Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=1.[NH2:16][C:17]1[O:18][C:19]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[N:20][N:21]=1.CO>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13]([NH:16][C:17]2[O:18][C:19]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[N:20][N:21]=2)=[O:14])=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2F)o1
Reactant: Nc1nnc(-c2ccco2)o1
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1nnc(-c2ccco2)o1)c1ccc(-c2ccccc2F)o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.7 %

Procedure:
Commercially available 5-(2-fluorophenyl)-2-furancarbonyl chloride (93 mg, 0.41 mmol) was added to a solution of commercially available 2-amino-5-(2-furyl)-1,3,4-oxadiazole (50 mg, 0.33 mmol) in pyridine (1.3 mL) under ice-cooling, followed by stirring at room temperature for 2.5 hr and then at 60° C. for 2 hr. Methanol was added to the reaction solution. The solvent was distilled off, and water was added to the residue. The precipitated crystals were collected by filtration, washed with water, methanol, and ethyl acetate sequentially, and then dried to obtain the title compound (77 mg, 0.23 mmol) (yield: 70%).
Reaction SMILES: ClCCl.[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:19]([OH:20])=[C:18]([O:21][CH3:22])[C:17]([O:23][CH3:24])=[CH:16][C:15]=1[CH3:25].N1C=CC=CC=1.[O:32]=O>C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:19](=[O:20])[C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:16](=[O:32])[C:15]=1[CH3:25]
Reactant: COc1cc(C)c(CCCCCCCCCO)c(O)c1OC
Reactant: O=O
Agent: [Co+2]
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(CCCCCCCCCO)=C(C)C1=O

Procedure:
To a dichloromethane solution (30 ml) of 6-(9-hydroxynonyl)-2,3-dimethoxy-5-methylphenol (1.8 g) are added pyridine (0.5 ml) and bis(salicylidene)ethylenediiminocobalt(II) (32 mg). The mixture is stirred in oxygen streams at atmospheric temperature and pressure. The reaction product is isolated as in Example 7 and recrystallized from hexane. The above procedure yields 6-(9-hydroxynonyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (1.2 g) as orange-yellow needles melting at 45° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[Br:10][CH2:11][C:12](O)=[O:13]>C(Cl)Cl>[Br:10][CH2:11][C:12]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:13]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(O)CBr
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=O)CBr
Temperature: 25 °C
Yield: 112.1 %

Procedure:
See FIG. 2, Formula T2. 8.1 Preparation of 2-bromo-N-(2, 60-dimethylphenyl)acetamide DCC (14.5 g; 70 mmol) was added to a cold solution of 2,6-dimethylaniline (8.5 g; 70 mmol) and bromoacetic acid (9.75 g; 70 mmol) in dry CH2Cl2 (400 mL) in portions over 30 min. The mixture was allowed to warm to room temperature overnight with stirring. It was then filtered, and the filtrate evaporated to dryness. The residual solid was dissolved in EtOAc (200 mL) and CH2C2 (200 mL). The mixture was filtered, and the filtrate evaporated to dryness to yield 2-bromo-N-(2,6-dimethylphenyl)acetamide (19 g). 8.2 Preparation of 1-(2,6-dimethylphenyl)-2,8,8-trioxo-1,4-diaza-7,8-dithianonane
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].[CH3:21][As:22]([CH3:24])Cl.N1C=CC=CC=1>COCCOC>[CH3:21][As:22]([CH3:24])[S:13][CH2:12][C@@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: C[As](C)Cl
Solvent: c1ccncc1
Solvent: COCCOC
Product: C[As](C)SC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 500 mL flask, 7 g of glutathione was used as received from the Aldrich Chemical Co., purity 98% and dissolved in 250 mL of 1,2-dimethoxyethane. To this solution was added 3.3 g of dimethylchloroarsine. This was followed by the addition of 3.5 g of pyridine (redistilled after drying over NaOH pellets). The solution was refluxed for one hour after which time it was stirred at room temperature for three hours.
Reaction SMILES: CO.N.[C:4]([CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)#[N:5]>[Ni].C(O)(=O)C>[NH2:5][CH2:4][CH:6]([C:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(C#N)C2(O)CCCCC2)cc1
Agent: [Ni]
Agent: N
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C(CN)C2(O)CCCCC2)cc1
Yield: 70 %

Procedure:
The reactor was charged with 25.0 g of Raney-Ni (Kawaken, Grace 2400, 2724, Degussa B111W, 112W), and 250 ml of MeOH and 25 ml of an ammonia solution (25% NH3) were added. To the mixture was added 50g of 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol, followed by 250 ml of MeOH. The reactor was settled and purged with N2 gas two or three times. After fully purged with N2, the reactor was purged with H2 gas two or three times. Internal pressure of the reactor was adjusted to 60 psi and the reaction mixture was stirred. After 20 to 30 hours of reaction at room temperature (about 10 to 20° C.), in-process analysis of a sample of mixture was made. After the reaction was completed, Ra—Ni was removed by filtration with a celite pad. The filtrate was distilled under reduced pressure until all of the solvent was evaporated, and 200 ml of isopropyl alcohol and 400 ml of ethyl acetate were added to the residue oil to dissolve the resulting product to give a clear or a little hazy solution. To the solution was added 10 ml of acetic acid dropwise, and an exothermic reaction began with some fumes given off. After about 10 to 20 minutes of adding all of the acetic acid, a solid began to form. The solution was stirred for about one hour, filtered and washed with ethyl acetate to give the desired product, 1-[2-amino-1-(4-methoxyphenyl)ethyl]-cyclohexanol, 44.2 g (yield 70%, purity 99%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cnc2ccncc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccncc2c1Cl

Procedure:
A mixture of 9.3 g of ethyl 4-hydroxy-1,6-naphthyridine-3-carboxylate (prepared according to J. Org. Chem. 15, 1224 (1950)) and 56 ml of phosphorous oxychloride is refluxed for 2 hours 40 minutes, then evaporated to dryness and the residue is treated with cold dilute ammonium hydroxide and methylene chloride. Insoluble material is removed by filtration, then organic layer is separated, washed with brine, dried over sodium sulfate and evaporated to dryness to yield ethyl 4-chloro-1,6-naphthyridine-3-carboxylate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CN(C)C=O.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([N:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)N1CCN(NC(=O)c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCN(N(Cc2ccccc2)C(=O)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide (230 mg) and N,N-dimethylformamide (3 ml) was added sodium hydride (60% oil dispersion, 35 mg) in one portion at 0° C. The mixture was stirred at 0° C. for 1 hour then benzyl bromide (0.17 ml) was added to this mixture at 0° C. After stirring at 0° C. for 1.5 hours, water was added and the solvent was evaporated. The residue was taken up in ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography eluting with a mixture of methanol and ethyl acetate (1:5) to give crystals. Crystallization from ethyl acetate and n-hexane to give N-(4-acetyl-1-piperazinyl)-N-benzyl-4-fluorobenzamide (260 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH3:16]>>[CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[C:8]([S:12]([NH2:16])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N
Reactant: Cc1cc(Br)c(S(=O)(=O)Cl)cc1C(=O)O
Product: Cc1cc(Br)c(S(N)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
74.1 g of 2-methyl-4-bromo-5-chlorosulphonylbenzoic acid [obtainable by reacting 2-methyl-4-bromobenzoic acid with chlorosulphonic acid] are stirred, at 10° and over a period of 1.5 h, into 170 ml of a 32% aqueous solution of ammonia, and this mixture is subsequently stirred at room temperature for 3 h. After that, the reaction mixture is concentrated, 50 ml of water are added, and this mixture is acidified with conc. HCl. The resulting precipitate is filtered off with suction and recrystallized from methanol. 2-Methyl-4-bromo-5-aminosulphonylbenzoic acid is obtained, m.p. 237°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[NH:11][CH2:10][C:9]1(C)[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].NCC(N)C.OC1(C#N)CCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[NH:11][CH2:10][CH:9]1[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2(CCCC2)NCC1(C)C
Agent: CC(N)CN
Agent: N#CC1(O)CCCC1
Product: CC1CNC2(CCCC2)CN1C(=O)OC(C)(C)C

Procedure:
8-Methyl-6,9-diaza-spiro[4.5]decane-9-carboxylic acid tert-butyl ester was synthesized in analogy to 8,8-Dimethyl-6,9-diaza-spiro[4.5]decane-9-carboxylic acid tert-butyl ester starting from 1,2-diamino-propane and 1-hydroxycyclopentane-1-carbonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:19]=[C:5]2[C:6]([CH:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[OH:11])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:20][C:21]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[S:23][N:22]=1.[B][B][B][B][B][B][B][B][B][B].[CH3:43]O>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]([O:11][CH3:43])[C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][CH:29]4[CH2:30][CH2:31][N:26]([C:24]5[S:23][N:22]=[C:21]([CH3:20])[N:25]=5)[CH2:27][CH2:28]4)[N:19]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:13][CH:14]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1nc2c(C(O)c3ccc(F)cc3)cccn2n1
Reactant: CO
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: COC(c1ccc(F)cc1)c1cccn2nc(NC3CCN(c4nc(C)ns4)CC3)nc12
Yield: 4 %

Procedure:
Prepared in analogy to example 219f), starting from (2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)(4-fluorophenyl)methanol and 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-one. As a reducing agent 1 eq decaborane in methanol was used at 50° C. over night. The crude product was purified by column chromatography on silica gel using a gradient from CH2Cl2 to CH2Cl2/MeOH 19:1 (v/v) as eluent to yield eluting first {8-[(4-fluoro-phenyl)-methoxy-methyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine (yield: 4%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22](Cl)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)c(F)c4)nc23)CC1
Yield: 85.9 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.055 mMol) 3,4-difluorobenzoyl chloride, 0.014 gm (80%) of the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: C(O)C.[OH-].[K+].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[C:7]1=[O:16].[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>CS(C)=O>[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[C:7]2=[O:16])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Oc1ccc(CBr)cc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC(=O)Oc1ccc(CN2C(=O)C(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
An ethanol solution of potassium hydroxide (16.6 g. in 400 ml.) was added to a stirred solution of indoline-2,3-dione (isatin) (43.6 g.) in dimethyl sulphoxide (400 ml.). After 10 minutes a solution of 4-acetoxybenzyl bromide (76.3 g.) in dimethyl sulphoxide (40 ml.) was added. The mixture was stirred for 72 hours and then poured into ice/water (~1000 ml.). The gum which first formed slowly crystallised. The solid which formed was recrystallised from methanol (500 ml.) to give 1-(4-acetoxybenzyl)indoline-2,3-dione as a solid, m.p. 159°-161° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.ClC(Cl)(O[C:21](=[O:27])OC(Cl)(Cl)Cl)Cl.[CH3:29][C:30]1[O:34][N:33]=[C:32]([NH2:35])[CH:31]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.C(Cl)Cl.C(Cl)Cl>[CH3:29][C:30]1[O:34][N:33]=[C:32]([NH:35][C:21]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)=[O:27])[CH:31]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)no1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)no1
Temperature: 20 °C
Reaction time: 1 h
Yield: 281.2 %

Procedure:
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (100 mg, 0.46 mmol), and triphosgene (47 mg, 0.16 mmol) were dissolved in a mixture of dry pyridine:DCM (4:1) and stirred at room temperature (20° C.) under nitrogen atmosphere for 1 h. 5-methylisoxazol-3-amine (49 mg, 0.50 mmol) dissolved in dry DCM was added dropwise, and stirring allowed overnight. Saturated NaHCO3 solution was added to the reaction mixture, and stirring allowed for 15 mins before partitioning between water and DCM. The organic layer was recovered, dried over MgSO4, filtered and solvent removed in vacuo, affording the title compound (155 mg, 0.45 mmol, 99% yield).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[NH:48][CH:49]=[CH:50][N:51]=3)=[CH:43][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:48]1[CH:49]=[CH:50][N:51]=[C:47]1[C:44]1[CH:45]=[CH:46][C:41]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[CH:9]=3)[NH:4][CH:3]=2)=[CH:42][CH:43]=1
Reactant: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Reactant: CC1(C)OB(c2ccc(-c3ncc[nH]3)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(-c5ncc[nH]5)cc4)c3c2)cc(OC)c1OC
Yield: 22.1 %

Procedure:
3-Iodo-1-(toluene-4-sulfonyl)-5-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (Intermediate CJ, 30 mg, 0.053 mmol), 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole (Intermediate CG, 18 mg, 0.064 mmol) and dichlorobis(triphenylphosphine)palladium (II) (2 mg, 0.003 mmol) were combined in CH3CN (1 ml) and 1 M Na2CO3 (1 ml) and stirred at 60° C. for 2 d. Additional Intermediate CG (18 mg, 0.064 mmol) was added and stirring was continued for another day. EtOAc was added and the mixture was washed with water, dried, evaporated and purified by silica gel chromatography using 0-5% MeOH:DCM to yield 5 mg (22%) of the title compound. MS ESI (m/z): 427.2 (M+1)+, calc. 426.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[S-2:13].[Na+].[Na+].[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1>CS(C)=O>[Cl:16][C:17]1[C:22]([S:13][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: O=[N+]([O-])c1cc(CO)ccc1Cl
Reactant: [S-2]
Reactant: Clc1nccnc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(CO)ccc1Sc1nccnc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.3 %

Procedure:
1.876 g of 4-chloro-3-nitrobenzyl alcohol was dissolved in 20 ml of dimethyl sulfoxide. After adding 820 mg of anhydrous sodium sulfide, the resulting mixture was stirred at room temperature for 15 hours. After adding 1.19 g of 2,3-dichloropyrazine thereto, the reaction mixture was stirred at 100° C. for 1 hour. After adding ice/water, the reaction mixture was extracted with ethyl acetate, washed successively with water, 1 N hydrochloric acid, water, 1 N sodium hydroxide, and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 1.60 g of the title compound as yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[C:28](Cl)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].O>ClCCl>[CH2:31]([O:30][C:28]([NH:1][CH2:2][C@@H:3]([OH:18])[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11]([O-:13])=[O:12])[CH2:9][CH2:10]1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[CH2:31]([O:30][C:28]([NH:1][CH2:2][C@@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][CH2:6]1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@H](O)CN)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C[C@H](O)CNC(=O)OCc2ccccc2)CC1
Product: O=C(NC[C@@H](O)CN1CCN(C(=O)[O-])CC1)OCc1ccccc1
Reaction time: 12 h
Yield: 52.6 %

Procedure:
The crude compound tert-butyl 4-[(2R)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 20b (4.50 g, 17.40 mmol) was dissolved in 80 mL of dichloromethane in an ice-water bath followed by the addition of diisopropylethylamine (2.50 g, 19.10 mmol) and dropwise addition of 20 mL of a solution of carbobenzoxy chloride (2 g, 19.10 mmol) in dichloromethane successively, stirred for 12 hours. The resulting mixture was added with 20 mL of water and stirred for 10 minutes. The reaction solution was concentrated under reduced pressure, added with 100 mL of water and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2R)-3-benzyloxycarbonylamino-2-hydroxy-propyl]piperazine-1-carboxylate 20c (1.80 g, yield: 26.0%) as a light yellow oil.
Reaction SMILES: CCOC(C)=O.[CH3:7][C:8]1[CH:9]=[CH:10][C:11](S(O)(=O)=O)=[CH:12][CH:13]=1.O.[O:19]1C=CC=[N:20]1.[F-].[K+]>O>[O:19]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:7]=[N:20]1
Reactant: c1cnoc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2oncc2c1
Temperature: 40 °C

Procedure:
To a 100 L cylindrical vessel with heating coils were charged EtOAc (20 L) and TsOH/H2O (2.304 kg, 12.11 mol), and the mixture was heated to 35-45° C. to dissolve. The acid solution was fed into the isoxazole batch with further distilling, maintaining a constant volume of 25 L. An additional 20 L of EtOAc was distilled to azeotropically dry the mixture. A slurry began to form, and it continued to thicken on addition and concentration. The final KF was 400 ppm water. The batch was heated to 60° C. and allowed to slowly cool to ambient temperature overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[Cl:10])[C:5]#[N:6].[Br:14][CH2:15][C:16](Br)=[O:17]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:14][CH2:15][C:16]([NH:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[Cl:10])=[O:17]
Reactant: O=C(Br)CBr
Reactant: N#Cc1cc(N)c(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cc(NC(=O)CBr)c(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To the solution of 3-amino-4-chloro-5-nitrobenzonitrile (300 mg, 1.518 mmol) in DCM (12 mL) at 0° C. was added TEA (0.635 mL, 4.56 mmol) and then 2-bromoacetyl bromide (0.291 mL, 3.34 mmol) was added drop wise. The reaction mixture was stirred at 0° C. for 1 h. LC-MS indicated a new peak. Then it was diluted with DCM and saturated aqueous sodium bicarbonate solution was added. After separating the layers, the aqueous layer was further extracted with DCM. The combined organic extracts were washed with water, brine, dried over MgSO4, filtered and concentrated. Purification via flash chromatography (0-70% EtOAc in DCM, 40 g) gave 2-bromo-N-(2-chloro-5-cyano-3-nitrophenyl)acetamide (400 mg) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C1C(=O)N([Br:20])C(=O)C1.O>CN(C=O)C>[Br:20][C:9]1[CH:10]=[CH:11][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(Br)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.3 %

Procedure:
A solution of 3-(dimethylamino)benzoic acid (5.13 g, 31.0 mmol) in DMF (20 mL) was cooled to 5° C. To this cold solution was added NBS (6.23 g, 35.0 mmol) in several portions in order to keep the internal reaction temperature at 5° C. The reaction mixture was allowed to stir at this temperature for 15 min and then to warm to rt. The mixture was poured into water and extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated to give 2-bromo-5-(dimethylamino)benzoic acid (7.89 g, 93%) which was used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH:5]=[N:6][OH:7].[Cl:12]Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([Cl:12])=[N:6][OH:7]
Reactant: ClCl
Reactant: ON=Cc1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: ON=C(Cl)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
A cold solution of 18.9 g of 3,4-dichlorobenzaldoxime in 150 ml of chloroform was treated with chlorine gas until no more chlorine was absorbed. The green mixture was stirred for 1 hour at 5°, then heated under reflux for 30 minutes, when the solid went into solution and the clear green solution changed to yellow. The solution was evaporated under reduced pressure to give a white solid, m.p. 104°-106°, which was used without further purification.