Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[CH2:23]([C@@H:30]1[CH2:35][C@@H:34]([N:36]([CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[CH:46][CH:45]=2)C(=O)C(F)(F)F)[CH2:33][CH2:32][NH:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[F:54][C:55]([F:70])([F:69])[C:56]1[CH:57]=[C:58]([CH:62]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:64]=1)[C:59](O)=[O:60]>C(Cl)Cl>[CH2:23]([C@@H:30]1[CH2:35][C@@H:34]([NH:36][CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[CH:46][CH:45]=2)[CH2:33][CH2:32][N:31]1[C:59](=[O:60])[C:58]1[CH:62]=[C:63]([C:65]([F:66])([F:67])[F:68])[CH:64]=[C:56]([C:55]([F:54])([F:69])[F:70])[CH:57]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
143 mg (561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine are added to a solution of 200 mg (467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 113 mg (561 mmol) of 3,5-bis-(trifluoromethyl)-benzoic acid in 3 ml of methylene chloride, and the reaction mixture is left to stir at room temperature for 16 hours. It is then diluted with methylene chloride, and the organic phase is washed once each with 10% strength citric acid, 1N sodium bicarbonate solution and with brine, dried over magnesium sulfate and evaporated to dryness. The yellowish foam is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (1000:50:1). The title compound is obtained as yellow oil. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.34, FD-MS: M+ =667.
Reaction SMILES: B(Br)(Br)Br.[NH:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][N:12]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.O>C(Cl)Cl>[NH:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][N:12]=1
Reactant: COc1ccc(Cc2ncc[nH]2)nc1
Agent: BrB(Br)Br
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Cc2ncc[nH]2)nc1
Reaction time: 0.5 h
Yield: 342.9 %

Procedure:
Boron tribromide (1.0 ml) was added dropwise to a stirred solution of 2-(1-imidazolylmethyl)-5-methoxy-pyridine (0.0378 g.) (prepared similarly to Example 18 but without converting the end product to the dihydrochloride) in dry methylene chloride (20 ml) at -70° and the resulting mixture was stirred at -70° for 30 minutes, and then at room temperature for 3 hours. Water was then added and the layers were separated. The aqueous layer was made just alkaline with solid sodium bicarbonate and evaporated to dryness. The residue was extracted several times with hot ethyl acetate and the combined extracts were filtered and evaporated until crystallisation commenced. The mixture was allowed to cool and the solid was filtered off to give 2-(1-imidazolylmethyl)-5-hydroxypyridine (0.120 g), m.p. 149°-151°.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:35])=[C:16]([N:22](S(CCC)(=O)=O)[S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2.[CH3:36][C:37]1[NH:38][CH:39]=[CH:40][N:41]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:35][C:15]1[C:14]([C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([N:38]2[CH:39]=[CH:40][N:41]=[C:37]2[CH3:36])=[N:11]3)=[O:13])=[C:19]([F:20])[C:18]([F:21])=[CH:17][C:16]=1[NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:24])=[O:25]
Reactant: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F)S(=O)(=O)CCC
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(-n4ccnc4C)nc3c2)c1F
Temperature: 90 °C
Reaction time: 4 h
Yield: 0.7 %

Procedure:
To a solution of N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 9.6 mmol, 1.0 eq.) in DMF (2 mL) was added 2-methyl-1H-imidazole (18 mg, 24 mmol, 2.5 eq.) and Cs2CO3 (59 mg, 19.2 mmol, 2.0 eq.). The resulting mixture was stirred at 90° C. for 4 h, then washed with water and extracted with EA (20 mL×3). The combined organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (DCM/MeOH-30/1, v/v) to afford N-(2,4,5-trifluoro-3-(3-(2-methyl-1H-imidazol-1-yl)quinoxaline-6-carbonyl)phenyl)propane- 1-sulfonamide (34 mg, 73%). LRMS (M+H+) m/z calculated 490.1, found 489.9. 1H NMR (DMSO, 400 MHz) δ 10.13 (brs, 1 H), 9.46 (s, 1 H), 8.56 (s, 1 H), 7.95 (s, 1 H), 8.36 (brs, 2 H), 7.77 (m, 1 H), 7.94 (s, 1 H), 2.69 (s, 3 H), 3.21 (m, 2 H), 1.75 (m, 2 H), 0.97 (s, 3 H).
Reaction SMILES: [C:1]1([S:7]([N:10]([CH2:12][C:13]([OH:15])=O)[CH3:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([N:52]3[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]3)=[N:48][CH:49]=[CH:50][N:51]=2)=[CH:42][CH:41]=1>ClCCl>[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([N:52]3[CH2:53][CH2:54][N:55]([C:13](=[O:15])[CH2:12][N:10]([CH3:11])[S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:8])=[O:9])[CH2:56][CH2:57]3)=[N:48][CH:49]=[CH:50][N:51]=2)=[CH:42][CH:41]=1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: CN(CC(=O)O)S(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CN(CC(=O)N1CCN(c2nccnc2-c2ccc(F)cc2)CC1)S(=O)(=O)c1ccccc1
Yield: 69 %

Procedure:
Dissolve (benzenesulfonyl-methyl-amino)-acetic acid (0.150 g, 0.654 mmol) in dichloromethane (5 mL). Add 1-hydroxybenzotriazole hydrate (0.081 g, 0.595 mmol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.114 g, 0.595 mmol). Add 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.154 g, 0.595 mmol) and stir at ambient temperature for 18 hr. Add dichloromethane and water and separate layers. Extract the aqueous layer three times with dichloromethane. Dry the combined organic layers over magnesium sulfate, filter and concentrate under reduced pressure to give residue. Purify the residue by chromatography on silica gel eluting with 50-100% ethylacetate/hexanes to give the title preparation (193 mg, 69% yield). MS (ES+) m/z: 470 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:18][CH:17]([CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([NH:31][C@H:32]([C:37]#[CH:38])[CH2:33][C:34]([OH:36])=[O:35])=[O:30])[CH2:24]2)=[O:22])[CH2:16]1)=O)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:15]1[CH2:18][CH:17]([CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([NH:31][C@H:32]([C:37]#[CH:38])[CH2:33][C:34]([OH:36])=[O:35])=[O:30])[CH2:24]2)=[O:22])[CH2:16]1
Reactant: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)CCC2CN(C(=O)OC(C)(C)C)C2)C1
Solvent: O=C(O)C(F)(F)F
Product: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)CCC2CNC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
Trifluoroacetic acid (3 ml) was added to N-[(R)-1-[3-(1-tert-butoxycarbonyl-3-azetidinyl)propanoyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine (1.11 g, 2.55 mmol). The reaction mixture was stirred for 1 hour at room temperature. Solvent was evaporated in vacuo. The residue was purified by HPLC to give N-[(R)-1-[3-(3-azetidinyl)propanoyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine trifluoroacetate (270 mg, 23.6%).
Reaction SMILES: [O:1]([CH2:8][C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:15]#[N:16])(C)C>C1(C)C=CC=CC=1>[NH2:10][CH:9]([CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:15]#[N:16]
Reactant: C[Si](C)(C)C#N
Reactant: N#CCOc1ccccc1
Solvent: Cc1ccccc1
Product: N#CC(N)COc1ccccc1
Temperature: 0 °C
Yield: 20 %

Procedure:
10 millimoles (1.33 g) of phenoxyacetonitrile are dissolved in 10 ml of anhydrous toluene at 0° C., under an argon atmosphere. A solution of vitridenide (NaH2AL1 [0-CH2 -CH2OCH3 ]2) at 70% in toluene (1,4 ml viz 0.5 eq) in 3 m of anhydrous toluene is added, dropwise, at this temperature. The stirring is maintained for 1 hour at 0° C., then 2 ml (1.5 eq) of trimethylsilyl cyanide are added. The reaction mixture is maintained at room temperature for 3 hours, while stirring, then hydrolyzed by usual way. After purification by acid base extraction, there are obtained 0.300 g of 2-amino-3-phenoxy propionitrile with a yield of 20%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[CH3:14]>CCOC(C)=O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([NH:6]/[N:7]=[C:13](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[CH3:14])=[O:5]
Reactant: CC(=O)c1ccccc1
Reactant: NNC(=O)c1cc(F)ccc1F
Solvent: CCOC(C)=O
Product: C/C(=N\NC(=O)c1cc(F)ccc1F)c1ccccc1

Procedure:
A solution of 2,5-difluorobenzohydrazide (1-2, 90 mg, 0.52 mmol, 1 equiv) and acetophenone (61 μL, 0.52 mmol, 1.0 equiv) was heated in EtOAc (10 mL) at 75° C. for 3 d. The reaction mixture was concentrated to give 2,5-difluoro-N′-[(1E)-1-phenylethylidene]benzohydrazide (2-1); LRMS m/z (M+H) 275.1 found, 275.1 required. A solution of 2-1 in acetic anhydride (5 mL) was heated at reflux for 1.5 h. The reaction mixture was concentrated and the residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 3-acetyl-5-(2,5-difluorophenyl)-2-methyl-2-phenyl-2,3-dihydro-1,3,4-oxadiazole (2-2) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.56 (m, 2H), 7.48 (m, 1H), 7.39 (m, 3H), 7.14 (m, 2H), 2.35 (s, 3H), 2.30 (s, 3H). LRMS m/z (M+H) 317.2 found, 317.1 required.
Reaction SMILES: [CH3:1][CH:2]([CH:8]([N+]([O-])=O)[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+].[OH:20]P([O-])(O)=O.[K+].[OH-].[Na+].CCOCC>CO.[Cl-].[Cl-].[Ti+2]>[CH3:1][CH:2]([C:8](=[O:20])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(C)C(CC=C(C)C)[N+](=O)[O-]
Reactant: O=P([O-])(O)O
Agent: [Ti+2]
Agent: C[O-]
Agent: [Cl-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)CC(C)C(=O)CC=C(C)C
Reaction time: 1 h
Yield: 35 %

Procedure:
A solution of methyl 3,7-dimethyl-4-nitro-6-octenoate (24.55 g, 0.107 m) in methanol (10 ml) is added dropwise to a solution of sodium methoxide (6.37 g, 0.118 m) in methanol (250 ml) at room temperature under nitrogen. The mixture is stirred for 1 hour, added to a mixture of 20% titanous chloride (170 ml, 0.267 m) and pH 7 buffer (potassium phosphate monobasic-sodium hydroxide buffer) solution (340 ml). The resulting mixture is stirred for 30 minutes after which it is treated with ether (1 l). The organic phase is separated, dried (Na2SO4) and evaporated in vacuo to give the crude product (15.4 g). This material is purified by column chromatography on silica gel (300 g, 2% ethyl acetate in hexane) to give methyl 3,7-dimethyl-4-oxo-6-octenoate as a colorless liquid (6.8 g, 35%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]3[CH2:26][CH2:25][CH:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)[CH:16]=2)=[O:13])=[CH:7][C:6]=1[O:31][CH3:32].[NH2:33][CH2:34][CH2:35][OH:36].C(N(CC)CC)C.C(Cl)(Cl)Cl>C(#N)C>[C:27]([CH:24]1[CH2:25][CH2:26][CH:21]([C:17]2[CH:16]=[C:15]([NH:14][C:12](=[O:13])[CH2:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:33][CH2:34][CH2:35][OH:36])=[C:6]([O:31][CH3:32])[CH:7]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:22][CH2:23]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: NCCO
Reactant: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1OCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1OCCNCCO
Yield: 88.5 %

Procedure:
Intermediate 5 (200 mg), 2-aminoethanol (122 mg) and triethylamine (45 mg) are dissolved in acetonitrile (5 ml), and the mixture is heated under reflux for 18 hours. To the reaction solution is added chloroform, and the mixture is washed with water. The organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 20% chloroform/methanol) to give the desired compound (170 mg).
Reaction SMILES: [C:1]1([C:7](=[O:11])[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(C)C.C1C=CC=CC=1.C1C=CC=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[C:1]1([CH:7]([OH:11])[C:8]#[C:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)c1ccccc1
Agent: Cl[Ru]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: c1ccccc1
Product: CC#CC(O)c1ccccc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Benzeneruthenium(II) chloride dimer (1.0 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=t-Bu, Ar=3,5-t-Bu2C6H3—, 2.6 μmol, 0.65 mol %) were dissolved in i-propanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 85° C. After the mixture was cooled to room temperature, 1-phenylbutan-1-one (0.4 mmol), i-propanol (2 mL) and a solution of sodium hydroxide in i-propanol (0.4 mL, 0.4 M) were added thereto. Thereafter, the reaction system were placed in an autoclave, and stirred for 12 h under H2 (10 atm) at 40° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/8). Accordingly, pure 1-phenylbutynol was obtained and the ee value (ee=99.2%) was measured by GC analysis.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.[Br:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20](Br)[CH:19]=1>>[Br:17][C:18]1[CH:19]=[C:20]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(Br)c3)cc21

Procedure:
6-(3-Bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one was prepared, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1,3-dibromo-5-fluorobenzene following the procedure of Example 5, as a white solid: mp 182-183° C.; 1H-NMR (DMSO-d6) δ 10.36 (s, 1H, D2O exchangeable), 7.78 (s, 1H), 7.58-7.65 (m, 3H), 7.49 (dd, 1H, J=8.3, 1.8 Hz), 6.96 (d, 1H, J=8.5 Hz), 1.69 (s, 6H); 19F-NMR (DMSO-d6) δ −112.46 (m, 1F); MS (CI) m/z 352 ([M+H]+, 78%), 350 ([M+H]+, 75%); Anal. Calcd. For C16H13BrFNO2: C, 54.88; H, 3.74; N, 4.00. Found: C, 54.83; H, 3.82; N, 3.95.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11](=[O:40])[N:12]([CH3:39])[CH:13]=[C:14]([CH2:19][CH2:20][O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]=1[C:16]([OH:18])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN=C=NCCCN(C)C.[Cl:75][C:76]1[CH:77]=[C:78]([CH:81]=[CH:82][CH:83]=1)[CH2:79][NH2:80]>CN(C)C=O.O>[C:1]([O:9][C:10]1[C:11](=[O:40])[N:12]([CH3:39])[CH:13]=[C:14]([CH2:19][CH2:20][O:21][Si:22]([C:35]([CH3:36])([CH3:38])[CH3:37])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:15]=1[C:16](=[O:18])[NH:80][CH2:79][C:78]1[CH:81]=[CH:82][CH:83]=[C:76]([Cl:75])[CH:77]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C(=O)O)c(OC(=O)c2ccccc2)c1=O
Reactant: NCc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C(=O)NCc2cccc(Cl)c2)c(OC(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzoyloxy-5-[2-(tert-butyldiphenylsilanyloxy)ethyl]-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.956 g) in dimethylformamide (10 ml) were added 1-hydroxybenzotriazole hydrate (HOBT) (0.395 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, (WSC) (0.495 g) and 3-chlorobenzylamine (0.274 ml) and the mixture was stirred at room temperature for 2 hr. Water was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under,reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give 5-[2-(tert-butyldiphenylsilanyloxy)ethyl]-4-(3-chlorobenzylcarbamoyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl benzoate (0.615 g). This compound was dissolved in tetrahydrofuran (20 ml), and acetic acid (0.259 ml) and tetrabutylammonium fluoride (0.474 g) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1) to give 4-(3-chlorobenzylcarbamoyl)-5-(2-hydroxyethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl benzoate (0.213 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[C:11]([C:26]2[O:27][CH:28]=[CH:29][N:30]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1.[Ni]>[CH2:1]([NH:8][C:9]1[C:14]([NH2:15])=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[C:11]([C:26]2[O:27][CH:28]=[CH:29][N:30]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(-c2ncco2)nc1NCc1ccccc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1c(NCc2ccccc2)cc(-c2ncco2)nc1NCc1ccccc1
Yield: 100.1 %

Procedure:
N*2*,N*4*-Dibenzyl-3-nitro-6-oxazol-2-yl-pyridine-2,4-diamine (1.02 g, 2.54 mmol) was dissolved in THF (60 ml) then MeOH (60 ml) was added. The solution was hydrogenated over Raney nickel (210 mg, 0.25 mmol) under a hydrogen atmosphere (80 psi) for 1 hour. The reaction mixture was filtered through a Celite pad then evaporated to yield the title compound as a brown gum (944 mg, 100%). Taken on without further purification due to stability concerns.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C[Si](C)(C)N[Si](C)(C)C>>[CH2:7]([C:8]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CNCCN1
Reactant: O=C(O)Cc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: O=C(Cc1ccccc1)N1CCNCC1
Yield: 82.2 %

Procedure:
The procedures of Example 1 were followed except that phenyl acetic acid (3.4 grams, 25 mmole), piperazine (4.3 grams, 50 mmole) and 1,1,1,3,3,3-hexamethyldisilazane (4.0 grams, 25 mmole) were reacted for 5 hours under 110° C. After extraction purification, 4.2 grams of Compound 10 was obtained. Yield: 82%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:12]=[C:13]([C:26]2[C:27]([S:32]([NH:35][CH3:36])(=[O:34])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:14]=[CH:15][C:16]=1B1OC(C)(C)C(C)(C)O1>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:16]2[CH:15]=[CH:14][C:13]([C:26]3[C:27]([S:32]([NH:35][CH3:36])(=[O:33])=[O:34])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:12][C:11]=2[F:10])=[N:3][C:4]=1[CH3:9]
Reactant: CNS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: Cc1nc(Br)cnc1N
Product: CNS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)c(C)n2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-bromo-3-methylpyrazin-2-amine and 3′-fluoro-N-methyl-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide. MS (ESI): mass calcd. for C18H17FN4O2S, 372.11; m/z found, 373.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.27 (s, 1H), 8.09-8.00 (d, J=7.9, 1H), 7.96-7.87 (m, 1H), 7.71-7.63 (m, 1H), 7.63-7.55 (m, 1H), 7.44-7.38 (d, J=7.5, 1H), 7.34-7.21 (m, 2H), 2.46 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([N:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([NH2:40])[C:34]=2[C:33]([I:41])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O.C(OCC)C>[CH2:24]([N:31]1[C:39]2[C:34](=[C:35]([NH:40][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:17])[CH:36]=[CH:37][CH:38]=2)[C:33]([I:41])=[N:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Reactant: Nc1cccc2c1c(I)nn2Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3c(I)nn4Cc3ccccc3)cnc2c1

Procedure:
7-(2-M ethoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (150 mg; 0.635 mmol) was suspended in methylene chloride (2 mL), with stirring, under an atmosphere of dry nitrogen. Oxalyl chloride (0.698 mmol) was added as a 2N solution in dichloromethane (0.35 mL). A catalytic amount of dimethylformamide (1 drop) was added. The mixture was stirred until effervescence had ceased (30 minutes). 1-Benzyl-3-iodo-1H-indazol-4-amine (product of step G) (222 mg; 0.635 mmol) was added as a solution in dichloromethane (2 mL). Diisopropylethylamine (213 mg; 0.29 mL; 1.65 mmol) was added and the mixture was stirred under nitrogen in a sealed vessel for 24 hours. A thick suspension formed. The mixture was diluted with diethyl ether (20 mL) and the solids were collected by filtration. The solids were washed with ether and water and then dried under vacuum. This gave the desired product, N-(1-Benzyl-3-iodo-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide, as an off white solid (139 mg). MS (APCI), positive scan, m/z=568.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1C#N
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Methyl 3-cyano-4-methoxybenzoate (879 mg) was dissolved in tetrahydrofuran (8 mL) and water (4 mL), and lithium hydroxide monohydrate (772 mg) was added to the solution, and then the mixture was stirred at mom temperature for 1 hour. The organic solvent was distilled off under reduced pressure and acidified with 2N hydrochloric acid, and then the precipitated crystal was collected by filtration to obtain the title compound (754 mg) as a colorless crystal.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH:23](OS(C(F)(F)F)(=O)=O)[CH:22]4[C:16]([CH2:17][CH2:18][N:19]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:20][CH2:21]4)=[N:15]3)[CH2:10][CH2:9]2)C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:23]=[C:22]3[C:16]([CH2:17][CH2:18][N:19]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:20][CH2:21]3)=[N:15]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2=NN(C3CCN(Cc4ccccc4)CC3)C(OS(=O)(=O)C(F)(F)F)C2CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cn(C3CCNCC3)nc2CC1

Procedure:
A mixture of 1,1-dimethylethyl 2-[1-(phenylmethyl)-4-piperidinyl]-3-{[(trifluoromethyl)sulfonyl]oxy}-3,3a,4,5,7,8-hexahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 48) (355 mg, 0.64 mmol) in ethyl acetate (9 ml) and methanol (3 ml) was treated with triethylamine (0.443 ml, 3.18 mmol) and then Pd(OH)2/C (20% w/w, 70 mg) and the resulting mixture stirred under an atmosphere of H2 for 18.5 h. The mixture was then filtered through kieselguhr and reduced under vacuum. Purification by Mass Directed Autopreparation afforded the title compound (D49). MS (ES+) m/e 321 [M+H]+.