Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[F:10][C:11]1[CH:12]=[C:13]([CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:2]2[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: N#Cc1ccc(Cl)nn1
Reactant: NC1CCN(Cc2cc(F)cc(C(F)(F)F)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1ccc(NC2CCN(Cc3cc(F)cc(C(F)(F)F)c3)CC2)nn1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A mixture of 6-chloro-pyridazine-3-carbonitrile (D4) (1.39 g, 9.95 mmol), 1-(3-fluoro-5-trifluoromethyl-benzyl)-piperidin-4-ylamine (D7) (2.5 g, 9.04 mmol) and diisopropylethylamine (2.63 ml, 14.92 mmol) in acetonitrile (2 ml) was stirred at 120° C. for 30 min, under microwave irradiation ((Biotage MW-oven). The mixture was then diluted with dichloromethane (50 ml) and extracted with a saturated solution of sodium carbonate. The organic layer was separated, dried (Na2SO4), filtered, evaporated in vacuo and the residue purified by column chromatography (silica gel; 0-2.5% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The residue precipitated from diisopropylether to yield E17 (2.76 g, 73%) as a solid. C18H17F4N5 requires 379. Found 380 (MH+); mp: 151.4° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:7]=1[CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:2][CH2:3][CH3:4].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O.CO>[C:29]([O:28][C:26](=[O:27])[NH:25][CH2:24][C:7]1[N:8]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:9](=[O:19])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)([CH3:30])([CH3:31])[CH3:32]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C(=O)O)cc12
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(CO)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
To a solution of 4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (Example 146 (9)) (0.45 g, 3.5 mmol) and N-methylmorpholine (0.13 mL, 1.2 mmol) in tetrahydrofuran (10 mL) was added ethyl chloroformate (0.12 mL, 1.2 mmol) at 0° C. and the mixture was stirred at 0° C. for 10 min. To the obtained mixture were added sodium tetrahydroborate (0.11 g, 3 mmol) and methanol (5 mL), and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl(4-butoxy-2-cyclopropylmethyl-6-hydroxymethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.33 g, 76.7%) as crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[O:13]=[CH:14][C:15]([Cl:18])([Cl:17])[Cl:16]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:16][C:15]([Cl:18])([Cl:17])[CH:14]([OH:13])[CH:4]([N:5]1[CH:9]=[N:8][CH:7]=[N:6]1)[C:3](=[O:10])[C:2]([CH3:12])([CH3:11])[CH3:1]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=O)Cn1cncn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(C(O)C(Cl)(Cl)Cl)n1cncn1
Temperature: -5 °C
Reaction time: 3 h
Yield: 31.6 %

Procedure:
33.4 g (0.2 mol) of 3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one were dissolved in 150 ml of methylene chloride and the solution was cooled to -5° C. 19 g (0.1 mol) of titanium tetrachloride, and then 29.5 g (0.2 mol) of chloral, were slowly added dropwise to this solution. The internal temperature was kept constant at -5° C. during the metering. Thereafter, the mixture was warmed slowly to the reflux and stirred for 3 hours. The reaction solution was poured onto ice and the white curdy precipitate which formed was filtered off. After boiling up in 250 ml of methanol and then drying, 19.9 g (32% of theory) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one of melting point 220°-222° C. were obtained.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[C:12]([OH:27])[C:13]2[C:18]3[CH:19]=[C:20]([O:23]C)[CH:21]=[CH:22][C:17]=3[C:16](=[O:25])[O:15][C:14]=2[CH:26]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].B(Br)(Br)Br.O>ClCCl>[CH3:9][C:2]([C:10]1[CH:11]=[C:12]([OH:27])[C:13]2[C:18]3[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:17]=3[C:16](=[O:25])[O:15][C:14]=2[CH:26]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1cc(O)c2c(c1)oc(=O)c1ccc(OC)cc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)oc(=O)c1ccc(O)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.4 %

Procedure:
3-(1,1-Dimethylheptyl)-1-hydroxy-9-methoxy-6H-dibenzo[b,d]pyran-6-one (4b) (200 mg, 0.54 mmol) was dissolved in 12 mL of dry dichloromethane, 2 mL of a 1M solution of boron tribromide in dichloromethane (2 mmol) was added and the resulting mixture was stirred at room temperature for 3 days. Water was added and the mixture was extracted with diethyl ether. The organic extract was dried and rotary evaporated. The residue was chromatographed on silica gel (50% ethyl ether-petroleum ether) to afford 150 mg of a flaky off-white foam: m.p. 103-108° C.; Rf; 0.28 (50% diethyl ether-petroleum ether); 1H NMR δ 8.60 (m, 1H), 8.35 (d, 1H), 7.05 (d, 1H), 6.90 (s, 1H), 6.73 (s, 1H), 6.10 (br s, 2H), 1.70-0.98 (series of m, 10H), 1.27 (s, 6H), 0.82 (t, J=6.6 Hz, 3H); Anal. calcd. for C23H28O4 74.55% C, 7.39% H. Found 72.70% C, 7.25% H.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[NH2:10])(OC)=[O:2].CC(C)([O-])C.[K+].[CH:21]([NH2:23])=O.O>CS(C)=O.C(O)(=O)C>[OH:2][C:1]1[C:5]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[C:9]=2[N:10]=[CH:21][N:23]=1
Reactant: NC=O
Reactant: COC(=O)c1sc2ccccc2c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Oc1ncnc2c1sc1ccccc12
Temperature: 90 °C

Procedure:
To a solution of 2-carbomethoxy-3-aminobenzothiophene (2.07 g.; 0.02 mole) and potassium t-butoxide (2.24 g.; 0.02 mole) in dimethylsulfoxide (30 ml.) is added an excess of formamide (ca 5 ml./g. of 2-carbomethoxy-3-aminobenzothiophene). This is heated to 90° C. until the reaction is complete as evidenced by thin layer chromatography (~30 minutes). The solution is cooled, poured into water, acidified with glacial acetic acid and the resultant solid is filtered. Washing with isopropyl alcohol and then ether yields a white solid, 1.76 g., m.p. 300°-301° C.
Reaction SMILES: FC1C=C(OC)C=C(F)C=1C[NH2:5].C(N(CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[F:41][C:42]1[CH:71]=[C:70]([O:72][CH3:73])[CH:69]=[C:68]([F:74])[C:43]=1[CH2:44][N:45]1[C:50]2[N:51]=[CH:52][CH:53]=[CH:54][C:49]=2[S:48](=[O:56])(=[O:55])[N:47]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])C=2)[C:46]1=[O:67]>CN(C=O)C>[F:74][C:68]1[CH:69]=[C:70]([O:72][CH3:73])[CH:71]=[C:42]([F:41])[C:43]=1[CH2:44][N:45]1[C:50]2[N:51]=[CH:52][CH:53]=[CH:54][C:49]=2[S:48](=[O:55])(=[O:56])[N:47]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[N:5]=2)[C:46]1=[O:67]
Reactant: COc1cc(F)c(CN)c(F)c1
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)n3)S(=O)(=O)c3cccnc32)c(F)c1

Procedure:
The title compound (112 mg, 0.23 mmol) was prepared in two steps from (IntC3) (165 mg, 0.5 mmol), 2,6-difluoro-4-methoxybenzylamine (90 uL, 0.6 mmol) and N,N-diisopropylethylamine (180 uL, 1.0 mmol); followed by 1,1′-carbonyldiimidazole (253 mg, 1.56 mmol), triethylamine (0.11 mL, 0.79 mmol) in DMF (1.5 mL) using the methods of (95).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([OH:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([O:18][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Oc1cc2ccccc2nc1-c1ccc(F)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3ccc(F)cc3)c2cc1OC
Temperature: 145 °C
Reaction time: 5 h
Yield: 63.7 %

Procedure:
2-(4-Fluoro-phenyl)-quinolin-3-ol (52 mg), 4-chloro-6,7-dimethoxyquinoline (145 mg), and 4-dimethylaminopyridine (214 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 145° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (59 mg, yield 64%).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4]1.[CH3:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[C:16](=[O:21])[CH:15]=[CH:14][C:13]2=[O:22].C1C=CC=CC=1>[Pd].CO>[CH2:4]([CH:5]1[C:14]2[C:13](=[O:22])[C:12]3[C:17](=[CH:18][C:19]([CH3:20])=[C:10]([CH3:9])[CH:11]=3)[C:16](=[O:21])[C:15]=2[CH2:8][CH2:7][CH2:6]1)[CH2:3][CH2:2][CH3:1]
Reactant: Cc1cc2c(cc1C)C(=O)C=CC2=O
Reactant: C=CC1CC=CCC1
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Product: CCCCC1CCCC2=C1C(=O)c1cc(C)c(C)cc1C2=O
Reaction time: 8 h
Yield: 36 %

Procedure:
A 3.0 g. sample of the butadiene dimer-6,7-dimethylnaphthoquinone adduct was dissolved in 100 ml. benzene. After the addition of 0.30 g. 10% Pd/C catalyst, the mixture was hydrogenated at 35 psi for four hours. After removal of catalyst by filtration, five drops DBN were added and the mixture was stirred overnight while exposed to air. The benzene was then blown off with air and the residue chromatographed on acidic alumina with a 9:1 benzene-ethyl acetate solution. The crude product (1.1 g.; 36% yield) was recrystallized from methanol to give an analytical sample with m.p. 88°-90°C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]>C1COCC1>[Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: O=C(CCCl)c1ccccc1
Solvent: C1CCOC1
Product: O[C@@H](CCCl)c1ccccc1
Reaction time: 7 h

Procedure:
A solution of 3-chloropropiophenone (8.93 g, 50 mmol in 25 ml THF) was added to (-) diisopinocampheylchloroborane (Ipc2BCl, 18.0 g, 56 mmole, in 25 ml THF at -24° C.). The reaction was complete within 7 hours after which all volatiles were removed under reduced pressure. The residue was dissolved in ether, and diethanolmine (2 equivalents) was added. The resulting suspension was stirred for two hours and filtered. The solid residue was washed with ether and the combined washings and filtrate were concentrated. Distillation furnished[S]-(-)-1-chloro-3-phenyl-3-propanol. Yield: 6.1g, 72%; mp 56°-57° C.; D23-25.25, c=7.05, CHCl3 ; 97% ee.
Reaction SMILES: [Cl-].[NH4+].[OH-].Br[CH2:5][CH:6]1[C@H:11]([C:12]([O:14][CH2:15][C:16](Cl)([Cl:18])[Cl:17])=[O:13])[N:10]2[C:20](=[O:32])[C@@H:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:9]2[S@@:8](=[O:33])[CH2:7]1.Cl>O.CC(C)=O.CN(C)C=O.[Zn]>[C:25]1([CH2:24][C:23]([NH:22][C@@H:21]2[C:20](=[O:32])[N:10]3[C@@H:11]([C:12]([O:14][CH2:15][CH:16]([Cl:17])[Cl:18])=[O:13])[C:6](=[CH2:5])[CH2:7][S@:8](=[O:33])[C@H:9]23)=[O:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1[S@@](=O)CC(CBr)[C@@H]2C(=O)OCC(Cl)(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: C=C1C[S@](=O)[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OCC(Cl)Cl
Temperature: 4 °C
Reaction time: 1.17 h
Yield: 12.4 %

Procedure:
1.2 g (22.4 mmoles) of ammonium chloride in 2.2 ml of water and 1.2 ml of a 4N hydroxide solution at -10° C. were added to a stirred solution of 1.68 g (purity 92%; 2.78 mmoles) of trichloroethyl (1S,4R,6R,7R)-3-bromomethyl-1-oxo-7-phenylacetamidocepham-4-carboxylate in 15 ml of acetone and 2 ml of dimethylformamide. After adding 1.5 g (15.3 mmoles) of activated zinc powder the mixture was stirred at 4° C. for 70 min. Then 3 ml of water and 3.6 ml of a 4N hydrochloric acid solution were added and the solid material was filtered off. To the filtrate 50 ml of warm water was added. After cooling to 0° C. the crystals were filtered off, washed and dried giving 153 mg of dichloro-ethyl (1S,4R,6R,7R)-7-phenylacetamido-3-methylene-1-oxo-cepham-4-carboxylate with a purity of 83%. Yield 10%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[O:21]1[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]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>CN(C=O)C.O>[O:21]1[CH2:26][CH2:25][CH:24]([C:27]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)[CH:5]=[CH:4][C:3]=2[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:28])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: O=C(O)C1CCOCC1
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
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)C1CCOCC1
Yield: 78.2 %

Procedure:
A solution of tert-butyl (2-amino-4-(thiophen-2-yl)phenyl)carbamate (1.2 g, 4.13 mmol, 1.0 eq.), tetrahydro-2H-pyran-4-carboxylic acid (0.65 g, 4.96 mmol, 1.2 eq.), HATU (3.14 g, 8.27 mmol, 2.0 eq.) and Hünigs base (1.80 mL, 10.33 mmol, 2.5 eq.) in DMF (15 mL) was stirred for 18 h at room temperature. The reaction mixture was diluted with water. The solid was isolated by filtration and washed with hexanes to afford tert-butyl (2-(tetrahydro-2H-pyran-4-carboxamido)-4-(thiophen-2-yl)phenyl)carbamate (1.3 g, 78% yield).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f28) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]([NH:22][CH:23]([CH3:25])[CH3:24])[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=O)C>ClCCl.[O-]CC.[Na+]>[NH2:4][C:5]1[N:6]=[C:7]([NH:22][CH:23]([CH3:25])[CH3:24])[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CC(=O)Nc1nc(NC(C)C)c2nc(-c3ccc(F)cc3)ccc2n1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Nc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
The crude 2-acetamido-4-(N-isopropylamino)-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidine of example 3 (0.5 mmol) was suspended in a mixture of dichloromethane (10 ml) and 0.5 N sodium ethoxide (10 ml). The reaction mixture was stirred for 16 hours at room temperature. The solvents were evaporated in vacuo and the crude residue was purified by preparative thin layer chromatography on silica, using a mixture of methanol and dichloromethane (in a volume ratio of 10:90) as a mobile phase providing, in a yield of 61%, the pure title compound which was characterized by its mass spectra as follows: MS (m/z): 298 ([M+H]+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][C:19](Cl)=[CH:20][C:11]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[K+]>C(O)(CC)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][C:19]([NH:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])=[CH:20][C:11]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCC(C)(C)O
Product: COc1ccccc1Nc1cnc2[nH]c3c(c2c1)CN(C(=O)OC(C)(C)C)CC3
Temperature: 95 °C
Reaction time: 8 h
Yield: 7.1 %

Procedure:
3-Chloro-5,7,8,9-tetrahydro-dipyrido[2,3-b;3′,4′-d]pyrrole-6-carboxylic acid tert-butyl ester (100 mg, 0.32 mmol), o-anisidine (48 mg, 0.39 mmol), Pd(OAc)2 (3 mg, 0.01 mmol), X-Phos (12 mg, 0.03 mmol), and KOH (0.03 ml, 0.97 mmol) were suspended in tert-amyl alcohol (2 mL), and stirred overnight at 95° C. The crude mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with a gradient of 0 to 100% EtOAc in hexanes to provide 45 (9 mg, 7% yield) as a brown oil. LC-MS (M+H=395, obsd.=395).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:18][CH:17]=3)[CH:12]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[N:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])=[CH:20][CH:21]=3)[CH:12]=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=c1n(-c2ccc(OCC(F)(F)C(F)F)cc2)cnn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-n2ncn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1
Yield: 90.2 %

Procedure:
2-(4-Nitrophenyl)-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (5.5 g) and 10% palladium-carbon (50% wet, 0.5 g) were added to methanol (200 ml). The mixture was subjected to catalytic hydrogenation at ordinary temperature under ordinary pressure. When hydrogen absorption stopped, dichloromethane (200 ml) was added thereto and the catalyst was removed by filtration. The catalyst was washed with dichloroethane (50 ml). The washings and the filtrate were combined and distilled under reduced pressure to give 2-(4-aminophenyl)-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (4.6 g, 90%) as a white solid. This compound was used for the next process without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][C:18]([F:25])=[C:19]([F:24])[CH:20]=2)[N:15]=1)[CH2:11][C:12]#[CH:13]>>[F:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[F:25])[N:15]=[C:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[CH:23]=[N:22]2
Reactant: C#CCCc1cnc2cc(F)c(F)cc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCc2cnc3cc(F)c(F)cc3n2)n1
Reaction time: 0.25 h
Yield: 13.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (70 mg, 0.37 mmol) and 2-but-3-ynyl-6,7-difluoro-quinoxaline (80 mg, 0.37 mmol). Microwave conditions: 120° C. for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 16 mg (50 μmol, 14%) of 6,7-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline as a yellow solid (M.P.: 134.9-138.5° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].I[CH:11]([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH:11]([CH3:13])[CH3:12]
Reactant: Oc1cc(F)ccc1Br
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(F)ccc1Br
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Bromo-5-fluoro-phenol Compound 4a (3.0 g, 15.7 mmol), 2-iodo-propane Compound 4b (4.0 g, 23.6 mmol), K2CO3 (3.3 g, 23.6 mmol) and DMF (50 mL) were heated and stirred at 80° C. for 8 hrs. The excess DMF was removed under reduced pressure and the white residue was mixed with AcOEt (100 mL), washed with water and dried (Na2SO4). The filtered dry solution was evaporated to provide 1-bromo-4-fluoro-2-isopropoxy-benzene Compound 4c (3.48 g, 95%) as a yellowish oil.
Reaction SMILES: [CH2:1]([C@@H:11]1[CH2:28][C:27]2[CH:26]=[C:25]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:24]=[CH:23][C:22]=2[C@@H:21]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:20]2[F:37])([CH3:18])[C:16](=[O:38])[CH2:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:39]([OH:47])(=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[CH2:30]([O:29][C:25]1[CH:24]=[CH:23][C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][C@@H:20]3[F:37])([CH3:18])[C:16](=[O:38])[CH2:15][CH2:14]4)[C@H:11]([CH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:39](=[O:47])[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:28][C:27]=2[CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCCCCNCCCC[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCN(CCCC[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)C(=O)c1ccccc1
Temperature: 0 °C
Yield: 59.7 %

Procedure:
A solution of 275 mg of 7α-(5-azadecyl)-3-benzyloxy-11β-fluor-estra-1,3,5(10)-trien-17-one in 7.8 ml of dimethylformamide is stirred with 175 mg of benzoic acid and 250 mg of 1-hydroxybenzotriazole and 0.2 ml of N,N′-diisopropylcarbodiimide for 24 hours at room temperature. Then, the reaction mixture is added to ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a methylene chloride-methanol gradient, 197 mg of N-[4-(3-benzyloxy-11β-fluor-estra-1,3,5(10)-trien-17-on-7α-yl)-butyl)-N-pentyl-benzamide is obtained.
Reaction SMILES: C([O:5][C:6](=[O:36])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:35])[CH:13]([CH2:30][S:31][C:32](=[O:34])[CH3:33])[CH2:14][CH2:15][CH2:16][NH:17]C(OCC1C=CC(OC)=CC=1)=O)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C1(OC)C=CC=CC=1>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[C:32]([S:31][CH2:30][CH:13]([CH2:14][CH2:15][CH2:16][NH2:17])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:36])=[O:5])=[O:35])(=[O:34])[CH3:33]
Reactant: COc1ccc(COC(=O)NCCCC(CSC(C)=O)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC(CCCN)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-[2-Acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-L-proline tert-butyl ester (2 g) is dissolved in a mixture of trifluoroacetic acid (15 ml) and anisole (6 ml). The solution is stored at room temperature for one hour, the solvents are removed in vacuo and the residue is precipitated from ethyl acetate-ether to yield 1-(2-acetylthiomethyl-5-aminopentanoyl)-L-proline trifluoroacetate.