Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](OS(C(F)(F)F)(=O)=O)=[C:8]([CH:18]=1)[O:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=[O:3])[CH3:2].[C:27]1([C:33]#[CH:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(N(CC)CC)C.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.[Cu]I>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:34]#[C:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:8]([CH:18]=1)[O:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(OCC(=O)OC(C)(C)C)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C#Cc2ccccc2)c(OCC(=O)OC(C)(C)C)c1

Procedure:
A solution of t-butyl { 5-acetyl-2[(trifluoromethyl)sulfonyloxy]-phenoxy}acetate(1.0 g, 1.3 mmol) and phenylacetylene (0.33 mL, 3.0 mmol) in 20 mL triethylamine in a thick walled pyrex tube is degassed with nitrogen for 15 minutes. Bis(triphenylphosphine)-palladium(II) chloride (35 mg, 0.05 mmol) and copper (I) iodide (10 mg, 0.05 mmol) are added, and the vessel is sealed, and heated to 60° for 18 hours. After cooling, the triethylamine is removed in vacuo, and the residue is dissolved in ether (100 mL) and washed with 1 N HCl (1×100 mL) and brine (1×50 mL), dried over MgSO4, and concentrated in vacuo. Chromatography (silica, 5:1 hexane/EtOAc) yields t-butyl [5-acetyl-2-(2-phenylethynyl)-phenoxy]-acetate, along with 10% starting material. This mixture is carried on to the next step.
Reaction SMILES: C([O:3][CH:4]([O:8][CH2:9][CH3:10])N(C)C)C.[CH3:11][C:12]1[N:16]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2C(O)=O)[N:15]=[N:14][N:13]=1>ClCCl>[CH3:11][C:12]1[N:16]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[C:4]([O:8][CH2:9][CH3:10])=[O:3])[N:15]=[N:14][N:13]=1
Reactant: CCOC(OCC)N(C)C
Reactant: Cc1nnnn1-c1cnccc1C(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccncc1-n1nnnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylformamide diethyl acetal (46 mL) was added to a suspension of 3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylic acid (36 g) in dichloromethane (800 mL). The reaction mixture was stirred at ambient temperature overnight then washed six times with water (500 mL), dried over magnesium sulfated, and concentrated under vacuum. The residue was recrystallized from ethyl acetate/hexanes to provide 40 g of ethyl 3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylate as a solid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14]C(=O)C)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OCCCCS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=S(=O)(CCCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of acetic acid 4-benzenesulfonylbutylester (6.5 g, 25.3 mmol) in MeOH (30 mL) at RT is added NaOH (1.5 g, 37.5 mmol) in water (5 mL). The mixture is stirred at RT for 1 h then the solvent is removed under reduced pressure. To the residue is added 1N HCl (40 mL) then the mixture is extracted with EtOAc. The organic phase is dried over MgSO4 and the solvent is removed under reduced pressure to afford the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][CH:6]=1.[Cl:31]Cl>C(O)(=O)C.[Zn]>[NH2:28][C:26]1[CH:25]=[CH:24][C:3]([O:4][C:5]2[CH:14]=[C:13]3[C:8]([CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]3)=[CH:7][C:6]=2[Cl:31])=[C:2]([F:1])[CH:27]=1
Reactant: ClCl
Reactant: CCOC(=O)C1=Cc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2OC1C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(N)cc3F)cc2OC1C(F)(F)F
Reaction time: 2 h

Procedure:
A solution of the ester from Step 1 (0.5 g, 1.17 mmole) in acetic acid was stirred at 10° C. The pre-prepared solution of Cl2 (gas) in acetic acid (10 mL, 4.0 mmole was added to the above solution. The mixture was stirred for 2 hour. After Cl2 (gas) was blown away, Zn powder (5 eq) was added to the mixture and stirred for 30 min. The Zn salts were removed by filtration and the filtrate was evaporated to dryness. The residue was purified by normal phase silica chromatography with 20% ethyl acetate in hexane to give the ester as a yellow oil, which solidified upon standing (0.43 g, 85%): LCMS m/z 431.75 (M+H). 1NMR (CDCl3/400 MHz) 7.61 (s, 1H), 7.27 (s, 1H), 6.95 (dd, 1H, J=8.4 Hz), 6.50 (dd, 1H, J=12, 2.4 Hz ), 6.42 (m, 1H), 5.61 (q, 1H, J=6.8 Hz), 4.30 (q, 2H, J=7.2 Hz), 1.33 (t, 3H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Br[CH2:28][CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:32][C:31]([F:34])([F:33])[CH2:30][CH2:29][CH2:28][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:1])([F:25])[F:26])=[N:4][N:5]=4)[N:8]=3)[CH2:13][CH2:14]2)=[CH:19][CH:20]=1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)CCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 200 °C
Yield: 36.5 %

Procedure:
4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenol (obtained as described in Example 5.2, preparation of starting materials) (200 mg, 0.55 mmol), 4-bromo-1,1,1-trifluorobutane (526 mg, 2.75 mmol) and potassium carbonate (152 mg, 1.10 mmol) were suspended in DMA (4 mL) and sealed into a microwave tube. The reaction was heated to 200° C. for 30 minutes in the microwave reactor and cooled to room temperature. The mixture was evaporated to dryness and redissolved in DCM (20 mL) and the solution was washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-{4-[4-(4,4,4-trifluorobutoxy)phenyl]piperidin-1-yl}-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (95 mg, 37%) as a solid.
Reaction SMILES: COCO[C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15](=[O:17])C>C(O)C>[CH3:14][O:13][CH2:12][O:11][C:9]1[CH:10]=[CH:5][C:6]([CH:15]=[O:17])=[CH:7][CH:8]=1
Reactant: COCOc1ccc(C(C)=O)c(OCOC)c1
Solvent: CCO
Product: COCOc1ccc(C=O)cc1
Yield: 91.7 %

Procedure:
In 50 ml of ethanol were dissolved 6.31 g of the 2',4'-bis(methoxymethoxy)acetophenone obtained in Production Example 10 and 4.00 g of the p-methoxymethoxybenzaldehyde obtained in Production Example 25, and the solution was cooled to 0° C. and 30 ml of a saturated solution of potassium hydroxide in ethanol was added to the solution. The temperature of the reaction liquid was elevated to room temperature and the liquid was stirred for 2 days. The reaction liquid was diluted with water, neutralized with 6 N hydrochloric acid and extracted with ethyl acetate, and the organic layer was dried with sodium sulfate and concentrated under reduced pressure to obtain a reaction mixture in the form of a syrup. The syrup was subjected to the column chromatography (320 g of 270-400 mesh Kieselgel 60; 0.5 kg/cm2 ; eluting solvent: hexane/ethyl acetate=1/1). Fractions of 50 ml were collected and the 66th to 87th fractions were combined to obtain 5.64 g (yield= 55.9%) of 2',4,4'-tris(methoxymethoxy)chalcone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:21]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[O:22])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:9]([C:21]([NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[O:22])[N:10]=2)=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(Cl)cc3)[nH]2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(Cl)cc3)[nH]2)cc1

Procedure:
5-(4-Chlorophenyl)-2-(4-cyanophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide obtained in Example 193 is reduced with LiAlH4 to give 2-(4-aminomethylphenyl)-5-(4-chlorophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[C:27]([CH:32]([CH3:34])[CH3:33])[CH:26]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:31][C:28]1[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][C:27]=1[CH:32]([CH3:34])[CH3:33]
Reactant: Cc1ccc(S)c(C(C)C)c1
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccc(SC2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)c(C(C)C)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.1 mmol of 4-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 75°-76° C.). 1H NMR (DMSO-d6) δ1.15 (m, 6H), 2.16 (s, 3H), 2.19-2.36 (m, 3H), 2.62 (m, 1H), 3.21 (m, 1H), 3.44 (q, 2H), 5.82 (d, 1H), 6.40 (dd, 1H), 6.95 (d, 1H), 7.10-7.18 (m, 3H), 7.25 (m, 2H), 7.44 (m, 5H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[F:33][C:34]([F:40])([F:39])[S:35](Cl)(=[O:37])=[O:36]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:35]([C:34]([F:40])([F:39])[F:33])(=[O:37])=[O:36])[CH2:31][CH2:32]2)[N:10]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)C(F)(F)F)CC2)nc1N

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and trifluoromethanesulfonyl chloride (Aldrich), to give [4-amino-2-(1-trifluoromethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone. MS (M+H)+, 478.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[OH-:11].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([OH:11])[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1
Reactant: [OH-]
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1nc(Cl)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of 2,4,5,6-tetrachloropyrimidine (5 g, 22.9 mmol) in THF (50 mL) was added 1N NaOH (31 mL, 31.2 mmol) dropwise, and the mixture was stirred overnight at RT. The solution was acidified with 1N HCl and extracted with DCM (3×). The organics were combined, dried, and concentrated in vacuo. The solids were slurried in Et2O for 30 min at RT, filtered, washed with Et2O, and dried to give 3.0 g (66%) of the title compound. [M+H] Calc'd for C4HCl3N2O, 201. Found, 201.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2cccs2)c2ccccc12
Temperature: 100 °C
Yield: 73 %

Procedure:
A mixture of 28.6 g (100 mmol) of 1,4-dibromonaphthalene, 15.35 g (120 mmol) of thiophen-2-ylboronic acid, 2.31 g (2 mmol) of tetrakis(triphenyl phosphine)palladium, 75 ml of 2M Na2CO3, 150 ml of EtOH and 300 ml toluene was degassed and placed under nitrogen, and then heated at 100° C. for 4 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica(hexane-dichloromethane) to give product (21.1 g, 73 mmol, 73%) as a white solid.
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]2[CH2:14][C@H:13]([CH2:15][OH:16])[CH:12]=[CH:11]2)[C:6]([N:17]=NC2C=CC(Cl)=CC=2)=[C:5]([Cl:26])[N:4]=1.[C:27](O)(=O)C.O>O1CCCC1.[Zn]>[NH2:2][C:3]1[N:8]=[C:7]2[C:6]([N:17]=[CH:27][N:9]2[C@@H:10]2[CH2:14][C@H:13]([CH2:15][OH:16])[CH:12]=[CH:11]2)=[C:5]([Cl:26])[N:4]=1
Reactant: Nc1nc(Cl)c(N=Nc2ccc(Cl)cc2)c(N[C@H]2C=C[C@@H](CO)C2)n1
Reactant: CC(=O)O
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A suspension of (1 S,4R)-4-((2-Amino-6-chloro-5-((4chlorophenyl)azo)-4-pyrimidinyl)amino)-2-cyclopentene-1-methanol hydrate (1.96 g, 5 mmol) in tetrahydrofuran (15 mL) was treated with acetic acid/water (1:1, 5 mL), then with zinc dust (1.63g, 25 mmol) in portions so as to keep the pot temperature below 35° C. The deep yellow color faded after 10 min, and after an additional 50 min the solution was filtered to remove precipitated zinc salts. The filter cake was rinsed with tetrahydrofuran and the filtrate was refiltered to remove additional zinc salts, then concentrated in vacuo with addition of toluene to facilitate removal of water and acetic acid. The residue was rinsed with toluene/hexane to separate some of the 4-chloroaniline byproduct, taken up in triethyl orthoformate (40 mL), cooled on an ice bath (5° C.), and treated dropwise with concentrated hydrochloric acid (1.9 mL). The mixture was stirred at 5° C. for 5 h (tan suspension soon formed), slowly warmed to room temperature, and stirred for an additional 18 h, then cooled on an ice bath and filtered. The filter cake was rinsed with ether (save filtrate), and this solid was taken up in water (30 mL), filtered, and the solids washed with water. The aqueous filtrate was basified with sodium carbonate to pH-9, then extracted with 5% isopropanol-hloroform (3×25 mL) The combined extracts were dried (Na2SO4) and concentrated in vacuo to a residual tan foam (0.85 g). The organic filtrate from above was concentrated in vacuo and the residue taken up in 1N hydrochloric acid (30 mL), stirred for 1h, filtered, and the filtrate adjusted to pH-6 with 5 N sodium hydroxide (6 mL, then basified with sodium carbonate. This aqueous suspension was extracted with 5% isopropanol-chloroform (3×25 mL), and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to a tan foam (0.55 g ). The two batches were combined, dissolved in warm chloroform, and loaded onto a silica gel column, which was eluted with 7% methanol-chloroform to afford pure fractions containing the subject compounds. These were concentrated in vacuo and the residual foam crystallized from ethyl acetate(2 crops) to afford 0.86 g (65%) of the title compound as a pale tan solid; mp 160°-162° C. 1H-NMR (DMSO-d6)δ: 8.04(s,1H); 6.91(s,2H); 6.15(m,1H); 5.90 (m,1H); 5.45 (m,1H); 4.73 (t, 1H,J =5 Hz); 3.45 (t,2H,J=5 Hz); 2.80-2.95(m, 1H); 2.55-2.70(m,1H); 1.60-1.70(m,1H). Ms(Cl): m/z 170 (m-C5ring, 100); 230 (m-Cl, 50); 266 (m+H+, 100). [α]20589 -104°, [α]20436 -267°(c=0.29, methanol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5]1.C(Cl)Cl.[OH2:18].CC#N>O>[C:10]([O:9][C:8]([NH:7][C:4]1([CH2:3][C:2]([OH:18])=[O:1])[CH2:5][CH2:6]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1(CCO)CC1
Reactant: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
RuCl3.H2O (124 mg, 0.6 mmol) was added to a solution of tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate (6.1 g, 30 mmol), and NaIO4 (19.0 g, 90 mmol) in DCM/H2O/CH3CN (20 mL/40 mL/20 mL). The mixture was stirred at rt for 3 hrs. The mixture was then diluted with H2O (100 mL), and extracted with DCM (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (0˜30% gradient elution EtOAc/petroleum ether) to afford 2-(1-(tert-butoxycarbonylamino)cyclopropyl)acetic acid (6.0 g, 90%) as a white solid. ESI-MS (EI+, m/z): 238 [M+Na]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[NH2:6].[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(Cl)Cl>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[C:3]([CH:4]=1)[CH2:2][NH:1][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCS(=O)(=O)c1ccc(N)cc1CN
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(N)cc1CNC(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of 3-(aminomethyl)-4-(ethylsulfonyl)aniline (1.1 g, 5.1 mmol) in DMF (5 mL) and TEA (2.75 mL) was added benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.4 g, 5.7 mmol) in DCM (15 mL). The solution was stirred for 18 h before quenching with water (25 mL). The reaction mixture was extracted with DCM (2×30 mL), washed with brine and dried (MgSO4). The organic layer was concentrated in vacuo and the residue purified by flash chromatography (0-100% EtOAc/Hexane) to afford 28A (1.0 g, 59%) as an oil. MS (ESI) m/z 349.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([C:22]4[S:26][C:25]5[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:24]=5[CH:23]=4)(=[O:21])=[O:20])[CH2:15][C:14]3=[O:32])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N-:33]=[N+:34]=[N-:35].[Na+].O>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:33]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([C:22]4[S:26][C:25]5[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:24]=5[CH:23]=4)(=[O:21])=[O:20])[CH2:15][C:14]3=[O:32])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1ccc2c(Cl)ccnc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccnc2cc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)ccc12
Temperature: 65 °C
Yield: 101 %

Procedure:
1-(4-Chloroquinolin-7-ylmethyl)-4-(6-chlorobenzo[b]thiophen-2-sulfonyl)-piperazin-2-one (0.52 g, 1.03 mmol) is dissolved in DMF (15 mL), treated with sodium azide (0.52 g, 8.0 mmol), tetrabutyl ammonium chloride (0.1 g, 0.36 mmol) and heated to 65° C. overnight. The reaction mixture is cooled, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried (sodium sulfate) and concentrated to give the title compound (0.5 g, 1.04 mmol). 1H NMR (CD3OD, 300 MHz) δ9.0 (d, 1H), 8.2 (d, 1H), 8.0 (s, 1H), 7.9 (d, 2H), 7.8 (d, 1H), 7.6 (d, 1H), 7.5 (d, 1H), 6.9 (s, 1H), 4.85 (s, 2H), 4.0 (s, 2H), 3.5-3.7 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)=[C:4]([OH:32])[CH:3]=1.Cl[CH2:34][CH2:35][OH:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)=[C:4]([O:32][CH2:34][CH2:35][OH:36])[CH:3]=1
Reactant: OCCCl
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1OCCO

Procedure:
The title compound was prepared in analogy to example 49, from N-[4-(4-fluoro-2-hydroxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 48) and 2-chloroethanol (CAS RN 107-07-3). Off-white solid (62%). MS (ESI): m/z=502.9 [M+H]+.
Reaction SMILES: F[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:13])[CH:3]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:6]([C:5]1[C:4]([CH3:13])=[CH:3][C:2]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=1)#[N:7]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1C#N
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1C#N
Temperature: 80 °C
Yield: 110 %

Procedure:
A solution of 4-fluoro-2-methyl-5-nitrobenzonitrile (D90) (3 mmol, 540.3 mg) in dimethylformamide (20 mL) was treated with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (3 mmol, 600.9 mg, 1 eq) and diisopropylethylamine (3 mmol, 387.6 mg, 1 eq) under argon at room temperature and then heated at 80° C. overnight. The mixture was then concentrated under reduced pressure then treated with 10% aqueous sodium carbonate solution and extracted with ether/ethyl acetate. The organics were dried and concentrated under reduced pressure to give the title compound as a solid (3.3 mmol, 1.19 mg, >100% yield). M+H 304.97 for main fragment (loss of tert-butyl group).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1.O>CC(N(C)C)=O>[NH2:19][C:20]1[N:25]=[C:24]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Nc1nccc(Cl)n1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nccc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Temperature: 25 °C

Procedure:
252 mg (1.15 mmol) 2,2,2-trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 2 mL dry dimethylacetamide under argon atmosphere, and 56 mg (2.31 mmol) NaH is added. 100 mg (0.77 mmol) 2-amino-4-chloro-pyrimidine (2) is added and the solution stirred at room temperature over night. 1 mL water is added carefully to quench all excess NaH and the mixture poured into 50 ml of 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (ethyl acetate:cyclohexane 1:1). Yield: 160 mg (63%). ESI-MS m/z 327.4 [M+H]+.