Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[CH:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[S:47][C:25]2[N:26]=[CH:27][N:28]=[C:29]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[O:38][C@H:39]3[CH2:44][CH2:43][C@H:42]([O:45][CH3:46])[CH2:41][CH2:40]3)[C:24]=2[C:23]=1[CH3:48])=[O:21].[NH:49]1[CH2:53][CH2:52][CH:51]([OH:54])[CH2:50]1.C(O)(=O)C>C(Cl)Cl>[OH:54][CH:51]1[CH2:52][CH2:53][N:49]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[S:47][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[O:38][C@H:39]4[CH2:44][CH2:43][C@H:42]([O:45][CH3:46])[CH2:41][CH2:40]4)[C:24]=3[C:23]=2[CH3:48])=[O:21])[CH2:50]1
Reactant: CO[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NCCC=O)c(C)c23)CC1
Reactant: OC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CO[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NCCCN4CCC(O)C4)c(C)c23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.155 g sodium triacetoxyborohydride were added to a solution of the 0.21 g 4-[4-fluoro-2-(trans-4-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (3-oxo-propyl)-amide and 43 μl 3-pyrrolidinol in methylene chloride followed by addition of 49 μl acetic acid. The mixture was stirred at rt overnight, diluted with methylene chloride and then washed with 10% aq. K2CO3. The mixture was passed through a hydrophobic frit. The filtrate was evaporated and purified by chromatography.
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:22]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([P:32](=[O:35])([OH:34])[OH:33])[CH3:31])=[O:28])[CH3:26])=[O:23])[CH3:21])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:22]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([P:32](=[O:33])([OH:35])[OH:34])[CH3:31])=[O:28])[CH3:26])=[O:23])[CH3:21]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to Example 7(b), starting from the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-alanyl-L-alanyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(L-alanyl-L-alanylamino)-ethylphosphonic acid of melting point 283°-284° C (decomposition); [α]D20 = -66.8° (c = 0.5% in water).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C@H:13]([C:18]([NH:20][C:21]2([C:24]#[N:25])[CH2:23][CH2:22]2)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C=O)C>[C:24]([C:21]1([NH:20][C:18](=[O:19])[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[NH:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[CH:33][C:28]([S:27][CH3:26])=[CH:29][CH:30]=3)=[CH:3][CH:4]=2)[CH:9]([F:11])[F:10])[CH2:23][CH2:22]1)#[N:25]
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)C(F)F)C(=O)NC1(C#N)CC1
Reactant: CSc1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2ccc([C@H](N[C@@H](CC(C)C)C(=O)NC3(C#N)CC3)C(F)F)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A stream of nitrogen was passed through a suspension of the aryl bromide from Step 5 (65 mg), 4-(methylthio)phenylboronic acid (40 mg), 2 M Na2CO3 (0.22 mL) and DMF (1.0 mL) for 5 minutes. PdCl2dppf was then added and the reaction was warmed to 80° C. and stirred under nitrogen for 4 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL) and poured into a saturated solution of sodium bicarbonate. The ethyl acetate layer was separated and the aqueous further extracted with ethyl acetate (2×15 mL). The combined ethyl acetate extracts were washed with brine and dried with magnesium sulfate. Removal of the solvent left a residue that was purified by chromatography on SiO2 using a gradient of hexanes and ethyl acetate (90:10 to 50:50) to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CS(C)=O.O>[O:18]1[CH2:19][CH2:20][N:15]([C:6]2[N:5]=[C:4]([NH2:8])[CH:3]=[CH:2][CH:7]=2)[CH2:16][CH2:17]1
Reactant: Nc1cc(Cl)ccn1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cccc(N2CCOCC2)n1
Temperature: 190 °C
Reaction time: 10 h
Yield: 47.4 %

Procedure:
A mixture containing 4-chloro-2-aminopyridine (164; 26 g, 0.20 mol), K2CO3 (0.40 mol) and morpholine (48; 0.6 mol) in DMSO (150 mL) was stirred at 190° C. for 10 h. Upon cooling to room temperature, the reaction mixture was diluted with water (300 mL) and the resulting mixture was extracted with ethyl acetate (4×150 mL). The combined organic layers were washed with water (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:ethyl acetate=10:1) to afford 6-morpholinopyridin-2-amine 165 (17 g, 47%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:16])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)=[O:5].[CH2:17]([N:19]1[C:31]2[CH:30]=[CH:29][C:28]([C:32](O)=[O:33])=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][NH:6][C:4](=[O:5])[CH:3]([CH3:16])[CH2:2][NH:1][C:32]([C:28]2[CH:29]=[CH:30][C:31]3[N:19]([CH2:17][CH3:18])[C:20]4[C:25]([C:26]=3[CH:27]=2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:33])=[CH:13][CH:12]=1)#[N:15]
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Reactant: CC(CN)C(=O)NCc1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(C(=O)NCC(C)C(=O)NCc3ccc(C#N)cc3)ccc21
Yield: 69.2 %

Procedure:
A solution (2.5 mL) of the compound obtained in Step 2 (112 mg, 0.52 mmol), 9-ethyl-9H-carbazole-3-carboxylic acid (123 mg, 0.52 mmol), HATU (255 mg, 0.67 mmol) and TEA (0.216 mL, 1.55 mmol) in DMF was stirred at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; ethyl acetate) to give the title compound (158 mg, 0.360 mmol, 69.9%) as a white powder.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36]5[N:37]=[C:38]([CH3:41])[O:39][CH:40]=5)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=O)=CC=1)([O-])=O.[OH-].[Li+]>C1COCC1.C(OCC)(=O)C>[OH:10][C@@:11]([C:18]1[N:19]=[N:20][N:21]([CH2:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28]([C:36]4[N:37]=[C:38]([CH3:41])[O:39][CH:40]=4)=[CH:29][C:30]([C:34]#[N:35])=[N:31]3)=[CH:26][CH:25]=2)[CH:22]=1)([C:14]([F:16])([F:15])[F:17])[CH2:12][CH3:13]
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4coc(C)n4)cc(C#N)nc3c2)nn1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4coc(C)n4)cc(C#N)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-(1-{[2-cyano-4-(2-methyl-1,3-oxazol-4-yl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (36 mg, 0.06 mmol) in THF (1.4 mL) was added lithium hydroxide 2M (150 uL, 0.3 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with an ammonium chloride solution, brine, dried over MgSO4, filtered and concentrated to yield the title compound. The crude residue was purified by flash chromatography (10% acetone-90% dichloromethane) to give the desired product. 1H NMR (400 MHz, acetone-d6): δ 8.9 (d, 1H), 8.73 (s, 1H), 8.24 (d, 2H), 8.11 (s, 1H), 7.80 (d, 1H), 6.02 (s, 2H), 5.49 (s, 1H), 2.6 (s, 3H), 2.35 (m, 1H), 2.05 (m, 1H), 0.86 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:21]=[C:20]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)[CH:19]=[CH:18][C:10]=2[C:11]([O:13]C(C)(C)C)=[O:12])[CH:5]=[CH:6][CH:7]=1>FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:21]=[C:20]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)[CH:19]=[CH:18][C:10]=2[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1Nc1cccc(O)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(N2CCc3ccccc32)cc1Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-((3-hydroxyphenyl)amino)-4-(indolin-1-yl)benzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 50-90% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-((3-hydroxyphenyl)amino)-4-(indolin-1-yl)benzoic acid 13 mg of a white solid.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>ClCCCl>[CH2:1]([C:8]1[C:9]([NH:22][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:33])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: COc1ccc(N=C=O)cc1
Solvent: ClCCCl
Product: COc1ccc(NC(=O)Nc2ncc(-c3ccc(OC)cc3)nc2Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 19 h
Yield: 59.2 %

Procedure:
Under an argon atmosphere, to a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced Int., 33, 477-485 (2001)) (306 mg, 1.05 mmol) in anhydrous 1,2-dichloroethane (10 mL) was added 4-methoxyphenyl isocyanate (13) (191 L, 1.00 mmol) at room temperature, and the mixture was heated with stirring at 80° C. for 19 hours. After cooling to room temperature, the solid precipitated was collected by filtration and dried in vacuo to give the crude product (293 mg, <664 μmol, <63.2%) as a colorless solid. An aliquot (93.0 mg, <211 μmol) was recrystallized from methanol to give Compound 11u (54.9 mg, 125 μmol, 59.2%) as a colorless solid. Rf=0.50 (n-hexane/ethyl acetate=1/1); 1H NMR (400 MHz, DMSO-d6) δ 3.73 (s, 3H), 3.81 (s, 3H), 4.36 (s, 2H), 6.98-6.93 (AA′BB′, 2H), 7.02-7.08 (AA′BB′, 2H), 7.17-7.25 (m, 1H), 7.28-7.32 (m, 4H), 7.43-7.48 (AA′BB′, 2H), 7.95-8.01 (AA′BB′, 2H), 8.79 (s, 1H), 9.04 (s, 1H), 10.58 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ 38.5, 55.18, 55.24, 114.0 (2C), 114.4 (2C), 121.1 (2C), 126.3, 127.2 (2C), 128.2, 128.3 (2C), 129.0 (2C), 131.7, 134.5, 137.9, 144.4, 145.0, 145.4, 152.2, 155.1, 160.1; IR (KBr, cm−1) 704, 746, 824, 1038, 1173, 1242, 1329, 1369, 1416, 1481, 1510, 1570, 1607, 1668, 2833, 3030, 3261; Anal. Calcd. For C26H24N4O3: C, 70.89; H, 5.49; N, 12.72. Found: C, 70.66; H, 5.49; N, 12.61.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:37]([C:34]3[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=3)(=[O:39])=[O:38])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NS(=O)(=O)c3ccc(Cl)cc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 91, Step 3, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 4-chlorobenzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C(OCC)C>[C:16]([O:15][C:13]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:12])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 23 °C
Reaction time: 12 h

Procedure:
To the suspension of 10 g (76.2 mmol ) of L-leucine in 140 mL of diethyl ether was added 80 mL of 10% NaOH. After all solid dissolves, 20 mL (87.1 mmol) of BOC2O was added to the reaction mixture. The resulting reaction mixture was stirred at 23° C. for 12 h. After this period, the layers were separated and the aqueous layer was acidified to pH 1 by careful addition of 1N aqueous HCl at 0° C. The resulting mixture was extracted with ethyl acetate (3×100 mL). The organic layers were combined and washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to provide title product which was used directly for next reaction without further purification (yield, 97%). 1H NMR (400MHz, CDCl3) δ 4.89 (broad d, 1H, J =8.3 Hz), 4.31 (m, 1H), 1.74-1.49 (m, 3H), 1.44 (s, 9H), 0.95 (d, 6H, J=6.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.[C:29]1([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.CCCCCC>[CH3:24][N:23]([CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:40])=[CH:3][C:4]=3[F:28])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1)[CH3:25]
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (62.7 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.6 ml) at room temperature, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure. The resultant residue was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) to provide the titled compound (48.0 mg, 54%) as white powder.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH3:27]>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:25][CH2:26][CH3:27])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCCNCCOC
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: CCCN(CCOC)Cc1ccc(C(=O)N2CCN(C(C)C)CC2)cc1

Procedure:
Prepared from the product of Example 15 and (2-methoxy-ethyl)-propyl-amine.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]([O:32]C2CCCCO2)[C:12]2[CH:31]=[CH:30][C:15]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:27])[CH2:25][CH3:26])=[C:20]([OH:28])[C:19]=3[CH3:29])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)=O.[NH2:39][C:40]([NH2:42])=[S:41].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:42][C:40]1[S:41][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:11]([OH:32])[C:12]3[CH:31]=[CH:30][C:15]([CH2:16][O:17][C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:27])[CH2:25][CH3:26])=[C:20]([OH:28])[C:19]=4[CH3:29])=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[N:39]=1
Reactant: CCC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)CCl)c3)cc2)c(C)c1O
Reactant: NC(N)=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCC(=O)c1ccc(OCc2ccc(C(O)c3cccc(-c4csc(N)n4)c3)cc2)c(C)c1O
Yield: 52.1 %

Procedure:
Heat a solution of 1-(4-{4-[[3-(2-chloro-acetyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-2-hydroxy-3-methyl-phenyl)-propan-1-one (0.250 mg, 0.466 mmol) and thiourea (71 mg, 0.931 mmol) in ethanol (0.20 M) overnight at 70° C. Add p-toluenesulfonic acid (10 mg) and stir overnight. Evaporate solvents and chromatograph residue. Major fraction isolated was the title compound (0.115 g, 0.243 mmol, 52%): 1H NMR (400 MHz, DMSO-d6) δ 1.09 (t, J=10.5 Hz, 3H), 2.02 (s, 3H), 3.03 (q, J=14.4 Hz, 2H), 5.20 (s, 2H), 5.75 (s, 1H), 6.70 (d, J=9.0 Hz, 1H), 7.14 (s, 1H), 737 (d, J=6.43 Hz, 1H), 7.42 (m, 6H), 7.60 (m, 1H), 7.80 (m, 2H), 12.89 (s, 1H). MS (m/z): 473 (M−H).
Reaction SMILES: C(OC([C:11]1([NH2:25])[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[C:12]1=[O:24])=O)C1C=CC=CC=1.[ClH:26].[H][H]>CO.[Pd]>[ClH:26].[NH2:25][CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=2)[C:12]1=[O:24]
Reactant: [H][H]
Reactant: N#Cc1ccc(N2CCC(N)(C(=O)OCc3ccccc3)C2=O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N#Cc1ccc(N2CCC(N)C2=O)cc1
Reaction time: 0.67 h
Yield: 80 %

Procedure:
50 g (0.15 mol) of 3-benzyloxycarbonyl-amino-1-(4-cyano-phenyl)-2-oxo-pyrrolidine are suspended in 600 ml of methanol, and 14.1 ml of 36% hydrochloric acid are added. After the addition of 2.5 g of 5% palladium on activated carbon, hydrogen is passed through at 45° C. After 40 minutes, the mixture is cooled, the catalyst is filtered off and the filtrate is concentrated to dryness. Recrystallisation from methanol/isopropanol yields 28.5 g (80%) of 3-amino-1-(4-cyanophenyl)-2-oxo-pyrrolidine hydrochloride.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([NH2:13])=[O:12]>N1C=CC=CC=1>[C:1]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([NH2:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1ccsc1N
Solvent: c1ccncc1
Product: CC(=O)Nc1sccc1C(N)=O
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Acetyl chloride (4.2 mL, 59 mmol) was added dropwise to a solution of 2-amino-thiophene-3-carboxylic acid amide (7.7 g, 54.2 mmol) in pyridine (100 mL) at 0° C. The temperature of the reaction mixture was raised to room temperature over a 3 h period until no remaining starting material was present based on LC-MS. The solvent was then removed under vacuum to give the above titled compound as brown solid (9.7 g, 52.7 mmol, 97.2% yield). LCMS [M+H]]+ m/z 185.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][C:33]1[S:34][C:35]([S:39]([NH2:42])(=[O:41])=[O:40])=[C:36]([CH3:38])[N:37]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:35]3[S:34][C:33]([CH3:32])=[N:37][C:36]=3[CH3:38])(=[O:40])=[O:41])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nc(C)c(S(N)(=O)=O)s1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nc(C)c(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)s1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2,4-dimethyl-1,3-thiazole-5-sulfonamide: 1H-NMR [CDCl3/CD3OD(10:1)] δ 7.46-7.22 (9H, m), 6.20 (1H, br.s), 3.48-3.45 (2H, m), 2.88-2.82 (2H, m), 2.64 (3H, s), 2.59 (3H, s), 2.30 (3H, s), 2.20 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=4)=[CH:22][C:21]=3[Cl:37])[C:15]2=[O:38])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:21]([Cl:37])=[CH:22][C:23]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][CH:32]=4)=[CH:24][C:25]=3[Cl:26])[C:15]2=[O:38])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c(Cl)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1
Yield: 96.5 %

Procedure:
Treat a solution of 4-[(R)-3-(3,5-Dichloro-4′-methoxycarbonyl-biphenyl-4-ylmethyl)-2-oxo-pyrrolidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Preparation 16) (0.4 g, 0.7 mmol) in THF (5 mL) with 1N aqueous LiOH (3.6 mL). Stir the reaction overnight at room temperature. Quench the reaction with 1N HCl and extract with EtOAc. Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 0.37 g (96%) of desired product. MS (m/e): 569 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1.[BH4-].[Na+].[OH-].[Na+]>CO>[Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:17][CH:14]1[CH2:16][CH2:15]1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1cccc(CNC2CC2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
The mixture of 2-chloro-3-trifluoromethylbenzaldehyde (37.4 g, 179.5 mmol) and cyclopropylamine (25.2 mL, 359.1 mmol) in MeOH (500 mL) was stirred at rt overnight. Subsequently, NaBH4 (9.2 g, 233.4 mmol) was added at 0° C. and the mixture was allowed to warm to rt overnight. 1M NaOH was added (100 mL) and the solvent was evaporated under reduced pressure. Brine (100 mL) was added and extracted with EtOAc (3×100 mL). 2N HCl (100 mL) was added and extracted with Et2O (3×100 mL). The org. phase was washed with 2N HCl (100 mL). To the combined water phase 2N NaOH was added (to pH=14) and the mixture was extracted with EtOAc (3×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The corresponding product was isolated as a colourless liquid (33.7 g, 75%). LC-MS: tR=0.66 min; ES+: 250.17.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH2:16][OH:17])[CH:12]=[C:13]([CH3:15])[CH:14]=2)[C:5]([CH:18]([CH3:20])[CH3:19])=[C:4]([Cl:21])[N:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH:16]=[O:17])[C:5]([CH:18]([CH3:19])[CH3:20])=[C:4]([Cl:21])[N:3]=1
Reactant: Cc1cc(CO)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: Cc1cc(C=O)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A mixture of (5) (2.36 g, 7.22 mmol), PCC (1.56 g, 7.22 mmol), and dried celite (2 g) was stirred in dichloromethane (20 ml) for 2 hr. at room temperature. The mixture was then filtered through a short silica gel pad and washed with EA. The combined filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:15)) to afford 1.71 g (73%) of a pale yellow syrup; 1H NMR (200 MHz, CDCl3) δ 1.42 (6H, d, J=7.2 Hz), 2.49 (3H, s), 3.61 (1H, m), 7.20 (1H, s), 7.44 (1H, s), 7.62 (1H, s), 10.01 (1H, s).