Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[C:13]2[C:8](=[C:9]([F:20])[CH:10]=[CH:11][C:12]=2[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:7]=[C:6]([CH2:21][CH3:22])[C:5]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[CH:34]1([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)[CH2:36][CH2:35]1.N1C=CC=CC=1>O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:9]([F:20])=[C:8]2[C:13]=1[C:4]([O:3][CH:2]([F:33])[F:1])=[C:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:39]3[CH:38]=[C:37]([CH:34]4[CH2:36][CH2:35]4)[CH:41]=[N:40]3)=[CH:26][CH:25]=1)[C:6]([CH2:21][CH3:22])=[N:7]2
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B(O)O)cc1
Reactant: c1n[nH]cc1C1CC1
Solvent: c1ccncc1
Solvent: O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cc(C3CC3)cn2)cc1
Temperature: 40 °C
Yield: 79.3 %

Procedure:
A mixture of (4-{[4-difluoromethoxy-2-ethyl-8-fluoro-5-(2-methoxy-2-oxoethoxy) quinolin-3-yl]methyl}phenyl)boronic acid (0.1 g), 4-cyclopropyl-1H-pyrazole (0.047 g), cuprous acetate (0.078 g) and pyridine (3 mL) was heated at 40° C. for 24 hours. The mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 7:3 by volume) gave title compound as pale green oil (0.09 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[C:3]=1[O:12][C:13]([F:16])([F:15])[F:14].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C@H:25]2[CH3:37])=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C@H:25]3[CH3:37])=[N:22][CH:23]=2)=[O:8])=[C:4]([F:11])[C:3]=1[O:12][C:13]([F:16])([F:15])[F:14]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)cn1
Reactant: O=C(O)c1ccc(Br)c(OC(F)(F)F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(NC(=O)c2ccc(Br)c(OC(F)(F)F)c2F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 4-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (150 mg, 0.50 mmol, Preparation 52), (R)-tert-butyl 4-(5-aminopyridin-2-yl)-3-methylpiperazine-1-carboxylate (145 mg, 0.50 mmol), and HATU (235 mg, 0.62 mmol) dissolved in DMF (1 mL) was added DIPEA (0.43 mL, 2.48 mmol). The reaction mixture was stirred at RT for 1 h, extracted with EtOAc (80 mL) washed with water (3×20 mL) and brine (20 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (12 g silica gel, 0-40% EtOAc:hexanes over 20 min), to provide the title intermediate (203 mg, 71% yield) as a yellow solid. (m/z): [M+H]+ calcd for C23H25BrF4N4O4 577.10; 579.10. found 579.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C([Li])CCC.[C:19](=[O:21])=[O:20].CO>O1CCCC1>[F:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C=O
Reactant: Fc1ccc(-c2ccccc2)nc1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccccc2)ncc1F
Temperature: -45 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 5-fluoro-2-phenylpyridine (760.0 mg, 4.39 mmol) in tetrahydrofuran (15.0 ml) was added n-butyllithium (2.11 ml, 2.50 M in THF, 5.27 mmol) at −45° C. The mixture was stirred for 1 h at −45° C., then poured into THF containing dry ice. Stirred for 1 h, then MeOH (2 ml) was added. The solution was concentrated, and purified on Flashmaster II to get 560 mg (58%) of 5-fluoro-2-phenylisonicotinic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[OH:9][C:10]([CH3:14])([CH3:13])[C:11]#[CH:12].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(N(CC)CC)C.[Pd].[Cu]I>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[C:11][C:10]([OH:9])([CH3:14])[CH3:13])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of 35.2 g (0.19 mole) of 4-bromofluorobenzene and 25.2 g (0.3 mole) of 3-hydroxy-3-methyl-1-butine in 250 ml of triethylamine are added, under nitrogen, 1 g of the palladium complex PdCl2 [P(C6H5)3 ]2 and 0.2 g of copper(I) iodide. The reaction mixture is subsequently stirred for 24 hours at 70° C. After filtering off triethylammonium bromide and removing excess triethylamine by evaporation, the residue is taken up in 200 ml of ether and the solution is washed twice with 100 ml of 5% aqueous HCl solution and 100 ml of water, dried, treated with activated charcoal, and evaporated to dryness. The residue is chromatographed on silica gel with a 1:1 mixture of ether/hexane, affording 26.4 g (78%) of 1-fluoro-4-(3-hydroxy-3-methyl-1-butyn-1-yl)-benzene with a melting point of 124° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.F[B-](F)(F)F.[N:16]1([O:25][C:26](N(C)C)=[N+](C)C)[C:20]2C=CC=CC=2N=N1.CNOC>C(N(CC)C(C)C)(C)C.CN(C)C=O>[Br:1][C:2]1[C:3]([C:8]([N:16]([O:25][CH3:26])[CH3:20])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1cc(Br)c(C(=O)O)n1
Agent: CNOC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1nn(C)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
A mixture of 4-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (2.04 g, 10 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (3.21 g, 10 mmol), N,O-dimethylhydroxylamine (1.22 g, 20 mmol) in N,N-Diisopropylethylamine (5 mL) and N,N-Dimethylformamide (20 mL) was stirred for 12 h at room temperature. The mixture was concentrated in vacuum, and the residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=5:1 to give the titled product as a colorless oil (2.4 g, 97%). LC/MS m/z 247 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C-:12]#[N:13].[Na+].ClC(Cl)C>CN(C)C=O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[C:12]#[N:13]
Reactant: [C-]#N
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: N#Cc1c(Cl)cccc1[N+](=O)[O-]
Yield: 78.3 %

Procedure:
2,3-dichloronitrobenzene (19.2 g), cuprous chloride (2.4 g), anhydrous cupric sulfate (1.0 g), sodium cyanide (purity of 90%, 5.4 g) and dimethylformamide (3.0 g) were heated together to 190° C. and made to react for 3.5 hours at the temperature. After the reaction was over, 100 ml of dichloroethane were added to the reaction mixture and the mixture was filtered. After separating the filtrate, 100 ml of an aqueous 5% solution of ammonia were added to the filtrate and after well shaking the mixture, it was separated into layers. After distilling off dichloroethane from the organic layer and washing the residue with ethanol, 14.3 g of 2-chloro-6-nitrobenzonitrile was obtained as a pale yellow crystal. The yield was 78% theoretical.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([C@H:15]2[C@H:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:18]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:17]([CH2:45][O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[O:16]2)=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8](N)=[N:7][N:6]=1.N([O-])=O.[Na+].[ClH:58]>C(O)(=O)C.O.[Cu]>[Cl:58][C:8]1[S:9][C:5]([CH2:4][C:3]2[CH:11]=[C:12]([C@H:15]3[C@H:20]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@@H:19]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:18]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:17]([CH2:45][O:46][CH2:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[O:16]3)[CH:13]=[CH:14][C:2]=2[Cl:1])=[N:6][N:7]=1
Reactant: Cl
Reactant: Nc1nnc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)s1
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1nnc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
To a mixture of 5-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzyl)-1,3,4-thiadiazol-2-amine (4.0 mmol) from Step 1 and copper (0.04 g, 0.62 mmol) in hydrochloric acid (37%, 6 mL) and acetic acid (30 mL) at 0° C. was slowly added sodium nitrite (2.8 g, 40 mmol) while maintaining an internal reaction temperature below 10° C. After 1 h stirring at 0° C., the resulting mixture was stirred with gradual warming to ambient temperature over 2 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. Flash chromatography on a Biotage® purification apparatus (silica gel, 10 to 60% ethyl acetate in hexanes) yielded the title compound (0.66 g, 0.86 mmol, 22%) as yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C@H:13]1[C@@H:19]([OH:20])[C@H:18]([OH:21])[C@@H:17]([CH2:22][OH:23])[O:16][CH:14]1[OH:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:28](=[O:30])[CH3:29])(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:15][CH:14]1[O:16][C@H:17]([CH2:22][O:23][C:28](=[O:30])[CH3:29])[C@@H:18]([O:21][C:14](=[O:15])[CH3:13])[C@H:19]([O:20][C:10](=[O:11])[CH3:9])[C@@H:13]1[NH:12][C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(COCc1ccccc1)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@@H](NC(=O)COCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 192.8 %

Procedure:
A solution of 31 (512 mg, 1.56 mmol) in pyridine (5 mL) was cooled to 0° C. To this solution was added acetic anhydride (2.5 mL, 27 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight and allowed to warm to rt. The resulting light yellow solution was diluted with CH2Cl2 (100 mL) and washed with 1 N HCl (3×50 mL), sat. NaHCO3 (2×50 mL), water (2×50 mL) and sat. NaCl (1×50 mL). The combined aqueous layers were back extracted with 50 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 1:4 to 1:1 EtOAc/hexanes to afford 745 mg (96%) of a light yellow oil. IR (thin film): 3409, 2959, 2357, 1750, 1692, 1520 cm−1. 1H NMR (300 MHz, CDCl3): δ 1.90 (s, 6H), 1.99 (s, 6H), 2.06 (s, 6H), 2.18 (s, 6H), 3.79-3.84 (m, 1H), 3.91-3.99 (m, 1H), 4.02 (d, 2H, J=2.8), 4.04-4.07 (m, 2H), 4.14 (dd, 2H, J=2.7, 17.8), 4.20 (dd, 1H, J=3.9, 9.1), 4.55 (app t, 1H, J=6.3), 4.60-4.65 (m, 4H), 4.66-4.68 (m, 1H), 4.79 (ddd, 1H, J=1.6, 3.8, 13.2), 5.07 (dd, 1H, J=3.9, 9.8), 5.19 (app t, 1H, J=4.7), 5.24 (app t, 1H, J=9.8), 5.35 (dd, 1H, J=4.2, 10.2), 5.90 (d, 1H, J=1.6), 6.03 (d, 1H, J=1.6), 6.89 (d, 1H, J=9.6), 7.03 (d, 1H, J=9.3), 7.32-7.39 (m, 10H). 13C NMR (125 MHz, CDCl3): δ 20.3, 20.4, 20.6, 20.7, 20.8, 48.6, 61.7, 65.1, 65.2, 68.9, 69.1, 69.3, 70.2, 71.3, 73.3, 73.5, 73.6, 77.8, 97.1, 127.8, 127.9, 128.2, 128.3, 128.4, 128.6, 128.7, 136.4, 136.6, 169.4, 169.7, 170.1, 170.5. MS (FAB) m/z 496 (MH+). Anal. Calcd for C23H29NO11: C, 55.75; H, 5.90; N, 2.83; Found: C, 55.54; H, 5.93; N, 2.68.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([S:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:21]=3[N:20]([CH3:22])[CH2:19][CH2:18][CH2:17]4)[NH:9][C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([S:10]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:21]=3[N:20]([CH3:22])[CH2:19][CH2:18][CH2:17]4)=[O:33])[NH:9][C:5]=2[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2nc(SCc3cccc4c3N(C)CCC4)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2nc(S(=O)Cc3cccc4c3N(C)CCC4)[nH]c2c1
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 8-(5-methoxy-2-benzimidazolyl)thiomethyl-1-methyl-1,2,3,4-tetrahydroquinoline (0.80 g) in dichloromethane (30 ml) was added a solution of m-chloroperbenzoic acid (80%, 0.51 g) in dichloromethane (10 ml) by use of a pipet at -60° C. The mixture was stirred for 30 minutes at the same temperature. Aqueous sodium carbonate was added to the reaction mixture and the mixture was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent:ethyl acetate-n-hexane (2:3)] and recrystallized from ethyl acetate to give 8-(5-methoxy-2-benzimidazolyl)sulfinylmethyl-1-methyl-1,2,3,4-tetrahydroquinoline (0.38 g).
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH+]1([O-])CCOCC1.C(#N)C>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.ClCCl>[C:23]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=[O:16])[N:10]=[CH:9]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: [O-][NH+]1CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C

Procedure:
A mixture of 1 g (2.72 mmol) of 1-(triphenylmethyl)-4-[3-hydroxypropyl]imidazole, 0.55 g (4.07 mmol; 1.5 equivalents) of morpholine oxide and 1.36 g of powdered 4 Å molecular sieve in an anhydrous mixture of acetonitrile and dichloromethane (10:4) is stirred at room temperature under nitrogen. 0.047 g (0.135 mmol; 5 mol %) of tetrapropylammonium perruthenate (VII) is added in a single portion and the mixture is stirred at room temperature for 48 hours. The reaction mixture is filtered through silica gel (preloaded with ethyl acetate) and the filtrate is evaporated under reduced pressure. The oil obtained is purified by chromatography on a column of silica gel with diethyl ether as eluent to yield 3-(1-triphenylmethyl-4-imidazolyl)propionaldehyde.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH2:27][C:28](O)=[O:29])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][NH:33][O:34][CH3:35].C(N(CC)CC)C>ClCCl>[CH3:35][O:34][N:33]([CH3:32])[C:28](=[O:29])[CH2:27][O:26][CH2:25][C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:24]=1
Reactant: CNOC
Reactant: O=C(O)COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4.03 mmol of (1-trityl-1H-imidazol-4-ylmethoxy)acetic acid and 4.44 mmol of N,O-dimethylhydroxylamine hydrochloride in 100 ml of dichloromethane is mixed with 20.2 mmol of triethylamine and 4.44 mmol of propanephosphonic acid cyclic anhydride [68957-94-8] (50% in ethyl acetate). The reaction mixture is stirred at room temperature for 3 hours and diluted with dichloromethane. The phases are separated and the organic phase is washed with 1M HCl and brine, dried with sodium sulphate and evaporated. The title compound is obtained as a pale yellowish solid from the residue by flash chromatography (SiO2 60 F). Rf=0.45 (dichloromethane-methanol 95:5); Rt=4.11 (gradient I).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]#[CH:16])[C:5](OC)=[O:6].[CH3:17][NH2:18]>>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]#[CH:16])[C:5]([NH:18][CH3:17])=[O:6]
Reactant: CN
Reactant: C#Cc1ccccc1C(=NOC)C(=O)OC
Product: C#Cc1ccccc1C(=NOC)C(=O)NC
Reaction time: 0.75 h

Procedure:
1 g (4.6 mmol) of the acetylene compound prepared in Example 1 is added to 20 ml of a 40% strength methylamine solution, and the mixture is stirred for 45 minutes at 40°-50° C. The solution is extracted with methyl tert-butyl ether, dried and evaporated down. 700 mg (70%) of the compound remain as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetate (1 eq) was dissolved in dichloromethane (10 ml/mmol), cooled, and trifluoroacetic acid (13 eq) was added slowly at room temperature. After stirring for 2 h at room temperature, the reaction mixture was concentrated to small volume under vacuum and dried. The crude product was used in the next stage with no further purification. Yield: quantitative
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1.[Br:10]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:10][C:8]1[CH:9]=[C:4]2[CH2:3][CH2:2][NH:1][C:5]2=[N:6][CH:7]=1
Reactant: c1cnc2c(c1)CCN2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 36.4 %

Procedure:
The resulting 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (614 mg, 5.11 mmol) and N-bromosuccinimide (1.09 g, 6.13 mmol) were dissolved in N,N-dimethylformamide (12 mL), and the solution was stirred for 2.5 hours at room temperature. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=3:1), and 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (370 mg, 1.86 mmol, 36%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nc(N2CCOCC2)c2ccc(-c3cncnc3)cc2n1
Temperature: 95 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (0.2 g, 0.0006 mol), pyrimidine-5-boronic acid (0.068 g, 0.0005 mol), sodium carbonate (0.129 g, 0.0012 mol), DMF (10 mL) and water (3 mL) were added and degassed the reaction vessel with N2 for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (0.029 g, 0.00004 mol) was added and again degassed with N2 for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified; using column chromatography (60-120 silica gel, 60% ethyl acetate in hexane) to yield the desired product [150 mg, 75%]. 1H NMR (300 MHz, CDCl3): δ 9.27 (s, 1H), 9.04 (s, 2H), 7.85-8.45 (m, 2H), 7.60-7.64 (m, 1H), 3.82-3.91 (m, 8H); LC-MS (ESI): Calculated mass: 327.09; Observed mass: 328.0 [M+H]+ (RT: 0.98 min).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(O)[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:9]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:8]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Br:42])(=O)C.CO>C1(C)C=CC=CC=1>[Br:42][C:11]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C2(O)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1
Reactant: CC(=O)Br
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(C2(Br)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1

Procedure:
54.19 g (0.11 mol) of 1,2,3,4-tetraphenyl-5-p-methoxyphenylcyclopenta-1,3-dien-5-ol were suspended in 300 ml of toluene. 74 g (0.6 mol) of acetyl bromide were added dropwise in the course of 20 minutes at room temperature and the reaction batch was then refluxed for 2 hours. Toward the end of the reaction, 2 ml of methanol were also added dropwise. Excess acetyl bromide and toluene were distilled off in vacuo. The remaining oil crystallized after addition of 100 ml of petroleum ether. The orange precipitate was filtered off with suction, rinsed with petroleum ether and dried. The product was used for the further syntheses. Analytically pure orange product was obtained by recrystallization from toluene. (Yield: 54. 32 g (89%); elemental analysis for C36H27OBr: found: C, 77.06%, H, 4.90%. calculated: C, 77.84%, H, 4.90%).
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.C([O:36][C:37](=[O:43])[CH:38](Br)[CH:39]([CH3:41])[CH3:40])C>>[CH:1]1([N:7]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]2)[C:8](=[O:9])[NH:10][C:11]2[S:12][C:13]([S:16][CH:38]([CH:39]([CH3:40])[CH3:41])[C:37]([OH:36])=[O:43])=[CH:14][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(C)C(Sc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and ethyl-2-bromoisovalerate.