: c1ccc(Oc2ccc(C3CCN(CC4(c5ccccc5)OCCO4)CC3)cc2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 2-bromomethyl-2-phenyl-1,3-dioxolane to produce the above.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.Cl[CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18].C(C1C=CC(C=O)=CC=1)(C)C.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>>[CH:25]([C:22]1[CH:21]=[CH:20][C:19]([C:15]2[O:16][C:17]([CH3:18])=[C:13]([CH2:12][O:1][C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=3)[N:14]=2)=[CH:24][CH:23]=1)([CH3:27])[CH3:26]
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Reactant: Cc1cc(O)ccc1C=O
Agent: CC(C)c1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)ccc1C=O

Procedure:
In analogy to the procedure described in example 120 f], 4-hydroxy-2-methyl-benzaldehyde (for the preparation of 4-hydroxy-2-methyl-benzaldehyde see: H. H. Hodgson, T. A. Jenkinson, J. Chem. Soc. 1929, 469, 1639-1641) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole (prepared from 4-isopropyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 21 a] and b]) in the presence of potassium carbonate to yield 4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-benzaldehyde. 4-[2-(4-Isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-benzaldehyde was reacted with (ethoxy-ethoxy-carbonyl-methyl)-triphenyl-phosphonium chloride [for the preparation of (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride see: K. K. Bach, H. R. El-Seedi, H. M. Jensen, H. B. Nielsen, I. Thomson, K. B. G. Torssell, Tetrahedron 1994, 50, 7543-7556] in the presence of DBU in analogy to the procedure described in example 120 c] to give 2Z-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield 2Z-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylic acid as light green solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc2cc(OC)ccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc2cc(O)ccc12
Temperature: -5 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4.72 g (20 mMol) 6-methoxy-benzo[b]thiophene-3-carboxylic acid ethyl ester in 200 ml CH2Cl2 at −10° C., 40 ml of a 1 M solution of BBr3 in CH2Cl2 are added via syringe during 12 min. The solution is stirred for 3.5 h at −10 to 0° C., then diluted with 600 ml EtOAc and poured into 450 ml of a mixture of sat. NaHCO3 and ice. After 5 min, the aq. layer is separated off and extracted 3× with 120 ml EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and after addition of SiO2 concentrated. The resulting powder is put on top of a SiO2-column and the title compound eluted with hexan/EtOAc 4:1: m.p.: 128-129° C.; TLC(hexane/EtOAc 4:1): Rf=0.18.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH:11]([N:13]1[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:14]1)=[O:12].[ClH:25].[NH4+].[Cl-]>>[ClH:25].[CH:11]([N:13]1[CH2:18][CH2:17][N:16]([C:8](=[O:10])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:15]([CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:14]1)=[O:12]
Reactant: O=C(O)Cc1ccccn1
Reactant: O=CN1CCNC(CN2CCCC2)C1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: O=CN1CCN(C(=O)Cc2ccccn2)C(CN2CCCC2)C1

Procedure:
The compound was prepared by coupling of 2-pyridinylacetic acid with 4-formyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine; mp: (HCl salt) 125-128° C.; 1H NMR (free base, 200 MHz, CDCl3) δ 1.5-1.7 (4H, m), 2.1-3.6 (10H, m), 3.7-4.9 (5H, m), 6.9-7.3 (2H, m), 7.6 (1H, m), 8.0 (1H, m), 8.6 (1H, m); MS (FAB) 317 (M+H)+; Anal. Calcd. for C17H24N4O2.2HCl.NH4Cl: C, 46.11; H, 6.83; N, 15.82. Found: C, 46.37; H, 6.51; N, 16.35.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: O=C(O)c1cccc(-c2ccc(F)cc2)n1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3ccc(F)cc3)n2)c1

Procedure:
Carboxylic acid (152) (50 mg, 0.23 mmol) was coupled to aniline (60) (44 mg, 0.23 mmol) using Method C. The crude residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.BrC1C=CC(C([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[CH:23]2)=O)=CC=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[CH:23]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NCCCn1cnc(-c2ccccc2)c1)c1ccc(Br)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(NCCCn1cnc(-c2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
When 4-chlorobenzoyl chloride was substituted for the 4-bromobenzyl chloride of Example 76, There was obtained the title compound, m.p. 103°-105° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CO>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:42](=[O:43])[CH2:41][N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CCN(CC(=O)Nc2nc3ccc(Oc4cccc(NC(=O)c5cccc(C(C)(C)C#N)c5)c4)cc3s2)CC1
Reaction time: 14 h
Yield: 28.6 %

Procedure:
To a solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (452 mg, 1.05 mmol) produced in Example A12(iv) in pyridine (10 mL) were added (4-methylpiperazin-1-yl)acetic acid dihydrochloride (273 mg, 1.18 mmol), N,N-dimethylpyridine-4-amine (89.1 mg, 729 μmol), triethylamine (10 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (492 mg, 2.57 mmol) at room temperature, and the mixture was stirred for 14 hr. To the reaction mixture were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (483 mg, 2.52 mmol) and N,N-dimethylpyridine-4-amine (292 mg, 2.39 mmol) and the mixture was further stirred for 4 hr. To the reaction mixture was added methanol (10 mL), and the mixture was stirred at room temperature for 30 min, and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride solution (50 mL×2) and saturated aqueous sodium hydrogencarbonate solution (50 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→20/80) and triturated with ethyl acetate and diisopropyl ether to give the title compound (171 mg, 29%) as a colorless solid.
Reaction SMILES: [O:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][Mg]Br.[Cl-].[NH4+]>C(OCC)C>[CH3:10][C:9]([CH3:12])([OH:11])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(=O)COc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(O)COc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
To a stirred solution of 24.2 g (0.16 mole) of phenoxy-2-propanone (Eastman) in 150 mL of dry ethyl ether was added 56 ml (0.17 mole) of methylmagnesium bromide (3.0M solution in ethyl ether, Aldrich) and the reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 4 hr. The reaction mixture was treated with 100 ml of saturated ammonium chloride solution and vigorously stirred for 1 hr. The layers were separated and the organic layer was washed twice with 200 ml portions of water, dried (magnesium sulfate) and the solvent evaporated under reduced pressure to yield 24.3 g (91%) of a vicous oil. A 2.3 g sample of the oil was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500 A; PrepPAK® 500 silica; ethyl acetate-hexanes, 1:20; flow rate 150 ml/min). The desired fractions were combined and the solvents evaporated under reduced pressure to yield 2.1 g (91% recovery) of the title compound as a colorless liquid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([S:13](Cl)(=[O:15])=[O:14])[CH:11]=2)[C:6]([CH3:19])([CH3:18])[CH2:5]1)(=[O:3])[CH3:2].I[CH2:21][CH3:22].[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[CH2:21]([S:13]([C:10]1[CH:11]=[C:12]2[C:7]([C:6]([CH3:19])([CH3:18])[CH2:5][N:4]2[C:1](=[O:3])[CH3:2])=[CH:8][C:9]=1[F:17])(=[O:15])=[O:14])[CH3:22]
Reactant: CC(=O)N1CC(C)(C)c2cc(F)c(S(=O)(=O)Cl)cc21
Reactant: CCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Product: CCS(=O)(=O)c1cc2c(cc1F)C(C)(C)CN2C(C)=O
Yield: 54.5 %

Procedure:
The title compound was prepared from 1-acetyl-5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole-6-sulfonyl chloride (300 mg, 0.98 mmol), iodoethane (396 μL, 4.9 mmol), Na2SO3 (236 mg, 1.87 mmol), NaHCO3 (165 mg, 1.96 mmol) and TBABr (2 mg, 0.006 mmol) following similar methods to those described in Prep 64, to give the title compound (160 mg). 1H NMR (CDCl3): 8.67 (1H, d), 6.98 (1H, d), 3.86 (2H, s), 3.38-3.19 (2H, m), 2.22 (3H, s), 1.38 (6H, s), 1.34-1.27 (3H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][N:4]=1.[SH:12][C:13]1[NH:17][C:16]2[CH:18]=[C:19]3[C:23](=[CH:24][C:15]=2[N:14]=1)[C:22]([CH3:26])([CH3:25])[C:21](=[O:27])[C:20]3([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S:12][C:13]2[NH:14][C:15]3[CH:24]=[C:23]4[C:19](=[CH:18][C:16]=3[N:17]=2)[C:20]([CH3:28])([CH3:29])[C:21](=[O:27])[C:22]4([CH3:26])[CH3:25])[C:8]=1[CH3:9]
Reactant: COc1ccnc(CCl)c1C
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 690 mg of 2-chloromethyl-3-methyl-4--methoxypyridine and 400 mg of 5,7-dihydro-2-mercapto-5,5,7, 7-tetramethylindeno[5,6-d]imidazol-6(lH)-one in 40 ml of absolute acetone was treated with 1.9 g of finely ground potassium carbonate, whereupon the mixture was stirred at room temperature under argon for 18 hours. After concentrating the mixture in vacuo the residue was chromatographed on silica gel with methylene chloride/ethyl acetate (10:1) as the elution agent, the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. By recrystallization from ethyl acetate/ ether there was obtained 5,7-dihydro-2-[[(4-methoxy-3-methyl-2 -pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(lH)-one of melting point 218-220° .
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:22]([NH2:24])=[O:23])=[C:8]1[C:18]([NH:20][CH3:21])=[O:19].[CH3:25][C:26]1[O:30][N:29]=[C:28]([C@:31]([OH:35])([C:33]#[CH:34])[CH3:32])[CH:27]=1>>[F:16][C:15]1[CH:14]=[C:13]2[C:4]([C:5]3[N:9]([CH:10]4[CH2:17][CH:12]2[CH2:11]4)[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:7]([C:22]([NH2:24])=[O:23])[N:6]=3)=[CH:3][C:2]=1[C:34]#[C:33][C@@:31]([OH:35])([C:28]1[CH:27]=[C:26]([CH3:25])[O:30][N:29]=1)[CH3:32]
Reactant: CNC(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: CNC(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(C#C[C@@](C)(O)c3cc(C)on3)cc1-2

Procedure:
9-Bromo-10-fluoro-3-N-methyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-3,4-dicarboxamide (125 mg) was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure E to afford 19.5 mg of 10-fluoro-9-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-3-N-methyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-3,4-dicarboxamide following reverse phase hplc purification. MS (Q1) 464 (M)+. 1H NMR (400 MHz, DMSO) δ 10.59 (q, J=4.6 Hz, 1H), 8.85 (d, J=7.5 Hz, 1H), 8.28 (s, 1H), 7.74 (s, 1H), 7.32 (d, J=10.1 Hz, 1H), 6.58 (s, 1H), 6.36 (s, 1H), 6.19-6.03 (m, 1H), 3.73-3.61 (m, 1H), 3.18-3.05 (m, 2H), 2.78 (d, J=4.5 Hz, 3H), 2.41 (s, 4H), 1.68 (d, J=12.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][N:11]1[C:15](=[O:16])[CH2:14][C:13]([C:17]([F:20])([F:19])[F:18])=[N:12]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([O:16][C:15]2[N:11]([CH3:10])[N:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CN1N=C(C(F)(F)F)CC1=O
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(Oc2cc(C(F)(F)F)nn2C)nc(Cl)n1
Yield: 68 %

Procedure:
5 g 2,4-Dichloro-6-methylpyrimidine, 5.3 g 1-methyl-3-trifluoromethyl-2-pyrazolin-5-one, and 6.2 g potassium carbonate in 100 mL dry acetonitrile are refluxed for 2 hours. The mixture is poured into water, extracted with ethyl acetate and chromatographed to give 6.1 g of the title compound (m.p. 65° C.)
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].O>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)(=[O:23])[CH3:22]
Reactant: C[C@]12CC[C@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
3-Hydroxy-9β-oestra-1,3,5(10)-trien-17-one (370 mg., 1.4 mmole) was treated with acetic anhydride (3 ml.) in pyridine (3 ml.) at steam-bath temperature for 45 min. The cooled solution was poured into water (50 ml.), and extracted with ether (50 ml.). The ether extract was washed with 2N-sulphuric acid (25 ml.), then water (2 × 25 ml.) and the solvent evaporated in vacuo to give the title compound as a chromatographically pure oil (390 mg., 90%), υmax. 1758, 1735 and 1200 cm. -1.
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[CH:37][CH:36]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[F:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][CH2:41][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][O:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][NH:9][CH:10]3[CH2:19][CH2:18][CH2:17][C:16]4[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]3=4)=[CH:40][CH:39]=2)=[CH:44][CH:45]=1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(CCc2ccc(F)cc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1OCc1ccc(CCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12 ml of a 4 N solution of hydrogen chloride in dioxane were added to 3180 mg (4.87 mmol) of ethyl 5-[(tert-butoxycarbonyl){2-[2-({4-[2-(4-fluorophenyl)ethyl]benzyl}oxy)phenyl]ethyl}-amino]-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 131A), and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated to dryness. This gave 3290 mg of the target product which was reacted further without further analytical characterization.
Reaction SMILES: [C:1]1([C:7]2([N:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+].Cl.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:26][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][N:13]1[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: [BH3-]C#N
Reactant: O=C1CCN(C2(c3ccccc3)CCCCC2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: NC1CCCCN1C1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(1 phenylcyclohexyl)-4 piperidone (0.245 q) and ammonium acetate (I q) were dissolved in 3.5 mL dry methanol. After stirring at room temperature for 10 minutes, sodium cyanoborohydride (0.1 q) was added and the reaction was stoppered. After 20 hours, 0.1 mL of concentrated hydrochloric acid was added followed by 10 mL water and the mixture was stirred for 1.5 hours. The solution was basified with potassium carbonate to pH 9 and extracted with methylene chloride. The methylene chloride was dried over Na2SO4 and removed in vacuo. The product distilled as a colorless, clear oil at 90°-130° C. in vacuo (about 5 mmHg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[C:19](=[O:20])[O:18][C@H:17]3[C:21]4[C@@:26]([CH3:29])([CH2:27][CH2:28][C:16]23[OH:31])[CH2:25][CH2:24][CH2:23][C:22]=4[CH3:30])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[OH:31][C:16]12[CH2:28][CH2:27][C@:26]3([CH3:29])[CH:21]([CH:22]([CH3:30])[CH2:23][CH2:24][CH2:25]3)[C@@H:17]1[O:18][C:19](=[O:20])[CH:15]2[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC1=C2[C@@H]3OC(=O)C(CN4CCN(Cc5ccccc5)CC4)C3(O)CC[C@@]2(C)CCC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CCC[C@]2(C)CCC3(O)C(CN4CCNCC4)C(=O)O[C@H]3C12

Procedure:
Compound of example 27 (100 mg, 0.47 mmol) was dissolved in methanol (10 mL) and 10% Pd(OH)2/C was added to it. The reaction mixture was hydrogenated (hydrogen pressure, 1 atm) for 30 hours. The reaction mixture was filtered over celite and concentrated to obtain the title compound
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[C:14](=[O:18])[CH2:13]1
Reactant: CN1CCNC(=O)C1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)C(=O)C1
Temperature: 90 °C

Procedure:
204 a) An oven dried tube was charged with 1-iodo-3-nitro-benzene (2.60 g, 10.4 mmol), 4-methyl-piperazin-2-one (1.00 g, 8.76 mmol), copper(I) iodide (85.0 mg, 0.446 mmol), (1R,2R)-N,N′-dimethyl-cyclohexane-1,2-diamine (0.14 mL, 0.89 mmol), potassium phosphate (3.75 g, 17.7 mmol) and 1,4-dioxane (10 mL). The tube was carefully evacuated and backflushed with nitrogen three times then sealed. The mixture was heated at 90° C. for 24 hours then cooled to room temperature and diluted with dichloromethane (20 mL). The mixture was filtered through a plug of diatomaceous earth and the filtrate was evaporated. The residue was purified via chromatography using an ISCO automated purification apparatus (silica gel column 40 g and 0%→4% methanol:dichloromethane). 4-Methyl-1-(3-nitro-phenyl)-piperazin-2-one was isolated as a red-brown waxy solid (1.13 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.20 (s, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.57 (t, J=8.2 Hz, 1H), 3.79 (t, J=5.1 Hz, 2H), 3.31 (s, 2H), 2.83 (t, J=5.2 Hz, 2H), 2.42 (s, 3H). MS=236 (MH)+.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.CCCCCC.Br[C:22]1[CH:23]=[CH:24][C:25]2[C:26]3[CH2:35][CH2:34][CH2:33][C:27]=3[C:28](=[O:32])[NH:29][C:30]=2[CH:31]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd](Cl)Cl>[N:36]1([C:22]2[CH:23]=[CH:24][C:25]3[C:26]4[CH2:35][CH2:34][CH2:33][C:27]=4[C:28](=[O:32])[NH:29][C:30]=3[CH:31]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: C1COCCN1
Reactant: O=c1[nH]c2cc(Br)ccc2c2c1CCC2
Agent: Cl[Pd]Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(N3CCOCC3)ccc2c2c1CCC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
A solution of 1,1,1,3,3,3-hexamethyldisilazane (2.6 ml, 12.5 mmol) in toluene (100 ml) is mixed at 0° C. with 1.6 M of n-BuLi in hexane (7.5 ml, 12.0 mmol) and stirred for 15 minutes at 0° C. 7-Bromo-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one (1.34 g, 5.0 mmol), morpholine (0.65 ml, 7.5 mmol), palladium dichloride (44 mg, 0.25 mmol) and tri-o-tolylphosphine (152 mg, 0.5 mmol) are added to it. The batch is refluxed for 5 hours, diluted with ethyl acetate, washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Purification of the residue on silica gel with dichloromethane-ethanol yields 1.17 g of product.