Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.[Si:12]([O:19][C@H:20]([CH3:23])[C:21]#[CH:22])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[F:24][C:25]1[CH:26]=[C:27]([NH:37][C:38]([C:40]2[CH:45]=[N:44][CH:43]=[CH:42][N:41]=2)=[O:39])[CH:28]=[CH:29][C:30]=1[C:31](N(OC)C)=[O:32]>O.O1CCCC1>[Si:12]([O:19][C@H:20]([CH3:23])[C:21]#[C:22][C:31]([C:30]1[CH:29]=[CH:28][C:27]([NH:37][C:38]([C:40]2[CH:45]=[N:44][CH:43]=[CH:42][N:41]=2)=[O:39])=[CH:26][C:25]=1[F:24])=[O:32])([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:13])[CH3:14]
Reactant: CON(C)C(=O)c1ccc(NC(=O)c2cnccn2)cc1F
Reactant: C#C[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C[C@H](C#CC(=O)c1ccc(NC(=O)c2cnccn2)cc1F)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.8 ml of n-butyllithium (2.46 M hexane solution was added to a tetrahydrofuran (80 ml) solution of 4.92 g of (3R)-3-(tert-butyl(dimethyl)silyl)oxy-1-butyne at −78° C., and the reaction liquid was stirred at the same temperature for 1 hour. A tetrahydrofuran (60 ml) solution of 2.7 g of N-(3-fluoro-4-((N-methoxy-N-methylamino)carbonyl)phenyl)pyrazine-2-carboxamide was added to it at −78° C., and the reaction liquid was heated up to room temperature and stirred for 2 hours. Water was added to the reaction liquid, extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 1/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16](=[O:29])[C@H:17]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:30]12([CH2:40][CH:41]=O)[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.C(OCC)(=O)C.C(Cl)Cl>C(Cl)Cl>[C:30]12([CH2:40][C@@H:41]3[C:21]4[NH:22][C:23]5[C:28]([C:20]=4[CH2:19][C@@H:17]([C:16]([O:15][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[O:29])[NH:18]3)=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:31][CH:32]3[CH2:38][CH:36]([CH2:35][CH:34]([CH2:33]3)[CH2:39]1)[CH2:37]2
Reactant: O=CCC12CC3CC(CC(C3)C1)C2
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1Cc2c([nH]c3ccccc23)[C@@H](CC23CC4CC(CC(C4)C2)C3)N1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Trifluoroacetic acid (270 μl, 3.5 mmol) was added to a solution of L-tryptophan benzyl ester (10.23 g, 34.8 mmol) and 1-adamantylacetaldehyde (6.2 g, 34.8 mmol) in dry DCM (300 ml) wth 3A molecular sieves (46.5 g) at -10° C. The reaction mixture was allowed to warm to room temperature and stirred for 7 hours. The mixture was cooled to 0° C. trifluoroacetic acid (5.6 ml, 72.7 mmol) added, and stirring continued at room temperature for 16 hours. The reaction mixture was filtered, washed successively with saturated NaHCO3 solution (200 ml), brine (2×200 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product. The compound was obtained by isolation of the more polar component by flash chromatography on silica gel with ethyl acetate-DCM (1:40) as eluant. (6.2 g, 39%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([N:23](CC)CC)C.CS(Cl)(=O)=O.O>C1COCC1.CN(C=O)C.[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:21]#[N:23])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of Example 39A (1.88 g, 6.6 mmol) and triethylamine (0.92 mL, 6.6 mmol) in THF (20 mL) at 0° C. under nitrogen was added methanesulfonyl chloride (1.51 g, 13.2 mmol). The mixture was allowed to warm up to room temperature and stirred for 12 hours after which it was concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to provide a yellow liquid. The yellow liquid was taken up in 100 mL of dry DMF under nitrogen and tetrabutylammonium cyanide (5 g, 20 mmol) was added to the solution. The mixture was heated to 50° C. for 60 hours after which the mixture was poured into cold water and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried (MgSO4), filtered, concentrated under reduced pressure and purified by flash silica gel chromatography eluting with 50% ethyl acetate/50% hexane to provide the titled compound. MS (DCI/NH3) m/e 294 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 1.43 (s, 5 H) 1.49 (s, 4 H) 1.86 (m, 2 H) 1.99 (m, 2 H) 2.03 (m, 1 H) 2.10 (m, 2 H) 3.40 (m, 2 H) 3.52 (m, 2 H) 3.69 (m, 1 H) 4.58 (m, 1 H) 4.65 (m, 1 H).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:25]=[CH:24][C:13]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:23]=3)[C:21]#[N:22])=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>>[OH:31][C:5]1[C:6]([CH2:28][CH2:29][CH3:30])=[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([C:21]4[N:32]=[N:33][NH:34][N:22]=4)[CH:23]=3)=[O:15])=[CH:24][CH:25]=2)[CH:26]=[CH:27][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2ccc(C(=O)c3cncc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2ccc(C(=O)c3cncc(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O
Yield: 68.4 %

Procedure:
Using the general procedure of Example 1 using 5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinonitrile (448 mg, 1.08 mmol), sodium azide (703 mg, 10.8 mmol), and triethylamine hydrochloride (1.49 g, 10.8 mmol) to yield the title product as a white solid (338 mg, 66%): 1H NMR (DMSO-d6) δ 0.90 (t, 3H), 1.53 (sextet, 2H), 2.59 (s, 3H), 2.64 (t, 2H), 5.43 (s, 2H), 6.76 (d, 1H), 7.67 (d, 2H), 7.84 (d, 1H), 7.92 (d, 2H), 8.68 (t, 1H), 9.05 (d, 1H), 9.46 (d, 1H), 12.86 (s, 1H); MS (esi negative) m/z (rel intensity) 456 (100).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[F:13][C:14]1[CH:15]=[C:16]([SH:20])[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>O>[F:13][C:14]1[CH:15]=[C:16]([S:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cccc(S)c1
Reactant: O=C(O)CCc1ccccc1I
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCc1ccccc1Sc1cccc(F)c1

Procedure:
3-(2-Iodo-phenyl)-propionic acid (0.3 g, 1.1 mmol) was dissolved in water (2.8 mL). 3-Fluoro-benzenethiol (0.13 g, 0.99 mmol), KOH (0.15 g, 2.6 mmol) and Cu (13 mg, 0.2 mmol) was added. The mixture was refluxed overnight. The hot solution was filtered and the filtrate was made acidic with concentrated HCl. The mixture was extracted with dichloromethane (2×25 mL). The combined organic phases were washed with water (15 mL), dried (MgSO4), filtered and evaporated. Yield: 0.26 g, 96%.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[O:8].[Br-:18].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[Br:18][C:5]1[S:4][C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: CCCc1ccc(C(=O)c2sccc2C)cc1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCc1ccc(C(=O)c2sc(Br)cc2C)cc1
Temperature: 50 °C
Yield: 64.4 %

Procedure:
To a solution of (3-methylthiophen-2-yl)(4-propylphenyl)methanone (44, 1.12 g, 4.58 mmol) in acetic acid (4.67 mL) was added pyridinium tribromide (3.67 g, 11.5 mmol). The reaction mixture was heated to 50° C. for 3 hours. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc (100 mL). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by silica column chromatography (Biotage) to provide (5-bromo-3-methylthiophen-2-yl)(4-propylphenyl)methanone (45, 0.95 g, 2.95 mmol, 64%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[C:35]([CH3:34])[C:36]([N:44]4[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]4)=[CH:37][C:38]=3[O:42][CH3:43])[N:7]=2)[CH:18]=1
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 49.1 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (90 mg, 0.195 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (57 mg, 0.175 mmol), and p-toluenesulfonic acid (89 mg, 0.47 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (65 mg, 0.086 mmol, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 9.39 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.22 (d, J=5.31 Hz, 1H), 8.04 (d, J=7.69 Hz, 1H), 7.80 (d, J=7.87 Hz, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.59 (t, J=7.69 Hz, 1H), 7.42-7.51 (m, 2H), 7.34-7.42 (m, 1H), 7.13-7.23 (m, 2H), 6.97 (t, J=6.68 Hz, 1H), 6.75 (s, 1H), 6.48 (d, J=5.31 Hz, 1H), 3.79 (s, 3H), 3.30-3.35 (m, 2H), 3.05 (s, 3H), 2.82-2.90 (m, 4H), 2.76 (t, J=6.68 Hz, 2H), 2.53-2.64 (m, 4H), 2.13 (s, 3H). MS (ESI): 753 [M+H]+.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.C(O)(C(F)(F)F)=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[CH:30]=[CH:29]2>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][CH:29]2[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[CH:34]=[CH:33][C:32]=3[C:31](=[O:35])[CH:30]2[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COc1ccc2c(c1)C=CC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(Methoxymethyl)-N-(trimethylsilylmethyl) benzylamine (17.3 mL, 67.6 mmol) and TFA (3.4 mL) were added to a solution of 5-methoxy-inden-1-one (5.4 g, 33.8 mmol) in CH2Cl2 (165 mL) at 0° C. The reaction was stirred for 3 hours at room temperature and quenched with saturated aqueous NaHCO3 (165 mL). The organic layer was separated, washed with brine (100 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C19H19NO2+H: 294, observed: 294.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:28]([C:30]4[O:34][N:33]=[C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:31]=4)[CH3:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)C.CCO.[OH-].[Na+]>C1COCC1>[CH3:26][C:23]1[C:22]([NH:27][CH:28]([C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:31]=2)[CH3:29])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([CH2:5][C:4]([OH:41])=[O:3])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)c4cc(-c5ccccc5)no4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(CC(=O)O)CC4)cc3)cc2)c1NC(C)c1cc(-c2ccccc2)no1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
[1-(4′-{3-Methyl-4-[1-(3-phenyl-isoxazol-5-yl)-ethylamino]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropyl]-acetic acid ethyl ester (0.0861 g, 0.157 mmol) was dissolved in THF (2 mL) then EtOH (1 mL) and NaOH (3N aq., 0.157 mL, 0.472 mmol) was added and the reaction stirred at 60° C. overnight. The reaction was submitted to standard workup procedure and purified via preparatory HPLC (0.1% TFA/H2O/ACN) to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11]Br)=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:7]=1)=[O:5])[CH3:2].[CH:27]([NH2:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][NH:30][CH:27]([CH3:29])[CH3:28])=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CNC(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 21 %

Procedure:
A mixture of 4-bromomethyl-1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-4b (200 mg, 0.44 mmol), isopropyl amine (26 mg, 0.44 mmol), K2CO3 (182 mg, 1.32 mmol) in CH3CN (5 ml) was stirred for 17 hours at room temperature. The reaction mixture was filtered to remove insoluble material and concentrated under vacuum. The residue was diluted with EtOAc and the organic solution was washed with H2O and sat'd aq. NaCl, dried, and concentrated in vacua. The crude residue was purified on SiO2-gel chromatography using a solvent gradient of 20% EtOAc/hexanes to 75% EtOAc/hexanes to give the product (I-4c) as an amorphous solid (40 mg, 21%): +APCI MS (M+1) 432.2.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:36][CH2:37][C:38]=5[C:39]5[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=5)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]6)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[F:46][CH2:47][C:48]([CH2:50][F:51])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:36][CH2:37][C:38]=5[C:39]5[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=5)[CH2:31][CH2:32][N:33]([CH:48]([CH2:50][F:51])[CH2:47][F:46])[CH2:34][CH2:35]6)[CH2:25][CH2:26]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(CF)CF
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCNCC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCN(C(CF)CF)CC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 265H (320 mg) in dichloromethane (5 mL) was added 1,3-difluoroacetone (139 mg) and sodium triacetoxyborohydride (157 mg). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with 2N aqueous NaOH, water and brine. After drying over Na2SO4, the mixture was filtered and the solvent was evaporated under vacuum to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[N+:27]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O)([O-:29])=[O:28]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[N+:27]([O-:29])=[O:28])[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccccc3[N+](=O)[O-])CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with 2-nitrobenzaldehyde to provide 32 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: I(O)(=O)(=O)=O.[Cl:6][CH2:7][C:8]([OH:25])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])CO.C(OCC)(=O)C.CCCCCC>CCOCC>[Cl:6][CH2:7][C:8](=[O:25])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCC(O)(CO)CCl
Agent: [O-][I+3]([O-])([O-])O
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCC(=O)CCl
Yield: 91.2 %

Procedure:
Periodic acid (excess) was added to a solution of 2-chloromethylhexadecan-1,2-diol (23a, 0.021 g, 0.068 mmole) in wet ether (15 ml). The progress of the reaction was followed by TLC (30% ethyl acetate-hexane) and within 70 minutes, the diol 23a was completely transformed to a new, nonpolar product. Additional ether (15 ml) was added and the organic solution was washed with water (2×) and brine. The ether layer was dried (MgSO4), filtered, and concentrated, leaving 0.017 g (0.062 mmole, 91%) of a crystalline material. Recrystallization from methanol gave 0.009 g of 1-chlorohexadecan-2-one (25), mp. 52.5°-53.5° C. (lit.16 mp., 52°-52.5° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.CC#N.C(=O)=O.C([Li])CCC.[O:20]1CC[CH2:22][CH2:21]1.CN(C)C(=O)C>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:21](=[O:20])[CH3:22])=[N:3][CH:4]=1
Reactant: C1CCOC1
Reactant: Brc1ccc(Br)nc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(Br)cn1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
In a 3-neck 1000 ml round bottom flask, 2,5-dibromopyridine (10.0 g, 42.2 mmol) was dissolved in toluene (400 ml) and cooled to −40° C. (CH3CN/dry ice). 1.6 M of n-butyllithium in tetrahydrofuran (26.38 mL, 42.21 mmol) was slowly added to the cooled solution to form a deep reddish solution, which was stirred at −40° C. for 40 minutes. N,N-Dimethylacetamide (7.14 mL, 76.8 mmol) was added with no discernable change. The mixture was allowed to slowly warm to room temperature. Then, the mixture was quenched by adding 25 ml sat'd ammonium chloride. Added 100 ml H2O and extracted with EtOAc (250 ml). The organic phase was washed with water (200 ml). The combined aqueous phases were extracted with EtOAc (100 ml). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to generate 6.31 g of a tan solid. 1H-NMR (CDCl3): δ 8.74 (d, J=1.9 Hz, 1H), 7.96 (m, 2H), 2.70 (s, 3H). HPLC: RT=3.237 min., 60 area % @ 210 nm; RT=3.238 min., 87area % @254 nm.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH3:17])=[CH:11][CH:10]=1.N1C=CC=CC=1>C(O)C>[CH3:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[N:2][OH:3])[CH2:16][CH3:17])=[CH:11][CH:10]=1
Reactant: CCC(=O)c1ccc(OCCOC)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCC(=NO)c1ccc(OCCOC)cc1
Yield: 96.7 %

Procedure:
Hydroxylamine hydrochloride (2.27 g, 32.7 mmol) was added to a stirred solution of 1-(4-(2-methoxyethoxy)phenyl)propan-1-one (3.4 g, 16.3 mmol) and pyridine (3.87 g, 49.0 mmol) in ethanol (25 mL) and the mixture heated at reflux for 4 hours then allowed to cool. Most of the ethanol was removed by concentration, and the residue was partitioned between water and dichloromethane. The layers were separated and the aqueous phase extracted 2× with dichloromethane. The combined extracts were washed twice with water, then with sat brine and dried over magnesium sulfate. The solvent was removed by concentration, and then the residue was dissolved in toluene and again concentrated; this process was repeated once more, and the residue was dried under in vacuo to afford 3.52 g of the product as a cream-colored crystalline solid; mp 74-80° C.; mass spec ES+m/z=224 (m+1).
Reaction SMILES: [CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+:34]>C(Cl)Cl>[CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([O-:26])=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1.[Na+:34]
Reactant: COc1cc(C(=O)O)ccc1Cn1ncc2ccc(NC(=O)OC3CCCC3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)[O-])ccc1Cn1ncc2ccc(NC(=O)OC3CCCC3)cc21
Yield: 78 %

Procedure:
A mixture of 306 mg. 4-[6-(cyclopentyloxycarbonyl)aminoindazol-1-ylmethyl]-3-methoxybenzoic acid in 4 ml. methanol and 6 ml. methylene chloride was treated with 0.75 ml. of 1 M sodium hydroxide solution. After 15 minutes the mixture was evaporated and the residue was recrystallised from ether/methylene chloride/methanol to give sodium 4-[6-(cyclopentyloxycarbonyl)aminoindazol-1-ylmethyl]-3-methoxybenzoate in 78% yield as a solid, m.p. >280° C. (d); microanalysis, found: C,59.80; H,5.06; N,9.20%; C22H22H3O5Na.0.5H2O requires C, 59.99; H,5.26; N,9.54%.