Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.O[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:22]=1
Reactant: COC(=O)C(C)(C)CO
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)COc1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
40% Diethyl azodicarboxylate-toluene solution (9.54 mL) was added to a tetrahydrofuran (40 mL) solution containing 4-bromophenol (2.0 g), methyl hydroxypivalate (2.77 g) and triphenylphosphine (5.49 g), and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10) to obtain methyl 3-(4-bromophenoxy)-2,2-dimethylpropanoate (3.2 g).
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[CH2:23]([N:3]1[CH2:2][CH2:1][C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1CC[C@H]2c3ccccc3CC[C@@H]2C1
Yield: 34.8 %

Procedure:
Following the procedure of Example 3, step 4, 0.152 g (0.810 mmol) of crude trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in 10 ml of anhydrous DMF was reacted with 0.123 g (0.890 mmol) of anhydrous potassium carbonate and 0.074 ml (0.855 mmol) of allyl bromide. Chromatography on flash silica, eluting with 3-7% methanol/dichloromethane, then on alumina, eluting with 2-5% ethyl acetate/petroleum ether, gave 0.064 g (35%) of the title product as a colourless oil. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent and recrystallisation from ethanol/ethyl acetate, the title product hydrochloride was obtained as a white solid, m.p. 204°-214° C. NMR δ(D2O) 1.57 (1H, m), 1.69 (1H, m), 1.80-1.92 (2H, m), 2.66-2.77 (2H, m), 2.88-2.95 (3H, m), 3.18 (1H, t, J=11.4 Hz), 3.60 (1 H, m), 3.77 (1H, m), 3.81 (2H, d, J=7.2 Hz), 5.60-5.65 (2H, m), 5.98 (1H, m), 7.22-7.29 (3H, m), 7.35-7.37 (1H, m). m/z (CI+, NH3) 228 (M+H)+. Analysis calcd. for C16H22ClN: C, 72.85; H, 8.41; N, 5.31%. Found: C, 72.84; H, 8.40; N, 5.26%.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(Cn2c(-c3ccc(C=O)cc3)nc3cc(Cl)c(Cl)cc32)cc1

Procedure:
Methyl 4-[5,6-dichloro2-(4-formylphenyl)benzimidazol-1-ylmethyl]benzoate was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and methyl 4-bromomethylbenzoate by following General Procedure 3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH:15]=O)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH3-]C#N.[Na+]>CC(O)=O.CO>[CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH2:15][NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=CC12CC1CCN(Cc1ccccc1)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CN2CCC3CC3(CNc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-Benzyl-3-aza-bicyclo[4.1.0]heptane-1-carbaldehyde (174) (300 mg, 1.39 mmol) in 5% HOAc in MeOH (2 ml) was added aniline (0.38 ml, 4.18 mmol) and NaCNBH3 (250 mg, 3.97 mmol). The mixture was stirred at room temperature 2 hrs. MeOH was removed by evaporation. Water (5 mL) was added to the residue. The mixture was neutralized with 2N KOH to pH=10. Extraction with CH2Cl2 (2×10 ml) followed by standard work-up provided crude 175 which was purified by silica gel chromatography (1% MeOH in CH2Cl2). LRMS (calculated for C20H25N2, M+1) 293, found 293.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([N:9](C2C=CC(OC)=C(OC3CCCC3)C=2)[C:10](=O)C)[C:3]=1[OH:27]>C1(C)C=CC=CC=1.P(Cl)(Cl)(Cl)=O>[O:27]1[C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[CH:10]1
Reactant: COc1ccc(N(C(C)=O)c2cc(Cl)cc(Br)c2O)cc1OC1CCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: c1ccc2ocnc2c1
Reaction time: 1 h
Yield: 261.4 %

Procedure:
A suspension of 32.9 g (72.4 mM) of the 2-Bromo-4-chloro-6-(3-cyclopentyloxy-4-methoxy-phenyl-acetylamino)-phenol in 400 ml of toluene and 39.7 ml (434 mM) of phosphorus oxychloride was refluxed for 1.5 hr. Some solid material was filtered off and the filtrate evaporated to dryness in vacuo. The honey-like residue was suspended in 200 ml of sodium bicarbonate solution for 1 hr. The solid was collected, washed and dried at 25° C. to give 22.53 g (71.2%) of crude benzoxazole.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)#[N:5].CCN(C(C)C)C(C)C>C(O)C>[OH:3][NH:2][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[NH:5]
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(C#N)CC2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(C(=N)NO)CC2)cc1
Reaction time: 2 h

Procedure:
256.4 mg (3.69 mmol) Hydroxylamine hydrochloride are added to a mixture of 1.0 g (3.69 mmol) (S)-N-{1-[4-(1-cyano-piperidin-4-yl)-phenyl]ethyl}-acetamide (XXVII.1) and 0.63 mL (3.69 mmol) DIPEA in 20 mL ethanol. The mixture is refluxed for 4 h, an additional amount of 50 mg hydroxylamine hydrochloride is added and refluxing is continued for 2 h. The solvent is removed in vacuo and water is added. The mixture is then purified by HPLC (RP C18 Xbridge, water (+0.1% ammonia)/MeOH) to yield the desired product.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:3]=1[C:4]#[N:5].[NH2:29][NH2:30]>>[O:22]([C:19]1[CH:18]=[CH:17][C:16]([C:6]2[CH:7]=[C:8]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[N:9]=[C:2]3[NH:29][N:30]=[C:4]([NH2:5])[C:3]=23)=[CH:21][CH:20]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NN
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cc(N2CCCCC2)nc1Cl
Product: Nc1n[nH]c2nc(N3CCCCC3)cc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
Following conditions described in Step 4 of Example 8, 2-chloro-4-(4-phenoxyphenyl)-6-(piperidin-1-yl)nicotinonitrile was reacted with hydrazine to give Example 9. 1H NMR (400 MHz, methanol-d4) δ ppm 7.47-7.65 (2H, m), 7.32-7.48 (2H, 7.15 (1H, t, J=7.40 Hz), 6.97-7.08 (2H, m), 6.96-7.13 (4H, m), 6.41 (1H, s), 3.52-3.73 (4H, m), 1.50-1.76 (6H, m). MS (ES+) m/z: 386 (M+H); LC retention time: 3.501 min (analytical HPLC Method A).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].CC([O-])(C)C.[K+].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=3)([C:14]([F:17])([F:16])[F:15])[CH2:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C=N2)cc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2-(3-bromo-4-fluorophenyl)-4-(3,5-dichlorophenyl)-4-(trifluoromethyl)-3,4-dihydro-2H-pyrrole (0.88 g) in THF (13 ml), t-BuOK (0.24 g) was added under ice cooling. The mixture was returned to room temperature and stirred for 16 hours. Water was added to the reaction mixture, and the aqueous layer was separated and extracted with ethyl acetate. The combined organic layers, were washed with saturated brine, and dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 5-(3-bromo-4-fluorophenyl)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrole (0.88 g) at a yield of 100%.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CI.[CH:17]([N-]C(C)C)(C)C.[Li+]>>[CH3:17][C:8]1([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: COC(=O)C1CCC2(CC1)OCCO2
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Product: COC(=O)C1(C)CCC2(CC1)OCCO2

Procedure:
According to the process described in the literature (JP83-118577), methyl 1,4-dioxaspiro [4.5]decan-8-carboxylate was reacted with methyl iodide in the presence of LDA (lithium diisopropylamide) to obtain methyl 8-methyl-1,4-dioxaspiro [4.5]decan-8-carboxylate (the compound (1) of the above figure).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:26][C:27]1[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][N:28]=1)[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15].[Li+].[BH4-]>C1COCC1.CO>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([CH2:12][N:13]([CH2:26][C:27]2[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][N:28]=2)[S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])=[C:4]([CH2:3][OH:2])[CH:9]=1)#[N:11]
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(C)cc1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cnc(CN(Cc2ccc(C#N)cc2CO)S(=O)(=O)c2ccccc2[N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
To a solution of 5-cyano-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(2-nitro-benzenesulfonyl)-amino]-methyl}-benzoic acid methyl ester (0.83 g, 1.68 mmol) dissolved in THF (30 mL) and MeOH (10 mL), LiBH4 (0.37 g, 16.8 mmol) was slowly added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and redissolved in CH2Cl2 (50 mL). Water (50 mL) was added and the resulting mixture was extracted with CH2Cl2 (4×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give crude N-(4-cyano-2-hydroxymethyl-benzyl)-N-(3,5-dimethyl-pyridin-2-ylmethyl)-2-nitro-benzene-sulfonamide (0.82 g, 78%) as a yellow foam. 1H NMR (CDCl3) δ 2.16 (s, 3H), 2.25 (s, 3H), 4.58 (s, 2H), 4.67 (s, 2H), 4.76 (br s, 1H), 4.88 (s, 2H), 7.10 (s, 1H), 7.36 (m, 2H), 7.50 (m, 1H), 7.65-7.72 (m, 3H), 7.80 (s, 1H), 7.89 (d, 1H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.O[C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:34][O:33][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][C:27]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:28][CH:29]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3ccccc32)cc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-benzoimidazol-1-yl]-2-cyclohexyl-ethanol and methyl 4-hydroxy-benzoate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White solid (58%). MS (Turbo Spray): m/z=489.3 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[O:10])[CH:6]=[N:7][CH:8]=1.[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH:9]([OH:10])[C:12]([F:14])([F:13])[F:11])[CH:4]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1cncc(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cncc(C(O)C(F)(F)F)c1
Yield: 100.5 %

Procedure:
According to Reference Example 8-12, by use of 5-methoxy-3-pyridinecarboxaldehyde (300 mg, 2.19 mmol), (trifluoromethyl)trimethylsilane (388 μL, 2.63 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 220 μL, 0.220 mmol) and tetrahydrofuran (6.0 mL), the mixture was stirred and reacted at room temperature for 30 minutes. Then, purification by silica gel column chromatography (chloroform/methanol=9/1) was performed to give 3-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound CV) (456 mg, yield: quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[C:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)cc23)CC1
Yield: 59.2 %

Procedure:
Beginning with 2.69 gm (11.1 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 1.45 mL (12.3 mMol) 4-fluorobenzoyl chloride, 2.39 gm (59.0%) of the title compound were recovered as a burnt orange powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH:15]1([C:18](=[O:23])[CH2:19][C:20](=O)[CH3:21])[CH2:17][CH2:16]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:15]1([C:18]([C:19]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]3[CH:5]=[CH:4][S:3][C:2]3=[N:1][C:20]=2[CH3:21])=[O:23])[CH2:17][CH2:16]1
Reactant: Nc1sccc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sccc2c(-c2ccccc2)c1C(=O)C1CC1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 8.2 %

Procedure:
To a stirred solution of 60 mg (0.29 mmol) (2-amino-thiophen-3-yl)-phenyl-methanone (the preparation of which is described in example 20) in 2 ml acetic acid was added 50 mg (0.39 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 7 mg (8%) cyclopropyl-(6-methyl-4-phenyl-thieno[2,3-b]pyridin-5-yl)-methanone as a colorless oil. ES-MS m/e (%): 294 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5](=[O:31])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[NH2:30])=[CH:9][CH:8]=1.C([C:36]1[C:37]([N:45]=[CH:46][N:47]([CH3:49])C)=[N:38][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=1)#N>C(O)(=O)C>[Cl:33][C:2]([Cl:1])([Cl:32])[CH2:3][O:4][C:5](=[O:31])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[NH:30][C:49]2[C:36]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:43])[CH3:44])=[N:38][C:37]=3[N:45]=[CH:46][N:47]=2)=[CH:11][CH:12]=1
Reactant: CC(C)c1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Oc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CC(=O)O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Oc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)ncnc2n1
Temperature: 140 °C
Yield: 64 %

Procedure:
A mixture of the products of Example 361E (2.39 g, 4.2 mmol) and Example 8E (N′-(3-cyano-6-isopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine) (0.91 g, 4.2 mmol) in 10 mL of glacial acetic acid was heated in a 140° C. preheated oil bath for 45 minutes. The reaction mixture was cooled, evaporated in vacuo and the residue partitioned between ethyl acetate (250 mL) and water (100 mL). The organic phase was then washed with saturated aqueous sodium bicarbonate and then brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was triturated with methanol, filtered, and dried in vacuo to provide the title compound (2.0 g, 64%) as a beige solid. MS (ESI+) m/z 743/745 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.31 (d, J=6.62 Hz, 6 H), 3.10-3.27 (m, 1 H), 4.93 (s, 2 H), 6.93-7.05 (m, 3 H), 7.39-7.62 (m, 5 H), 7.77 (d, J=8.82 Hz, 2 H), 8.17 (s, 1 H), 8.60 (s, 1 H), 8.78 (d, J=8.09 Hz, 1 H), 10.08 (s, 1 H), 10.16 (s, 1 H), 10.35 (s, 2 H).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[C:35]([C:37]([OH:40])([CH3:39])[CH3:38])[CH:34]=[C:33]([F:41])[C:32]=1[C:42]1[N:47]=[C:46]([C:48](O)=[O:49])[CH:45]=[CH:44][C:43]=1[F:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:48]([C:46]3[CH:45]=[CH:44][C:43]([F:51])=[C:42]([C:32]4[C:31]([F:30])=[CH:36][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:34][C:33]=4[F:41])[N:47]=3)=[O:49])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(C(C)(C)O)cc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (299 mg, 0.739 mmol), 6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (230 mg, 0.739 mmol) and HATU (562 mg, 1.48 mmol) in DMF (0.7 mL) and DIPEA (0.386 mL, 2.22 mmol) was stirred at room temperature for 2 h. The reaction mixture was quenched with water, the mixture was extracted with EtOAc (2 times). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to give an amide intermediate, 4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH2:11]([CH:13]([CH2:17][CH3:18])[C:14](=O)[CH3:15])[CH3:12]>>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:11]([CH3:12])[C:13]2([CH2:17][CH3:18])[CH2:14][CH3:15]
Reactant: CCC(CC)C(C)=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Product: CCC1(CC)c2cc(Br)ccc2NC1C
Yield: 63.8 %

Procedure:
This compound was prepared according to the procedure for Example 1 using 4-bromo-phenyl hydrazine hydrochloride (5.9 g, 26.3 mmol) and 3-ethyl-2-pentanone (3.0 g, 26.3 mmol). The subtitled compound (4.5 g) was obtained in 65% yield as a yellowish oil: 1H-NMR (CDCl3) δ0.81 (t, J=7.4 Hz, 3H), 0.83 (t, J=7.4 Hz, 3H), 1.18 (d, J=6.5 Hz, 3H), 1.42 (dq, J=14.0, 7.4 Hz, 1H), 1.66 (dq, J=14.0, 7.4 Hz, 3H), 3.73 (q, J=6.5 Hz, 1H), 6.47 (d, J=8.2 Hz, 1H), 7.02 (d, J=2 Hz, 1H), 7.09 (dd, J=8.2, 2.0Hz, 1H); 13C-NMR (CDCl3) δ10.46, 10.66, 17.70 (q), 26.5, 29.67 (t), 52.25 (s), 64.80 (d), 111.64 (s), 112.41, 129.07, 131.58 (d), 139.57, 151.04 (s); MS (EI) m/z 268, 270 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:30])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]I>O1CCCC1>[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:30])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([NH:2][CH3:1])[CH3:28]
Reactant: CN
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCI)[C@H]3[C@@H]1CCC2=O
Solvent: C1CCOC1
Product: CNC(C)CCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
718 mg of methylamine is condensed in a solution of 960 mg of 11β-fluoro-3-hydroxy-7α-(6-iodohexyl)-estra-1,3,5(10)-trien-17-one in 9 ml of anhydrous tetrahydrofuran at −78° C., and it is stirred overnight at room temperature in a pressurized reactor. After the pressurized reactor was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. Then, the reaction solution is added to saturated sodium bicarbonate solution, extracted 3 times with ethyl acetate, dried on sodium sulfate and concentrated by evaporation in a vacuum. 763 mg of 11β-fluoro-3-hydroxy-7α-[5-(methyl-amino)-hexyl]-estra-1,3,5(10)-trien-17-one is obtained as a crude product.
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(O)C.O>[C:18]([NH:1][CH2:2][C:3]12[CH2:17][CH:10]([C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=31)[C:11]1[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: NCC12CC(c3ccccc31)c1ccccc12
Solvent: O
Solvent: CCO
Product: CC(=O)NCC12CC(c3ccccc31)c1ccccc12

Procedure:
A solution of 9-aminomethyl-9,10-dihydro-9,10-methanoanthracene (235 mg) and acetic anhydride (217 mg) in ethanol (5.0 ml) was refluxed for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-acetylaminomethyl-9,10-dihydro-9,10-methanoanthracene. M.P. 184°-185.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:30][CH2:31][CH2:32][NH2:33]>>[NH2:30][CH2:31][CH2:32][NH:33][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Reactant: NCCN
Product: NCCNc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1

Procedure:
The product of Example 47, and 1,2-diaminoethane were reacted by the procedure of Example 60 to afford the title compound 2-(2-amino-ethylamino)-4,8-bis-(2-chloro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 2.59 (m, 2H), 3.11 (m, 2H), 5.91 (br s, 1H), 6.40 (d, 1H, J=9.6 Hz), 7.25-7.61 (m, 9H). LC MS (m/e)=426 (MH+).