Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(OC2CCNCC2)cc1
Temperature: 22 °C
Reaction time: 0.25 h

Procedure:
1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[1-(tert-butoxy)carbonyl-piperidin-4-yloxy]phenyl}urea (Example 1. below, 2.25 g, 4.77 mmol) is suspended in a solution of trifluoroacetic acid in dichloromethane (25% v/v, 100 mL). The reaction mixture is stirred at 22° C. for 15 min. After removal of the solvent, the oily residue is neutralized with sodium hydroxide solution to pH 12 and extracted with dichloromethane (6×50 mL). The combined-organic phases are dried over anhydrous sodium sulfate and concentrated to yield a yellow solid (2.28 g, ES+(m/z) 372.1 [M+H]).
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[S:11][C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(N(CC)CC)C.O1C[CH2:29][CH2:28][CH2:27]1.C#CC>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.C1(C)C=CC=CC=1.O>[C:27]([C:2]1[N:3]=[C:4]2[S:11][C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1)#[C:28][CH3:29]
Reactant: C1CCOC1
Reactant: CCCCCCSc1nn2c(=O)cc(I)nc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#CC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC#Cc1cc(=O)n2nc(SCCCCCC)sc2n1
Reaction time: 1 h
Yield: 72 %

Procedure:
Into a solution of 8.6 g of the thus obtained 7-iodo-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, 11 g of triethylamine, 0.15 g of bis(triphenylphosphine)palladium(II) chloride, 0.04 g of cuprous iodide and 33 ml of tetrahydrofurane, 2.6 g of 1-propyne was introduced through a bubbling glass tube under ice-cold-water chilling and constant stirring over a 1 hour period. Thereafter, the solution was further stirred at room temperature for 30 minutes, and 0.23 g of bis(triphenylphosphine)palladium(II) chloride and 0.06 g of cuprous iodide were added. The solution was stirred further for 4 hours. Then toluene was added, and the solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene, the solution was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized from an ethanol/hexane mixture and thus 3.9 g of 7-(1-propynyl)-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 94°~97° C. Yield 72%.
Reaction SMILES: [OH:1][CH:2]1[CH2:15][C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]2)[CH2:3]1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:24]([O:1][CH:2]1[CH2:3][C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:5]2)[CH2:15]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CC2(CC(O)C2)C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(CC(OS(C)(=O)=O)C2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (505 mg, 2.37 mmol) was dissolved in DCM (6.0 mL). The solution was cooled to 0° C. with an external ice-bath. Et3N (330 μL, 2.37 mmol) and DMAP (3.0 mg, 0.0237 mmol) were added. Methanesulfonyl chloride (184 μL, 2.37 mmol) was then added dropwise by syringe. The solution was stirred at 0° C. for 2.0 hrs, was then allowed to warm to room temperature and stirred at room temperature for 18 hrs. A saturated solution of NH4Cl (20 mL) was added and stirred at room temperature for 10 min. The layers were separated. The aqueous phase was extracted with DCM (3×30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated by evaporation in vacuo to afford tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (684 mg, 99%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=[O:5].[C:11]([CH2:13][NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([S:33][CH2:34][CH2:35][NH2:36])=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[O:16])#[N:12].C(N(C(C)C)CC)(C)C>O1CCCC1>[S:24]([OH:25])(=[O:26])(=[O:5])[CH3:27].[C:11]([CH2:13][NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([S:33][CH2:34][CH2:35][NH:36][C:3]2[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=2)=[CH:29][CH:28]=1)(=[O:25])=[O:26])=[O:16])#[N:12]
Reactant: O=C(O)c1cccnc1Cl
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(SCCN)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(SCCNc2cccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-chloronicotinic acid (20 mg, 0.112 mmol), and trans-N-cyanomethyl-2-[4-(aminoethylsulfanyl)benzenesulfonylmethyl]cyclohexanecarboxamide (50 mg, 0.102 mmol) in tetrahydrofuran (1 mL) was added diisopropylethylamine (71 μL, 0.407 mmol). The reaction mixture was stirred overnight at room temperature, then purified directly on a short plug of silica gel (0-10% methanol/dichloromethane) to give the title compound. MS [ESI, (M+H)+] m/z 535 amu, MS [ESI, (M+Na)+] m/z=557 amu.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:25]2[CH2:26][CH2:27][N:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:29][CH:30]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(C2=CCNCC2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1
Solvent: ClCCl
Product: CCOC(=O)N1CC=C(c2cc(C)cn3nc(NC4CCN(c5cc(C)ncn5)CC4)nc23)CC1

Procedure:
Prepared in analogy to example 164b, starting from 6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidin-4-yl)-8-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine and ethyl chloroformate. The title compound was obtained as a light yellow solid (yield: 36%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (v/v) as eluent.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:23]N1C(=O)CCC1=O>O1CCCC1>[Br:23][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[C:16]([C:19]([F:21])([F:20])[F:22])=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(C(F)(F)F)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(C(F)(F)F)nnc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To the mixture of 9-pentyl-3-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (50 mg, 0.16 mmol) in tetrahydrofuran (10 mL) was added N-bromosuccinimide (42 mg, 0.24 mmol). The mixture was stirred at 70° C. for 3 hour. The reaction mixture was concentrated and purified by preparative LCMS to yield the desired product. 1HNMR (300 MHz, CD3OD): δ 4.44 (t, J=7.6 Hz, 2H), 1.94 (m, 2H), 1.42 (m, 4H), 0.93 (m, 3H). LCMS calculated for C12H13BrF3N6O (M+H): 393.0. Found: 393.0, 395.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].Br[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[OH:6])[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: COc1ccccc1C=O
Reactant: COc1cc(Br)cc(OC)c1
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2ccccc2OC)c1
Yield: 84.6 %

Procedure:
2-Methoxybenzaldehyde (0.81 g, 5.95 mmol), 1-bromo-3,5-dimethoxybenzene (1.42 g, 6.54 mmol), and n-butyl lithium (2.62 ml, 6.54 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give (3,5-dimethoxy-phenyl)-(2-methoxy-phenyl)-methanol as a greenish oil (1.38 g, 85%): 1HNMR (CDCl3) 7.30-7.18 (m, 2H, Ar), 6.96-6.88 (m, 2H, Ar), 6.57 (d, J=1 Hz, 2H, Ar), 6.36 (t, J=2 Hz, 1H, Ar), 5.99 (d, J=5 Hz, 1H, CHOH), 3.84 (s, 3H, OCH3), 3.77 (s, 6H, 2OCH3), 3.04 (d, J=5 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[CH3:16])[CH:6]=1>C(OCC)(=O)C.C(O)C>[CH3:16][C:8]1[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2C)cn1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cn(-c2ccc(N)cc2C)cn1
Yield: 99.4 %

Procedure:
A mixture of 4-methyl-1-(2-methyl-4-nitro-phenyl)-1H-imidazole (1.26 g, 5.8 mmol) and of stannous chloride dihydrate (6.81 g, 30.2 mmol) in ethyl acetate (40 mL) and ethanol (20 mL) was stirred for 1 hour at 70° C. The reaction mixture was quenched by addition of water, neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude title compound (1.08 g, 99%) as a yellowish gum. MS ISP (m/e): 188.4 (100) [(M+H)+].
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[O:14]1[CH2:5][CH2:4][N:3]([C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][Br:8])[C:6]2[CH:7]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: O=C(Cl)CCCCBr
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CCCCBr)N1CCOc2ccccc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 3,4-dihydro-2H-benzo[b]oxazine (500 mg, 1 eq, 3.7 mmol), triethylamine (1.54. ml, 3 eq, 11.1 mmol) and catalytic amount of DMAP in dry DCM (20 ml) was added 5-bromo pentanoyl chloride (870 μl, 2 eq, 7.40 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 4 h and then diluted with excess ethyl acetate. The ethyl acetate layer was washed with dil. HCl, water and then with brine. The residue was chromatographed with ethyl acetate and hexane to yield the title compound liquid (535 mg, yield 53%) as viscous liquid.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[N:24]=[N:25][C:26](Cl)=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1.O>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[N:24]=[N:25][C:26]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)nnc2CC1
Reactant: OB(O)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3ccccc3)nnc2CC1
Temperature: 90 °C
Yield: 149.9 %

Procedure:
5 g phenylboronic acid in 30 mL dioxane was added to 3.2 g 3-chloro-5,6,8,9-tetrahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester and 388 mg (1,1′-bis(diphenyl-phosphinoferrocene)palladium(II)dichloride in 50 mL dioxane under argon. The reaction was stirred at 90° C. over night. The mixture was cooled to RT diluted with water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydroxide and brine. The solvent was removed and the precipitate was purified by column chromatographie to yielded 5.5 g of the desired product. (M+H)+=325
Reaction SMILES: NC1C=CC=CC=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O:20]Cl)(C)(C)C.[CH3:22][S:23][CH2:24][C:25](OCC)=[O:26]>C(Cl)Cl>[C:4]([O:5][C:25](=[O:26])[CH2:24][S:23][CH3:22])(=[O:20])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OCl
Reactant: CCOC(=O)CSC
Reactant: Nc1ccccc1C(=O)c1ccccc1
Solvent: ClCCl
Product: CSCC(=O)OC(=O)c1ccccc1

Procedure:
In process (c) a solution of a selected aminobenzophenone (X) in a halogenated organic solvent, e.g., methylene chloride, is treated at -50° to -78°C. with t-butylhypochlorite and then with a lower alkyl α-(methylthio)acetate as, for example, ethyl α-(methylthio)acetate to give an ethyl 2-amino-3-(5- or 7-) benzoyl-α-(methylthio)acetate (XI) which can be isolated or can be converted in situ by the addition of a dilute mineral acid such as dilute hydrochloric acid to a 3-methylthio-4-(5- or 7-) benzolindolin-2-one (XII). The 3-methylthio group is removed by stirring a dry tetrahydrofuran solution of the 3-methylthio compound (XII) with Raney-Ni under an inert gas to give a benzoylindolin-2-one of Formula I.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[OH-].[Li+]>O1CCCC1>[N:9]1([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: O=Cc1cnc(Cl)s1
Reactant: C1CNCCN1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1cnc(N2CCNCC2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.2 %

Procedure:
To a solution of 2-chlorothiazole-5-carboxaldehyde (Example 53; 378 mg, 2.6 mmol) in aqueous tetrahydrofuran (9.75 mL tetrahydrofuran, 0.25 mL of water, 40:1) at 25° C. was added piperazine (0.55 g, 6.4 mmol) followed by lithium hydroxide (129 mg, 3.0 mmol). After stirring for 24 h at room temperature, the solvents were removed under reduced pressure. The residual solid was diluted with water (50 mL) and neutralized to pH 7 with 1N hydrochloric acid solution. The resulting solids were filtered, washed with water, dried under vacuum and flash chromatographed (silica gel, 10% methanol in dichloromethane) to yield 2-(piperazin-1-yl)thiazole-5-carboxaldehyde (191 mg, 38% yield) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH:6]=[C:7]([C:18]#[N:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)C.S(=O)(=O)(O)O>C1(OC2C=CC=CC=2)C=CC=CC=1.C(OCC)C>[CH3:17][O:16][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][C:11]=1[O:14][CH3:15])[C:4](=[O:3])[NH:5][CH:6]=[C:7]2[C:18]#[N:19]
Reactant: CCOC(=O)NC=C(C#N)c1ccc(OC)c(OC)c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2c(C#N)c[nH]c(=O)c2cc1OC
Temperature: 230 °C
Yield: 52 %

Procedure:
To a stirred solution of [2-cyano-2-(3,4-dimethoxy-phenyl)-vinyl]-carbamic acid ethyl ester (8 g, 29.0 mmol) in diphenyl ether (70 mL) was added concentrated sulfuric acid (0.5 mL). The reaction mixture was heated at 230° C. for 4 hrs, cooled and diluted with diethyl ether (400 mL). A brown solid was precipitated, filtered, collected and washed with diethyl ether to afford 6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbonitrile. (3.5 g, 52% yield).
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:7]=[C:8]([CH2:12][S:13](Cl)(=[O:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]>C1C=CC=CC=1>[N+:3]([C:6]1[CH:7]=[C:8]([CH2:12][S:13]([NH:2][CH3:1])(=[O:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CN
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Solvent: c1ccccc1
Product: CNS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
40% aqueous methylamine (10 mL, 0.1 mol) was added to a vigorously stirred solution of (3-Nitrophenyl)methanesulfonyl chloride (1.18 g, 5 mmol) in benzene (30 mL) and allowed to stir for 2 h at room temperature. To this end, the benzene layer was separated, and the aqueous layer extracted with CH2Cl2 (2×25 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (30 mL), water (30 mL), filtered over anhydrous Na2SO4, filtered and the solvent removed under reduced pressure to give 1.01 g (87%) of (3-nitrophenyl)-N-methylmethanesulfonamide as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>O>[N+:8]([C:5]1[CH:4]=[CH:3][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][N:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: C1CCNC1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCC2)cn1
Temperature: 120 °C
Yield: 72.4 %

Procedure:
A mixture of 600 mg (2.93 mmol) of 5-bromo-2-nitropyridine and 1.05 g (14.63 mmol) of pyrrolidine is heated in a Biotage microwave machine for 1 hour at 120° C. The reaction medium is diluted with water and then extracted with ethyl acetate. The organic phase is washed twice with water, dried over MgSO4 and then filtered. The filtrate is evaporated under reduced pressure and then chromatographed on silica gel, eluting with a heptane/ethyl acetate mixture from (100/0 v/v) up to (50/50 v/v) to give 410 mg of 2-nitro-5-pyrrolidin-1-ylpyridine.
Reaction SMILES: C(C1C=CC2[N:7](C(CNC(=O)OC(C)(C)C)=NN=2)N=1)=O.[CH:21]([C:23]1[CH:24]=[CH:25][C:26]2[N:27]([C:29]([CH2:32][NH:33]C(=O)OC(C)(C)C)=[N:30][N:31]=2)[N:28]=1)=[CH2:22].O.I([O-])(=O)(=O)=O.[Na+].[CH2:48]1[CH2:52][O:51][CH2:50][CH2:49]1>[Os](=O)(=O)(=O)=O>[CH:48]1([C:52]2[O:51][N:7]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]4[N:27]([C:29]([CH2:32][NH2:33])=[N:30][N:31]=4)[N:28]=3)[CH:22]=2)[CH2:49][CH2:50]1
Reactant: C=Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(C=O)nn12
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: NCc1nnc2ccc(-c3cc(C4CC4)on3)nn12
Reaction time: 0.08 h
Yield: 72 %

Procedure:
tert-butyl (6-formyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate. Tert-butyl (6-vinyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (485 mg, 1.76 mmol) was dissolved in 5 mL of THF and 5 mL of water then osmium tetroxide (0.687 mL (4% water solution), 0.0176 mmol) was added and stirred for 5 min. Sodium periodate was added (141, 3.53 mmol) and the reaction was stirred for 2 h. The reaction was then extracted with dichloromethane (3×10 mL), dried over Na2SO4 and concentrated. Purification via MPLC (DCM/MeOH+1% NH4OH) afforded title compound as a tan solid (350 mg, 72% yield).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([CH:38]2[CH2:40][CH2:39]2)=O)[C:31]=1[O:41][CH3:42]>C1COCC1>[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([CH:38]2[CH2:40][CH2:39]2)=[CH:2][O:3][CH3:4])[C:31]=1[O:41][CH3:42]
Reactant: COc1c(Cl)ccnc1C(=O)C1CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=C(c1nccc(Cl)c1OC)C1CC1
Temperature: -30 °C
Reaction time: 4 h
Yield: 62.8 %

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (1.6 g, 4.7 mmol) was dissolved in THF (20 ml) and cooled to −30° C. 2.5 Molar n-BuLi in hexanes (1.89 ml, 4.7 mmol) was and the mixture stirred for 1 h. (4-chloro-3-methoxypyridin-2-yl)-(cyclopropyl)methanone (500 mg, 2.4 mmol) dissolved in THF (5 ml) was added slowly and stirred for 4 h. The reaction mixture was quenched with saturated ammonium chloride (20 mL) and stirred overnight. 25 mL ethyl acetate was added and the layers partitioned. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to obtain crude product which was purified over silica gel using 0:1 to 3:7 ethyl acetate in heptane to obtain 4-chloro-2-(1-cyclopropyl-2-methoxyvinyl)-3-methoxy-pyridine as a clear oil (361 mg, 63%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:23]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 2-butylbenzimidazole (0.52 g) in DMF (4 ml) was added, under cooling with ice, sodium hydride (60% oil, 0.13 g), and then the mixture was stirred for 20 minutes. To the resultant mixture was added methyl 2-(4-bromomethylphenyl)benzoate (1.0 g), which was stirred for 1.5 hour at room temperature. To the mixture was added water, followed by extraction with ethyl acetate. The solvent was evaporated to dryness to give an oily residue. The oil was purified by column chromatography on silica gel to obtain a colorless oil (1.2 g, quantitatively).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.B(OC)(OC)OC.CO.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[OH:17][CH2:16][C:15]1[CH:19]=[CH:20][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][CH2:4][C:5]=3[CH:10]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Agent: COB(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid (200 mg, 0.74 mmol, 1.0 eq.), trimethyl borate (0.5 mL, 4.4 mmol, 6.0 eq.) in THF (7.0 mL) was added borane tetrahydrofuran complex solution (1.5 mL, 1.0 M in THF, 1.5 mmol, 2.0 eq.) dropwise under nitrogen atmosphere. The mixture was stirred at room temperature overnight. The mixture was carefully treated with MeOH (2 mL) and poured into EtOAc (10 mL) and sat. NaHCO3 (10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×10 mL). Combined organic extracts was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 5-(4-hydroxymethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol as a white solid. LCMS (m/z) 279 (M+23); 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.34-7.38 (m, J=8.7 Hz, 2H), 7.01-7.05 (m, 2H), 6.96 (dd, J=8.0, 2.1 Hz, 1H), 6.91-6.93 (m, 1H), 5.18 (t, J=5.7 Hz, 1H), 4.91 (s, 2H), 4.49 (d, J=5.7 Hz, 2H).