Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]2[N:9]=[C:10]([CH3:14])[O:11][C:12](=[O:13])[C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+]>C(O)(=O)C>[C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([N:9]2[C:10]([CH3:14])=[N:19][N:18]=[N:17]2)=[C:7]([CH:6]=1)[C:12]([OH:11])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2nc(C)oc(=O)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(-n2nnnc2C)c(C(=O)O)c1
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A solution of 6-acetoxy-2-methylbenzo[d][1,3]oxazin-4-one (143 g, 0.653 mol) in 1.44 L of glacial acetic acid was stirred overnight with sodium azide (44.66 g, 0.687 mol). The solution was concentrated under reduced pressure and toluene (1.2 L) was then added. After stirring for one hour, a solid formed. The solid was recovered by filtration and then dried overnight under reduced pressure. The solid was dissolved in 2 L of water and the pH was adjusted to 1 with concentrated hydrochloric acid. After stirring for 3 hours, the resulting solid was filtered and dried overnight under a flow of air to give 164.1 g of 5-acetoxy-2-(5-methyltetrazol-1-yl)benzoic acid as an off white solid.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](=[NH:6])OC.FC(F)(F)C1N=[N:13][C:14]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:15]=2[N:16]=1>COCCO>[F:8][C:2]([F:1])([F:7])[C:3]1[N:6]=[N:16][C:15]2[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][C:14]=2[N:13]=1
Reactant: COC(=N)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2nnc(C(F)(F)F)nc2C1
Solvent: COCCO
Product: CC(C)(C)OC(=O)N1CCc2nc(C(F)(F)F)nnc2C1

Procedure:
This material was obtained by reaction of tert-butyl 3,4-dioxopiperidine-1-carboxylate from Intermediate 35, Step C, with trifluoroacetamidrazone (2,2,2-trifluoroethanimidohydrazide), prepared from methyl 2,2,2-trifluoroethanimidoate according to the procedure of Brown and Wetzel, J. Org. Chem., 30: 3729-3733 (1965), essentially as described for Intermediate 35, Step D, except that completion of the condensation and ring closure required heating in 2-methoxyethanol at reflux for 2 d. Purification of the evaporation residue by flash chromatography (silica gel, 30% ethyl acetate/hexanes) provided the crude title compound in addition to a minor amount of the other regioisomer, tert-butyl 3-(trifluoromethyl)-7,8-dihydropyrido[3,4-e][1,2,4]triazine-6(5H)-carboxylate. Further purification of the product was achieved by preparative HPLC (YMC Pro C18 column, gradient elution, 40-70% acetonitrile/water containing 0.1% trifluoroacetic acid). To prevent decomposition during isolation, excess N,N-diisopropylethylamine was added to the pooled product fractions to neutralize the trifluoroacetic acid prior to concentration in vacuo. The residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give the pure title compound. The regioisomers were assigned on the basis of 1H NMR chemical shift differences reported in several papers for analogous compounds. (See, for example, Konno et al., Heterocycles, 22: 2241-2244 (1984) and Neunhoeffer and Böhnisch, Liebigs Ann. Chem., 153-162 (1976).) 1H NMR (500 MHz, CDCl3) δ 5.08 (s, 2H), 3.90 (m, 2H), 3.21 (m, 2H), 1.54 (s, 9H). LC/MS: 249 (M+1-isobutene).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:9]([O:21][CH3:22])[C:10](=[O:20])[CH:11]=[C:12]2[C:16](=O)[O:15]C(C)(C)[O:13]2)=[CH:4][CH:3]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].N12CCCN=C1CCCCC2>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:9]([O:21][CH3:22])[C:10](=[O:20])[CH:11]=[C:12]([OH:13])[C:16]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:15])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CON(C(=O)C=C1OC(C)(C)OC1=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CON(C(=O)C=C(O)C(=O)NS(C)(=O)=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A solution of N-[bis-(4-fluoro-phenyl)-methyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide (0.175 g, 0.43 mmol) and methanesulfonamide (0.062 g, 0.52 mmol) in anhydrous N,N-dimethylformamide (3 ml) was treated at 25° C. with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 ml). After 1 h, the reaction mixture was then quenched by the addition of ethyl acetate and 1 N hydrochloric acid. The organic phase was washed successively with water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution ethyl acetate-methanol 0-20%) gave 0.129 g (67% yield) of the title amide as a white solid. 1H NMR (400 MHz, DMSO) δ: mixture of rotamers: 2.78, 2.81,2.87 and 2.88 (3H, 4 s, SO2CH3), 3.15, 3.16, 3.18 and 3.20 (3H, 4 s, OCH3), 6.22, 6.25 and 6.27 (1H, 3 s, CH), 6.75-6.89 (1H, m, CH), 7.17-7.54 (8H, m, aromatics). HRMS (ESI/neg) calculated for C19H17F2N2O6S, [M−H]−: 439.077540; found: 439.077728.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH3:25][NH:26][O:27][CH3:28]>CN(C)C=O>[CH3:28][O:27][N:26]([CH3:25])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of benzo[1,3]dioxole-5-carboxylic acid (69 g, 415 mmol) in dimethylformamide (1L) was added di-imidazol-1-yl-methanone (74 g, 1.1 equiv), and the resulting reaction mixture was stirred at ambient temperature for 90 minutes. N,O-Dimethyl-hydroxylamine (43 g, 1.1 equiv) was added to the reaction mixture. The resulting reaction mixture was stirred at ambient temperature for 18 hours, and then concentrated in vacuo to ¼ of the volume, poured into 5% aqueous sodium hydrogen carbonate (1L), stirred at ambient temperature for 20 minutes, and then extracted with methyl tert-butyl ether (2×300 mL). The combined organics extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting residue was azeotroped with toluene (800 mL) and dried under vacuum for 3 hours. The crude product was used in the next step without further purification.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH3:4].O>C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[C:13]([Br:1])[CH:14]=1)[CH3:4]
Reactant: CCOC(=O)CCc1ccc(OC)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)CCc1ccc(OC)c(Br)c1

Procedure:
87.5 g of bromine are added dropwise at 25° C. over 3 hours to a solution of ethyl3-(4-methoxyphenyl)propanoate (113.9 g; 0.545 mol) in 900 ml of chloroform. The mixture is poured into water and the organic phase is separated out by settling of the phases and washed with 10% sodium hydrosulfite solution. After drying and evaporating off the solvents, a yellow oil is collected (154 g; 98%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3]OS(C(F)(F)F)(=O)=O.[CH2:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[CH2:14]([NH:22][CH2:3][C:2]([F:13])([F:12])[F:1])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1C
Product: FC(F)(F)CNCCc1ccccc1

Procedure:
1.9 g (8.3 mmol) 2,2,2-trifluoroethyltrifluoromethanesulphonate were added to 2.0 g (16.5 mmol) phenethylamine in 50 mL xylene and the reaction mixture was refluxed overnight. After cooling the precipitate formed was suction filtered, washed with DIPE and the filtrate washed evaporated down i.vac. The residue was purified by flash chromatography. The product fractions were combined and evaporated down i.vac.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1.CN(C)[CH:34]=[O:35]>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[C:21]([CH:34]=[O:35])[N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.6 M n-Butyllithium in hexanes (1.6 mL, 2.6 mmol) was added dropwise to a solution of N,N-diisopropylamine (0.38 mL, 2.7 mmol) in THF (5.5 mL) at −78° C. Upon complete addition, the reaction temperature was raised to 0° C. for 30 minutes. After re-cooling to −78° C., 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (0.50 g, 1.7 mmol, prepared as in Example 2, Step 1) in THF (2.5 mL) was added dropwise. After stirring for 1 hour at −78° C., N,N-dimethylformamide (0.26 mL, 3.4 mmol) was added. After 25 minutes, the reaction was quenched by the addition of saturated NH4Cl solution into the −78° C. mixture. After warming to room temperature, the mixture was diluted with water and extracted with EtOAc. The combined extracts were washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded product as a white solid (0.43 g, 78%).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][C@H:8]([NH:12][C:13]([C:15]1([CH2:35][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:19][N:18]=[C:17]([C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH:21]([CH3:23])[CH3:22])[CH2:16]1)=[O:14])[C:9](=[O:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:28]([O:27][C:25]([NH:24][C@H:20]([C:17]1[CH2:16][C:15]([CH2:35][O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:13]([NH:12][C@H:8]([C:9](=[O:11])[CH3:10])[CH2:7][C:6]([OH:43])=[O:5])=[O:14])[O:19][N:18]=1)[CH:21]([CH3:22])[CH3:23])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)C1(COc2ccccc2)CC([C@@H](NC(=O)OCc2ccccc2)C(C)C)=NO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)[C@H](CC(=O)O)NC(=O)C1(COc2ccccc2)CC([C@@H](NC(=O)OCc2ccccc2)C(C)C)=NO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (3S)-3-{3-[(1S)-1-phenylmethyloxycarbonylamino-2-methyl-propyl]-5-phenoxymethyl-4,5-dihydro-isoxazole-5-carbonyl-amino}-4-keto-pentanoic acid t-butyl ester (less polar diastereomer) (44 mg) in CH2Cl2 (2 mL) at 0° C. was treated with TFA (1 mL). The reaction mixture was stirred for 2 h while slowly warming to room temperature. Concentration gave the title compound (compound 10, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][OH:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[C:4]([CH3:19])[CH:3]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:18][CH2:17][CH:14]2[CH2:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[CH3:19])[C:16]=3[O:15]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(Cl)ccc1-c1cccc2c1OC(CO)C2
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(Cl)cc4C)c3O2)cc1
Yield: 93.2 %

Procedure:
Treatment of (±)-[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (2.78 g, 10.11 mmol) with p-toluenesulfonyl chloride (2.31 g, 12.14 mol) generally according to the procedure described for Intermediate 10 gave 4.04 g (93%) of (±)-[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C23H21ClO4S: C, 64.4; H, 4.93. Found: C, 64.24; H, 4.93.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][N:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN1CCCC1=O>[N:17]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)=[N:4][N:3]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: Clc1nnc(-c2ccco2)c2ccccc12
Solvent: CN1CCCC1=O
Product: c1coc(-c2nnc(-n3ccnc3)c3ccccc23)c1
Temperature: 150 °C
Reaction time: 10 h
Yield: 4.3 %

Procedure:
300 mg of 1-chloro-4-(2-furyl)phthalazine and 707 mg of imidazol were dissolved in 2 ml of N-methylpyrrolidone, and the solution was stirred at 150° C. for 10 hours. After the solution was subjected to after-treatment, it was purified by column chromatography, thereby obtaining 14.5 mg of 1-(1-imidazolyl)-4-(2-furyl)phthalazine.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[O:3]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([O:8][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:5][C:4]([CH3:10])([CH3:9])[O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(O)CC(C)(C)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(OS(C)(=O)=O)CC(C)(C)O1
Yield: 102.8 %

Procedure:
In a manner similar to the method described in example 32a, 2,2,6,6-Tetramethyl-tetrahydro-pyran-4-ol (5.5 g, 35 mmol) was reacted with methanesulfonyl chloride (6 g, 52 mmol, Aldrich) and triethylamine in dichloromethane to give methanesulfonic acid 2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl ester as a yellow oil (Yield 8.5 g, 100%). The starting material 2,2,6,6-Tetramethyl-tetrahydro-pyran-4-ol was prepared according to the procedures described by Nemeroff, N. et al in J. Org. Chem. 1978, 43(2), 331-334 with slight modification.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:47]=[C:46]2[C:42]([CH2:43][C:44](=[O:49])[N:45]2[CH3:48])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:39]2[CH:47]=[C:46]3[C:42]([CH2:43][C:44](=[O:49])[N:45]3[CH3:48])=[CH:41][CH:40]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Reactant: CN1C(=O)Cc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1C(=O)Cc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Yield: 21.8 %

Procedure:
A solution of (S)-tert-butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 200 mg) and 6-bromo-1-methylindolin-2-one (87 mg) in acetonitrile (5 mL) was treated with potassium carbonate (107 mg) and purged with nitrogen. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (15 mg) was added and the reaction stirred is under reflux under nitrogen for 4 h and then evaporated in vacuo. The residue was partitioned between water (40 mL) and ethyl acetate (40 mL). The aqueous was further extracted with ethyl acetate (40 mL) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude product was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (45 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:11]([N:13]([CH2:18][CH2:19]OS(C)(=O)=O)[S:14]([CH3:17])(=[O:16])=[O:15])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:11]([CH3:12])[N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:18][CH2:19][N:25]1[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]([C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)N(CCOS(C)(=O)=O)S(C)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](COCc2ccccc2)N(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Reaction time: 0.75 h
Yield: 100.2 %

Procedure:
A solution of (2R,3R)-O-benzyl-2-tert-butoxycarbonylamino-3-[N-(2-methanesulfonyloxyethyl)-N-methanesulfonylamino]butanol (2.6 g) in dry DMF (15 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 189 mg) in dry DWF (10 ml) at 4° C. over 20 minutes. The mixture was stirred at same temperature for 45 minutes and then poured into a mixture of ice and 1N HCl (8 ml). The mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4 and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: AcOEt in n-hexane 40% and 50%) to give 2.1 g of (2R,3R)-2-benzyloxymethyl-1-tert-butoxycarbonyl-4-methanesulfonyl-3-methylpiperazine as an oil.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[CH3:13][C:14]1[CH:20]=[C:19]([C:21]([F:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:15]=1[NH2:16]>C(#N)C>[I:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([C:21]([F:30])([C:22]([F:23])([F:24])[F:25])[C:26]([F:27])([F:28])[F:29])=[CH:20][C:14]=2[CH3:13])=[O:6])[C:3]=1[C:8]([OH:7])=[O:9]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N
Reactant: O=C1OC(=O)c2c(I)cccc21
Solvent: CC#N
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1NC(=O)c1cccc(I)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
In acetonitrile (100 ml) was dissolved 5.5 g (20 mmol) of 3-iodophthalic anhydride, and a solution (20 ml) of 5.5 g (20 mmol) of 2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline in acetonitrile was slowly dropped thereinto. After the resulting mixture was stirred at room temperature for 3 hours, two-thirds of the acetonitrile was distilled off under reduced pressure and the crystals precipitated were filtered and then washed with acetonitrile to obtain 5.6 g (yield 51%) of 6-iodo-N-{2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl}phthalamic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:15](O)[CH3:16])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:19]>C(Cl)(Cl)Cl>[Br:19][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][N:13]=1)[CH3:16]
Reactant: COc1ccc(-c2ccc(C(C)O)nc2)cc1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccc(C(C)Br)nc2)cc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a stirred solution of 1-(5-(4-methoxyphenyl)pyridin-2-yl)ethanol (0.2 g, 0.8 mmol) in chloroform (4 mL) was added PBr3 (0.3 mL, 1.3 mmol) at 0° C. and the reaction was stirred at 0° C. to rt for about 1 h. The reaction mixture was quenched with saturated NaHCO3 solution (10 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane eluent to provide 2-(1-bromoethyl)-5-(4-methoxyphenyl)pyridine (0.15 g, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.76 (d, 1H), 7.84 (dd, 1H), 7.51 (dd, 3H), 7.01 (d, 2H), 5.32-5.26 (m, 1H), 3.86 (s, 3H), 2.11 (d, 3H), LC-MS m/z calcd for [M+H]+ 292.0. found 292.3.
Reaction SMILES: Cl.CO.[C:4]1([C:10]2[N:21]=[C:13]3[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][N:12]3[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>[C].[Pd].C(Cl)Cl>[C:4]1([C:10]2[N:21]=[C:13]3[CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17][N:12]3[N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(O)c1ccn2nc(-c3ccccc3)nc2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C1CCn2nc(-c3ccccc3)nc2C1
Temperature: 40 °C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
10% Palladium-carbon (3 g) and concentrated hydrochloric acid (3.1 ml) were added to a mixed solution of methanol (200 ml) and methylene chloride (150 ml) containing the 2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (3 g) obtained in (Example 3.18) <Step 4>, and the obtained mixture was then stirred in a hydrogen atmosphere for 15 hours. Thereafter, the reaction solution was heated to 40° C., and then, it was further stirred for 4 hours. Thereafter, the reaction solution was filtered with Celite, and was then washed with methanol. The filtrate was concentrated under reduced pressure, and the solvent was then distilled away. After that, methanol (20 ml) and a 4 N sodium hydroxide aqueous solution (9 ml) were added to the residue, and the obtained mixture was then stirred at 50° C. for 30 minutes. Thereafter, the solvent was distilled away under reduced pressure, and a 1 N hydrochloric acid aqueous solution (9 ml) was then added to the residue. The generated solid was collected by filtration, and was then washed with water (10 ml). The obtained solid was dried under reduced pressure at 45° C. for 15 hours, so as to obtain the title compound (2.4 g) in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](O)=[O:8].Cl.[CH:16](N)=[NH:17]>[OH-].[Na+]>[CH3:13][O:12][C:11]1[CH:10]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:14]=[CH:16][NH:17][C:7]2=[O:8]
Reactant: N=CN
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 210 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
36.9 g of 4,5-dimethoxyanthranilic acid was mixed with 25.0 g of formamidine hydrochloride, and the mixture was stirred at 210° C. for 30 minutes. After completion of the reaction, the solid thus obtained was cooled to room temperature, stirred with 200 ml (0.33 M) of aqueous sodium hydroxide and filtered under a reduced pressure. The solid thus obtained was washed with water and air-dried to obtain the title compound (24.6 g, 64%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH2:9])[CH2:4][O:3]1.[F:15][C:16]1[C:21]([F:22])=[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])[C:19]([NH2:32])=[C:18]([O:33][CH3:34])[CH:17]=1>N1C=CC=CC=1>[F:22][C:21]1[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:19]([NH:32][S:10]([C:8]([CH2:7][C@@H:5]2[CH2:4][O:3][C:2]([CH3:14])([CH3:1])[O:6]2)=[CH2:9])(=[O:12])=[O:11])[C:18]([O:33][CH3:34])=[CH:17][C:16]=1[F:15]
Reactant: C=C(C[C@@H]1COC(C)(C)O1)S(=O)(=O)Cl
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Solvent: c1ccncc1
Product: C=C(C[C@@H]1COC(C)(C)O1)S(=O)(=O)Nc1c(OC)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
(R)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)prop-1-ene-2-sulfonyl chloride from STEP C was dissolved in pyridine (12 mL) and 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamine (2.56 g, 6.5 mmol) added. The solution was stirred at 100° C. for 2 hours and then partitioned with water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), concentrated under reduced pressure and purified by flash column chromatography on silica (30% ethyl acetate/hexanes eluant) to afford (R)—N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)prop-1-ene-2-sulfonamide (651 mg, 17%).