Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].C(O)C.[Br:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[NH:17][C:18](=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-])=O>O.[Fe]>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[CH:8][C:7]([Br:6])=[CH:16]2)=[O:28]
Reactant: O=C(Nc1cccc2cc(Br)cnc12)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1C(=O)Nc1cccc2cc(Br)cnc12
Temperature: 50 °C
Yield: 86.6 %

Procedure:
To a solution of ammonium chloride (50.9 mg) in water (2 ml) was added ethanol (10 ml), and the mixture was stirred at 50° C. To the mixture were added 3-bromo-8-(2-nitrobenzoylamino)quinoline (590 mg) and iron (531 mg), and the mixture was refluxed for 1 hour. After filtration, the filtrate was concentrated in vacuo, and the residue was suspended in hot 80% ethanol and allowed to cool to ambient temperature. The resulting precipitates were collected by filtration to give 8-(2-aminobenzoylamino)-3-bromoquinoline (470 mg) as pale tan solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]([O-:10])=O)[C:4]([O:6]C)=[O:5].[NH3:11]>C(Cl)Cl>[CH3:1][O:2][CH:3]([C:8]([NH2:11])=[O:10])[C:4]([OH:6])=[O:5]
Reactant: N
Reactant: COC(=O)C(OC)C(=O)[O-]
Solvent: ClCCl
Product: COC(C(N)=O)C(=O)O

Procedure:
A solution of 10.4 g of monomethyl methoxymalonate in 70 ml of methylene chloride was added dropwise at -10° C. to 26 ml of 25 percent aqueous ammonia. After stirring the mixture was evaporated and the residue was dissolved in water and chromato- graphed on a cation exchanger with water. The eluate was concentrated and the residue was triturated with diethyl ether and filtered off. The precipitate was washed with water and dried. There were obtained 8.9 g of methoxymalonamic acid, m.p. 128°-130° C.
Reaction SMILES: C(C1C=CC(NC2C(F)=CN=C(NC3C=CC4OC(C(O)=O)CC=4C=3)N=2)=CC=1)(C)(C)C.C([O:34][C:35]([C:37]1[NH:38][C:39]2[C:44]([CH:45]=1)=[CH:43][C:42]([NH:46][C:47]1[N:52]=[C:51]([NH:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([OH:60])[CH:55]=3)[C:50]([F:61])=[CH:49][N:48]=1)=[CH:41][CH:40]=2)=[O:36])C.[Li+].[OH-]>>[C:35]([C:37]1[NH:38][C:39]2[C:44]([CH:45]=1)=[CH:43][C:42]([NH:46][C:47]1[N:52]=[C:51]([NH:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([OH:60])[CH:55]=3)[C:50]([F:61])=[CH:49][N:48]=1)=[CH:41][CH:40]=2)([OH:36])=[O:34]
Reactant: CCOC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2[nH]1
Agent: CC(C)(C)c1ccc(Nc2nc(Nc3ccc4c(c3)CC(C(=O)O)O4)ncc2F)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2[nH]1

Procedure:
In a manner similar to the preparation of N4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine, N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine upon LiOH treatment gave N2-(2-carboxyindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.83 (m, 1H), 7.73 (s, 1H), 7.50 (bd, 1H, J=8.7 Hz), 7.30-7.11 (m, 5H), 6.68 (bd, 1H); LCMS: ret. time: 16.50 min.; purity: 97%; MS (m/e): 380 (MH+).
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:37][CH:36]=2)[C:31]([F:45])=[CH:30][N:29]=1.[NH2:46][C:47]1[CH:48]=[CH:49][C:50]2[O:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52][C:51]=2[CH:59]=1>>[F:45][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:37][CH:36]=2)=[N:33][C:28]([NH:46][C:47]2[CH:48]=[CH:49][C:50]3[O:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52][C:51]=3[CH:59]=2)=[N:29][CH:30]=1
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Reactant: CC(C)Oc1ccc(Nc2nc(Cl)ncc2F)cc1
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC(C)C)cc4)n3)ccc2O1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to yield 5-fluoro-N2-(2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.87 (d, 1H, J=3.0 Hz), 7.47-7.42 (m, 3H), 7.12 (dd, 1H, J=2.4 and 8.4 Hz), 6.87 (d, 2H, J=9.6 Hz), 6.80 (d, 1H, J=8.7 Hz), 6.63 (d, 1H, J=2.4 Hz), 5.21 (dd, 1H, J=6.3 and 10.5 Hz), 4.53 (2q, 1H, J=5.7 Hz), 3.80 (s, 3H), 3.52 (dd, 1H, J=10.5 and 15.9 Hz), 3.35 (dd, 1H, J=6.3 and 15.9 Hz), 1.34 (d, 6H, J=5.7 Hz); 19F NMR (CDCl3): −47664; LCMS: ret. time: 23.78 min.; purity: 95%; MS (m/e): 439 (MH+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:4][CH2:3]1.[CH:28]1[C:33]([C@H:34]([OH:37])[CH2:35][NH2:36])=[CH:32][C:31]([OH:38])=[C:30]([OH:39])[CH:29]=1>>[OH:38][C:31]1[CH:32]=[C:33]([C@@H:34]([OH:37])[CH2:35][NH:36][CH:2]2[CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH2:6][CH2:7]2)[CH:28]=[CH:29][C:30]=1[OH:39]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2N2CCC(=O)CC2)cc1
Reactant: NC[C@@H](O)c1ccc(O)c(O)c1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2N2CCC(NC[C@H](O)c3ccc(O)c(O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-{(4-[2-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 222) and L-norepinephrine according to the procedure of Example 255 as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.30–1.52 (m, 2 H), 1.70–1.90 (m, 2 H), 1.89 (s, 3 H), 2.50–3.50 (m, 7 H), 4.40–4.55 (m, 1 H), 6.00 (brs, 1 H) 6.50–6.80 (m, 3 H), 6.95–7.15 (m, 2 H), 7.25–7.40 (m, 2 H), 7.60–7.75 (m, 4 H), 10.30 (s, 1 H); MS (ES) m/z: 541.4 (MH+); HRMS Calcd. for C27H33N4O6S (MH+): 541.2121. Found: 541.2110.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][CH:33]1[CH2:38][O:37][CH2:36][CH2:35][NH:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH:33]3[CH3:32])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CC1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@@H](CN1CCOCC1C)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (960 mg, 2.076 mmol; Example 210, Step A) in 1,2-dichloroethane (15 mL) was added 3-methylmorpholine (Enamine Ltd, Kiev, Ukraine) (0.471 mL, 4.15 mmol) and sodium triacetoxyborohydride (880 mg, 4.15 mmol).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)CCc2ccccc2)sc1C(=O)NCc1ccccc1
Yield: 25 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-phenylpropionyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 25% yield; m.p. 63-65° C.; 1H NMR (CDCl3, 300 MHz) δ 7.34-7.14 (m, 10H), 5.97 (t, J=4.9 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 3.06-2.93 (m, 2H), 2.79-2.64 (m, 2H), 2.54 (s, 3H); MS (ES+) m/z 380.2 (M+1).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.CC(C)=[O:19].O>[B-](F)(F)(F)F.[Ag+].CO>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[C:5](=[O:7])[CH2:6][CH:2]([OH:19])[CH:3]=1)([OH:16])=[O:15]
Reactant: CC(C)=O
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 1.5 h

Procedure:
To a stirred solution of 10.6 g. (ca. 34 moles) of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1 -one (Example 93) in 100 ml. of acetone and 65 ml. of water is added 8.80 g. (45.2 mmoles) of silver fluoborate during 2 minutes. The temperature is maintained at 25°-30° C. by external cooling. The mixture is stirred for 90 minutes, filtered, saturated with sodium chloride, and extracted with ether. The extract is extracted with half saturated sodium bicarbonate solutions. The basic solutions is reacidified with dilute hydrochloric acid, saturated with sodium chloride, and extracted with ether. The extract is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by partition chromatography on Celite to give an oil; λmax.MeOH =233 mμ. (7360); νmax.=3380 (hydroxyl groups), 1710 (carbonyl groups), and 1632 cm-1 (olefin group).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:36])([CH3:35])[CH:32](O)[C:31]=4[C:38]=3[CH3:39])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:35])([CH3:36])[CH:32]([N:10]5[CH2:9][CH2:8][CH:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[CH2:12][CH2:11]5)[C:31]=4[C:38]=3[CH3:39])[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(N3CCC(c5ccccc5)CC3)C(C)(C)O4)CC2)cc1
Yield: 45 %

Procedure:
Using 4-phenylpiperidine and 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 18, the title compound was synthesized in the same manner as in Example 57. Yield 45%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>>[CH3:15][S:16]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ccc(CCOCCO)cc1
Product: CSc1ccc(CCOCCOS(C)(=O)=O)cc1
Yield: 90 %

Procedure:
The 2-[2-(4-methylthiophenyl)ethoxy]ethanol obtained according to the preceding paragraph was sulfonylated with methanesulfonyl chloride in a manner analogous to that described in Example 1(c) to give 2.41 g (90%) of 2-[2-(4-methylthiophenyl)ethoxy]ethyl methanesulfonate in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[CH:16]=[C:15]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:14]([CH3:23])=[CH:13][C:11]=1[NH2:12]>C1(C)C=CC=CC=1>[CH3:5][N:4]([CH3:6])[CH:3]=[N:12][C:11]1[CH:13]=[C:14]([CH3:23])[C:15]([C:17]#[C:18][Si:19]([CH3:21])([CH3:20])[CH3:22])=[CH:16][C:10]=1[CH3:9]
Reactant: Cc1cc(C#C[Si](C)(C)C)c(C)cc1N
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(N=CN(C)C)c(C)cc1C#C[Si](C)(C)C
Temperature: 110 °C
Reaction time: 9 h
Yield: 41 %

Procedure:
N,N-dimethylformamide dimethyl acetal (5.97 g) and 10 ml of toluene were added to 1.09 g of the 2,5-dimethyl-4-(2-trimethylsilyl-1-ethynyl)aniline (Compound 4-27) produced in Production Example 3, and the mixture was stirred at 110° C. for 9 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), thereby obtaining 0.56 g of N,N-dimethyl-N′-[2,5-dimethyl-4-(2-trimethylsilyl-1-ethynyl)phenyl]formamidine (Compound 59).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:22](Cl)[CH:23]=[CH2:24].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH2:24]([N:13]1[N:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:14]1=[O:21])[CH:23]=[CH2:22]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: C=CCCl
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: C=CCN1N=C(c2ccc(OC)c(OC)c2)[C@@H]2CCCC[C@@H]2C1=O

Procedure:
Prepared from compound 1 and allylchloride as described for compound 8. Purified by chromatography (dichloromethane). Crystallized from petroleum ether (60-95° C.). M.p. 99-101° C.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([C@@H:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](O)=[O:9])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:56][C:57]1[S:58][CH:59]=[CH:60][N:61]=1>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][C:4]([C@@H:7]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:8]([NH:56][C:57]2[S:58][CH:59]=[CH:60][N:61]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: Nc1nccs1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)[C@H](CC1CCCC1)c1ccc(-c2ccccc2)cc1
Yield: 60.1 %

Procedure:
A solution of 2(R)-biphenyl-4-yl-3-cyclopentylpropionic acid (36.9 mg, 0.13 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (52.3 mg, 0.14 mmol), N,N-diisopropylethylamine (66 μL, 0.38 mmol), and 2-aminothiazole (25.1 mg, 0.25 mmol) in dry N,N-dimethylformamide (627 μL) was stirred at 25° C. under nitrogen for 13 h. The reaction mixture was concentrated in vacuo to remove the N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (100 mL). The organic layer was washed with a 10% aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded (2R)-2-biphenyl-4-yl-3-cyclopentyl-N-thiazol-2-yl-propionamide (29.4 mg, 62%) as a white foam: mp 132-134° C.; FAB-HRMS m/e calcd for C23H24N2OS (M+H)+ 377.1687, found 377.1696.
Reaction SMILES: C([O-])(O)=O.[Na+].[C:6](=[S:9])([NH2:8])[CH3:7].Cl[CH2:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([NH:23][C:24](=[O:40])[C:25]3[C:30]([F:31])=[CH:29][CH:28]=[C:27]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])[C:26]=3[F:39])[CH:21]=2)[NH:16][CH:15]=1)=O.CO>C1COCC1>[F:39][C:26]1[C:27]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:34])=[O:35])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:20]1[CH:21]=[C:22]2[C:14]([C:12]3[N:8]=[C:6]([CH3:7])[S:9][CH:11]=3)=[CH:15][NH:16][C:17]2=[N:18][CH:19]=1)=[O:40]
Reactant: CC(N)=S
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(-c4csc(C)n4)c3c2)c1F
Temperature: 70 °C
Reaction time: 9 h
Yield: 18.5 %

Procedure:
NaHCO3 (0.00098 g, 0.012 mmol) and ethanethioamide (0.00096 g, 0.013 mmol) were added to N-(3-(2-chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.005 g, 0.011 mmol) in THF (0.1 mL), and the reaction mixture was warmed to 70° C. for 4 hours. MeOH (0.2 mL) was added, along with another equivalent of ethanethioamide (0.00096 g, 0.013 mmol) and NaHCO3 (0.00098 g, 0.012 mmol). After 9 hours at 70° C., the reaction mixture was cooled and partitioned between EtOAc and aqueous sodium bicarbonate. The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified via column chromatography (10% MeOH-DCM) to provide 2,6-difluoro-N-(3-(2-methylthiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (1 mg, 19%). 1H NMR (400 MHz, CHCl3-d1) δ 8.84-8.85 (m, 1H), 7.86 (s, 1H), 7.60-7.66 (m, 1H), 7.32 (s, 1H), 7.02-7.06 (m, 1H), 3.06-3.12 (m, 2H), 2.80 (s, 3H), 1.85-1.93 (m, 2H), 1.04-1.08 (m, 3H); m/z (APCI-pos) M+1=492.1.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][F:30])=[CH:22][CH:21]=1)[C:12]([O:14]C(C)(C)C)=[O:13])=O)(C)(C)C.COC1C=CC=CC=1>FC(F)(F)C(O)=O>[F:30][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C@@H:9]([C:31]([OH:33])=[O:32])[NH2:8])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](C[C@H](Cc1ccc(OCCCF)cc1)C(=O)O)C(=O)O

Procedure:
60 mg (0.11 mmol) of di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-[4-(3-fluoropropoxy)-benzyl]-L-glutamate were taken up in 2 mL of trifluoro acetic acid and 1 mL of methoxybenzene and stirred overnight at room temperature. The excess of trifluoro acetic acid was evaporated and the residue was taken up three times in tetrahydrofuran and then evaporated. The resulting oil was chromatographed on C-18 reversed phase silica gel using a water/acetonitrile gradient, the appropriate fractions were combined and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:13]4[C:18]([C:10]=3[CH2:9][C:8](=[O:30])[NH:7][C:6]=2[CH:31]=1)=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=4.Cl[CH2:33][C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[C:13]4[C:18]([C:10]=3[CH2:9][C:8](=[O:30])[N:7]([CH2:33][C:34](=[O:35])[N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:6]=2[CH:31]=1)=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=4
Reactant: CCOC(=O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2NC(=O)C1
Reactant: O=C(CCl)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2N(CC(=O)N2CCCCC2)C(=O)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a suspension of ethyl 3-chloro-12-cyclohexyl-6-oxo-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (772 mg, 1.77 mmol) in N,N-dimethylformamide (7.7 ml) were added a solution of 1-(2-chloroacetyl)piperidine (343 mg, 2.12 mmol) in N,N-dimethylformamide (2 ml) and potassium carbonate (488 mg, 3.53 mmol), and the mixture was stirred at 90° C. for 1 hr. Furthermore, a solution of 1-(2-chloroacetyl)piperidine (171 mg, 1.06 mmol) in N,N-dimethylformamide (1 ml) and potassium carbonate (244 mg, 1.77 mmol) were added, and the mixture was stirred at 90° C. for 1.5 hr. The mixture was allowed to cool to room temperature, water (10 ml) was added, and the precipitated solid was collected by filtration. The obtained solid was washed with water (10 ml) and dried in vacuo to give ethyl 3-chloro-12-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (911 mg, yield 92%).
Reaction SMILES: C(O)(=[O:3])C.[C:5](#[N:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.[Zn]>[C:5]([NH2:12])(=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccccc1
Agent: [Zn]
Solvent: O
Product: NC(=O)c1ccccc1
Yield: 24 %

Procedure:
Watanabe, in Bull. Chem. Soc. Japan, 37, 1325 (1964), teaches the conversion of benzonitrile to benzamide with precipitated copper and Urushibara copper (U-Cu). The precipitated copper was prepared from a cupric chloride solution and zinc dust and was reacted with benzonitrile in water for 8 hours to give a 7% yield of benzamide. U-Cu-A was prepared by mixing zinc dust with a solution of cupric chloride and then leaching the resultant product with 13% acetic acid. The reaction of benzonitrile in water with U-Cu-A for 8 hours gave a 24% yield of benzamide with no recovery of benzonitrile.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1Br
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of phenylboronic acid (5.12 g, 42 mmol), 2-bromophenol (3.55 g, 21 mmol), Cu(OAc)2 (7.63 g, 42 mmol), pyridine (8 ml, 103 mmol) and 4 Å molecular sieves (2.1 g) in CH2Cl2 was stirred at r.t. overnight. The mixture was diluted with CH2Cl2, filtered through celite, washed with 1M NaOH, brine and dried. Removal of solvent gave 1-bromo-2-phenoxybenzene, crystals (1.40 g, 27%). LRMS (ESI+): 248 (M+1). 1-Bromo-2-phenoxybenzene was coupled to piperazine using the Buchwald chemistry described in preparation 1A to afford the title compound. LRMS (ESI+) 255 (M+1)
Reaction SMILES: [CH2:1]([C:3]([CH3:5])=O)[CH3:2].[CH3:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[CH3:14])[NH2:10]>C1C=CC=CC=1>[CH:3]([NH:10][C:9]1[CH:11]=[CH:12][C:13]([CH3:14])=[C:7]([CH3:6])[CH:8]=1)([CH2:1][CH3:2])[CH3:5]
Reactant: Cc1ccc(N)cc1C
Reactant: CCC(C)=O
Solvent: c1ccccc1
Product: CCC(C)Nc1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Molecular sieves (Type 5A, 300 gm.) are added to 79.2 g. (1.0 mole) of methyl ethyl ketone and 121.0 g. (1.0 mole) of 3,4-dimethylaniline in 1 liter of dry benzene solvent. The reaction mixture is stirred at room temperature for 16 hours. The mixture is then filtered from the molecular sieves which are washed with dry benzene. The benzene solutions are combined and evaporated in vacuo leaving 198 g. (100%) of the desired product. The product is sensitive to hydrolysis and is therefore reduced immediately in a Parr hydrogenator using a 5% palladium on carbon catalyst to give N-sec-butyl-3,4-xylidine.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@:19]2([CH3:20])[C:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])=[CH:5][C:4](=[O:22])[CH2:3]1.[CH2:23](OC([O-])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CNC1C=CC=CC=1.C=O>>[CH3:1][C@@H:2]1[C@@:19]2([CH3:20])[C:6]([C:7](=[CH2:23])[CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])=[CH:5][C:4](=[O:22])[CH2:3]1
Reactant: C[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Reactant: CCOC([O-])OCC
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CNc1ccccc1
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@]2(C)C1=CC(=O)C[C@@H]2C
Yield: 75 %

Procedure:
With a procedure similar to the one described in Example 1, 3 g of 1α-methylandrost-4-ene-3,17-dione, 3 ml of diethylorthoformate, 80 mg of p-toluenesulphonic acid, 1.1 ml of N-methylaniline and 1,2 ml of a 40% formic aldehyde aqueous solution give 2.34 g (75% yield) of the title compound.