Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1C(O)=O.Cl.[F:13][C:14]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[CH:17][C:15]=1[NH2:16].[H-].[Na+].Cl.C[N:39]1CCC[C:40]1=[O:44]>>[Cl:11][C:9]1[N:10]=[C:2]2[N:16]([C:15]3[CH:17]=[C:18]([O:23][CH2:24][C:25]4[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=4[F:34])[C:19]([O:21][CH3:22])=[CH:20][C:14]=3[F:13])[C:40](=[O:44])[NH:39][C:3]2=[CH:7][CH:8]=1
Reactant: CN1CCCC1=O
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: COc1cc(F)c(N)cc1OCc1c(OC)ccc(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1cc(F)c(-n2c(=O)[nH]c3ccc(Cl)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,6-dichloronicotinic acid (0.58 g) and 2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline hydrochloride (0.7 g) in 1-methyl-2-pyrrolidone (4 mL) was added sodium hydride (55%, 0.35 g), and the mixture was stirred at 120° C. overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=2/1), and collected by filtration. The collected solids were washed with the same solvent, and dried under reduced pressure. To the obtained solids were added 1,4-dioxane (5 mL), triethylamine (0.31 mL) and diphenylphosphoryl azide (0.24 mL), and the mixture was stirred at room temperature for 1 hour, and then heated at reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/3) to give the title compound (0.16 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:31][CH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: OCC1CCNCC1
Solvent: CO
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(CO)CC3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and piperidin-4-ylmethanol (35 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 20-50% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (55 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 8H) 1.65-1.95 (m, 3H) 2.96-3.15 (m, 2H) 3.34 (d, J=6.06 Hz, 2H) 4.39-4.56 (m, 2H) 6.35 (d, J=2.02 Hz, 1H) 7.38 (s, 1H) 7.60 (d, J=8.59 Hz, 2H) 8.00 (d, J=8.59 Hz, 2H) 8.08 (d, J=2.27 Hz, 1H) 10.87 (s, 1H). ESI-MS: m/z 410.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].[Cl-].[Mg+2:21].[Cl-]>>[OH2:15].[OH2:15].[OH2:15].[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O-:19])=[O:18].[Mg+2:21].[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O-:19])=[O:18]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Product: Nc1c(CC(=O)[O-])cccc1C(=O)c1ccccc1
Product: O
Reaction time: 0.25 h

Procedure:
An aqueous solution of 6.36 g. (0.02 mole) of 2-amino-3-benzoylphenylacetic acid was treated with an aqueous solution of magnesium chloride (0.01 mole). A precipitate formed immediately. After 15 min. of stirring, the bright yellow precipitate was filtered and dried. The yield was 4.06 g. and the salt melted over the broad range of 150°-190° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:12]1[C:13]2[CH:21]=[CH:20][N:19]=[CH:18][C:14]=2[N:15]=[CH:16][N:17]=1>>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:12]3[C:13]4[CH:21]=[CH:20][N:19]=[CH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Clc1ncnc2cnccc12
Reactant: Nc1ccc2[nH]ccc2c1
Product: c1cc2c(Nc3ccc4[nH]ccc4c3)ncnc2cn1
Yield: 15 %

Procedure:
This product was prepared in 15% yield from 5-aminoindole (1.1 eq.) and 4-chloropyrido[3,4-d]pyrimidine (1 eq.). MP 265° C.; LC-MS: 262 (MH+).
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@:16]([F:18])([CH3:17])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@:16]([F:18])([CH3:17])[CH2:15][N:14]([C:28]([C:25]4([C:23]#[N:24])[CH2:27][CH2:26]4)=[O:29])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: C[C@]1(F)CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: N#CC1(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: I
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@]1(F)CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A mixture of 6-bromo-4-(((3R,4S)-4-fluoro-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (100 mg, 0.207 mmol), 1-cyanocyclopropanecarboxylic acid (27.5 mg, 0.248 mmol), Hunig's base (0.144 mL, 0.826 mmol) and BOP (110 mg, 0.248 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with ethyl acetate (80 mL) and washed with saturated NaHCO3, water, brine, dried (MgSO4) and concentrated to give crude 6-bromo-4-(((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-fluoro-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (70 mg), which was taken to the next step without purification. MS (ES+) m/z: 449.0 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[N:11]=[CH:10][N:9]=1.C(O[CH:22](OCC)[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28](F)=[N:29][CH:30]=1)C.[CH3:35][NH:36][CH3:37].O1CCCC1>>[CH3:35][N:36]([CH3:37])[CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[N:29][CH:30]=1
Reactant: CCOC(COc1ccc(F)nc1)OCC
Reactant: Oc1ccc2ncnc(Nc3cnccn3)c2c1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(Oc2ccc3ncnc(Nc4cnccn4)c3c2)nc1

Procedure:
Using 4-(pyrazin-2-ylamino)quinazolin-6-ol, 5-(2,2-diethoxyethoxy)-2-fluoropyridine and 2 M dimethylamine/tetrahydrofuran solution, and in the same manner as in Example 31 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (13 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C:16]1[S:17][CH:18]=[C:19]([C:21]([NH:23][C:24]2[C:25]([O:30][CH:31]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)=[N:26][CH:27]=[N:28][CH:29]=2)=[O:22])[N:20]=1>C(Cl)Cl>[F:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[C:10]=1[C:16]1[S:17][CH:18]=[C:19]([C:21]([NH:23][C:24]2[C:25]([O:30][CH:31]3[CH2:35][CH2:34][NH:33][CH2:32]3)=[N:26][CH:27]=[N:28][CH:29]=2)=[O:22])[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncncc2NC(=O)c2csc(-c3c(F)cccc3F)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cncnc1OC1CCNC1)c1csc(-c2c(F)cccc2F)n1
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
At room temperature, TFA (trifluoroacetic acid) (0.5 mL) was added to a solution of Compound 1A (20 mg, 0.0394 mmol) in CH2Cl2 (1 mL) and stirred for 10 min. The mixture was the concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL) and washed with NaOH (5 mL) and brine (5 mL), dried over Na2SO4 and concentrated in vacuo to obtain the title compound 1 (12 mg, 0.0298 mmol)
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:5])=[O:4].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH:20]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)CCc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Temperature: 40 °C

Procedure:
2-(1H-indol-5-yl)-ethanesulfonic acid methylamide (100 g) was dissolved in ethanol (1000 ml) and N-methyl-4-piperidone (200 ml) was added thereto at 25° C. and a solution of trifluoroacetic acid in ethanol (10 ml in 100 ml) was added over a period of 1 hour. The reaction mass was refluxed for 18-24 hours and cooled to 40° C. The reaction mass was concentrated under vacuum to obtain a residue and water (1500 ml) was added. The mixture was cooled to 10-15° C. and pH of the reaction mass was adjusted to 8 using 5% sodium bicarbonate solution and stirred. The resulting solid was filtered and dried at 50-55° C. under vacuum to obtain title compound (Yield: 93 g, HPLC Purity: 99%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]1=[O:13].[Br:17]Br>CC(O)=O>[Br:17][C:8]1[C:7](=[O:13])[N:6]([CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][C:9]=1[OH:12]
Reactant: O=c1cc(O)ccn1Cc1cccc(F)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1c(Br)c(O)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To an ice-cold solution of 1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one (0.67 g, 3.1 mmol) in AcOH (5.7 mL) was added a solution of bromine (0.52 g, 3.24 mmol) in AcOH (10.8 mL), and the reaction mixture was stirred for 5 min. The reaction mixture was warmed to room temperature and concentrated under reduced pressure to afford 3-bromo-1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one as a yellow solid (1.07 g, crude): 1H NMR (500 MHz, MeOD) δ 7.64 (d, J=8 Hz, 1H), 7.35-7.30 (m, 1H), 7.05-6.90 (m, 3H), 6.20 (d, J=8 Hz, 1H), 5.18 (s, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH2:23][CH3:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2].Cl>C(OCC)(=O)C.CCOCC.C(O)C.[C].[Pd]>[C:1]([O:4][CH2:5][C:6]([NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])([CH2:23][CH3:24])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CCC(CCc1ccc(OCc2ccccc2)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(CCc1ccc(O)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Reaction time: 2.67 h
Yield: 129.2 %

Procedure:
To a solution of 4-(4-benzyloxyphenyl)-2-tert-butoxycarbonylamino-2-ethylbutyl acetate (7 g) in ethyl acetate (80 ml) were added a 1 M solution of hydrochloric acid in ether (1 ml) and 10% palladium-carbon (0.4 g) and the suspension was subjected to catalytic reduction under an oridinary atmosphere at room temperature for 160 minutes. Catalyst was filtered off from the reaction mixture and the solvent was distilled away under reduced pressure. The residue obtained was dissolved in ethyl acetate (50 ml) and ethanol (50 ml). To the solution were added 10% palladium-carbon (0.4 g) and a 1 M solution of hydrochloric acid in ether (1 ml) and the suspension was subjected to catalytic reduction under an ordinary atmosphere at room temperature for 140 minutes. Catalyst was filtered off from the reaction mixture and the filtrate was concentrated under reduced pressure to give the subject compound (7.2 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][OH:14])[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].C1COCC1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)(=O)C>[CH3:27][S:28]([O:14][CH2:13][CH2:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCCOc1cccc(CCCO)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCOc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-(3-propoxyphenyl)-1-propanol (731 mg) and THF (20 ml) were added at 0° C. triethylamine (1.57 ml) and methanesulfonyl chloride (0.44 ml). The resulting mixture was stirred at 0° C. for 20 minutes and at room temperature for 0.5 hour. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 3-(3-propoxyphenyl)propyl methanesulfonate (1.10 g) as a colorless oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C@H:22]([OH:25])[CH2:23][OH:24])[CH:20]=3)[CH:15]=[N:14]2)=[CH:10][CH:9]=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:25][C@@H:22]([C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[N:14][N:13]2[CH2:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:27][CH:26]=2)=[CH:17][CH:18]=1)[CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: COc1ccc(Cn2ncc3ccc([C@H](O)CO)cc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3ccc([C@@H](COS(C)(=O)=O)OS(C)(=O)=O)cc32)cc1
Yield: 83.2 %

Procedure:
Methanesulfonyl chloride (0.88 mL, 11.3 mmol) was added dropwise to a solution of (S)-1-(1-(4-methoxybenzyl)-1H-indazol-6-yl)ethane-1,2-diol (1.68 g, 5.63 mmol), Et3N (2.0 mL, 14.1 mmol) and CH2Cl2 (30 mL) at 0° C. After 1 h diluted with CH2Cl2 (100 mL) and washed with 0.5 M HCl, saturated aqueous NaHCO3, brine, and then dried over MgSO4. After the solvent was removed, purification using Biotage Isolera (silica gel, 50-66% EtOAc in hexane) gave the title compound as a sticky white solid (2.13 g, 83%); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.18-7.12 (m, 3H), 6.82 (d, J=8.5 Hz, 2H), 5.90-5.87 (m, 1H), 5.59-5.50 (m, 2H), 4.55-4.50 (m, 1H), 4.42-4.38 (m, 1H), 3.76 (s, 3H), 3.04 (s, 3H), 2.77 (s, 3H); MS ESI 455.1 [M+H]+, calcd for [C19H22N2O7S2+H]+ 455.1.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6]O.[Cl:22]C(N(C)C)=C(C)C>C(Cl)Cl>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][Cl:22]
Reactant: C[Si](C)(C)CCOCOc1ccc(CO)cc1C(F)(F)F
Reactant: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCOc1ccc(CCl)cc1C(F)(F)F

Procedure:
Compound 93-4 (28.5 g) was dissolved in methylene chloride (450 ml), 1-chloro-N,N,2-trimethyl-1-propenylamine (12.9 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. The reaction mixture was diluted with methylene chloride (200 ml), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-90:10) to give the object product (14.5 g) as a colorless oil.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:17][C:18]([CH3:22])([CH3:21])[CH:19]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[C:18]([C:22]1[N:16]=[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[C:2]2[C:3]=1[N:4]1[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]1)=[N:1]2)([CH3:21])([CH3:19])[CH3:17]
Reactant: CC(C)(C)C=O
Reactant: Nc1ccccc1-c1cn2ccccc2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1nc2ccccc2c2nc3ccccn3c12

Procedure:
Preparation analogous to S. Sharma et al., J. Comb. Chem. 2007, 9, 783. A mixture of 20.9 g (100 mmol) of 2-imidazo[1,2-a]pyridin-2-ylphenylamine [127219-06-1], 42.1 g (500 mmol) of 2,2-dimethylpropanal [630-19-3] and 1.9 g (10 mmol) of p-toluenesulfonic acid hydrate in 500 ml of xylene is heated under reflux for 16 h, during which the water formed is removed by azeotropic distillation and a gentle stream of air is passed into the solution. After cooling, the solvent is removed in vacuo, the residue is taken up in 1000 ml of ethyl acetate, washed twice with 500 ml of water each time, once with 500 ml of saturated sodium chloride solution and dried over magnesium sulfate. After recrystallisation from ethanol twice, the solid is freed from low-boiling and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 180° C.). Yield: 9.1 g (33 mmol), 33%, purity: about 99.5% (NMR).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[C:10]([NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[C:9]([CH3:20])=[CH:8][C:7]=1[CH3:21])(=[O:5])=[O:4].C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>O1CCCC1>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[C:10]([N:12]([C:29](=[O:32])[CH2:30][CH3:31])[S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])[C:9]([CH3:20])=[CH:8][C:7]=1[CH3:21])(=[O:5])=[O:4]
Reactant: CCC(=O)Cl
Reactant: CNS(=O)(=O)c1cc(NS(=O)(=O)C(F)(F)F)c(C)cc1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)N(c1cc(S(=O)(=O)NC)c(C)cc1C)S(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of N-methyl-2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonamide (2 g) and triethylamine (0.7 g) in tetrahydrofuran (20 ml), propionyl chloride (0.45 g) was added, and the resultant mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated, admixed with 5% hydrochloric acid and extracted with chloroform. The extract was concentrated to give an oily substance, which was purified by silica gel chromatography. Recrystallization from a mixture of toluene and hexane gave 1.17 g of N-methyl-2,4-dimethyl-5-(N-propionyl-N-trifluoromethanesulfonylamino)benzenesulfonamide (Compound No. 16). M.P., 101°-103° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:9])([F:19])[F:20])=[CH:18][CH:17]=2)=[N:3][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Br)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: FC(F)(F)c1ccc(CNc2ccc(Br)cn2)cc1

Procedure:
Into a round bottom flask fitted with stirrer and reflux condenser was added 2-amino-5-bromopyridine (15, 1.73 mol, 300 g) and p-trifluoromethylbenzaldehyde (16, 1.723 mol, 300 g) to a solution of trifluoroacetic acid (400 mL), triethylsilane (825 mL) and acetonitrile (7500 mL). The reaction was heated to reflux overnight (24 hours). Solvents were removed and the residue was poured into aqueous K2CO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The crude compound was crystallized with diethyl ether/hexane to afford compound 17, 420 g (73.6%) as off white solid. MS (ESI) [M+H+]+=331.1 and 333.1 (1:1 ratio).
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.[N:12]1([CH:18](O)[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(OCCCCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].[OH:36][C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43]C)=[O:42])=[CH:39][CH:38]=1>C(Cl)Cl>[ClH:10].[N:12]1([CH2:18][CH2:19][O:36][C:37]2[CH:46]=[CH:45][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCOC(C)=O
Solvent: ClCCl
Product: Cl
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 145 °C
Reaction time: 12 h
Yield: 17.4 %

Procedure:
Into a 50 ml round bottom flask is placed 6.40 g (33.6 mmol) of p-toluenesulfonyl chloride and 25 ml of methylene chloride. The resulting solution is cooled with an ice bath as 4.00 g (31.0 mmol) of 1-piperidinoethanol in 6 ml of methylene chloride is added dropwise. After the addition is complete, the ice bath is removed and the resulting slurry is stirred for about 12 hours. The reaction mixture is concentrated on a rotary evaporator to yield a solid residue. The solid residue is transferred to a 100 ml round bottom flask with 45 ml of amyl acetate. Potassium carbonate (6.87 g, 49.7 mmol) and methyl 4-hydroxybenzoate (2.82 g, 18.5 mmol) are added to the slurry. The resulting mixture is heated to 145° C. for 2 hours. The reaction mixture is cooled to room temperature and washed twice with water. The organic layer is extracted with 11 ml of 8N hydrochloric acid. The aqueous layer is heated at gentle reflux for 3 hours. The resulting slurry is cooled to 50° C. and 11 ml of acetone is added. The slurry is cooled to 0°-5° C. and stirred for 1 hour. The product is filtered, washed with cold acetone, and dried at 50° C. in vacuo to yield 920 mg of product, (17%). 1 H NMR. Potency 97.6%. TRS 1.16%
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH:18]1([CH2:24][CH2:25][CH2:26][C@@H:27]([C:36]2[O:40][N:39]=[C:38]([CH2:41]OS(C3C=CC(C)=CC=3)(=O)=O)[N:37]=2)[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:18]1([CH2:24][CH2:25][CH2:26][C@@H:27]([C:36]2[O:40][N:39]=[C:38]([CH2:41][C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)[N:37]=2)[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CC(C)(C)OC(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ncc[nH]2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A solution of tert-butyl 1H-imidazole-1-carboxylate (133 mg, 0.79 mmol) in anhydrous tetrahydrofuran (2 ml), cooled to −78° C., treated with n-butyl lithium, 2.5M in hexanes (320 μl, 0.79 mmol) and stirred under a nitrogen atmosphere for 1 hour. A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(([(4-methylphenyl)sulfonyl]oxy)methyl)-1,2,4-oxadiazol-5- yl]hexanoate (Preparation 92) (400 mg, 0.79 mmol) in anhydrous tetrahydrofuran (2 ml) was added slowly and the mixture was allowed to warm to room temperature and stirred at this temperature for 18 to hours. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was washed once more with water (20 ml), dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a pale yellow oil (307 mg).