Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:10]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:14]([N:24]([C:26](=[O:44])[C:27]([C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)([CH3:29])[CH3:28])[CH3:25])=[CH:13][N:12]=1)C1C=CC=CC=1>CO.CN(C)C=O.[Pd]>[CH2:45]([NH:10][C:11]1[N:12]=[CH:13][C:14]([N:24]([CH3:25])[C:26](=[O:44])[C:27]([C:30]2[CH:35]=[C:34]([C:36]([F:38])([F:37])[F:39])[CH:33]=[C:32]([C:40]([F:41])([F:42])[F:43])[CH:31]=2)([CH3:29])[CH3:28])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH:16]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: Cc1ccccc1-c1cc(N(Cc2ccccc2)C(=O)OCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1cc(NCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of 973 mg (1.35 mmol) benzyl-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-carbamic acid benzyl ester in 13 ml methanol and 1 ml N,N-dimethylformamide was added 40 mg 10% palladium on activated charcoal and the mixture was hydrogenated (room temperature, 1 bar) for 1 h. Filtration of the catalyst and evaporation of the filtrate afforded 795 mg (quantitative) of the title compound as a yellow oil.
Reaction SMILES: O[CH:2]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:18][OH:19])[CH:8]=2)[O:3]1.[CH:20]([NH:23][CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>CO>[CH:20]([N:23]([CH:24]([CH3:26])[CH3:25])[CH2:2][CH2:11][CH:10]([C:9]1[CH:8]=[C:7]([CH2:18][OH:19])[CH:6]=[CH:5][C:4]=1[OH:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:22])[CH3:21]
Reactant: OCc1ccc2c(c1)C(c1ccccc1)CC(O)O2
Reactant: CC(C)NC(C)C
Solvent: CO
Product: CC(C)N(CCC(c1ccccc1)c1cc(CO)ccc1O)C(C)C
Reaction time: 1 h

Procedure:
(2-Hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl)methanol (Example 13, 830 g, 3.24 mol, 1.0 eq) was stirred in methanol (4150 mL, 5.0 mL/g). Diisopropylamine (1362 mL, 9.72 mol, 3.0 eq) was then added over 15 minutes via dropping funnel. The resulting solution was then stirred for one hour under nitrogen.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:15]=1[N:24]=[C:25]=[O:26].O>CN(C)C=O>[C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:25]([NH:24][C:15]1[C:16]([O:22][CH3:23])=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[O:13][CH3:12])=[O:26])#[N:9]
Reactant: COc1cc(OC)c(N=C=O)c(OC)c1
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(NC(=O)C(C#N)c2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
Phenylacetonitrile (2.64 mL, 22.8 mol) was added dropwise to an ice-cooled solution of sodium hydride (0.91 g, 22.8 mmol) in dimethyl formamide (50 mL), and the mixture stirred for 15 minutes while allowing to warm to room temperature. 2,4,6-Trimethoxyphenyl-isocyanate (4.78 g, 22.8 mmol) was added portionwise over 2 minutes, and then the mixture was stirred vigorously for 0.5 hour and poured into water (200 mL). The solid obtained was washed with water (100 mL) and taken up in chloroform (1 n). The organic layer was separated and dried with MgSO4, filtered, and concentrated to yield a pale purple solid (6.13 g, 82%). % (found): C, 65.94; H, 5.56; N, 8.10.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:23][C:24]1[S:25][C:26]([O:29][C:30]2[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH:39]=2)[C:35]([O:37][CH3:38])=[O:36])=[CH:27][N:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:14]([NH:23][C:24]3[S:25][C:26]([O:29][C:30]4[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH:39]=4)[C:35]([O:37][CH3:38])=[O:36])=[CH:27][N:28]=3)=[O:16])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(Oc2cnc(N)s2)ccc1C
Reactant: O=C(O)C(O[C@@H]1CCOC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2cnc(NC(=O)C(O[C@@H]3CCOC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)ccc1C
Yield: 85.5 %

Procedure:
The compound of example A3 was obtained by similar method described in example A2 using 2-(4-Cyclopropanesulfonyl-phenyl)-2-[(R)-(tetrahydro-furan-3-yl)oxy]-acetic acid (preparation 5, 0.200 g, 0.613 mmol), methyl 5-(2-aminothiazol-5-yl)oxy-2-methyl-benzoate (preparation 26; 0.194 g, 0.736 mmol), HOBt (0.099 g, 0.736 mmol), and EDCl (0.140 g, 0.736 mmol), N-methyl morpholine (0.0154 g, 1.53 mmol) in DCM (8 mL) to provide the title compound (0.3 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[CH:31]([N:27]1[C:26]([C:20]2[S:21][C:22]3[CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:35]=[CH:34][C:17]=4[C:18]=3[N:19]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc1-2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Reaction time: 18 h
Yield: 27.7 %

Procedure:
Alternatively, to a suspension of 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (470 mg, 0.95 mmol) in MeOH (10 mL) was added 1M HCl in ether (1.9 mL, 1.90 mmol). The reaction mixture was stirred for 18 hours then the volatiles were removed in vacuo. The resultant residue was stirred in diethyl ether (20 mL) for 20 minutes then the solid was filtered off and further triturated with a mixture of MeOH and ether to give 375 as a white solid (104 mg, 28%). LCMS: RT=7.82 min, [M+H]+=396. 1H NMR δ (ppm) (DMSO-d6): 8.86 (2 H, s), 8.26 (1 H, d, J=8.20 Hz), 8.05 (1 H, s), 7.03 (1 H, dd, J=8.26, 1.83 Hz), 6.87 (1 H, d, J=1.78 Hz), 5.81-5.71 (1 H, m), 4.31 (2 H, t, J=5.01 Hz), 3.37 (2 H, t, J=5.01 Hz), 3.30 (2 H, d, J=12.46 Hz), 2.93 (2 H, d, J=11.52 Hz), 2.84-2.75 (1 H, m), 1.92-1.75 (4 H, m), 1.49 (6 H, d, J=6.59 Hz)
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl-].[Cl-].[Ca+2].N1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]([O:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CO)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(COC(=O)CBr)cc1

Procedure:
20.2 g (0.1 mol) of bromoacetyl bromide are dissolved in 100 ml of toluene, this solution is cooled to -10° C. (CaCl2 tube) and 8.7 g (0.11 mol) of pyridine are added dropwise at -10° C. Thereafter, 13.8 g (0.1 mol) of 4-methoxybenzyl alcohol, dissolved in 20 ml of toluene are added dropwise to this mixture in the course of 20 minutes at -10° C., and the mixture is allowed to react for 1 hour at this temperature.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:15]=2)[CH3:13])=[C:4]([CH3:28])[N:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.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>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([C:32]3[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=3)=[CH:18][CH:19]=2)[CH3:13])=[C:4]([CH3:28])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1CCCC(C)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1CCCC(C)c1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 115 °C
Yield: 26.1 %

Procedure:
A solution of 2.0 grams (0.005 mole) of 2,4-diamino-5-[4-(4-trifluoromethylsulfonyloxyphenyl)pentyl]-6-methylpyrimidine (prepared in Step K of this Example), 2.4 grams (0.01 5 mole) of 3,5-difluorophenylboronic acid, and 0.3 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0) in 90 mL of N,N-dimethylformamide was stirred, and 3.5 grams (0.025 mole) of potassium carbonate was added in one portion. Upon completion of addition, the reaction mixture was warmed slowly to 115 ° C. where it was maintained for about 40 hours. The reaction mixture was cooled and poured into 250 mL of water. The mixture was then extracted with three 150 mL portions of ethyl acetate. The combined extracts were washed with three 150 mL portions of an aqueous 10% lithium chloride solution and dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on neutral alumina (deactivated with 6% wt/wt water), using 2°-10% methanol in methylene chloride as the eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.5 gram of 2,4-diamino-5-[4-[4-(3,5-difluorophenyl)phenyl]pentyl]-6-methylpyrimidine, mp 129°-134° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][CH2:17][NH:16][C:15]2=[O:19])[CH:9]=1)(=O)=O.[CH3:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[N:22]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[N:31]2[CH2:36][CH2:35][N:34]([CH2:6][CH2:7][C:8]3[CH:9]=[C:10]([N:14]4[CH2:18][CH2:17][NH:16][C:15]4=[O:19])[CH:11]=[CH:12][CH:13]=3)[CH2:33][CH2:32]2)[N:22]=1
Reactant: Cc1ccc2c(N3CCNCC3)cccc2n1
Reactant: CS(=O)(=O)OCCc1cccc(N2CCNC2=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Temperature: 75 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
2-[3-(2-Oxo-1-imidazolidinyl)phenyl]ethyl methanesulfonate (1.32 wt) and 2-methyl-5-(1-piperazinyl)quinoline (1 wt.) were suspended in acetonitrile (5 vol) at room temperature under nitrogen. Diisopropylethylamine (1.53 vol) was added dropwise over 30 minutes, and the mixture was then stirred at 75° C. for 4 hours. The reaction mixture was cooled to room temperature, concentrated to 2 vol, and diluted with ethyl acetate (7 vol). The organic layer was washed with saturated aqueous ammonium chloride solution (2×3 vol), followed by water (1×3 vol). The organic layer was evaporated to dryness, yielding the title compound as a brown foam (70% th).
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:11][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:11][O:9][C:8]([C:2]1([NH2:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:10]
Reactant: NC1(C(=O)O)CCCCC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1(N)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.5 %

Procedure:
In a round-bottomed flask 1-amino-1-cyclohexanecarboxylic acid (1.00 g, 7.0 mmol) was suspended in dichloromethane (26 mL) and MeOH (13 mL). (Trimethylsilyl)diazomethane (2.0 M in hexanes, 6.0 mL, 12.0 mmol) was added dropwise and the reaction mixture gradually became homogeneous as it was stirred at room temperature overnight. The reaction mixture was quenched with a small portion of acetic acid and concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated aqueous Na2CO3. The aqueous layer was extracted with dichloromethane and the combined organics were dried over Na2SO4 and concentrated to afford 1.15 g of 1-amino-1-cyclohexanecarboxylic acid methyl ester as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:16][OH:17].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>>[Br:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH:16]=[O:17]
Reactant: OCc1cccc2c(Br)c3ccccc3cc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: O=Cc1cccc2c(Br)c3ccccc3cc12

Procedure:
Using the procedure outlined in 2D, oxidation of (10-bromo-1-anthryl)methanol with PCC gave 10-bromo-1-anthracenecarbaldehyde mp 134.5°-135.5°, (PhCH3 /hexane), (C,H,Br).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][CH:10]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCCCC(CC=Cc2ccccc2)N1
Agent: [Pd]
Solvent: CO
Product: O=C1CCCCCC(CCCc2ccccc2)N1

Procedure:
The title material of Example 68 in MeOH is hydrogenated over Pd on carbon in a standard Parr apparatus by the method of Example 35 to generate the title product.
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([OH:39])=O)=[CH:32][CH:31]=1.[CH:40]1[C:48]2[C:47]3[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:46]=3[O:45][C:44]=2[CH:43]=[CH:42][C:41]=1[NH2:54]>ClCCl>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:54][C:41]2[CH:42]=[CH:43][C:44]3[O:45][C:46]4[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][C:47]=4[C:48]=3[CH:40]=2)=[O:39])=[CH:34][CH:35]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(F)cc1)Nc1ccc2oc3c(c2c1)CCCCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
Triethylamine (0.52 mL, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.37 g, 1.9 mmol), N-hydroxybenzotriazole (0.26 g, 1.9 mmol) and 4-fluorophenylacetic acid (0.27 g, 1.8 mmol) were added sequentially to a solution of 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.30 g, 1.5 mmol) in dichloromethane (20 mL). The reaction mixture was stirred overnight at ambient temperature and then concentrated. The crude material was dissolved in ethyl acetate and washed with 1 N NaOH and water, dried (MgSO4) and concentrated to give 2-(4-fluorophenyl)-N-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl)acetamide (0.47 g). MS (ESI) m/z 338 ([M+H]+).
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:31][CH3:32])=[CH:11][C:12]2[CH:13]3[CH:21]([CH2:22][CH2:23][C:24]=2[CH:25]=1)[CH:20]1[C:16]([CH3:30])([C:17](=[CH:26][CH2:27][O:28][CH3:29])[CH2:18][CH2:19]1)[CH2:15][CH2:14]3)C1C=CC=CC=1.CC(O)C>C(O)(C)(C)C>[CH2:31]([C:10]1[C:9]([OH:8])=[CH:25][C:24]2[CH2:23][CH2:22][CH:21]3[CH:13]([CH2:14][CH2:15][C:16]4([CH3:30])[CH:20]3[CH2:19][CH2:18][C:17]4=[CH:26][CH2:27][O:28][CH3:29])[C:12]=2[CH:11]=1)[CH3:32]
Reactant: CCc1cc2c(cc1OCc1ccccc1)CCC1C2CCC2(C)C(=CCOC)CCC12
Solvent: CC(C)(C)O
Solvent: CC(C)O
Product: CCc1cc2c(cc1O)CCC1C2CCC2(C)C(=CCOC)CCC12
Temperature: 25 °C

Procedure:
A solution of 3-benzyloxy-2-ethyl-17-(2-methoxy-ethylidene)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene (0.43 g, 1 mmol) in 50 ml tert-butanol was reflux and Na (0.46 g, 20 mmol) was added in small portions over a period of 6 hours. The mixture was refluxed for 18 h, cooled to room temperature and 2-propanol added to destroy excess sodium. The solvents were evaporated and the residual solid poured in water (20 ml). The organics were extracted with ethyl acetate and the organic layer was washed with water, brine, dried over MgSO4. The solvent was evaporated under vacuum. The crude oil was purified by chromatography (hexane/ethylacetate 15/1 to 8:1) to give 2-ethyl-17-(2-methoxy-ethylidene)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-ol as a white powder, 230 mg (68%), mp=133-134° C.; 1H NMR (CDCl3, 270 MHz): 0.79 (s, 3H, CH3), 1.22 (t, J=7.4 Hz, 3H, CH3), 1.28-1.60 (m, 6H), 1.75-1.96 (m, 3H), 2.18 (m, 1H), 2.39 (m, 3H), 2.59 (q, J=7.4 Hz, 2H, CH2), 2.79 (m, 2H, H6), 3.35 (s, 3H, CH3O), 3.94 (m, 2H, CH2OMe), 5.11 (s, 1H, OH), 5.24 (m, 1H, CHCH2OH), 6.48 (s, 1H, ArH), 7.05 (s, 1H, ArH). 13C NMR (CDCl3, 400 MHz): 14.9 (CH3), 19.2, 23.5, 24.4, 26.7, 27.1, 28.1, 29.7, 36.4, 39.1, 44.4, 44.8, 53.5, 58.2, 70.2, 112.8, 115.7, 126.4, 127.5, 132.6, 135.5, 151.5, and 157.1. HPLC: 98%; HRMS (FAB+): found 340.24023 calcd. C23H32O2 340.24023.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.CN1CCOCC1.Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25]>C1COCC1>[CH2:27]([O:26][C:24]([O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1)=[O:25])[CH:28]([CH3:30])[CH3:29]
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)COC(=O)OC(=O)c1ccc(-c2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
With the exclusion of air, 6.0 g (30 mmol) of 4-(pyridin-2-yl)-benzoic acid are suspended at -20° C. in 90 ml of THF, and 9.90 ml (90 mmol) of N-methyl-morpholine and 4.32 ml (33 mmol) of isobutyl chloroformate are added. After 30 min, the mixture is filtered, washed with a small amount of cold THF, and the filtrate is partially concentrated by evaporation; the residue is diluted with methylene chloride, washed with ice-water and cold brine, dried (Na2SO4) and concentrated by evaporation to form the title compound: 1H-NMR (CDCl3) i.a. 8.75 (m, 1H), 8.16 (AB, J=8, 4H), 7.81 (m, 2H), 7.32 (4-line system, J=5, 1 H), 4.16 (d, J=7, 2H), 2.10 (9-line system, J=7, 1 H), 1.02 (d, J=7, 6H).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[CH:29][C:30]([OH:39])=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]3[CH:28]=[CH:29][C:30]([OH:39])=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:32]=3)[CH2:25][CH2:26]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1O
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)ccc1O

Procedure:
Example 150 was prepared from diphenylacetyl chloride and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-hydroxyphenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.30–7.11 (m, 10H), 7.10–6.9 (m, 2H), 6.74 (d, 1H, J=8.3 Hz), 6.63 (dd, 1H, J=8.3, 2.0 Hz), 4.93 (s, 1H), 3.51 (t, 1H, J=5.4 Hz), 3.36 (quintet, 1H, J=6.5 Hz), 3.24–3.18 (m, 2H), 3.07–3.00 (m, 2H), 2.54–2.45 (m, 3H), 2.37–2.28 (m, 1H), 2.19–2.09 (m, 2H), 1.79–1.54 (m, 4H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 514.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:26]([O:25][C:23]([N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14])[CH2:9][CH2:10]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
To a solution of 4.94 g piperidin-4-yl-carbamic acid tert-butyl ester, 300 mg DMAP and 5.2 ml triethylamine in 50 ml dichloromethane were added 6.3 ml benzyl chloroformate dropwise at 0° C. After 8 h the suspension was diluted with dichloromethane and washed with half-saturated NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was suspended in heptane, the supernatant solution being decanted yielding the product as colorless solid. Yield: 7.9 g.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.O1CCOCC1.[Cl:16][C:17]1[C:21]([CH3:22])=[CH:20][S:19][C:18]=1[C:23]1([C:28]([NH:30][NH2:31])=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[Cl:16][C:17]1[C:21]([CH3:22])=[CH:20][S:19][C:18]=1[C:23]1([C:28]2[N:9]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[N:31][N:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1csc(C2(C(=O)NN)CCCC2)c1Cl
Reactant: COC1=NCCCCC1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1csc(C2(c3nnc4n3CCCCC4)CCCC2)c1Cl
Temperature: 100 °C
Reaction time: 72 h

Procedure:
7-Methoxy-3,4,5,6-tetrahydro-2H-azepine (0.5 ml) was added to a dioxane (20 ml) and toluene (15 ml) solution of 1-(3-chloro-4-methyl-2-thienyl)cyclopentane-carbohydrazide (800 mg), followed by stirring at 100° C. for 3 days. The reaction solution was subjected to evaporation under reduced pressure and the resulting crude product was purified by column chromatography (chloroform:methanol=40:1). The resulting solid was washed with hexane to obtain 770 mg of 3-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine (colorless solid).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH:19]=O)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].C(N(C(C)C)C(C)C)C.ClC1[N:39]=[C:38]([S:40][C:41]#[N:42])[C:37]([N+:43]([O-:45])=[O:44])=[CH:36][N:35]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]3[N:39]=[C:38]([S:40][C:41]#[N:42])[C:37]([N+:43]([O-:45])=[O:44])=[CH:36][N:35]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:21]=[CH:22][CH:23]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(NC=O)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Nc3ncc([N+](=O)[O-])c(SC#N)n3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-[3-(formylamino)phenyl]benzamide (676 mg, 2.42 mmol) in tetrahydrofuran (10 mL) were added N-ethyl-N-isopropylpropane-2-amine (643 μL, 3.63 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (576 mg, 2.66 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (933 mg, 84%) as a yellow solid.