Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][N:10]1[CH2:17][CH:16]2[O:18][CH:12]([CH2:13][NH:14][CH2:15]2)[CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:26]([C:28]1[CH:47]=[CH:46][C:31]([NH:32][CH2:33][CH2:34][CH2:35]OS(C2C=CC=CC=2)(=O)=O)=[CH:30][CH:29]=1)#[N:27].N.[Mn]([O-])(=O)(=O)=O.[K+]>C1(C)C=CC=CC=1.CO.C(Cl)(Cl)Cl.C(Cl)Cl.O.C(O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][N:10]1[CH2:11][CH:12]2[O:18][CH:16]([CH2:15][N:14]([CH2:35][CH2:34][CH2:33][NH:32][C:31]3[CH:46]=[CH:47][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)[CH2:13]2)[CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN1CC2CNCC(C1)O2
Reactant: N#Cc1ccc(NCCCOS(=O)(=O)c2ccccc2)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCN1CC2CN(CCCNc3ccc(C#N)cc3)CC(C1)O2
Temperature: 70 °C

Procedure:
To the solution of [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acid tert-butyl ester generated in Example 3 (Alternative III) above (assumed 24.15 g, 1.0 mol eq., 1.0 wt./vol.) in a mixture of toluene (approx. 100 mL), ethanol (approx. 200 mL) and water (approx. 14 mL), was added anhydrous potassium carbonate (18.58 g, 1.5 mol eq.). Solid 3-(4-cyanoanilino)propyl-4-benzenesulfonate (28.17 g, 1.0 mol eq., see step (a) above) was added and the combined mixture was heated to 70° C. for six hours. The reaction was monitored by TLC using a silica plate with mobile phase X:DCM 1:1 v/v (in which X is chloroform:methanol:concentrated ammonia 80:18:2 v/v). Visualisation was by UV light (254 nm) and by staining with aqueous potassium permanganate. This showed the complete disappearance of starting material and the appearance of the title compound. The reaction mixture was cooled, and the solvent was concentrated in vacuo. The residue was partitioned between toluene (200 mL) and water (200 mL). The layers were separated, and the organic phase was concentrated in vacuo to afford a yellow solid (38.6 g). This was dissolved in iso-propanol (190 mL, 5.0 rel. vol.) at 60° C., and the hot solution was filtered. The filtrate was stirred, and left to cool to room temperature. A white solid crystallised. The mixture was cooled from room temperature to approximately 8° C. The product was collected by filtration and was washed with iso-propanol (50 mL, 2.0 vol.). The damp product was dried in vacuo at 40° C. to constant weight to give the title compound as a white crystalline solid (30.96 g, 81%).
Reaction SMILES: [H-].[Na+].[Br-].C[PH+](C)C.[C:8]1([N:14]([C:21]2[CH:28]=[CH:27][C:24](C=O)=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO[CH2:31][CH2:32]OC>>[CH:31]([C:22]1[CH:23]=[CH:24][CH:27]=[CH:28][C:21]=1[N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:32]
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: COCCOC
Agent: C[PH+](C)C
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccccc1N(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
Into a three-necked flask, 14.6 g of sodium hydride and 700 ml of 1,2-dimethoxyethane were placed, and 130.8 g of trimethylphosphonium bromide was added thereto with stirring at room temperature. Next, after a drop of absolute alcohol was added, the reaction was allowed to proceed at 70° C. for 4 hours. Then, 100 g of 4-(N,N-diphenylamino)benzaldehyde was added thereto, and the temperature was raised to 70° C. to carry out reaction for 5 hours. The resulting reaction solution was filtered, and the filtrate and an ether-extract of the precipitate were put together and washed with water. Then, the ether solution was dehydrated with calcium chloride, and ether was removed to obtain a crude reaction product. After recrystallized from ethanol, accusal pale yellow vinyltriphenylamine was obtained in an amount of 83.4 g (yield: 84.0%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[C:11]([CH3:16])[N:12]=[CH:13][CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:26][OH:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C>[CH3:30][CH:29]([CH3:31])[CH2:28][C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:26][O:27][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[C:11]([CH3:16])[N:12]=[CH:13][CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1nccc2c1COc1cc(Cl)ccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nccc2c1COc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Temperature: 80 °C
Yield: 187.3 %

Procedure:
A mixture of 8-chloro-4-methyl-5H-chromeno[3,4-c]pyridine (60 mg, 0.259 mmol), (S)-(−)-2-(tert-butoxycarbonylamino)-4-methyl-1-pentanol (113 mg, 0.518 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (6.60 mg, 0.016 mmol), Cs2CO3 (127 mg, 0.388 mmol) and Pd(OAc)2 (1.744 mg, 7.77 μmol) in toluene (5 mL) was heated at 80° C. for 16 h. After cooling to rt, the mixture was diluted with EtOAc (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford (S)-tert-butyl (4-methyl-1-((4-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate, (0.2 g, 0.485 mmol, 30% yield) as a yellow solid. LCMS (ESI) m/e 413.39 [(M+H)+, calcd for C24H33N2O4 413.24]; LC/MS retention time (Method F): tR=0.97 min.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:19]1([CH3:28])[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:28][C:19]1[CH:20]=[C:21]([C:2]2[N:11]=[C:10]([NH:12][C:13]3[NH:14][N:15]=[C:16]([CH3:18])[CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cc(Nc2nc(Cl)nc3ccccc23)n[nH]1
Reactant: Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(Nc3cc(C)n[nH]3)c3ccccc3n2)c1
Temperature: 80 °C
Yield: 101.8 %

Procedure:
A suspension of 1H-quinazoline-2,4-dione (10.0 g, 61.7 mmol) in POCl3 (60 mL, 644 mmol) and N,N-dimethylaniline (8 mL, 63.1 mmol) was heated under reflux for 2 h. The excess POCl3 was removed in vacuo, the residue poured into ice, and the resulting precipitate collected by filtration. The crude solid product 2,4-dichloro-quinazoline (6.5 g, 53% yield) was washed with water and dried under vacuum for next step use without further purification. To a solution of the 2,4-dichloro-quinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150 mL) was added 5-methyl-1H-pyrazol-3-yl amine (3.2 g, 32.9 mmol) and the resulting mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 4.0 g (93% yield) of (2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which was used in the next step without further purification. To a solution of the (2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (50 mg, 0.19 mmol) in DMF (1.0 mL) was added m-tolyl boronic acid (0.38 mmol), 2M Na2CO3 (0.96 mmol), and tri-t-butylphosphine (0.19 mmol). The flask was flushed with nitrogen and the catalyst PdCl2(dppf) (0.011 mmol) added in one portion. The reaction mixture was then heated at 80° C. for 10 hours, cooled to room temperature, and poured into water (2 mL). The resulting precipitate was collected by filtration, washed with water, and purified by HPLC to afford III-50 as a pale yellow solid (61 mg, 75%): 1H NMR (500 MHz, DMSO-d6) δ12.3 (br s, 1H), 10.4 (br s, 1H), 8.75 (d, 1H), 8.30 (s, 1H), 8.25 (d, 1H), 7.78 (s, 2H), 7.55 (m, 1H), 7.45 (m, 1H), 7.35 (m, 1H), 6.80 (s, 1H), 2.47 (s, 3H), 2.30 (s, 3H); MS 316.1 (M+H).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].[K+].I[C:40]1[S:41][CH:42]=[CH:43][CH:44]=1>C(OCC)C>[S:41]1[CH:42]=[CH:43][CH:44]=[C:40]1[C:3]#[C:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1
Reactant: C[Si](C)(C)C#Cc1cc2ccccc2s1
Reactant: Ic1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C(#Cc1cc2ccccc2s1)c1cccs1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
The reaction mixture from Step A containing 2-trimethylsilylethynylbenzothiophene was stirred, and 4.96 grams (0.0157 mole) of tetrabutylammonium fluoride trihydrate and 10.1 grams (0.173 mole) of potassium fluoride were added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 4.5 hours. After this time 36.3 grams (0.173 mole) of 2-iodothiophene was added via syringe. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 60 hours. After this time the reaction mixture was dissolved in diethyl ether and a small amount of methylene chloride, and it was washed with two portions of an aqueous solution of 10% ammonium chloride, one portion of water and one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished with hexane and 20% methylene chloride in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 35.1 grams of 2-(thien-2-ylethynyl)benzothiophene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:30]=[CH:29][S:28][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([O:26]C)=[O:25])[CH2:20][CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:30]=[CH:29][S:28][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C1CCN(c2nc(Nc3ccc(OC)c(OC)c3)c3ncsc3n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCC(C(=O)O)CC3)nc3scnc23)cc1OC
Temperature: 60 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a stirred solution of methyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-4-carboxylate (150 mg, 0.35 mmol) in 7.5 mL of 1,4-dioxane and 7.5 mL of H2O was added NaOH (140 mg, 3.5 mmol) at room temperature. Then the reaction was stirred at 60° C. for 3 hours. The solvent was evaporated and the residue was suspended in 50 mL of H2O, then treated by 1N HCl until pH=5. The white solid was appeared and then filtered the solid was dried to give 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-4-carboxylic acid (130 mg, 90%) as a yellow solid
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:40])([CH3:39])[CH2:4][NH:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[CH2:23][CH2:22]3)[N:17]=[C:16]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])[N:15]=2)=[C:9]([F:37])[CH:8]=1.[CH3:41][N:42]([CH3:48])[C:43](=[O:47])[C:44](O)=[O:45].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2([NH:20][C:18]3[N:17]=[C:16]([O:31][CH2:32][C:33]([F:35])([F:36])[F:34])[N:15]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:4][C:3]([CH3:40])([CH3:39])[CH2:2][NH:1][C:44](=[O:45])[C:43]([N:42]([CH3:48])[CH3:41])=[O:47])=[O:38])=[CH:8][C:9]=4[F:37])[N:19]=3)[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: CN(C)C(=O)C(=O)O
Reactant: CC(C)(CN)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=O)NCC(C)(C)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamide (20 mg, 0.034 mmol) and 2-(dimethylamino)-2-oxoacetic acid (4.83 mg, 0.041 mmol) in DMF (1 mL) were added O-(benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (16.5 mg, 0.052 mmol) and iPr2NEt (0.012 ml, 0.069 mmol). After stirring at rt for 16 hs, the mixture was purified by preparative HPLC to give N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamido)-2,2-dimethylpropyl)-N2,N2-dimethyloxalamide (13.8 mg, 56%) as product. 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.03 (6H, s), 1.31-1.53 (4H, m), 3.06 (3H, s), 3.10-3.21 (2H, m), 3.29 (2H, d, J=6.0 Hz), 3.39 (3H, s), 4.75 (2H, m), 7.14-7.29 (3H, m), 7.33-7.48 (1H, m), 7.70-7.81 (1H, m), 7.92-8.04 (1H, m), 8.07-8.15 (1H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-])=[C:5]([C:10]2[CH:11]=[N:12][N:13]([CH2:15][CH3:16])[CH:14]=2)[C:4]=1[C:17]([O:19][CH3:20])=[O:18])#[N:2].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:7]1[CH:8]=[C:3]([C:1]#[N:2])[C:4]([C:17]([O:19][CH3:20])=[O:18])=[C:5]([C:10]2[CH:11]=[N:12][N:13]([CH2:15][CH3:16])[CH:14]=2)[N:6]=1
Reactant: CCn1cc(-c2c(C(=O)OC)c(C#N)cc[n+]2[O-])cn1
Reactant: O=P(Cl)(Cl)Cl
Product: CCn1cc(-c2nc(Cl)cc(C#N)c2C(=O)OC)cn1
Yield: 90 %

Procedure:
A solution of 4-cyano-2-(1-ethyl-1H-pyrazol-4-yl)-3-(methoxycarbonyl)pyridine 1-oxide (210 mg, 0.771 mmol) in POCl3 (2 mL) was heated at 80° C. for 3-4 h. The mixture was concentrated and purified by flash chromatography (SiO2, 10-100% EtOAc in Hexane). The fractions were collected and the solvent was removed in vacuo to give the title compound (201 mg, 90%).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][CH:17]=2)[CH3:15])=[CH:9][C:8]=1[CH3:31])C.[Li+].[OH-]>>[CH2:33]([O:32][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)=[N:18][CH:17]=2)[CH3:15])=[CH:9][C:8]=1[CH3:31])[C:4]([OH:35])=[O:3])[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(OC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)s2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)s2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], 2-ethoxy-3-(2-methyl-4-{1-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid ethyl ester (mixture of two diastereomeric racemates) was treated with LiOH to obtain 2-ethoxy-3-(2-methyl-4-{1-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid as a mixture of two diastereomeric racemates as light yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26](O)=[O:27])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]1.Cl.C(N=C=NCCCN(C)C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:29]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]2)=[O:27])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: O=S1(=O)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid, thiomorpholine 1,1-dioxide and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a yellow solid (95%).
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[F:58][C:59]1[CH:64]=[CH:63][C:62]([S:65]([C:68]2[CH:73]=[CH:72][C:71]([NH:74][CH:75]3[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]3)=[CH:70][CH:69]=2)(=[O:67])=[O:66])=[CH:61][CH:60]=1>CN(C)C=O.ClCCl.O1CCCC1>[F:58][C:59]1[CH:60]=[CH:61][C:62]([S:65]([C:68]2[CH:73]=[CH:72][C:71]([NH:74][CH:75]3[CH2:80][CH2:79][N:78]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:13]4[CH2:14][CH2:15][N:10]([C:7]5[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:23])[F:22])=[CH:9][CH:8]=5)[CH2:11][CH2:12]4)[CH2:77][CH2:76]3)=[CH:70][CH:69]=2)(=[O:67])=[O:66])=[CH:63][CH:64]=1
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(NC2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc(S(=O)(=O)c3ccc(F)cc3)cc2)CC1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 3), diisopropylethyl amine (18 μL; 0.10 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution [4-(4-fluoro-benzenesulfonyl)-phenyl]-piperidin-4-yl-amine hydrochloride (19 mg; 0.05 mmol, prepared in accordance with Example 32) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 45 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (16 mg; 0.03 mmol). The structure was confirmed using Protocol I-B. Calculated mass=633; observed mass=633; HPLC retention time=4.90 min.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+].CO>C(OCC)(=O)C.CCCCCC>[OH:17]/[N:16]=[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)\[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: NO
Reactant: COC(=O)CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CC/C(=N\O)c1ccccc1
Yield: 91 %

Procedure:
A mixture of methyl 3-benzoylpropionate (15.0 9), hydroxylamine hydrochloride (6.50 g), sodium acetate (9.60 g) and methanol (150 ml) was heated under reflux for 8 hours. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate The ethyl acetate layer was washed with water, dried (over MgSO4) and concentrated. The residue was subjected to a silica gel column chromatography and, from an eluate with ethyl acetate-hexane (1:3, volume ratio), methyl (E)-4-hydroxyimino-4-phenylbutyrate (14.7 g; yield: 91%) was obtained as an oily product.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C@@H:7]([CH3:50])[C@H:8]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[CH2:9][C@@H:10]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C>C(Cl)Cl.C1(C)C=CC=CC=1>[Si:13]([O:12][CH2:11][C@H:10]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[CH2:9][C@@H:8]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[C@H:7]([CH3:50])[CH:6]=[CH:5][CH2:4][OH:3])([C:26]([CH3:29])([CH3:27])[CH3:28])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C=C[C@@H](C)[C@@H](C[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCc1ccc(OC)cc1)OCc1ccc(OC)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(CO[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H](OCc2ccc(OC)cc2)[C@H](C)C=CCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a stirred solution of ester 91 (600 mg, 0.84 mmol) in CH2Cl2 (6 mL) at −40° C. under argon was added slowly over 10 min via syringe DibalH in toluene (9 mL, 1M). After 30 min at −40° C., the reaction mixture was quenched by slow addition of MeOH (0.6 mL) and warmed to rt. The reaction mixture was poured into a vigorously stirred solution of saturated Rochelle salt in H2O (8 mL) and EtOAc (12 mL) and stirred overnight. The aqueous layer was separated and extracted with EtOAc (3×5 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (20% EtOAc in hexanes) to produce 450 mg (80%) of the alcohol, a clear liquid: 1H NMR (300 MHz, CDCl3) δ 7.70-7.66 (m, 4H), 7.39-7.35 (m, 6H), 7.21-7.18 (m, 4H), 6.85-6.82 (m, 4H), 5.68-5.65 (m, 2H), 4.64 (d, J=11.1 Hz, 1H), 4.51 (d, J=11.0 Hz, 1H), 4.46 (d, J=11.1 Hz, 1H), 4.24 (d, J=11.0 Hz, 1H), 4.10-4.06 (m, 2H), 3.78 (s, 6H), 3.81-3.52 (m, 4H), 2.60-2.56 (m, 1H), 1.57-1.51 (m, 2H), 1.05 (s, 9H), 1.03 (d, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.0, 135.6, 135.1, 133.5 (2C), 131.1, 130.3, 130.0, 127.6, 129.4, 129.6, 83.1, 75.2, 72.4, 72.2, 64.4, 63.7, 55.2, 34.7, 26.8, 19.2, 15.4; IR (thin film) 3295, 3045, 2958, 2941, 2910, 2857, 1241, 1097 cm−1; HRMS (EI) cald for C41H52O6Si 668.3599, found 668.3596.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of tert-butyl 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate (4.5 g, 12.05 mmol) in DCM (60.3 mL) was added TFA (60.3 mL). The reaction mixture was stirred for 2 h. After diluted with toluene (30 mL), the volatile materials were removed in vacuo twice to provide 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoic acid (5.2 g, 12.06 mmol, 100%) as a TFA salt. The crude product was used for the next step without further purification. LCMS (m/z): 318.5 (MH+), 0.55 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:23][CH2:19][CH2:20][CH2:21][CH3:22])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CCCCN
Solvent: COCCOC
Product: CCCCNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and butylamine in DME. ES-MS m/e (%): 258 (M+H+, 100).