Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C@H:2]1[N:5]([C:6](=[C:19]([CH3:21])[CH3:20])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:22])[C@@H:3]1[Br:23].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C.[Ag]>[CH2:24]([S:1][C@H:2]1[N:5]([C:6](=[C:19]([CH3:20])[CH3:21])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:22])[C@@H:3]1[Br:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(COC(=O)C(=C(C)C)N2C(=O)[C@H](Br)[C@H]2S)cc1
Reactant: BrCc1ccccc1
Agent: [Ag]
Solvent: CC#N
Product: COc1ccc(COC(=O)C(=C(C)C)N2C(=O)[C@H](Br)[C@H]2SCc2ccccc2)cc1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
A solution of the silver salt of p-methoxybenzyl 2-[(3S, 4R)-4-mercapto-3-bromo-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (10 g, 20 mmol) in dry acetonitrile (100 ml) was treated with benzyl bromide (4 g, 24 mmol) and the resulting mixture refluxed for 30 mins. the reaction was cooled to room temperature, filtered, evaporated to dryness and the residue purified by flash chromatography using 1:1 ether:pentane as the eluting solvent. Evaporation of the appropriate fractions gave the product as a white solid (5.8 g, 59%), mp 70-72° C. 1H NMR δ (CDCl3)1.93 (3H, s, CH3), 2.23 (3H, s, CH3), 3.66 (1H, dd, J=2.9, 17.5 Hz, SCH2), 3.79 (3H, s, OCH3), 4.52 (1H, d, J=1.8 Hz, H3), 4.95 (1H, d, J=1.9 Hz, H4), 5.08 (2H, q, J=12.0 Hz, CO2CH2), 6.84-6.90 (2H, m, 2.6Ph--H), 7.13-7.31 (7H, m, 3,5Ph--H,Ph--H).
Reaction SMILES: [N:1]([C@@:4]1([OH:20])[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].[CH3:21]OC(OC)N(C)C>C(Cl)(Cl)Cl>[CH3:21][N:14]1[C:15](=[O:16])[C:17]([CH3:18])=[CH:19][N:11]([C@@H:6]2[O:7][C@H:8]([CH2:9][OH:10])[C@@:4]([N:1]=[N+:2]=[N-:3])([OH:20])[CH2:5]2)[C:12]1=[O:13]
Reactant: COC(OC)N(C)C
Reactant: Cc1cn([C@H]2C[C@@](O)(N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: ClC(Cl)Cl
Product: Cc1cn([C@H]2C[C@@](O)(N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(C)c1=O

Procedure:
3'-Azidothymidine (0.5 g; 1.9 mMol) and N,N-dimethylformamide dimethylacetal (Zemlicksa, Coll. Czech. Chem. Comm. 35, 3572 (1972)) (0.9 mL; 7.5 mMol) were refluxed to 20 mL CHCl3 for 48 hours. The solvent was removed in vacuo and the material placed on a silica column. Elution with EtOAc/CHCl3 (1:1 v/v) resulted in pure material as a viscous oil: 0.26 g (0.9 mMol, 47%).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([F:25])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+].CN1CCCC1=O.Cl>O.[Br-].[Zn+2].[Br-]>[F:25][CH:16]([C:17]1[CH:24]=[CH:23][CH:22]=[C:19]([C:20]2[NH:34][N:33]=[N:32][N:21]=2)[CH:18]=1)[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:7]2[CH:26]=[CH:27][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:31])[C:6]=2[CH2:28][CH2:29][CH3:30])=[CH:15][CH:14]=1
Reactant: CCCc1c(OCc2ccc(C(F)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCc1c(OCc2ccc(C(F)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-fluoro-methyl}-benzonitrile (4.7 g, 11.26 mmol), zinc (II) bromide (10.1 g, 45 mmol), sodium azide (5.85 g, 90 mmol), and N-methylpyrrolidinone (50 ml) is heated to 140° C. and stirred 1 hr. The reaction is cooled to room temperature and diluted with water (200 mL). The pH is adjusted to 2 with 5N aqueous hydrochloric acid and extracted with ethyl acetate (3×100 mL). The extracts are combined, dried over magnesium sulfate, filtered, and concentrated. The residue is purified via reversed phase C18 chromatography eluting with 4:6 acetonitrile: (0.1% trifluoroacetic acid) water to 7:3 acetonitrile:(0.1% trifluoroacetic acid) water in 8 runs to give 3.08 g, 59%, of the title compound as fine white needles. 1H NMR (DMSO-d6) δ 12.86 (s, 1H), 8.13 (s, 1H), 8.03 (d, 1H), 7.81 (d, 1H), 7.61-7.70 (m, 2H), 7.48 (m, 4H), 6.78-6.93 (d, 1H), 6.72 (d, 1H), 5.29 (s, 2H), 2.58-2.63 (m, 5H), 1.46-1.53 (m, 2H), 0.88 (t, 3H). LCMS M−1 459.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=2)=[C:4]([CH3:35])[CH:3]=1.O1CCOCC1>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)=[C:4]([CH3:35])[CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)c(-c3ccc(F)cc3C)sc2c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccc(F)cc3C)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a 30 mL screw cap vial, (E)-tert-butyl 3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (100 mg, 0.204 mmol) was dissolved in 4M HCl in dioxane (153 μl, 0.612 mmol) and the reaction mixture was stirred for 10 min at room temperature. The reaction mixture was concentrated to dryness to afford (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (88 mg, 0.202 mmol, 99% yield). 1H NMR (400 MHz, CD3OD) δ ppm=2.25 (s, 3H) 3.78 (s, 3H) 6.21 (d, J=15.66 Hz, 1H) 6.68-6.84 (m, 3H) 6.84-6.92 (m, 2H) 7.16-7.29 (m, 2H) 7.31-7.41 (m, 3H) 7.46 (d, J=16.17 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:22]([O:25][C@@H:26]([CH2:28][CH2:29][CH:30]=[CH2:31])[CH3:27])[CH2:23][CH3:24])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20]C)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:22]([O:25][C@@H:26]([CH2:28][CH2:29][CH:30]=[CH2:31])[CH3:27])[CH2:23][CH3:24])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCC[C@@H](C)O[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCC[C@@H](C)O[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,4R)-methyl 1-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-((R)-hex-5-en-2-yloxy)pentanoyl)-4-hydroxypyrrolidine-2-carboxylate (all material from step 2, 1.39 mmol), THF (5 mL) and MeOH (5 mL). To the solution was added aq. lithium hydroxide (2.0 M, 4.51 mmol). The mixture was stirred at room temperature for 16 h; then was concentrated to afford an aqueous solution. This solution was acidified and then transferred to a separatory funnel. The solution was twice extracted with EtOAc. The combined organics were washed with brine; dried over MgSO4; filtered; then concentrated in vacuo to afford (2S,4R)-1-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-((R)-hex-5-en-2-yloxy)pentanoyl)-4-hydroxypyrrolidine-2-carboxylic acid as a white solid (489 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[C:21]([CH3:22])=[CH:20][C:18]([NH2:19])=[C:17]([CH3:23])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC.C1CCCCC1.C(OC(=O)C)C.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[C:17]([CH3:23])[C:18]([NH2:19])=[CH:20][C:21]=2[CH3:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)c(C)cc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(C)(C)C)cc2)c(C)cc1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
The reaction is carried out using inert conditions (argon or nitrogen atmosphere, dry solvents). A suspension of 6.4 g (36.0 mmol) of (4-tert-butylphenyl)boronic acid, 6.0 g (30.0 mmol) of 4-bromo-2,5-dimethylaniline, 29.3 g (90 mmol) caesium carbonate and 0.7 g (0.6 mmol) tetrakis(triphenylphosphin)palladium in 75 ml of 1,2-dimethoxyethan was stirred for 16 hrs at 80° C. At room temperature 25 ml of water and 75 ml of toluene were added. The organic layer was separated, the watery layer was again extracted using 75 ml of toluene. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Column chromatographic (cyclohexane/ethylacetate:2/1) yielded 5.5 g (21.7 mmol) 72% of 4′-tert-butyl-2,5-dimethylbiphenyl-4-amine (log P (pH 2.3)=3.65.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(OCC)(=[O:12])C>O.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH3:9])=[O:12])=[N:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CSc1ccc(Br)cn1
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NalO4 (0.52 g) dissolved in water (0.5 mL) was added to a solution of 5-bromo-2-methylsulfanyl-pyridine (0.25 g) in acetic acid (3 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. Then, water and ethyl acetate were added and the mixture was stirred for another 10 min. The organic phase was separated and washed with 10% aqueous Na2S2O3 solution, 10% aqueous K2CO3 solution, and brine. After drying (MgSO4), the solvent was evaporated to afford the title compound. Yield: 0.20 g (72% of theory); Mass spectrum (ESI+): m/z=220/222 (Br) [M+H]+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]([C:33](O)=O)[N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[N:26]=[C:25]([C:33]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=4)[N:14]=3)[N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1nc(-c2ccc(Cl)c(Cl)c2)cc(C(F)(F)F)n1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)n2)c1

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.74 mmol) and 4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.6) (0.17 g, 0.50 mmol) according to the general procedure V. Obtained as a light yellow solid (0.055 g, 21%). MS (ISP) 516.1 [(M+H)+]; mp 258° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[NH2:17].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][N:26]=[C:27]=S>C(#N)C>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][C:27]1[NH:1][C:2]2[C:7]3[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=3[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=2[N:17]=1
Reactant: COC(=O)c1cc(N)c(N)c2c1OC(C)(C)C2
Reactant: S=C=NCc1ccccc1Cl
Solvent: CC#N
Product: COC(=O)c1cc2nc(NCc3ccccc3Cl)[nH]c2c2c1OC(C)(C)C2
Yield: 48.9 %

Procedure:
The title compound was prepared following the procedure described for Step-1 of Intermediate-3 using methyl 4,5-diamino-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylate (Intermediate-1, 2.5 g, 10.59 mmol), 1-chloro-2-(isothiocyanatomethyl)benzene (2.5 g, 13.6 mmol), N,N-di-isopropyl carbodimide (0.5 mL) and acetonitrile (10.0 mL) to afford 2.00 g of the desired product. 1HNMR (DMSO-d6): δ 1.41 (s, 6H), 3.00 (s, 2H), 3.71 (s, 3H), 4.60 (d, J=5.3 Hz, 2H), 7.30-7.45 (m, 5H), 7.55 (t, J=6.6 Hz), 10.80 (s, 1H); MS [M+H]+: 386.05.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][CH2:46]Cl>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[N:10]=[C:11]1\[S:12][CH2:44][CH2:45][CH2:46][N:13]\1/[N:14]=[CH:15]/[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CC(C)c1ccccc1/N=C1\SCCCN1/N=C/c1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 60 °C
Yield: 13.2 %

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (200 mg, 0.393 mmol) and potassium carbonate (217 mg, 1.57 mmol) in butanone (10 ml) in a 25 mL vial equipped with a stir bar and vigruex column was added 1-bromo-3-chloropropane (0.047 ml, 0.472 mmol). The reaction was heated to 60° C. overnight. The reaction was determined to be complete by LCMS. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided two compounds. The minor compound was dried overnight under house vacuum providing the title compound 87C (2Z,NE)-2-((2-isopropylphenyl)imino)-N-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)-1,3-thiazinan-3-amine (28.5 mg, 13%) as a yellow solid: mp 187-189° C.; 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.66 (s, 1H), 8.21 (d, J=8.3 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.81 (t, J=10.2 Hz, 4H), 7.30-7.26 (m, 2H), 7.17-7.04 (m, 1H), 6.83 (d, J=6.4 Hz, 1H), 3.96 (t, J=6.1 Hz, 2H), 3.13 (heptet, J=6.9 Hz, 1H), 2.97-2.90 (m, 2H), 2.47-2.38 (m, 2H), 1.25 (d, J=7.5 Hz, 6H); ESIMS m/z 550 (M+H). The major compound was recrystallized with MeOH. The solid was filtered, washed with MeOH and dried at 50° C. under vacuum. The solid was then azeotroped with acetone (3×) and the resultant solid was dried at 50° C. under vacuum providing the title compound 179C (Z)-3-(2-isopropylphenyl)-2-((E)-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazono)-1,3-thiazinane as a yellow solid (92.3 mg, 0.168 mmol, 43%): mp 212-213° C.; 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.15 (d, J=8.4 Hz, 2H), 8.06 (s, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.79 (d, J=8.6 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.38 (dd, J=7.8, 1.6 Hz, 1H), 7.33 (td, J=7.5, 1.4 Hz, 1H), 7.29-7.23 (m, 1H), 7.18 (dd, J=7.8, 1.4 Hz, 1H), 3.78-3.72 (m, 1H), 3.59-3.48 (m, 1H), 3.18-3.04 (m, 3H), 2.40-2.30 (m, 2H), 1.26-1.20 (m, 6H); ESIMS m/z 550 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>CN1C(=O)CCC1>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=2[C:4]#[N:5])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C#N)cc1
Reaction time: 0.5 h

Procedure:
A solution of 0.15 g of 2-amino-5-chloro-benzonitrile and 0.23 g of 4-tert.butyl-benzenesulfonyl chloride is dissolved in 2 ml of NMP (N-methyl 2-pyyrolidone) and cooled in an ice bath to 5°. 2.5 ml of a solution of potassium-tert.butylat (1 N in THF) is added, the mixture obtained is stirred for 30 min, quenched with water and from the mixture obtained solvent is evaporated. The evaporation residue is dissolved in EtAc, washed with saturated NaHCO3 solution and dried. Solvent is evaporated and the evaporation residue is subjected to chromatography on a reversed phase column. 4-tert.Butyl-N-(4-chloro-2-cyano-phenyl)-benzenesulfonamide is obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[N:13]1([C:18]([C:20]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:10]([C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][C:20]([C:18]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:19])=[CH:25][CH:24]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:12])=[O:11]
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCCC1
Reactant: O=Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc(C(=O)N3CCCC3)cc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 178.9 %

Procedure:
To a solution of 4-bromo-2-nitrobenzaldehyde (20.2 g, 87.9 mmol), 4-(pyrrolidine-1-carbonyl)phenylboronic acid (21.2 g, 96.7 mmol), and Pd(PPh3)4 (508 mg, 0.440 mmol) in toluene (200 mL) was added EtOH (40 mL) followed by Na2CO3 (70.0 mL, 140 mmol, 2 M aq solution) at room temperature. The resulting mixture was heated at 100° C. for 18 h. The reaction mixture was cooled to room temperature and the organic layer was separated. The aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (500 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was combined with another batch of the crude material obtained from an additional run in the same reaction scale. The combined crude material was purified by silica gel flash column chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to afford 51 g (90%) of 3-nitro-4′-(pyrrolidine-1-carbonyl)biphenyl-4-carbaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:26]2[CH2:31][CH2:30]S[CH2:28][CH2:27]2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.O[O:33][S:34]([O-:36])=O.[K+].S(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:26]2[CH2:31][CH2:30][S:34](=[O:36])(=[O:33])[CH2:28][CH2:27]2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(N2CCSCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: O=S([O-])OO
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N2CCS(=O)(=O)CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
To a solution of 4-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine (156 mg, 0.36 mmol) in dichloromethane (2 mL) and methanol (2 mL) was added oxone (331 mg, 0.54 mmol) and the reaction mixture was stirred for 18 h at ambient temperature and then for 4 h at 50° C. After cooling to ambient temperature oxone (331 mg, 0.54 mmol) was added and stirred for 18 h at 50° C. before it was cooled to ambient temperature and sodium bisulfite solution (38%, 1.5 mL) was added and stirred for 15 min. After the addition of aqueous sodium carbonate (saturated, 10 mL) the mixture was extracted with ethyl acetate (20 mL) and washed with aqueous sodium carbonate (20 mL). After drying over sodium sulfate the concentrated residue was dissolved in dichloromethane (5 mL) and diluted with tert-butylmethylether (20 mL). The dichloromethane was distilled off and the resulting suspension was filtered affording the title compound (116 mg, 69%) as a white solid. MS: m/e=467.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C@H:15]([N:18](C)[C:19](=O)OCC1C=CC=CC=1)[CH2:16][OH:17].[H][H]>CO.[Pd]>[OH:17][CH2:16][C@@H:15]([NH:18][CH3:19])[CH2:14][CH2:13][CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1]
Reactant: CN(C(=O)OCc1ccccc1)[C@H](CO)CCCN1C(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN[C@H](CO)CCCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of (S)-benzyl 5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl(methyl)carbamate (5.01 g, 12.65 mmol) in MeOH (100 mL) was added Pd/C (1.0 g). The mixture was transferred to an autoclave reactor, charged with 50 psi of hydrogen, and stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give (S)-2-(5-hydroxy-4-(methylamino)pentyl)isoindoline-1,3-dione (3.2 g, 97%). LRMS (M+H+) m/z 263.1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[N:33]=[N:34][N:35]([C:37]3[CH:45]=[CH:44][C:40]([C:41]([OH:43])=O)=[CH:39][CH:38]=3)[CH:36]=2)=[N:24]1.CCN(C(C)C)C(C)C.[NH:55]1[CH2:59][CH2:58][CH:57]([OH:60])[CH2:56]1>CN(C=O)C.C(Cl)Cl>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[N:33]=[N:34][N:35]([C:37]3[CH:45]=[CH:44][C:40]([C:41]([N:55]4[CH2:59][CH2:58][CH:57]([OH:60])[CH2:56]4)=[O:43])=[CH:39][CH:38]=3)[CH:36]=2)=[N:24]1
Reactant: O=C(O)c1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Reactant: OC1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1)N1CCC(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of TBTU (137 mg; 0.33 mmol; 1.3 eq.) and 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) in DMF (2 mL) was stirred for 1 h at RT before the addition of DIEA (111 μl; 0.66 mmol; 2.0 eq.) and 3-pyrrolidinol (43 mg; 0.49 mmol.; 1.5 eq.). The reaction mixture was stirred at RT overnight. It was then diluted with DCM and washed with an aqueous saturated solution of NaHCO3. Organic phase was dried over magnesium sulfate, filtered and concentrated. The crude was purified by preparative HPLC to afford the title compound as a yellow solid. 1H NMR (300 Mz, DMSO-d6) δ 13.38 (s, 1H), 9.41 (s, 1H), 8.37 (d, J=8.1 Hz, 1H), 8.15 (d, J=8.7 Hz, 2H), 7.78 (dd, J=3.2, 8.6 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.51-7.39 (m, 1H), 7.27 (t, J=7.1 Hz, 1H), 4.32 (brd, J=26.0 Hz, 1H), 3.76-3.54 (m, 2H), 3.54-3.20 (m, 3H), 2.06-1.75 (m, 2H). HPLC (Condition A): Rt 2.58 min (purity 96.7%). MS (ESI+): 375.2, MS (ESI−): 373.2.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl.O>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:17]
Reactant: O=C(Cl)CCCCl
Reactant: NCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCCCl)NCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a solution of phenethylamine (2.42 g, 20 mmol) and NaOH (0.88 g, 22 mmol) in DCM/H2O (20 mL/20 mL) was added 4-chloro-butyryl chloride (2.82 g, 20 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 20 min. The mixture was partitioned between DCM (20 mL) and H2O (10 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a white solid. This residue was purified with silica gel column (Hexane/EtOAc=3/1 to 1/1) to obtain HJC-1-48 (4.2 g, 93%) as a white solid. 1H NMR (600 MHz, CDCl3) δ 7.32 (t, 2H, J=7.8 Hz), 7.23-7.26 (m, 1H), 7.20 (d, 2H, J=7.8 Hz), 5.46-5.47 (m, 1H), 3.52-3.58 (m, 4H), 2.82 (t, 2H, J=7.2 Hz), 2.31 (t, 2H, J=7.2 Hz), 2.07-2.11 (m, 2H).