Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:40][C:41]1[CH:42]=[C:43]([S:47]([NH2:50])(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([S:47]([NH2:50])(=[O:48])=[O:49])[CH:42]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccccc1C1CCCCC1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cccc(NC(=O)c2ccccc2C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-cyclohexyl benzoic acid (20 mg, 0.10 mmol) and HATU (38 mg, 0.10 mmol) in DMF (1 mL) was stirred at room temperature 3 min. To this solution was added 3-amino-benzenesulfonamide (17 mg, 0.10 mmol) and triethylamine (14 μL, 0.10 mmol). The reaction was stirred at room temperature for 16 h and purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 2-cyclohexyl-N-(3-(aminosulfonyl)phenyl)benzamide. LC/MS: m/z 359.1 (M+H)+ at 3.85 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:14][CH:13]=1>>[C:1]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:17]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)Cl
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: CCCCCCCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 78.9 %

Procedure:
In a manner similar to that described in Example 3, octanoyl chloride (0.063 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.063 g of 4-[4-(octanoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+320.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C:21]([F:24])([F:23])[F:22])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Zn]>[C:15]1([C:13]2[N:14]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[O:11][C:12]=2[C:21]([F:22])([F:23])[F:24])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3ccccc3)c(C(F)(F)F)o2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc(-c3ccccc3)c(C(F)(F)F)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
to a solution of 2-(4-nitrophenyl)-4-phenyl-5-(trifluoromethyl)oxazole (437 mg, 1307 μmol) in 20 mL acetic acid at room temperature was added zinc dust (1282 mg, 19611 μmol) all at once. An exotherm resulted. The mixture was stirred at room temperature for 2 hours then filtered. The filtrate was concentrated under reduced pressure, taken up in 25 mL toluene and concentrated under reduced pressure again to afford a yellow, foamy solid (350 mg, 88%). ESI+ m/z=305.0 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:56]([CH3:58])[CH3:57])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:50](=[CH:51][CH:52]=3)[C:31]3[NH:32][C:33]([C@@H:35]5[CH2:39][C@H:38]([CH2:40][O:41][CH3:42])[CH2:37][N:36]5C(OC(C)(C)C)=O)=[N:34][C:30]=3[CH:29]=[CH:28]4)=[C:21]([C:53]#[C:54][CH3:55])[CH:20]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.[CH3:60][O:61][C:62]([NH:64][C@H:65]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:66]([OH:68])=O)=[O:63].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CCOC(C)=O.CN(C=O)C.CO>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:56]([CH3:58])[CH3:57])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:50](=[CH:51][CH:52]=3)[C:31]3[NH:32][C:33]([C@@H:35]5[CH2:39][C@H:38]([CH2:40][O:41][CH3:42])[CH2:37][N:36]5[C:66](=[O:68])[C@H:65]([NH:64][C:62](=[O:63])[O:61][CH3:60])[C:69]5[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=5)=[N:34][C:30]=3[CH:29]=[CH:28]4)=[C:21]([C:53]#[C:54][CH3:55])[CH:20]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: CC#Cc1cc(-c2cnc([C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]2)ccc1-c1ccc2c(ccc3nc([C@@H]4C[C@H](COC)CN4C(=O)OC(C)(C)C)[nH]c32)c1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC#Cc1cc(-c2cnc([C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]2)ccc1-c1ccc2c(ccc3nc([C@@H]4C[C@H](COC)CN4C(=O)[C@H](NC(=O)OC)c4ccccc4)[nH]c32)c1
Reaction time: 2 h
Yield: 21.7 %

Procedure:
(2S,4S)-tert-butyl 2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-2-(prop-1-ynyl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (66 mg, 0.084 mmol) was dissolved in DCM (2 mL), MeOH (0.5 mL) and HCl (4 M in dioxane, 0.5 mL) was added. The reaction mixture was stirred for 2 h and then concentrated under reduced pressure. The crude residue was treated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (18 mg, 0.084 mmol), COMU (40 mg, 0.084 mmol) and DMF (3 mL), then DIPEA (0.73 mL, 0.42 mmol) was added dropwise. After 15 h, the mixture was diluted with 10% MeOH/EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by HPLC to afford methyl (R)-2-((2S,4S)-2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-2-(prop-1-ynyl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (16 mg, 21%). LCMS-ESI+: calculated for C50H54N8O7: 878.41; observed [M+1]+: 879.60.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@H:12]1[C:15](=[O:16])[NH:14][C@H:13]1[CH2:17][I:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[O:21].B(F)(F)F.CCOCC>O1CCCC1>[O:1]([CH2:8][C:9]([NH:11][C@H:12]1[C:15](=[O:16])[N:14]([CH:20]([OH:21])[C:19]([O:23][CH3:24])=[O:22])[C@H:13]1[CH2:17][I:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C=O
Reactant: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1CI
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(O)N1C(=O)[C@H](NC(=O)COc2ccccc2)[C@@H]1CI
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of 0.360 g (1.0 mmol) of cis-3-phenoxyacetamido-4-oxo-2-azetidinylmethyl iodide, 0.440 g (5.0 mmol) of methyl glyoxylate, and 246 μl (2.0 mmol) of boron trifluoride etherate in 10 ml of anhydrous tetrahydrofuran is stirred at ambient temperature under an argon atmosphere for 5 hours. At this time 123 μl (1.0 mmol) of boron trifluoride etherate is added and the mixture is stirred for an additional 2 hours. The tetrahydrofuran is removed in vacuo and the residue is taken up in ethyl acetate and extracted with aqueous NaHCO3 and brine. The ethyl acetate solution is dried, filtered and evaporated to give 0.350 g of crude product which is purified by preparative thin-layer chromatography (silica gel GF); 0.174 g of pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[O:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1.C1COCC1>O>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:18])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:13][C:12]=1[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:9]
Reactant: COc1ccc(C(=O)c2ccc3noc(-c4cccc(Cl)c4)c3c2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)c2ccc(N)c(C(=O)c3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
Intermediate 10 (0.0536 mol) was added at room temperature to THF (200 ml). TiCl3 15% in water (120 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 3 hours, poured out into ice water and extracted with DCM. The organic layer was separated, washed with K2CO3 10% then with water, dried (MgSO4), filtered and the solvent was evaporated, yielding 20.5 g (quantitative) of [2-amino-5(4-methoxybenzoyl)phenyl](3-chlorophenyl)-methanone (intermediate 11).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[C:3]1[CH:8]1[C:17](=O)[C:16]2[C:15]([C:19]([O:21]CC)=O)=[CH:14][CH:13]=[CH:12][C:11]=2[NH:10][CH:9]1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.O.[NH2:32][NH2:33]>CO>[CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[C:3]1[CH:8]1[C:17]2=[N:32][NH:33][C:19](=[O:21])[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=32)[NH:10][CH:9]1[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nnc(C)n1C)C(c1ccc(F)cc1)N2
Solvent: CO
Solvent: O
Product: Cc1nnc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(F)cc2)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
A mixture of ethyl 3-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (170 mg) in 85% hydrazine monohydrate (1 mL) and methanol (3 mL) was stirred at 25° C. for 3 h. The mixture was purified by prep-HPLC to obtain the title compound as a yellow solid (40 mg, yield: 26%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.23 (s, 3H), 3.38 (s, 3H), 4.78-4.80 (d, J=11.0 Hz, 1H), 4.99-5.02 (d, J=11.0 Hz, 1H), 7.11-7.18 (m, 3H), 7.35-7.40 (m, 2H), 7.47-7.51 (m, 2H), 7.57-7.61 (t, J=7.6 Hz, 1H), 12.19 (s, 1H); LC-MS (ESI) m/z: 377 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].CO[C:19]([CH3:21])=[CH2:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[CH3:20][CH:19]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14])[CH3:21]
Reactant: C=C(C)OC
Reactant: COC(=O)c1sc(-c2ccncc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccncc2)cc1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a mixture of methyl 3-amino-5-(pyridin-4-yl)thiophene-2-carboxylate (0.469 g, 2.00 mmol), 2-methoxypropene (0.29 mL, 3.0 mmol) and acetic acid (0.114 mL, 2.00 mmol) in dichloromethane (6 mL) was added sodium triacetoxyborohydride (0.636 g, 3.00 mmol), and the reaction was stirred at room temperature overnight. Then, the reaction mixture was poured into sat. NaHCO3 (70 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated, and the residue was purified by flash chromatography (Combiflash, silica gel, hexanes to ethyl acetate) to give the title compound (0.256 g, 46%) as a yellow solid:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:18])=[O:6].[H-].[Na+].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[N:27]=1>CN(C)C=O>[Br:25][C:26]1[N:27]=[C:28]([CH2:32][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:2]([CH3:1])[CH:3]=3)=[C:8]2[CH3:18])[CH:29]=[CH:30][CH:31]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cc1ccc(C(=O)c2c(C)[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2c(C)n(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 57 mg (0.20 mmol) of 3-(3,4-dimethyl-benzoyl)-2-methyl-1H-quinolin-4-one, 9 mg (0.24 mmol) of 60% sodium hydride, 59 mg of 2-bromo-6-bromomethyl-pyridine and 0.7 mL of N,N-dimethylformamide. Yield: 44 mg of a white solid: LC-MSD, m/z for C25H21BrN2O2 [M+H]+=461.1, 463.1; HPLC retention time: 2.7 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1)=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[N:9]=[N:8][N:7]([CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[C:6]=2[CH2:4][OH:3])=[N:12][CH:13]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cn2)nnn1C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)Cn1nnc(-c2ccc(F)cn2)c1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
To a solution of 5-(5-fluoro-pyridin-2-yl)-3-trimethylsilanylmethyl-3H-[1,2,3]triazole-4-carboxylic acid ethyl ester (530 mg, 1.64 mmol) in toluene (15 mL) at −7° C. was added sodiumdihydro-bis(2-methoxyethoxy)aluminate (705 μL, 2.47 mmol) and the reaction mixture was stirred at room temperature for 16 h. The mixture was then cooled with ice and NaOH (1 N, 3.3 mL) and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated to afford the title compound (440 mg, 84%) as a light brown oil. MS: m/e=281.1 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]([NH:18]C(=O)OC(C)(C)C)[C:12]1=[O:26])(C(C)(C)C)(C)C.[ClH:27].O1CCOCC1>ClCCl>[ClH:27].[NH2:18][C@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][N:11]([CH2:10][CH2:9][OH:8])[C:12]1=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(CCO[Si](C)(C)C(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CCCCN(CCO)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxoazepan-3-ylcarbamate (prepared according to Example 15; 243 mg, 0.629 mmol) in dichloromethane (2 mL) was added 4M hydrogen chloride in dioxane (2 mL, 8 mmol), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was concentrated to yield (S)-3-amino-1-(2-hydroxyethyl)azepan-2-one hydrochloride (131 mg, 100%), which was taken on to the next reaction without further purification.
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:51]([O:52][Si](C(C)(C)C)(C)C)[CH:41]6[CH:42]([O:43][CH2:44][C:45]7[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=7)[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:60]([CH3:62])[CH3:61])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH2:44]([O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:60]([CH3:62])[CH3:61])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:51]([OH:52])[CH:41]1[O:40]3)[O:36]2)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(OCc6ccccc6)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(OCc6ccccc6)C5O2)C4O)C13C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
15 mg of compound (75) was dissolved in 1 ml of ethyl acetate and allowed to react in the presence of a catalytic amount of 10% palladium-carbon under stirring under a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The reaction product was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×30 cm) and eluted with chloroform-methanol (20:1). The fraction containing the desired product was concentrated to dryness to give 10.0 mg of compound (76).
Reaction SMILES: [CH2:1]1[O:7][CH2:6][C@@H:4](O)[C@H:2]1O.I([O-])(=O)(=O)=O.[Na+].[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[C:22]1[CH:23]=[N:24][O:25][C:26]=1[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[C:33]([C:36]3[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH:37]=3)[CH:34]=2)[NH:29][CH:28]=1.C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>O.CO>[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[C:22]1[CH:23]=[N:24][O:25][C:26]=1[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[C:33]([C:36]3[CH2:41][CH2:40][CH:39]([N:42]4[CH2:2][CH2:1][O:7][CH2:6][CH2:4]4)[CH2:38][CH:37]=3)[CH:34]=2)[NH:29][CH:28]=1
Reactant: O[C@@H]1COC[C@@H]1O
Reactant: NC1CC=C(c2cnc3[nH]cc(-c4oncc4-c4cccc(F)c4F)c3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(-c2cnoc2-c2c[nH]c3ncc(C4=CCC(N5CCOCC5)CC4)cc23)c1F
Yield: 36 %

Procedure:
A solution of 1,4-anhydroerythritol (208 mg, 2 mmol) in water was treated with sodium periodate (400 mg, 4 mmol)for 12 h, transferred to a solution of 4-{3-[4-(2,3-difluoro-phenyl)-isoxazol-5-yl]-1H-pyrrolo [2,3-b]pyridin-5-yl}-cyclohex-3-enylamine (50 mg, 0.12 mmol) in methanol (5 ml). The resulting solution was treated with sodium cyanoborohydride. After the reaction was completed, TFA was added, and the mixture was concentrated and purified by HPLC to give the morpholine product (20 mg) in 36% yield.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:26])[NH:19]2)(=[O:3])N.[OH-:27].[K+].Cl>O.C(O)C>[OH2:3].[C:1]([CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:26])[NH:19]2)([OH:3])=[O:27].[C:1]([CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:26])[NH:19]2)([OH:3])=[O:27]
Reactant: [OH-]
Reactant: COc1ccc(-c2nc3ccccn3c2CC(N)=O)c2ccc(=O)[nH]c12
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc3ccccn3c2CC(=O)O)c2ccc(=O)[nH]c12
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of 5-{3-carbamoylmethylimidazo-[1,2-a]pyridine-2-yl}-8-methoxycarbostyril (1.6 g), potassium hydroxide (2.6 g), water (3 ml) and ethanol (9 ml) was refluxed for 1 hour. After completion of reaction, water was added to the reaction mixture, which was then treated with activated carbon and adjusted to pH of about 1 by the addition of concentrated hydrochloric acid followed by allowing to stand overnight. Crystals which precipitated were collected by filtration and recrystallized from dilute hydrochloric acid to give 0.9 g of 5-{3-carboxymethylimidazo[1,2-a]pyridine-2-yl}-8-methoxycarbostyril hemihydrate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])[CH3:2].S(Cl)([Cl:17])=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:5]=1[C:6]([Cl:17])=[O:7])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1cc(C#N)ccc1C(=O)O
Solvent: ClCCl
Product: CCOc1cc(C#N)ccc1C(=O)Cl
Yield: 99 %

Procedure:
2-Ethoxy-4-cyanobenzoic acid (10 g, 52.3 mmol), prepared as in Preparation 10, and thionyl chloride (50 ml,) were refluxed in CH2Cl2 (80 ml) for 5 h. Solvent was removed under vacuum to leave 10.9 g of an off white solid (52 mmol, yield 99%) that was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1)([O-])=O.C1CCCCC=1>CCO.[Pd]>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1
Reactant: O=C1NS(=O)(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Nc1ccc2c(c1)S(=O)(=O)NC2=O
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of 6-nitro-1,1-dioxo-1,2-dihydro-1lambda*6*-benzo[d]isothiazol-3-one (11.4 g, 50.0 mmol) and cyclohexene (25.4 mL, 250 mmol) in EtOH (100 mL) was added 5% Pd—C (35 g) at about 0° C. The mixture was refluxed overnight with stirring and then cooled to rt, filtered through Celite® several times until the filtrate became clear. The filtrate was concentrated under reduced pressure. The material was dissolved in saturated aqueous NaHCO3 (200 mL), filtered and to the filtrate was added concentrated hydrochloric acid (pH=7). The precipitate was collected by filtration and washed with water (2×50 mL) to provide 6-amino-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (8.0 g, 68%): 1H NMR (DMSO-d6) δ: 7.61 (s, 1H), 7.59 (s, 1H), 6.95 (d, J=2.0 Hz, 2H), 6.91 (d, J=2.4 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](NC1C=CC(NC2C=CC=CC=2)=CC=1)(=O)C>>[C:1]1([C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][O:9]1)=[O:8]
Reactant: O=C(O)c1ccccc1
Reactant: CC(=O)Nc1ccc(Nc2ccccc2)cc1
Product: O=C1OCc2ccccc21

Procedure:
Following procedure similar to that described in Example 4 but employing 5.1 g of 2-[4-(diethylamino)-2-ethoxy)-benzoyl]benzoic acid and 3.4 g of 4-acetamido-N-phenylaniline there was obtained 4.8 g of 3-[4-(diethylamino)-2-ethoxyphenyl]-3-](4-acetamidophenyl)phenylamino]phthalide, m.p. 126°-131° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed and orange-colored image.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:14]\[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)/[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.Cl>O1CCCC1.CO.[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:14]\[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)/[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/C(=O)O)c2ccc(Br)cc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
Ethyl E-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (600 mg) was dissolved in tetrahydrofuran (6 ml)-methanol (3 ml), and 1N aqueous solution of sodium hydroxide (3 ml) was added and the mixture was stirred for 1 hour at 40° C. 1N HCl (3.3 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystals were recrystallized from ethyl acetate to obtain E-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid (516 mg, yield 99%) as colorless crystals. m.p. 159-160° C. (decomposition)
Reaction SMILES: Cl[C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[C:5]([C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([CH:9]=[CH:8][CH:7]=1)[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1)#[N:6]
Reactant: N#Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: Nc1ccc(CCO)cc1
Product: N#Cc1cccc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-chloro-2-nitrobenzonitrile (step 2) and 4-aminophenylethyl alcohol.