Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:12]([NH:14][CH3:15])=O)[CH:3]=[N:2]1.C(O)(C(F)(F)F)=O.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:12][NH:14][CH3:15])[CH:3]=[N:2]1
Reactant: CNC(=O)CC(c1ccccc1)c1cccc2cn[nH]c12
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Product: CNCCC(c1ccccc1)c1cccc2cn[nH]c12

Procedure:
[3-(1H-Indazol-7-yl)-3-phenyl-propyl]-methyl-amine CCLX was prepared from 3-(1H-indazol-7-yl)-N-methyl-3-phenyl-propionamide and TFA using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(#N)C.CO>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Yield: 100 %

Procedure:
A mixture of tert-butyl N′-(3-nitroquinolin-4-yl)hydrazinecarboxylate (5.00 g, 16.4 mmol) and 5% platinum on carbon (0.50 g) in acetonitrile (90 mL) and methanol (30 mL) was shaken under hydrogen pressure on a Parr apparatus. When the reaction was complete, the mixture was filtered through a layer of CELITE filter agent. The filter cake was rinsed with 3:1 acetonitrile:methanol. The filtrate was concentrated under reduced pressure to yield 4.50 g of crude tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:16][C:11]=2[C:12]([O:14]C)=O)=[CH:4][CH:3]=1.[OH-].[Li+].Cl.C(N(C(C)C)CC)(C)C.[NH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>O1CCCC1.CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:16][C:11]=2[C:12]([NH:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(CCCN2CCOCC2)ccc1OCc1ccc(F)cc1
Reactant: Nc1cccnc1
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Li+]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cc(CCCN2CCOCC2)ccc1OCc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-[3-(4-morpholinyl)propyl]benzoate (may be prepared as described in Description 124; 166 mg, 0.43 mmol) in tetrahydrofuran (6 ml) was added lithium hydroxide (61.6 mg, 2.57 mmol) and water (1.5 ml). The mixture was stirred at 50° C. for 3 hours, cooled and the acidified with 2M hydrochloric acid (1.29 ml, 2.57 mmol). The solvent was removed in vacuo to give a residue. The residue was redissolved in N,N-dimethylformamide (3 ml) and diisopropylethylamine (0.15 ml, 0.86 mmol), 3-aminopyridine (52.4 mg, 0.56 mmol), 1-hydroxy-7-azabenzotriazole (70.0 mg, 0.51 mmol) and EDC (140 mg, 0.73 mmol). The solution was stirred overnight, the solvent removed in vacuo and the residue was purified by MDAP to yield the title compound as a white solid. 25 mg.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[NH:23][C:22]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:21]=4[N:20]=3)[CH2:14][C:13]2=[O:29])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH2:30]([N:32](CC)CC)C.C(O)(=O)C.N1C=CC=NN=1>C(O)C>[NH2:6][C:5]1[C:4]2[C:3](=[CH:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][C:19]4[NH:23][C:22]5[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:21]=5[N:20]=4)[CH2:14][C:13]3=[O:29])=[CH:8][CH:7]=2)[N:2]=[CH:30][N:32]=1
Reactant: N#Cc1ccc(CN2CCC(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1N
Reactant: CCN(CC)CC
Agent: Cl
Agent: c1cnnnc1
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ncnc2cc(CN3CCC(Cc4nc5ccc(Cl)cc5[nH]4)CC3=O)ccc12
Yield: 84.9 %

Procedure:
To a solution of 2-Amino-4-[4-(6-chloro-1H-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-1-ylmethyl]-benzonitrile hydrochloric acid salt (143 mg, 0.308 mmol), EXAMPLE 814, Part E, in 2 mL of ethanol is added triethylamine (0.05 mL, 0.366 mmol), glacial acetic acid (0.02 mL, 0.366 mmol) and triazine (15 mg, 0.183 mmol). The resulting mixture is refluxed overnight. The volatile solvents are removed on the rotovap, and the residue is purified by reverse phase HPLC (0-50% Acetonitrile/H2O). The desired product (110 mg, 55% yield) is isolated as a white powder with a melting point of 128-132 ° C. C22H21ClN6O MS m/z: 421, 423. Anal. calcd. for C22H21ClN6O: C, 48.12; H,3.57; N, 12.95. Found: C, 45.79; H, 3.68; N, 11.94. H NMR (CD3OD) δ: 8.67 (s, 1H); 8.31 (d, 1H, J=4.0 Hz); 7.83-7.55 (m, 5H); 4.93-4.73 (m, 2H); 3.48-3.42 (m, 2H); 3.31-3.21 (m, 2H); 2.71-2.58 (m, 2H); 2.43-2.33 (m, 1H); 2.07-2.01 (m, 1H); 1.82-1.69 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:41])[C@H:21]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](Br)=[CH:36][CH:35]=1)[NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31]>>[CH3:18][O:19][C:20](=[O:41])[C@H:21]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:38][CH:39]=1)[NH:22][C:23](=[O:32])[C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2NC(=O)OC(C)(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 73.5 %

Procedure:
2-(tert-Butoxycarbonylamino)benzeneboronic acid (0.3 g) was coupled with N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine methyl ester (270 mg) by a similar procedure as described in Examples 15 to give 250 mg of N-(2,6-dichlorobenzoyl)-4-[2-(tert-butoxycarbonylamino)phenyl]-L-phenylalanine methyl ester. ESMS: m/z 543 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].C(=O)([O-])OC.[Cl:23][C:24]1[C:30]([OH:31])=[CH:29][C:27]([NH2:28])=[C:26]([F:32])[CH:25]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[NH4+]>CO.CC(C)=O.O>[Cl:23][C:24]1[C:30]([OH:31])=[CH:29][C:27]([NH:28][C:2]2[C:11]3[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=3[O:12][CH3:13])[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:26]([F:32])[CH:25]=1
Reactant: COc1ccc(OC)c2c(Cl)c(C#N)cnc12
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: CCOC(C)O
Agent: COC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc(OC)c2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc12
Temperature: 50 °C

Procedure:
A mixture of 0.223 g of 4-chloro-5,8-dimethoxy-3-quinolinecarbonitrile, 0.22 g of the methyl carbonate of 4-chloro-2-fluoro-5-hydroxy-aniline, and 15 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried. The solids thus obtained were dissolved in a mixture of 30 ml of methyl alcohol and 20 ml of acetone. To this mixture was added 1.5 ml of 28-30% ammonium hydroxide solution. The mixture was heated at 50° C. for 30 minutes and concentrated. The product was collected, washed with ethyl acetate, and dried to give 0.237 g of 4-(4-chloro-2-fluoro-5-hydroxy-phenylamino)-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 240° C. (decomposed); mass spectrum (electrospray, m/e): M+H 373.9.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[C:44]([CH3:53])=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>C(#N)C>[CH3:53][C:44]1[C:43]([Cl:42])=[CH:48][CH:47]=[CH:46][C:45]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(Cl)cccc1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 49.9 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-chloro-2-methylbenzenesulfonyl chloride (0.0440 g, 0.195 mmol) to obtain 4-(2-methyl-3-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0211 g, yield 50%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24](B(O)O)=[CH:23][N:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[N:22][C:21]([O:20][CH3:19])=[N:26][CH:25]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ncc(B(O)O)cn1
Product: CCCNC(=O)c1nnc2c(-c3cnc(OC)nc3)cccc2c1N
Yield: 76.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.324 mmol) and (2-methoxypyrimidin-5-yl)boronic acid (104 mg, 0.68 mmol) were reacted to afford the title compound (84 mg, 77% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.1-9.3 (m, 1.5H), 8.96 (s, 2H), 8.47 (dd, J=8.4, 1.0 Hz, 1H), 8.1-8.4 (bm, 0.5H), 7.99 (dd, J=7.2, 1.0 Hz, 1H), 7.83 (dd, J=8.4, 7.2 Hz, 1H), 4.01 (s, 3H), 3.32 (apparent q, J=7.4 Hz, 2H), 1.60 (apparent sextet, J=7.2 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H). MS APCI, m/z=339 (M+H) HPLC 1.75 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([NH2:12])=[CH:7]2.CN(C=O)C.[H-].[Na+].Br[CH2:21][CH2:22][O:23][CH3:24]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([NH:12][CH2:21][CH2:22][O:23][CH3:24])=[CH:7]2
Reactant: Nc1cnc2c(Cl)ccnc2c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COCCNc1cnc2c(Cl)ccnc2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 33.1 %

Procedure:
A round bottom flask under nitrogen atmosphere was charged with 8-chloro-1,5-naphthyridin-3-amine (160 mg, 0.89 mmol), DMF (2.2 mL, 0.89 mmol). This was cooled to 0° C. and SODIUM HYDRIDE (60% dispersion in oil) (107 mg, 4.45 mmol) added portionwise. This was quickly followed by addition of 1-bromo-2-methoxyethane (0.12 mL, 1.25 mmol) dropwise via syringe. Ice bath removed and reaction mixture heated to 85° C. and stirred at this temperature for 16 hours. Reaction diluted with 5 mL of 5% MeOH/Dichloromethane, loaded onto silica gel column and eluted with 2% MeOH/DCM to afford 8-chloro-N-(2-methoxyethyl)-1,5-naphthyridin-3-amine (70 mg, 33% yield) as a light yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][NH:27]2)=[CH:23][N:22]=1>>[C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][C:21]3[N:29]=[C:28]4[C:24]([N:25]=[CH:26][NH:27]4)=[CH:23][N:22]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ncc2nc[nH]c2n1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Product: O=S(=O)(CCc1ccccc1)N1CCC(CNc2ncc3nc[nH]c3n2)CC1

Procedure:
EXAMPLE 82 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-chloro-9H-purine (2-chloro-9H-purine was prepared according to S. R. Brashears, S. S. Wang, S. G. Bechtolt, B. E. Christensen, J. Am. Chem. Soc., 81:3789–3792(1959)): MS (m+1)=401.
Reaction SMILES: C(OC(N1CCN(C2C(=O)N(CC(C)C)N=C(C3C=CC(F)=C(F)C=3)C=2C)CC1)=O)(C)(C)C.[C:34]([C:37]1[C:38](=[O:55])[N:39]([CH2:51][CH:52]([CH3:54])[CH3:53])[N:40]=[C:41]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[F:50])[CH:42]=1)(O)=[O:35]>>[F:50][C:44]1[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=1[C:41]1[CH:42]=[C:37]([CH2:34][OH:35])[C:38](=[O:55])[N:39]([CH2:51][CH:52]([CH3:53])[CH3:54])[N:40]=1
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(C(=O)O)c1=O
Agent: Cc1c(-c2ccc(F)c(F)c2)nn(CC(C)C)c(=O)c1N1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Yield: 45 %

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one was reacted to yield the title compound as a pale yellow oil (yield: 45.0%).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([CH2:31][N:32]([CH3:34])[CH3:33])[CH2:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[ClH:1].[ClH:1].[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([CH2:31][N:32]([CH3:34])[CH3:33])[CH2:17][CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH2:11][CH2:10]1
Reactant: CN(C)CC(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)CC(CC1CCNCC1)CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 4N hydrogen chloride in ethyl acetate (1 ml; 4 mmol) was added to a solution in ethyl acetate (0.5 ml) of 1,3-bis(1-tert-butoxycarbonyl-4-piperidinyl)-2-[(dimethylamino)methyl]propane (67 mg; 0.14 mmol) synthesized by the process described in Referential Example 5, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain crude crystals of 1,3-bis(4-piperidinyl)-2-[(dimethylamino)methyl]propane trihydrochoride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[SH:18].[O-]CC.[Na+].[CH2:23]1O[CH:24]1[CH3:25]>C(O)C>[CH3:23][CH:24]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:4][C:3]=2[S:18][CH2:25]1
Reactant: CC1CO1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1CSc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N1

Procedure:
To a solution of 4-amino-3-mercapto[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-benzene in ethanol containing a trace of sodium ethoxide can be added propylene oxide to the cold solution. An exothermic reaction occurs. When reaction subsides, the solution is heated on the steam bath. The product can be isolated and distilled to give 3,4-dihydro-3-methyl-7-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-2H-1,4-benzothiazine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([CH2:29][CH:30]4[CH2:34][CH2:33][N:32]([CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[C:31]4=[O:41])=[C:24]([Cl:42])[CH:23]=3)=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:35]1([N:32]2[CH2:33][CH2:34][CH:30]([CH2:29][C:25]3[C:24]([Cl:42])=[CH:23][C:22]([C:19]4[CH:18]=[CH:17][C:16]([C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[O:15])=[CH:21][CH:20]=4)=[CH:27][C:26]=3[Cl:28])[C:31]2=[O:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCNCC1
Temperature: 0 °C
Yield: 93.1 %

Procedure:
Dissolve racemic 4-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.843 g, 1.37 mmol) in dichloromethane (25 mL) and cool in ice bath to 0° C. while stirring under an inert atmosphere. Add triethylsilane (0.5 mL) and trifluoroacetic acid (5.0 mL) to the mixture and allow the temperature to rise to room temperature. Monitor the reaction via TLC. Once starting material is consumed, dilute the reaction with dichloromethane and quench with saturated sodium bicarbonate. Collect the organic phase and the extract aqueous phase with dichloromethane (2×50 mL). Combine organic phases and dry over magnesium sulfate. Extract desired material with resin bound acidic media (SCX) to obtain 0.656 g (93%) of white solid: MS (m/z): 514.0 (M+1).
Reaction SMILES: C([Mg]Br)=C.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=O)[CH2:12][CH2:11][CH2:10]2.[NH4+].[Cl-]>C1COCC1>[CH2:16]1[CH:7]([OH:6])[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15]1
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 127.8 %

Procedure:
A solution of vinylmagnesium bromide (1.0 M in THF, 1700 mL) was transferred in a 12 L 3-neck round bottom flask fitted with a thermocouple probe, a 2 L dropping funnel, an inlet argon, and a mechanical stirrer. At rt, a solution of 6-methoxy-1-tetralone (250 g, 1.42 mol) in 830 mL of THF was added dropwise over a period of 2.5 h, maintaining the internal temperature below 30° C. The mixture was stirred at rt for 0.5 h. At rt, a solution of saturated aqueous NH4Cl (1 L) was slowly added by maintaining the internal temperature below 30° C. The THF was decanted and rotary concentrated. The residual aqueous phase was extracted with ethyl acetate (3×1 L). The combined organic phase was washed with brine, dried over magnesium sulfate and rotary evaporated to give 269 g (93%) of crude tetralol 46. 1H NMR (400 MHz, CDCl3) δ 1.80-2.05 (m, 4H), 2.70-2.90 (m, 2H), 3.81 (s, 3H), 5.21 (d, J=10.6 Hz, 1H), 5.33 (d, J=17.1 Hz, 1H), 6.04 (dd, J1=17.1 Hz, J2=10.6 Hz, 1H), 6.64 (m, 1H), 6.77 (m, 1H), 7.32 (d, J=8.6 Hz, 1H) ppm (described in Tetrahedron, 18, 1355 (1962)).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24]C(C)(C)C)=O)[CH2:18][CH2:17]1)[CH2:6][CH3:7])(=[O:3])[CH3:2].Cl.[C:30]([N:34]1[CH2:38][C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[F:46])[C@H:36](C(O)=O)[CH2:35]1)([CH3:33])([CH3:32])[CH3:31].F[P-](F)(F)(F)(F)F.CN(C)C(O)=[N+](C)C.CCN(C(C)C)C(C)C>ClCCl.O1CCOCC1.CCOCC>[C:30]([N:34]1[CH2:38][C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[F:46])[C@H:36]([C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:9]3[CH:10]=[C:11]([Cl:15])[C:12]([CH3:14])=[CH:13][C:8]=3[CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH3:7])[CH2:21][CH2:20]2)=[O:24])[CH2:35]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Reactant: CC[C@H](NC(C)=O)c1cc(C)c(Cl)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(O)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC(NC(C)=O)c1cc(C)c(Cl)cc1N1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {circle around (R)} or (S)-tert-butyl 4-{2-[1-(acetylamino)propyl]-5-chloro-4-methylphenyl}piperazine-1-carboxylate 23-6 (440 mg, 1.4 mmol) in dichloromethane (10 mL) was added 4 N HCl in dioxane (10 mL) and the mixture was stirred at room temperature for 30 minutes. Then the volatiles were removed under reduced pressure to dryness, and the resulting residue was dissolved in DMF (10 mL) and (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)-pyrrolidine-3-carboxylic acid Y-6 (440 mg 1.5 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′, -tetramethyluroniumhexafluoro-phosphate (HATU, 550 mg, 1.4 mmol), and DIEA (1.49 g, 11.28 mmol) were added. The mixture was stirred at room temperature overnight, diluted with ether, quenched with 1N NaOH aqueous solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by a flash column chromatography with silica gel and eluted with 10% MeOH in dichloromethane containing 1% of a 30% NH4OH aqueous solution. The eluates were concentrated and 1N NaOH aqueous solution was added and the aqueous mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the {circle around (R)} or (S) stereoisomer of title compound 26-1 as white solid. Mass Spectrum: ES-MS: Calcd. for C31H41ClF2N4O2: 575. Found: 576 (M++1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[C:7]1[C:8]([F:30])=[C:9]([F:29])[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:11]([CH:19]=1)[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13].CN(C)C=O.CON(C(C)=O)[C:39](=[O:41])[CH3:40]>CO>[C:39]([NH:1][CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[C:7]1[C:8]([F:30])=[C:9]([F:29])[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:11]([CH:19]=1)[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])(=[O:41])[CH3:40]
Reactant: CON(C(C)=O)C(C)=O
Reactant: NCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)NCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.8 %

Procedure:
To a solution of (E)-5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (8.14 mg, 0.02 mmol) described in Step C in a mixed solvent of dimethylformamide (1 ml) and methanol (5 ml) was added N-methoxydiacetamide (100 mg, 0.76 mmol), and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resultant residue was purified with Mega Bond Elut silica gel (Varian, 5 g). (E)-5-[(2-Acetylamino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (8.10 mg, 92% yield) was obtained as a pale yellow solid from fractions eluted with 6% methanol/methylene chloride.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH:16]=[O:17])=[CH:14][C:13]([CH:18]=[O:19])=[N:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC>C1COCC1>[O:17]=[C:16]1[C:15]2=[CH:14][C:13]([CH:18]=[O:19])=[N:12][N:11]2[CH2:10][CH2:9][O:8]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1nc(C=O)cc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: C1CCOC1
Product: O=Cc1cc2n(n1)CCOC2=O
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazole-3,5-dicarbaldehyde (1.02 g, 6.07 mmol) in THF (30 ml) was added 6.68 ml of a 1.0 M solution of tetrabutylammonium fluoride in THF at 0° C. After stirring for 1 hr, the mixture was treated with 10 ml of saturated ammonium chloride solution and extracted with ethyl acetate. The organic solution was washed with brine, dried over anhydrous sodium sulfate, filtered through Magnesol and evaporated. The crude gum was washed with hexanes, dried in vacuo, and then dissolved in methylene chloride (20 ml). To this solution was added 4-methylmorpholine-N-oxide (2.89 g, 24 mmol) and molecular sieve 4A (6 g). The mixture was stirred at room temperature for 10 min. and then treated with tetrapropylammonium peruthenate (0.11 g, 0.3 mmol). Stirring was continued for 2 hr. The methylene chloride solution was concentrated and diluted with ethyl acetate (40 ml). The mixture was filtered through a pad of silica gel (40 g) and the filter pad was eluted with 2×20 ml ethyl acetate. The combined eluent was washed with 1N HCl and brine, dried over anhydrous sodium sulfate, and evaporated to give 0.30 g of a white solid; mp 135–136° C.; MS m/e 167 (MH+).