Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([NH:7][O:8][CH2:9][CH2:10]Cl)=[NH:6].[H-].[Na+]>CN1CCCC1=O>[CH3:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]([C:5]2[NH:6][CH2:10][CH2:9][O:8][N:7]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(C(=N)NOCCCl)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(C2=NOCCN2)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 12 h

Procedure:
1.4 g (5.4 mmol) of 3-methyl-N-(2-chloroethoxy)-2-nitrobenzamidine are initially charged in 45 ml of 1-methyl-2-pyrrolidone, and 0.18 g (6 mmol) of sodium hydride (80% pure) is added slowly. The mixture is stirred at 100° C. for 12 h, cooled, poured onto water and extracted with ethyl acetate. After drying over sodium sulphate, the solvent is distilled off under reduced pressure.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(N)cc1
Agent: O=S(=O)(O)O
Product: CCc1ccc(N)cc1[N+](=O)[O-]
Temperature: 8 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
4-Ethylaniline (10.3 mL, 82.5 mmol) was added dropwise to sulfuric acid (96%, 63 mL), cooled to 8° C., maintaining the temperature below 10° C. After the addition, the reaction mixture was cooled to −5° C., before the addition of a mixture of nitric acid (100%, 4 mL) and sulfuric acid (96%, 10 mL), keeping the temperature below 0° C. The reaction mixture was then stirred at the same temperature for 1 h. The reaction mixture was poured into ice (200 mL) and the precipitate filtered and washed with water. The solid was suspended with water (100 mL) and neutralized with ammonium hydroxide (35%). The precipitate was filtered and dried in the oven to obtain a light-brown solid (10 g, 73%).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.[OH-].[Na+]>C(Cl)Cl.O>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH2:21][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:30]=[CH:29][C:27]=1[OH:28]
Reactant: C1CCNC1
Reactant: COc1cc(C=O)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(CN2CCCC2)ccc1O
Yield: 74.6 %

Procedure:
NaB(OAc)3H (8.7 g, 0.041 mol) was added in portions for 30 min to a mixture of pyrrolidine (3.4 mL, 0.041 mol) and vanillin (5 g, 0.033 mol) in CH2Cl2 (50 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 2 h and cooled. Then 10 N NaOH (4.1 mL) and water (30 mL) were added. The organic layer was separated; the aqueous one was extracted with chloroform (2×50 mL). The organic fractions were evaporated. The residue was distributed between water and CH2Cl2. Concentrated HCl (2.98 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 6 and extracted with chloroform (2×100 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (5.1 g, 75%) was obtained as white crystals. 1H-NMR (400 MHz)-data (dmso-d6): 8.72 (s, 1H ArOH), 6.81-6.84 (m, 1H, Ar—H), 6.64-6.70 (m, 2H, Ar—H), 3.74 (s, 3H, ArOCH3), 3.43 (s, 2H, ArCH2), 2.36-2.41 (m, 4H, pyrrolidine (CH2)2N), 1.64-1.70 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C([O-])(O)=O.[Na+].C(Cl)Cl>[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1
Reactant: Cc1ccc2c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@H](N)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 0.5 h

Procedure:
To (S)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (174 mg, 0.41 mmol) at room temperature was added 1.4 mL of a 1:1 TFA:CH2Cl2 solution. The reaction mixture was stirred for 30 min and diluted with 10 mL of saturated NaHCO3 and 10 mL of CH2Cl2. The organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure to give (S)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol. LC/MS: m/z 321.2 (M+H)+ at 1.89 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) which was used for the next step.
Reaction SMILES: COC([CH:5]1[C:20](=[O:21])[C:9]2([CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)[CH2:8][NH:7][C:6]1=[O:22])=O>C(#N)C.O>[C:16]([O:15][C:13]([N:11]1[CH2:12][C:9]2([C:20](=[O:21])[CH2:5][C:6](=[O:22])[NH:7][CH2:8]2)[CH2:10]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)C1C(=O)NCC2(CN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2(CNC(=O)CC2=O)C1

Procedure:
7,9-Dioxo-2,6-diaza-spiro[3.5]nonane-2,8-dicarboxylic acid 2-tert-butyl ester 8-methyl ester (Example 156g)(8.3 g; 26.6 mmol) is dissolved in acetonitrile/water (170 ml; 9/1) and refluxed for 1 hour. The reaction mixture is evaporated to dryness and delivers the title compound as white crystals (6.35 g; 94%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16]>>[C:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: O=C1NCCN1
Reactant: CC(=O)c1cccc(Br)c1
Product: CC(=O)c1cccc(N2CCNC2=O)c1
Yield: 18 %

Procedure:
The title compound was prepared in 18% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 1-(3-bromophenyl)ethanone and 2-imidazolidinone.
Reaction SMILES: C(OC([NH:8][CH:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=O)(C)(C)C.[NH2:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:27][CH2:26]1)[OH:24]>>[NH2:8][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:17]([NH:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:27][CH2:26]1)[OH:24])=[O:19]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccn1)C(=O)O
Product: NC(Cc1ccccn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described above, by the condensation of N-(tert-butoxycarbonyl)-3-(pyridin-2-yl)-D,L-alanine [J. Gen. Chem. USSR, 40, 2488 (1970)1 and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol followed by acidic hydrolysis there were obtained (S or R)-α-amino-N-[(1S,2R,3 S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(pyridin-2-yl)propionamide, MS: 267 (M+H)+, and (R or S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(pyridin-2-yl)propionamide, MS: 267 (M+H)+, each as a colourless foam.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21].C(N(CC)CC)C.CS(Cl)(=O)=O.[P:34]([O-])([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>O1CCCC1>[CH2:45]([O:44][P:34](=[O:35])([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[O:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1COP(=O)(OCc1ccccc1)OCc1ccccc1
Reaction time: 8 h

Procedure:
5.0 g (17.7 mmol) of 3-(hydroxymethyl)-5,5-diphenylimidazolidine-2,4-dione (hydroxymethylphenytoin) and 7.5 g (74.1 mmol) of triethylamine were dissolved in 30 g of tetrahydrofuran (THF). A solution of 2.4 g (21.0 mmol) of methanesulfonyl chloride in 33.3 g of THF was added at −10 to −5° C. A white suspension formed. The suspension was filtered and the clear filtrate was added to a suspension of 5.8 g (20.8 mmol) of dibenzyl phosphate in 5.0 g of THF at room temperature. After stirring overnight, the mixture was concentrated on a rotary evaporator, 50 g of ethyl acetate and 25 g of water were then added to the residue and the phases were separated. The organic phase was washed once with 20 g of water and then extensively concentrated on a rotary evaporator. 2.5 g of acetone and seed material were added to the residue obtained and the mixture was stirred overnight at 0 to 10° C. The resulting colourless precipitate was filtered off and dried under vacuum. Yield: 6.9 g (72%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[Br:20]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:20][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[N:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=1
Reactant: BrBr
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccc(F)cc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-1H-indole (Intermediate 1; 1.0 g; 3.6 mmol) in DCM (20 mL) at 0° C. was added a solution of bromine (0.64 g; 4.0 mmol) in DCM (20 mL) dropwise. The mixture was stirred at 0° C. for 0.5 h, then added saturated aqueous Na2S2O3 (10 mL), and stirred at r.t. for 10 minute. The organic layer was separated and the aqueous layer was extracted with DCM (10 mL×2). The combined organic layers were washed with saturated aqueous NaHCO3 (20 mL×2), water (20 mL×2), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.26 g (99%) of the title compound as a pink solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1
Yield: 71.4 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in dimethoxyethane (5.6 mL), and the solution was added with 4-methoxyphenylboronic acid (62 mg, 0.41 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (13.2 mg, 0.0166 mmol), potassium carbonate (93.0 mg, 0.675 mmol) and water (0.049 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=8/1) to obtain 4-(4-methoxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (53.2 mg, yield 71%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])O.[Na+]>ClCCl>[CH:19]1([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: NC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc2c(NC3CCCC3)nnc(Cc3ccncc3)c2c1
Temperature: 115 °C
Reaction time: 6 h

Procedure:
A mixture of 0.3 g (1.173 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.4 g (4.692 mmol) cyclopentylamine is stirred for 6 h at 115° C. The cooled reaction mixture is then distributed between dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic solution washed with brine and dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol (9:1). Title compound is obtained after crystallization of the product-containing fractions from acetonitrile/water and drying under HV (8 h, 100° C.); m.p. 163-165° C.; ESI-MS: (M+H)+=305.
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:16][CH2:17][CH3:18])[CH2:9][CH:8](C(OCC)=O)[C:7](=[O:15])[CH2:6][CH2:5]1)[CH3:2].[OH-].[K+]>>[CH2:17]([O:16][C:4]1([O:3][CH2:1][CH3:2])[CH2:9][CH2:8][C:7](=[O:15])[CH2:6][CH2:5]1)[CH3:18]
Reactant: CCOC(=O)C1CC(OCC)(OCC)CCC1=O
Agent: [K+]
Agent: [OH-]
Product: CCOC1(OCC)CCC(=O)CC1
Temperature: 25 °C

Procedure:
Into a flask are successively added 38.7 g of ethyl 5,5-diethoxy-2-oxocyclohexane carboxylate and 215 ml of a 10% potassium hydroxide solution. The mixture is refluxed for 16 hours, then cooled to room temperature. The organic phase is extracted twice with ether; the aqueous solution is salted out with potassium carbonate and an oily phase separates which is extracted with ether. The ethereal phases are united, dried over potassium carbonate and evaporated to dryness. The crude residue weighing 26.4 g is purified by distillation under reduced pressure. The yield amounts to 22.3 g of a liquid boiling at 110°-112° under 12 mm Hg -- nD22 = 1.449.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6](O)=[O:7])#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:29][NH2:30]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([NH:29][NH2:30])=[O:7])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(=O)NN)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (0.300 g, 1.46 mmol) in tetrahydrofuran (10.0 mL) was treated with 1,1′-carbonyldiimidazole (0.261 g, 1.61 mmol). After stirring 2 h at ambient temperature, hydrazine monohydrate (0.213 mL, 4.39 mmol) was added. After stirring an additional 2 h at ambient temperature, the reaction mixture was concentrated in vacuo. Purification via flash column chromatography (0-5% MeOH/EtOAc) gave the title compound as a white solid (0.304 g; 95%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.51 (br. s., 1H) 8.06 (d, J=2.3 Hz, 1H) 8.02 (dd, J=8.8, 2.3 Hz, 1H) 7.00 (d, J=8.8 Hz, 1H) 5.15 (br. s., 2H) 4.71 (qq, J=6.1 Hz, 1H) 1.40 (d, J=6.1 Hz, 6H). MS (ES+) m/e 220 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5](OC)=[O:6].O.[NH2:14][NH2:15].O>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5]([NH:14][NH2:15])=[O:6]
Reactant: NN
Reactant: COC(=O)c1cc(I)cc(I)c1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc(I)cc(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To Methyl 3,5-diiodobenzoate (5.0 g, 12.89 mmol) in ethanol (70.0 ml) was added hydrazine hydrate (20.0 ml) under stirring. During heating, white solid was appeared. The reaction was kept 50° C. for 1 h. Heating was stopped and then water (100.0 ml) was added. After cooling down to room temperature, the white product solid was collected by filtration. The product was washed with water and dried under vacuum. Final white product was obtained in 4.6 g (92.0%). 1H NMR (400 MHz, DMSO-d6, δ): 9.92 (s, 1H, NH), 8.22 (t, J=1.6 Hz, 1H), 8.12 (d, J=1.6 Hz, 2H), 4.53 (s, 2H, NH2).
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][C@@H:11]([CH2:14][O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[N+:26]([O-:28])=[O:27])[CH:2]=C.[O:29]=[O+][O-].O=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([O:15][CH2:14][CH:11]2[O:10][C:9]3[C:4]([CH2:1][CH:2]=[O:29])=[C:5]([N+:26]([O-:28])=[O:27])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:17])=[O:18])=[CH:24][CH:23]=1
Reactant: O=[O+][O-]
Reactant: C=CCc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])c(CC=O)c3O2)cc1
Reaction time: 24 h

Procedure:
A solution of 4.2 g (10 mmole) of toluene-4-sulfonic acid (2R)-8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester in 400 mL of methylene chloride was cooled in a dry ice/isopropanol bath and saturated with ozone. It was then purged with oxygen and 2.6 g (20 mmole) of diisopropylethylamine added. The mixture was allowed to come to room temperature and stirred under nitrogen for 24 hours. It was then washed with 300 mL portions of 2 N HCl (aq), water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to give 3.8 g of the (R)-enantiomer of the title compound as a white solid one-quarter hydrate, m.p. 116-120° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][O:34][Si](C(C)(C)C)(C)C)=[C:27]([C:44]([F:47])([F:46])[F:45])[CH:26]=3)=[O:23])=[CH:17][C:16]=2[F:48])=[C:11]([O:49][CH2:50][CH3:51])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][OH:34])=[C:27]([C:44]([F:45])([F:47])[F:46])[CH:26]=3)=[O:23])=[CH:17][C:16]=2[F:48])=[C:11]([O:49][CH2:50][CH3:51])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2ccc(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c(C(F)(F)F)c2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2ccc(CC(C)(C)CO)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a mixture of 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (4.5 g, 4.83 mmol) in DCM (30 mL) was added TFA (4.46 mL, 57.9 mmol). The mixture was stirred at 25° C. for 2 h. Then the reaction residue was concentrated, added to MeCN (50 mL), made basic with NH4OH and concentrated. The crude material was purified by silica column chromatography (PE/EA=1:1). All fractions found to contain product by TLC (PE/EA=1:1, Rf=0.6) were combined and concentrated to yield a light yellow solid of 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (4.2 g, 4.19 mmol, 87% yield): 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.88 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.51-7.43 (m, 3H), 7.38 (t, J=7.2 Hz, 2H), 7.35-7.29 (m, 2H), 7.26-7.16 (m, 2H), 6.50 (s, 1H), 5.38 (s, 2H), 4.14-4.11 (m, 2H), 3.77 (s, 2H), 2.80 (s, 2H), 2.03 (s, 2H), 1.32 (t, J=6.8 Hz, 3H), 0.86 (s, 6H); ES-LCMS m/z 611.2 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:15]=[C:16]([CH2:18][O:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[N:17]=3)[C:10]([C:13]#[N:14])=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[NH2:30][OH:31]>CCO>[OH:31]/[N:30]=[C:13](/[C:10]1[N:9]2[CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[N:17]=[C:8]2[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:12][CH:11]=1)\[NH2:14]
Reactant: NO
Reactant: N#Cc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Solvent: CCO
Product: N/C(=N\O)c1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12

Procedure:
A mixture of compound 55a (100 mg, 0.26 mmol) and hydroxylamine (50% wt, 0.086 mL, 1.4 mmol) in EtOH (2 mL) was heated to 90° C. for 5 h. The precipitate obtained was collected by filtration, washed with EtOH, and dried to give compound 55b. Mass Spectrum (LCMS, ESI pos.) Calcd. for C21H21N7O3: 420.2 [M+H]. found 420.2
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12]O)[CH:9]=[CH:10][CH:11]=1.P(Br)(Br)[Br:15]>C(Cl)Cl>[Br:15][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=1
Reactant: COCCOc1cccc(CO)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COCCOc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 171.7 %

Procedure:
To a solution of 27C (18.2 g, 100 mmol) in CH2Cl2 (300 mL) was added PBr3 (4.5 mL, 48 mmol) at 0° C., then the resulting mixture was allowed to warm to RT overnight. The reaction mixture was quenched with saturated NaHCO3 (50 mL) and stirred at RT for an addition 0.5 h. The mixture was extracted with CH2Cl2, and the combined extracted were dried (MgSO4), filtered, and evaporated in vacuum to give the product as a yellow oil (20.2 g, 82%, two steps). 1H NMR (300 MHz, CDCl3): δ 3.45 (s, 1H), 3.75 (t, 2H, J=4.8 Hz), 4.12 (t, 2H, J=4.8 Hz), 4.45 (s, 2H), 6.85-6.99 (m, 3H), 7.21-7.26 (m, 1H). LC-MS: purity >95%, ESI-MS: M/Z 245 (M+H)+, 247 (M+2+H)+.
Reaction SMILES: C(O)C.[O-]CC.[Na+].C(O)C.[F:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:14][C:13]=1[NH:25][NH2:26].[C:27](OCC)(=[O:35])/[CH:28]=[CH:29]\[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(O)(=O)C>[F:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:14][C:13]=1[N:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][C:27]([OH:35])=[N:26]1
Reactant: Cc1cc(F)c(NN)cc1SCC(F)(F)F
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reaction time: 0.01 h
Yield: 25.5 %

Procedure:
14 g of a 20 mass % sodium ethoxide ethanol solution was added to 20 mL of ethanol, and 10 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine was rapidly added under reflux with heating. After stirring for 30 seconds, 7.8 g of diethyl maleate was dropwise added, followed by stirring under reflux with heating for 10minutes. The reaction solution was cooled to 50° C. or below, and 4.5 g of acetic acid was added. Then, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 80 mL of toluene, 0.68 g of tetra n-butyl ammonium bromide was added, and 3.5 g of a 10 mass % aqueous solution of potassium permanganate was gradually added. After completion of the reaction, ethyl acetate and 20 mL of a saturated aqueous solution of citric acid were added, and the solution was washed with an aqueous sodium thiosulfate solution and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 3.80 g of ethyl 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole-5-carboxylate.