Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]=[O:15])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:15][N:14]=[C:11]1[CH:12]=[CH:13][C:8](=[N:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:9]=[CH:10]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=Nc1ccc(Nc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(ON=C1C=CC(=Nc2ccccc2)C=C1)c1ccccc1
Temperature: 5 °C

Procedure:
A solution was prepared by dissolving 4-nitrosodiphenylamine, 25.0 grams, (0.126 mole) and triethylamine, 13.4 grams, (0.132 mole) in 300 mL of toluene. The solution was put in a suitable reaction flask and cooled to 5° C. A solution of benzoyl chloride, 17.7 grams, (0.126 mole), was dissolved in 50 mL of toluene and added slowly to the stirred solution of 4-nitrossodiphenylamine. The materials were allowed to react and the triethylamine hydrochloride precipitate was filtered. The toluene solution was concentrated and the product that crystallized was filtered and dried. The yield was 15.96 grams of product melting at 122-124° C.
Reaction SMILES: C([Li])CCC.[C:6]([Si:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([F:34])=[CH:27][C:26]=1[O:35][CH3:36])([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].B(OC)(OC)[O:38]C.C(O)(=O)C.OO>C1COCC1.O>[Si:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[C:29]([CH:31]([CH3:32])[CH3:33])[C:28]([F:34])=[C:27]([OH:38])[C:26]=1[O:35][CH3:36])([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:12])[CH3:11]
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1c(-c2ccc(C(F)(F)F)cc2CO[Si](C)(C)C(C)(C)C)cc(C(C)C)c(F)c1O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
n-Butyllithium (1.6M in hexanes, 261 μL, 0.417 mmol) was added dropwise over 30-45 min with a syringe pump to a stirred solution of tert-butyl{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methoxy}dimethylsilane (200 mg, 0.438 mmol) in dry THF (0.5 mL) at −78° C. under N2. The reaction was stirred for a further 2 h at −78° C. after the addition to give a violet colored solution. Trimethyl borate (43.4 mg, 47 μL, 0.417 mmol) was added dropwise and the reaction was stirred at −78° C. for 3 h. The reaction mixture was warmed to 0° C. and acetic acid (25.1 mg, 24 μL, 0.626 mmol) was added quickly followed by 30% aqueous hydrogen peroxide (52 μL, 0.459 mmol) dropwise. The reaction was stirred at room temperature overnight, diluted with water (10 mL) and extracted with Et2O (3×20 mL). The combined extracts were washed with 50% saturated FeSO4 (20 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-100% EtOAc in hexanes gradient) to afford 2′-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol. Rf=0.32 (10% EtOAc in hexanes). LCMS calc.=473.1; found=473.2 (M+1)+. 1H NMR (600 MHz, CDCl3) δ 7.95 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 6.53 (d, J=7.8 Hz, 1H), 5.65 (s, 1H), 4.68 (br s, 1H), 4.54 (br s, 1H), 3.42 (s, 3H), 3.26-3.20 (m, 1H), 1.25 (d, J=6.9 Hz, 6H), 0.90 (s, 9H), 0.02 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:20](=[O:21])[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[C:12]3=[O:13])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CN(C)C=O.O>[CH2:30]([O:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:20](=[O:21])[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[C:12]3=[O:13])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1)[CH:29]=[CH2:28]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc2onc(O)c2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1noc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc12

Procedure:
A mixture of N-(3-hydroxy-1,2-benzisoxazol-5-yl)-1-cyclohexene-1,2-dicarboximide (0.75 g, 2.64 mmol), potassium carbonate (0.6 g, 4.35 mmol) and allyl bromide (1 g, 8.3 mmol) in N,N-dimethylformamide is heated at 60°-70° C. for 2 hours and diluted with water. The aqueous mixture is extracted with ether. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a yellow oil. Column chromatography of the oil using silica gel and ether/hexanes solutions yields a gum. A solution of the gum in an ether/hexanes mixture is passed through a plug of silica gel and crystallized to give the title product as a pale yellow solid, mp 88°-89° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]3)[CH2:3][CH2:2]1.Cl.Cl.Cl.[N:21]1([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:34][CH2:35]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(O)c1cc2c(OCC3CC3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCC3CC3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid 77 (preparation see below) and amine 5.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:14]2)[C:3]=1[C:4]([OH:6])=[O:5].[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[C:26]1([CH2:25][CH2:24][CH2:23][N:22]([CH2:21][CH2:20][O:19][C@H:15]2[CH2:16][CH2:17][CH2:18][C@@H:13]([O:12][CH2:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[C:3]=3[C:4]([OH:6])=[O:5])[CH2:14]2)[C:39]([NH:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(CO[C@@H]2CCC[C@H](OCCNCCCc3ccccc3)C2)c1C(=O)O
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cccc(CO[C@@H]2CCC[C@H](OCCN(CCCc3ccccc3)C(=O)Nc3ccccc3)C2)c1C(=O)O
Reaction time: 0.5 h

Procedure:
160 mg of 2-methyl-6-{(1R,3S)-3-[2-(3-phenylpropylamino)ethoxy]cyclohexyloxymethyl}benzoic acid are dissolved in 2 ml of dimethylformamide, and 0.1 ml of phenyl isocyanate is added. After 30 minutes, the reaction mixture is purified by RP-HPLC. This gives 54 mg of 2-{(1R,3S)-3-[2-(1-[3-phenylpropyl]-3-phenylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoic acid as a white lyophilizate. C33H40N2O5 (544.70), MS(ESI): 545 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[NH2:28][CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>C1COCC1.C(Cl)Cl>[NH2:34][C:33]1[CH:35]=[CH:36][C:30]([CH2:29][NH:28][C:2]2[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=3)[N:3]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Reactant: NCc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(N)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
To a solution of the tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (2 g, 4.94 mmol) in THF (10 mL) was added 4-(aminomethyl)aniline (0.616 mL, 5.44 mmol) and Hunig's Base (3.45 mL, 19.76 mmol). The resulting mixture was stirred for 16 h. The reaction was then warmed to 65° C. for 2 h at which point the reaction became a homogeneous solution. The reaction was cooled and diluted with DCM and washed with water and brine. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum to give an oily residue. The residue was purified by silica gel chromatography using 40% EtOAc/Hexanes to give tert-butyl 4-(4-(4-aminobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.5 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:4][C:3]=1[NH2:25].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[N:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:5]2[N:6]=[N:7][C:2]([C:29]3[CH:30]=[N:31][CH:32]=[C:27]([F:26])[CH:28]=3)=[C:3]([NH2:25])[N:4]=2)=[N:9]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1Cl
Reactant: OB(O)c1cncc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1COCCO1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1-c1cncc(F)c1
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
Under an argon atmosphere, 100 mg (purity 65%, 0.183 mmol) of 6-chloro-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5-amine were suspended in 4 ml of absolute dioxane. 103 mg (0.731 mmol) of (5-fluoropyridin-3-yl)boronic acid and 25 mg (0.183 mmol) of potassium carbonate were added and argon was passed through the suspension for 10 min with stirring. Then, 3 mg (4.020 mol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride were added and again argon was passed through the mixture for 1 min. The reaction mixture was stirred for 20 min in the microwave at 140° C. 5 mg (0.018 mmol) of tricyclohexylphosphine were added and the mixture was again stirred for 20 min in the microwave at 140° C. After cooling, the mixture was filtered over an Extrelut cartridge and after-washed with a mixture of dichloromethane/methanol (v/v=20:1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80→100:0). 59 mg of the target compound were obtained (58% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][O:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: O=C1Cc2ccc(O)cc2CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1Cc2ccc(OCc3cccc(Cl)c3)cc2CCN1

Procedure:
In an analogous manner to that described in Example 17 c), the alkylation of 7-hydroxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one [Example 19 b)] by 3-chlorobenzylbromide in the presence of potassium carbonate in 2-butanone yielded the 7-(3-chloro-benzyloxy)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one as a white solid; MS: m/e=302 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:24]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([O:21]CC)=[O:20])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1.O.[OH-].[Li+]>CO.O>[Br:1][C:2]1[N:24]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([OH:21])=[O:20])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(Br)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(Br)nc2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
A mixture of ethyl 5-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (1.2 g, 3.05 mmol) and lithium hydroxide hydrate (512 mg, 12.2 mmol) in methanol (40 ml) and water (10 ml) was stirred for 4 hours at 50° C. The solvent was evaporated, the residue was dissolved with water and acidified to pH=0 using hydrochloric acid 37%. The precipitated solid was filtered off and washed with water and dried in vacuo affording 5-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (929 mg, 83.4%) as a light brown solid. mp: >250° C., MS: m/z=362.7/364.8 (M+H+)
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[C:9]([O:13][C:14](=[O:17])[CH2:15][NH2:16])([CH3:12])([CH3:11])[CH3:10].C>O1CCOCC1>[N-:16]=[C:4]=[O:3].[C:9]([O:13][C:14](=[O:17])[CH2:15][NH2:16])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CC(C)(C)OC(=O)CN
Solvent: C1COCCO1
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of glycine tert-butyl ester and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is redissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give glycine tert-butyl ester isocyanate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=3)=[O:13])=[C:9]([NH:22][C:23]([C@H:25]3[CH2:30][CH2:29][C@H:28]([N:31]([CH:33]=[O:34])[CH3:32])[CH2:27][CH2:26]3)=[O:24])[C:8]=2[CH:35]=1)(O)=[O:2].Cl.[CH3:37][NH:38][CH3:39].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.N1C=CC=CC=1>[CH3:37][N:38]([CH3:39])[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=3)=[O:13])=[C:9]([NH:22][C:23]([C@H:25]3[CH2:26][CH2:27][C@H:28]([N:31]([CH:33]=[O:34])[CH3:32])[CH2:29][CH2:30]3)=[O:24])[C:8]=2[CH:35]=1)=[O:2]
Reactant: CNC
Reactant: CN(C=O)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)O)cc23)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trans-5-carboxy-3-[4-(N-formyl-N-methylamino)cyclhexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (196 mg) obtained in Example 258 is suspended in N,N-dimethylformamide/pyridine (1:1, 8 ml), and thereto are added successively dimethylamine hydrochloride (49 mg), 1-hydroxybenzotriazole (108 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg) under ice-cooling, and the mixture is stirred at room temperature for 48 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate. The extract is washed with water and a saturated brine, dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate). The resulting residue is suspended in diethyl ether/n-hexane, and the precipitates are collected by filtration to give the title compound (141 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[O:16][CH3:17])[C:5](=O)[CH3:6].Cl.[NH2:21]O>>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:6])=[N:21][O:18][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[O:16][CH3:17])=[O:19]
Reactant: NO
Reactant: COC(=O)C(C(C)=O)C(=O)c1ccc(Br)cc1OC
Agent: Cl
Product: COC(=O)c1c(C)noc1-c1ccc(Br)cc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 3 using 2-(4-bromo-2-methoxy-benzoyl)-3-oxo-butyric acid methyl ester and hydroxylamine hydrochloride.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[C:13]=1[C:14]#[N:15]>CN(C=O)C>[CH2:3]([O:10][C:12]1[CH:19]=[N:18][CH:17]=[C:16]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:13]=1[C:14]#[N:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCc2ccccc2)cncc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
To a mixture of NaH (60% in mineral oil) (2.77 g, 69.25 mmol, 2.5 eq.) in DMF (40.0 mL) was added benzyl alcohol (6.6 g, 61.0 mmol, 12 eq.) at 0° C. The mixture was stirred at 0° C. for 10 min, added 3,5-dichloroisonicotinonitrile (4.8 g, 27.7 mmol, 1 eq.), continued to stir at 0° C. for 30 min, gradually warm to rt, stirred at rt O/N, and quenched with NH4Cl(sat.) solution. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-bis(benzyloxy)isonicotinonitrile (4.94 g, 56%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 2H), 7.58-7.30 (m, 10H), 5.33 (s, 4H). LRMS (M+H+) m/z 317.1
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=2[CH3:39])=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:33][C:32]=2[CH3:39])=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (53 mg, 41%).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([C:16]1([CH2:19][CH3:20])[CH2:18][NH:17]1)[CH2:13][CH2:14][CH3:15]>CO>[CH2:12]([C:16]1([CH2:19][CH3:20])[NH:17][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][CH2:18]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1(CC)CN1
Reactant: COC(=O)c1ccccc1S
Solvent: CO
Product: CCCCC1(CC)CSc2ccccc2C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of methyl thiosalicylate (25.0 g, Aldrich) in methanol (95 ml) at 0° C. was added 2-butyl-2-ethylaziridine (20.0 g, Synthetic Example 1(f)) and the mixture was stirred at room temperature for 18 hours. Solvent was evaporated and toluene (200 ml) and sodium methoxide (8.2 g) were added. The mixture was heated to reflux for 4.5 hours, removing water through a Dean-Stark trap. Solvent was evaporated and the residue was partitioned between 5% HCl (500 ml) and dichloromethane (400 ml). The organic layer was separated, dried and concentrated. Crystallization from hexanes/ethyl acetate provided the title compound as a white solid (38.0 g), mp 92°-93° C. 1H NMR consistent with the proposed structure.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[CH2:7]([C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH2:10][CH3:11].Cl>CO>[CH2:7]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:2][OH:3])=[O:17])=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCc1ccc(C(=O)OC)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCc1ccc(C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Hydroxylamine hydrochloride (17.4 g, 250 mmol.) was dissolved in AR Grade methanol (50 mL) under argon, then added to NaOMe (25% w/w in MeOH) 132 mL, 580 mmol) under argon with ice cooling. A solution of methyl 4-pentylbenzoate, prepared above (25.15 g. 123 mmol) in methanol was then added, and the reaction stirred at room temperature under N2 for 3 days. The reaction mixture was acidified to pH 6 with conc. HCl (caution!). The mixture was filtered and the filtrate evaporated to give a precipitate. This was extracted with CHCl3, the combined extracts dried (MgSO4) and the solvent evaporated. The residue was recrystallised from EtOH to give 4-pentylbenzohydroxamic acid acid as crystals, m.p. 89.9°-90.1° C. (12.35 g, 49%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:15]2[C:16](=[O:19])[CH2:17][O:18][C:14]=2[C:13]([CH3:20])=[C:12]([CH3:21])[CH:11]=1>C(Cl)Cl>[Br:1][C:11]1[C:12]([CH3:21])=[C:13]([CH3:20])[C:14]2[O:18][CH2:17][C:16](=[O:19])[C:15]=2[C:10]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c2c(c1C)OCC2=O
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1Br)C(=O)CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.4 %

Procedure:
N-bromosuccinimide (27.1 g, 152 mmol) was added to a solution of methylene chloride (200 mL) containing 4,6,7-trimethyl-1-benzofuran-3(2H)-one (20.7 g, 117 mmol) synthesized in Reference Example 44, and the mixture was stirred at room temperature for 24 hours. After that, the solvent was removed under reduced pressure, and water was added to the residue. The generated crystals were collected by filtration, and recrystallized from ethyl acetate to give 24.0 g of the title compound (yield: 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1.C(N(CC)CC)C.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([Cl:25])=[O:14])[CH2:11][CH2:10]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1(c2ccc(Cl)cc2Cl)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2ccc(Cl)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1-(2,4-Dichlorophenyl)-cyclopropanecarboxylic acid (0.086 g, 0.37 mmol) and triethylamine (0.08 mL, 0.56 mmol) were combined in CH2Cl2 (2 mL) and cooled to 0° C. Oxalyl chloride (0.05 mL, 0.56 mmol) was added, followed by DMF (3 drops), and the reaction was stirred for 20 minutes at 0° C. and then warmed to room temperature to give the title compound, which was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[ClH:13].[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22](C)(C)C[C:20]=2[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:43]=[CH:42][C:41]([C:44](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:45])=[CH:40][CH:39]=3)[N:28]=2)=[CH:18][CH:17]=1>>[ClH:13].[ClH:13].[CH3:22][O:23][C:24]1[CH:20]=[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:39]=[CH:40][C:41]([C:44]([N:9]4[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:12])[CH2:11][CH2:10]4)=[O:45])=[CH:42][CH:43]=3)[N:28]=2)[CH:18]=[CH:17][C:16]=1[O:15][CH3:14]
Reactant: CN(C)CCCN1CCNCC1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CCCN(C)C)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from intermediate product A6 and 1-(3-dimethylaminopropyl)piperazine as described for compound 8. M.p. 223–226° C.