Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]([F:24])([F:23])[O:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]O>O1CCOCC1.C(OCC)(=O)C>[F:5][C:6]([F:24])([F:23])[O:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][Br:2]
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1Oc1cccc(OC(F)(F)F)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1cccc(Oc2ccccc2CBr)c1
Reaction time: 1.5 h
Yield: 32.5 %

Procedure:
Phosphorus tribromide (5 ml, 53 mmol) was added to a solution of [2-(3-(trifluoromethoxy)phenoxy)phenyl]methanol (5.33 g, 18.9 mmol) in dioxane (100 ml). The reaction mixture was stirred for 1.5 hours. Another portion of phosphorus tribromide (5 ml, 53 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature. It was diluted with ethyl acetate (500 ml) and washed with a 10% aqueous solution of sodium hydrogen sulphate (300 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (200 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified on silica (200 g), using ethyl acetate/heptane (1:4) as eluent, to give 2.13 g of 2-(3-(trifluoromethoxy)phenoxy)benzyl bromide.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([Cl:24])=[CH:10][CH:11]=2)[C:6]1=[O:25].[CH3:27][CH:28]([NH2:30])[CH3:29]>CN1C(=O)CCC1>[Cl:24][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=3)[N:5]([CH2:4][C:3]([NH:30][CH:28]([CH3:29])[CH3:27])=[O:2])[C:6]2=[O:25])=[CH:11][CH:10]=1
Reactant: CC(C)N
Reactant: COC(=O)Cn1c(-c2ccc(F)c(OC)c2)cc2ccc(Cl)cc2c1=O
Solvent: CN1CCCC1=O
Product: COc1cc(-c2cc3ccc(Cl)cc3c(=O)n2CC(=O)NC(C)C)ccc1F

Procedure:
[7-Chloro-3-(4-fluoro-3-methoxyphenyl)-1-oxo-1H-isoquinolin-2-yl]acetic acid methyl ester (crude product from the previous experiment) was dissolved in NMP (4 mL). Propan-2-amine (973 mg, 1.402 mL, 16.46 mmol) was added dropwise with stirring and an exotherm was observed. LCMS analysis indicated that the reaction had gone to about 75% completion. Further propan-2-amine (348 mg, 0.5 mL, 5.88 mmol) was added and the reaction mixture heated at reflux temperature for 5 min followed by stirring at room temperature overnight. The resultant precipitate was filtered and washed with diethyl ether (150 mL). This afforded product contaminated with isopropylamine. The solid was dissolved in DCM (50 mL) and washed with water (2×10 mL). The organics were dried (MgSO4) and concentrated to afford 2-[7-chloro-3-(4-fluoro-3-methoxyphenyl)-1-oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (300 mg, 0.745 mmol).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C(Cl)CCl>[C:12]1([C:7]2[NH:8][C:9]3[C:5]([C:6]=2[C:16]([C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]([OH:18])=[O:23])=[O:17])=[CH:4][CH:3]=[CH:11][CH:10]=3)[CH:5]=[CH:4][CH:3]=[CH:11][CH:10]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc2[nH]c(C)cc2c1
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 5.0 g (0.03 mole) of 5-methoxy-2-methylindole and 4.6 g (0.03 mole) of phthalic anhydride in 25 ml of ethylene dichloride was refluxed for ten hours, cooled to room temperature and the separated solid was collected by filtration and dried to obtain 2-[(2-methyl-5-methoxy-3-indolyl)carbonyl]benzoic acid (Formula VIII: R0 =R1 =R2 =R3 =R6 =H; R5 =CH3 ; Y1 =OCH3), as a pale pink-colored solid which decomposed at 203°-204° C. The nuclear magnetic resonance and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C(O)[CH2:32][CH2:33][OH:34].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:1][C:2]([F:29])([F:30])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH2:26][CH2:32][CH2:33][OH:34])=[O:24])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(OCCCO)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A mixture of 2.25 g. of methyl 4-[15-(trifluoromethyl)pentadecylamino]benzoate, 280 mg. of 1,3-propanediol and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield the product as a white solid.
Reaction SMILES: [NH:1]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33]N)=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl.C(N(CC)CC)C.N[C@H:51]([C:56]([OH:58])=[O:57])[CH2:52][CH2:53][S:54][CH3:55].[NH2:59][CH:60]([CH2:63][OH:64])[CH2:61][OH:62]>CN(C=O)C.O1CCOCC1.C(ON=O)(C)(C)C>[NH:1]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:51]([C:56]([OH:58])=[O:57])[CH2:52][CH2:53][S:54][CH3:55])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:59][CH:60]([CH2:63][OH:64])[CH2:61][OH:62]
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reactant: CSCC[C@H](N)C(=O)O
Agent: CC(C)(C)ON=O
Agent: Cl
Agent: NC(CO)CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.17 h

Procedure:
To 2.5 g of Boc-Tyr-(D)-Ala-Gly-Phe-NHNH2 in 40 ml of DMF are added 2.7 ml of 5.6 N HCl in dioxane and 0.52 ml of tert.butylnitrite at -20° and, after 10 minutes, 3.4 ml of triethylamine and 2 g of H-Met-serinol trifuloroacetate. After 4 hours at 0° and 15 hours at room temperature, the mixture is concentrated under vacuum, the residue taken up in ethyl acetate and washed repeatedly with dilute HCl and water and the organic phase evaporated. The residue crystallizes from methanol/ether to yield the title compound. M.P. 140° (decomp.). [α]D20 =-15 (C=1 in DMF).
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].[O:12]=[C:13]1[NH:17][CH:16]([C:18](O)=[O:19])[CH:15]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[S:14]1>>[N+:5]([O:8][CH2:9][CH2:10][NH:11][C:18]([CH:16]1[CH:15]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[S:14][C:13](=[O:12])[NH:17]1)=[O:19])([O-:7])=[O:6]
Reactant: O=C1NC(C(=O)O)C(c2cccnc2)S1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2cccnc2)S1

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 300 mg of N-(2-nitrooxyethyl)-amine nitrate and 330 mg of 2-oxo-5-(3-pyridyl)thiazolidine-4-carboxylic acid, to obtain 140 mg of the title compound as colorless crystals, melting at 139°-140° C. (after recrystallization from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:22]2[CH2:27][C@@H:26]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]2)=[O:20])[N:10]=[N:9]1.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:22]2[CH2:27][C@@H:26]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH2:25][NH:24][CH2:23]2)=[O:20])[N:10]=[N:9]1
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nnn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 193.6 %

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(2-chlorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (280 mg) was dissolved in ethyl acetate (0.5 ml), 4N hydrogen chloride-ethyl acetate solution (0.5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to give the object product (245 mg).
Reaction SMILES: C(C[CH2:4][CH:5]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)#N.S(=O)(=O)(O)O.[C:20]([OH:23])(=[O:22])[CH3:21]>O>[O:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH:5]1[CH2:4][CH2:21][C:20]([OH:23])=[O:22]
Reactant: CC(=O)O
Reactant: N#CCCC1COc2ccccc2O1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCC1COc2ccccc2O1

Procedure:
72 g 2-(2-cyanoethyl) (2,3-dihydro [4H] 1,4-benzodioxin) are suspended in 100 ml acetic acid, 100 ml water and 40 g sulphuric acid. The whole is heated to reflux for 48 hours and the mixture is thereafter poured in water. The aqueous phase is extracted with ether. The ethereous solution is separated, washed, dried and concentrated off. 76 g of 3-(2,3-dihydro [4H] 1,4-benzodioxin-2 yl) propionic acid are obtained, melting at 102°. This acid is esterified with methanol and p toluene sulphonic acid at the boiling point for 18 hours. After the usual purifications 71 g of the methyl ester are obtained. MP: 55°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.FC(F)(F)S(O)(=O)=O.[O:18]1[CH2:23][CH2:22][CH:21]([CH2:24]O)[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH2:24][CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)[CH:5]=[CH:4][N:3]=1
Reactant: OCC1CCOCC1
Reactant: OCc1ccnc(F)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cc(COCC2CCOCC2)ccn1
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To a mixture of (2-fluoropyridin-4-yl)methanol (300 mg), triethylamine (239 mg), and dichloromethane (24 mL) was added anhydrous trifluoromethanesulfonic acid (666 mg) under ice-cooling, followed by stirring at the same temperature for 1 hour. (Tetrahydro-2H-pyran-4-yl)methanol (1.37 g) was added to the reaction liquid at room temperature, followed by stirring at the same temperature for 8 hours. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, followed by extraction with chloroform (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=8/1) to obtain 2-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethoxy)methyl]pyridine (132 mg).
Reaction SMILES: CO/[CH:3]=[C:4]1\[C:5](=[O:20])[N:6]([C:17](=[O:19])[CH3:18])[N:7]([C:14](=[O:16])[CH3:15])[C:8]2[C:13]\1=[CH:12][CH:11]=[CH:10][CH:9]=2.Cl.[OH:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:26][NH2:27].C(N(CC)CC)C.CN(C)C=O>O1CCCC1>[C:14]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)/[C:4](=[CH:3]/[NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:23]([OH:22])[CH:24]=2)/[C:5](=[O:20])[N:6]1[C:17](=[O:19])[CH3:18])(=[O:16])[CH3:15]
Reactant: CO/C=C1\C(=O)N(C(C)=O)N(C(C)=O)c2ccccc21
Reactant: COc1ccc(CN)cc1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CN/C=C2\C(=O)N(C(C)=O)N(C(C)=O)c3ccccc32)cc1O
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of (Z)-1,1′-(4-(methoxymethylene)-3-oxo-3,4-dihydrocinnoline-1,2-diyl)diethanone (0.18 g, 0.66 mmol) in tetrahydrofuran (5 mL) is added 3-hydroxy-4-methoxybenzylamine hydrochloride (0.13 g, 0.66 mmol). The suspension is treated with triethylamine (0.21 mL) and dimethylformamide (1 mL). The mixture is stirred at room temperature until LC/MS analysis revealed the consumption of the starting materials. Following concentration under reduced pressure, the crude mixture is purified by semi-preparative reverse-phase HPLC, employing a gradient elution from 40% acetonitrile in water with 0.1% trifluoroacetic acid to 70% acetonitrile in water over 60 minutes. The desired fractions were concentrated under reduced pressure to afford 0.14 g of (4Z)-1,2-diacetyl-4-{[(3-hydroxy-4-methoxybenzyl)amino]methylene}-1,4-dihydrocinnolin-3(2H)-one.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][C:5]=1[S:13](=[O:16])(=[O:15])[NH2:14])([CH3:3])[CH3:2].[N+](=[CH2:19])=[N-].C(O)COCCO.COC.[ClH:30]>CCOCC>[Cl:30][CH2:19][C:8]([C:7]1[CH:11]=[CH:12][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([S:13](=[O:16])(=[O:15])[NH2:14])[CH:6]=1)=[O:9]
Reactant: C=[N+]=[N-]
Reactant: Cl
Reactant: CC(C)c1ccc(C(=O)Cl)cc1S(N)(=O)=O
Agent: COC
Solvent: OCCOCCO
Solvent: CCOCC
Product: CC(C)c1ccc(C(=O)CCl)cc1S(N)(=O)=O

Procedure:
13.5 g of 4-isopropyl-3-sulfamoylbenzoyl chloride were reacted as prescribed in Example 66b) with diazomethane in ether, the 4'-isopropyl-3'-sulfamoyldiazoacetophenone remaining in solution without precipitating as crystals. The solution so obtained was allowed to flow into a mixture of 200 ml of diethylene glycol-dimethyl ether and 100 ml of concentrated hydrochloric acid while stirring and cooling with ice, whereafter the solvent was largely distilled off under reduced pressure. To the oily residue, 500 ml of water were added and the solution was extracted with 200 ml of ethyl acetate. Drying followed over sodium sulfate and the solvent was distilled off under reduced pressure. The oily residue crystallized in the course of 1 to 3 days and was then triturated under a small amount of xylene and filtered off. Melting point: 141° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:29]2[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: c1ccc(N2CCNCC2)nc1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccccn2)CC1
Yield: 88 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2-pyridyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 88%). 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H), 3.61-3.71 (m, 8H), 4.12 (s, 3H), 6.66 (d, J=8 Hz, 2H), 7.07-7.74 (m, 5H), 8.20 (dd, J=5.4, 1.8 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.C(OC([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([NH2:36])[CH:34]=2)[C:29](=[O:37])[NH:28]1)=O)(C)(C)C>>[CH:14]1([C:12]2[CH:13]=[C:9]([NH:8][C:6]3[N:7]=[C:2]([NH:36][C:33]4[CH:34]=[C:35]5[C:30]([C:29](=[O:37])[NH:28][NH:27]5)=[CH:31][CH:32]=4)[CH:3]=[CH:4][C:5]=3[N+:17]([O-:19])=[O:18])[NH:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)n[nH]1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Product: O=c1[nH][nH]c2cc(Nc3ccc([N+](=O)[O-])c(Nc4cc(C5CC5)n[nH]4)n3)ccc12
Yield: 16.2 %

Procedure:
6-[6-(5-Cyclopropyl-2H-pyrazol-3-ylamino)-5-nitro-pyridin-2-ylamino]-1,2-dihydro-indazol-3-one was prepared by the reaction of (6-Chloro-3-nitro-pyridin-2-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine and 6-Amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester in a similar manner as described above to afford 17 mg of the desired product as a bright yellow solid (16.2% yield). H-NMR (CD3OD) δ 8.32(d, 1H), 7.68(d, 1H), 7.65(s, 1H), 7.17(d, 1H), 6.38(d, 1H), 6.24(s, 1H), 1.79(m, 1H), 0.84(m, 2H), 0.48(m, 2H). MS (ES+): m/e=393.2 (M+H), 391.2 (M−H); LC/Method A/4.149 min, 100% purity by area %.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C.O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reaction time: 4 h

Procedure:
[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (3.0 g, 10.6 mmol) was dissolved in methylene chloride (50 ml, 0.2 M), to which solution were added dropwise MsCl (1.23 ml, 15.9 mmol) and triethylamine (2.23 ml, 16 mmol-), and a reaction was performed at room temperature for 4 hours. The completion of the reaction was confirmed by liquid chromatography, 5 ml of water was added to the mixture, and the resulting solution was extracted with water and methylene chloride. The organic solvent layer was distilled under reduced pressure to obtain a crude solid compound. This was recrystallized from hexane:ethyl acetate (5:1) to obtain methanesulfonic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as a white solid compound.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C@H:11]2[CH3:23])=[O:9])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl>[F:24][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@@H:11]2[CH3:23])=[O:9])[CH2:6][CH2:7]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1CCC(F)(F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CNCCN1C(=O)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(R)-tert-butyl 4-(4,4-difluorocyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate 54 (1.89 g, 5.46 mmol) was dissolved in dichloromethane (30 ml). Trifluoroacetic acid (4.20 ml, 54.6 mmol) was added and the reaction stirred at RT for 1.5 hours. The reaction was added to aqueous K2CO3 (100 ml) and extracted three times with dichloromethane (50 ml). The combined organic extracts were dried (MgSO4) and evaporated to give (S)-(4,4-difluorocyclohexyl)(2-methylpiperazin-1-yl)methanone 55 as a yellow oil, 1.35 g. LC/MS m/z=247 (M+H+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:17][CH:16]([O:18]C)[CH:15]([OH:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].O>N1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH:16]([O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]([OH:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: COC1CN(C(=O)OC(C)(C)C)CC1O
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(O)C(OS(C)(=O)=O)C1
Reaction time: 8 h
Yield: 76.4 %

Procedure:
11.5 g (0.1 mole) of methanesulfonyl chloride were added dropwise, whilst ice-cooling to a solution of 13.0 g (0.06 mole) of 1-t-butoxycarbonyl-3-hydroxy-4-methoxypyrrolidine [prepared as described in Step (c) above] in 100 ml of pyridine, and the mixture was stirred overnight whilst ice-cooling. The reaction mixture was then poured into 800 ml of water and extracted with diethyl ether. The extract was washed with water and dried, and the solvent was removed by evaporation under reduced pressure to afford 12.9 g of 1-t-butoxycarbonyl-3-hydroxy-4-methanesulfonyloxypyrrolidine as a brown oily substance. The whole of this oily substance was placed in a 100 ml stainless steel autoclave, and 50 ml of liquid ammonia was added thereto. The mixture was then heated with stirring at 140° C. under pressure for 8 hours. At the end of this time, the excess ammonia was removed by evaporation, and the residue was subjected to silica gel column chromatography eluted with ethanol, to afford 8.0 of cis-3-amino-1-t-butoxycarbonyl-4-methoxypyrrolidine as a brown oily substance.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([CH3:15])[C:3]1=[O:16].[C:17]([NH:24][C@H:25]([C:29](O)=[O:30])[CH2:26][CH2:27][CH3:28])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[C:20]([O:19][C:17]([NH:24][C@H:25]([C:29]([C:2]1([NH2:1])[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([CH3:15])[C:3]1=[O:16])=[O:30])[CH2:26][CH2:27][CH3:28])=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: CN1C(=O)C(N)C(=O)N(C)c2ccccc21
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)C1(N)C(=O)N(C)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D using the product from Example 4-R, Step C and Boc-L-norvaline (BACHEM) the title intermediate was prepared. HPLC purification eluting with EtOAc/Hexanes (60:40) afforded the title intermediate as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][CH2:21][CH:22]([NH2:25])[CH2:23][CH3:24]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:25][CH:22]([CH2:21][O:20][CH3:19])[CH2:23][CH3:24])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCC(N)COC
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Product: CCC(COC)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Yield: 82.3 %

Procedure:
2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.25 g, 0.82 mmol) and 1-methoxymethyl-propylamine (0.23 g, 1.65 mmol) were treated substantially as described in Part D of Example 9 to produce 0.25 g (83%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (AP) m/z 370.2 [(M+H)+, 98].
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([OH:21])=O)=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH2:41]([N:43]([CH2:49][CH3:50])[CH:44]1[CH2:48][CH2:47][NH:46][CH2:45]1)[CH3:42]>CC#N>[CH2:41]([N:43]([CH2:49][CH3:50])[CH:44]1[CH2:48][CH2:47][N:46]([C:19]([C:16]2[N:17]([CH3:18])[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=3)=[N:14][C:15]=2[I:22])=[O:21])[CH2:45]1)[CH3:42]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)O)n2C)c1
Reactant: CCN(CC)C1CCNC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N(CC)CC)C3)n2C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
A solution of 0.41 g (1.0 mmol) of 2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-carboxylic acid (intermediate 1) in 10 ml of MeCN was treated with 0.192 g (1.1 mmol) of 2-chloro-4,6-dimethoxy-[1,3,5]triazine and cooled down to 0° C. 0.33 ml=0.30 g (3.0 mmol) of N-methylmorpholine was added and stirring continued at 0° C. for another 2 hours. Then, a solution of 0.159 g (1.1 mmol) of (rac)-diethyl-pyrrolidin-3-yl-amine in 5 ml of MeCN was added and the reaction mixture was allowed the reach RT. After stirring at RT for 18 hours, it was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.39 g (73%) of the title compound as light brown oil. MS: 537.3 (MH+).