Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)=[O:4].[CH3:15][NH2:16]>CN(C=O)C>[CH3:15][NH:16][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH3:2])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: CN
Reactant: CCC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CNc1ccc(C(C)=O)cc1[N+](=O)[O-]

Procedure:
1-(4-Methylamino-3-nitro-phenyl)-ethanone (153 mg) was prepared by following General Procedure A starting from methyl 1-(4-fluoro-3-nitro-phenyl)-ethanone (183 mg) and methylamine (2 M in THF, 1.0 ml) in DMF (5 mL). The crude product was used in the next step without further purification.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li].CN(C)P(N(C)C)(N(C)C)=O.[CH3:20][C:21]1([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[O:25][CH2:24][CH2:23][O:22]1.C(I)CC>C1COCC1>[CH3:20][C:21]1([CH2:26][CH:27]([CH2:7][CH2:5][CH3:6])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[O:22][CH2:23][CH2:24][O:25]1
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)CCC1(C)OCCO1
Agent: [Li]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCI
Solvent: C1CCOC1
Product: CCCC(CC1(C)OCCO1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a cooled (−78° C.) solution of lithium diisopropylamine (30 mL; 60 mmol; 2N in THF) in THF (8 mL) was added hexamethylphosphoramide (12 mL) and the solution was stirred for 30 min. A solution of ethyl 3-(2-methyl-1,3-dioxolan-2-yl)propanoate (9.4 g; 50 mmol), in THF (9 mL), was added over 30 min and stirring was continued for 1 h. Propyl iodide (6.84 mL; 70 mmol) was slowly added and the solution was allowed to warm to room temperature for 4 h. the reaction was quenched by adding a saturated aqueous solution of ammonium chloride. The two phases were separated and the aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers were dried with sodium sulphatesulphate, filtered and concentrated under reduced pressure. The crude residue was purified by flash-chromatography on silica gel using a gradient of ethyl acetate (0-40%) in heptane to furnish 9.8 g (85%) of ethyl 2-((2-methyl-1,3-dioxolan-2-yl)methyl)pentanoate as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.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.[CH2:60]([NH2:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:67][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then benzylamine (56.4 mg, 0.526 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to afford the title compound (210 mg) as a yellow solid. LC-MS (ES) m/z=445 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:34]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:37])[NH:35][NH2:36]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:36][NH:35][C:34]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=[O:16])=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: NNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)NNC(=O)OCc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
A solution containing 4-t-butoxycarbonylaminomethylbenzoic acid (5.0 g) and triethylamine (3.0 ml) in dry THF (180 ml) was treated at 10° C. with isobutyl chloroformate (2.7 ml) and the resulting mixture was stirred for 10 minutes. A solution of benzyl carbazate (3.4 g) in THF (20 ml) was added and the mixture was stirred for 15 hours at ambient temperature. The resulting precipitate was removed by filtration and the filtrate was diluted with ethyl acetate (500 ml) and washed with water (3×100 ml) and with saturated brine (100 ml). The organic solution was dried (MgSO4) and evaporated to a volume of 150 ml. After 1 hour the mixture was filtered to give benzyl 3-(4-t-butoxycarbonylaminomethylbenzoyl)carbazate (3.6 g) as colourless prisms; m.p. 160°-162° C.; NMR Spectrum 1.4 (9H, s); 4.2 (2H, d); 5.1 (2H, s); 7.2-7.5 (2H+5H, m); 7.8 (2H, d); 9.3 (1H, s); 10.3 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([NH:4][C:3]2[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=2[CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2c(C)cc(C)cc2C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.7 %

Procedure:
A 250-mL round-bottomed flask was charged with 2,4,6-trimethylaniline (mesidine, 11.88 mL, 84.62 mmol) and 50 mL of pyridine. To this mixture, a solution of p-toluenesulfonyl chloride (16.13 g, 84.62 mmol) in pyridine (50 mL) was added, and the reaction mixture was stirred at room temperature for 17 h. The reaction mixture was poured into 800 mL of acidic ice water containing 125 ml of 37% HCl. The mixture was cooled to 0° C. for 3 h, and a yellow solid precipitated. The yellow solid was collected by filtration and dissolved in 18 L of 5% NaOH. To this solution, 1850 mL of 37% HCl was added until the mixture reached a pH of 5. The resulting white precipitate was collected and washed with 800 mL of water and then dried in vacuo to give N-(p-toluenesulfonyl)-2,4,6-trimethylaniline (N-(p-toluenesulfonyl)mesidine) (21.73 g, 89%). 1H NMR (300 MHz, CDCl3): δ7.6 (d, 2H), 7.2 (d, 2H), 6.8 (s, 2H), 5.9 (s, 1H), 2.4 (s, 3H), 2.3 (s, 3H) 2.0 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11]1.C(N(C(C)C)CC)(C)C>>[C:20]([O:19][C:18](=[O:24])[NH:17][CH2:16][CH:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:2]2[CH:7]=[N:6][C:5](=[O:8])[NH:4][C:3]=2[NH2:9])[CH2:11]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Nc1nc(=O)[nH]cc1Br
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CCCN(c2cnc(=O)[nH]c2N)C1

Procedure:
Method 8 was followed using 1 eq. of 5-bromocytosine, 1.05 eq. of tert-butyl piperidin-3-ylmethylcarbamate and 1.05 eq. of diisopropylethylamine yielding tert-butyl(1-(6-amino-2-oxo-1,2-dihydropyrimidin-5-yl)piperidin-3-yl)methylcarbamate as an orange crunchy solid (18%). LCMS (m/z): 324.1 (MH+); LC Rt=1.90 min.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:16]([NH2:18])=O)=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([CH2:16][NH2:18])=[CH:3][CH:2]=1
Reactant: NC(=O)c1cccc2c1CCCc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc2c1CCCc1ccccc1-2
Yield: 14.9 %

Procedure:
Under a dry nitrogen atmosphere 6,7-dihydro-5H-dibenzo[a,c]-cyclohepten-4-carboxamide (0.78 gram, 0.0033 mole) was reacted with lithium aluminum hydride (0.2 gram, 0.0053 mole) in tetrahydrofuran (100 ml) to produce a white solid. The solid was recrystallized from a solution of diethyl ether and petroleum ether to provide 6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-methanamine (0.11 g, mp 200°-210°). The solvent was removed from the mother liquor to yield an additional 0.5 gram of the amine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:11]([CH3:12])=[C:10]([CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[O:22][CH3:23])[C:9](=O)[NH:8][C:6]=2[N:7]=1.C[N+](C)=C[Cl:29].[Cl-].S(Cl)(Cl)=O.N1C2C=CC=NC=2C=NC=1.N>C(Cl)(Cl)Cl.CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:11]([CH3:12])=[C:10]([CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[O:22][CH3:23])[C:9]([Cl:29])=[N:8][C:6]=2[N:7]=1
Reactant: COc1ccc(OC)c(Cc2c(C)c3c(N)nc(N)nc3[nH]c2=O)c1
Reactant: C[N+](C)=CCl
Agent: N
Agent: [Cl-]
Agent: c1cnc2cncnc2c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(OC)c(Cc2c(Cl)nc3nc(N)nc(N)c3c2C)c1

Procedure:
2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine (8 g) was chlorinated by treatment with Vilsmeier reagent prepared by slowly adding thionyl chloride (28.6) in dry chloroform (25 ml) to a solution of dimethylformamide (17.5) in chloroform (100 ml) at 0°-5° C. The cold mixture of the pyridopyrimidine and Vilsmeier reagent was stirred, gradually allowed to reach ambient temperatures and then heated at reflux for 3 hours. It was then treated with ethanolic base (80 ml) maintaining the temperature at 25°-30° C. with cooling. The brown product formed was isolated, treated further with aqueous ammonia and then recrystallized from ethanol to give 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)-7-chloropyrido[2,3-d]pyrimidine, m.p. 193°-196° (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH3:19])[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH2:34])[CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2([C:6]3[N:5]=[C:4]([CH3:19])[N:3]=[C:2]([NH:34][C:24]4[CH:25]=[CH:26][C:27]([N:28]5[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]5)=[C:22]([O:21][CH3:20])[CH:23]=4)[CH:7]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:13][CH:14]=1
Reactant: Cc1nc(Cl)cc(C2(c3ccc(Cl)cc3)CCC2)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(C3(c4ccc(Cl)cc4)CCC3)nc(C)n2)ccc1-n1cnc(C)c1
Yield: 81 %

Procedure:
The title compound was prepared in analogous manner as described in example 62 from 4-chloro-6-[1-(4-chloro-phenyl)-cyclobutyl]-2-methyl-pyrimidine and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine Obtained as a pale-yellow solid in 81% yield after column chromatography of the crude product on silica gel using dichloromethane/methanol (19:1 v/v) as eluent.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.Cl[Sn]Cl>CCO.Cl>[Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(F)cnc1Br
Temperature: 60 °C
Yield: 81.2 %

Procedure:
A suspension of 2-bromo-5-fluoro-3-nitropyridine (4.42 g, 20 mmol) and SnCl2 (22.56 g, 100 mmol) in EtOH (40 mL) and concentrated HCl (40 mL) was heated at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure. To the residue was added EtOAc (100 mL) and sat'd aq. NaHCO3 solution (200 mL), and the mixture was filtered with Celite® and extracted with EtOAc (100 mL×3). The organic layer was washed with saturated NaHCO3, water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure to afford 3.1 g (80%) of 2-bromo-5-fluoropyridin-3-amine as a brown solid. MS (ESI): m/z=191.1 [M+1]+.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([CH:10]([NH:18][CH:19]=O)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O=P(Cl)(Cl)Cl.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([CH:10]([N+:18]#[C-:19])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A stirred suspension of α-(p-toluenesulfonyl)-4-fluorobenzylformamide produced in step (a) above, (100 g, 325 mmoles) in THF (650 mL, 6.5 volumes) was cooled to 0° C. and POCl3 (46 mL, 487 mmoles, 1.5 equiv.) was added. A 1° C. exotherm was observed. After 15 minutes at 0° C., the white slurry was cooled to -5° C. Triethylamine (166 g, 1.62 moles, 5 equiv.) was added dropwise to the slurry over 45 minutes at such a rate to keep the reaction temperature below 0° C. but above -5° C. Caution should be exercised at the beginning of the addition because the reaction has a tendency to exotherm quickly. After complete addition, the yellow slurry was stirred for 30 minutes at 0° C. The reaction slurry has a tendency to darken during the stirring period. The reaction was poured into a mixture of saturated aqueous sodium bicarbonate (1 L) and ethyl acetate (1 L), both pre-cooled to 0° C. The organic phase was subsequently washed with water followed by brine. The organic phase was concentrated under vacuum via rotary evaporation until about 10% of the initial volume remained. i-Propanol (200 mL) was added and concentrated again under vacuum at 35° C. until about 10% of the initial volume remained. This process was repeated with fresh 1-propanol (200 mL). A fine, yellow precipitate was observed. The precipitate was cooled to 0° C. and the product was collected by suction filtration and rinsed with 1-propanol (50 mL). The off-white solid was dried to a constant weight at 40° C./<1 mm to give 65.7 g (227 mmoles) of desired product, affording a 70% yield. 1H NMR (300 MHz, CDCl3) δ 7.62 (2H, d, J=6.7 Hz), 7.46 (4H, m), 7.08 (2H, t, J=8.6 Hz), 5.62 (1H, s), 2.46 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:37][NH:38][O:39][CH3:40]>ClCCl.O.C(N(CC)CC)C>[CH3:40][O:39][N:38]([CH3:37])[C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]2[CH:8]=1)=[O:13]
Reactant: O=C(O)c1cn2cc(Cl)ccc2n1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cn2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.8 %

Procedure:
To a solution of 0.784 g of 6-chloroimidazo[1,2-a]pyridine-2-carboxylic acid in 12 mL of dichloromethane are added 1.67 mL of triethylamine, 1.53 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.08 g of 1-hydroxybenzotriazole. The reaction mixture is stirred for 20 minutes at room temperature. 0.39 g of N,O-dimethylhydroxylamine hydrochloride is added. The reaction mixture is stirred for 4 hours at room temperature. 60 mL of dichloromethane and 30 mL of water are added. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered, evaporated to dryness under reduced pressure, and then purified on a column of silica, eluting with a 95/5 mixture by volume of dichloromethane and methanol. The fractions containing the product are combined and concentrated to dryness under reduced pressure to give 0.6 g of N-methoxy-N-methyl-6-chloroimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: Br[CH2:2][C:3](=[O:7])[CH:4]([CH3:6])[CH3:5].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[K]>>[CH3:5][CH:4]([CH3:6])[C:3](=[O:7])[CH2:2][N:12]1[C:8](=[O:18])[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]1=[O:13]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)C(=O)CBr
Agent: [K]
Product: CC(C)C(=O)CN1C(=O)c2ccccc2C1=O
Yield: 74.1 %

Procedure:
The same operation as in Example (15b) was performed using 1-bromo-3-methylbutan-2-one obtained in Example (35a) (3.94 g, 23.9 mmol) and potassium phthalimide (4.4 g, 23.8 mmol), to obtain 4.08 g of the title compound as a white solid (74%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH3:25][CH:26]1[O:31][CH:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>>[CH3:32][CH:30]1[O:31][CH:26]([CH3:25])[CH2:27][N:28]([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:29]1
Reactant: CC1CNCC(C)O1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: CC1CN(Cc2ccc3cc(-c4csc(-c5ccncc5)n4)c(=O)[nH]c3c2)CC(C)O1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and 2,6-dimethylmorpholine to give a yellow solid. MS m/z: 433.1 (M+1).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:9]([O:8][C:6](=[O:7])[C:5]1[CH:13]=[CH:14][C:2]([O:15][C:16]2[CH:23]=[CH:22][CH:21]=[C:18]([C:19]#[N:20])[CH:17]=2)=[CH:3][CH:4]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Oc2cccc(C#N)c2)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 24.6 %

Procedure:
To the solution of tert-butyl 4-fluorobenzoate (500 mg, 2.55 mmol) and 3-hydroxybenzonitrile (306 mg, 2.55 mmol) in N,N-dimethylformamide (80 mL) was added potassium carbonate (528 mg, 3.8 mmol), the mixture was stirred at 130° C. for 1 hour under microwave. Then evaporated the solvent purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=10:1) to give tert-butyl-4-(3-cyanophenoxy)benzoate (185 mg, 57%), as oil, 1H-NMR (300 MHz, CD3OD) δ 8.00 (m, 2H), 7.56 (m, 2H), 7.43 (m, 2H), 7.05 (m, 2H), 1.59 (s, 9H).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:31])[CH2:29][OH:30])[CH:26]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])=[C:9](Cl)[C:8]=2[F:35])=[O:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CO>[N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:31])[CH2:29][OH:30])[CH:26]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])=[CH:9][C:8]=2[F:35])=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 168 h
Yield: 39.8 %

Procedure:
3-[4-(Azetidin-1-ylcarbonyl)-2-chloro-3-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (162 mg; 0.322 mmol) was dissolved in methanol (10 mL). Triethylamine (97 mg, 0.967 mmol) was added and the flask evacuated and purged with nitrogen (3 times). 10% Palladium on carbon (25 mg) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 7 days until completion. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off, the filtrate concentrated in vacuo and purified by preparatory reverse phase HPLC using a gradient of 5-95% acetonitrile in water (containing 0.2% TFA) on a Phenomenex Luna 10u C18 (2) 100A column to give the title compound (60 mg).
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH3:15][O:16][C:17]1[C:18]([OH:36])=[CH:19][C:20]2[CH2:21][CH:22]=[C:23]3[C@@H:32]([C:33]=2[CH:34]=1)[CH2:31][CH2:30][C@@:28]1([CH3:29])[C@H:24]3[CH2:25][CH2:26][C:27]1=[O:35].Cl>C1COCC1.CO.[OH-].[K+].OO.O>[CH3:15][O:16][C:17]1[C:18]([OH:36])=[CH:19][C:20]2[CH2:21][CH:22]=[C:23]3[C@@H:32]([C:33]=2[CH:34]=1)[CH2:31][CH2:30][C@@:28]1([CH3:29])[C@H:24]3[CH2:25][CH2:26][C@@H:27]1[OH:35]
Reactant: COc1cc2c(cc1O)CC=C1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: OO
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1O)CC=C1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 0 °C
Yield: 74 %

Procedure:
Under nitrogen, a solution of L-Selectride in THF (1 M, 0.081 mL, 0.081 mmol) was added dropwise to a solution of 2-methoxy-3-hydroxyestra-1,3,5(10),7-tetraen-17-one (19) (0.008 g, 0.027 mmol) in dry THF (1.0 mL) cooled to 0° C. in an ice bath. The reaction was allowed to warm to room temperature and stirred for 45 m. Methanol (3 drops) followed by methanolic KOH (3%, 3 drops) were added and the mixture was cooled to 0° C. in an ice bath. Hydrogen peroxide solution (30%, 5 drops) was added and the mixture was allowed to warm to room temperature. The reaction was diluted with water, acidified with HCl, and extracted with methylene chloride (3x). The organic fractions were washed with water (1x) and brine (1x), filtered through sodium sulfate, combined and concentrated in vacuo to give 0.006 g residue. This material was crystallized from ether/hexanes to give the purified product (20) (0.0037 g, 45.9%). NMR (300 MHz, CDCl3) δ 0.662 (s, 18-CH3), 3.376 (m, 17-H), 3.867 (s, 2-OMe), 5.402 (t, J=1.65 Hz, 7-H), 6.662 (s, 4-H), 6.692 (s, 1-H) ppm. Analysis Calc. for Cl9H24O3
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2OC)[C:10](=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH-].[NH4+]>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:22][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C1CCN(Cc2ccccc2)CC1=O
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: c1ccc(CN2CCc3c(oc4ccccc34)C2)cc1
Temperature: 25 °C
Yield: 32 %

Procedure:
The crude 1-benzyl-4-(2-methoxyphenyl)piperidin-3-one (0.7 g, 2.37 mmol) obtained in the previous step was dissolved in 4 mL of glacial acetic acid. To this solution, 48% hydrobromic acid (4 mL) was added, and the mixture was refluxed under N2 for 4 h. After cooling to room temperature, the reaction mixture was poured over ice cold ethyl acetate (50 mL) and concentrated ammonium hydroxide solution (50 mL). The organic phase was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 2-benzyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine (200 mg, 33%). 1H NMR (200 MHz, CDCl3): δ 2.70-2.76 (m, 2H) 2.85-2.91 (m, 2H), 3.67 (t, J=1.8 Hz, 2H), 3.78 (s, 2H), 7.18-7.45 (m, 9H); m/e=263 (M+).