Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=[CH:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[Cl:20][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=[CH:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc2c1C=Cc1ccccc1C2O
Solvent: c1ccccc1
Product: Cc1cccc2c1C=Cc1ccccc1C2Cl

Procedure:
23 g. of 5-Hydroxy-1-methyl-5H-dibenzo[a,d]cycloheptene in 200 ml. of absolute benzene are heated with 45 ml. of thionylchloride for two hours under reflux conditions. The mixture is subsequently evaporated under reduced pressure. The resulting white crystalline residue is recrystallized from carbon tetrachloride. 5-Chloro-1-methyl-5H-dibenzo[a,d]cycloheptene, melting at 158°-160° C., is obtained.
Reaction SMILES: [C:1]([C:4]([C@@:6]([C:25](=[O:27])C)([C@:8]([C:22](=[O:24])[CH3:23])([C@@:10]([C:19](=[O:21])[CH3:20])([C@@H:12]([CH:14]([C:16](=[O:18])[CH3:17])[OH:15])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5])(=O)C.[C:28]([C:31]([C@@:33]([C:47](=[O:49])C)([C@:35]([C:44](=[O:46])[CH3:45])([C@@:37]([C:41](=[O:43])[CH3:42])([CH2:39][OH:40])[OH:38])[OH:36])[OH:34])=[O:32])(=O)C>>[C:4]([C@:6]([C@:8]([C:22](=[O:24])[CH3:23])([C@@:10]([C:19](=[O:21])[CH3:20])([C@@H:12]([CH:14]([C:16](=[O:18])[CH3:17])[OH:15])[OH:13])[OH:11])[OH:9])([OH:7])[CH:25]=[O:27])(=[O:5])[CH3:1].[C:31]([C@:33]([C@:35]([C:44](=[O:46])[CH3:45])([C@@:37]([C:41](=[O:43])[CH3:42])([CH2:39][OH:40])[OH:38])[OH:36])([OH:34])[CH:47]=[O:49])(=[O:32])[CH3:28]
Reactant: CC(=O)C(=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@](O)(CO)C(C)=O
Reactant: CC(=O)C(=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@H](O)C(O)C(C)=O
Product: CC(=O)C(O)[C@@H](O)[C@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@@](O)(C=O)C(C)=O
Product: CC(=O)[C@@](O)([C@@](O)(C=O)C(C)=O)[C@](O)(CO)C(C)=O

Procedure:
The precursors of the invention can be prepared by selectively hydrolysing the most reactive acyl-group of 1,2,3,4,6-pentaacetyl glucose (PAG), or 1,2,3,4-tetraacetylxylose (TAX), or 1,2,3,6-2',3',4',6'-octaacetyllactose (OAL) to produce 2,3,4,6-tetraacetylglucose, or 2,3,4-triacetylxylose, or 2,3,6-2',3',4',6'-heptaacetyllactose respectively, which may then be reacted with an acid chloride or anhydride of choice. In the same way other sugar deratives, such as 1,2,3,4,6-pentaacetylgalactose, 1,2,3,4-tetraacetyllyxose, 1,2,3,4-tetraacetylarabinose, and 1,2,3,6-2',3',4',6'-octa acetylmaltose, after hydrolysis of the most reactive anomeric acetyl group, will produce 2,3,4,6-tetraacetylglactose, 2,3,4-triacetyllyxose, 2,3,4-triacetylarabinose, and 2,3,6-2',3',4',6'-hepta acetylmaltose respectively, which can then be reacted with an acid chloride or anhydride of choice. Other examples of suitable precursors are those derived from acetylated cellibiose, mannose, fructose, melibiose and ribose.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1.O[C:19]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C:21](=[O:31])[CH:20]=1.C([O-])(=O)C.[NH4+:36]>C(O)(=O)C>[CH3:16][C:15]1[NH:36][C:19]2[CH2:23][NH:22][C:21](=[O:31])[C:20]=2[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:12]=1[C:13]#[N:14]
Reactant: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(C)c2c1
Reactant: CC(C)(C)OC(=O)N1CC(O)=CC1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C2=C(CNC2=O)N1

Procedure:
A solution of 200 mg (0.888 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 2A), 353 mg (0.888 mmol, approx. 50% purity) tert-butyl 4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [W.-R. Li et al., J. Org. Chem. 2002, 67, 4702-4706] and 102 mg (1.332 mmol) ammonium acetate in acetic acid (4 ml) was stirred at 100° C. for 45 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified first by flash chromatography (silica gel; dichloromethane/methanol gradient, final mixture 10:1 v/v) and then by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to give 31 mg (11% of th.) of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22]([OH:24])=O)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=[N:43][C:38]2[CH:39]=[CH:40][CH:41]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NCC1CC1>ClCCl.CN(C=O)C>[CH:39]1([CH2:38][NH:43][C:22]([CH:20]2[CH2:21][CH:19]2[C:16]2[CH:17]=[CH:18][C:13]([NH:12][CH2:11][C:10]3[CH:25]=[CH:26][CH:27]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)=[CH:14][CH:15]=2)=[O:24])[CH2:41][CH2:40]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)C1CC1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reaction time: 0.25 h
Yield: 9.7 %

Procedure:
To a mixture of (+)-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid (III-3b) (0.09 g, 0.25 mmol) in dichloromethane (2 mL) and DMF (1 mL) was added HATU (0.14 g, 0.37 mmol). The mixture was stirred for 15 min followed by addition of aminomethylcyclopropane (0.03 g, 0.37 mmol). The solution stirred for 4 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The crude material was purified on silica gel eluting with an increasing gradient from hexanes to 30% ethyl acetate/hexanes to give the title compound as a white powder (0.01 g, 11%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.28 (m, 3H), 7.10-7.08 (m, 2H), 7.02-6.98 (m, 3H), 6.92-6.89 (m, 3H), 6.55 (d, J=8.3 Hz, 2H), 5.68 (s, 1H), 4.29 (s, 2H), 4.01 (s, 1H), 3.15-3.12 (m, 2H), 2.39 (s, 1H), 1.57-1.46 (m, 2H), 1.17-1.14 (m, 1H), 0.95 (s, 1H), 0.51 (d, J=7.7 Hz, 2H), 0.20 (d, J=4.6 Hz, 2H). ES-MS m/z 413.3 (MH+).
Reaction SMILES: [C:1](=O)([O:43]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32]([O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)=[O:33])[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][CH:4]=1.[CH3:54][NH:55][CH3:56].O1CCCC1.C(OCC)(=O)C>O1CCCC1>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][C@@H:11]([OH:30])[C@@H:10]([NH:31][C:32](=[O:33])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][C:1]([N:55]([CH3:56])[CH3:54])=[O:43])=[CH:4][CH:5]=3)(=[O:20])=[O:19])=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: CNC
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)N(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenyl 4-nitrophenyl carbonate (60 mg) in tetrahydrofuran (0.5 mL) was added 2M dimethylamine/tetrahydrofuran (0.5 mL) and the mixture is was stirred at ambient temperature for 30 min. Ethyl acetate was added and the mixture was washed with saturated sodium bicarbonate/water (4×), dried (sodium sulfate), evaporated, and purified by chromatography (silica gel, hexanes/ethyl acetate, 3:7) to provide the title compound as a solid foam. 1H NMR (DMSO-d6): δ 0.76 (3H, d), 0.82 (3H, d), 1.1-1.2 (1H, m), 1.2 (1H, br quintuplet), 1.9-2.0 (if, m), 2.2 (1H, t), 2.6-2.8 (3H, m), 2.81 (3H, s), 2.9 (3H, s), 3.0 (1H, br s), 3.2-3.3 (2H, m), 3.4-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dt), 5.0 (1H, br s), 5.5 (1H, d), 6.1 (2H, s), 6.9 (2H, d), 7.0 (1H, d), 7.15 (2H, d), 7.19 (1H, s), 7.22 (2H, br d); MS: 664 (MH+); C31H41N3O11S.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].CC[O-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:24]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])=[N:23][CH:22]=[N:21][C:20]=3[O:19][C:18]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:13][CH:12]=1>CS(C)=O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:25]3[C:24]([NH:26][CH2:27][CH2:28][CH2:29][O:30][CH2:3][CH2:2][C:1]#[N:4])=[N:23][CH:22]=[N:21][C:20]=3[O:19][C:18]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:15][CH:16]=1
Reactant: C=CC#N
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCO)c23)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCOCCC#N)c23)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Add 47 mg (0.89 mmol) acrylonitrile and 57 mg (0.83 mmol) sodium ethylate to 300 mg (0.80 mmol) of the compound from Stage 1. Stir the mixture overnight at 80° C. After cooling, take up the mixture in DMSO and purify directly by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). 160 mg (47% of theor.) of the title compound is obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:24]([C:25]#[N:26])=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C@@H:35]([OH:38])[CH2:36][OH:37])=[CH:29][CH:28]=4)[C:22]4[C:21](=[O:39])[CH2:20][CH2:19][CH2:18][C:17]=4[N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:24]([C:25]#[N:26])=[C:23]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH2:34][C@@H:35]([OH:38])[CH2:36][OH:37])=[CH:31][CH:32]=4)[C:22]4[CH:21]([OH:39])[CH2:20][CH2:19][CH2:18][C:17]=4[N:16]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc2c(c1-c1ccc(OC[C@@H](O)CO)cc1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc2c(c1-c1ccc(OC[C@@H](O)CO)cc1)C(O)CCC2

Procedure:
25 mg (0.043 mmol) of the compound from Example 3 were initially charged in 1 ml of THF and 0.1 ml of methanol, 0.8 mg (0.022 mmol) of sodium borohydride was added with stirring and the mixture was stirred at RT for 16 h. The reaction solution was diluted with about 2 ml of water and purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% TFA).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][C:5]2[N:6]([CH3:10])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.[F:14][C:15]([F:31])([F:30])[S:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:18])=[O:17]>ClCCl>[F:14][C:15]([F:31])([F:30])[S:16]([O-:19])(=[O:18])=[O:17].[Cl:13][C:12]1[C:2]([Cl:1])=[CH:3][C:4]2[N+:8]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:7]([CH3:9])[N:6]([CH3:10])[C:5]=2[CH:11]=1
Reactant: Cc1nc2cc(Cl)c(Cl)cc2n1C
Reactant: CCOC(=O)CCCCCOS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCCC[n+]1c(C)n(C)c2cc(Cl)c(Cl)cc21
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To 2 (2 g, 1 eq) in 10 mL dichloromethane was added 4 (2.8 g, 1 eq) and stirred in dark for 24 hrs at room temperature. Solvent was evaporated under reduced pressure and the residue was recrystalized from MeOH/diethyl ether to get the white powder as product (4.1 g, 87% yield.) See FIG. 11. 1H NMR: (DMSO) 1.16 (t, 3H), 1.37 (m, 2H), 1.57 (m, 2H), 1.75 (m, 2H), 2.28 (t, 2H), 2.88 (s, 3H), 3.96 (s, 3H), 4.04 (q, 2H), 4.46 (t, 2H), 8.48 (s, 1H), 8.52 (s, 1H). 13C NMR: (DMSO): 10.61, 13.98, 23.90, 25.04, 28.11, 31.98, 33.20, 45.09, 59.58, 114.73, 114.78, 128.76, 128.79, 130.06, 130.91, 154.24, 172.63. ESI-MS (m/z) calcd (found): 357.1 (357.3) for [M]+.
Reaction SMILES: [F:1][C:2]([F:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.CC(O)=O.COC1C=CC(C[O:29][C:30](=[O:50])[C@H:31]([N:36]2[CH2:40][C@H:39]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[C@@H:38]([CH:48]=O)[CH2:37]2)[CH2:32][CH:33]2[CH2:35][CH2:34]2)=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[F:17][C:2]([F:1])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:48][C@@H:38]2[C@@H:39]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[CH2:40][N:36]([C@H:31]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:30]([OH:50])=[O:29])[CH2:37]2)[CH2:7][CH2:6]1
Reactant: FC(F)(CCC1CCNCC1)c1ccccn1
Reactant: COc1ccc(COC(=O)[C@@H](CC2CC2)N2C[C@H](c3cccc(F)c3)[C@@H](C=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)[C@@H](CC1CC1)N1C[C@H](CN2CCC(CCC(F)(F)c3ccccn3)CC2)[C@@H](c2cccc(F)c2)C1
Reaction time: 3 h
Yield: 89.4 %

Procedure:
A solution of 4-(3,3-difluoro-3-(2-pyridyl)propyl) piperidine (20 mg. 0.083 mmol, from EXAMPLE 202, Step E) and AcOH (0.0050 mL, 5.2 mg, 0.087 mmol) in 1,2-dichloroethane (1.1 mL) was transferred to a vial containing 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclopropyl)propanoic acid (4-methoxy)benzyl ester (30 mg, 0.076 mmol, from EXAMPLE 21, Step E). Molecular sieve pellets (100 mg, 3 Å) were added and the mixture was stirred for 10 min. at RT before the addition of sodium triacetoxyborohydride (19 mg, 0.090 mmol). After 3 h, the mixture was diluted with EtOAc (40 mL) and washed with saturated aq. NaHCO3 (20 mL) followed by saturated aq. NaCl (20 mL). The aq. layers were extracted with EtOAc (40 mL) and the combined organic layers were dried (Na2SO4), decanted, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 50:50 v/v CH2Cl2/EtOAc, to give 36 mg of the title compound. Further purification by preparative HPLC on a 20×250 mm Chiralcel OD column, eluting with 98:2 v/v hexanes/i-PrOH, gave 23 mg of the title compound: 1H NMR (500 MHz, CD3OD) δ 8.60 (d, J=5, 1H), 7.94 (td, J=8, 2, 1H), 7.66 (d, J=8, 1H), 7.48 (dd, J=8, 5, 1H), 7.35 (d, J=8, 2H), 7.25 (td, J=8, 6, 1H), 7.01-6.95 (m, 2H), 6.92-6.87 (m, 2H), 5.13 (s, 2H), 3.77 (s, 3H), 3.33 (dd, J=9, 6, 1H), 3.10 (q, J=9, 2H), 2.84-2.74 (m, 2H), 2.66-2.59 (m, 2H), 2.52 (dd, J=9,7, 1H), 2.36-2.21 (m, 5H), 1.81 (bt, J=12, 1H), 1.73 (bt, J=12, 1H), 1.71-1.51 (m, 4H), 1.30-1.24 (m, 2H), 1.21-0.99 (m, 3H), 0.72-0.64 (m, 1H), 0.45-0.55 (m, 2H), 0.07-0.00 (m, 2H); ESI-MS 650 (M+H); HPLC A: 3.33 min.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1C(OCC)=O.Cl>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:18])[CH:3]=1
Reactant: CCOC(=O)C1=C(O)c2ccccc2[C@@](C)(CCC(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC[C@@]1(C)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 87.7 %

Procedure:
A solution of Example 39D (3.10 g, 9.80 mmol) in 1,4-dioxane (25 mL) was treated with aqueous 1N hydrochloric acid solution (25 mL) and refluxed for 3 hours. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in hot hexane and filtered. The precipitate was dried to give the title compound (2.10 g, 88%). 1H NMR (300 MHz, CDCl3): δ ppm 0.44 m, 0.5 H) 0.73 m, 3.5 H) 0.80 m, 3 H) 1.06 m, 1 H) 1.39 m, 1 H) 1.56 (s, 1.5 H) 1.59 (s, 1.5 H) 2.04 m, 1 H) 2.30 m, 1 H) 3.74 (s, 0.5 H) 3.75 (s, 0.5 H) 6.63 (s, 0.5 H) 7.46 m, 2 H) 7.66 m, 1 H) 8.08 m, 0.5 H) 8.20 m, 0.5 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-])=O.[H][H]>C(OCC)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOCC
Product: Nc1ccc2c(c1)C(=O)OC2=O
Temperature: 245 °C
Yield: 52.7 %

Procedure:
In 200 ml of dry ethyl ether, (C2H5)2O, was dissolved 1.93 g of 4-nitrophthalic anhydride (~1% solution) to which was added 0.10 g of 5% palladium-on-charcoal and the mixture hydrogenated in a Paar hydrogenator at 39 psi at room temperature, until no more hydrogen was consumed. The catalyst was removed by filtration and the ether removed from the filtrate, maintained at 0° to -5° C, under vacuo, yielding a yellow crystalline solid mixed with non-crystalline viscous mass. When a small sample of this mixture was placed on a metal plate heated to 245° C, the product melted and polymerized immediately to a tough polymer. Extraction of the crystalline-non-crystalline mixture with ether left 0.46 g of polymer; concentration of the ether followed by cooling, yielded 0.86 g of 4-aminophthalic anhydride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](C2C=CC=CC=2)=O)[CH:5]=[CH:6][C:7]=1[CH3:8].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]3[N:31]([C:32]=2[CH:33]=O)[CH:30]=[CH:29][S:28]3)=[CH:21][CH:20]=1.[OH-:35].[Na+]>C(O)C.C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:35])/[CH:10]=[CH:33]/[C:32]2[N:31]3[C:27]([S:28][CH:29]=[CH:30]3)=[N:26][C:25]=2[C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=Cc1c(-c2ccc(F)cc2)nc2sccn12
Reactant: Cc1ccc(CC(=O)c2ccccc2)cc1C
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: Cc1ccc(C(=O)/C=C/c2c(-c3ccc(F)cc3)nc3sccn23)cc1C
Temperature: 27 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
To a stirred solution of 3,4-dimethylphenyl acetophenone (148 mg, 1.0 mmol) and a 6-(4-fluorophenyl)imidazo[2,1-b]thiazol-5-carbaldehyde (246 mg, 1.0 mmol) in ethanol (20 ml) 10% aqueous solution of NaOH was added (5 ml). The reaction mixture was stirred at room temperature 27° C. for 4 h and the reaction was monitored by TLC using ethyl acetate-hexane (3:7) as a solvent system. The solvent was evaporated under vacuum then the residue was dissolved in ethylacetate/water. The organic layer was washed with brine and evaporated. This was further purified by column chromatography using ethyl acetate:hexane (2:8) as a solvent system to obtain the pure product (9e) as yellow solid (286 mg, 76% yield). Mp: 210-213° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([CH:21]=3)[C:19]#[N:20])[N:10]=2)=[CH:5][CH:4]=1)=O.[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.C(O)(=O)C.C([BH3-])#N>CO.ClCCCl>[C:19]([C:18]1[CH:21]=[C:14]([C:11]2[N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)=[CH:8][CH:7]=3)[O:13][N:12]=2)[CH:15]=[CH:16][C:17]=1[O:22][CH:23]([CH3:25])[CH3:24])#[N:20]
Reactant: O=C(O)C1CNC1
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1C#N
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(CN4CC(C(=O)O)C4)cc3)n2)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
5-(5-(4-formylphenyl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.077 g, 0.231 mmol) and azetidine-3-carboxylic acid (0.028 g, 0.277 mmol) were combined in methanol (11.55 ml) and DCE (11.55 ml) in a sealed vial. Acetic acid (0.066 ml, 1.155 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hr. MP-cyanoborohydride (0.265 g, 0.570 mmol) was added and the reaction stirred for about 24 h. The solution was filtered, the solid was washed with methylene chloride and methanol, and the filtrate was concentrated to afford a white solid, which was recrystallized by methanol (5 mL) to give 1-(4-(3-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)azetidine-3-carboxylic acid (0.025 g, 0.060 mmol, 25.9% yield) as white solid: LC/MS (Table 1, Method a) Rt=2.10 min.; MS m/z: 420.26 (M+H)+. 1H NMR (400 MHz, Solvent d-DMSO) ppm 8.35-8.28 (m, 2H), 8.17-8.11 (d, J=8.00 Hz, 2H), 7.56-7.50 (m, 8.69 Hz, 3H), 4.98-4.89 (m, 1H), 3.68 (s, 2H), 3.43 (s, 2H), 3.25-3.23 (m, 3H), 1.38 (d, J=6.03 Hz, 6H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3F)[C:7](=[O:17])[C:6]([C:18](O)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C1N=CN([C:26](N2C=NC=C2)=[O:27])C=1.[N+:33]([CH3:36])([O-:35])=[O:34].[H-].[Na+]>C1COCC1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[O:27][CH3:26])[C:7](=[O:17])[C:6]([C:18](=[O:19])[CH2:36][N+:33]([O-:35])=[O:34])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(F)c(F)cc2c(=O)c(C(=O)C[N+](=O)[O-])cn(C3CC3)c12
Yield: 66.6 %

Procedure:
566 mg of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 648 mg of CDI were put into 20 ml of THF and the mixture solution is stirred under reflux for 24 hours (A solution). 366 mg of nitromethane was mixed in 5 ml of THF and 240 mg of 60% NaH added thereto. The mixture solution was stirred for 24 hours at room temperature and the above A solution was added thereto. The resulting solution was stirred under reflux for 14 hours. The reaction mixture was cooled and the solvent was evaporated under reduced pressure. The produced residue was purified by column chromatography (nucleic acid: ethylacetate =5 : 1) to give 450 mg of the above title compound (yield: 69%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[C:33](O)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:33]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:40])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: O=C(O)c1cccnc1
Product: Cc1c(N2CCN(C(=O)c3cccnc3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure Q using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and nicotinic acid to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(pyridin-3-yl)methanone. 1H NMR (DMSO-d6) δ ppm 2.10 (s, 3H), 3.05 (br s, 4H), 3.32-3.40 (br s, 4H), 3.54 (br s, 2H), 3.68 (br s, 4H), 3.84 (br s, 2H), 6.50 (br s, 1H), 7.16 (br s, 1H), 7.28 (br s, 1H), 7.56 (br s, 2H), 7.78 (s, 1H), 7.90 (d, J=7.6 Hz, 1H), 8.36 (s, 1H), 8.67 (s, 2H). Mass Spectrum (ESI) m/e=545.7 (M+1).
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[CH3:13]>C(O)C.[Pt](=O)=O>[F:12][C:6]1[CH:5]=[C:4]([CH3:13])[C:3]([O:2][C:1]([O:14][CH3:15])=[O:16])=[CH:8][C:7]=1[NH2:9]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(=O)Oc1cc(N)c(F)cc1C
Reaction time: 1 h

Procedure:
A solution of (4-fluoro-2-methyl-5-nitrophenyl) methyl carbonate (3 g, 13 mmol), (prepared as described in EP 0307777 A2), in ethanol (60 ml) containing platinum(IV)oxide (300 mg) was stirred under hydrogen at 0.3 atmosphere for 1 hour. After filtration and evaporation of the solvent, 2-fluoro-5-methoxycarbonyloxy-4-methylaniline was isolated as a solid (2.6 g, 100%). 1H NMR Spectrum: (CDCl3) 2.07(s, 3H); 3.87(s, 3H); 6.52(d, 1H); 6.80(d, 1H)