Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[CH3:6][O:7][C:8]1[C:9](=[O:19])[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16](=[O:18])[CH:17]=1.[N-:20]=[N+]=[N-].[Na+]>CO>[CH3:6][O:7][C:8]1[C:9](=[O:19])[NH:20][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16](=[O:18])[CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=CC(=O)C2=C(CCCC2)C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc(=O)c2c([nH]c1=O)CCCC2
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
To stirred, ice bath cold, concd H2SO4 (10 mL, Baker), there was added 2-methoxy-5,6,7,8-tetrahydronaphthalene-1,4-dione (600 mg, 3.12 mmol) in portions. A deep red solution resulted. To this cold solution, NaN3 (406 mg, 6.24 mmol, Aldrich) was added in portions. The reaction was allowed to slowly attain rt with stirring under N2. Gas evolution was noted. After 16 h, the reaction was judged complete by TLC analysis (10% MeOH/90% CHCl3). The reaction was added to crushed ice (100 mL) to give a yellow/brown solution. This was extracted with 30% MeOH/70% CHCl3 (4×30 mL) and CHCl3 (2×30 mL). The extract was washed with water (1×20 mL), saturated NaHCO3 (1×20 mL) and brine (1×20 mL), filtered through cotton and the solvent removed in vacuo to give a red solid (280 mg). An additional portion was obtained in exactly the same manner (350 mg). The combined solids were subjected to vacuum chromatography (silica gel, 2.5×25 cm, initial CHCl3 elution to remove mobile impurities, 2% EtOH/98% CHCl3 elution to remove product) to yield a pink solid. Crystallization from 95% EtOH (dissolved in 20 mL, hot filtered, concd to 8 mL, allowed to cool to rt) yielded a pink solid (242 mg, 19%, >95% pure by 1H NMR, mp 227.5°-228.5° C.). A sample was further purified by recrystallization from 95% EtOH (25 mg dissolved in 2 mL, allowed to cool to rt, yielded a pale pink solid, 14 mg, 56% recovery); mp 228.5°-229.5° C.; 1H NMR (DMSO-d6) δ1.55 (m, 4H), 2.28 (m, 2H), 2.43 (m, 2H), 3.72 (s, 3H), 6.23 (s, 1H), 10.57 (s, 1H); MS m/z 207 (M+, 85).
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.C(N(CC)[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1>O1CCCC1.C1CCCCC1>[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[O:34]2)=[CH:31][CH:30]=1
Reactant: CCN(CC)C(=O)c1ccccc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CN(C)c1ccc(C2OC(=O)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
To a solution of 1.28 g of N,N,N',N'-tetramethylethylene-diamine in 25 ml of tetrahydrofuran was added 10.5 ml of 1.05 M cyclohexane solution of sec-butyl lithium under a nitrogen gas atmosphere, and a solution of 1.77 g of N,N-diethylbenzamide in 15 ml of tetrahydrofuran was added to the solution at -78° C. After stirring for 10 minutes at -78° C., a solution of 2.24 g of 4-dimethylaminobenzaldehyde in 10 ml of tetrahydrofuran was added to the mixture. After stirring at -78° C. for 1.5 hours, the temperature was gradually elevated to 5° C. and the reaction mixture was concentrated under reduced pressure. To the residue were added 50 ml of water and 50 ml of ethyl ether, and pH of the mixture was adjusted to 0.5 with 4N-hydrochloric acid. After shaking, the organic layer was discarded and 50 ml of methylene chloride was added to the aqueous layer. The pH was adjusted to 12 with 10N-sodium hydroxide solution. After shaking, the aqueous layer was discarded and the organic layer was washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure. The crude product obtained was subjested to silica gel column chromatography (eluting solvent, ethyl acetate:hexane:triethylamine=50:50:5). A fraction eluted secondly was concentrated under reduced pressure and the concentrate was tritylated with methyl alcohol to give 0.54 g of 3-(4-dimethylaminophenyl)-1,3-dihydro-isobenzofuran-1-one (Compound A).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[N:3]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:20][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[N+:7]([O-:9])=[O:8]
Reactant: Cn1cc([N+](=O)[O-])cn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
Following WO 2007/99326, to a 500 mL 3-neck-round bottom flask was added 1-methyl-4-nitro-1H-pyrazole (4.30 g, 33.8 mmol) and THF (12 mL). The mixture was cooled to −78° C. and lithium hexamethyldisilazide in THF (1M, 88.4 mL, 90 mmol) was added dropwise via an addition funnel over 20 min. The brown mixture was stirred for 30 min and warmed to −45° C. over 30 min. The mixture was cooled back down to −78° C. and hexachloroethane (10.5 g, 44.2 mmol) dissolved in THF (20 mL) was added via an addition funnel over 15 min. The mixture was stirred for 2.5 h, warmed from −78° C. to −40° C. and the reaction was monitored by LCMS. Upon completion of the reaction, the reaction was quenched with a solution of saturated NH4Cl (150 mL), and ethyl acetate (100 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water (150 mL), dried over Na2SO4 and the organic solvent was distilled off. The crude product was purified via flash chromatography (CH2Cl2/7% MeOH) to yield 5-chloro-1-methyl-4-nitro-1H-pyrazole as a white solid (1.40 g, 20%). 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 3.92 (s, 3H); ESIMS m/z=162.0 (M+1)
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([NH2:14])[C:12]#[CH:13].CCN(CC)CC>CC#N>[CH2:11]([NH:14][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)[C:12]#[CH:13]
Reactant: Clc1nc2ccccc2o1
Reactant: C#CCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#CCNc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-chlorobenzoxazole (1.53 g, 10 mmol) in CH3CN (5 mL) was added dropwise to a mixture of propargyl amine (550 mg, 9.9 mmol) and Et3N (2.09 mmol, 15 mmol) and CH3CN (10 mL) under N2, and the resulting mixture was heated to reflux for 4 h, then stirred overnight at rt. The mixture was filtered, and the filtrate was partitioned between EtOAc (100 mL) and brine. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4) and concentrated to dryness. The crude solid was diluted with heptane (20 mL) and Et2O (50 mL) and the mixture was heated to boiling and filtered hot. The filtrate was concentrated to dryness, then taken up in boiling Et2O (50 mL) and the solution was cooled and filtered. The filtrate was diluted with hexane (125 mL) and cooled to −20° C. for 4 h, and the crystallized product was collected by filtration (1.1 g, 64%). MS (APCI(+)) m/e 173.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cccc(F)c1F
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of 12.0 g (75.42 mmol) of 3,4-difluoronitrobenzene (2) in 150 mL of acetonitrile was treated with 16.24 g (188.6 mmol) of piperazine, followed by warming at reflux for 3 hours. The solution was cooled to ambient temperature and was concentrated in vacuo. The residue was diluted with 200 mL of water and was extracted with ethyl acetate (3×250 mL). The combined organic layers were extracted with water (200 mL) and saturated NaCl solution (200 mL), followed by drying (Na2SO4). The solution was concentrated in vacuo to afford an orange oil which was chromatographed over 450 g of 230-400 mesh silica gel eluting initially with dichloromethane until the least polar fractions had eluted and then elution was continued with 2% (v/v) methanol-chloroform and then with 10% (v/v) methanol-chloroform. These procedures afforded 13.83 g (81%) of the desired piperazine derivative 3, mp=68.5°-71° C.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[C:30]([C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1)([OH:32])=[O:31]>>[C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29][S:39]([C:36]3[CH:35]=[CH:34][C:33]([C:30]([OH:32])=[O:31])=[CH:38][CH:37]=3)(=[O:41])=[O:40])=[CH:27][CH:28]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(N)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
In the same manner as in Example 377, 3-acetyl-2-(4-aminobenzyl)-6-bromo-4-phenyl-2H-isoquinolin-1-one was reacted with 4-carboxybenzenesulfonyl chloride to give the title compound. yield: 45 mg (26%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[CH:27]=[CH:28][C:29]([O:33][CH3:34])=[C:30]([CH:32]=1)[NH2:31])([CH3:25])=[O:24].[OH-].[Na+]>COCCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:31][C:30]2[CH:32]=[C:26]([P:23]([CH3:22])([CH3:25])=[O:24])[CH:27]=[CH:28][C:29]=2[O:33][CH3:34])=[N:3][CH:4]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1ccc(P(C)(C)=O)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: COc1ccc(P(C)(C)=O)cc1Nc1ncc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 90 °C
Yield: 48.7 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as prepared in Example 17: 0.077 g, 0.22 mmol) in 1.5 mL of 2-methoxyethanol was added 5-(dimethylphosphoryl)-2-methoxyaniline (0.050 g, 0.21 mmol) as its hydrochloride salt. The mixture was heated in a sealed tube at 90° C. for 16 h. The mixture was basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by prep-HPLC to afford the final compound (52 mg, 48% yield). MS/ES+: m/z=509.
Reaction SMILES: C([O:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH3:16])[CH:6]=1)(=O)C>CO>[OH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH3:16])[CH:6]=1
Reactant: CC(=O)Oc1cc(-c2ccccc2)n(C)c1
Solvent: CO
Product: Cn1cc(O)cc1-c1ccccc1
Reaction time: 0.25 h

Procedure:
To a mixture of deoxygenated methanol (15.5 ml) and 3-acetoxy-1-methyl-5-phenylpyrrole (11) (1.3 g, 6.2 mmole), under argon, was added deoxygenated NaOH (2N, 12.5 ml). The reaction mixture was stirred in an ice-bath for 15 minutes. Then deoxygenated citric acid (2M, 7 ml) was added and the resulting mixture was stirred in an ice bath for 8 minutes. The reaction mixture was concentrated under reduced pressure, then 20 ml of water was added and was extracted twice with ethylacetate (EtOAc) (50 ml). The EtOAc layers were combined, dried ovr MgSO4, filtered and concentrated under reduced pressure to give 3-hydroxy-1-methyl-5-phenylpyrrole (12) as an orange residue. Under argon, a cold solution of anhydrous THF (12.4 ml), pyridine (0.6 ml, 7.4 mmole, 1.2 eq) and trifluoroacetic acid (1.2 ml, 15 mmole, 2.4 eq) was added to the orange residue, followed immediately by the addition of a solution of freshly prepared N-tosyl-L-alaninyl chloride (1.2 g, 7.4 mmole, 1.2 eq) in anhydrous THF (12.4 ml). The resulting mixture was stirred for one hr at 0° C. Then the reaction was quenched by the addition of aqueous citric acid (1M, 5 ml) and EtOAc (30 ml). After a brief mixing, the layers were separated and the organic layer was successively washed with saturated NaCl solution, twice with 5% NaHCO3 solution and again with saturated NaCl solution. The EtOAc extract was then dried over MgSO4, treated with Norit 211, filtered and concentrated under reduced pressure to give the crude product (13) as an orange residue. This was dissolved in hexane:EtOAc (1:1) (5 ml) and chromatographed on a column (SiO2, 100 g) by elution with hexane:EtOAc (7:3) to give 1 g of (13) as a thick light orange oil. A portion of this crude product was further purified by semi-preparative HPLC (column, IBM silica, 1 cm×25 cm; mobile phase, hexane:EtOAc 8:2; flow rate, 4.0 ml/min; pressure, 0.2 psi) to yield a honey color thick oil (13).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[OH:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.I[CH:24]([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[O:14][CH:24]([CH3:26])[CH3:25])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC(C)I
Reactant: CCOC(=O)c1cn(C2CC2)c2c(O)c(F)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(C)C)c(F)c(F)cc2c1=O
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A solution of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxoquinoline-3-carboxylate (1.10 g, 3.56 mmol), 2-Iodopropane (0.534 mL, 5.34 mmol) and K2CO3 (738 mg, 5.34 mmol) in DMF (10 mL) was stirred at room temperature for 1 h and at 70° C. for 3 h. After cooled to room temperature, the reaction mixture was poured into ice-water and the resulting precipitate was collected by filtration, washed with water and dried to yield ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-4-oxoquinoline-3-carboxylate (611 mg, 49%) as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[O:5][N:4]=1.C1N2CN3CN(C2)C[N:15]1C3.Cl>CCO>[Cl:13][C:10]1[S:9][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH2:15])[CH:7]=2)=[CH:12][CH:11]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: Cl
Solvent: CCO
Product: NCc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.00 g (3.59 mmol) 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole and 503.3 mg (3.59 mmol) urotropin were dissolved in 40 mL EtOH. The reaction mixture was stirred at room temperature for 16 h. The next day 3 mL of a conc. HCl-solution were added and the resulting mixture was refluxed for 45 minutes. After cooling the precipitate was filtered off and washed with water. The white crystalline material was dried under reduced pressure at 40° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([NH2:11])[CH2:3]1.[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15].CCN(C(C)C)C(C)C>C1COCC1>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([NH:11][C@@H:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:12])([CH3:1])[CH2:3]2)[N:16]=1
Reactant: CC1(C)C[C@H](N)c2ccccc21
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)C[C@H](Nc2nc(Cl)nc(Cl)n2)c2ccccc21
Reaction time: 1.5 h
Yield: 59.4 %

Procedure:
To a solution of (1S)-3,3-dimethylindan-1-amine (0.67 g, 4.2 mmol) in THF (3 mL) cooled to 0° C. was added cyanuric chloride (0.874 g, 4.74 mmol) resulting in a white solid. DIPEA (0.724 mL, 4.16 mmol) was added and the yellow mixture was stirred for 1.5 hours. The reaction was quenched with H2O and extracted with DCM (3×). The combined organic layers were dried (Na2SO4), filtered and collected in vacuo to give a pale yellow oil. The residue was; purified by flash chromatography (0 to 25% EtOAc/hexanes) to afford the title compound (0.771 g, 60%) as a white solid. LC/MS: Rt=2.20 min, ES+ 310 (FA standard).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13]S(C2SC3C=CC=CC=3N=2)(=O)=O)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12](/[CH:13]=[CH:43]/[C:42]2[CH:45]=[CH:46][C:39]([F:38])=[CH:40][CH:41]=2)[CH2:11][O:10][C:9]1([CH3:26])[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@H](CS(=O)(=O)c2nc3ccccc3s2)COC1(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](/C=C/c2ccc(F)cc2)COC1(C)C
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 53305.5 %

Procedure:
To a stirred, cooled (−78° C.) solution of (S)-4-(benzothiazole-2-sulfonylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.484 mg) in THF (12 ml) under an argon atmosphere was added slowly a 1 M solution of LiHMDS in THF (1.1 ml). The mixture was warmed to −40° C. and stirring at that temperature was continued for 30 min. The mixture was cooled again to −78° C. and a solution of 4-fluorobenzaldehyde (0.112 g) in THF (3 ml) was then added slowly via a syringe. Stirring at −78° C. was continued for 2 h, and then the reaction mixture was slowly allowed to warm to 0° C. The mixture was quenched by the addition of sat. aq. NH4Cl (15 ml) and H2O (15 ml) and extracted with EtOAc. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: cyclohexane ->cyclohexane/EtOAc 85:15) to give (R)-4-[(E)-2-(4-fluoro-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.201 g) as colorless viscous oil. MS (ISP): 322.4 ([M+H]+))
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[NH:7][CH:6]=1.[CH3:17]C(C)([O-])C.[K+]>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[CH2:17])[CH:12]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc2[nH]cc(CCN(C)C)c2c1
Yield: 88.7 %

Procedure:
To a solution of 3-(2-dimethylamino-ethyl)-1H-Indole-5-carbaldehyde (Example 13) (0.216 g, 1 mmol) in THF (5 mL), methyl triphenyl phosphonium bromide (0.393 g, 1.1 mmol) is added. To the obtained slurry, under an argon atmosphere potassium tert-butoxide (0.118 g, 1.05 mmol) is added in three portions at ambient temperature. When thin layer chromatography (TLC) indicates complete conversion of the aldehyde, the mixture is poured on ice and extracted with ethyl acetate. Removal of the solvent gives a residue which is chromatographed on silica (25 g, CHCl3, MeOH, NEt3 19:1:0.5 v:v:v) to give the title product as pale yellow oil (0.190 g, 88%). 1H-NMR (CDCl3, 300 MHz) δ 2.37 (s, 6H, N(CH3)2); 2.64-2.70 (m, 2H, CH2NMe2); 2.92-2.99 (m, 2H, CH2); 5.13 (d, 1H, J=10.9 Hz, cis H2C═CH); 5.69 (d, 1H, J=17.6 Hz, trans H2C═CH); 6.84 (dd, 1H, H2C═CH); 6.94 (br s, 1H, H-2); 7.24 (d, 1H, J=8.2 Hz, H-7); 7.31 (dd, J=1.8 Hz, H-6); 7.58 (d, 1H, H-4); 8.66 (br 5, 1H, NH). 13C-NMR (CDCl3, 75 MHz) δ 24.00 (CH2); 45.73 (N(CH3)2); 60.62 (CH2NMe2); 110.93 (H2C═CH); 111.50 (C-7); 114.66 (C-3); 117.41 (C-4); 120.20 (C-6); 122.42 (C-2); 127.83 (C-5); 129.34 (C-9); 136.45 (C-8); 138.22 (H2C═CH).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=1.[H-].[Na+].I[CH3:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2CO)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2COC)cc1
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
Ethyl 2'-hydroxymethyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carboxylate (D54) (0.51 g, 1.5 mmol) was stirred in dry DMF (8 ml) under argon. Sodium hydride (80% dispersion, 0.07 g, 2.3 mmol) was added, and the resulting suspension was stirred for 10 min. Iodomethane (0.19 ml, 3.0 mmol) was added; the mixture was stirred for 30 min, diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated to a yellow gum. Chromatography on silica gel, eluting with 0-50% ethyl acetate/dichloromethane, gave the title compound (0.34 g, 64%) as a colourless gum, solidifying on standing. A little methyl ester was also present.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[NH:37]1[CH2:42][CH2:41][O:40][CH:39]([C:43]([OH:45])=[O:44])[CH2:38]1>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:37]3[CH2:42][CH2:41][O:40][CH:39]([C:43]([OH:45])=[O:44])[CH2:38]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCOC(C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Yield: 75.1 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (1.6 g, 4 mmol), N,N-diisopropylethylamine (3.5 mL, 20 mmol) and morpholine-2-carboxylic acid hydrochloride (1.0 g, 6 mmol) in methylene chloride (10 mL). Obtained 1.5 g of crude product which was carried over to step A. 1H NMR (400 MHz, METHANOL-D4) δ 1.53 (d, J=13.67 Hz, 2 H), 1.59 (s, 12 H), 1.63-1.78 (m, 6 H), 1.98-2.12 (m, 3 H), 3.22 (q, J=7.36 Hz, 1 H), 3.72 (m, 1 H), 4.42 (d, J=7.42 Hz, 2 H), 7.69 (d, J=8.40 Hz, 1 H), 7.81 (d, J=8.40 Hz, 1 H), 8.05 (s, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([F:35])=[C:25]([C:28]5[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([CH2:40][CH2:41][NH2:42])(=[O:39])=[O:38]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([F:35])=[C:25]([C:28]5[O:32][C:31]([CH2:33][NH:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:30][CH:29]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cc2F)o1
Product: CS(=O)(=O)CCNCc1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cc2F)o1

Procedure:
Prepared according to Procedure D from 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). δ 1H NMR (400 MHz, DMSO-d6) 10.16 (s, 1H), 8.91 (d, 1H), 8.46 (s, 1H), 8.11 (s, 2H), 7.65 (m, 3H), 7.26 (m, 5H), 6.93 (m, 1H), 6.54 (d, 2H), 5.65 (s, 2H), 3.89 (s, 2H), 3.28 (m, 2H), 2.99 (m, 5H). ESI-MS m/z 569 (M−1).