Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:16])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1cc(-c2ccc(Cl)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (45 mg, 78%), MS (ISP) m/z=311.4 [(M+H)+], mp 269° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 10) (52 mg, 0.186 mmol) and commercially available 4-chloro-phenylboronic acid (37.9 mg, 0.24 mmol).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][CH2:16][CH2:15][C:14]3[N:10]([N:11]=[C:12]([C:18]4[N:19]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:20]=[CH:21][N:22]=4)[CH:13]=3)[C:9]=2[CH:28]=1)=[O:4].[OH-].[Li+]>O1CCOCC1.O>[F:26][C:24]([F:25])([F:27])[CH2:23][N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([N:11]=2)[C:9]2[CH:28]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[O:17][CH2:16][CH2:15]3)=[N:22][CH:21]=[N:20]1
Reactant: COC(=O)c1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid methyl ester (553 mg, 1.4 mmol) in dioxane (12.5 mL) and water (12.5 mL) was added lithium hydroxide (67 mg, 2.8 mmol) and the reaction mixture stirred at RT for 2 h. The reaction mixture was concentrated in vacuo to remove the dioxane and the resultant solution acidified to pH 1 by the addition of HCl (12 N). The precipitate formed was collected by filtration, washed with water and dried in vacuo at 40° C. to give the title compound (519 mg, 98%). LCMS: RT=4.04 min, M+H+=380
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=[O:12].[CH:18]1([CH2:24]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O>CN(C=O)C>[CH:18]1([CH2:24][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:11]=[O:12])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCC1CCCCC1

Procedure:
In 175 ml of DMF containing 138 g of anhydrous potassium carbonate (1.0 m) was added 100 g of 3-hydroxy-4-methoxybenzaldehyde and 127 g of cyclohexylmethybromide. The mixture was heated at reflux temperature overnight and then poured into cold water and extracted with ethyl acetate. The extracts were dried and evaporated in vacuo to render the desired subtitled intermediate, b.p. 130°-135 ° C.
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]2)[CH:3]([CH3:5])[CH3:4].Cl.Cl.Cl.[N:22]1([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([NH:37][C:16]([C:10]3[NH:11][C:12]4[C:8]([CH:9]=3)=[C:7]([O:6][CH:2]([CH3:1])[CH:3]([CH3:4])[CH3:5])[CH:15]=[CH:14][CH:13]=4)=[O:18])[CH2:35][CH2:36]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)C(C)Oc1cccc2[nH]c(C(=O)O)cc12
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: CC(C)C(C)Oc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-(1,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid 88 (preparation see below) and amine 5.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[C:6](Cl)(=[O:13])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[OH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(O)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)CNC(=O)c1ccncc1
Yield: 161.3 %

Procedure:
289 g 1-amino-propan-2-ol was added to 75 g isonicotinoyl chloride and 549 mL triethylamine in 2 L anhydrous dichlormethane at 0° C. under nitrogen atmosphere. After 30 min at 0° C. the reaction was concentrated under vacuum and the residue was re-suspended in 5 L ethyl acetate. The precipitate was removed by filtration. The filtrate was concentrate and recrystallized from ethyl acetate to give 154 g of the desired product.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Br[CH:9]([CH3:23])[C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])([OH:14])[C:11]#[C:12][CH3:13]>CS(C)=O.[Cl-].[Na+].O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:10]([OH:14])([CH:9]([N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)[CH3:23])[C:11]#[C:12][CH3:13]
Reactant: CC#CC(O)(c1ccc(Cl)cc1Cl)C(C)Br
Reactant: c1nc[nH]n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC#CC(O)(c1ccc(Cl)cc1Cl)C(C)n1cncn1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A suspension of sodium hydride (2.54 g) in dry dimethylsulphonyl (200 ml) was stirred at room temperature under argon and 1,2,4-triazol 21.9 g) was added in portions over 10 minutes, followed by further stirring for 10 minutes. A solution of 5-bromo-4-(2,4-dichlorophenyl)-4-hydroxy-hex-2-yne (17 g) in dry DMSO (50 ml) was added over 15 minutes. The resultant solution was heated at 100° C. for about 100 hours. Concentrated brine solution (200 ml) was added and the mixture extracted with ethyl acetate (3×150 ml). The extracts were combined, washed with water until neutral, dried over anhydrous magnesium sulphate and the solvent removed in vacuo to give 14.38 g of a brown solid. This solid was purified by flash chromatography, eluted with portions of ethyl acetate (50-100%) in hexane). Fractions containing the fastest running major triazole-active spot on thin-layer chromatography were combined to give 2.91 g (18%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[C:17]([Cl:22])[CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[N:15]=[CH:14][N:13]=[C:12]2[N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: Clc1ncnc2c(Cl)cccc12
Reactant: Clc1ccc2c(c1)NCC2
Product: Clc1ccc2c(c1)N(c1ncnc3c(Cl)cccc13)CC2
Yield: 47 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 47% yield from 6-chloro-indoline and 4,8-dichloro-quinazoline. (M.P. 190° C.; LC-MS: 316 (MH+)).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH2:10][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]I>C1COCC1>[CH2:1]([N:8]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:23])([CH3:15])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(O)CCCN(Cc1ccccc1)Cc1ccccc1
Solvent: C1CCOC1
Product: COC(C)(C)CCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
Treat a 0° C. solution of 5-(dibenzylamino)-2-methylpentan-2-ol (3 g, 10.2 mmol) in THF (25 mL), under N2, portion-wise with KH (30%, 1.5 g, 11.3 mmol), stir at 0° C. for 0.5 h, add MeI (1.6 g, 11.3 mmol) drop-wise, warm to RT and stir for 3 h. Cool to 0° C., quench with satd. NH4Cl, partially concentrate under reduced pressure, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography to afford the title compound (3.1 g, 97%). 1H NMR (400 MHz, DMSO-d6): δ 7.38-7.21 (m, 10H), 3.57 (s, 4H), 3.14 (s, 3H), 2.42 (t, J=7.2 Hz, 2H), 1.58-1.52 (m, 2H), 1.43-1.39 (m, 2H), 1.11 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:18]=2)[C@@H:10]([OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:18]=2)[C@@H:10]([O:35][CH2:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2ccc3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
14.6 g (30.0 mmol) of (3R,4R,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-hydroxy-piperidine-1-carboxylic acid tert-butylester and 7.74 g (35.0 mmol) of 2-bromomethyl-naphthalene were dissolved in 110 ml of dimethylformamide under argon and then 1.77 g (40.0 mmol) of sodium hydride dispersion (55% in mineral oil) was added. Subsequently, the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured onto ice-water, the resulting product was extracted 3 times with dichloromethane, the organic phases were washed twice with distilled water, then dried over magnesium sulfate, filtered and concentrated in a water-jet vacuum. The resulting crude product was chromatographed on silica gel with dichloromethane and methanol to yield (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butylester as colorless oil; MS: 626.5(M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[N:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27][CH2:26][CH2:25][C:24]=2[CH:23]=[N:22][CH:21]=1>N1C=CC=CC=1>[N:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[N:27]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[CH2:26][CH2:25][C:24]=2[CH:23]=[N:22][CH:21]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)NCCc1cncnc1-2
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3cncnc3-c3ccccc32)cc1

Procedure:
As described for Example 1, 5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido[5,4-d] [1]benzazepine in pyridine to give the product as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:7]=[C:8]3[CH:14]=[CH:13][NH:12][C:9]3=[N:10][CH:11]=2)[CH:3]=[N:2]1.C1C(=O)N([I:22])C(=O)C1>CC(C)=O>[I:22][C:14]1[C:8]2[C:9](=[N:10][CH:11]=[C:6]([C:4]3[CH:5]=[N:1][NH:2][CH:3]=3)[N:7]=2)[NH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1cc2nc(-c3cn[nH]c3)cnc2[nH]1
Solvent: CC(C)=O
Product: Ic1c[nH]c2ncc(-c3cn[nH]c3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of 28 (0.27 g) and acetone (20 mL) was added in one portion NIS (0.36 g). The mixture was stirred at RT for 30 min and then concentrated to afford 0.55 g of crude material which was purified by SiO2 chromatography using an EtOH/EtOAc gradient (1 to 15% EtOH over 15 min) to afford 0.29 g of pure 7-iodo-2-(1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (30).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:12])([F:11])[C:6]([O:8]CC)=O.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[O:15].Cl>C1(C)C=CC=CC=1.O>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([C:14](=[O:15])[CH2:13][C:6](=[O:8])[C:5]([F:4])([F:11])[F:12])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
216 g (4 mol) of anhydrous sodium methylate and 3.5 l of toluene are introduced into a 10 liter round-bottomed flask and, under vigorous stirring, 705 g (5 mol) of ethyl trifluoroacetate are then run in; the temperature rises slowly to 30° C. After cooling in an ice bath, a solution of 720 g (4 mol) of 3,4-dimethoxyacetophenone in 0.5 l of toluene is added dropwise to the reaction mixture; a white precipitate slowly forms. The mixture is next left stirred overnight and then heated to 50° C. for three hours. After cooling, 2 1 of water and 330 ml of concentrated hydrochloric acid are added, the organic phase is separated off after settling has taken place, dried over magnesium sulphate, filtered and evaporated to obtain 1060 g (96%) of a yellow solid melting at 87°-89° C.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:23][CH:22]([C:24](OC)=[O:25])[CH2:21]2)=[CH:16][CH:15]=1.Cl>CCCCCC.O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[CH2:21][CH:22]([C:24](=[O:25])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])[CH2:23]2)=[CH:18][CH:19]=1
Reactant: COC(=O)C1CC(c2ccc(Cl)cc2)C1
Reactant: COP(C)(=O)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C1CC(c2ccc(Cl)cc2)C1)OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl lithium (16.2ml. of a 1.23M solution in hexane) was added dropwise to a stirred solution of dimethyl methylphosphonate (2.48g.) in dry tetrahydrofuran (25ml.) at -78° C. in an atmosphere of argon. After 10 minutes, a solution of methyl 3-(4-chlorophenyl)cyclobutanecarboxylate mixed isomers (2.24g.) in dry tetrahydrofuran (25ml.) was added dropwise, and stirred at -78° C. for 2 hours. The reaction mixture was warmed to room temperature and neutralised by the addition of 1N hydrochloric acid (20ml.) to the stirred solution. The tetrahydrofuran was evaporated, and the residue was partitioned between ethyl acetate and water. The ethyl acetate extract was dried over sodium sulphate and the solvent was evaporated. The crude product was purified by dry column chromatography on "Kieselgel 60" (100g.) eluting with ethyl acetate, to give dimethyl 2-[3-(4-chlorophenyl)cyclobutyl]-2-oxoethylphosphonate, as a mixture of cis and trans isomers, RF = 0.35 and 0.40 (ethyl acetate). The n.m.r. spectrum in deuteriochloroform showed the following characteristic signals (δ values):
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[C:7]([O:9]C)=[O:8].Cl.C1C=CC=CC=1>O>[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CON=C(C(=O)OC)c1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CON=C(C(=O)O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
A 2N aqueous solution of sodium hydroxide (40 ml.) was added with stirring at ambient temperature to a suspension of methyl 2-methoxyimino-2-(3-hydroxyphenyl)acetate (syn isomer) (7.55 g.) in water (70 ml.) and the mixture was stirred for 1 hour at ambient temperature. The reaction mixture was adjusted to pH 6.5 with 10% hydrochloric acid, subjected to salting-out and washed with ether (60 ml.). The aqueous layer was adjusted to pH 1 with conc. hydrochloric acid and extracted once with 100 ml. of and twice with 60 ml. of ether. The extract was washed twice with a saturated sodium chloride aqueous solution (60 ml.) and dried over magnesium sulfate. Ether was distilled off to give oil. Benzene was added thereto and removed (twice) to give crystals of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (6.44 g.), mp 98° to 101° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[N:11]2)=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][NH2:32])[CH:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][NH:32][C:21]([C:17]2[S:16][C:15]([C:12]3[CH:13]=[CH:14][N:10]([CH2:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])[CH:25]=1
Reactant: NCCc1cccnc1
Reactant: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)NCCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
To a solution of 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (0.1 g, 0.30 mmol) in methylene chloride (5 mL) was added 2-pyridin-3-yl-ethylamine (0.04 g, 0.33 mmol), benzotriazol-1-yloxytris(dimethylamino)-hexafluorophosphate (0.146 g, 0.33 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.60 mmol) and the mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (50 mL), washed with water (50 mL) and brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel eluting with 50% ethyl acetate, 50% hexane to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (2-pyridin-3-yl-ethyl)-amide as a white solid (0.095 g, 73%). 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=2 Hz, 2H), 7.58 (d, J=4 Hz, 1H), 7.25-7.28 (m, 1H), 7.14 (d, J=2 Hz, 1H), 6.90-7.03 (m, 4H), 6.70 (d, J=2 Hz, 1H), 5.96-6.03 (m, 1H), 4.34 (t, J=7 Hz, 2H), 3.65-3.73 (m, 2H), 3.17 (t, J=7 Hz, 2H), 2.95 (t, J=7 Hz, 2H), 2.68 (s, 3H). MS (M+H)+=436.2; Rt=1.28 min; HRMS (M+H)+=436.16.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH2:7].Cl.Cl[CH2:10][C:11]1[N:12]=[C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]2[CH:21]=1>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][CH2:10][C:11]1[N:12]=[C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]2[CH:21]=1
Reactant: N#Cc1ccn2cc(CCl)nc2c1
Reactant: NCC1OCCO1
Agent: Cl
Solvent: ClCCl
Product: N#Cc1ccn2cc(CNCC3OCCO3)nc2c1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
To a DCM solution of 1-(1,3-dioxolan-2-yl)methanamine (799 mg, 7.83 mmol) was added 2-(chloromethyl)imidazo[1,2-a]pyridine-7-carbonitrile hydrochloride (Intermediate 17) (500 mg, 2.61 mmol). After heating to reflux for 1 hr, the reaction mixture was cooled room temperature, concentrated under reduced pressure, chromatographed on silica gel eluting with a gradient solvent mixture (5% MeOH-DCM to 15% MeOH-DCM) to give the title compound as oil (410 mg). LC/MS: m/z 259(M+H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15](=[O:25])[C:16]1C=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1O.Cl>N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:15](=[O:25])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][C:5]=2[O:4][C:2]1=[O:3]
Reactant: COC(=O)Cl
Reactant: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(O)c1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(=O)n(-c3ccc(F)cc3F)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl chloroformate (0.1 mL, 1.2 mmole) was added dropwise to a stirred solution of compound 4a (0.28 g, 1 mmole) in dry pyridine (8 mL) at 0° C. The mixture was refluxed for 2 hr. After 16 hr stirring at room temperature, the pH of the reaction mixture was adjusted to pH=6 from 1 M HCl(aq). The resulting white mixture was cooled to obtain solid compound. The product was filtered off and recrystallized from hot ethanol. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: [NH2:1][OH:2].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][N:9]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:10][CH2:11][C:12](OCC)=[O:13])=[CH:6][CH:5]=1>>[OH:2][NH:1][C:12](=[O:13])[CH2:11][CH2:10][N:9]([CH2:8][C:7]1[CH:28]=[CH:29][C:4]([Cl:3])=[CH:5][CH:6]=1)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: NO
Reactant: CCOC(=O)CCN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(OC)cc1
Product: COc1ccc(S(=O)(=O)N(CCC(=O)NO)Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
Freshly prepared NH2OH solution (1 M in methanol) (0.2 mL, 0.2 mmol) was added to ethyl 3-[(4-chlorobenzyl)-(4-methoxybenzenesulfonyl)-amino]-propionate (44 mg, 0.1 mmol). After being stirred at room temperature for 18 h, the reaction mixture was concentrated. The crude product was triturated in ether and the residue was lyophilized from water to give N-hydroxy-3-[(4-chlorobenzyl)-(4-methoxybenzene-sulfonyl)-amino]-propionamide (30 mg, 0.08 mmol) as a light yellow solid. 1H-NMR (360 MHz, DMSO-d6) δ 7.75 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 4.28 (s, 2H), 3.85 (s, 3H), 3.20 (br t, J=7.8 Hz, 2H), 1.86 (t, J=8.1 Hz, 2H).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])C1C2C(=CC=CC=2)C=CC=1.O[C:22]1[C:31]2C(=CC=CC=2)C=C[C:23]=1[CH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1>>[Cl:17][C:6]1[C:5]2[C:18](=[CH:19][CH:20]=[CH:3][CH:4]=2)[CH:31]=[CH:22][C:23]=1[CH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1
Reactant: COc1cccc(C(Cl)c2cccc3ccccc23)c1
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccc3ccccc3c2O)cc1
Product: CCN(CC)C(=O)c1ccc(Cc2ccc3ccccc3c2Cl)cc1

Procedure:
The compound 36 was prepared by following the synthesis procedure as described for compound 2, but substituting compound 1 for compound 35.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[N+:17]([CH3:20])([O-:19])=[O:18].C(N(CC)CC)C>CO>[OH:2][CH:1]([C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]=[C:5]([CH:4]=1)[C:13]([O:15][CH3:16])=[O:14])[CH2:20][N+:17]([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)c1cc(C=O)cc(C(=O)OC)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)OC)cc(C(O)C[N+](=O)[O-])c1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a solution of 2.45 g (11.0 mmol) of dimethyl 5-formylisophthalate in 30 mL of methanol was added 1.48 mL (27.6 mmol) of nitromethane and 1.53 mL (11.0 mmol) of triethylamine (TEA). The solution was stirred at 22° C. for about 16 h, evaporated then coevaporated with xylenes. The residue was purified by flash chromatography on silica gel, eluting first with 5% ethyl acetate/hexane and then gradually increasing to 20% ethyl acetate/hexane which gave dimethyl 5-(1-hydroxy-2-nitroethyl)isophthalate as a solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][CH2:6][NH2:7])[CH2:4][CH2:3]1.[CH2:8]([O:15][C:16]([CH2:18][N:19]1[C:24]([CH3:25])=[C:23]([Cl:26])[N:22]=[C:21](Cl)[C:20]1=[O:28])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[CH:2]1([CH2:5][CH2:6][NH:7][C:21]2[C:20](=[O:28])[N:19]([CH2:18][C:16]([O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:17])[C:24]([CH3:25])=[C:23]([Cl:26])[N:22]=2)[CH2:4][CH2:3]1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: NCCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(Cl)nc(NCCC2CC2)c(=O)n1CC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2-cyclopropylethylamine hydrochloride (73 mg, 0.60 mmol), 1-benzyloxycarbonylmethyl-3,5-dichloro-6-methylpyrazinone (164 mg, 0.50 mmol) and sodium hydrogen carbonate (101 mg, 1.20 mmol) in toluene (1 mL) and water (0.5 mL) was stirred at 80° C. for 3 h. The reaction was then cooled and partitioned between methylene chloride and 10% citric acid solution. The organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound as a crystalline solid: