Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[C:10]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[C:10]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1OCC(=O)N1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.500 g of methyl 2-chloro-3-(pyrrolidinocarbonylmethoxy)-4-ethylsulfonylbenzoate were dissolved in 20 ml of THF and 20 ml of water, 0.056 g of NaOH was added and the mixture was stirred at RT for 12 hours. The mixture was admixed with 6 N HCl and extracted with CH2Cl2. Drying of the organic phase over Na2SO4 gave 2-chloro-3-(pyrrolidinocarbonylmethoxy)-4-ethylsulfonylbenzoic acid as a viscous colorless oil.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1Br.C([Li])(C)(C)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]([C:23]2[C:18]([O:17][CH3:16])=[N:19][CH:20]=[CH:21][CH:22]=2)[OH:31])=[CH:28][CH:27]=1
Reactant: COc1ccccn1
Reactant: COc1ccc(C=O)cc1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cccnc2OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of mesityl bromide (0.77 g) in tetrahydrofuran(2.6 mL) was added tert-butyllithium (1.48 mol/L solution in pentane, 5.3 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 1 hour. To the reaction mixture was added a solution of 2-methoxypyridine (0.33 g) in tetrahydofuran (3 mL). The temperature was raised to 0° C., and the mixture was stirred for 1 hour. The temperature was raised to room temperature, and the reaction mixture was stirred for additionally 1 hour. To the reaction mixture was added a solution of 4-methoxybenzaldehyde (0.57 g) in tetrahydrofuran (4.2 mL), and the mixture was stirred for 1 hour. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1-2/1) to give 4-methoxyphenyl 2-methoxypyridin-3-yl methanol (0.43 g). To a solution of the obtained 4-methoxyphenyl 2-methoxypyridin-3-yl methanol (0.41 g) in acetic acid (2.1 mL) was added 10% palladium carbon powder (0.21 g), and the mixture was stirred for 10 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1-4/1) to give 2-methoxy-3-(4-methoxybenzyl)-pyridine (0.29 g). To a solution of the obtained 2-methoxy-3-(4-methoxybenzyl)pyridine (0.023 g) in dichloromethane (0.5 mL) was added boron trichloride (1 mol/L solution in dichloromethane, 0.06 mL) at 0° C. The temperature was raised to room temperature, and the mixture was stirred for 1 hour. After boron trichloride (1 mol/L solution in dichloromethane, 0.06 mL) was added to the reaction mixture, the mixture was stirred for additionally 15 hours. To the reaction mixture was added water, and the mixture was extracted with a mixture of dichloromethane and ethanol (10/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloromethane/methanol=8/1) to give 3-(4-methoxy-benzyl)-1H-pyridin-2-one (0.0017 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[CH:15]=1)=[O:4].[I:18]N1C(=O)CCC1=O.O>C(#N)C>[F:17][C:2]([F:16])([F:1])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[C:15]=1[I:18])=[O:4]
Reactant: O=C(Nc1cn2cc(F)ccc2n1)C(F)(F)F
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O
Product: O=C(Nc1nc2ccc(F)cn2c1I)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,2,2-trifluoro-N-(6-fluoroimidazo[1,2-a]pyridin-2-yl)acetamide (0.89 g, 0.0036 mol) was dissolved in acetonitrile (20 mL) and was cooled at 0° C. N-Iodosuccinimide (0.89 g, 0.0040 mol) was added and the reaction was stirred for 30 minutes. The mixture was poured into water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were dried with magnesium sulfate and the solvent removed. The residue was chromatographed on silica (60% ethyl acetate/hexanes) to give 2,2,2-trifluoro-N-(6-fluoro-3-iodoimidazo[1,2-a]pyridin-2-yl)acetamide 4 Rf 0.40, 60% ethyl acetate/hexanes; MS m/z 374 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]#[N:19].[C:20](Cl)(=[O:22])[CH3:21]>>[C:18]([C:3]1[C:4]([CH3:17])=[N:5][N:6]([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=2)[C:2]=1[NH:1][C:20](=[O:22])[CH3:21])#[N:19]
Reactant: Cc1nn(-c2ccc(S(C)(=O)=O)cc2)c(N)c1C#N
Reactant: CC(=O)Cl
Product: CC(=O)Nc1c(C#N)c(C)nn1-c1ccc(S(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
To a 50 mL round-bottomed equipped with a reflux condenser and N2 inlet septum was placed a stir bar, 5-amino-1-(4-methanesulfonyl-phenyl)-3-methyl-1H-pyrazole-4-carbonitrile (85 mg, 0.31 mmol), and acetyl chloride (5 mL). The reaction mixture was stirred under N2 for 24 hrs at 60° C. The acetyl chloride was removed under reduced pressure and solid residue washed with CH2Cl2 and EtOAc and collected by filtration. The crude product was then purified by flash chromatography (EtOAc:Hex=1:1) and recrystalized from methanol. 55 mg of product was obtained (56% yield). 1H NMR (DMSO-d6, 400 MHz) δ 2.07 (s, 3H), 2.36 (s, 3H), 3.29 (s, 3H), 7.81 (d, 2H), 8.09 (d, 2H), 10.7 (s, 1H). LCMS: calculted C14H14N4O3S 318.08, observed 319.1 (MH+)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.Cl[C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[CH:13][N:12]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][CH3:1])[N:4]=2)[CH:16]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CNc1cccc(N)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cccc(Nc2cc(Cl)ncn2)n1
Temperature: 120 °C
Yield: 31.5 %

Procedure:
A mixture of 2-methylamino-6-aminopyridine (0.5 g, 4.04 mmol), 4,6-dichloropyrimidine (1.51 g, 10.13 mmol), DIPEA (1.5 g, 12.17 mmol) in n-butanol (5 mL) was heated at 120° C. for 16 h. The reaction mixture was cooled, was concentrated under reduced pressure and the residue was taken in dichloromethane (25 mL). The dichloromethane solution was washed with NaHCO3 solution (2 mL), water (2 mL) and brine (2 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, petroleum ether/ethyl acetate, 6/4) to give N2-(6-chloropyrimidin-4-yl)-N6-methylpyridine-2,6,diamine (0.3 g, 33%) as a yellow solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH:26]=2)[C:21]([OH:23])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C:64]1[S:65][C:66]([CH3:69])=[CH:67][N:68]=1>CN(C=O)C>[CH2:16]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:36])([CH3:37])[CH3:35])([CH3:32])[CH3:33])[CH:26]=1)[C:21]([NH:63][C:64]1[S:65][C:66]([CH3:69])=[CH:67][N:68]=1)=[O:23])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cnc(N)s1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
DIPEA (7.5 mL) was added to a suspension of 3-{(phenylmethyl)oxy}-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (4.5 g, 0.011 mol), HATU (8.6 g, 0.023 mol) and 2-amino-5-methylthiazole (2.46 g, 0.022 mol) in DMF (70 mL). The resulting mixture was stirred at ambient temperature for 72 hours. The DMF was removed in vacuo. Water (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The extracts were combined and washed with brine (100 mL). The solution was dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound. (1.7 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=O)[CH2:10][CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:7])([CH3:4])[CH3:3].Cl.C[N:27](C)[CH2:28][CH2:29]CN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N)C>CN(C=O)C.[OH-].[Na+].C(N(CC)CC)C>[C:2]([O:5][C:6]([NH:8][C@H:9]([C:22](=[O:24])[NH:27][CH2:28][CH3:29])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
337 mg (1.0 mmol) of Boc-Glu (OBzl)-OH, 191 mg (1.0 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 152 mg (1.0 mmol) of 1-hydroxybenzotriazole monohydrate and 0.5 ml of triethylamine were suspended in 4.0 ml of DMF, to which 150 μl of 33% aqueous ethylamine solution was added. Following agitation at room temperature overnight, extraction was performed with ethyl acetate/water. The organic layer was washed with saturated saline and added with sodium sulfate for drying. The organic layer was subjected to vacuum condensation. The resulting residue was dissolved in 4.0 ml of 10% aqueous sodium hydroxide solution and stirred overnight. Purification step A was used to obtain a crude product of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:10][CH:9]=1)=[O:7].[OH-].[Na+]>CO.O>[N:18]1([CH2:17][CH2:16][CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][C:3]([OH:23])=[O:2])=[CH:9][CH:10]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: COC(=O)CCC(=O)c1ccc(CCCCn2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCC(=O)c1ccc(CCCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
15 g of 4-{4-[4-(1-imidazolyl)-butyl]-phenyl}-4-oxo-butyric acid methyl ester are dissolved in 180 ml of methanol, and 2.3 g of sodium hydroxide, dissolved in a little methanol, are added. The mixture is stirred at room temperature for 24 hours, the solvent is stripped off and the residue is taken up in water. The solution is extracted several times with chloroform and the chloroform phase is discarded. The aqueous solution is adjusted to about pH 6 with dilute hydrochloric acid and the solid which has precipitated is filtered off with suction, washed with a little water and dried.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9]2[S:17][CH:16]=[C:15]([CH2:18][O:19][C:20]3[CH:25]=[C:24]([C:26]4[O:27][C:28]([C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)=[N:29][N:30]=4)[CH:23]=[CH:22][C:21]=3[CH3:38])[C:10]=2[C:11]([NH2:14])=[N:12][CH:13]=1)=[O:7])C>O1CCCC1.CO>[NH2:14][C:11]1[C:10]2[C:15]([CH2:18][O:19][C:20]3[CH:25]=[C:24]([C:26]4[O:27][C:28]([C:31]5[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=5)=[N:29][N:30]=4)[CH:23]=[CH:22][C:21]=3[CH3:38])=[CH:16][S:17][C:9]=2[C:8]([C:6]([OH:7])=[O:5])=[CH:13][N:12]=1
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(-c5ccc(Cl)cc5)o4)ccc3C)csc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1OCc1csc2c(C(=O)O)cnc(N)c12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of sodium hydroxide (2 N, 2.0 mL, 1.0 mmol) was added to a solution of 4-amino-3-{5-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.22 g, 0.42 mmol) (from Example 47 supra) in tetrahydrofuran/methanol (3:1, 8 mL) and the mixture was heated at 50° C. for 1 day. The reaction mixture was concentrated and azeotroped with toluene. The solid residue was triturated with ethyl acetate. The solid was then suspended in water and treated with hydrochloric acid (1 N). After stirring 30 minutes, the solid was collected, washed with water and dried to give 4-amino-3-{5-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid. (Yield 0.20 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]N(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(C)nc1Cl
Reaction time: 5 h

Procedure:
To a suspension of 2-chloro-6-methylnicotinic acid (5.3 g, 30.8 mmol) in dichloromethane (100 ml) at 0° C. were added DMF (1 ml) and oxalyl chloride (3.2 ml, 36.9 mmol). The mixture was allowed to warmn to room temperature and stirred for 5 h. The solvents were removed in vacuo and the residue was dissolved in dichloromethane (50 ml) and methanol (50 ml). The mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was dissolved in chloroform, washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a brown oil; yield 5.70 g (100%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[N:10][C:9]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15](CC4C=CC=CC=4)[CH2:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>CO.[Pd]>[N:1]1([C:6]2[N:11]=[N:10][C:9]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1ccc(CN2CCCC(Oc3ccc(-n4ccnc4)nn3)C2)cc1
Agent: [Pd]
Solvent: CO
Product: c1cn(-c2ccc(OC3CCCNC3)nn2)cn1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]-1-benzylpiperidine (400 mg) in methanol (20 mL) was added 10% Pd/C (0.4 g), and HCO2NH4 (0.6 g). The mixture was heated at reflux under N2 for 1 hour. After cooling to ambient temperature, Pd/C was filtered off. The filtrate was concentrated in vacuo, giving 3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]piperidine (240 mg) as an oil, which was used in Example 3 without further purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([C:30]([F:33])([F:32])[F:31])[CH:16]=2)=[CH:11][CH:10]=1.O>CN(C=O)C.[Cu]>[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:19]([C:20]4[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=4)[N:18]=[C:17]([C:30]([F:32])([F:31])[F:33])[CH:16]=3)=[CH:11][CH:10]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1
Reactant: c1c[nH]cn1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-n3ccnc3)cc2)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
To a suspention of sodium hydride (0.04 g: 1 mmol) (60% mineral oil dispersion; washed with dry hexane (3 mL)) in DMF(2 mL) was added imidazol (0.068 g) at room temperature and the mixture was stirred 30 minutes. Then, 4-[5-[4-Bromophenyl]-3-trifluoromethyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole (0.445 g) and copper powder (0.0063 g) were added and the whole was heated at 150° C. for 3hours. After cooling, water (30 mL) was added to the reaction mixture and the whole was extracted with CH2Cl2 (30 mL×2), the extract was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/methanol (1/0.03). The resulting solid was recrystallized with dichloroethane-diisopropyl ether to give the title compound (0.07 g).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:12]([CH:13]([C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])[CH3:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)[C@@H](C[N+](=O)[O-])c1ccccc1
Temperature: -20 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-(pentamethylbenzenesulfonyl)-1,2-diphenylethylenediamine](hexamethylbenzene)ruthenium (13.7 mg, 0.02 mmol, S/C=50), trans-β-nitrostyrene (149 mg, 1.0 mmol), diethyl malonate (152 μl, 1.0 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at −20° C. for 48 hours. The reaction solution was purified by flash column chromatography (hexane/acetone=80/20, SiO2), showing that the yield of the product was 89%. The optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=95:5, flow rate 0.5 ml/min, detection by 210 nm), resulting to 93% ee.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7](O)[CH3:8])[N:2]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:12][CH:7]([C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cccnn1
Solvent: ClCCl
Product: CC(Cl)c1cccnn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(pyridazin-3-yl)ethanol (3) (50 mg, 0.40 mmol) in DCM (1 mL), there was added sulfurous dichloride (0.2 mL). The resulting solution was stirred at room temperature for 3 hrs. Solvent was removed to give 3-(1-chloroethyl)pyridazine (4), which was used for the next step without purification.
Reaction SMILES: CS(O)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2(O)[CH2:18][CH2:17][CH2:16][N:15]3[N:19]=[C:20](/[CH:22]=[CH:23]/[C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]5)=[C:26]([O:36][CH3:37])[CH:25]=4)[N:21]=[C:14]23)=[CH:9][CH:8]=1.[N-:39]=[N+:40]=[N-:41].[Na+].O.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[N:39]([C:13]1([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)[CH2:18][CH2:17][CH2:16][N:15]2[N:19]=[C:20](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]4)=[C:26]([O:36][CH3:37])[CH:25]=3)[N:21]=[C:14]12)=[N+:40]=[N-:41]
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3(O)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3(N=[N+]=[N-])c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonic acid (0.3 mL) was added to a solution of 8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol synthesized by the method in Examples 70 and 71 (45 mg) and sodium azide (66 mg) in TFA (1 mL), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate. The solution was added to saturated sodium bicarbonate water, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 28 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]2[N:15]([CH:19]([C:21]3[C:22]([O:40][CH3:41])=[C:23]([CH:29]4[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)[C:24]([CH3:28])=[C:25]([Cl:27])[CH:26]=3)[CH3:20])[N:16]=[C:17]([Br:18])[C:10]=12>C(Cl)Cl.[OH-].[Na+]>[NH:31]1[CH2:32][CH:29]([C:23]2[C:22]([O:40][CH3:41])=[C:21]([CH:19]([N:15]3[C:11]4=[N:12][CH:13]=[N:14][C:9]([NH2:8])=[C:10]4[C:17]([Br:18])=[N:16]3)[CH3:20])[CH:26]=[C:25]([Cl:27])[C:24]=2[CH3:28])[CH2:30]1
Reactant: COc1c(C(C)n2nc(Br)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(C)n2nc(Br)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1.2 mL, 16 mmol) was added to a solution of tert-butyl 3-{3-[1-(4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate (224 mg, 0.407 mmol) in methylene chloride (2.5 mL) and stirred for 2 h at room temp. The mixture was diluted with dichloromethane and 1 N NaOH was added and stirred rapidly for a few minutes. The layers were separated and the aqueous extracted with dichloromethane. The combined organics were dried (MgSO4), filtered, and concentrated. Drying in vacuo gave 163 mg (91%) of the freebase. LCMS calculated for C18H21BrClN6O (M+H)+: m/z=451.1; Found: 451.0.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([CH2:27][OH:28])[CH2:25][OH:26])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:35])=[N:5]1)([CH3:3])[CH3:2].CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)([CH2:27][O:28][S:44]([CH3:43])(=[O:46])=[O:45])[CH2:25][O:26][S:44]([CH3:43])(=[O:46])=[O:45])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:35])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)(CO)c4ccccc4)cc2OCC3)n(C(C)C)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(COS(C)(=O)=O)(COS(C)(=O)=O)c4ccccc4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
To a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-phenylpropane-1,3-diol (115 mg, 0.242 mmol) and Et3N (101 μL, 0.725 mmol) in DCM (15 mL) cooled at 0° C. was added methanesulfonyl chloride (47 μL, 0.605 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% MeOH in DCM) affording the title compound (124.5 mg, 81%) as a colourless gum. LCMS (Method J): RT 3.26 min [M+H]+ 632
Reaction SMILES: [Na].[C:2]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][N:13]1[C:21]2[C:16](=[N:17][C:18]([Cl:23])=[N:19][C:20]=2[Cl:22])[N:15]=[C:14]1Cl.Cl>CN(C=O)C>[Cl:23][C:18]1[N:17]=[C:16]2[C:21]([N:13]([CH3:12])[C:14]([NH:11][S:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:10])=[O:9])=[N:15]2)=[C:20]([Cl:22])[N:19]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cn1c(Cl)nc2nc(Cl)nc(Cl)c21
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: Cn1c(NS(=O)(=O)c2ccccc2)nc2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.8 g (50.0 mmol) of the sodium salt of benzenesulfonamide was suspended in 100 ml of DMF; at 60° C., 11.9 g (50.0 mmol) of 7-methyl-2,6,8-trichloropurine was added. After 8 hours at 80° C. and cooling to room temperature, H2O/ice was added, the mixture was acidified with 10% strength hydrochloric acid and the precipitate was suction filtered and dried.