Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([Cl:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[S:13](=[O:15])=[O:14].[ClH:16]>O.C(O)(=O)C.[Cu]Cl>[Cl:12][C:7]1[C:6]([S:13]([Cl:16])(=[O:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=S=O
Reactant: Cl
Reactant: Nc1cccnc1Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(Cl)c1cccnc1Cl

Procedure:
A solution of sodium nitrite (6.5g) in water (15 ml) was added gradually to a solution of 3-amino-2-chloropyridine (10 g) in acetic acid (100 ml) and concentrated hydrochloric acid (37 ml) at 0-5° C. This cold solution was then added portion-wise to a stirred and cooled (5° C.) mixture of copper(I) chloride (2.33 g) in acetic acid (160 ml) saturated with sulphur dioxide keeping the temperature below 10° C. After the addition was complete the cooling bath was removed and the mixture was stirred a further 90 minutes at ambient temperature. Volatile material was removed by evaporation and water (300 ml) was added to the residue to give a solid. The water was decanted off and the solid was dissolved in ether (500 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (200 ml), water (200 ml) and saturated sodium chloride solution and was then dried (MgSO4). Volatile material was removed by evaporation to give 2-chloropyridine-3-sulphonyl chloride (12.1 g) as an oil which solidified upon refrigeration and was used without further purification; 1H NMR (CDCl3): 7.5 (dd, 1H), 8.5 (dd, 1H), 8.7 (dd, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([CH:23]4[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]4)=[O:22])[C@@H:17]([CH3:31])[CH2:16]3)=[C:11]3[CH:32]=[N:33][CH:34]=[CH:35][C:10]=23)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:46]([O:48][CH3:49])=[O:47]>CN(C=O)C.C(OCC)(=O)C>[F:29][C:26]1([F:30])[CH2:27][CH2:28][CH:23]([C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:12]3[N:13]=[N:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:46](=[O:47])[O:48][CH3:49])=[CH:8][CH:7]=4)=[C:10]4[CH:35]=[CH:34][N:33]=[CH:32][C:11]=34)[CH2:16][C@@H:17]2[CH3:31])=[O:22])[CH2:24][CH2:25]1
Reactant: COC(=O)Cl
Reactant: C[C@H]1CN(c2nnc(-c3ccc(CN)cc3)c3ccncc23)CCN1C(=O)C1CCC(F)(F)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)NCc1ccc(-c2nnc(N3CCN(C(=O)C4CCC(F)(F)CC4)[C@@H](C)C3)c3cnccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-(4-(1-(4-(aminomethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone 51 (120 mg, 250 μmol) was dissolved in DMF (3 ml) and N,N-diisopropylethylamine (0.300 ml, 1.72 mmol). Methyl chloroformate (0.0211 ml, 275 μmol) was added and the reaction stirred at RT for 2 hours. The reaction was the taken up in ethyl acetate (80 ml) and washed with aqueous K2CO3 (10%), water, and brine. The organic phase was dried (MgSO4) and evaporated to give an orange oil. The residue was chromatographed over silica with a gradient of dichloromethane with 2.5% triethylamine and 0-5% methanol. The product (S)-methyl (4-(4-(4-(4,4-difluorocyclohexanecarbonyl)-3-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)phenyl)methylcarbamate 52 was isolated as a yellow solid. LC/MS m/z=539 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:21]=[CH:20][CH:19]=[CH:18][C:11]=2[C:12]([NH:14][CH2:15][C:16]#[CH:17])=[O:13])=[CH:5][CH:4]=1.[N:22]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](OC2C=CC=CC=2)[CH:27]=1)=[N+:23]=[N-:24].O.[O:40]=[C:41]1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[CH3:41][O:40][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[CH:17]=[C:16]([CH2:15][NH:14][C:12](=[O:13])[C:11]3[CH:18]=[CH:19][CH:20]=[N:21][C:10]=3[NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:24]=[N:23]2)=[CH:31][CH:30]=1
Reactant: [N-]=[N+]=NCc1cccc(Oc2ccccc2)c1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: C#CCNC(=O)c1cccnc1Nc1ccc(OC)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(Cn2cc(CNC(=O)c3cccnc3Nc3ccc(OC)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 708.7 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-methoxyaniline (9e, 123 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10e as pure product. To a solution of 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10e, 150 mg, 0.53 mmol) and 1-(azidomethyl)-4-methoxybenzene (12c, 95 mg, 0.58 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 12 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 5e (189 mg, 80%); %); 1H NMR (300 MHz, CDCl3) δ 10.31 (s, 1H), 8.19 (dd, J=4.9, 1.7 Hz, 1H), 7.7.81 (dd, J=7.7, 1.7 Hz, 2H), 7.52-7.48 (m, 3H), 7.25-7.19 (m, 2H), 6.85-6.81 (m, 4H), 6.55-6.51 (m, 1H), 5.42 (s, 2H), 4.55 (d, J=5.4 Hz, 2H), 3.78 (s, 3H), 3.77 ppm (s, 3H); yield 80%
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)=[CH:3]1.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C)C=O>[O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([Cl:27])=[O:23])=[CH:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-oxoandrost-4-ene-17β-carboxylic acid (30 g) in methylene chloride (300 mL) and dimethylformamide (1.82 mL) a solution of oxalyl chloride (9.28 mL) in methylene chloride (30 mL) was added dropwise at 0° C. under nitrogen atmosphere. After stirring at 0° C. for 1 hour the reaction was completed. The volatile compounds were removed under vacuum, the solid was taken up with cyclohexane (200 mL) and evaporated to dryness (twice). The 3-oxo-androst-4-ene-17β-carbonyl chloride (30.33 g) so obtained was dissolved in chloroform (1.5 L), cooled to 0° C. and treated with 1,1,1,3,3,3-hexafluorophenylpropyl amine (46.078 g) and pyridine (38.3 mL). The reaction mixture was heated at reflux for 7 hours. After staying overnight at room temperature the reaction mixture was washed with 1N HCl (2×100 mL), with brine, with water until neutral and dried over sodium sulfate. The solvent was evaporated under vacuum and the brownish solid purified by flash chromatography on silica gel (eluant: n-hexane/ethyl acetate 70/30) to yield 9.2 g of the title compound.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:34])[CH:31]([CH3:33])[CH3:32])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:34])[CH:31]([CH3:32])[CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])([CH3:5])([CH3:4])[CH3:6]
Reactant: CCCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(O)C(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
20 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 297 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-2-methylpropyl)imidazole-5-carbonitrile [prepared as described in step (b) above] in 20 ml of ethanol, and the resulting mixture was heated under reflux for 8 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to afford 151 mg of the title compound as an amorphous solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:7](=[O:14])[CH:8]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[N:10]=1)[CH2:2][CH2:3][CH3:4].[Br:30]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:30][C:8]1[C:7](=[O:14])[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:10][C:9]=1[CH:11]1[CH2:13][CH2:12]1
Reactant: CCCCc1nc(C2CC2)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C2CC2)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 4′-[(2-butyl-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (5.22 g) in acetic acid (60 mL) was added bromine (1.39 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (5.4 g, 80%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[Cl:10])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NNc1ccc(F)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNc1ccc(F)cn1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO 2010/022076, which is incorporated herein by reference; 1.0 g, 7.87 mmol) and 2-chloro-benzoyl chloride (1 mL, 7.87 mmol) in DCM (50 mL) was added dropwise DIPEA (2.74 mL, 15.75 mmol). The reaction mixture was stirred at RT for 1 h then washed with water. The organic layer was dried through a phase separator and then concentrated in vacuo to afford the title compound (1.95 g, 93%) as a brown solid. LCMS (Method 3): Rt 2.82 min, m/z 266 [MH+].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:7]([OH:20])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[O:20][C:7]=2[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccncc2)c(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc2nc(-c3ccncc3)oc2c1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
A mixture of 1.22 g of N-(4-tert-butyl-2-hydroxyphenyl)isonicotinamide, 15 ml of carbon tetrachloride, 3.55 g of triphenylphosphine and 1.37 g of triethylamine was heated to reflux for three hours. The mixture was cooled to room temperature, and then water was poured into the mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.30 g of 6-tert-butyl-2-(pyridin-4-yl)-benzoxazole (hereinafter, referred to as “active compound 8”).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.C1COCC1>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([CH2:19][N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: c1cc2oc(N3CCN(C4CC4)CC3)nc2cc1CN1CCCC1
Yield: 39.9 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carboxaldehyde (400 mg, 1.48 mmol) and pyrrolidine (210 mg, 2.96 mmol) in CH3OH/THF (36 mL, 1:3) was added acetic acid (142 mg, 2.37 mmol), followed by NaCNBH3 (137 mg, 2.37 mmol). The mixture was heated at reflux for 12 h. The volatiles were removed and the residue was diluted with water (5 mL). The resulting mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (elute: 2% dichloromethane in methanol) to give 193 mg (40%) of 2-(4-cyclopropylpiperazin-1-yl)-5-pyrrolidin-1-ylmethylbenzooxazole.
Reaction SMILES: [Na].C(O)C.[CH:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:10][CH2:11][C:12](OCC)=[O:13]>C(OCC)C>[Cl:10][CH:11]([CH:12]=[O:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC=O
Reactant: CCOC(=O)CCl
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(Cl)C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
To a flask was added sodium (4.45 g, 194 mmol) and ethanol (56.5 mL, 968 mmol) and the mixture was stirred at room temperature for 4 hours until all of the metal had dissolved. Diethyl ether (100 mL) was added, followed by the slow addition of a solution of ethyl formate (17.20 mL, 213 mmol) and ethyl chloroacetate (22.79 mL, 213 mmol) in diethyl ether (100 mL). The reaction solution was stirred at room temperature for 16 hours. The resulting precipitate that formed was filtered and washed with ether, and dissolved in water. The aqueous layer was acidified with HCl (1N) to pH 4 and the product was extracted with diethyl ether (3×). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give ethyl 2-chloro-3-oxopropanoate (4.5 g, 29.9 mmol, 15.44% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10]>Cl.O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH3:10]
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Zn]
Solvent: O
Product: CCc1cc(Cl)ccc1Cl
Temperature: 25 °C

Procedure:
A suspension of mossy zinc (10 g) and mercuric chloride (0.5 g) in concd HCl (0.5 mL) and water (5 mL) was shaken for ~5 min. The aqueous layer was then decanted. To the residue was added concd HCl (7.5 mL) and water (7.5 mL) followed by 2',5'-dichloroacetophenone (3.106 g, 16.43 mmol) and the suspension was refluxed for 4 h during which time, hourly addition of concd HCl (90.5 mL) was carried out. The resulting suspension was cooled to room temperature and the aqueous layer was decanted. The residual solid was washed with ether (3×30 mL). The aqueous layer was extracted with ether (3×50 mL). The combined ether layer was washed with brine, dried over anhydrous Na2SO4, and removed under vacuum. The residue was dried further under vacuum to obtain 2.664 g crude product, which was purified on silica gel (hexane) to obtain 0.813 g (28%) pure (1H NMR) title compound as a colorless liquid; 1H NMR (DMSO-d6) δ1.23 (t, 3H, J=7.5 Hz), 2.73 (q, 2H, J=7.5 Hz), 7.09-7.27 (m, 3H).
Reaction SMILES: O[C:2]12[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH:7]1[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[C:5]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([CH3:26])[NH:3]2>C1(C)C=CC=CC=1>[CH3:26][C:4]1[NH:3][C:2]2[CH2:10][CH2:9][S:8](=[O:11])(=[O:12])[C:7]=2[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:5]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1=C(C)NC2(O)CCS(=O)(=O)C2C1c1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC2=C(C1c1ccccc1[N+](=O)[O-])S(=O)(=O)CC2

Procedure:
A mixture of methyl 2,3,3a,4,7,7a-hexahydro-3a-hydroxy-5-methyl-7-(2-nitrophenyl)-1,1-dioxothieno[3,2-b]pyridine-6-carboxylate (2.5 g, 0.0065 moles) and toluene (60 mL) was refluxed for 24 hours. The solvent was removed in vacuo and the resulting solid was recrystallized from ethanol. The crystals were washed with diethyl ether 2× and dried at 65° C. under high vacuum for 48 hours. This gave 1.78 g product; mp 215°-217° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>CN1C(=O)CCC1>[F:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[S:3][C:4]=2[CH:10]=1
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: Nc1ccc(O)cc1
Solvent: CN1CCCC1=O
Product: Oc1ccc(Nc2nc3ccc(F)cc3s2)cc1

Procedure:
2-Chloro-6-fluorobenzo[d]thiazole (7.0 g, 0.037 mol) and 4-aminophenol (4.0 g, 0.037 mol) in NMP (50 mL) was heated at 160° C. for 7 h. The reaction was quenched with 2N NaOH (100 mL) and then extracted with EtOAc (2×100 mL). The organic layer was washed with 2 N NaOH (50 mL) and to the combined aqueous layer was added 5 N HCl until pH 6 and then extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The crude was purified by column chromatography (silica gel 100-200 mesh; 80% ethyl acetate in hexanes) to afford 4-(6-fluorobenzo[d]thiazol-2-ylamino)phenol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH3:20]>C1C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4]([NH2:20])=[O:5]
Reactant: N
Reactant: O=C(O)c1c(C(F)(F)F)ccc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NC(=O)c1c(C(F)(F)F)ccc(Cl)c1Cl
Temperature: 5 °C

Procedure:
To a solution of 250 g of 2,3-dichloro-6-trifluoromethylbenzoic acid in 2 liters of benzene was added 5 drops of pyridine and 172 g of thionyl chloride and then the mixture was heated at reflux for 22 hours. After cooling down, the solution was concentrated under reduced pressure, and 2,3-dichloro-6-trifluoromethylbenzyl chloride obtained was added into 1 liter of 28% aqueous ammonia solution, which has been cooled down to 5° C. over 10 minutes with stirring. Then, the solution was further stirred for 1 hour at room temperature. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and then with saturated saline solution, and was dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the crude crystals obtained were washed with n-hexane and then filtered to give 229 g of the title compound(mp. 118-20° C.).
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[C:5]([Cl:23])=[C:4]([C:24]([NH:26][NH:27][C:28](=[O:44])[C:29]([CH3:43])([O:31][N:32]2C(=O)C3=CC=CC=C3C2=O)[CH3:30])=[O:25])[CH:3]=1.CNN>O1CCCC1>[ClH:23].[NH2:32][O:31][C:29]([CH3:43])([CH3:30])[C:28]([NH:27][NH:26][C:24]([C:4]1[CH:3]=[C:2]([Br:1])[C:7]2[O:8][C:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:10][C:6]=2[C:5]=1[Cl:23])=[O:25])=[O:44]
Reactant: CC(C)(ON1C(=O)c2ccccc2C1=O)C(=O)NNC(=O)c1cc(Br)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Agent: CNN
Solvent: C1CCOC1
Product: CC(C)(ON)C(=O)NNC(=O)c1cc(Br)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Product: Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
1-[(7-Bromo-4-chloro-2,2-diphenyl-1,3-benzodioxol-5-yl)carbonyl]-2-[2-methyl-2-(phthalimidooxy)propionyl]hydrazine 500 mg (0.77 mmol) are dissolved in 10 ml of tetrahydrofuran and treated at 0° C. with 35 mg (0.77 mmol) of methylhydrazine. After stirring at 0° C. for 2 hours and stirring at room temperature for 3 hours the mixture is concentrated in a vacuum. The residue is chromatographed on 20 g of silica gel (0.06-02 mm). The product is eluted with dichloromethane/ethanol (95:5 v/v). The eluate is concentrated and the residue is treated with ethanolic hydrochloric acid. After crystallization from ethanol/diethyl ether there are obtained 220 mg of 1-[2-(aminooxy)-2-methylpropionyl]-2-[(7-bromo-4-chloro-2,2-diphenyl-1,3-benzodioxol-5-yl)carbonyl]hydrazine hydrochloride (1:1) as white crystals of melting point 216°-218° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])=[N:8][CH:9]=1.[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19]>C(OCC)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([O:15][S:18]([C:17]([F:23])([F:22])[F:16])(=[O:20])=[O:19])[C:11]([F:12])([F:13])[F:14])=[N:8][CH:9]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: OC(c1ccc(Br)cn1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OC(c1ccc(Br)cn1)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a stirred suspension of sodium hydride (765 mg, 60% dispersion in mineral oil) in dry diethyl ether (20 ml) under an argon atmosphere at 0° C. was added dropwise a solution of (RS)-1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethanol (3.06 g) in diethyl ether (10 ml) and the resulting mixture was stirred at room temperature for 30 min. Trifluoromethanesulfonyl chloride (1.4 ml) was added and stirring was continued for a further 15 min at room temperature. The reaction mixture was quenched by addition of 10% aq. sodium bicarbonate solution and the mixture was extracted with diethyl ether. The phases were separated and the organic phase was washed with saturared brine. The organic phase was separated, dried over sodium sulphate, and concentrated in vacuo. The reside was purified by Kugelrohr distillation (60° C. oven temperature, 0.3 mbar) to give trifluoro-methanesulfonic acid (RS)-1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (3.6 g, 78%) as a white solid. MS (EI): 389 ([{81Br}M]+), 387 ([{79Br}M]+), 320 ([{81Br}M-CF3]+), 318 ([{79Br}M-CF3]+), 256 ([{81Br}M-CF3—SO2]+), 254 ([{79Br}M-CF3—SO2]+), 240 ([{81Br}M-OSO2CF3]+), 238 ([{79Br}M-OSO2CF3]).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:51]([O:55][C:56](=[O:77])[NH:57][C@H:58]([CH2:64][NH:65][C:66]([C:68]1[C:73]([NH2:74])=[N:72][C:71]([NH2:75])=[C:70]([Cl:76])[N:69]=1)=[O:67])[CH2:59][CH2:60][CH2:61][CH2:62][NH2:63])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C>[C:51]([O:55][C:56](=[O:77])[NH:57][C@H:58]([CH2:64][NH:65][C:66]([C:68]1[C:73]([NH2:74])=[N:72][C:71]([NH2:75])=[C:70]([Cl:76])[N:69]=1)=[O:67])[CH2:59][CH2:60][CH2:61][CH2:62][NH:63][C:17](=[O:19])[CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)CNC(=O)c1nc(Cl)c(N)nc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)CCc1ccc(OCc2ccccc2)cc1)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(4-benzyloxyphenyl)propionic acid (0.19 g, 0.74 mmol) and HATU (0.29 g, 0.75 mmol) in DMF (10 mL) is added N-methylmorpholine (0.32 mL, 2.91 mmol) followed by ((S)-5-amino-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-pentyl)-carbamic acid tert-butyl ester (Intermediate B) (0.30 g, 0.75 mmol). The resulting mixture is stirred at RT for 16 h. The solvent is removed in vacuo and the residue is purified by column chromatography (basic alumina, 2% MeOH in DCM) to afford the title compound as yellow solid. [M-Boc+H]+ 540.