Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=S(Cl)Cl.Cl.[NH2:6][C@H:7]1[C:15]2[C:10](=[CH:11][C:12]([F:19])=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8]1.[CH3:20]O>>[NH2:6][C@H:7]1[C:15]2[C:10](=[CH:11][C:12]([F:19])=[C:13]([C:16]([O:18][CH3:20])=[O:17])[CH:14]=2)[CH2:9][CH2:8]1
Reactant: CO
Reactant: N[C@@H]1CCc2cc(F)c(C(=O)O)cc21
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2c(cc1F)CC[C@H]2N
Temperature: 25 °C
Reaction time: 14 h
Yield: 89 %

Procedure:
SOCl2 (0.75 ml, 10.365 mmol, 2.4 eq) was added dropwise at 0° C., with stirring, to a suspension of (R)-3-amino-6-fluoro-2,3-dihydro-1H-indene-5-carboxylic acid hydrochloride (commercially available from NetChem (Order No. 573243)) (1 g, 4.319 mmol, 1 eq) in methanol (20 ml). The reaction mixture was stirred for 14 h at room temperature. When the reaction was complete according to TLC monitoring, concentration under reduced pressure was carried out and the residue was diluted with saturated sodium hydrogen carbonate solution (50 ml) and extracted with 10% methanol/dichloromethane (100 ml). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The desired product was in the form of a light-green solid. Yield: 89% (800 mg, 3.827 mmol)
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:16]=1)[C:11]([OH:13])=O.Cl.[CH2:22]([O:29][C:30](=[O:44])[NH:31][CH2:32][C@@H:33]([OH:43])[C@@H:34]([NH2:42])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30](=[O:44])[NH:31][CH2:32][C@@H:33]([OH:43])[C@@H:34]([NH:42][C:11]([C:10]1[CH:9]=[C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C:3]2=[O:2])[CH:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:14]=1)=[O:13])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNC(=O)OCc1ccccc1
Reactant: CC(C)Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: Cl
Product: CC(C)Nc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNC(=O)OCc2ccccc2)cc(N2CCCC2=O)c1

Procedure:
Description 107 was prepared in an analogous manner to Description 105 from 3-(2-oxo-pyrrolidin-1-yl)-5-isopropylamino-benzoic acid hydrochloride (A44) and ((2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-carbamic acid benzyl ester (D104).
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][C:4]2[S:7][C:8]([NH:13][C:14]([C:16]34[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]5)[O:17]3)[CH2:23]4)=[O:15])=[C:9]([C:10](O)=[O:11])[C:3]1=2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[F:60][C:61]1([F:65])[CH2:64][NH:63][CH2:62]1>CN(C)C=O.C(OCC)(=O)C>[F:60][C:61]1([F:65])[CH2:64][N:63]([C:10]([C:9]2[C:3]3[CH:2]([CH3:1])[O:6][CH2:5][C:4]=3[S:7][C:8]=2[NH:13][C:14]([C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[O:17]2)[CH2:23]3)=[O:15])=[O:11])[CH2:62]1
Reactant: CC1OCc2sc(NC(=O)C34CC5CC(CC(C5)O3)C4)c(C(=O)O)c21
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1OCc2sc(NC(=O)C34CC5CC(CC(C5)O3)C4)c(C(=O)N3CC(F)(F)C3)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the product from example 43A (90 mg, 0.25 mmol) in N,N-dimethylformamide (0.5 mL) was added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol), N,N diisopropylethylamine (0.3 mL, 1.7 mmol), and 3,3-difluoroazetidine hydrochloride (130 mg, 1 mmol). The mixture was stirred at room temperature for 18 hours, diluted with ethyl acetate (10 mL) and washed with water and brine. The organic extract was dried over MgSO4 and concentrated. Purification by chromatography (0 to 75% ethyl acetate in hexane gradient) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.4 Hz, 3H) 1.63-2.06 (m, 11H) 2.18 (s, 2H) 4.35-4.71 (m, 4H) 4.81-5.00 (m, 2H) 5.29-5.42 (m, 1H) 11.12 (s, 1H). MS (DCI/NH3) m/z 439.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Cl:7][C:6]1[C:2]([NH:1][S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])=[N:3][O:4][C:5]=1[CH3:8].[NH2:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([S:15]([N:1]([C:2]2[C:6]([Cl:7])=[C:5]([CH3:8])[O:4][N:3]=2)[S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cc1onc(N)c1Cl
Product: Cc1onc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1Cl
Product: Cc1onc(NS(=O)(=O)c2ccccc2)c1Cl
Yield: 40 %
Yield: 7 %

Procedure:
N-(4-chloro-5-methyl-3-isoxazolyl)benzenesulfonamide was prepared from 3-amino-4-chloro-5-methylisoxazole and benzenesulfonyl chloride as described in Example 41b in 40% yield. The crude product was purified by column chromatography with 10-100% ethyl acetate/hexanes as eluent. A crystalline solid was obtained after recrystallization from ethyl acetate/hexanes, m.p. 139°-141° C. 3-Amino-4-chloro-5-methylisoxazole (25% recovery) and N-(benzenesulfonyl)-N-(4-chloro-5-methyl-3-isoxazolyl)benzen esulfonamide (7% yield) were also obtained as less polar products.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[O:15]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>CO.[Cl-].[Na+].O>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:28][CH:27]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Oc2ccccc2)cc1
Yield: 68.4 %

Procedure:
To 2.0 g of 4-chloro-6-fluoro-[1,7]naphthyridine-3-carbonitrile in 50 mL of methanol was added 2.2 g of 4-phenoxyaniline. After stirring the reaction under an inert atmosphere for 18 hr, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals filtered and washed with water. The product was then recrystallized from chloroform/hexanes. Drying in vacuo yielded 2.35 g (69%) of 6-fluoro-4-(4-phenoxy-phenylamino)-[1,7]naphthyridine-3-carbonitrile as yellow needles: melting point 211-213° C.; mass spectrum (m/e): M+H 356.9.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[CH:12]=[C:13](/[C:16](=O)[CH3:17])\[C:14]#[N:15])[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[O:19]1[CH2:23][C:22](=O)[CH2:21][C:20]1=[O:25].C([O-])(=O)C.[NH4+:30]>>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]3[C:13]([C:14]#[N:15])=[C:16]([CH3:17])[NH:30][C:22]4[CH2:23][O:19][C:20](=[O:25])[C:21]3=4)[CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: O=C1COC(=O)C1
Reactant: [NH4+]
Reactant: CCc1n[nH]c2ccc(/C=C(\C#N)C(C)=O)cc12
Agent: CC(=O)[O-]
Product: CCc1n[nH]c2ccc(C3C(C#N)=C(C)NC4=C3C(=O)OC4)cc12

Procedure:
The title compound was prepared from 600 mg (2.508 mmol) (2E)-2-[(3-ethyl-1H-indazol-5-yl)-methylidene]-3-oxobutanenitrile (Example 7A), 256 mg (2.508 mmol) furan-2,4(3H,5H)-dione and 232 mg (3.010 mmol) ammonium acetate in analogy to the procedure described in Example 1 yielding 98 mg (12% of th.) of the racemic compound after purification by flash chromatography (silica gel; dichloromethane/methanol gradient, final mixture 30:1 v/v).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH:15]=[O:16])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:20]([F:23])([F:22])[F:21].[F-].[Cs+].C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH:15]([OH:16])[C:20]([F:23])([F:22])[F:21])[O:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(=O)c(OCc2ccccc2)co1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1cc(C(O)C(F)(F)F)occ1OCc1ccccc1
Reaction time: 0.17 h
Yield: 57 %

Procedure:
The entire experiment was performed under an inert atmosphere by bubbling argon gas into the ice-salt cooled reaction mixture. To a cloudy solution of 5-benzyloxy-4-oxo-4H-pyran-2-carbaldehyde (5.00 g, 21.7 mmol) in dry tetrahydrofuran (185 mL) previously purged with argon for 35 min was added trimethyl(trifluoromethyl)silane (10.8 g, 76.0 mmol) dropwise, followed by caesium fluoride (0.34 g, 2.2 mmol). The color of the reaction mixture turned to yellow and almost clear within a min. TLC was used to monitor the reaction (eluant: 50:50, ethyl acetate:hexanes, v:v). The reaction was completed within 10 min. The reaction mixture was quenched with a 6.0N hydrochloric acid solution (20 mL) under cooling, followed by addition of a brine solution (50 mL). The mixture was stirred for 10 min, and then transferred to a separatory funnel. The organic THF fraction was collected, and then concentrated in vacuo to about 10 mL using the rotary evaporator. The residual solution was diluted with dichloromethane (80 mL). The mixture was transferred to a separatory funnel, and the separated dichloromethane layer was collected, dried over Na2SO4 and filtered. Upon concentration under reduced pressure, a first crop of the titled compound was obtained as a solid product (3.72 g, 57% yield, HPLC Method 1 (Example 24), RT=16.8 min, HPLC purity (peak percent area): 96% at λ=280 nm). 1H NMR (DMSO-d6+D2O) δ ppm: 8.20 (s, 1H), 7.36 (br m, 5H), 6.57 (s, 1H), 5.11 (q, J=7 Hz, 1H), 4.92 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=2)=[CH:4][CH:3]=1.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][NH:23][C:22]1=[O:26]>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][NH:23][C:22]3=[O:26])[N:8]=2)=[CH:4][CH:3]=1
Reactant: NCCN1CCNC1=O
Reactant: Cc1cnc(S(C)(=O)=O)nc1-c1ccc(Br)s1
Solvent: Cc1ccccc1
Product: Cc1cnc(NCCN2CCNC2=O)nc1-c1ccc(Br)s1
Temperature: 120 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
4-(5-Bromothiophen-2-yl)-5-methyl-2-(methylsulfonyl)pyrimidine (2 g, 6 mmol) in toluene (10 mL) was treated with 1-(2-aminoethyl)imidazolidin-2-one (1.489 g, 10.2 mmol) and the reaction stirred at 120° C. overnight. The volatiles were removed in vacuo and the residue purified by flash chromatography using a gradient of 2 to 10% methanol in dichloromethane to obtain a light yellow solid (1.8 g). MS (M+H)+ 383.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([OH:36])([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:14]=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:38][CH2:39][CH2:40][CH2:41]O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([O:36][CH2:41][CH2:40][CH2:39][Br:38])([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[C:14]=3[CH2:15][C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCCBr
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Solvent: ClCCl
Product: COc1ccc(C2(OCCCBr)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Reaction time: 48 h

Procedure:
To 100 mL dichloromethane was added 3-Benzo[1,3]-dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 5.0 g (9.87 mmol), giving a suspension. 1-Bromo-3-propanol 3.07 g (22.15 mmol) was added, and the mixture was purged with anhydrous HCl gas until saturated. After 48 hours at room temperature, the mixture was evaporated in vacuo and the residue was suspended in ethyl ether. The ether suspension was washed exhaustively with 0.5 N NaOH, followed by water and saturated sodium chloride solution. The ether phase was dried over anhydrous magnesium sulfate, filtered, and diluted with hexane, giving a solid. Filter and dry in vacuo, giving a white solid, 4.79 g. The product was identified by 1H NMR, MS [M--H]+ =628, 629 Da.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:10]=1)[C:5]([OH:7])=O.Cl.[F:19][C:20]([F:32])([F:31])[CH2:21][O:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:10]=1)[C:5]([NH:30][CH2:29][C:26]1[CH:27]=[N:28][C:23]([O:22][CH2:21][C:20]([F:32])([F:19])[F:31])=[CH:24][CH:25]=1)=[O:7]
Reactant: NCc1ccc(OCC(F)(F)F)nc1
Reactant: Cc1cc(C(=O)O)cc(NC(=O)C(C)(C)C)n1
Agent: Cl
Product: Cc1cc(C(=O)NCc2ccc(OCC(F)(F)F)nc2)cc(NC(=O)C(C)(C)C)n1

Procedure:
The title compound is prepared from 2-methyl-6-pivalamidoisonicotinic acid (30 mg, 0.06 mmol, Step-1) and (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (15 mg, 0.06 mmol) by the similar manner in Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH3:27])=[C:21]2[C:28]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[S:31](=[O:39])(=[O:38])[NH:30][N:29]=1.Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CC#N.O.C(Cl)Cl>[C:45]([O:44][C:42](=[O:43])[CH2:41][N:23]1[C:24]2[C:20](=[CH:19][C:18]([F:17])=[CH:26][CH:25]=2)[C:21]([C:28]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[S:31](=[O:38])(=[O:39])[N:30]([CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:29]=2)=[C:22]1[CH3:27])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cccc(CCl)c1
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COc1cccc(CN2N=C(c3c(C)n(CC(=O)OC(C)(C)C)c4ccc(F)cc34)c3ccccc3S2(=O)=O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Methoxybenzyl chloride (10 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1ccc(Br)cc1

Procedure:
Into a 250-mL round-bottom flask were placed a solution of 4-bromoaniline (17.1 g, 99.42 mmol) and triethylamine (30 g, 297 mmol) in dichloromethane (100 mL). Then, 2-phenylacetyl chloride (18.6 g, 120 mmol) was added dropwise with stirring, and the resulting solution was stirred at room temperature for 6 hours. The solids were filtered out, and the filtrate was concentrated under vacuum. The crude product was purified by re-crystallization from ethyl acetate to provide the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[N:6].CC([O-])(C)C.[K+].COCCOC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:41]3[C:36](=[CH:37][C:38](F)=[CH:39][CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.CC(C)=O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:41]3[C:36](=[CH:37][C:38]([O:1][CH2:2][CH2:3][CH2:4][C:5]#[N:6])=[CH:39][CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: N#CCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCC#N)ccc23)CC1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 4-hydroxybutyronitrile (24.2 mg, 285 μmol) [Organometallics (1996), 15(4), 1236-41], KOtBu (34.8 mg, 311 μmol), and DME was stirred at rt, followed by the addition of 4-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (48.8 mg, 147 μmol) (prepared as described in Example 12b). The resulting homogeneous solution was stirred at rt for 2 hr, and was then directly loaded onto a 5 g Jones silica cartridge pre-equilibrated with 9:1 DCM/acetone, and eluted with 9:1→8:2 DCM/acetone to afford the title intermediate (24.5 mg, 42%) as a colorless oil. LC/MS (ESI) calcd mass 396.2, found 397.1 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1
Yield: 74.5 %

Procedure:
A solution of 56 g of 4-nitrophenol, 90 g of methyl bromoacetate and 100 g of potassium carbonate in 500 ml of dimethylformamide was stirred at room temperature for 2 days. At the end of this time, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue thus obtained was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was crystallized by trituration with hexane, to give 63.3 g of the title compound, melting at 98°-99° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:24].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CO>[CH2:1]([O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH2:21][Br:24])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(OCCNC(=O)OCc2ccccc2)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: O=C(NCCOc1ccc(C(=O)CBr)cc1)OCc1ccccc1
Yield: 90 %

Procedure:
Benzyl-[2-(4-acetyl-phenoxy)-ethyl]-carbamate (10.2 g, 32.5 mmol) was dissolved in methylene chloride (100 ml) and methanol (50 ml), and tetrabutylamonium tribromide (15.7 g, 32.5 mmol) was added in one portion. The reaction mixture was stirred for about sixteen hours, and then quenched with water. The aqueous phase was extracted with ethyl acetate and then washed with saturated aqeous sodium bicarbonate, and saturated Na2S2O3. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo, and the resulting crude material was purified by column chromatography (silica gel; hexanes to 2:1 hexanes/ethyl acetate) to afford a colorless oil which solidified upon standing. (11.5 g, 90% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1>CN(C)C=O.ClCCl>[O:8]([CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
4-Pyridylcarbinol (8.5 g, 0.08 mol) was dissolved in a 9:1 mixture of N,N-dimethylformamide and dichloromethane (150 mL). t-Butyldimethylsilylchloride (13 g, 0.09 mol) and imidazole (6.4 g, 0.09 mol) were added and the solution was stirred for 12 hours at room temperature. The reaction mixture was concentrated at reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure to give the title compound (17.4 g, 92%) as a colorless oil; MS(ES) m/e 244 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=[O:5].[O:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH2:18][CH:17]1[CH2:26][NH2:27].C(N(CC)CC)C.O>CN(C)C=O>[O:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH2:18][CH:17]1[CH2:26][NH:27][CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=[O:5]
Reactant: NCC1COc2ccccc2O1
Reactant: O=C(CCCl)Nc1ccc2c(c1)OCO2
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCNCC1COc2ccccc2O1)Nc1ccc2c(c1)OCO2
Temperature: 50 °C
Reaction time: 20 h
Yield: 87.5 %

Procedure:
To a solution of 10 g of N-(3-chloropropionyl)-3,4-methylenedioxyaniline in 50 ml of dimethylformamide are added 8.7 g of 1,4-benzodioxan-2-ylmethylamine and 8.9 g of triethylamine and the mixture is stirred for 20 hours at 50° C. After completion of the reaction, water is added and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate and the solvent is distilled off. The residue is dissolved in ethyl acetate and 20% hydrogen chloride in ethyl acetate is added. The resulting crystals are collected by filtration and recrystallized from ethanol to give 13.7 g (77%) of N-[3-{(1,4-benzodioxan-2-ylmethyl)amino}propionyl]-3,4-methylenedioxyaniline.
Reaction SMILES: [F:1][C:2]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:3]=1[CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:7]([CH3:49])=[N:6]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:3]=1[CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:7]([CH3:49])=[N:6]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cc(F)ccc4F)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nn(Cc2cc(F)ccc2F)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Yield: 25.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(2,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (230 mg, 0.305 mmol) was hydrolyzed by lithium hydroxide (129 mg, 3.05 mmol), THF/Methanol/water (12/4/4 ml) to afford 46 mg (25.2% yield) of the titled compound. MS: m/z=599.3 (M+1).