Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[NH:38][C:39]([C:41]1[N:42]([CH3:50])[C:43]2[C:48]([CH:49]=1)=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:3]=[C:2]([C:27]3[CH:26]=[CH:25][C:24]([NH:38][C:39]([C:41]4[N:42]([CH3:50])[C:43]5[C:48]([CH:49]=4)=[CH:47][CH:46]=[CH:45][CH:44]=5)=[O:40])=[C:23]([O:22][CH3:21])[CH:28]=3)[C:10]=12
Reactant: Nc1ncnc2c1c(I)nn2CCCN1CCOCC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(CCCN3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 56.2 %

Procedure:
A solution of 3-iodo-1-(3-morpholinopropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.244 g, 0.629 mmol) in ethylene glycol dimethyl ether (16 mL) was treated with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.281 g, 0.692 mmol), tetrakis(triphenylphosphine)palladium (0.044 g, 0.038 mmol), and a solution of sodium carbonate (0.160 g, 1.51 mmol) in water (8 mL). The reaction mixture was stirred for 4.5 h at 80° C. The organic solvent was removed under reduced pressure and ethyl acetate (200 mL) was added. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (400 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a step-wise gradient of 10% methanol in dichloromethane to 50% methanol in dichloromethane as the eluent. The column afforded 0.191 g (56%) of pure N2-{4-[4-amino-1-(3-morpholinopropyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.440 (s, 1H), 8.260 (s, 1H), 8.1229-8.1026 (d, 1H, J=8.12 Hz), 7.7184-7.6986 (d, 1H, J=7.92 Hz), 7.5983-7.578 (d, 1H, J=8.08 Hz), 7.345-7.290 (m, 4H), 7.172-7.133 (m, 1H), 4.421-4386 (m, 2H), 4.04 (s, 3H), 3.958 (s, 3H), 3.521-3.500 (m, 4H), 2.349-2.314 (m, 6H), 2.035-2.001 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.05 min (100%), MH+ 541.3.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C:4]([CH3:26])([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([CH3:25])[S:23][CH:24]=2)=[CH:16][CH:15]=1)[C:5]([O:7]CC)=[O:6]>C(O)C>[CH3:3][C:4]([CH3:26])([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([CH3:25])[S:23][CH:24]=2)=[CH:16][CH:15]=1)[C:5]([O-:7])=[O:6].[Na+:2]
Reactant: CCOC(=O)C(C)(C)CCCOc1ccc(-c2csc(C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccc(OCCCC(C)(C)C(=O)[O-])cc2)cs1

Procedure:
In 5 ml of ethanol was dissolved in 1.40 g of ethyl 2,2-dimethyl-5-[p-(2-methyl-4-thiazolyl)phenoxy]pentanoate obtained in EXAMPLE 5. The solution was added to an aqueous sodium hydroxide solution (0.4 g of sodium hydroxide in 5 ml of water) and the mixture refluxed for 10 hours. After cooling, the precipitated crystals was washed with water to obtain the desired product, sodium 2,2-dimethyl-5-[p-(2-methyl-4-thiazolyl)phenoxy]pentanoate as white crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][C:51]1[CH:52]=[C:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[NH:63][C:64](=[O:66])[CH3:65])[CH:54]=[CH:55][CH:56]=1>CN(C=O)C>[C:64]([NH:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[C:53]1[CH:54]=[CH:55][CH:56]=[C:51]([NH:50][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:52]=1)(=[O:66])[CH3:65]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: CC(=O)Nc1ccccc1-c1cccc(N)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: COc1cccc2cc(C(=O)Nc3cccc(-c4ccccc4NC(C)=O)c3)c(=O)oc12
Temperature: 25 °C
Yield: 70.7 %

Procedure:
DIEA (0.013 mL, 0.073 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.015 g, 0.066 mmol) and HATU (0.028 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, N-(3′-Amino-biphenyl-2-yl)-acetamide (0.015 g, 0.066 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.020 g of product in 69% yield: LCMS (ESI) m/z 429 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[F:31]C1C=C(C=C(F)C=1)C=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[C:6]([F:31])[CH:7]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2cc(F)cc(F)c2)Oc2ccc(O)cc21

Procedure:
2-(3,5-Difluorophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 1.0 g of 2′,5′-dihydroxyacetophenone and 1.12 g of 3,5-difluorobenzaldehyde. The product was recrystallised from acetic acid. 1H NMR (400 MHz, d6-DMSO) δ: 9.47 (s, 1H), 7.30-7.23 (m, 3H), 7.12 (d, 1H, J 2.9 Hz), 7.06 (dd, 1H, J 8.8, 2.9 Hz), 7.00 (d, 1H, J 8.8 Hz), 5.60 (dd, 1H, J 13.1, 2.8 Hz), 3.15 (dd, 1H, J −16.8, 13.1 Hz), 2.85 (dd, 1H, J −16.8, 2.8 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[CH3:12][CH:13]([CH2:15][CH:16]([NH2:20])[CH2:17][CH2:18][CH3:19])[CH3:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:20][CH:16]([CH2:17][CH2:18][CH3:19])[CH2:15][CH:13]([CH3:14])[CH3:12])=[O:7]
Reactant: CCCC(N)CC(C)C
Reactant: Cc1ccc(C(=O)O)cc1C
Product: CCCC(CC(C)C)NC(=O)c1ccc(C)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 3,4-dimethylbenzoic acid and 2-methylheptan-4-amine (example 2a). 1H NMR (500 MHz, CDCl3): δ 0.94 (m, 9H); 1.40 (m, 5H); 1.53 (m, 1H); 1.68 (m, 1H); 2.29 (s, 3H); 2.30 (s, 3H); 4.24 (m, 1H); 5.69 (d, 1H); 7.17 (d, 1H); 7.46 (d, 1H); 7.54 (s, 1H). MS (262, M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[O:3]1.[I:17]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:17][C:8]1[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]2[O:3][C:2]([CH3:16])([CH3:1])[CH2:6][C:5]=2[CH:7]=1
Reactant: CCOC(=O)c1cccc2c1OC(C)(C)C2
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CCOC(=O)c1cc(I)cc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a solution of ethyl 2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (2.03 g, 9.22 mmol) in methanol (40 mL) was added iodine (2.57 g, 10.14 mmol) and silver sulfate (3.45 g, 11.06 mmol). The reaction was stirred for 3 hours at room temperature and was filtered through celite to remove the solids formed. The solvent was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide ethyl 5-iodo-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (829) (3.12 g, 98%) as a red solid.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)=[O:11])[CH2:3]1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)#[N:24]>>[CH3:1][C@H:2]1[N:7]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([C:23]#[N:24])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)=[O:11])[CH2:3]1
Reactant: C[C@@H]1CN(CC(=O)Nc2cccc3ncccc23)C[C@H](C)N1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Product: C[C@@H]1CN(CC(=O)Nc2cccc3ncccc23)C[C@H](C)N1S(=O)(=O)c1ccc(C#N)cc1

Procedure:
The title compound was prepared from the product of Example 58 step (i) (0.503 mmol) and 4-cyanobenzenesulphonyl chloride (0.503 mmol) by the method of Example 58 step (ii) as a white solid. Yield: 4 mg
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8]OS(C)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:58])([F:57])[F:56])[C:24]=1[CH2:25][N:26]1[C:31]([CH3:32])=[C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[O:41][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:43][CH:44]=3)[CH2:35][CH2:34]2)[C:29](=[O:49])[NH:28][C:27]1=[O:50].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([Si:5]([CH3:20])([CH3:21])[O:6][C@H:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:8][N:28]1[C:29](=[O:49])[C:30]([N:33]2[CH2:34][CH2:35][N:36]([CH2:39][C:40]3[O:41][C:42]([C:45]([F:46])([F:47])[F:48])=[CH:43][CH:44]=3)[CH2:37][CH2:38]2)=[C:31]([CH3:32])[N:26]([CH2:25][C:24]2[C:51]([C:55]([F:57])([F:58])[F:56])=[CH:52][CH:53]=[CH:54][C:23]=2[F:22])[C:27]1=[O:50])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)CC2)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](COS(C)(=O)=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)CC2)c(=O)n(C[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-ethanol (85 mg, 0.337 mmol) in dichloromethane (2 mL) were added triethylamine (61 μl, 0.44 mmol) and methanesulfonyl chloride (27 μl, 0.35 mmol) in the order, followed by stirring at room temperature for 20 min. The solution was washed with an aqueous saturated sodium bicarbonate solution to separate an organic layer. The organic layer was dried over sodium sulfate and filtrated. The filtrate was concentrated and dried for 30 min in a vacuum to give methanesulfonic acid (R)-2-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-ethyl ester. Methanesulfonic acid (R)-2-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-ethyl ester, 1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (5-3) (60 mg, 0.112 mmol) and potassium carbonate (77 mg, 0.560 mmol) were dissolved at 70° C. for 12 hrs in DMF (1 ml) in a nitrogen atmosphere with stirring. The solution was cooled to room temperature, washed with an aqueous saturated sodium bicarbonate solution and concentrated. The residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate, 5/1) and dried in a vacuum to afford 83 mg of the compound as a white solid (yield 97%). 1H NMR (300 MHz, CDCl3) δ −0.23 (3H, s), −0.11 (3H, s), 0.80 (9H, s), 2.25 (2H, m), 2.33 (3H, s), 2.47 (2H, m), 2.80 (2H, m), 3.50-3.70 (2H, m), 3.62 (2H, s), 3.83 (1H, dd), 4.36 (1H, dd), 5.13 (1H, dd), 5.26-5.50 (2H, m), 6.30 (1H, d), 6.73 (1H, m), 7.16-7.43 (7H, m), 7.53 (1H, d)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([O:25][CH2:26][CH3:27])=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([O:23][CH3:24])=[C:11]([CH:22]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:25][CH2:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:23][CH3:24])=[C:11]([CH:22]=1)[C:12]([OH:14])=[O:13])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(OC)c(C(=O)OCc2ccccc2)c1)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OC)c(C(=O)O)c1)OCC
Yield: 97.3 %

Procedure:
1.6 g of benzyl 5-(3-ethoxy-2-ethoxy-3-oxo-1-propenyl)-2-methoxybenzoate was dissolved in 30 ml ethanol, 0.35 g of 10% palladium-carbon was added, and the mixture was stirred for 16 hours in a hydrogen atmosphere. The catalyst was filtered through Celite and the solvent was evaporated. Then, the residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (2:1), 1.2 g of 5-(3-ethoxy-2-ethoxy-3-oxopropyl)-2-methoxybenzoic acid was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([CH:25]4[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]4)[C:20]([F:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]([OH:14])CO)[C:3]=12.C(O)(=O)C.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([CH:25]4[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:28]4)[C:20]([F:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]=[O:14])[C:3]=12
Reactant: COc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1c(C(C)n2nc(C=O)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of tert-butyl 3-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate (0.40 g, 0.74 mmol) in tetrahydrofuran (5.6 mL)/water (3.4 mL) was added acetic acid (0.011 mL, 0.19 mmol) and sodium periodate (0.478 g, 2.23 mmol) at 0° C. After stirring for 2 h, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated to give the desired product (0.35 g, 92%) which was used directly in the next step. LCMS calculated for C23H27ClFN6O4 (M+H)+: m/z=505.2; Found: 505.1.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][C:12]#[N:13])=[CH:9][CH:8]=1.O>CC(N(C)C)=O>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][C:12]#[N:13])=[CH:9][CH:8]=1)=[O:4]
Reactant: N#CCc1ccc(N)cc1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#CCc1ccc(NC(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
2-Chloroacetyl chloride (3.3 ml, 5.0 g, 44 mmol) was added dropwise at 10°-15° C. to a solution of 4-aminobenzylcyanide (5.3 g, 40 mmol) in dimethyl acetamide (20 ml) and the mixture was stirred at room temperature for one hour. After pouring into water the precipitate was collected, washed with water and dried over P2O5 under reduced pressure to give the title compound (7.33 g) as nearly colorless crystals, yield: 87.8%, mp 124°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH:10]=4)[C@H:7]([CH3:22])[CH2:6][C:5]=2[CH:4]=1>[Pd].C(O)C.ClCCl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[C@H:7]([CH3:22])[CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C[C@@H](C)[C@H]1C3=CC[C@H](O)[C@@]3(C)CC[C@H]21
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2c(c1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@@]2(C)[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.6 %

Procedure:
i)—A mixture of (7α,17β)-3-methoxy-7-methylestr-1,3,5(10),14-tetraen-17-ol [Segaloff, et al, Steroids 22, 99 (1973); 86.2 g] and palladium on activated carbon (5%; 34.5 g) in ethanol (578 ml) and dichloromethane (414 ml) was stirred under hydrogen (3 bar) at room temperature for 24 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to give (7α,14β,17β)-3-methoxy-7-methylestr-1,3,5(10)-trien-17-ol (83.0 g). The product was used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:5][C:4]=1[N+:19]([O-])=O>C(OCC)(=O)C.[C].[Pd]>[NH2:19][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1cncc(-c2ccc(OC)c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(-c2ccc(OC)c(N)c2)c1
Temperature: 50 °C
Yield: 81.5 %

Procedure:
990 mg of the resulting nitro compound was dissolved in 60 ml of ethyl acetate, and 0.3 g of 10% palladium-carbon was added. The nitro compounds was thus catalytically reduced with stirring at 50° C. The catalyst was removed in a customary manner, and the resulting yellow crystals were recrystallized from methylene chloride-ether to give 723 mg (yield 81%) of methyl 5-(3-amino-4-methoxyphenyl)nicotinate as pale yellow needles having a melting point of 98° to 99° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[CH3:49][C@H:50]1[CH2:55][O:54][CH2:53][CH2:52][NH:51]1>>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:51]2[CH2:52][CH2:53][O:54][CH2:55][C@@H:50]2[CH3:49])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: C[C@H]1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@H]1COCCN1C(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and (S)-3-methylmorpholine (EXAMPLE 23, Step A) and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C20H19BrN4O4S, 490.0; m/z found, 489/491 [M−H]−. HPLC (reverse phase): RT=8.36 min. 1H NMR (400 MHz, CDCl3, rotameric broadening): 9.05 (d, J=1.8 Hz, 1H), 9.01 (br s, 1H), 9.00 (d, J=1.8 Hz, 1H), 8.56 (dd, J=7.0, 1.5 Hz, 1H), 8.37 (dd, J=8.4, 1.4 Hz, 1H), 7.91 (dd, J=8.4, 7.4 Hz, 1H), 7.72 (d, J=1.4 Hz, 1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 4.30 (br m, 1H), 3.91-3.82 (m, 1H), 3.68-3.63 (m, 1H), 3.50 (dd, J=11.5, 2.7 Hz, 1H), 3.38-3.22 (m, 2H), 1.35-1.15 (br m, 3H), 1.0-0.9 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][C@H:39]1[O:44][C@@H:43]([CH3:45])[CH2:42][NH:41][CH2:40]1>>[CH3:45][C@H:43]1[O:44][C@@H:39]([CH3:38])[CH2:40][N:41]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:42]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: C[C@@H]1CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)C[C@H](C)O1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and (2R,6S)-2,6-dimethylmorpholine according to conditions described in general procedure C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]([Br:22])[CH:16]=1.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25]>C1COCC1>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]([Br:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:23](=[O:26])[CH:24]=[CH2:25])=[CH:11][CH:10]=2)#[N:13]
Reactant: C=CC(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)c(Br)c1
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Br)c(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
6-Amino-4-(3,4-dibromophenylamino)quinoline-3-carbonitrile (0.750 g. 1.79 mmol) in mL of THF was treated with 0.217 g (2.15 mmol) of EtN and 0.195 g (2.15 mmol) of acryloyl chloride at 0° C. under N2. After stirring overnight at 25° C., the solvent was evaporated and the residue was slurried with water and collected. The residue was boiled twice with EtOAc and then dried in vacuo (50° C.) to give 0.609 g of N-[3-cyano-4-(3,4-dibromophenylamino)quinolin-6-yl]acrylamide as a brown solid: mass spectrum (electrospray, m/e): 470.9, 472.9.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].Cl[C:7]1[N:12]=[N:11][C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[CH:9][CH:8]=1.[Cl-].[Na+]>CS(C)=O>[CH2:3]([O:5][C:7]1[N:12]=[N:11][C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[CH:9][CH:8]=1)[CH3:4]
Reactant: CC(C)(CO)c1ccc(Cl)nn1
Reactant: CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOc1ccc(C(C)(C)CO)nn1

Procedure:
1.6 g (0.053 mol) of 80% strength sodium hydride in white oil are suspended in 50 ml of dimethyl sulfoxide and 2.5 g (0.055 mol) of ethanol are added dropwise at 15°-20° C. After completion of gas evolution, a solution of 1.0 g (0.005 mol) of 2-(6-chloro-pyridazin-3-yl)-2-methylpropanol in 20 ml of dimethyl sulfoxide is allowed to run in and the mixure is warmed to 90°-100° C. for 1.5 hours. After cooling, the mixture is poured into concentrated sodium chloride solution and extracted with ether. After removing the solvent, a yellow oil remains as the crude product. Yield: 0.6 g (61% of theory).
Reaction SMILES: C1(N=[N:8][C:9]2[C:10](=[O:23])[S:11][CH2:12][C:13]=2[NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])C=CC=CC=1>O1CCCC1.[Pt]>[NH2:8][C:9]1[C:10](=[O:23])[S:11][CH2:12][C:13]=1[NH:14][C@@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16]
Reactant: C[C@@H](NC1=C(N=Nc2ccccc2)C(=O)SC1)c1ccccc1
Agent: [Pt]
Solvent: C1CCOC1
Product: C[C@@H](NC1=C(N)C(=O)SC1)c1ccccc1

Procedure:
0.49 g Platin 5 percent on charcoal is inserted to an autoclave together with a solution of 5 g 3-phenylazo-4-[(R)-(1-phenylethyl amino)]-thien-2(5H)-one in 30 ml of tetrahydrofurane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:16][CH2:15][CH2:14][C@@H:13]3[N:9]2[C:10](=[O:17])[CH:11]=[CH:12]3)=[CH:4][CH:3]=1.[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:16][CH2:15][CH2:14][C@@H:13]3[N:9]2[C:10](=[O:17])[CH2:11][CH2:12]3)=[CH:4][CH:3]=1
Reactant: O=C1C=C[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: O=C1CC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Yield: 82.1 %

Procedure:
Platinum oxide (10 mg) was added to a solution of (5R*,8aS*)-5-(4-fluorophenyl)-6,7,8,8a-tetrahydro-5H-indolizin-3-one (105 mg) in methanol (5 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for three hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 87 mg of the title compound. The property value of the compound is as follows.