Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)(O)[O-].[Na+].[S:6]([O-:9])([O-])=[O:7].[Na+].[Na+].[O:12]=[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]([OH:25])=[O:24])=[CH:15][NH:14]1.Cl>O>[CH3:1][S:6]([C:20]1[CH:21]=[C:22]2[C:17]([C:16]([C:23]([OH:25])=[O:24])=[CH:15][NH:14][C:13]2=[O:12])=[CH:18][CH:19]=1)(=[O:9])=[O:7]
Reactant: O=S([O-])[O-]
Reactant: O=C([O-])O
Reactant: O=C(O)c1c[nH]c(=O)c2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc2c(C(=O)O)c[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
To a solution of sodium bicarbonate (500 mg) and sodium sulfite (353 mg) in 4 ml of water at 0° C. was added portionwise the 7-chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (see Preparation 16) (400 mg). The reaction was warmed to room temperature and then heated at 80° C. for 2 h. The reaction was cooled to 0° C. and acidified to pH-1 with concentrated hydrochloric acid. The suspension was diluted with 4 ml of water and stirred for 15 minutes at 0° C. then filtered under nitrogen. The solid was washed twice with water and was added to a degassed aqueous solution (3 ml) of potassium hydrogen carbonate (280 mg) at 45° C. Ethanol was then slowly added until the solution became slightly cloudy. Iodomethane (262 μl) was then added and the reaction refluxed (45-50° C.) for 5 h. The reaction was concentrated under vacuum, extracted with ethyl acetate and the aqueous phase acidified with concentrated hydrochloric acid. The reaction was stirred at 0° C. for 30 min. and the solid collected by filtration then recrystalised from acetone to yield the title compound as a white solid (325 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH:12]=2)=[CH:4][C:3]=1[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C>CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][C:14]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:16])[CH:12]=2)=[CH:4][C:3]=1[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1
Reactant: Nc1ncc(-c2cnn(CC(=O)O)c2)cc1-c1nc2ccccc2s1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2cnn(CC(=O)N3CCOCC3)c2)cc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of [4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-acetic acid (5.00 mg, 0.0142 mmol), morpholine (10.0 mg, 0.11 mmol), TBTU (9.14 mg, 0.0284 mmol), DIPEA (0.02 mL, 0.1 mmol) and DMF (2 mL, 0.03 mol) was stirred at rt for 10 min. The solution was transferred to a separatory funnel, diluted with EtOAc and washed 3× with water. The organic layer was concentrated in vacuo and loaded onto a prep TLC plate, eluting with 5% MeOH/DCM. The band containing the pure product was filtered off using 1:1 MeOH/DCM, and the filtrate was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=3.60-3.64 (m, 4H), 3.72 (dt, J=12.8, 4.7 Hz, 4H), 5.17 (s, 2H), 7.40-7.45 (m, 1H), 7.48-7.54 (m, 1H), 7.85 (s, 1H), 7.94-7.98 (m, 2H), 8.02 (d, J=7.8 Hz, 1H), 8.16 (d, J=2.3 Hz, 1H), 8.30 (d, J=2.3 Hz, 1H). MS (ES+): m/z=421.12 (100) [MH+]. HPLC: tR=2.79 min (ZQ3, polar—5 min).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([O:16][CH2:17][CH3:18])[CH2:15][CH2:14]2)=[C:9]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:8]=1)(=O)=O.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>C(N(CC)CC)C.CN(C=O)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>[CH2:17]([O:16][C:13]1([C:10]2[CH:11]=[CH:12][C:7]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:8][C:9]=2[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH3:18]
Reactant: CCOC1(c2ccc(OS(=O)(=O)C(F)(F)F)cc2C(C)(C)C)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC1(c2ccc(C#C[Si](C)(C)C)cc2C(C)(C)C)CC1
Temperature: 95 °C

Procedure:
Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-tert-butyl-phenyl 1,1,1-trifluoromethansulfonate (Intermediate 110, 260.0 mg, 0.71 mmol) in triethylamine (4 mL) and DMF (6 mL) was sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (40.0 mg, 0.06 mmol). The resulting reaction mixture was heated to 95° C. for 18 hours. The title compound, 215.0 mg (96%), was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.O.[NH2:15][NH2:16]>C(O)C>[Cl:1][C:2]1[C:11]([NH:15][NH2:16])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: NN
Reactant: Clc1ccc2nc(Cl)c(Cl)nc2c1
Solvent: O
Solvent: CCO
Product: NNc1nc2cc(Cl)ccc2nc1Cl

Procedure:
A mixture consisting of 23 g. (0.10 mole) of 2,3,6-trichloroquinoxaline and 11 g. (0.22 mole) of hydrazine hydrate in 500 ml. of ethanol was stirred at room temperature (~20° C.) overnight (~16 hours). The precipitate which formed was separated by filtration and washed with ethanol to ultimately afford 22.2 g. (97%) of pure 2,6-dichloro-3-hydrazinoquinoxaline, m.p. <250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[Br:12][C:13]1[CH:17]=[CH:16][N:15]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:14]=1[C:27](OC)=[O:28].O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Br:12][C:13]1[CH:17]=[CH:16][N:15]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:14]=1[C:27]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:28]
Reactant: Nc1ccccc1
Reactant: COC(=O)c1c(Br)ccn1S(=O)(=O)c1ccccc1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)c1c(Br)ccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 114.7 %

Procedure:
In a three-necked round-bottom flask aniline (1.57 mL, 17.20 mmol) was dissolved in 80 mL of toluene under inert atmosphere. To this solution was added trimethy aluminium (7.82 mL, 15.64 mmol) and the mixture was stirred at room temperature during 10 minutes. Afterwards, a solution methyl 3-bromo-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (2.0 g, 5.81 mmol) in 20 mL of toluene were added and the reaction mixtures was heated at 80° C. for 3 h. Next, the mixture was allowed to cool to room temperature and 20-30 mL of water was added to hydrolyze unreacted trimethyl aluminium and a 0,5M aqueous solution of disodium tartrate dihydrate was also added. After stirring for a while, the two layers were separated and the aqueous phase was extracted with ethyl acetate. The organic mixture was washed with the same 0,5M aqueous solution of disodium tartrate dehydrate (200 mL), water and brine, dried and concentrated in vacuum to afford 2.7 g of a residue that was used in the following step without further purification.
Reaction SMILES: CC(C)(O[C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])C.[CH3:14][N:15](C)[C:16](Cl)=O.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[CH3:14][N:15]([CH3:16])[C:5]([N:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCNCC1

Procedure:
To a solution of 1.92 g 1-(1,1-dimethylethyloxycarbonyl)piperazine in 11 mL of dichloromethane and 1.5 mL of triethylamine at room temperature was added dropwise 1 mL of dimethylcarbamylchloride. After 16 hours 5% aqueous sodium hydrogencarbonate and dichloromethane were added, the organic layer separated, dried over magnesium sulfate and concentrated. Column chromatography on silica gel (dichloromethane/methanol=95/5 v/v) yielded 1.34 g 1-1,1-dimethylethyloxycarbonyl)-4-(dimethylaminocarbonyl)piperazine. This compound was dissolved in a 3N hydrogen chloride solution in methanol at 0° C. After 15 min the reaction mixture was allowed to warm to room temperature and After stirring for 3 days at room temperature the reaction mixture was concentrated to give 1.06 g of 1-(dimethylaminocarbonyl)piperazine hydrochloride. rf=0.29, SiO2: dichloromethane/methanol=4/1 v/v.
Reaction SMILES: [F:1][CH:2]([F:18])[C@@H:3]([C@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:11]1[CH:16]=[CH:15][N:14]=[C:13](F)[N:12]=1)[CH3:4].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[C:29]([C@@H:31]([NH2:33])[CH3:32])[O:28][N:27]=2)=[CH:22][CH:21]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[N:45]=[C:44]([C@H:46]([NH2:48])[CH3:47])[O:43][N:42]=2)=[CH:37][CH:36]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:30]=[C:29]([C@@H:31]([NH:33][C:13]3[N:12]=[C:11]([N:6]4[C@@H:5]([C@@H:3]([CH3:4])[CH:2]([F:18])[F:1])[CH2:9][O:8][C:7]4=[O:10])[CH:16]=[CH:15][N:14]=3)[CH3:32])[O:28][N:27]=2)=[CH:24][CH:25]=1.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[N:45]=[C:44]([C@H:46]([NH:48][C:13]3[N:12]=[C:11]([N:6]4[C@@H:5]([C@@H:3]([CH3:4])[CH:2]([F:18])[F:1])[CH2:9][O:8][C:7]4=[O:10])[CH:16]=[CH:15][N:14]=3)[CH3:47])[O:43][N:42]=2)=[CH:39][CH:40]=1
Reactant: C[C@@H](N)c1nc(-c2ccc(Cl)cc2)no1
Reactant: C[C@H](N)c1nc(-c2ccc(Cl)cc2)no1
Reactant: C[C@@H](C(F)F)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)C(F)F)n1)c1nc(-c2ccc(Cl)cc2)no1
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)C(F)F)n1)c1nc(-c2ccc(Cl)cc2)no1
Reaction time: 0.25 h

Procedure:
A mixture of (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (40 mg, 0.153 mmol), (S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine/(R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (mixture of diastereomers ˜3/1, 37.7 mg, 0.168 mmol) and Huenig's base (0.059 mL, 0.337 mmol) in DMSO (0.7 mmol) under argon atmosphere was heated/radiated in the microwave at 140° C. for 15 min. The mixture was diluted with DMSO and water, filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (31.8 mg; first eluted product) and (S)-3-(2-(((R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (11.5 mg; second eluted product) as their trifluoroacetic acid salts. 410: First eluted product: 1H NMR (500 Mhz, CD3OD) δ ppm 8.22 (s, 1H), 8.03-7.93 (m, 2H), 7.54-7.46 (m, 3H), 5.84 (m, 1H), 5.49 (q, J=7.2 Hz, 1H), 5.13 (dt, J=8.4, 3.1 Hz, 1H), 4.60-4.21 (m, 2H), 2.74 (m, 1H), 1.75 (d, J=7.2 Hz, 3H), 0.90 (br. s, 3H). HRMS m/z 465.1260 (M+H)+; Rt-2.41 min.
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[Br:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]=[CH:17][N+:18]([O-])=O>C1COCC1>[Br:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH2:16][CH2:17][NH2:18]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1Br
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 87.2 %

Procedure:
To a stirred suspension of lithium borohydride (0.39 g; 18.0 mmol) in 25 mL THF at ambient temperature was added chlorotrimethylsilane (3.9 g; 36.0 mmol), dropwise over 2 minutes. Gas was evolved and the mixture warmed slightly. After stirring for 20 minutes, gas evolution had ceased, and argon gas was bubbled through the mixture for 2 minutes to try to remove the remaining trimethylsilane that had formed. A solution of 2-bromo-4-chloro-1-(2-nitrovinyl)benzene (1.18 g; 4.5 mmol) in 20 mL tetrahydrofuan was then added dropwise with stirring at ambient temperature over 4 minutes. The resulting mixture was stirred and heated to reflux. After 2 hours, the heat was removed, and after cooling to ambient temperature, the mixture was cooled in an ice bath and carefully quenched with 25 mL methanol. The solvent was evaporated, and the residue was partitioned between 50 mL of 20% KOH and 25 mL of dichloromethane. The organic layer was dried over sodium sulfate and evaporated to give 0.92 g of 2-(2-bromo-4-chlorophenyl)ethanamine as a cloudy yellow oil. MS (apci, pos) m/z=234.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[NH2:23].Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:23][C:22]3[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:20]([O:19][CH3:18])[CH:21]=3)=[C:3]([C:16]#[N:17])[CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Solvent: O
Product: COc1cc(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)cc(OC)c1OC
Temperature: 105 °C

Procedure:
A mixture of 500 mg (1.86 mmol) of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile, 342.0 mg (1.86 mmol) of 3,4,5-trimethoxyaniline and 215.5 mg (1.86 mmol) of pyridine hydrochloride in 25 mL of 2-ethoxyethanol is heated at 100-110° C. for 1.5 hours. After cooling, the mixture is diluted with water and neutralized with an aqueous solution of saturated sodium carbonate. The solid is collected by filtration and is washed with water. After drying in vacuo, this yields 621.0 mg (80.5%) of the product as a deep yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:17]([O:22]C)(O[CH3:21])(=[O:19])=[O:18]>>[CH3:1][S:17]([O-:22])(=[O:19])=[O:18].[CH3:21][N+:11]1([CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COS(=O)(=O)OC
Reactant: c1ccc(CCCCN2CCCCC2)cc1
Product: CS(=O)(=O)[O-]
Product: C[N+]1(CCCCc2ccccc2)CCCCC1

Procedure:
Following the procedure set out in Example 25, N-(4-phenylbutyl)piperidine was reacted with dimethyl sulfate to afford N-methyl-N-(4-phenylbutyl)piperidinium methanesulfonate. M.P. 54°-56° C.
Reaction SMILES: [H-].[Na+].C(S)C.C[O:7][C:8]1[C:16]2[O:15][C:14]([CH:17]3[CH2:21][CH2:20][O:19][CH2:18]3)=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>CN(C)C=O>[O:19]1[CH2:20][CH2:21][CH:17]([C:14]2[O:15][C:16]3[C:8]([OH:7])=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=2)[CH2:18]1
Reactant: COc1cccc2cc(C3CCOC3)oc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: Oc1cccc2cc(C3CCOC3)oc12
Temperature: 140 °C
Yield: 79.1 %

Procedure:
Sodium hydride (0. 19 g, 60% in mineral oil) was added to a stirred solution of ethane thiol (0.34 ml) in N, N-dimethylformamide (6 ml) at room temperature under a dry nitrogen atmosphere. After stirring for 15 minutes 7-methoxy-2-(tetrahydrofuran-3-yl)-benzofuran (0.5 g) in N,N-dimethylformamide (6 ml) was added and the reaction heated to 140° C. for 2 hours. After cooling to room temperature the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic extract was dried over magnesium sulphate, filtered and preadsorbed onto silica. Purification by column chromatography on silica eluting with 50% ethyl acetate in heptane afforded the title compound as a brown oil (0.37 g).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.N1C=CC=CC=1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>C(Cl)Cl>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18])[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a round-bottomed flask equipped with magnetic stir bar was charged 1a (3.0 g, 20 mmol), pyridine (4.7 g, 59 mmol, 3 equiv) and CH2Cl2 (25 mL). The mixture was cooled in a dry ice-acetone bath and Tf2O (6.6 mL, 11.1 g, 39 mmol, 2 equiv) was added dropwise over 30 min Afterwards, the mixture was stirred at room temperature for 2 h. The reaction mixture was washed with H2O (2×25 mL) followed by brine (25 mL). The organic phase was separated, dried over anhydrous MgSO4 and evaporated under reduced pressure leaving a brownish oil (5.12 g, 90%). The crude product could be further purified by short-path distillation at reduced pressure (0.1 ton) to give the product as colorless oil. However, the compound appears to be heat sensitive as there was a significant decomposition residue in the distillation pot. 1H NMR (CDCl3): δ 9.98 (s, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.51 (dd, J=8.2 and 1.8 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 3.99 (s, 3H); 13C NMR (CDCl3): δ 190.53, 152.49, 142.97, 137.06, 124.27, 123.45, 121.06, 118.92 (q, 1JCF=321.5 Hz), 112.06, 56.75; 19F {13C} NMR (CDCl3): δ −74.2. The product was used in the synthesis of compound 3a without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([C:33]([F:36])([F:35])[F:34])=[CH:27]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([C:33]([F:36])([F:34])[F:35])=[CH:27]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Oc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C(F)(F)F)cc4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 90 °C
Yield: 46.4 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (50 mg, 0.155 mmol), (prepared as described for the starting material in Example 10), and 5-hydroxy-2-trifluoromethylindole (34 mg, 0.17 mmol) in DMF (1.5 ml) containing potassium carbonate (43 mg, 0.31 mmol) was heated at 90° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methanol/ethyl acetate/methylene chloride (10/50/40) followed by 2.5M ammonia in methanol/ethyl acetate/methylene chloride (10/50/40) to give 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline (35 mg, 48%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:14][CH2:15][CH2:16][CH3:17])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O.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>[CH2:15]([O:14][C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][CH3:18])[CH:21]=2)=[CH:3][CH:4]=1)[C:10]([O:12][CH3:13])=[O:11])[CH2:16][CH3:17]
Reactant: CCCO[C@@H](Cc1ccc(Br)cc1)C(=O)OC
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCO[C@@H](Cc1ccc(-c2cccc(NC)c2)cc1)C(=O)OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
38 mg (0.033 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution of 100 mg (0.33 mmol) of methyl (S)-3-(4-bromophenyl)-2-(propyloxy)propionate and 90 mg (0.39 mmol) of methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine in 1 ml of dimethylformamide. 0.2 ml of a 2M potassium phosphate solution is added and the reaction mixture is stirred at 90° C. for 2 hours. The reaction is halted by the addition of 10 ml of water and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (heptane/ethyl acetate 80/20). 76 mg of methyl (S)-2-propyloxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate are obtained in the form of an oil. Yield=70%.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:27])[C@H:7]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])[CH3:3].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-:45]S(C(F)(F)F)(=O)=O.[CH3:53][C:54]#N>O.C1OC1>[CH3:4][C:2]([O:5][C:6](=[O:27])[C@H:7]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[N:8]([CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:53][CH2:54][OH:45])([CH3:1])[CH3:3]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CC(C)(C)OC(=O)CN[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Reactant: CC#N
Agent: [Yb+3]
Solvent: O
Solvent: C1CO1
Product: CC(C)(C)OC(=O)CN(CCO)[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Temperature: -80 °C
Reaction time: 15 h
Yield: 77 %

Procedure:
A jacketed reactor is loaded with a solution of N-[2-(1,1-dimethylethoxy)-2-oxoethyl]-L-tryptophan 1,1-dimethylethyl ester (5 g; 13.35 mol) prepared at point B, in CH3CN (25 mL). To the solution cooled to −80° C. is added ethylene oxide (13 mL; 0.26 mol) and ytterbium triflate (0.83 g; 1.34 mol). The mixture is then slowly warmed to room temperature then, after 15 hours, diluted with water (50 mL) and extracted with Et2O (3×50 mL). The organic phases are evaporated to dryness to obtain a crude which is purified by flash chromatography (eluent n-hexane/EtOAc 7:3) to give the desired product as a pale yellow oil (4.32 g; 10.32 mol).