Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][N:16]=3)=[CH:27][N:26]=2)=[O:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccc(-c2cnccn2)cn1
Reactant: O=C(O)Cc1ccc(Br)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(Br)c(C(F)(F)F)c1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-bromo-3-(trifluoromethyl)phenyl)acetic acid 46-6 (128 mg, 0.5 mmol), 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (95 mg, 0.55 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 214 mg, 0.55 mmol) in DMF (2 mL) was added diispropylethyl amine (DIEA, 250 μL, 1.5 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, and concentrated by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give 2-(4-bromo-3-(trifluoromethyl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 118-1 as pale orange solid. MS m/z 438.2 (M+1)
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC(C)([O-])C.[K+].C(NC1C=C([C:44]2[C:49]([C:50]([C:52]3[C:53]([C:58]4C=CC=[C:60]([NH:64][C:65](=[O:67])[CH3:66])[CH:59]=4)=NC=C[CH:57]=3)=O)=[CH:48][CH:47]=[CH:46][N:45]=2)C=CC=1)(=O)C.O>O1CCCC1>[C:65]([NH:64][C:60]1[CH:57]=[C:52]([C:50]([C:49]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)=[CH:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[CH:53]=[CH:58][CH:59]=1)(=[O:67])[CH3:66]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1cccc(-c2ncccc2C(=O)c2cccnc2-c2cccc(NC(C)=O)c2)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc(C(=CCCCC(=O)O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 217 g of 4-carboxybutyl-triphenylphosphonium bromide and 154 g of potassium tert.butoxide in 1.8 liters of tetrahydrofuran are added, at -25° C., 94 g of 3-acetylaminophenyl-3-pyridyl ketone. After 2 hours stirring at ambient temperature the reaction mixture is combined with 200 ml of water and then substantially evaporated down. The residue is taken up in 500 ml of water and washed with ethyl acetate. The aqueous phase is then neutralised by the addition of citric acid and extracted with ethyl acetate. The organic phase is evaporated down and the residue is recrystallised from ethyl acetate/acetone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[C@H:9]1[C:14]([O:16][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,3S)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester [187039-57-2] (500 mg, 2.16 mmol) in MeOH (9.0 mL), cooled to 0° C., was added with stirring a solution of Cs2CO3 (704 mg, 2.162 mmol) in water (6.0 mL). The mixture was concentrated by rotary evaporation and the residue was suspended in DMF (17.0 mL). The suspension was cooled to 0° C., followed by addition of benzylbromide (0.514 mL, 4.32 mmol) and stirring overnight at RT. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organics were washed with aqueous NaHCO3 (2×) and water (2×), dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 2:3) to give the title compound as a white solid. MS (LC/MS): 665 [2M+Na]+, 266 [MH−tBu]+, 222 [MH−Boc]+; tR (HPLC conditions b): 4.18 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1.[CH2:19]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[OH-].[Na+]>C1(C)C(C)=CC=CC=1.O>[CH2:19]([N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[C:2]1[N:7]=[C:6]([N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:20][CH2:21][CH3:22])[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCNCCCC
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCN(CCCC)c1nc(N(CCCC)CCCC)nc(N2C(C)(C)CCCC2(C)C)n1
Reaction time: 2 h

Procedure:
57.8 g of 2,4-dichloro-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine are suspended in 200 ml of xylene at room temperature. 25.8 g of dibutylamine are added dropwise to this during the course of 15 minutes, the temperature climbing to 40°. A solution of 8.87 g of sodium hydroxide in 40 ml of water is added to the reaction mixture in about 15 minutes and it is subsequently stirred at 60° for 2 hours. The aqueous phase is then separated off and 28.4 g of dibutylamine and a solution of 9.6 g of sodium hydroxide in 20 ml of water is added to the clear organic phase. The mixture is then heated in a water separator until an internal temperature of about 135° is reached and is then stirred for 12 hours at this temperature. The contents of the flask are cooled to 90°, a solution of 3 g of sodium hydroxide in 100 ml of water is added and the mixture is vigorously stirred at 90° for 30 minutes. The aqueous phase is then separated off, the xylene solution is washed five times, each with 100 ml of water, and evaporated in vacuo. The yellowish, oily residue is distilled in a high vacuum. 2,4-Bis-dibutylamino-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine is obtained as a colorless oil having a boiling point of 173° at 6.5 Pa.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.FC(F)(F)C(O)=O.[NH2:72][CH2:73][CH2:74][N:75]([CH3:88])[C:76](=[O:87])[CH2:77][CH2:78][CH2:79][N:80]1[C:84](=[O:85])[CH:83]=[CH:82][C:81]1=[O:86].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:86]=[C:81]1[CH:82]=[CH:83][C:84](=[O:85])[N:80]1[CH2:79][CH2:78][CH2:77][C:76]([N:75]([CH3:88])[CH2:74][CH2:73][NH:72][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:87]
Reactant: CN(CCN)C(=O)CCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NCCN(C)C(=O)CCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 mg (7 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 61) were combined with 2.8 mg (8 μmol) of N-(2-aminoethyl)-4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-methylbutanamide trifluoroacetate, 10.1 mg (27 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 5 μl of N,N-diisopropylethylamine in 2 ml of DMF and stirred at RT overnight. Then another 5 mg (23.5 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 3 μl of N,N-diisopropylethylamine were added. After stirring at RT for a further 5 h, the solvent was removed under reduced pressure and the remaining residue was purified by means of preparative HPLC. The corresponding fractions were concentrated and, by lyophilization from dioxane, 1.3 mg (15% of theory) of the title compound were obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11](O)[CH2:10][CH2:9]2.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C>[N:30]([CH:11]1[C:12]2[C:8](=[CH:7][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)=[N+:31]=[N-:32]
Reactant: OC1CCc2cc(-c3cccs3)ccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1CCc2cc(-c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.6 %

Procedure:
To a solution of 5-(2-thienyl)-2,3-dihydro-1H-inden-1-ol (0.30 g, 1.39 mmol) in tetrahydrofuran (6 mL ) was added diphenylphosphoryl azide (0.58 g, 2.10 mmol) at 0° C. The reaction was stirred for 5 min prior to the addition of 1,8-diazabicyclo{5.4.0]undec-7-ene (DBU, 0.32 g, 2.10 mmol). The reaction was further stirred for 15 min at 0° C. before the reaction was allowed to warm to room temperature. The reaction was stopped after 1 h when the reaction was completed as monitored by thin layer chromatography. Diluted with ethyl acetate (200 mL), washed with water, saturated aqueous sodium chloride (brine), and dried over anhydrous magnesium sulfate. Filtration, concentration and column chromatography on silica (7:3 hexanes/ethyl acetate) gave 2-(1-azido-2,3-dihydro-1H-indene-5-yl)thiophene (0.24g, 72% yield) as oil. 1H NMR (400 MHz, CDCl3) 7.54 (m, 2H), 7.40 (m, 2H), 7.24 (m, 1H), 7.08 (m, 1H), 5.85 (t, 1H), 3.12 (m, 1H), 2.90 (m, 1H), 2.45 (m, 1H), 2.19 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C([Mg]Br)C.[CH3:13][C:14]1([CH3:23])[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[O:22])[CH2:15]1.C(OCC)(=O)C>C1COCC1>[CH3:20][C:18]1([CH3:21])[CH2:19][C:14]([CH3:23])([CH3:13])[CH2:15][C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)([OH:22])[CH2:17]1
Reactant: C#Cc1ccccn1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: CC[Mg]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)CC(O)(C#Cc2ccccn2)C1
Temperature: 25 °C
Yield: 9.7 %

Procedure:
To a solution of 2-ethynylpyridine (1.0 g, 10 mmol) in THF at −78° C. was added a 1.0 M solution of ethyl magnesium bromide in THF (10 mL, 10 mmol). After stirring at reduced temperature for 30 minutes a solution of 3,3,5,5-tetramethyl-cyclohexanone (1.5 g, 10 mmol) in THF was added rapidly. The mixture was allowed to warm to ambient temperature over 16 hours, then partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and concentrated in vacuo. The resultant product was purified by flash column chromatography on silica gel eluting with 1:1 hexane:ethyl acetate to afford 3,3,5,5-tetramethyl-1-(2-pyridinylethynyl)cyclohexanol (250 mg, 10% yield) as a white solid. M.p. 126-127° C. 1H NMR (DMSO-d6, 300 MHz) Δ8.57 (m, 1H), 7.64 (m, 1H), 7.39 (d, J=5 Hz, 1H), 7.22 (m, 1H), 1.91 (d, J=9 Hz, 2H), 1.71 (d, J=9 Hz, 2H), 1.26 (s, 2H), 1.14 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3].[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28].C1CCC(N=C=NC2CCCCC2)CC1.CCCCCC>C(OCC)(=O)C>[CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([O:10][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[F:17])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOCc1c(OC)cccc1C(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCOCc1c(OC)cccc1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Yield: 110 %

Procedure:
Into a 200 mL round bottom flask was added 6.6 g (0.0297 mol) of 2-allyloxymethyl-3-methoxy benzoic acid and 40 mL of ethyl acetate. 24.05 g of a 25% pentafluorophenol (6.01 g, 0.0327 mol) solution in ethyl acetate was added while stirring. The reaction flask was placed into a water bath and while stirring small portions of DCC (6.2 g, 0.030 mol) were added. The stirring continued overnight at room temperature. The reaction was filtered through two Whatman #541 filters to remove the DCU precipitate. The ethyl acetate solution was concentrated to yield 12.8 g (110% yield), indicating presence of DCC and DCU. This was confirmed by TLC (1:1 ethyl acetate:hexane), which indicated a Rf of 0.72 plus other less polar compounds (12 stain indicates about 85% purity). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.7 (d, 1H), 7.45 (t, 1H), 7.15 (d, 1H), 6.0-5.9 (m, 1H), 5.3-5.1 (2d, 2H), 4.88-4.83 (d, 2H), 4.06 (d, 2H), 3.90 (s, 3H).
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:18]([O:20][CH:21]([O:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH2:24][NH2:25])[CH3:19].CCN(CC)CC>C(Cl)Cl>[CH2:27]([O:26][CH:21]([O:20][CH2:18][CH3:19])[CH2:22][CH2:23][CH2:24][NH:25][S:1]([C:4]1[C:16]2[C:8](=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH3:28]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CCOC(CCCN)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(CCCNS(=O)(=O)c1cccc2c(N(C)C)cccc12)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of dansyl chloride (270 mg, 1.00 mmol) in CH2Cl2 (10 mL) was added 4-aminobutyraldehyde diethyl acetal (237 μL, 1.20 mmol) and Et3N (170 μL, 1.20 mmol). The solution was stirred for 1 h at 25° C. and was then evaporated to dryness under reduced pressure. The material left was processed and purified under conditions identical to those described for the processing and purification of 11. Fractions containing the product were collected and evaporated to dryness under low pressure affording 13 (366 mg, 930 μmol) as a solid in a yield of 93%. 1H NMR (300 MHz, DMSO-d6): δ 8.45 (dt, J=8.5, 1.1 Hz, 1H), 8.30 (dt, J=8.8, 0.9 Hz, 1H), 8.09 (dd, J=7.3, 1.2 Hz, 1H), 7.89 (t, J=5.5 Hz, 1H), 7.61 (t, J=8.5 Hz, 1H), 7.58 (t, J=8.5 Hz, 1H), 7.25 (dd, J=7.6, 0.7 Hz, 1H), 4.19 (t, J=5.3 Hz, 1H), 3.36 (m, 2H), 3.23 (m, 2H), 2.81 (s, 6H), 2.77 (t, J=5.5 Hz, 2H), 1.31 (m, 4H), 0.99 (t, J=7.0 Hz, 6H). 13C NMR (75 MHz, DMSO-d6): δ 151.2, 136.1, 129.2, 128.9, 128.1, 127.7, 123.5, 119.1, 114.9, 101.6, 60.2, 44.9, 42.2, 30.1, 24.4, 15.1. +ESI-HRMS: Calcd for C20H30N2O4S [M+H]+ 395.1999. found 395.2000.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[N:2]=1.S(Cl)(Cl)=O.[CH:13]1([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=3)[CH:19]=2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-]>C(Cl)Cl.CS(C)=O>[CH:13]1([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([NH:25][C:26](=[O:34])[C:27]3[CH:28]=[CH:29][C:30]([O:8][CH2:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:31][CH:32]=3)[CH:19]=2)[CH2:15][CH2:14]1
Reactant: OCc1cccnn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccnn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5.9 %

Procedure:
To a solution of 3-pyridazinylmethanol (140 mg, 1.27 mmol) in DCM (5 mL) was added thionyl chloride (103 μl, 1.42 mmol) and the resulting mixture stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure and then to the residue in DMSO (4 mL) was added N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (197 mg, 0.636 mmol), cesium carbonate (621 mg, 1.91 mmol) and tetrabutylanunonium iodide (235 mg, 0.636 mmol) and the resulting mixture stirred at 60° C. for 16 h. The reaction mixture was added to a 20 g SCX column and product eluted with methanol. Concentration under reduced pressure gave impure product which was further purified on silica column chromatography eluting with 0-20% methanol/ 1% anmmonium hydroxide SG 0.88 in ethyl acetate. Evaporation and trituration with DCM and diethyl ether and filtration gave the title compound as a solid (15 mg, 5.9%); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H), 2.86 (m, 1H), 5.54 (s, 2H), 7.21 (d, 2H), 7.34 (d, 1H), 7.64 (m, 1H), 7.79 (m, 2H), 7.86 (m, 1H), 7.99 (m, 2H), 8.37 (m, 1H), 9.24 (m, 1H), 9.86 (s, 1H); Mass Spectrum: M−H− 401.
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH:17]=O)=[N+:9]=[N-:10].[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[NH2:22]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1/[CH:17]=[N:22]/[C:21]1[C:23]([F:27])=[CH:24][CH:25]=[CH:26][C:20]=1[Cl:19])=[N+:9]=[N-:10]
Reactant: Nc1c(F)cccc1Cl
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1ccncc1/C=N/c1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (7.1 mL, 51 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (2.52 g, 17 mmol) and 2-chloro-6-fluoroaniline (2.47 g, 17 mmol) in DCM (60 mL) under nitrogen. Titanium tetrachloride (1 M, 10.2 mL, 10.2 mmol) was then added and the resulting mixture was stirred for 1 hour at 0° C. before warming to room temperature and stirring for a further 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene and filtered through a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid. This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.CN(C1C=CC=CN=1)C.[C:26]1(=[O:36])[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>ClCCl>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:26](=[O:36])[C:27]1[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:29]([OH:31])=[O:30]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: O=C(O)c1ccccc1C(=O)Nc1ccccc1-c1cc2ccccc2[nH]1
Reaction time: 0.17 h

Procedure:
958 mg (4.6 mmol) 2-(2-Aminophenyl) indole and 675 mg (5.52 mmol, 1.2 eq) DMAP (dimethylamino pyridine) were dissolved in 35 ml anhydrous dichloromethane. The mixture was stirred for 10 min. 954 mg (6.44 mmol, 1.4 eq) of phthalic anhydride in 3 ml anhydrous dichloromethane were added and the mixture was stirred at 23° C. for three hours. To the mixture were added 20 ml dichloromethane. It was extracted with 50 ml aqueous 1 M HCl. The aqueous phase was re-extracted with 30 ml dichloromethane. The combined organic phases were dried over magnesium sulfate. The crude product was chromatographed on silica using an ethylacetate/hexane gradient (10%–90%) as mobile phase. The solvent was removed and the product was re-crystallized from ethylacetate:hexane (70:30) to obtain 654 mg of ivory colored crystals in 40% overall yield.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[C:41]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[C:41]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: COc1cccc(F)c1B(O)O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(F)c1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 46 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with (2-fluoro-6-methoxyphenyl)boronic acid (137 mg, 0.81 mmol), sodium carbonate (86 mg, 0.81 mmols) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, dichloromethane-ethyl acetate) to give 50 mg (46% yield) of the title compound. Purity 87%.
Reaction SMILES: [CH3:1][CH:2]([NH:6][CH2:7][C:8]1[S:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH3:5].Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:11]4[S:12][C:8]([CH2:7][NH:6][CH:2]([CH3:1])[CH2:3][CH2:4][CH3:5])=[CH:9][CH:10]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:37])=[O:36])[CH3:39]
Reactant: CCCC(C)NCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCC(C)NCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 60 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (1-methylbutyl)amine (29 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 43 mg of crude (5-{[(1-methylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(1-methylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 35.2 mg of the title compound (60%).