Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH:7][C@@H:8]([C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([CH3:21])[CH:12]=1)[CH:9]=[CH2:10])=[O:6])([CH3:4])[CH3:3].[Li+].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:23][N:7]([C@@H:8]([C:11]1[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:14]=[C:13]([CH3:21])[CH:12]=1)[CH:9]=[CH2:10])[S@:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6]
Reactant: C=C[C@@H](N[S@@](=O)C(C)(C)C)c1cc(C)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C=C[C@H](c1cc(C)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of (S)-2-methyl-N-((R)-1-(3-methyl-5-(trifluoromethyl)phenyl)allyl) propane-2-sulfinamide (400 mg, 1.25 mmol) in THF (10 mL) under N2 atmosphere was dropwise added LiHMDS (1.9 ml, 1 M in THF, 1.9 mmol) at −60° C. The reaction was stirred for 30 min at −60° C. followed by addition of MeI (712 mg, 32 mmol). After stirring for another 3 h at room temperature, the reaction was quenched with water at 0° C. and then extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (300 mg, yield: 75%); m/z (ES+): 334 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29](O)=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([Cl:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.[O:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([Cl:28])[CH:21]=3)[C:29](=[O:30])[N:45]3[CH2:44][CH2:43][N:42]([CH:39]4[CH2:40][CH2:41][O:36][CH2:37][CH2:38]4)[CH2:47][CH2:46]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1O
Reactant: C1CN(C2CCOCC2)CCN1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(Cl)c1O

Procedure:
Prepared analogously to Example 7i from 80 mg (0.16 mmol) (R)-1-carboxy-2-(3-chloro-4-hydroxy-5-methyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 29.8 mg (0.18 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(OC([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][Cl:25])[CH2:19][CH2:18]1)=O)(C)(C)C.C(=O)([O-])O.[Cs+].Cl>CN1C(=O)CCC1.O1CCOCC1>[ClH:25].[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:24][C:23](=[O:26])[N:20]1[CH2:19][CH2:18][NH:17][CH2:22][CH2:21]1)=[O:5]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCNCC1
Yield: 41.4 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (1.00 g, 7.68 mmol) dissolved in NMP was reacted at ca. 55° C. with 1-(tert-butyloxycarbonyl)-4-chloroacetyl piperazine (2.42 g, 9.22 mmol) in the presence of CsHCO3 (1.78 g, 9.22 mmol). After work-up and removal of the solvent, the crude material was obtained as a white solid. The solid was reacted at room temperature with 15 mL of a 4 molar (4 M) solution of hydrogen chloride (HCl) in 1,4-dioxane. After removal of the solvents, the solid hydrochloride salt was further purified by mass-guided preparative HPLC to provide 0.93 g (41% yield) of the title compound (14) as a white solid after lyophilization of the solvents in the presence of an excess of aqueous 1 normal (1 N) hydrochloric acid. 1H NMR (D2O, 400 MHz): δ 6.93-6.86 (m, 2H), 4.92 (s, 2H), 3.70-3.63 (m, 7H), 3.23 (t, J=5.2 Hz, 2H), 3.17 (t, J=6 Hz, 2H). MS (ESI): m/z 257.13 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C(OCC)(=O)C>O.C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: NCCN1CCCC1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(NCCN1CCCC1)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Reaction time: 1 h
Yield: 26.4 %

Procedure:
4-(7-Chloro-4-quinazolinylamino)benzene sulphonyl chloride, hydrochloride (3.5 g, 0.011 mole) was added portionwise to a well-stirred mixture of sodium carbonate (11.5 g) in water (120 ml) and N-(2-aminoethyl)-pyrrolidine (1.26 g, 0.01 mole) in chloroform (120 ml) at about 10° C. After 1 hour at room temperature, the mixture was filtered. The chloroform layer was separated, dried (MgSO4) and evaporated under reduced pressure to give a gum. Trituration from ethyl acetate gave a white solid (1.14 g) which could be crystallised from ethanol-water, m.p. 203°-204.5° C.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1.C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:36]=1[CH2:37]Cl>O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:37][C:36]3[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:46])[F:45])=[CH:42][C:35]=3[F:34])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(O)c(Cl)c1
Reactant: Fc1cc(C(F)(F)F)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(OCc2ccc(C(F)(F)F)cc2F)c(Cl)c1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
To 20 ml of N,N-dimethylformamide are added 3-(2-chloro-6-fluorophenyl)-5-[3-chloro-4-hydroxyphenyl)-1-methyl-1H-1,2,4-triazole (0.90 g) and potassium carbonate (0.40 g) and 2-fluoro-4-trifluoromethylbenzyl chloride (0.50 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 5 hours. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.60 g of desired compound (melting point: 109.0°-111.0° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:26][C:25](=O)[O:24][C:22](=[O:23])[CH2:21]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH2:26][C:25]2[NH:1][C:2]3[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=3[N:12]=2)[CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:19]=1.[ClH:13]
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: COC(=O)c1ccc(N)c(N)c1
Product: COC(=O)c1ccc2nc(CC(CC(=O)O)c3ccc(Cl)cc3)[nH]c2c1
Product: Cl

Procedure:
By a procedure similar to that of example 1.4, starting from methyl 3,4-diaminobenzoate and 3-(4-chlorophenyl)glutaric anhydride, 3-(4-chlorophenyl)-4-(5-methoxycarbonyl-2-benzimidazolyl)-butanoic acid•HCl was obtained as light tan solid, provided that cyclisation of the crude glutaramic acid was carried out in commercial 4M HCl in 1,4-dioxane at reflux for 0.5 h.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].Cl[S:36]([NH2:39])(=[O:38])=[O:37].O>CN(C)C(=O)C>[S:36]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:38])(=[O:37])[NH2:39]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(N)(=O)=O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.145 g, 0.314 mmol) was dissolved in N,N-dimethylacetoamide (1.5 mL), and the solution was added with chlorosulfonamide (0.0440 mL, 0.377 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (chloroform/methanol=85/15) to obtain 4-sulfamoyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0914 g, yield 54%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][P:16]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][C:34]([CH3:43])([CH3:42])[C:35]([O:37]C(C)(C)C)=[O:36])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][P:16]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][C:34]([CH3:43])([CH3:42])[C:35]([OH:37])=[O:36])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)COCCOCCOP(=O)(OCc1ccccc1)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(COCCOCCOP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
TFA (6.63 mL, 86 mmol) was added dropwise to a stirred solution of tert-butyl 3-(2-(2-((bis(benzyloxy)phosphoryl)oxy)ethoxy)ethoxy)-2,2-dimethylpropanoate (50) (4.5 g, 8.61 mmol) in DCM (43 mL) and the reaction mixture was allowed to stir at RT for 16 h then concentrated in vacuo. The crude product was dissolved in EtOAc (150 mL) and washed with 1M HCl (aq.) (50 mL), water (2×50 mL), and brine (50 mL) the organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 3-(2-(2-((bis(benzyloxy)phosphoryl)oxy)ethoxy)ethoxy)-2,2-dimethylpropanoic acid (51) (3.98 g, 99%) as a colourless oil: m/z 467 (M+H)+ (ES+); 465 (M−H)− (ES−). 1H NMR (400 MHz, CDCl3) δ: 7.36-7.31 (m, 10H), 5.12-5.03 (m, 4H), 4.14-4.09 (m, 2H), 3.69-3.64 (m, 2H), 3.60 (s, 4H), 3.47 (s, 2H), 1.20 (s, 6H).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]([C:19]2[O:23][N:22]=[C:21]([OH:24])[CH:20]=2)[CH:16]=[CH:17][CH:18]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.Cl>C1(C)C=CC=CC=1.C1COCC1>[OH:24][C:21]1[CH:20]=[C:19]([C:15]2[CH:14]=[C:13]([B:25]([OH:30])[OH:26])[CH:18]=[CH:17][CH:16]=2)[O:23][N:22]=1
Reactant: Oc1cc(-c2cccc(Br)c2)on1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(-c2cc(O)no2)c1
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
Add a 2.5 M solution of n-butyllithium in hexane (0.60 mL, 1.10 mmol) to a solution of 5-(3-bromophenyl)isoxazol-3-ol (120 mg, 0.50 mmol) and triisopropyl borate (113 mg, 0.60 mmol) in a mixture of toluene (2.5 mL) and THF (2.5 mL) at −78° C. After 1.5 h, warm the mixture to −20° C. and add a 2.0 N aqueous HCl solution (1 mL). Extract the mixture with EtOAc after warm to room temperature. Dry, filter and concentrate the organic layer to a white solid.
Reaction SMILES: [OH:1][CH:2]([C:10]([F:13])([F:12])[F:11])[C:3]([F:9])([F:8])[S:4]([O-:7])(=[O:6])=[O:5].[C:14]1([S+:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:33][CH2:34][C:35](Cl)=[O:36].N1C=CC=CC=1>C(#N)C>[Cl:33][CH2:34][C:35]([O:1][CH:2]([C:10]([F:13])([F:11])[F:12])[C:3]([F:8])([F:9])[S:4]([O-:7])(=[O:6])=[O:5])=[O:36].[C:27]1([S+:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Reactant: O=C(Cl)CCl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(CCl)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
To a mixture of 148 g (0.30 mole) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate synthesized in Synthesis Example 1-11, 37.3 g (0.33 mole) of chloroacetyl chloride, and 600 g of acetonitrile, 28.5 g (0.36 mole) of pyridine was added dropwise, followed by stirring at room temperature for 3 hours. The reaction solution was then concentrated and combined with 300 g of 5% dilute hydrochloric acid and 600 g of dichloromethane whereupon the organic layer was separated. The organic layer was washed with 300 g of water, from which dichloromethane was distilled off under vacuum. To the residue was added 600 g of methyl isobutyl ketone. This was washed with 300 g of water, with 300 g of dilute aqueous ammonia, and three times with 300 g of water whereupon methyl isobutyl ketone was distilled off under vacuum. The residue was purified by adding ether for recrystallization, filtered and dried. The target compound was obtained as white crystals (158 g, yield 92%).
Reaction SMILES: C(O[C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=1)(C)(C)C.C=O.[CH3:21][C:22]([CH3:25])([O-:24])[CH3:23].[K+].CCCCCC.C[CH2:34][O:35]C(C)=O>CS(C)=O.C(Cl)Cl>[C:22]([O:24][C:6]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:14])[CH2:34][OH:35])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=1)=[O:18])([CH3:25])([CH3:23])[CH3:21]
Reactant: CC(C)(C)[O-]
Reactant: CCc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: C=O
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(CO)c1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a suspension of 4-ethyl-3-nitrobenzoic acid tert-butyl ester (11e) (10 g, 40 mmol) and paraformaldehyde (1.8 g, 60 mmol) in DMSO (10 mL) was added in portions potassium tert-butoxide (590 mg, 5.8 mmol), during which the colour of the reaction mixture was changing from yellow to purple. After stirring for 1 hour at room temperature, the reaction mixture was suspended in CH2Cl2, adsorbed onto silica gel (15 g) in vacuo and purified by flash chromatography (100 g silica, column: 3.5×14 cm, solvent: hexane/EA 3:1). The product was obtained as a yellow oil in 94% yield (10.57 g, 38 mmol). Rf=0.34 (hexane/EtOAc 3:1). 1H NMR (250 MHz, CDCl3) δ 8.27 (d, 1H, arom. H(3)), 7.58 (dd, 1H, arom. H(5)), 7.53 (d, 1H, arom. H(6)), 3.76 (m, 2H, α-CH2), 3.50 (sextet, 1H, β-CH), 1.81 (t, 1H, OH), 1.57 (s, 9H, 3×CH3 COOtBu), 1.31 (d, 3H, CH3).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[CH3:14][N:15]1[C:19]([NH2:20])=[CH:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([NH:20][C:19]1[N:15]([CH3:14])[N:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nccc1N
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nccc1NCc1ccccc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
Benzyl bromide (4.97 g) was added dropwise to a dimethylformamide (15 mL) mixture of 1-methyl-1H-pyrazol-5-amine (2.69 g) and potassium carbonate (4.02 g) at a room temperature, and the obtained solution was then stirred at 70° C. for 3 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (Chromatorex NH, hexane:ethyl acetate=2:1), so as to obtain the title compound (1.54 g) in the form of a light yellow oily substance.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Br-:1].[O:15]=[C:6]1[C:7]2[C:8](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:10])[N:5]1[CH2:4][CH2:3][CH2:2][P+:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A solution of N-(3-bromopropyl)phthalimide (25.0 g, 93.2 mmol) and triphenylphosphine (24.5 g, 93.2 mmol) in toluene (200 mL) was stirred and heated to reflux for 15 hours. The reaction mixture was cooled to ambient temperature and the resulting precipitate was collected by filtration, washed with toluene, and dried under vacuum to afford (3-(1,3-dioxoisoindolin-2-yl)propyl)triphenylphosphonium bromide as a white powder (17.9 g, 36% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][C:32]([C:31]([F:30])([F:41])[F:42])=[CH:33][CH:34]=4)[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C

Procedure:
(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 28 mg, 0.07 mmol) and 4-(trifluoromethyl)benzoic acid (14 mg, 0.07 mmol) were dissolved in DMF (0.265 ml). HBTU (30 mg, 0.08 mmol) and N,N-diisopropyl-ethylamine (0.026 ml, 0.16 mmol) were added and the mixture was stirred over night at r.t. Then it was diluted with acetonitrile and purified by semi-preparative HPLC. Yield 24 mg (59%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]([C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[S:14]([CH3:17])(=[O:16])=[O:15]>>[NH2:11][C:9]1[N:10]=[C:3]2[C:2]([C:21]3[CH:20]=[CH:19][C:18]([N:13]([CH3:12])[S:14]([CH3:17])(=[O:15])=[O:16])=[CH:23][CH:22]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CN(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Reactant: Nc1nc2c(Br)cccn2n1
Product: CN(c1ccc(-c2cccn3nc(N)nc23)cc1)S(C)(=O)=O

Procedure:
N-[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (300.0 mg, 1.408 mmol) and N-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (500.0 mg, 1.607 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.33 g, 73%). MP=245-247° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.55 (d, J=5.8 Hz, 1H), 8.12 (d, J=7.5 Hz, 2H), 7.72 (d, J=7.1, 1H), 7.52 (d, J=7.2 Hz, 2H), 6.98 (t, J=6.2 Hz, 1H), 6.11 (s, 2H), 3.29 (s, 3H), 2.98 (s, 3H). MS=318 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]=[O:26])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[P:34](Cl)([O:39][CH2:40][CH3:41])([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][P:34]([O:39][CH2:40][CH3:41])([O:36][CH2:37][CH3:38])=[O:35])=[C:20]([CH:25]=[O:26])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)c(C=O)c1)NC(=O)OCc1ccccc1
Reactant: CCOP(=O)(Cl)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1C=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 1.03 g 3C in 20 mL anhydrous dichloromethane in an ice-water bath were added 0.60 ml triethylamine and 0.48 mL diethyl chlorophosphate. The mixture was kept in the ice-water bath for 1 hour and then kept at room temperature overnight. After wash with water, with brine and drying with anhydrous sodium sulfate, the mixture was concentrated to an oily liquid and then purified by flash column chromatography (0.1% Et3N/20% EtOAc/CH2Cl2). The desired orthoformylated phosphotyrosine (3D) was obtained as colorless oil (1.21 g, 85%). 1H NMR (CDCl3, 200 MHz): δ 10.37 (s, 1H), 7.64 (s, 1H), 7.43-7.31 (m, 7H), 5.28 (d, J=7.7 Hz, 1H), 5.11 (s, 2H), 4.66 (m, 1H), 4.33-4.18 (m, 4H), 3.75 (s, 3H), 3.21 (dd, J1=14.1 Hz, J2=5.6 Hz, 1H), 3.09 (dd, J1=14.1 Hz, J2=6.1 Hz, 1H), 1.37 (m, 6H). 13C NMR (CDCl3, 50 MHz): δ 188.3, 171.4, 155.5, 152.0 (d), 136.5, 136.1, 133.4, 129.3, 128.6, 128.3, 128.1, 127.2 (d), 121.3, 67.1, 65.2 (d), 54.7, 52.6, 37.4, 16.1 (d). 31P NMR (CDCl3, 81 MHz): δ −6.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:27])[N:20]([CH2:22][C:23]([O:25]C)=[O:24])[N:21]=[C:8]2[N:7]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:6]=1[CH3:38])=[O:4].CO.[OH-].[Li+].Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:27])[N:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=[C:8]2[N:7]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=2)[C:6]=1[CH3:38])=[O:4]
Reactant: COC(=O)Cn1nc2n(c1=O)C(c1ccc(C#N)cc1)C(C(=O)OC)=C(C)N2c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)O)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of Intermediate 16 (108 mg, 0.21 mmol) in THF (1 mL), was added MeOH (1 mL) followed by lithium hydroxide (3 M in water, 68 μL, 0.21 mmol). The reaction mixture was stirred at RT for 2 hours, and then lithium hyroxide (3 M in water, 27 μL, 0.08 mmol) was added. After a further 1 hour stirring at RT, the reaction mixture was made acidic by addition of 1 M HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo to yield the title compound as a white solid (100 mg).