Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20]CCCCC.C([Li])CCC.CI.Cl>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=[O:18])=[C:16]([CH3:20])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1
Reactant: CCCCCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)sc2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
5-t-Butoxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid (300 mg, 1.1 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml), n-butyl lithium hexane solution (15%, 1.5 ml, 2.3 mmol) was added dropwise thereto at −78° C. in an atmosphere of argon, and then the mixture was stirred for 1 hour. The reaction solution was mixed with methyl iodide (1.6 ml, 2.7 mmol) and stirred for 1 hour and then at room temperature for 1 hour. The reaction solution was mixed with ethyl acetate and hydrochloric acid (1 N) to acidify the water layer, and then the reaction product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate, and then the solvent was removed by evaporation under a reduced pressure and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 180 mg (0.61 mmol, 57% in yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
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: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (40.2 g, 165 mmol) in CH2Cl2 (500 mL) and AcOH (60 mL) was added dihydro-2H-pyran-4-one (17.3 g, 173 mmol) and sodium triacetoxyborohydride (73.6 g, 330 mmol). The reaction mixture was stirred at RT for 20 hours. Then saturated NaHCO3 aq. was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 and the combined organic layer was concentrated in vacuo. The residue was triturated with ethyl ether, and resultant precipitate was collected to afford the titled compound as a white solid (39.1 g, 72%). 1H-NMR (400 MHz, DMSO-d6) δ ppm; 7.01 (s, 1H), 6.98 (s, 1H), 5.00 (d, J=7.6 Hz, 1H), 3.84-3.87 (m, 2H), 3.79 (s, 3H), 3.54-3.56 (m, 1H), 3.43 (m, 2H), 2.14 (s, 3H), 1.81-1.84 (m, 2H), 1.47-1.55 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][OH:13].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][O:13][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1
Reactant: C1=COCCC1
Reactant: Cc1cc(Cl)c(CO)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(Cl)c(COC2CCCCO2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To a solution of (2-chloro-4-methyl-5-nitrophenyl)methanol (23 g, 114 mmol) and 3,4-dihydro-2H-pyran (20.9 mL, 228 mmol) in CH2Cl2 (500 mL) was added pyridinium p-toluenesulfonate (5.7 g, 22.8 mmol), and then the mixture was stirred at room temperature for 11 h. The reaction was quenched by 5% aq. NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2. The organic layers were combined and washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by SiO2 column chromatography (heptane/EtOAc=96/4, isocratic) to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 8.10 (s, 1H), 7.49 (s, 1H), 4.81 (d, J=13.64 Hz, 1H), 4.72-4.78 (m, 1H), 4.59 (d, J=13.64 Hz, 1H), 3.77-3.92 (m, 1H), 3.34-3.60 (m, 1H), 2.54 (s, 3H), 1.68-1.91 (m, 2H), 1.43-1.68 (m, 4H).
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[C:8]2[CH2:9][CH2:10][N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12](=[O:17])[C:13]=2[C:14]=1[O:15][CH3:16])(=O)C.C[O-].[Na+]>CO>[OH:4][C:5]1[N:6]=[C:7]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[C:8]2[CH2:9][CH2:10][N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12](=[O:17])[C:13]=2[C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(CN2CCc3c(C(=O)N(C)C)nc(OC(C)=O)c(OC)c3C2=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN2CCc3c(C(=O)N(C)C)nc(O)c(OC)c3C2=O)cc1

Procedure:
1-[(dimethylamino)carbonyl]-4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl acetate (7.55 g) was dissolved in 50 mL MeOH and treated with 6.65 mL of a 30% by weight solution of NaOMe in MeOH at room temperature for 30 minutes. The reaction was concentrated and the remaining solid partitioned between 10% KHSO4 and chloroform. The organic layer was washed with brine, dried over Na2SO4, and then concentrated to pure product by HPLC/MS and NMR.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.OS(O)(=O)=O>CCOCC>[S:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH:4]([OH:11])[CH2:3][CH2:2]1
Reactant: O=C1CCSc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OC1CCSc2ccccc21

Procedure:
A solution of thiochroman-4-one (9 g) in ether (27 ml) was added slowly to a mixture of lithium aluminium hydride (0.53 g) in ether (54 ml). After the end of the addition, the mixture was refluxed for 2 hours. The reaction mixture was cooled and ice was added, followed by water and by a solution of 20% H2SO4. The water phase was washed twice with ether. The ether phase was washed twice with NaOH 2N, and once with water, dried over MgSO4 and evaporated. The clear oil (8.9 g) crystallised after few hours. Rdt=97%
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[N:13]=[CH:14][C:15]([NH:18][C:19](=[O:43])[C@@H:20]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH:37]3[CH2:39][CH2:38]3)(=[O:36])=[O:35])=[C:30]([CH:40]3[CH2:42][CH2:41]3)[CH:29]=2)[CH2:21][C@H:22]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]2)=[N:16][CH:17]=1)C1C=CC=CC=1>CO.[C].[Pd]>[CH:40]1([C:30]2[CH:29]=[C:28]([C@@H:20]([CH2:21][C@H:22]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]3)[C:19]([NH:18][C:15]3[CH:14]=[N:13][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:17][N:16]=3)=[O:43])[CH:33]=[CH:32][C:31]=2[S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:36])=[O:35])[CH2:42][CH2:41]1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)Nc2cnc(OCCOCc3ccccc3)cn2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Agent: [Pd]
Solvent: CO
Product: O=C1CC[C@H](C[C@@H](C(=O)Nc2cnc(OCCO)cn2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 69.2 %

Procedure:
To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propionic acid (120 mg) in dichloromethane (5 mL) was sequentially added a solution of 0.5 M oxalyl chloride in dichloromethane (0.77 mL) and DMF (10 μL) under ice-cooling, followed by stirring under ice-cooling for 1 hour. Thereafter, 5-[2-(benzyloxy)ethoxy]pyrazin-2-amine (86 mg) and pyridine (0.05 mL) were added thereto under ice-cooling, followed by stirring for 2 hours under ice-cooling. To the reaction mixture was added water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over anhydrous magnesium sulfate. The oily substance obtained by concentration was purified by silica gel column chromatography (hexane:ethyl acetate=5:1-1:1) to obtain (2R)—N-{5-[2-(benzyloxy)ethoxy]pyrazin-2-yl}-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanamide (175 mg) as a pale yellow amorphous substance. To a solution of the obtained (2R)—N-{5-[2-(benzyloxy)ethoxy]pyrazin-2-yl}-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanamide (175 mg) in methanol (10 mL) was added 10% palladium carbon (50 mg). Under a hydrogen atmosphere, it was stirred at room temperature at 4 atm for 7 hours. The reaction mixture was filtered through Celite and concentrated. To a solution of the obtained oily substance in THF (10 mL) was added 1 M hydrochloric acid (10 mL) at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The oily substance obtained by concentration was purified by silica gel column chromatography (wetting with hexane:ethyl acetate=1:1, chloroform:methanol=1:0-10:1) to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(2-hydroxyethoxy)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamide (103 mg) as a pale yellow amorphous substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:25][C@H:26]4[C@H:30]5[O:31][CH2:32][C@@H:33]([OH:34])[C@H:29]5[O:28][CH2:27]4)[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1.[N:36]1[NH:37][CH:38]=[C:39]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41][C:40]=12.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC.N1C=CC=N1>[Cu]I.CCOC(C)=O.CCCCCC.O1CCOCC1>[OH:34][C@@H:33]1[CH2:32][O:31][C@@H:30]2[C@H:26]([O:25][C:15]3[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]4[C:12]([N:14]=3)=[N:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:37]5[CH:38]=[C:39]6[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41][C:40]6=[N:36]5)=[CH:3][CH:4]=3)=[C:9]([Cl:35])[CH:10]=4)[CH2:27][O:28][C@H:29]12
Reactant: CC(C)(C)OC(=O)N1Cc2c[nH]nc2C1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1Cc2cn(-c3ccc(-c4nc5nc(O[C@@H]6CO[C@H]7[C@@H]6OC[C@H]7O)n(COCC[Si](C)(C)C)c5cc4Cl)cc3)nc2C1
Temperature: 100 °C

Procedure:
A vial was charged with (3R,3aR,6R,6aR)-6-[5-(4-bromophenyl)-6-chloro-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (501.8 mg, 0.861 mmol), tert-butyl 4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-carboxylate (240.3 mg, 1.148 mmol), tripotassium phosphate (581.6 mg, 2.74 mmol), and copper (I) iodide (37.2 mg, 0.195 mmol). The vial was evacuated (3×) and backfilled with nitrogen. Trans-N,N′-dimethylcyclohexane-1,2-diamine (55 μl, 0.348 mmol) and dioxane (1.7 ml) were added to the vial to give a hazy suspension that was heated to 100° C. for 24 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (100 ml) and water (100 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a pale green residue. Flash chromatography of the residue utilizing a 40 g silica RediSep Rf® column and employing a 0-100% EtOAc/hexane gradient afforded a mixture of the two pyrazole linked regioisomers as a pale amber foam. LC-MS: calculated for C34H43ClN6O7Si 710.27 observed m/e: 711.29 (M+H)+ (Rt 1.30/2 min)
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][NH:19][CH2:18]2>O1CCCC1.C(OCC)(=O)C>[CH:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][N:19]([C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9])[CH2:18]2
Reactant: N#Cc1cccnc1F
Reactant: C1CC2CCC1CNC2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cccnc1N1CC2CCC(CC2)C1
Reaction time: 12 h

Procedure:
To a solution of 2-fluoro-3-cyanopyridine (0.4 g, 3.27 mmol) in 30 mL tetrahydrofuran was added triethylamine (0.66 g, 6.5 mmol) and 3-aza-bicyclo[3.2.2]nonane (0.5 g, 3.9 mmol). The reaction was held at 50° C. for 12 hours, cooled and diluted with 100 mL ethyl acetate. The organics were washed with water (2×50 mL), brine (1×50 mL), dried (MgSO4) and concentrated. Column chromatography (20% ethyl acetate/hexanes) gave the title compound as a solid. MS (ESI/NH3) m/z 126 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Oc1cccc2[nH]ccc12
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: BrCCCCCOc1cccc2[nH]ccc12
Temperature: 90 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a stirred suspension of 4-hydroxyindole (10.0 g, 75.2 mmol) and 1,5-dibromo-pentane (26.0 g, 112.8 mmol) in N-methylpyrrolidinone (100 mL) was added potassium carbonate (16.0 g, 112.8 mmol). The resulting mixture was stirred at 90° C. for 4 hours and then quenched with water (30 mL) followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and then concentrated under vacuum. The resulting residue was purified by silica gel chromotography to give 4-(5-bromo-pentyloxy)-1H-indole (14.0 g, 49.6 mmol, 66%) as a white solid.
Reaction SMILES: [F:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH:15]1[CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(#N)C>[N:15]1([S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([F:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[CH2:18][CH2:17][CH2:16]1
Reactant: O=S(=O)(F)c1ccccc1S(=O)(=O)Cl
Reactant: C1CNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=S(=O)(F)c1ccccc1S(=O)(=O)N1CCC1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
In a flask was placed 9.24 g of 2-fluorosulfonylbenzenesulfonyl chloride and 200 ml of dry acetonitrile. The resultant solution was cooled to 0° C. An addition funnel was charged with 2 g of azetidine, 4.95 ml of triethylamine and 50 ml of acetonitrile. This solution was added dropwise to the first solution. After stirring overnight the solvent was evaporated under reduced pressure. The residue was partitioned between dichloromethane and 1N hydrochloric acid. The organic layer was separated, dried and concentrated to give 9.80 g of a solid, m.p. 93° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:8]O)=[C:5]([Cl:7])[N:6]=1.P(Br)(Br)[Br:11]>ClCCl>[Br:11][CH2:8][C:4]1[S:3][C:2]([Cl:1])=[N:6][C:5]=1[Cl:7]
Reactant: OCc1sc(Cl)nc1Cl
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Clc1nc(Cl)c(CBr)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2,4-dichloro-1,3-thiazol-5-yl)methanol (850 mg, 4.6 mmol) in anhydrous dichloromethane (40 mL) was added dropwise phosphorus tribromide (850 μL, 9.2 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated. The residue was dried in vacuo, affording 5-(bromomethyl)-2,4-dichloro-1,3-thiazole. The product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[CH:6]=[C:5]2[CH:17]=[O:18].[CH:19]1([NH:22][C:23](=[O:41])[C:24]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[C:27]([CH3:39])=[C:26]([F:40])[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:19]1([NH:22][C:23](=[O:41])[C:24]2[CH:25]=[C:26]([F:40])[C:27]([CH3:39])=[C:28]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[CH:6]=[C:5]4[CH:17]=[O:18])[CH:29]=2)[CH2:20][CH2:21]1
Reactant: O=Cc1cn(CC2CC2)c(=O)c2ccc(Br)cc12
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Temperature: 60 °C

Procedure:
To a mixture of the product of Example 59 step ii) (3.17 g), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (3.3 g) [prepared as described in WO06110173] and potassium carbonate (2.86 g) in DMF (40 mL) was added Pd-118 (0.20 g) and the mixture heated at 60° C. under nitrogen for 11 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried over magnesium sulphate, filtered and evaporated. The residue was purified (SiO2, eluting with 3:2 ethyl acetate:isohexane) to give the sub-title compound (4.24 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: COC(=O)CCBr
Product: CCOC(CNCCC(=O)OC)OCC
Reaction time: 8 h
Yield: 26.6 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-5 with the modification that the reaction was carried out overnight, 2,2-diethoxyethanamine (8.72 ml, 60 mmol) was reacted with methyl 3-bromopropionate (3.27 ml, 30 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: chloroform:methanol=100:0 to 98:2) to obtain the title compound (1.75 g, 27%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=3)[C:16]([CH3:25])([CH3:24])[C:15]2=[O:26])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>[OH-].[Pd+2].[OH-].C(O)C>[F:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:15](=[O:26])[C:16]2([CH3:25])[CH3:24]
Reactant: CC1(C)C(=O)N(C2CCN(Cc3ccccc3)CC2)c2ccc(F)cc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CCO
Product: CC1(C)C(=O)N(C2CCNCC2)c2ccc(F)cc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(1-benzylpiperidin-4-yl)-5-fluoro-3,3-dimethylindolin-2-one (171 mg, 0.485 mmol, EXAMPLE 44, Step 3), palladium hydroxide (20 wt % on carbon) (85 mg), formic acid (0.372 mL, 9.7 mmol) and ethanol (20 mL) was stirred at 50° C. for 1 h.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][OH:13].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[O:13][CH2:12][CH2:11][O:10]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=CCc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(CC2OCCO2)cc1
Yield: 55.1 %

Procedure:
A solution of 4-bromophenylacetaldehyde from Step 1 (44.5 g, 224 mmol), ethylene glycol (13.7 mL, 246 mmol) and p-toluenesulfonic acid monohydrate (85 mg, 0.45 mmol) in toluene (300 mL) was refluxed for 3 h with concomitant Dean-Stark water trapping. The reaction mixture was then washed successively with 5% aqueous NaHCO3 (2×), water and brine, dried (MgSO4) and concentrated. The residue was distilled under reduced pressure (bp 110°-115° C./0.5 mmHg) to afford the title compound as a colorless liquid (30.0 g, 55%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([NH2:15])=[O:14])[CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH:19]=1.CS(Cl)(=O)=O.[CH3:40][NH2:41]>COCCOC>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]([NH:24][C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=2)[CH2:17][NH:16][C:6]2[C:5]3[C:10](=[C:11]([C:13]([NH2:15])=[O:14])[CH:12]=[C:3]([CH2:2][NH:41][CH3:40])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[O:34])=[CH:27][CH:28]=1
Reactant: CN
Reactant: COc1ccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cc(CO)cc34)c2)cc1
Agent: CS(=O)(=O)Cl
Solvent: COCCOC
Product: CNCc1cc(C(N)=O)c2ncnc(NCc3cccc(NC(=O)c4ccc(OC)cc4)c3)c2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6-(hydroxymethyl)-4-({3-[(4-methoxybenzoyl)amino]benzyl}amino)quinazoline-8-carboxamide (12.40 mg; 0.03 mmol; 1.00 eq.) in 1,2-dimethoxyethane (1.00 ml) added methanesulfonyl chloride (0.00 ml; 0.04 mmol; 1.50 eq.) (1.0M solution) at 0° C., stirred for 30 min, then added methyl amine (0.07 ml; 2.00 M; 0.14 mmol; 5.00 eq.) and the reaction mixture was stirred at RT overnight. Purified by HPLC to collect the desired product. MS (M+1) 471.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(OCC)(=O)C>[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1Nc1ccc(I)cc1

Procedure:
According to the method of V. P. Chernetskii, A. I. Kiprianov, Zh. Obsch. Khim, 1956, 26, 3465, a mixture of 2-fluoronitrobenzene (14.0 g, 100 mmol), p-iodo aniline (10.95 g, 50 mmol) and triethylamine (13.9 ml, 100 mmol) was heated under reflux for 42 hours. The mixture was cooled, diluted with ethyl acetate (300 ml) washed consecutively with water (100 ml), 2N sodium hydroxide (100 ml) and brine (100 ml). The organic layer was dried (MgSO4), concentrated under reduced pressure and the residue was recrystallised from ethyl acetate to give N-(4-iodophenyl)-2-nitroaniline, 10.03 g, as bright orange needles, m.p. 171°-2° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C[O-].[Na+].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[CH2:9]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1nc[nH]n1
Reactant: ClCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(Cn2cncn2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a continuously stirred mixture of 13.8 grams of 1,2,4-triazole in 120 ml of methanol cooled at 0° was added 11.9 grams of sodium methoxide. The mixture was allowed to warm to room temperature and stir for 45 minutes whereupon the mixture was again cooled at 0° C. and there was added 25.3 ml of benzyl chloride. After being warmed to room temperature and continuously stirred for 14 hours, the mixture was concentrated and the residue extracted well with dichloromethane. The extract was washed with saturated brine, dried over magnesium sulfate, filtered, and evaporated to give a crude product that was purified by flash column chromatography over silica gel and eluted with dichloromethane/ ethyl acetate (2:1) to give 28.5 grams of pure 1-benzyl-1,2,4-triazole as a solid melting at 44°-45° C.