Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH:10]([CH3:18])[CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[C:1]([NH:9][CH:10]([CH3:18])[CH:11]([CH3:17])[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)C(C)NC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(NC(=O)c1ccccc1)C(C)C(=O)O
Temperature: 60 °C
Yield: 77.6 %

Procedure:
To ethyl 3-benzamido-2-methylbutanoate (0.08 g, 0.321 mmol) in MeOH (2 mL) and water (1.000 mL) was added lithium hydroxide (0.015 g, 0.642 mmol) at RT. Contents heated at 60° C. for 1.5 h. The reaction mixture was concentrated and partitioned between dichloromethane (10 mL) and 1N HCl (5 mL). The dichloromethane layer is washed with brine (10 mL), dried overt sodium sulfate and concentrated to yield the title compound (0.055 g, 0.249 mmol, 77% yield) as a foamy solid, which was used as such for the subsequent step without further purification. MS (ESI) m/z 222.16 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:23])[C:9]3[C:10]([CH:21]=[CH:22][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[N:11][CH:12]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:14]=3.[CH3:24]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:24][C:2]1[C:7]2[C:8](=[O:23])[C:9]3[C:10]([CH:21]=[CH:22][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[N:11][CH:12]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:14]=3
Reactant: O=c1c2cc(-c3ccccc3)cnc2ccc2cccc(Br)c12
Reactant: CB1OB(C)OB(C)O1
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: [K+]
Product: Cc1cccc2ccc3ncc(-c4ccccc4)cc3c(=O)c12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
6-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (10 mg, 0.027 mmol), trimethylboroxine (10 μL, 0.071 mmol), tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.004 mmol), and potassium carbonate (15 mg, 0.108 mmol) were combined in a dry flask. The flask was purged with argon and 0.5 mL of 10% aqueous dioxane were added. Argon was bubbled through the solution for 5 minutes and the solution was stirred and heated to 100° C. After 12 hours, the reaction mixture was filtered through a pad of Celite, eluted with EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated and purified by reverse phase HPLC (30-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 9.11 (d, 1H), 8.54 (d, 1H), 7.80 (d, 2H), 7.54 (m, 5H), 7.48 (m, 2H), 7.26 (d, 2H), 2.56 (s, 3H). LRMS (APCI) calculated for C21H16NO [M+H]+, 298.1; found 298.1
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12]3[N:17]=[C:16]([C:18]4[N:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:15]=[CH:14][CH:13]=3)=[CH:10][N:11]=2)[CH:2]=1.[B-](F)(F)(F)[F:25].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[F:25][C:10]1[N:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[S:8][C:9]=1[C:12]1[N:17]=[C:16]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: c1cnc(-c2cccc(-c3cnc(-c4cccnc4)s3)n2)nc1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Fc1nc(-c2cccnc2)sc1-c1cccc(-c2ncccn2)n1

Procedure:
0.5 g (1.57 mmol) of 2-[6-(2-pyridin-3-ylthiazol-5-yl)pyridin-2-yl]pyrimidine was dissolved in acetonitrile, 1.16 g (3.15 mmol) of 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (Selectfluor™) and 1 g (7.04 mmol) of sodium sulphate were added and the mixture was heated at reflux overnight and, after cooling, filtered through Celite. The filtrate was concentrated and purified by chromatography (cyclohexane/ethyl acetate, then ethyl acetate/methanol).
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=2)[CH2:5]1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.CC(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][CH2:2][CH2:3][C:4]2([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=3)[CH2:5]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1ccc2c(c1)CCC(CC=O)(C(=O)OC)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)CCC(CCNCc1ccc(OC)cc1)(C(=O)OC)C2
Reaction time: 18 h

Procedure:
A solution of (1)-dimethyl 2-(2-oxoethyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate from Step C (436 mg, 1.50 mmol), 4-methoxybenzylamine (247 mg, 1.80 mmol), and AcOH (0.206 mL, 3.60 mmol) was stirred in MeOH (10 mL) at ambient temperature for 5 min, then sodium cyanoborohydride (113 mg, 1.80 mmol) was added. After 18 h, the mixture was concentrated in vacuo, and the residue was partitioned between saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted further with CH2Cl2 (10 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=412 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@H:11]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[C:12]([OH:14])=O)=[CH:6][CH:5]=1)[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]2[C:7]([CH2:10][C@H:11]([N:15]3[C:23](=[O:24])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]3=[O:25])[C:12]2=[O:14])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C[C@@H](C(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc2c(c1)C(=O)[C@@H](N1C(=O)c3ccccc3C1=O)C2

Procedure:
(αS)-α-[(4-Ethoxyphenyl)methyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetic acid (XIV, EXAMPLE 14, 13.6 g, 40 mmol) is suspended in methylene chloride (40 mL). Trifluoroacetic anhydride (11.4 mL, 80 mmol) is added over 20 min at 20-25°. The resulting mixture is added dropwise to a solution of ferric chloride (6.81 g, 42 mmol) in methylene chloride (80 mL) over 1 hr. After the reaction is complete, it is quenched with water (80 mL). The organic layer is separated and concentrated. The residue is purified with a by column chromatography (silica gel; ethyl acetate/hexane, 20/80) to give the title compound, NMR δ7.85, 177.73, 177.38, 7.26, 5.10, 4.07, 3.52, 3.30 and 1.43; CMR δ200.0, 167.4, 159.0, 143.5, 135.9, 134.1, 132.0, 127.3, 125.3, 123.5, 106.2, 63.9, 54.2, 31.2 and 14.6; HRMS (FAB) calculated for C19H15NO4 [M+1]=322.1079, found=322.1085.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C@@H:32]([OH:34])[CH3:33])[N:25]=5)=[CH:22][N:21]([CH2:35][C:36]#[N:37])[N:20]=4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C1COCC1.CO>[OH:34][C@@H:32]([CH3:33])[CH2:31][NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:19]([C:17]3[CH:18]=[C:13]4[CH:12]=[CH:11][NH:10][C:14]4=[N:15][CH:16]=3)=[N:20][N:21]([CH2:35][C:36]#[N:37])[CH:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: C[C@H](O)CNc1nccc(-c2cn(CC#N)nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](O)CNc1nccc(-c2cn(CC#N)nc2-c2cnc3[nH]ccc3c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To solution of the {3-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-[2-((S)-2-hydroxy-propylamino)-pyrimidin-4-yl]-pyrazol-1-yl}-acetonitrile (C-1-6) (145 mg, 0.28 mmol) in THF (5 mL) at −40° C. was added sodium hydroxide (1.1 mL of a 10 mg/mL solution in MeOH, 0.28 mmol). The mixture was allowed to slowly warm to 0° C. After 2 hr the mixture was diluted with 10 mL THF and stirring continued at 0° C. for 2 hr. Mixture was partitioned between pH 7 phosphate buffer and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with saturated aqueous NaCl, dried over MgSO4 and reduced to minimum volume. The residue was purified by HPLC to give the [4-[2-((S)-2-Hydroxy-propylamino)-pyrimidin-4-yl]-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrazol-1-yl]-acetonitrile (C-1) in 23% yield. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 9.78 (br. s., 1H), 8.42 (d, J=2.02 Hz, 1H), 8.22 (s, 1H), 8.05-8.14 (m, 2H), 7.38-7.45 (m, 1H), 6.42-6.56 (m, 2H), 5.74 (br. s., 1H), 5.25 (s, 2H), 3.72 (br. s., 1H), 3.19 (br. s., 1H), 3.04 (br. s., 1H), 0.95 (br. s., 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:27]=[CH:26][C:7]([C:8]([N:10]([C@@H:12]3[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]3[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[CH:1]1([C:4]2[CH:27]=[CH:26][C:7]([C:8]([N:10]([C@@H:12]3[CH2:17][CH2:16][N:15]([C:38]([CH:35]4[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]4)=[O:39])[CH2:14][C@H:13]3[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)c1ccc(C2CC2)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)c1ccc(C2CC2)cc1)[C@@H]1CCN(C(=O)C2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in step 1 and 1-(methylsulfonyl)piperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 97, the title compound was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:6][C:4]=1[NH2:5].[C:15](O)(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>[OH-].[NH4+]>[Cl:10][C:8]1[C:7]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:6][C:4]2[NH:5][C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:2][C:3]=2[CH:9]=1
Reactant: CCCCCC(=O)O
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCCCCc1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]1

Procedure:
To 50 ml of 4 N hydrochloric acid containing 11.8 g of 2-amino-4-chloro-5-sulfamylaniline was added 9.2 g of hexanoic acid and the suspension refluxed for 6 hours. Concentration in vacuo provided a solid which was then slowly added with stirring to 100 ml of 38% ammonium hydroxide. After collecting the solid by filtration, the precipitate was added to 400 ml of methanol and the suspension brought to a boil. Charcoal was then added and the mixture filtered through filter paper, cooled, and filtered through Celite. Concentration in vacuo gave brown crystals which upon recrystallization from acetonitrile provided 2.6 g of product, mp 183°-185°.
Reaction SMILES: [N:1]1([C:10]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[N:1]1([CH:10]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C=C(c1ccc(CC)cc1)n1cnc2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(CC)cc1)n1cnc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate (E/Z mixture, 181 mg, 566 μmol) in a mixture of ethanol and water (10:1, 2.75 mL) was added palladium on carbon (27 mg, 10% w/w Pd) and ammonium formate (143 mg, 2.26 mmol). The suspension was brought to reflux for 3 hours, cooled to room temperature, and was filtered through a pad of Celite® and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (96:4) to afford the title compound, 1H NMR: (CDCl3), 8.03 (s, 1H), (d, J=6.96, 1H), 7.31-7.06 (m, 7H), 6.01 (dd, J=8.79, 6.59, 1H), 4.04 (t, J=6.96, 2H), 3.38 (dd, J=15.75, 8.79, 1H), 3.31 (dd, J=15.75, 6.59, 1H), 2.62 (q, J=7.69, 2H), 1.18 (t, J=7.69, 3H), 1.09 (t, J=6.96, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH3:17])[CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(Cl)=[S:19].C(N(CC)CC)C>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:18]2=[S:19])=[C:6]([CH3:17])[CH:5]=[CH:4][CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cccc(Cl)c1NCCCNCC(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cccc(Cl)c1N1CCCN(CC(C)C)C1=S
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
To a solution of the diamine of Step A (3.82 g) in dry chloroform (55 mL) was added dropwise at 0° C. under nitrogen triethylamine (4.18 mL) followed by thiophosgene (2.6 g). The mixture was stirred in the cold for 15 minutes and then at room temperature for 60 minutes. It was then diluted with water and after adjusting the pH to 8 with triethylamine, was extracted with dichloromethane. The combined extracts were washed with 20% aqueous sodium chloride, dried over anhydrous potassium carbonate and evaporated to dryness. The residue was flash chromatographed (on Merck-60 flash silica gel, 85:15 hexane-EtOAc) to provide 3.37 g of the title compound. Trituration and sonication with hexane and hexane-ether yielded an off-white solid (2.26 g, 51.1%), m.p. 119-121° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(O)(C)C.[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[N:22][C:21]2[CH:23]=[CH:24][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C=O)cc1
Solvent: CC(C)O
Product: COc1ccc(C=Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 66 %

Procedure:
To 50 g (370 mmol) of anisaldehyd in 160 ml of isopropanol 51 g (370 mmol) of para-nitroanilin are added. After 2 h at 80° C. the product precipitates. The reaction mixture cooled to room temperature and filtered. The residue is washed with isopropanol. After drying 62.9 g of product 2 is obtained (yield of 66%) in form of yellow crystals: C14H13N2O3 (257.27).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[N:28][OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1cc(Cl)ccc1Cl)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(CC(=NO)c1cc(Cl)ccc1Cl)c1ccc(Br)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-bromo-phenyl)-1-(2,5-dichloro-phenyl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.4:1) as a white foam, MS (EI): m/z=463 ([M]+, 1Br).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>C(O)C>[CH3:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:10][CH2:9]1
Reactant: CN1CCN(CCCN)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCO
Product: CN1CCN(CCCNc2ncccc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
In a two liter, three-necked flask fitted with condenser, dropping funnel, thermometer, magnetic stirrer and nitrogen inlet was placed 71.8 g. (0.456 mole) 1-(3-aminopropyl)-4-methyl piperazine and 150 ml. of ethanol. The solution was heated at reflux and a solution of 65.0 g. 2-chloro-3-nitropyridine dissolved in 500 ml. of warm ethanol was added dropwise over 90 minutes. The dark yellow reaction mixture was maintained at reflux of an additional hour then cooled to ambient temperature. The solvent was then removed in vacuo to obtain a yellow-brown semi-solid residue. The residue was partitioned between 200 ml. each of aqueous 1N HCl and methylene chloride, and aqueous phase washed with 100 ml. CH2Cl2. The aqueous portion was made basic with 6N NaOH and extracted with 3 × 250 ml. CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent evaporated to afford 2-[3-(4-methyl-1-piperazinyl)-propylamino]-3-nitropyridine as a red-yellow oil which crystallized on standing at room temperature; yield 82.9 g. (72%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16]C(=O)C)[S:15][C:11]=3[CH:10]=2)[CH:5]=[N:6][C:7]=1[Cl:8].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.O.C(OCC)(=O)C>[NH2:16][C:14]1[S:15][C:11]2[CH:10]=[C:9]([C:4]3[CH:3]=[C:2]([NH:1][S:33]([C:24]4[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:23]=4[Cl:22])(=[O:35])=[O:34])[C:7]([Cl:8])=[N:6][CH:5]=3)[CH:21]=[CH:20][C:12]=2[N:13]=1
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N)c3)cc2s1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)c3)cc2s1
Reaction time: 8 h

Procedure:
To a 50 ml round-bottom flask equipped with a stirbar and charged with N-(6-(5-amino-6-chloropyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.300 g, 0.9 mmol) in Pyridine (5 ml), was added DMAP (0.030 g, 0.2 mmol) and 2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (1 g, 5 mmol). The flask was allowed to stir under inert atmosphere overnight. The progress of the reaction was monitored by LC/MS, which showed desired (N-Acyl, m/z=562) and bis-sulfonated material. The mixture was diluted with water (30 ml) and ethyl acetate and then allowed the mixture to stir 10 minutes. The organic layer was extracted with EtOAc (3×25 ml). Then combined organics, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with MeOH (6 ml), then added the mixture into two microwave vials equipped with stirbars (with the organics equally distributed). Potassium carbonate (0.300 g) was added to each vial, then capped and placed into a CEM Microwave for 10 minutes at 80° C., while 60 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the de-sulfonylation/de-acylation reaction was monitored by LC/MS, which showed mostly desired product. The two mixtures were combined and concentrated in vacuo. Water (30 ml) was added to the flask, along with a stirbar and then neutralized the mixture with 1N HCl. The precipitate was collected by filtration and washed with Hexanes. The solid was dissolved in ethyl acetate, and then purified the crude material by ISCO Silica-Gel Chromatography (120 gram column) in a gradient of 1-5% MeOH/DCM over 30 minutes. The fractions with desired product were combined and concentrated in vacuo. The residue was recrystallized from EtOAc/Hexanes to give N-(5-(2-aminobenzo[d]thiazol-6-yl)-2-chloropyridin-3-yl)-2-chloro-4-(trifluoromethyl)benzenesulfonamide (0.040 g, 8% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 520 (MH+). Calc'd exact mass for C19H11Cl2F3N4O2S2: 519. 1H NMR (400 MHz, DMSO-d6): 7.38-7.44 (m, 1H), 7.49 (d, J=8.53 Hz, 1H), 7.68 (s, 2H), 7.89 (d, J=8.53 Hz, 1H), 7.99 (d, J=19.07 Hz, 2H), 8.12 (d, J=8.03 Hz, 1H), 8.58 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:17][CH:16]2[OH:31])=[CH:11][CH:10]=1.Cl[CH2:38][C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][O:51][Si:52]([CH:59]([CH3:61])[CH3:60])([CH:56]([CH3:58])[CH3:57])[CH:53]([CH3:55])[CH3:54])[C:43]=2[CH:62]=1>>[F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH2:17][CH:16]2[O:31][CH2:38][C:39]2[CH:40]=[CH:41][C:42]3[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][O:51][Si:52]([CH:53]([CH3:55])[CH3:54])([CH:56]([CH3:58])[CH3:57])[CH:59]([CH3:61])[CH3:60])[C:43]=3[CH:62]=2)=[CH:11][CH:10]=1
Reactant: CC(C)[Si](OCCN1C(=O)COc2ccc(CCl)cc21)(C(C)C)C(C)C
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(OCCCOc3cc(F)ccc3F)cc2)C(O)C1
Product: CC(C)[Si](OCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21)(C(C)C)C(C)C

Procedure:
Analogously to Method D, 1.34 g of benzyl 4-{4-[3-(2,5-difluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 1.43 g of 6-chloromethyl-4-(2-triisopropylsilanyloxyethyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.55 (1:1 EtOAc-heptane); Rt=7.03.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[S:6][N:5]=1.Cl[C:17]1[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:18]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH3:3][C:4]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][CH:12]([NH:15][C:17]3[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=4)[N:18]=3)[CH2:13][CH2:14]2)[S:6][N:5]=1
Reactant: Cc1nsc(N2CCC(N)CC2)n1
Reactant: CC(C)(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nsc(N2CCC(Nc3nc(-c4ccc(C(F)(F)F)cc4)cc(C(C)(C)O)n3)CC2)n1

Procedure:
A solution of 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-ylamine dihydrochloride (54.2 mg, 0.2 mmol), 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol (69.7 mg, 0.22 mmol) and N,N-diisopropylethyl amine (120 L, 0.7 mmol) in dioxane (2 mL) was heated at 200° C. in a microwave oven for 2 hours. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with CH2Cl2/MeOH 19:1 (v/v) as eluent. The title compound was obtained as a brown viscous oil (26 mg, 27%). MS ISP (m/e): 479.1 (100) [(M+H)+].
Reaction SMILES: [N:1]([C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=O)=[N:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6]C)=O.[CH2:17]([NH2:20])[CH:18]=[CH2:19]>CO>[N:2]([C:3]([CH3:8])([CH3:9])[C:4]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:6])=[N:1][C:10]([CH3:16])([CH3:15])[C:11]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:13]
Reactant: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Reactant: C=CCN
Solvent: CO
Product: C=CCNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCC=C

Procedure:
Dimethyl 2,2'-azobis(2-methylpropionate) in an amount of 41.9 g, 48 ml of methanol, and 43 g of a 28% CH3ONa methanol solution were mixed and stirred for dissolution, followed by dropwise addition of 25 g of allylamine to react at 19° to 21° C. for 20 hours.