Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[C:25]([C:27]([NH2:29])=[O:28])[CH:24]=[CH:23][N:22]=1>>[C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][C:21]3[N:26]=[C:25]([C:27]([NH2:29])=[O:28])[CH:24]=[CH:23][N:22]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: NC(=O)c1ccnc(Cl)n1
Product: NC(=O)c1ccnc(NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)n1

Procedure:
EXAMPLE 83 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-chloro-pyrimidine-4-carboxylic acid amide (2-chloro-pyrimidine-4-carboxylic acid amide was prepared according to G. D. Davies, D. E. O'Brien, L. R. Lewis, C. C. Cheng, J. Heterocyclic Chem., 1:130–131(1964): MS (m+1)=404.
Reaction SMILES: [B-](F)(F)(F)F.[N:6]#[O+:7].[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11].N1C=CC=CC=1>C(#N)C>[N:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7]
Reactant: N#[O+]
Reactant: O=C(O)[C@@H]1CCCN1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: O=NN1CCC[C@H]1C(=O)O

Procedure:
To a cooled suspension of 28.2 g of nitrosyl tetrafluoroborate in 300 ml of dry acetonitrile there is added, with vigorous stirring, over the course of 10 minutes, 18.4 g of L-proline, followed by a solution of 19 g of pyridine in 50 ml of acetonitrile during 15 minutes. The stirring is continued for an hour and the reaction mixture is then concentrated to dryness under reduced pressure. The residue is extracted with 3×200 ml of ethyl acetate, the ethyl acetate extracts are combined, washed twice with saturated sodium chloride solution that has been made slightly acidic with concentrated hydrochloric acid. The ethyl acetate solution is dried over anhydrous sodium sulfate, filtered and concentrated to dryness at room temperature under reduced pressure. The product, N-nitroso-L-proline melts at 108°-109° (dec.) after crystallization from a mixture of ether and petroleum ether (30°-60°).
Reaction SMILES: [N:1]1([C:5]([C:7]2[C:12]([F:13])=[CH:11][C:10](F)=[CH:9][C:8]=2[F:15])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:16][N:17]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:36]=[C:35]([OH:37])[C:28]3[CH2:29][CH:30]([CH:32]([F:34])[F:33])[O:31][C:27]=3[CH:26]=2)=[O:24])=[N:18]1>>[CH3:16][N:17]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:36]=[C:35]([O:37][C:10]3[CH:11]=[C:12]([F:13])[C:7]([C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])=[C:8]([F:15])[CH:9]=3)[C:28]3[CH2:29][CH:30]([CH:32]([F:34])[F:33])[O:31][C:27]=3[CH:26]=2)=[O:24])=[N:18]1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C(F)F)C3)n1
Reactant: O=C(c1c(F)cc(F)cc1F)N1CCC1
Product: Cn1ccc(NC(=O)c2cc(Oc3cc(F)c(C(=O)N4CCC4)c(F)c3)c3c(c2)OC(C(F)F)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 33, from azetidin-1-yl(2,4,6-trifluorophenyl)methanone (57.4 mg, 0.267 mmol) and 2-difluoromethyl-4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (223a) (75 mg, 0.24 mmol) to give a white solid (20 mg, 16% yield). 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1 H) 7.25-7.35 (m, 1 H) 7.12-7.21 (m, 2 H) 6.71-6.82 (m, 1 H) 6.54 (d, J=8.34 Hz, 2 H) 5.73-6.12 (m, 1 H) 5.02 (d, J=8.08 Hz, 1 H) 4.23 (t, J=7.83 Hz, 2 H) 4.00-4.10 (m, 2 H) 3.78 (s, 3 H) 3.17-3.29 (m, 2 H) 2.36 (t, J=7.71 Hz, 2 H); LCMS for C24H20F4N4O4 m/z 505.00 and 506.00 (M+H)+; Anal. Calcd. for C24H20F4N4O4: C, 53.77; H, 4.01; N, 9.95; Found: C, 53.79; H, 3.91; N, 9.87.
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[C:10]([CH3:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:28])=[N+:7]2[O-].C1(S(Cl)(=O)=O)C=CC=CC=1.[CH3:39][NH:40][CH3:41]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:15]([O:14][CH2:13][C@H:12]([C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:26])[N:7]=[C:6]([CH2:28][N:40]([CH3:41])[CH3:39])[CH:5]=[CH:4]2)[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CNC
Reactant: Cc1cc2c(ccc(C)[n+]2[O-])c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc2nc(CN(C)C)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 110 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a stirred solution of (S)-5-bromo-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline 1-oxide (25 mg, 0.055 mmol) in toluene (3 mL) was added benzenesulfonyl chloride (0.06 mL, 0.24 mmol). The mixture was stirred at 110° C. for 16 hours, then cooled to room temperature. Dimethylamine (2 mL 2 M solution in methanol, excess) was added. The mixture was stirred at room temperature for 16 h, then diluted in ethyl acetate (30 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product as a white solid (11 mg, 42%). LCMS-ESI+ (m/z): 479.3, 481.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([Br:1])=[CH:3][C:4]3[CH2:8][CH2:7][O:6][C:5]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: Nc1ccc(-c2cc3c(cc2Br)CCO3)cn1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cc3c(cc2Br)CCO3)cn1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of 5-(5-bromo-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (139) (13 mg, 0.044 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (11 μl, 0.088 mmol) followed by addition of DIEA (38 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(5-bromo(2,3-dihydrobenzo[3,4-b]furan-6-yl))(2-pyridyl)]carboxamide (140) (15.5 mg, yield: 81.6%, purity>90%) as white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[O:7]=[C:4]1[CH2:5][CH2:6][C:2](=[O:1])[N:3]1[O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:20](=[O:21])[N:19]([CH3:18])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:12][CH:11]=1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-Hydroxy-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized from methanol (74%, white crystals).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][Cl:13])(=[O:11])=[O:10])=[CH:6][C:5]([NH:14][C:15]([N:17]2[CH2:21][C@@H:20]([F:22])[CH2:19][C@@H:18]2[C:23](O)=[O:24])=[O:16])=[C:4]([F:26])[CH:3]=1.S(Cl)(Cl)=O>ClCCl.CN(C)C=O>[Cl:13][CH2:12][S:9]([NH:8][C:7]1[CH:6]=[C:5]([N:14]2[C:23](=[O:24])[C@H:18]3[CH2:19][C@H:20]([F:22])[CH2:21][N:17]3[C:15]2=[O:16])[C:4]([F:26])=[CH:3][C:2]=1[Cl:1])(=[O:10])=[O:11]
Reactant: O=C(O)[C@H]1C[C@H](F)CN1C(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1[C@H]2C[C@H](F)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 84.7 %

Procedure:
Crude (2R-trans)-1-[[[4-chloro-5-[[(chloromethyl)sulfonyl]amino]-2-fluorophenyl]amino]carbonyl]-4-fluoro-2-pyrrolidinecarboxylic acid (173.43 g) was suspended in 550 mL of dichloromethane and 0.65 mL (0.61 g, 8.4 mmol) of N,N-dimethylformamide was added, followed by the dropwise addition of 58 mL (95 g, 0.80 mol) of thionyl chloride at room temperature, and stirring was continued at room temperature. After 2.5 hours, the mixture became homogeneous. After 22 hours, the mixture was poured into 500 mL of ice-water, the layers were separated and the aqueous layer was extracted with dichloromethane (twice with 75 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (twice with 400 mL), dried over magnesium sulfate and evaporated under reduced pressure to afford 140.69 g of the crude title compound (84.7% yield from the isocyanate).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20].C(N(C(C)C)CC)(C)C.[C:30](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([N:3]1[N:2]=[N:1][C:5]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[N:4]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1nn[nH]n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.9 %

Procedure:
To a solution of 2-[4-(2H-tetrazol-5-yl)-butyl]-isoindole-1,3-dione (4.07 g, 15.0 mmol) and diisopropylethylamine (7.8 mL, 45.0 mmol) in DCM (60 mL) was added trityl chloride (5.86 g, 21.0 mmol). The solution was stirred at ambient temperature for 14 h, and concentrated. The resulting residue was partitioned between EtOAc/DCM (3:1) and H2O. Organic layer was separated, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with DCM/hexane (40, 80, and 100%) followed by EtOAc/DCM (1 and 2%) to give the title compound (5.08 g, 66% yield) as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:35])[CH3:38]
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Reactant: CCOC(=O)Cl
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)OCC)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A179) and ethyl chloroformate the title compound was obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[Br-:7].[CH2:8]([N+:4]1[CH:5]=[CH:6][N:2]([CH3:1])[CH:3]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Cn1ccnc1
Reactant: CCCCCCCCCCBr
Product: CCCCCCCCCC[n+]1ccn(C)c1
Product: [Br-]
Temperature: 90 °C
Yield: 95.8 %

Procedure:
A 35 mL glass pressure tube (Ace Glass Cat#8648-07) containing a stir bar was charged with 4.105 g (0.050 moles) of 1-methylimdazole followed by 11.059 g (0.050 moles) of 1-bromodecane. The tube was sealed with a threaded Teflon plug and an O-ring and the tubes were placed in an oil bath on a VWR stirring hot plate. The temperature was raised to 90° C. and maintained at this temperature for 16 hours during which time the solution became viscous and the stir bar had stopped. The tube was removed from the bath and mixed vigorously on a vortexing mixer to completely mix the two layers and the tube replaced into the oil bath at 90° C. and the temperature raised to 100° C. The tube was heated for another hour and then mixed vigorously a second time followed by another hour of heating at 100° C. The cycle was repeated once more until the viscous liquid was homogeneous. The liquid was extracted with equal volumes of ethyl acetate three times followed by rotary evaporation to remove the residual ethyl acetate to give 14.532 g of the 1-hexyl-3-methylimidazolium bromide as a viscous lightly yellow colored oil. Compound is also available from IoLiTec (Heilbronn, Germany).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[C:15]([CH3:23])[C:14]=1[O:24][CH3:25].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[C:15]([CH3:23])[C:14]=1[O:24][CH3:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C)c(C)c(OC)c(Cc2ccccc2)c1C
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
A 24.1 ml (38.6 mmole) of n-butyllithium.hexane solution was added dropwise to 10.0 g (38.6 mmole) of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene dissolved in anhydrous tetrahydrofuran (100 ml), under an atmosphere of argon at -40° C. over the period of 10 minutes, followed by stirring for another 20 minutes. Then, 3.32 g (38.6×0.6 mmole) of cuprous bromide was added, followed by stirring at -40° to -20° C. for 1 hour. After addition of a solution of 6.60 g (38.6 mmole)of benzyl bromide in tetrahydrofuran (15 ml), the cooling bath was removed, the reaction solution was stirred at 70° C. for 1 hour and cooled with ice, followed by addition of 1N hydrochloric acid (50 ml) and stirring. The tetrahydrofuran was distilled off under reduced pressure, and isopropyl ether was added to the residue. The insoluble matter was filtered through a bed of Hyflo Supercell, and the isopropyl ether layer was separated out, washed with water and aqueous sodium chloride solution successively, dried (magnesium sulfate) and evaporated. The residual solution was distilled under reduced pressure to give 8.62 g (83%) of 1-benzyl-2,5-dimethoxy-3,4,6-trimethylbenzene, b.p.140°-142° C. (0.3 torr) and m.p. 70° to 71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][C:11]([NH:14][C:15](=[O:20])[C:16](F)(F)F)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.[Cl:27][C:28]1[CH:36]=[CH:35]C(C(Cl)=O)=[CH:30][CH:29]=1>O>[Cl:27][C:28]1[CH:36]=[CH:35][C:16]([C:15]([NH:14][C:11]2[CH2:12][CH2:13][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[N:10]=2)=[O:20])=[CH:30][CH:29]=1
Reactant: O=C(NC1=NN(c2ccc(Cl)c(Cl)c2)CC1)C(F)(F)F
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1=NN(c2ccc(Cl)c(Cl)c2)CC1)c1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
A stirred mixture of 2.30 g. of 3-amino-1-(3,4-dichlorophenyl)-2-pyrazoline (prepared as described in Example 1) in 20 ml. of dry pyridine is cooled in an ice bath, then 2.10 g. of p-chlorobenzoyl chloride is added. The reaction mixture is allowed to stand at room temperature for 16 hours then is poured into water to separate a solid. The solid is collected by filtration and dissolved in dichloromethane. This solution is passed through a short column of a hydrous magnesium silicate. The effluent is refluxed and hexane is added until turbidity results. The solution is cooled and filtered to collect a product. The product is recrystallized from the same solvent pair to give 1.8 g. of the desired product as yellow needles, m.p. 177°-178° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[CH2:9]([C:11]([C:29]1[S:33][C:32]([S:34]([NH2:37])(=[O:36])=[O:35])=[C:31]([CH3:38])[CH:30]=1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([CH3:28])[CH:15]=1)[CH2:12][CH3:13])[CH3:10].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CC(OC(C)=O)=O>ClCCl>[C:1]([O:5][C:6](=[O:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:23]([CH3:24])([CH3:25])[C:22](=[O:27])[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]([C:29]2[S:33][C:32]([S:34]([NH2:37])(=[O:36])=[O:35])=[C:31]([CH3:38])[CH:30]=2)([CH2:9][CH3:10])[CH2:12][CH3:13])=[CH:15][C:16]=1[CH3:28]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Yield: 92.3 %

Procedure:
A mixture of (5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid tert-butyl ester (360 mg, 0.63 mmol), pyridinium dichromate (179 mg, 0.48 mmol) and Ac2O (66 μL, 0.7 mmol) in dichloromethane (10 ml) is refluxed for 3 h. The reaction is concentrated and chromatographed (Hex to 15% EtOAc/Hex) to give the title compound (330 mg, 92%); 1H NMR (CDC3): δ 6.96, 7.23 (m, 2H), 6.56 (s, 1H), 6.51 (d, 1H, J=8.3 Hz), 6.57 (s, 1H), 5.08 (t, 1H), 4.85 (s, 2H), 3.71 (d, 2H, J=5.4 Hz), 2.40 (s, 3H), 2.26 (s, 3H), 2.07 (q, 4H), 1.40 (s, 9H), 1.26 (s, 9H), 0.90 (s, 9H), 0.70 (t, 6H);
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10])([CH3:5])[CH3:4])#[N:2].Cl.Cl.[NH2:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([O:21][C:20]2[CH:19]=[C:18]([NH:17][C:9](=[O:10])[C:8]3[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Nc1cccc(Oc2ccc(N)nc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (50 mL) was added 5-(3-aminophenoxy)pyridine-2-amine dihydrochloride (3.5 g, 12.7 mmol) produced in Example A1(ii), and the mixture was stirred at room temperature for 18 hr. 5% Aqueous sodium hydrogen carbonate solution (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100) and triturated with ethyl acetate and hexane to give the title compound (3.44 g, 66%) as a colorless solid.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.O[CH2:42][C:43]1[CH:48]=[CH:47][N:46]=[C:45]([N:49]([CH3:51])[CH3:50])[CH:44]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl>[ClH:19].[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:42][C:43]4[CH:48]=[CH:47][N:46]=[C:45]([N:49]([CH3:51])[CH3:50])[CH:44]=4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: CN(C)c1cc(CO)ccn1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccnc(N(C)C)c1
Product: Cl
Temperature: 25 °C
Yield: 62.2 %

Procedure:
1,1′-(azodicarbonyl)dipiperidine (1.68 g, 6 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (640 mg, 2 mmol), 4-hydroxymethyl-2-(dimethylamino)pyridine (426 mg, 2.8 mmol) and tributylphosphine (1.6 ml, 6 mmol) in methylene chloride (50 ml) at 0° C. The mixture was allowed to warm to ambient temperature over 2 hours, the insolubles were removed by filtration and the filtrate was washed with water and brine, dried (Na2SO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (100:0 increasing to 95:5). The purified product was dissolved in acetone/methanol and a 1M solution of ethereal hydrogen chloride was added. The resulting precipitate was collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-7-(2-(dimethylamino)pyrid-4-yl)methoxy-6-methoxyquinazoline hydrochloride (305 mg, 30%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[N:8]=[C:9]([S:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]2[O:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:15])[S:10][CH:11]=1)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:20]2[CH2:21][CH2:22][O:23][C@@H:18]([CH2:17][NH:16][C:14](=[O:15])[CH2:13][S:12][C:9]3[S:10][CH:11]=[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:8]=3)[CH2:19]2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)Cc1csc(SCC(=O)NC[C@@H]2CNCCO2)n1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)cc3)CCO2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The resultant product (899 mg) of (75-3) was dissolved in methylene chloride (12.5 mL), 4-chlorobenzaldehyde (387 mg) and acetic acid (143 μL) were added and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (1.06 g) was added to the reaction mixture and the mixture was further stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and acetone as an eluent. The solvent was evaporated from the eluent to give the title compound (1.16 g) as a pale-yellow oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[Li]CCCC.[C:16](=[O:18])=[O:17].Cl>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([C:16]([OH:18])=[O:17])=[CH:9][N:10]=1
Reactant: c1csc(C2OCCO2)n1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cnc(C2OCCO2)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)thiazole (65 g, 0.41 mol) in THF (900 mL) under nitrogen was slowly added n-BuLi (180 mL, 2.5 M in hexanes) at −78° C. The mixture was stirred at −78° C. for 2 h, and then solid dry ice was added. The solution was then warmed to rt and stirred overnight. Hydrochloric acid (2 N) was added to the solution until pH<4. The mixture was then extracted with ether (5×300 mL). Combined organic phases were washed with water (200 mL), brine (200 mL), dried (Na2SO4), and concentrated to give a yellow solid. This solid was then rinsed with petroleum ether to give 2-(1,3-dioxolan-2-yl)thiazole-5-carboxylic acid (72.5 g, 87%). 1H NMR (dmso-d6, 400 MHz) δ 13.70 (s, 1H), 8.36 (s, 1H), 6.10 (s, 1H), 4.06 (m, 4H).