Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@@H:11]([NH2:13])[CH3:12].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>C(O)(=O)C>[CH3:19][O:18][C:14](=[O:17])[CH2:15][CH2:16][N:13]([CH2:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[C@H:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:12]
Reactant: C=CC(=O)OC
Reactant: C[C@H](N)c1ccc2ccccc2c1
Solvent: CC(=O)O
Product: COC(=O)CCN(CCC(=O)OC)[C@@H](C)c1ccc2ccccc2c1
Reaction time: 18 h
Yield: 80.6 %

Procedure:
(S)-(−)-1-(2-Naphthyl)ethylamine (2.28 g, 13 mmol) was added dropwise to a solution of methyl acrylate (5 mL, 55 mmol) and acetic acid (0.26 mL) with stirring in a sealed tube. A white crystalline solid precipitated out of solution. The temperature was then elevated to 80° C., at which time a clear solution was formed again. Stirring was continued for 18 hours. Excess methyl acrylate and acetic acid were removed under reduced pressure. The crude oil was purified by chromatography on silica gel with ethyl acetate/hexanes (1:4) to give the title compound (3.6 g, 77%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.45 (3H, d, J=6.78 Hz), 2.45 (4H, t, J=7.35 Hz), 2.73-2.94 (4H, m), 3.62 (6H, s), 4.00 (1H, q, J=6.78 Hz), 7.41-7.53 (3H, m), 7.70-7.84 (4H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:22][CH2:21][N:20]2[C:11](=[N:12][C:13]3[C:18]([C:19]2=[O:23])=[CH:17][CH:16]=[C:15]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:14]=3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:36]I>CN(C=O)C>[F:32][C:28]1[CH:27]=[C:26]([C:25]#[C:24][C:15]2[CH:14]=[C:13]3[C:18]([C:19](=[O:23])[N:20]4[CH2:21][CH2:22][CH:8]([N:7]([CH3:36])[C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][CH2:10][C:11]4=[N:12]3)=[CH:17][CH:16]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of tert-butyl-3-((3-fluorophenyl)ethynyl)-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-8-ylcarbamate (0.3 g, 0.67 mmol, 1 equiv) and NaH (64.3 mg, 2.68 mmol, 4 equiv) in DMF (15 mL) was added CH3I dropwise. After stirring at rt for 2 hours, the reaction mixture was quenched with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was purified by silica gel chromatography. MS (ESI): 462 (MH+).
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][N:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH:6]1[O:8][CH2:7]1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O1CCOCC1.[H-].[Na+]>O>[C:18]1([CH2:17][O:24][CH2:7][CH:6]2[CH2:5][N:4]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:3][CH:2]([CH2:16][OH:1])[O:8]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: c1ccc(CN(CC2CO2)CC2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCC1CN(Cc2ccccc2)CC(COCc2ccccc2)O1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
5.48 G (0.025 mole) of N,N-bis(2,3-epoxypropyl)benzylamine is added to a mixture of 2.70 g (0.025 mole) of benzyl alcohol in 75 ml of dioxane containing 1 equivalent of sodium hydride. The reaction is allowed to cool below 40° with an ice-bath for approximately 1/2 hour and is then heated at reflux overnight. After cooling to room temperature, the entire mixture is poured slowly, with stirring, into 150 ml of water. The aqueous mixture is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined, washed with 200 ml of water and 200 ml of saturated NaCl solution. The CHCl3 layer is then dried over anhydrous NaSO4, evaporated in vacuo to yield 6.1 g (74%) of crude product as a pale yellow oil. The oil is chromatographed on 300 g of neutral Alumina III to give 5.6 g (68%) of 6-[(phenylmethoxy)methyl]-4-(phenylmethyl)-2-morpholinemethanol.
Reaction SMILES: [NH2:1][C@H:2]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][C:14]3=[CH:16][N:17]=[C:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[N:13]3[C:12]2=[O:28])[CH2:7][CH2:6]1)=[O:4].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>C(#N)C>[Si:21]([O:20][CH2:19][C:18]1[N:13]2[C:12](=[O:28])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3]([C@H:2]([NH:1][C:41]([NH:40][C:37]4[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=4)=[O:42])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:4])[CH2:6][CH2:7]3)[CH2:15][C:14]2=[CH:16][N:17]=1)([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:22])[CH3:23]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)[C@@H](N)C(=O)N1CCC(N2Cc3cnc(CO[Si](C)(C)C(C)(C)C)n3C2=O)CC1
Solvent: CC#N
Product: CC(C)(C)[C@@H](NC(=O)Nc1ccc(Cl)cc1)C(=O)N1CCC(N2Cc3cnc(CO[Si](C)(C)C(C)(C)C)n3C2=O)CC1
Yield: 86.5 %

Procedure:
To a solution of 2-(1-((2R)-2-amino-3,3-dimethylbutanoyl)-4-piperidinyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one (0.33 g) obtained in Example 83k) in acetonitrile was added 4-chlorophenyl isocyanate (0.11 g), and then mixed at room temperature for 1 hour. Acetonitrile was distilled off under reduced pressure, and then the residue was purified with silica gel column (ethyl acetate) to obtain the title compound as a colorless solid (0.38 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1.I[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:29]([CH3:31])[CH3:30])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1
Reactant: CC1CC(c2c(O)cccc2F)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 5-(2-fluoro-6-hydroxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (50 mg; 0.13 mmol), 2-iodopropane (66 mg; 0.39 mmol), potassium carbonate (36 mg; 0.26 mmol), and cesium carbonate (8.5 mg; 0.026 mmol) in anh. DMF (0.7 ml) was stirred at rt, under nitrogen, for 17 h. Subsequent filtration and purification by preparative HPLC afforded the target compound 5-(2-fluoro-6-isopropoxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one. LC-MS (conditions A): tR=1.00 min.; [M+H]+: 426.01 g/mol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=O)[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:25][C:26]1[N:27]=[C:28]([CH3:31])[S:29][CH:30]=1>>[CH3:22][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:25][C:26]3[N:27]=[C:28]([CH3:31])[S:29][CH:30]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH3:21]
Reactant: Cc1nc(CCl)cs1
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CC(=O)N1CCC[C@H]1C
Agent: Cl
Product: Cc1nc(COc2ccc(-c3nc(CCN4CCC[C@H]4C)c(C)o3)cc2)cs1

Procedure:
The title compound is prepared in a manner substantially similar to Example 58 from 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-1-(2-(R)-methyl-pyrrolidin-1-yl)-ethanone (See Example 56) and 4-(chloromethyl)-2-methylthiazole hydrochloride. MS (m/e): 398.3 (M+1)
Reaction SMILES: [Na].F[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.O.[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16]>>[F:13][C:14]([F:18])([F:17])[CH2:15][O:16][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCC(F)(F)F
Agent: [Na]
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
Under a nitrogen atmosphere, 10.1 g (0.44 mol) of sodium was dissolved in 200 ml of 2,2,2-trifluoro ethanol in 300 ml of a three-necked flask, to which 40 ml (0.38 mol) of p-fluoronitro benzene was dropped and refluxed for 4 hours. After cooling to a room temperature, water was poured (about 1 liter), and precipitated solids were washed with water and dried, to obtain p-(2,2,2-trifluoroethoxy) nitrobenzene (yield: 62%; and melting point: 76.5° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH:26]2[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]2)=[CH:20][C:19]=1[NH:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:17].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:28]1[CH2:27][CH:26]([CH2:25][NH:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]([NH:15][C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][C:4]5[CH:44]=[C:45]([F:47])[CH:46]=[C:2]([F:1])[CH:3]=5)[CH:7]=4)[NH:11][N:10]=3)=[O:17])=[C:19]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:20]=2)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC(CNc2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc(NCC2CNC2)cc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
tert-butyl 3-({[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]amino}methyl)azetidine-1-carboxylate (738 mg, 1.1 mmol) was dissolved in DCM (12 mL) and TFA (3 mL) was added. The resulting reaction solution was stirred for 3 hours at room temperature. The mixture was diluted with DCM and extracted with 10% acqueous NH3. Acqueous phase was extracted several time with DCM. Collected organic phases were washed with brine, dried over sodium sulfate and evaporated to dryness. Column chromatography purification on silica gel using dichloromethane/methanol/NH3 5N in MeOH 70:30:1 as the eluant, afforded 150 mg of the title compound.
Reaction SMILES: [OH-:1].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1>CS(C)=O.O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([OH:1])=[CH:5][C:6]=1[O:13][CH3:14])([O-:12])=[O:11]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(O)ccc1[N+](=O)[O-]
Reaction time: 2.5 h

Procedure:
A solution of sodium hydroxide was added to a stirred solution of 4-fluoro-2-methoxynitrobenzene (11.1 g.) in DMSO (60 ml.) at ambient temperature and the mixture was heated at 85 degC. for 2.5 hr. The cooled solution was diluted with water (100 ml.) and extracted with ether (3×100 ml.) The combined ethereal solution was extracted with 2n NaOH (3×75 ml.) and the combined aqueous phase brought to pH 2 by the addition of 2N HCl. The precipitated product was collected and washed with water. The product was dried over phosphorous pentoxide. Yield 7.4 g. m/Z 170.1(M+H). It was used without further purification in the next step (cf Example 1c).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[N:5]1([CH2:11][CH2:12][C:13]([NH:15][NH2:16])=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1>CCO>[CH3:1][N:2]1[C:13]([CH2:12][CH2:11][N:5]2[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[N:15][N:16]=[C:3]1[SH:4]
Reactant: CN=C=S
Reactant: NNC(=O)CCN1CCOCC1
Solvent: CCO
Product: Cn1c(S)nnc1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Prepared according to a procedure reported for related compounds: Henichart, J. P. et al. J. Het Chem. 1977, 14, 615. Methyl isothiocyanate (9.08 g, 0.124 mol) in EtOH (50 mL) was added at room temperature to a stirred solution of 3-morpholin-4-ylpropanohydrazide (21.5 g, 0.124 mol) in EtOH (200 mL). The mixture was refluxed for 8 h, then removed from heat and stirred at room temperature for 16 h. The EtOh was removed under reduced pressure to give the crude material as a yellow oil. The oil was purified by column chromatography through silica gel, eluting with CH2Cl2/MeOH to afford the title compound. (6 g, 21.2%).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[CH3:7][CH:8]([CH3:24])[C:9]([O:11][CH2:12][O:13][C:14](ON1C(=O)CCC1=O)=[O:15])=[O:10]>>[CH3:2][N:1]([C:14]([O:13][CH2:12][O:11][C:9](=[O:10])[CH:8]([CH3:24])[CH3:7])=[O:15])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)C(=O)OCOC(=O)ON1C(=O)CCC1=O
Reactant: CNCC(=O)O
Product: CC(C)C(=O)OCOC(=O)N(C)CC(=O)O

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, sarcosine (0.123 g, 1.3 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)methyl 2-methylpropanoate (0.300 g, 1.1 mmol) were reacted to provide 0.138 g (5.1.3% yield) of the title compound (46) as a colorless semi-solid material after work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=5.78 (d, 2H), 4.12 (d, 3H), 3.02 (d, 3H), 2.62 (m, 1H), 1.2 (t, 6H). MS (ESI) m/z 256.05 (M+Na)+.
Reaction SMILES: [CH2:1](I)[CH3:2].[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:19]([NH2:21])=[O:20])[O:16][S:15](=[O:17])[NH:14][C:13]2=[O:18])[CH:8]=[CH:9][C:10]=1[Cl:11].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:14]1[C:13](=[O:18])[C:12]([C:7]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([Cl:4])[CH:6]=2)([C:19]([NH2:21])=[O:20])[O:16][S:15]1=[O:17])[CH3:2]
Reactant: NC(=O)C1(c2ccc(Cl)c(Cl)c2)OS(=O)NC1=O
Reactant: CCI
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(C(N)=O)(c2ccc(Cl)c(Cl)c2)OS1=O
Yield: 69.7 %

Procedure:
31.2 g (0.2 mole) of ethyl iodide are added to a solution of 6.2 g (0.02 mole) of 5-(3,4-dichlorophenyl)-5-aminocarbonyl-1,2,3-oxathiazolidin-4-one-2-oxide and 2.02 g (0.02 mole) of triethylamine in 50 ml of acetonitrile. The solution is heated to the boil for four hours and then evaporated down under reduced pressure. The residue is taken up in 50 ml of dichloromethane, and the solution is washed with three times 20 ml of water. The organic phase is evaporated down and the residue is triturated with diethyl ether. In this manner, 4.7 g (70% of theory) of 3-ethyl-5-(3,4-dichlorophenyl)-5-aminocarbonyl-1,2,3-oxathiazolidin-4-one-2-oxide of melting point 127°-128° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=[N:12][OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][F:23].Cl>CS(C)=O.O>[F:23][CH2:22][O:13][N:12]=[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])[C:3]([O:2][CH3:1])=[O:14]
Reactant: COC(=O)C(=NO)c1ccccc1C
Reactant: FCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(=NOCF)c1ccccc1C
Reaction time: 20 h

Procedure:
A mixture of 57 g of 2-tolylglyoxylic acid methyl ester oxime and 80 g of powdered potassium carbonate is mixed into 550 ml of dimethyl sulfoxide for 30 minutes at room temperature and then a solution of 40 g of bromofluoromethane in 30 ml of dimethyl sulfoxide is added dropwise at room temperature. The reaction mixture is stirred for a further 20 hours and then poured into 1200 ml of water, neutralised with 230 ml of hydrochloric acid and extracted four times with 250 ml of ethyl acetate each time. The combined organic phases are washed with 200 ml of saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in vacuo. Purification by flash chromatography (silica gel, ethyl acetate/hexane 1:9) yields 2-tolylglyoxylic acid methyl ester O-fluoromethyloxime in the form of a viscous oil.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.[Br:29]C1C2N=C(Cl)SC=2C=CC=1>>[Br:29][C:27]1[C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=[CH:2][CH:28]=1
Reactant: Clc1nc2c(Br)cccc2s1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(Br)cccc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 4-bromo-2-chloro-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=8.81 (s, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 8.08 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 4.68 (m, 1H), 3.59-3.63 (m, 2H), 2.38-2.41 (m, 4H). MS(ES+): m/z=455.01/456.92 [MH+]. HPLC: tR=1.59 min (polar—5 min, ZQ3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[C:16]([CH3:22])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:23].[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][C:16]([CH3:22])=[C:17]([CH3:21])[CH:18]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(N2CCNCC2)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,3,5,6-tetrachloropyridine (10 g), 1-Boc-piperazine (8.6 g) and potassium carbonate (13 g) was added 2-butanone (140 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g). To a mixture of 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g), palladium (II) acetate (516 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.9 g), potassium fluoride (24 g) and methylboronic acid (12 g) was added tetrahydrofuran (140 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g). 4-(3,5,6-Trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g) was dissolved in chloroform (28 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the mixture was filtered to give the title compound (11 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:29])[CH2:13][N:14]1[S:19](=[O:21])(=[O:20])[N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16][CH2:15]1)[CH2:8]2.[ClH:30]>C(Cl)Cl.O1CCOCC1>[ClH:30].[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:29])[CH2:13][N:14]1[CH2:15][CH2:16][CH2:17][NH:18][S:19]1(=[O:21])=[O:20])[CH2:8]2
Reactant: CC(C)(C)OC(=O)N1CCCN(CC(=O)NC2C3CC4CC(C3)CC2C4)S1(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(CN1CCCNS1(=O)=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 6-(2-(adamantan-2-yl amino)-2-oxoethyl)-1,2,6-thiadiazinan-2-carboxylate 1,1-dioxide (150 mg, 0.351 mmol) in CH2Cl2 (5 mL), was added an excessive amount of 4 M HCl in 1.4-dioxane. The reaction mixture was agitated for 4 hr at room temperature and evaporated to give N-(adamantan-2-yl)-2-(1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamide hydrochloride (120 mg, 92%, white solid). 1H NMR (300 MHz, DMSO-d6): δ 7.06-7.57 (brd, 1H), 7.00 (t, J=6.9 Hz, 1H), 3.85-3.82 (m, 1H), 3.59 (s, 2H), 3.33-3.23 (m, 4H), 1.90-1.48 (m, 16H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[F:25])=[O:5])[CH3:2].C1C=C[C:37]([N:40](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.CN>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:40][CH3:37])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[F:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2c(F)cc(Cl)cc2c1Cc1ccccc1Cl
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN
Product: CCOC(=O)c1c(NC)nc2c(F)cc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 61 step D from a crude mixture of 6-chloro-4-(2-chloro-benzyl)-8-fluoro-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester and N-phenylbis(trifluoromethanesulfonimide) and methylamine. Off white solid. MS (ESI): 407 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:21][C:22]1[C:23]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:29][C:28](=O)[C:24]=2[CH:25]=[N:26][CH:27]=1.Cl>C1COCC1>[Br:21][C:22]1[C:23]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:29][C:28](=[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])[C:24]=2[CH:25]=[N:26][CH:27]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1OC(c2ccccc2)c2c(Br)cncc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=C1OC(c2ccccc2)c2c(Br)cncc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.6 %

Procedure:
A solution of 1,3-dihydro-indol-2-one (225 mg, 1.55 mmol) in THF (6 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (3.5 mL of a 1 M solution in THF, 3.5 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 7-bromo-1-phenyl-1H-furo[3,4-c]pyridin-3-one (305 mg, 1.0 mmol, AcOH salt) is added as a solid to the reaction mixture. The resulting solution is stirred for 3.5 h. The reaction mixture is poured into aqueous 10% HCl solution (50 mL) and stirred at room temperature for 48 h. The precipitate which formed is collected by filtration and dried. The solid obtained is purified by chromatography (silica gel, 30% EtOAc/hexane). The product containing fractions are concentrated to give the title compound as a yellow solid (120 mg, 27%).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][OH:9].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Si:14]([O:9][CH2:8][C:7]1[NH:6][CH:5]=[N:4][C:3]=1[CH3:2])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: Cc1nc[nH]c1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1CO[Si](C)(C)C(C)(C)C
Reaction time: 72 h
Yield: 27.3 %

Procedure:
13.0 g(87.5 mmol) of 4-methyl-5-imidazolemethanol hydrochloride, 13.5 g(89.6 mmol) of t-butylchlorodimethylsilane and 14.5 g(105 mmol) of potassium carbonate were added to 200 ml of dimethylformamide and the resulting mixture was stirred for 3 days. After dimethylformamide was removed under reduced pressure, 500 ml of ethylacetate was added to the residue which was then washed with aqueous sodium chloride solution (200 ml×3). The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 5.4 g(23.9 mmol, Yield 27%) of the title compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[NH2:12][C:13]1[CH:18]=[C:17]([Br:19])[N:16]=[C:15]([CH3:20])[N:14]=1>>[Br:19][C:17]1[N:16]=[C:15]([CH3:20])[N:14]=[C:13]([NH:12][C:2]2[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)[CH:18]=1
Reactant: Cc1nc(N)cc(Br)n1
Reactant: CCOC(=O)c1cnc(Cl)s1
Product: CCOC(=O)c1cnc(Nc2cc(Br)nc(C)n2)s1
Yield: 75.5 %

Procedure:
Prepared from ethyl 2-chlorothiazole-5-formate and Compound 9: ethyl 2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formate was yielded (yield: 75.5%).