Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][NH:21]4)=[CH:15][N:16]=[C:11]2[N:10]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45]C([O-])(C)C.[K+].IC>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][N:21]4[CH3:45])=[CH:15][N:16]=[C:11]2[N:10]([C:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3cccc4[nH]ncc34)nc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1ncc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
To a solution of N-tert-butyl-2-(1H-indazol-4-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (375 mg, 0.65 mmol) in dry THF (20 mL) was added potassium 2-methylpropan-2-olate (109 mg, 0.975 mmol) at 0° C. After stirring for 30 minutes, iodomethane (138 mg, 0.975 mmol) was added at 0° C. Then it was warmed to room temperature and stirred for 1 hour. Reaction mixture was quenched by the addition of water (2 mL), extracted with ethyl acetate (100 mL), then organic phase washed with water (3×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with EtOAc: petroleum ether=1:3) to afford N-tert-butyl-2-(1-methyl-1H-indazol-4-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (154 mg, 40%) as a white solid. LCMS: (M+H)+=591; 1H NMR (300 MHz, CDCl3): δ 8.54 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 7.53-7.47 (m, 3H), 7.32-7.27 (m, 9H), 7.24-7.19 (m, 6H), 4.14 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:16]=O.C([O-])(O)=O.[Na+].O>O1CCOCC1>[C:18]1([C:15]2[N:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)=[CH:7][C:2]3=[N:1][CH:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CC(Br)c1ccccc1
Reactant: Nc1cc(-c2ccncc2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of 2-amino-4,4′-bipyridine (0.482 g, 2.815 mmol, 1 equiv) in dioxane (14 mL) was added bromophenylacetaldehyde (0.897 g, 4.50 mmol, 1.6 equiv) and NaHCO3 (0.473 g, 5.63 mmol, 2 equiv). The suspension was stirred at rt for 30 min and then heated to 80° C. for 6 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layer was dried, concentrated and purified by flash column chromatography (5% MeOH in CH2Cl2 ) to give 3-phenyl-7-(4-pyridyl)imidazo[1,2-a]pyridine as a solid. 1H NMR (CDCl3) δ 8.72 (d, 2H, J=6.1), 8.45 (d, 1H, J=7.3), 8.00 (s, 1H), 7.80 (s, 1H), 7.61–7.55 (m, 6H), 7.48–7.44 (m, 1H), 7.14 (d, 1H, J=7.3); LRMS m/z (M+H) Calcd: 272.3, found: 272.2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[C:24]([O:23][C:21]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][CH2:2][C:3]2[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=2)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:29][CH:28]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(NCc2cccc(C(=O)OC(C)(C)C)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of tert-butyl 3-(chloromethyl)benzoate (500 mg) in N,N-dimethylformamide (10.0 mL) were added tert-butyl 4-aminobenzoate (426 mg), potassium carbonate (610 mg), and potassium iodide (36.6 mg), followed by stirring at 60° C. overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-({[4-(tert-butoxycarbonyl)phenyl]amino}methyl)benzoate (671 mg).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])(=O)[CH2:2][CH2:3][CH3:4].Cl.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][NH2:30])=[CH:25][CH:24]=1.CC([O-])=O.[Na+]>CCO>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[C:6]([C:1](=[N:30][O:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH2:2][CH2:3][CH3:4])[CH:11]=1
Reactant: CCCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCC(=NOc1ccc(Cl)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 62.2 %

Procedure:
A solution of N-(2-butyryl-4-chlorophenyl)trifluoromethanesulfonamide 29A (333 mg, 1.0 mmol), O-(4-chlorophenyl)hydroxylamine hydrochloride (200 mg, 1.10 mmol) and anhydrous NaOAc (91 mg, 1.10 mmol) in EtOH (30 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 1:4) and the solvent removed under reduced pressure. The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19 to 3:7) to afford N-{4-chloro-2-[1-(4-chlorophenoxyimino)butyl]phenyl}trifluoromethanesulfonamide 166 (283 mg, 62%), as a yellow solid. M.p. 62.5-64.5° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.27, br s, 1H; 7.72, d, J=8.8 Hz, 1H; 7.57, d, J=2.4 Hz, 1H; 7.41, dd, J=2.4 and 8.8 Hz, 1H; 7.35, d, J=8.8 Hz, 2H; 7.11, d, J=8.8 Hz, 2H; 2.98, m, 2H; 1.71, sextet, 2H; 1.09, t, J=7.4 Hz, 3H.
Reaction SMILES: [NH2:1][CH:2]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24].[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]=O)[CH:45]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C([O-])(O)=O.[Na+].CCOC(C)=O>[Si:27]([O:26][CH2:25][CH:2]([NH:1][CH2:50][C:46]1[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=1)[CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24])([C:40]([CH3:43])([CH3:42])[CH3:41])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COc1ccc2c(=O)n(CC(N)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(C#N)c(-c3ccccc3)c2c1
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COc1ccc2c(=O)n(CC(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)NCc3cccnc3)c(C#N)c(-c3ccccc3)c2c1
Reaction time: 8 h

Procedure:
To a solution of amine 94 (51 mg, 0.075 mmol) in dichloroethane (2 mL) was added pyridine 3-carboxaldehyde (0.017 mL, 180 mmol). After stirring at RT for 15 min NaBH(OAc)3 (48 mg, 0.23 mmol) was added. After stirring overnight, added 1.2 equiv aldehyde and 1.5 equiv NaBH(OAc)3. After stirring for 5 h, the reaction mixture was diluted with NaHCO3/EtOAc and stirred for 10 min. It was then partitioned between EtOAc and NaHCO3. The organic phase was washed once with brine then dried (Na2SO4) and concentrated. The product was purified by automated flash chromatography (70-100% EtOAc/hexane).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=2)[CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:17].COC(C)(C)C>C(OCC)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=2)[CH2:12][Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2ccccc2)cc1CO
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Cc1ccc(-c2ccccc2)cc1CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 180.1 %

Procedure:
To a solution of 1.33 g (6.71 mmol) of 5-phenyl-2-methylbenzylalcohol in 30 ml of dry diethyl ether was added dropwise 0.91 g (3.02 mmol) of phosphorous tribromide with ice-cooling. After the mixture was stirred for 3 hours with ice-cooling, to the reaction solution were added ice water and tert-butyl methyl ether with ice-cooling. The mixture was stirred for 30 minutes and separated. The organic layer was washed successively with an about 5% aqueous solution of sodium hydrogencarbonate and water, then dried and concentrated to obtain 1.42 g (5.44 mmol) of 5-phenyl-2-methylbenzylbromide as an oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[OH-].[Na+]>C1C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Nc1ccc(-c2ccc(F)cc2)cc1F

Procedure:
2-Fluoro-4-bromoaniline (10.7 g), 4-fluorophenylboronic acid (11.9 g), 60 mL of 2 N NaOH and 200 mL of benzene are combined and degassed with N2. Palladium tetrakistriphenylphosphine (4.2 g) is added and the mixture stirred at reflux temperature overnight. After cooling, the reaction is filtered through Celite and concentrated. The oily residue is purified by flash chromatography (5–10% EtOAc/hexane) to afford 2-fluoro-4-(4′-fluorophenyl)aniline as a solid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[C:52]([O:56][C:57]([N:59]1[CH2:63][CH2:62][CH2:61][C@H:60]1[C@H:64]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[C:65](O)=[O:66])=[O:58])([CH3:55])([CH3:54])[CH3:53]>C(Cl)Cl>[Cl:3][C:4]1[C:5]([N:13]2[CH2:14][CH2:15][N:16]([C:65](=[O:66])[C@H:64]([C@@H:60]3[CH2:61][CH2:62][CH2:63][N:59]3[C:57]([O:56][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:58])[C:68]3[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=3)[CH2:17][CH2:18]2)=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1
Reactant: Clc1cnc2[nH]ncc2c1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2c(Cl)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1
Yield: 82.9 %

Procedure:
A solution of 5-chloro-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (75 mg, 0.205 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (“HATU”; 78.0 mg, 0.205 mmol), N-ethyl-N-isopropylpropan-2-amine (143 μL, 0.821 mmol), and (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (83.7 mg, 0.246 mmol, see Example C) in CH2Cl2 (5 mL) was stirred at room temperature for 1 hour. The solvent was removed, and the resulting residue was redissolved in EtOAc (20 mL) and washed with water. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude obtained was purified by C-18 reverse phase column chromatography (Biotage C-18 12M+) using 10-90% CHsCN/water gradient on Biotage SP4 unit. The fractions containing the product were pooled, and the solvents were removed and evaporated from CH3CN (3×10 mL). The residue was transferred to a 25 mL round bottom flask using EtOAc (about 5 to about 10 mL). The residue was concentrated in vacuo and dried under high vacuum for 2 hours to provide (S)-tert-butyl 2-((S)-2-(4-(5-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-(4-chlorophenyl)-2-oxoethyl)pyrrolidine-1-carboxylate (95 mg, 0.170 mmol, 82.7% yield) as a solid. LCMS (APCI+) m/z 459.1 [(M-Boc)+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Br[CH2:34][C:35]([NH2:37])=[O:36].CO>C(Cl)Cl>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:3][N:2]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:5]5)[CH:32]=[CH:31][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Reactant: NC(=O)CBr
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NC(=O)CN1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with bromo acetamide, the crude product was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 172 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.42 (s, 1H); 8.28 (s, 1H); 7.81 (td, J=8.75, 5.92 Hz, 1H); 7.63 (ddd, J=10.33, 9.01, 2.79 Hz, 1H); 7.39-7.27 (m, 2H); 7.11 (s, 1H); 7.03 (s, 1H); 6.96-6.89 (m, 2H); 4.23 (t, J=5.01 Hz, 2H); 3.66 (t, J=7.02 Hz, 2H); 3.62-3.52 (m, 1H); 3.16 (t, J=6.65 Hz, 2H); 3.10-2.98 (m, 4H). LCMS: RT=7.00 min, M+H+=478
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][C:12]1[C:21](N)=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1.O>CO>[CH2:1]([C:8]1[NH:9][C:21]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]3)=[CH:13][C:12]=2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc2ccccc2cc1N
Reactant: N#CCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: c1ccc(Cc2nc3cc4ccccc4cc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1M solution of benzyl cyanide in anhydrous methanol is treated with hydrogen chloride gas at 0° C. for about thirty minutes. The mixture is stirred for two hours at 0° C. and then a 1M solution of 2,3-diaminonaphthalene is added and the resulting solution is stirred at 0° C. The progress of the reaction is monitored by thin layer chromatography. The reaction mixture is then poured into water. The unreacted nitrile is extracted with ethyl acetate. The aqueous layer is neutralized with 1N sodium hydroxide. The organic fraction is extracted with ethyl acetate and condensed. The desired title product is recrystallized from methanol/water.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[H-].[Na+].Br[CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15]>CC#N>[CH3:15][O:14][CH:13]([O:16][CH3:17])[CH2:12][S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: OCCCCCCS
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COC(CSCCCCCCO)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-mercapto-hexan-1-ol (2.5 mL) in MeCN (30 mL) at 0° C. was added sodium hydride (60% suspension in mineral oil, 0.81 g). The mixture was stirred at 0° C. for 1 h then 2-bromo-1,1-dimethoxy-ethane (2.4 mL) was added. The resulting mixture was stirred at RT for 20 h, then was quenched by addition of saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (×3), then the combined organics were washed with saturated sodium bicarbonate solution, then with brine, dried over sodium sulfate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 25% ethyl acetate in cyclohexane to give the subtitled compound as a colourless liquid. Yield 1.85 g.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>ClCCl.CCCCCC>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[Cl:20])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12)c1ccccc1Cl

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and 2-chlorobenzoyl chloride. m.p.: 229-234° C. (dichloromethane/hexane)
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C:13]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:12][C@@H:11]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:10]1OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:52].[Li+]>C(#N)C>[CH2:1]([O:8][C@@H:9]1[C:13]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:12][C@@H:11]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:10]1[I:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1(COS(C)(=O)=O)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OS(=O)(=O)C(F)(F)F)[C@@H]1OCc1ccccc1
Reactant: [I-]
Agent: [Li+]
Solvent: CC#N
Product: CS(=O)(=O)OCC1(COS(C)(=O)=O)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](I)[C@@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 89.9 %

Procedure:
9-(3-O-Benzyl-5-O-methanesulfonyl-4-C-(methanesulfonyloxymethyl)-2-O-trifluoromethanesulfonyl-β-D-erythro-pentofuranosyl)-6-N-benzoyladenine (589 mg, 0.755 mmol) was dissolved in dry acetonitrile (15 ml), added lithiumiodide (202 mg, 2 equiv.) and heated to reflux. After 2 hrs, LCMS shows full conversion. Solvent was removed in vacuo and the residue was partitioned between DCM (50 ml) and water (50 ml). Layers were separated and the organic layer was washed with brine (50 ml), dried (Na2SO4), filtered and the solvent removed in vacuo to afford an orange foam (514 mg, 90% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:29]#[N:30])[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:29]#[N:30])[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:18][C:13]=2[NH:12][C:11](=[S:41])[CH2:10][N:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#Cc1cc2c(cc1OCCCN1CCOCC1)NC(=O)CN=C2c1ccccc1Cl
Product: N#Cc1cc2c(cc1OCCCN1CCOCC1)NC(=S)CN=C2c1ccccc1Cl

Procedure:
5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-thione (Ik) was prepared by reacting 0.00057 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-one (Ik) with Lawesson's reagent in a manner analogous to Example 38. MH+/Z=455.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COC(=O)c1ccc(Br)c(C(F)(F)F)c1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A mixture of methyl 4-bromo-3-(trifluoromethyl)benzoate (6 g; 21.2 mmol; 1 eq.), o-tolylboronic acid (3.17 g; 23.3 mmol; 1.1 eq.), potassium carbonate (14.65 g; 106 mmol; 5 eq.) and Pd(PPh3)4 (2.45 g; 2.12 mmol; 0.1 eq.) in toluene (30 mL) and water (30 mL) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of CELITE which was further washed with toluene (20 mL). The filtrate was concentrated in vacuo, the residue taken up in ethyl acetate (200 mL) and washed with sat. aq. NaHCO3 (100 mL), water (100 mL) and brine (100 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (5 g, 80%) as a brown oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.O.[NH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.Br[CH2:17][CH2:18][CH:19]1[O:24][CH2:23][CH2:22][CH2:21][O:20]1>C(#N)C>[O:20]1[CH2:21][CH2:22][CH2:23][O:24][CH:19]1[CH2:18][CH2:17][N:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1
Reactant: BrCCC1OCCCO1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1CCN(CCC2OCCCO2)CC1
Reaction time: 8 h
Yield: 69.1 %

Procedure:
Sodium carbonate (17.4 g, 125.9 mmol) was added to a solution of 4-piperidone monohydrate hydrochloride (6.45 g, 42.0 mmol) in acetonitrile (200 mL). After 30 minutes stirring at rt a solution of 2-(2-bromoethyl)-1,3-dioxane (8.45 g, 43.3 mmol) in acetonitrile (50 mL) was added dropwise to the reaction mixture and stirring was continued overnight at rt and at reflux for an additional 2 hours. The solvent was removed by evaporation under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was dried over sodium sulphate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with 7% methanol in dichloromethane, afforded 1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-one (6.19 g, 69%).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[O:36]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:19]1[C:14]([C:46]2[CH:47]=[CH:48][C:43]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:44][CH:45]=2)=[N:15][C:16]([CH3:35])=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(Oc4ccccc4)cc3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 4-phenoxyphenylboronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (53 mg, yield 96%).