Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.[CH3:36][C:37]1[C:41](B(O)O)=[C:40]([CH3:45])[O:39][N:38]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.O>[CH3:36][C:37]1[C:41]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)=[C:40]([CH3:45])[O:39][N:38]=1
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: Cc1noc(C)c1B(O)O
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: COCCOC
Solvent: O
Product: COc1cn(-c2ccc(-c3c(C)noc3C)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 58.8 %

Procedure:
A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (230 mg, 0.45 mmol); 3,5-dimethylisoxazole-4-boronic acid (70 mg, 0.50 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), Na2CO3 (106 mg, 1.0 mmol), DME (4 mL), and H2O (1 mL) was refluxed for 3 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with THF and recrystallized from MeOH/H2O to give the title compound (121 mg, 59% yield) as a white solid: mp 200-202° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.27 (3H, s), 2.42 (3H, s), 3.92 (3H, s), 6.49 (1H, t, J=8.3 Hz), 6.89 (1H, ddd, J=0.8, 1.9, 8.3 Hz), 7.08 (1H, dd, J=1.9, 12.1 Hz), 7.32 (1H, d, J=1.9 Hz), 7.35-7.47 (5H, m), 7.79 (1H, d, J=1.9 Hz), 7.85 (1H, d, J=2.3 Hz). LC-MS (ESI) m/z 458 [M+H]+. Anal. Calcd for C25H2FN5O3: C, 65.64; H, 4.41; N, 15.31. Found: C, 65.55; H, 4.32; N, 15.33.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][O:9][CH2:10][CH:3]1[CH2:4][N:5]([C:11]1[CH:12]=[N:13][C:14]([N+:17]([O-])=O)=[CH:15][CH:16]=1)[CH2:6]2.[H][H]>C1COCC1.CO.[Pd]>[CH3:1][N:2]1[CH:7]2[CH2:8][O:9][CH2:10][CH:3]1[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[N:13][CH:12]=1)[CH2:6]2
Reactant: [H][H]
Reactant: CN1C2COCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN1C2COCC1CN(c1ccc(N)nc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a solution of 112i (800 mg, 3.0 mmol) in THF (80 ml) was added Pd/C (50 mg) in MeOH (20 ml) at room temperature. The reaction mixture was hydrogenated at atmospheric hydrogen pressure and stirred at room temperature overnight. The mixture was filtered and the filtrate was evaporated to give 112j as a colorless oil (680 mg, 90%). MS: [M+H]+: 235
Reaction SMILES: CN.C(O)C.[CH:6]([N:9](CC)C(C)C)(C)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1>ClCCl>[Cl:15][C:16]1[N:21]=[C:20]([NH:9][CH3:6])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: CN
Solvent: ClCCl
Solvent: CCO
Product: CNc1nc(Cl)ncc1[N+](=O)[O-]
Yield: 85.4 %

Procedure:
A solution of methyl amine-ethanol (7.6 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (10.0 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for half an hour. Purification was conducted by a column chromatography to obtain a yellow solid (8.3 g) in a yield of 85.4%. 1H NMR (400 MHz, CDCl3): δ 9.05 (s, 1H), 8.41 (s, 1H), 3.22 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].CC1(C)C(C)(C)OB([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[OH:56])O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=6[OH:56])[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)c(Cl)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(-c6ccccc6O)c5)nn34)c(Cl)c21
Temperature: 90 °C

Procedure:
To a 2-5 ml microwave tube was added (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.240 g, 0.375 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.124 g, 0.563 mmol), and 2M aqueous K2CO3 (0.375 ml, 0.750 mmol) in 1,4-dioxane (3.0 ml) and water (0.75 ml). The reaction was sparged with nitrogen for 10 minutes, treated with Pd(Ph3P)4 (0.043 g, 0.038 mmol), then sparged for 15 min. The reaction tube was sealed and heated (90° C., heating block) for 90 min. The reaction was cooled, diluted with water (5 mL) and extracted with Et2O. The ether layer was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was adsorbed onto silica gel, then purified by biotage column chromatography (5%-55% EtOAc in hexanes). The product fractions were pooled and concentrated under reduced pressure to afford (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate. 1H NMR (500 MHz, CDCl3) δ 7.94 (t, J=1.5 Hz, 1H), 7.86 (dt, J=7.7, 1.4 Hz, 1H), 7.47-7.52 (m, 1H), 7.39-7.45 (m, 1H), 7.25 (s, 1H), 6.95-7.02 (m, 5H), 6.88-6.92 (m, 1H), 5.96-6.10 (m, 1H), 5.51 (br. s., 1H), 5.29-5.37 (m, 1H), 5.24 (dd, J=10.3, 1.5 Hz, 1H), 5.04-5.09 (m, 1H), 4.24 (t, J=4.4 Hz, 2H), 3.67-3.76 (m, 1H), 3.65 (s, 2H), 3.58 (dd, J=15.2, 6.1 Hz, 1H), 3.16-3.23 (m, 2H), 2.84 (s, 3H), 1.95 (s, 1H), 1.17 (s, 9H). LCMS (M+H)=653.4.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1ccccc1CCl
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccc2C(F)(F)F)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-(chloromethyl)-2-(trifluoromethyl)benzene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (55%) as a colorless solid: mp 207-208° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) 7.72 (d, J=7.6 Hz, 1H), 7.51-7.42 (m, 2H), 7.42-7.34 (m, 3H), 7.22-7.12 (m, 1H), 7.07-7.00 (m, 1H), 6.61 (d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.26 (d, J=17.1 Hz, 1H), 5.07 (d, J=17.0 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.24-4.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.9, 155.4, 144.8, 141.8, 138.4, 133.9, 132.5, 132.1, 129.0, 128.3 (q, J=30.8 Hz), 127.7, 126.8, 126.4 (q, J=5.8 Hz), 124.4 (q, J=273.7 Hz), 124.1, 123.8, 120.8, 111.5, 109.2, 99.5, 80.3, 64.5, 63.9, 58.2, 40.6; MS (ES+) m/z 454.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]>>[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20][NH:9][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: Cc1ccc(N)nc1C
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(C)c(C)n1)C(=O)OCC
Yield: 88.7 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 60 were used with 5 g (40.93 mmol) of 5,6-Dimethyl-pyridin-2-ylamine and 8.2 mL (40.93 mmol) of 2-ethoxymethylene malonic acid diethyl ester to afford 10.61 g of 2-[(5,6-Dimethyl-pyridin-2-ylamino)-methylene]-malonic acid diethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:5][C:6]([CH2:17][C:18](=[O:36])[N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:21][CH2:20]1)(C(OCC)=O)[C:7]([O:9]CC)=[O:8].[OH-].[K+]>CCO.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:5][CH:6]([CH2:17][C:18](=[O:36])[N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:21][CH2:20]1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1ccc(C)c(C)c1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C

Procedure:
A solution of 15.5 g (28.2 mmol) diethyl 2-(3,4-dimethyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-malonate in 100 mL EtOH was combined with 11.2 g (169.7 mmol) KOH dissolved in 150 mL water and the mixture was refluxed for 5 h. After the addition of another 11.2 g (169.7 mmol) KOH dissolved in 150 mL water the mixture was refluxed again for 5 h, then combined with 150 mL water and the precipitate was suction filtered. The filter cake was dissolved in 500 mL water, washed twice with 100 mL EtOAc and adjusted to pH 4 by the addition of conc. HCl. The precipitate formed was suction filtered and dried in the circulating air dryer.
Reaction SMILES: [CH2:1]([N:3](CC)[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11](O)[C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=1)[CH3:2].[CH2:27]([N:29](CC)[CH2:30][CH2:31]N)[CH3:28]>[Cl-].[Zn+2].[Cl-]>[CH2:27]([N:29]([CH2:30][CH3:31])[CH2:2][CH2:1][N:3]1[CH:11]([C:12]2[CH:13]=[CH:14][C:15]([N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:16][CH:17]=2)[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4]1=[O:24])[CH3:28]
Reactant: CCN(CC)CCN
Reactant: CCN(CC)C(=O)c1ccccc1C(O)c1ccc(N(CC)CC)cc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CCN(CC)CCN1C(=O)c2ccccc2C1c1ccc(N(CC)CC)cc1

Procedure:
Using 3.54 g of Compound C, 0.15 g of anhydrous zinc chloride and 5 ml of N,N-diethylethylenediamine, the same procedures as in Example 16 were repeated. The crude crystals obtained were crystallized from hexane to give 2.38 g of 2-(2-diethylaminoethyl)-3-(4-diethylaminophenyl)isoindolin-1-one (Compound 19).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:17])[C:5]([NH:7][C:8]1[S:12][C:11]([C:13]([F:16])([F:15])[F:14])=[N:10][N:9]=1)=[O:6].S(Cl)([Cl:20])=O>C1C=CC=CC=1>[Cl:20][CH2:2][CH2:3][N:4]([CH3:17])[C:5]([NH:7][C:8]1[S:12][C:11]([C:13]([F:16])([F:15])[F:14])=[N:10][N:9]=1)=[O:6]
Reactant: CN(CCO)C(=O)Nc1nnc(C(F)(F)F)s1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CN(CCCl)C(=O)Nc1nnc(C(F)(F)F)s1

Procedure:
The N-(β-hydroxyethyl)-N-methyl-N'-(2-trifluoromethyl-1,3,4-thiadiazol-5-yl)urea prepared in Example 6, thionyl chloride (5 ml) and benzene (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux with stirring, for a period of about one-half hour. After this time the benzene and unreacted thionyl chloride were stripped from the reaction mixture under reduced pressure to yield the desired product N-(β-chloroethyl)-N-methyl-N'-(2-trifluoromethyl-1,3,4-thiaidazol-5-yl)urea as a solid residue.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=1.[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O.C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=1
Reactant: Ic1ccc2c(c1)CCCNC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCc2cc(I)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.7 %

Procedure:
7-Iodo-2,3,4,5-tetrahydro-1H-2-benzazepine (Preparation 2) (450 mg, 1.648 mmol) was dissolved in DCM (30 ml) and treated with BOC2O (0.459 ml, 1.977 mmol) followed by triethylamine (0.459 ml, 3.30 mmol). The reaction mixture was stirred at RT for 30 minutes. LC/MS showed one major product. The reaction was washed with 0.5M HCl (20 ml), sat NaHCO3 (20 ml), dried over anhydrous MgSO4 and evaporated to yield the title compound (650 mg) as a colourless oil. MS (ES) C15H20INO2 requires 373; found 318 (M+H−56)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31]>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][C:21]=2[N+:30]([O-:32])=[O:31])[CH2:9][CH2:10]1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COCCN1CCC(N)CC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COCCN1CCC(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 90 °C

Procedure:
1-(2-Methoxy-ethyl)-piperidin-4-ylamine (2.01 g) and triethylamine (3.24 mL, 2.35 g) were added to 1,4-dioxane (60 mL). 4-Chloro-3-nitrobenzenesulfonamide (2.50 g) was added, and the mixture was heated to 90° C. for 16 hours. The mixture was cooled and the material purified by flash column chromatography on silica gel using 10% methanol in dichloromethane.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:24]=[C:25]([NH:29][C:30]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:31])[CH:26]=[CH:27][CH:28]=5)=[CH:21][N:22]=[C:16]4[CH:15]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:3][CH2:2]1.[C:38](Cl)(=[O:40])[CH3:39].CCN(CC)CC>CN(C=O)C>[C:38]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:24]=[C:25]([NH:29][C:30]([NH:32][CH2:33][C:34]([F:35])([F:36])[F:37])=[O:31])[CH:26]=[CH:27][CH:28]=5)=[CH:21][N:22]=[C:16]4[CH:15]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:3][CH2:2]1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cccc(OC5CCNCC5)c4)ccn23)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Oc2cccc(-c3ccn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(3-{7-[3-(Piperidin-4-yloxy)-phenyl]-imidazo[1,2-a]pyridine-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (50 mg, 98 μmol in DMF(10 ml) was added acetyl chloride (6.3 μl, 82 μmol) and Et3N (14 μl). The reaction was stirred at room temperature for 3 h, then partitioned between EtOAc and H2O. The aqueous layer was again extracted with EtOAc, the organics combined, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by preparative HPLC to give the title compound (17.5 mg).
Reaction SMILES: [CH:1]1([C:6]2[C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[N:25]=[C:24]([C:29]([O:31]C)=[O:30])[CH:23]=[CH:22]5)=[CH:15][CH:14]=3)=[C:9]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[O:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+]>C1COCC1>[CH:1]1([C:6]2[C:10]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[N:25]=[C:24]([C:29]([OH:31])=[O:30])[CH:23]=[CH:22]5)=[CH:17][CH:18]=3)=[C:9]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[O:8][N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(C5CCCC5)noc4C4CCCC4)cc3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2cc(-c3ccc(OCc4c(C5CCCC5)noc4C4CCCC4)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 844.8 %

Procedure:
A solution of methyl 6-(4-{[(3,5-dicyclopentyl-4-isoxazolyl)methyl]oxy}phenyl)-2-quinolinecarboxylate (65 mg, 0.13 mmol) in THF (1.3 mL) was placed in a microwave reaction tube. Methanol (0.7 mL) was added followed by 1.0 N sodium hydroxide (0.2 mL, 0.2 mmol) before the tube was sealed and stirred at room temperature for 30 minutes. The mixture was heated at 100° C. for 10 minutes. The solution was concentrated and the residue was suspended in water before neutralization with 1 N HCl. The resulting mixture was filtered and the sample was dried in a drying oven at 45° C. under reduced pressure with P2O5 to yield 6-(4-{[(3,5-dicyclopentyl-4-isoxazolyl)methyl]oxy}phenyl)-2-quinolinecarboxylic acid (0.53 g, 84%). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.18-8.11 (m, 2H), 8.07 (d, J=9 Hz, 1H), 7.82 (d, J=9 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 4.98 (s, 2H), 3.40-3.20 (m, overlapping H2O), 3.16-3.12 (m, 1H), 1.99 (m, 4H), 1.76-1.56 (m, 12H). HRMS C30H30N2O4 m/z 483.2278, (M+H)+Cal; 483.2277 (M+H)+Obs.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH:13]=[CH:12]3)(=[O:3])[CH3:2].[NH4+].[Cl-].[CH2:26]1[CH2:30]OC[CH2:27]1>>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:27][CH2:26][CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: CCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Reaction time: 0.5 h

Procedure:
After stirring for an additional 0.5 hr , a solution of 5.2 g of (17 beta)-17-(acetyloxy)estra-4,6-dien-3-one (1) in 20 ml of THF was added dropwise at −40 C. Upon stirring for an additional 15 minutes the reaction was complete, and the mixture was poured onto 300 ml of saturated NH4Cl solution, followed by extraction with ethyl acetate. The organic material, isolated after washing, drying and evaporation of the solvent, was taken up in 30 ml of THF and stirred in the presence of 3 ml of 6N H2SO4 to isomerize some Δ5,6 isomer to Δ4,5 isomer. After 1 hr the mixture was neutralized with saturated NaHCO3 solution and extracted with ethyl acetate. Chromatography of the crude product over silica gel (heptane/ethyl acetate 8/2) provided 2.1 g of 2, m.p. 97-100° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Mg].[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(O)(=O)C>C1COCC1>[C:25]([O:24][C:22]([N:13]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccccc1C(F)(F)F
Temperature: -75 °C
Yield: 81 %

Procedure:
2-Bromobenzotrifluoride (4.5 g, 20 mmol) and magnesium turnings (0.54 g, 22 mmol) were refluxed under a nitrogen atmosphere in 100 ml THF until the magnesium had dissolved. The resulting solution was cooled to -75° C. and added to 4.6 g (20 mmol) di-t-butyl azodicarboxylate in 100 ml THF at -75° C. The solution was warmed to -40° C., acetic acid (1.5 ml, 25 mmol) was added, and the mixture concentrated to 20 ml. Hexane and water were added, and the hexane solution was evaporated to leave a brown oil which was chromatographed on silica with 10% ether in CHCl3, providing 6.1 g (81% yield) of N,N'-bis(t-butoxycarbonyl)-2-(trifluoromethyl)phenylhydrazine as a brown gum. This material was dissolved in 200 ml isopropanol, and hydrogen chloride gas was passed into the solution resulting in a weight gain of 8 g. The solution was stirred at 50° C. for 30 minutes, then evaporated to dryness. The residue was treated with ether, and the solids collected by filtration and dried in vacuo, providing 2.7 g (79% yield) 2-(trifluoromethyl)phenylhydrazine hydrochloride as a white powder, mp 241°-242° C.
Reaction SMILES: [C:1]([N:4]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:28])[CH2:6]1)(=[O:3])[CH3:2]>CCO.C(Cl)Cl.[Pd]>[C:1]([N:4]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:28])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C=CC(=O)O)cc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCC(=O)O)cc2)c2ccccc21
Reaction time: 1 h
Yield: 99 %

Procedure:
(2S,4R)-3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-propionic acid was prepared from (2S,4R)-3-(4-{4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-acrylic acid. A solution of (2S,4R)-3-(4-{4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-acrylic acid (50 mg, 0.102 mmol) in EtOH (2 ml) and CH2Cl2 (10 drops for solubility) was subjected to Pd—C (10%, ca. 50 mg) and 1 atm H2 gas. After 1 hour, the mixture was filtered, concentrated and subjected to silica gel chromatography (2% MeOH in EtOAc to 10% MeOH in EtOAc), to afford the title compound (50 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[Si:15]([O:22][CH:23]1[CH2:28][CH2:27][C:26](=[CH:29][C:30]#[N:31])[CH2:25][CH2:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N12CCCN=C1CCCCC2>C(#N)C>[Si:15]([O:22][CH:23]1[CH2:24][CH2:25][C:26]([CH2:29][C:30]#[N:31])([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:27][CH2:28]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=CC#N)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C3(CC#N)CCC(O[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.09 g, 0.0159 mol) in acetonitrile (39.8 mL) was added (4-(tert-butyl(dimethyl)silyl)oxycyclohexylidene)acetonitrile (4.80 g, 0.0191 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.19 mL, 0.00797 mol). The resulting mixture was stirred at room temperature overnight, then evaporated to dryness. The mixture was purified on silica gel, eluting with 0 to 20% EtOAc in hexanes, to give the desired product as cis- and trans-mixture (2.33 g, 33%). LCMS (M+H) 446.3.