Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.O(C(C)(C)C)[Na]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)[CH2:9][CH2:8]1
Reactant: Ic1ccccc1
Reactant: COC(=O)CCCN1CCN(c2ccc(N)cc2)CC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Product: COC(=O)CCCN1CCN(c2ccc(Nc3ccccc3)cc2)CC1
Yield: 34 %

Procedure:
The title compound (120 mg, 34%) was prepared from the compound from step 2 (277 mg, 1 mmol) and iodobenzene (204 mg, 1 mmol) in the presence of Pd2(dba)3 (27 mg, 0.03 mmol), PtBu3 (60 mg. 0.3 mmol) and NaO-t-Bu (96 mg, 1 mmol) by the procedure described in step 3 of Example 1 MS (ESI) m/z 354 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.87 (m, 2H), 2.36-2.43 (m, 4H), 2.61 (b, 4H), 3.14 (b, 4H), 3.68 (s, 3H), 6.80-6.93 (m, 5H), 7.04 (d, J=8.8 Hz, 2H), 7.20 (t, J=8.0 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[C:27]([NH2:33])(=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[OH-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:26][C:4]1[N:3]=[C:2]([NH:33][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: CCCCC(N)=O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2cccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CCCCC(=O)Nc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Temperature: 85 °C
Yield: 11.9 %

Procedure:
A mixture of Example 7a (82.5 mg, 0.204 mmol), pentanamide (28.9 mg, 0.286 mmol), cesium carbonate (100 mg, 0.306 mmol), palladium (II) acetate (2.29 mg, 10.2 μmol), and Xantphos (8.86 mg, 0.015 mmol) was degassed and heated at 85° C. in a sealed vial for 6 hours. The reaction mixture was cooled and concentrated. The residue was treated with 20% brine and extracted with EtOAc (2×). The organic layers were dried and concentrated. The crude intermediate was dissolved in dioxane (1.5 mL) and treated with 20% sodium hydroxide (0.15 mL, 0.20 mmol). The mixture was heated at 50° C. for 2 hours. The solvent was evaporated. The residue was treated with water, sonicated, filtered, and washed with water, and purified by reverse-phase HPLC as described in Example 56 to give the title compound (8.0 mg) as trifluoroacetic acid salts. 1H NMR (500 MHz, DMSO-d6) ppm 0.90 (t, J=7.48 Hz, 3H), 1.27-1.38 (m, 2H), 1.54-1.64 (m, 2H), 2.43 (t, J=7.32 Hz, 2H), 7.29 (m, 1H), 7.57 (s, 1H), 8.28-8.37 (m, 3H), 8.60 (s, 1H), 10.74 (s, 1H), 12.36 (s, 1H). MS (ESI+) m/z 328.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][O:15][Si](C(C)C)(C(C)C)C(C)C)[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1.Cl.C(=O)=O.CC(C)=O.N.C([O-])(O)=O.[Na+]>CCO.CO>[CH3:1][C:2]1([CH2:14][OH:15])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1
Reactant: CC(C)[Si](OCC1(C)CCn2cc([N+](=O)[O-])nc2O1)(C(C)C)C(C)C
Agent: Cl
Agent: N
Agent: O=C([O-])O
Solvent: CO
Solvent: CC(C)=O
Solvent: CCO
Product: CC1(CO)CCn2cc([N+](=O)[O-])nc2O1
Temperature: 44 °C
Reaction time: 72 h
Yield: 88.5 %

Procedure:
A suspension of silyl ether 148 (2.518 g, 6.81 mmol) in a solution of 1% HCl in 95% EtOH (desilylation conditions described by Cunico et al., 1980) (90 mL) was stirred at 44° C. for 3 days. The resulting solution was cooled (CO2/acetone), neutralised by dropwise addition of 7M NH3 in MeOH (8 mL) and NaHCO3 (0.10 g, 1.19 mmol) with stirring, and then concentrated to dryness and the residue was chromatographed on silica gel. Elution with 0-1% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 1.5% MeOH/CH2Cl2 gave (7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl)methanol (149) (1.285 g, 88%) as a pale yellow solid: mp (MeOH/CH2Cl2/hexane) 199-201° C.; 1H NMR [(CD3)2SO] δ 8.03 (s, 1H), 5.22 (t, J=5.7 Hz, 1H), 4.13 (dt, J=12.9, 6.0 Hz, 1H), 4.05 (ddd, J=13.0, 8.1, 5.6 Hz, 1H), 3.54 (dd, J=11.6, 5.5 Hz, 1H), 3.48 (dd, J=11.6, 5.8 Hz, 1H), 2.21 (ddd, J=14.4, 8.1, 5.9 Hz, 1H), 2.00 (dt, J=14.4, 5.8 Hz, 1H), 1.32 (s, 3H). Anal. (C8H11N3O4) C, H, N.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[Cl:26][CH2:27][CH2:28][CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)=[O:31]>CN(C)C=O>[ClH:26].[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:30](=[O:31])[CH2:29][CH2:28][CH2:27][NH:17][CH:14]2[CH2:13][CH2:12][C:3]3([CH2:4][CH2:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:2]3)[CH2:16][CH2:15]2)=[CH:37][CH:36]=1
Reactant: NC1CCC2(CCc3ccccc3C2)CC1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C(CCCNC1CCC2(CCc3ccccc3C2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
The free base from 1.65 g. (0.0066 M) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)] (prepared in Example 10C), 1.34 g. of potassium iodide, 2.06 g. of potassium carbonate and 1.9 g. of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone in 35 ml. of dimethylformamide are heated in an oil bath at about 90° C. for about 18 hours. The solvent is removed under vacuum and the residue that remains is dissolved in benzene and water. The organic layer is washed with water and brine and evaporated to dryness. A mixture of the residue and 10 ml. of 2.5 N hydrochloric acid in 20 ml. of methanol is stirred at room temperature for about 4 hours. The methanol is then removed under vacuum and the solid collected on a filter. This material is recrystallized twice from methylene chloride: ethyl acetate to give 1.07 g. (39% yield) of 4'-fluoro-4-[[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]amino]butyrophenone hydrochloride [I(c)], having a melting point of 182° to 184° C.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:8]=3[N:9]=[C:2]12.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:22][CH3:23])=[O:15])=[CH:10][C:8]=3[N:9]=[C:2]12
Reactant: O=C(O)c1ccc2c(c1)nc1n2CCNC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2c(c1)nc1n2CCNC1
Yield: 84 %

Procedure:
In ethanol (200 ml), 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylic acid (2.94 g, 13.53 mmol) prepared in the Step 38-1-4 was suspended. Concentrated sulfuric acid (10 ml) was added thereto, and the mixture was heated under reflux for 72 hours. After being allowed to cool, the mixture was concentrated under a reduced pressure. The concentrate was neutralized with a saturated sodium bicarbonate solution and 25% ammonia water and then subjected to extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The concentrate was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound (2.78 g, 84%) as a light-yellow powder.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[S:9][C:10]2[CH:16]=[C:15]([C:17](OCC)=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.O.[OH-].[Na+]>C1COCC1>[CH3:7][C:8]1[S:9][C:10]2[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: CCOC(=O)c1ccc2nc(C)sc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2ccc(CO)cc2s1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
A cooled (−10° C.) suspension of LiAlH4 (188 mg; 4.97 mmol) in anh. THF (30 ml) was treated with a solution of commercially available ethyl 2-methylbenzo[d]thiazole-6-carboxylate (1.000 g; 4.51 mmol) in anh. THF (20 ml). The mixture was further stirred at −10° C. for 20 min. Water (0.19 ml), 15% aq. NaOH (0.19 ml), and water (0.57 ml) were then successively added, and the resulting mixture was further stirred at rt for 1 h. Filtration, concentration to dryness under reduced pressure, and additional drying under HV afforded (2-methylbenzo[d]thiazol-6-yl)methanol as a yellow oil. LC-MS (conditions A): tR=0.45 min.; [M+H]+: 180.16 g/mol.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[C:7]([F:13])[CH:6]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[Br:12][C:8]1[C:9]([F:11])=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][C:7]=1[F:13]
Reactant: [N-]=[N+]=NCc1cc(F)c(Br)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(F)c(Br)c(F)c1
Temperature: 55 °C

Procedure:
To a mixture of the crude azide (70 mg, 0.28 mmol) in THF (4 mL) were added polymer-supported Ph3P (3.0 eq.) and water (1 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.37 min; [M+CH3CN+H]+=263.15.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:20]=O)=[C:9]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[C:10]=1[CH2:11]C)=[O:5])C.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:39]=[C:38]3[C:34]([CH2:35][C:36](=[O:40])[NH:37]3)=[CH:33][CH:32]=2)[CH:28]=[CH:29][CH:30]=1)[CH3:23]>N1CCCCC1.C(O)C>[C:15]([CH2:14][CH2:13][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:20]=[C:35]1[C:34]2[C:38](=[CH:39][C:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH2:22][CH3:23])[CH:26]=3)=[CH:32][CH:33]=2)[NH:37][C:36]1=[O:40])([OH:17])=[O:16]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1CC
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C(=O)O)c(C)c2CCC(=O)O)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
A mixture of 5-formyl-4-(2-ethoxycarbonylethyl)-3-ethyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 6-(3-ethoxyphenyl)-2-oxindole (304 mg), and piperidine (2 drops) in ethanol (5 mL) were held at 90° C. overnight. The precipitate that formed was filtered, washed with ethanol. The precipitate, an orange solid, was stirred with potassium hydroxide (4 pellets) in ethanol (3 mL) at 90° C. for 2.5 hours. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 370 mg of 4-(2-Carboxyethyl)-5-[6-(3-ethoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH:34]([C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)[CH3:35])=[CH:4][N:3]=1.[F:46][C:47]1[CH:48]=[C:49]([NH2:55])[CH:50]=[N:51][C:52]=1[O:53][CH3:54].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[F:46][C:47]1[CH:48]=[C:49]([NH:55][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[N:9]=3)=[CH:6][C:5]([CH:34]([C:36]3[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=3)[CH3:35])=[CH:4][N:3]=2)[CH:50]=[N:51][C:52]=1[O:53][CH3:54]
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.7 %

Procedure:
4-(2-Fluoro-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (752 mg, 1.20 mmol) and 5-fluoro-6-methoxypyridin-3-amine (175.0 mg, 1.231 mmol) were dissolved in THF (12.0 mL) and the flask was cooled in an ice water bath under nitrogen. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran/ethylbenzene, 3.6 mL, 3.6 mmol) was added via syringe, and the reaction was stirred under nitrogen. After 15 min, the reaction was treated with ice water (1.5 mL) and diluted with DCM (150 mL). The solution was dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with 2 inches of silica gel; DCM to 100:1 DCM/MeOH to 50:1 DCM/MeOH). The fractions with product were collected, concentrated, and dried under high vacuum to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (744.3 mg). 1H NMR (CDCl3, 400 MHz) δ 11.82 (s, 1H), 8.66 (d, J=2.35 Hz, 1H), 8.17 (d, J=2.54 Hz, 1H), 8.03 (dd, J=12.13 Hz, 2.15 Hz, 1H), 7.95 (d, J=2.15 Hz, 1H), 7.81 (d, J=8.41 Hz, 2H), 7.40 (d, J=8.41 Hz, 2H), 7.24-7.14 (m, 4H), 7.90-7.81 (m, 4H), 4.87 (d, J=5.09 Hz, 2H), 4.77 (d, J=5.48 Hz, 2H), 4.21 (q, J=7.04 Hz, 1H), 4.01 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 2.98 (s, 3H), 2.58 (s, 3H), 1.67 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 750 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:23]([O-])=O)[CH:17]=1.O>Cl.[Fe].CCO>[NH2:23][C:18]1[CH:17]=[C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: COc1cc2ncnc(Oc3ccc(O)c([N+](=O)[O-])c3)c2cc1OC
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(O)c(N)c3)c2cc1OC

Procedure:
4-(6,7-Dimethoxyquinazolin-4-yloxy)-2-nitrophenol (Step c, 350 mg, 1.02 mmol) was combined with Fe (1.17 g), 6N HCl (2 drops), water (2.1 mL) and EtOH (9 mL) and heated at reflux for 2.5 h. The hot mixture was filtered through Celite and evaporated. The residue was purified by column chromatography using 0-30% of a 90:10:1 (CH2Cl2:MeOH:NH4OH) solution in CH2Cl2 as the eluent. MS(MH+)=NA; Calc'd 313.31 for C16H15N3O4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].Br[CH2:13][CH2:14][CH2:15][Cl:16]>CO>[Cl:16][CH2:15][CH2:14][CH2:13][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: ClCCCBr
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [Na]
Solvent: CO
Product: O=[N+]([O-])c1ccc(SCCCCl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
4-Nitrothiophenol (80%, 25.0 g, 129 mmol) was added to a solution formed by adding sodium (5.55 g, 242 mmol) to methanol (500 mL) maintained at 0° C. After 0.5 h the reaction was warmed to ambient temperature and 1-bromo-3-chloropropane (50.7 g, 322 mmol) was added in one portion. The reaction mixture was stirred overnight and filtered. The filtrate was reduced to half volume and the solid which formed was collected by filtration. Recrystallization from methanol afforded 15.4 g (52%) of yellow solid, mp 50°-52° C.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[C:7]([O:10][C:11]([F:14])([F:13])[F:12])[CH:6]=[C:5](Br)[C:3]=1[NH2:4].O.O.[Sn](Cl)Cl.C(O)(=O)C.Cl>C(OCC)(=O)C>[Br:1][C:2]1[C:8]([F:9])=[C:7]([O:10][C:11]([F:13])([F:12])[F:14])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1c(Br)cc(OC(F)(F)F)c(F)c1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(OC(F)(F)F)c(F)c1Br
Temperature: 115 °C

Procedure:
In a 40 mL vial was added 2,6-dibromo-3-fluoro-4-trifluoromethoxyaniline (172 mg, 0.489 mmol), followed by tin(II) chloride dihydrate (122 mg, 0.540 mmol, 1.1 eq.). Acetic acid (725 μL) and concentrated hydrochloric acid (580 μL) was added to make a solution. The reaction mixture was heated at 115° C. for 1.5 hours. After cooling the reaction to room temperature, most of acetic acid was removed under vacuum. Water was added and the product was extracted with dichloromethane three times. The organic layer was dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude material was purified using silica gel column chromatography. The recovered 2,6-dibromo-3-fluoro-4-trifluoromethoxyaniline was eluted using a gradient of 5˜10% ethyl acetate in hexanes followed by the desired product, 2-bromo-3-fluoro-4-trifluoromethoxyaniline, which was eluted with 15% ethyl acetate in hexanes (64.8 mg, 0.236 mmol, 48%). 1H NMR (400 MHz, CDCl3) δ 7.06 (dd, J=9.0, 9.0 Hz, 1H), 6.52 (dd, J=9.0, 2.0 Hz, 1H), 4.27 (br, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10](=[CH2:27])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.O>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10](=[CH2:27])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: C=C(COc1ccc(C(=O)CCC(=O)OC)cc1)COc1ccc(C(C)=O)c(O)c1CCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(COc1ccc(C(=O)CCC(=O)O)cc1)COc1ccc(C(C)=O)c(O)c1CCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of the compound from Step B (550 mg, 1.21 mmole) in THF (15 ml) was added 3 ml of 1N NaOH. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with H2O (50 ml) and acidified with concentrated HCl to pH=5. A white solid formed which was extracted with methylene chloride (2×). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound as a white solid, m.p. 136°-137°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30](I)=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34](#[N:37])[CH:35]=[CH2:36]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30](/[CH:36]=[CH:35]/[C:34]#[N:37])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: C=CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(/C=C/C#N)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 48 %

Procedure:
Using methods substantially equivalent to those described in Example 259-A, 2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide was condensed with acrylonitrile. From the reaction mixture was isolated (E)-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)benzamide (0.49 g, 48%), as well as the (Z)-isomer (see next example).
Reaction SMILES: [NH2:1][C:2]([CH2:14][CH3:15])([C:10]([O:12]C)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].O.CO>O1CCCC1>[NH2:1][C:2]([CH2:14][CH3:15])([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCC(N)(Cc1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCC(N)(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
To a stirring solution of D,L-Phe(αEt)-OMe (24 g, 116 mmol) in tetrahydrofuran (200 mL) was added 5N NaOH (24 mL, 120 mmol), followed by water (50 mL) and methanol (50 mL) and the solution was heated to reflux. After 16 h, the solution was cooled to room temperature and the solvents were removed in vacuo. The residue was dissolved in water and washed three times with diethyl ether. The pH was adjusted to 6 with 5N HCl and the solution was concentrated to a volume of about 50 mL in vacuo. The precipitate was filtered, washed with water and dried to give 17.5 g (78% yield) of white solid.
Reaction SMILES: [C:1]([C:9](=[CH:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24])[C:10](OCC)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:11][C:10]1[C:22]2[C:17](=[C:18]([C:23]([F:24])([F:26])[F:25])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:9]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CCOC(=O)C(=CNc1ccccc1C(F)(F)F)C(=O)c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1O
Yield: 63.8 %

Procedure:
A solution of ethyl 2-benzoyl-3-[2-(trifluoromethyl)phenylamino]acrylate (30.5 g, 84.0 mmol) in Dowtherm® (280 mL) was stirred at 260° C. for 11 hours. The reaction solution was returned to room temperature, then added with hexane and recrystallized. The title compound (17.0 g, yield 64%) was obtained as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.FC1C=C(C(F)(F)F)C=CC=1C=CC(C(C)C)C(O)=O.[CH2:37]([C:44]1[N:49]=[C:48]([CH2:50]O)[CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH2:50][C:48]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:49]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: OCc1cccc(Cc2ccccc2)n1
Reactant: CC(C)C(C=Cc1ccc(F)cc1)C(=O)O
Agent: CC(C)C(C=Cc1ccc(C(F)(F)F)cc1F)C(=O)O
Product: CC(C)C(C=Cc1ccc(F)cc1)C(=O)OCc1cccc(Cc2ccccc2)n1

Procedure:
Following the procedure of Example 1, the acid chloride of each of 4-(4-fluorophenyl)-2-isopropyl-3-butenoic acid, 4-(2-chloro-4-trfluoromethylphenyl)-2-isopropyl-3-butenoic acid and 4-(2-fluoro-4-trifluoromethylphenyl)-2-isopropyl-3-butenoic acid is reacted with (6-benzyl-2-pyridyl)methanol to give (6-benzyl-2-pyridyl)methyl 4-(4-fluorophenyl)-2-isopropyl-3-butenoate,
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: CN1CCCC1CCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCCC1CCOS(C)(=O)=O

Procedure:
The 1-methyl-2-pyrrolidineethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cnn(C)c3)ccc1-2

Procedure:
Following Example 267, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxyethyl)-isopropylamide and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted to give 268. MS: (ESI+)=413.1