Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4[CH:21]=[C:22]5[C:26](=[CH:27][C:17]3=4)[CH2:25][CH2:24][O:23]5)[C:9]2=[O:28])[CH2:3][CH2:2]1.[CH3:29][C:30]([CH3:32])=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO.C(=O)(O)[O-].[Na+]>[CH3:29][CH:30]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4[CH:21]=[C:22]5[C:26](=[CH:27][C:17]3=4)[CH2:25][CH2:24][O:23]5)[C:9]2=[O:28])[CH2:3][CH2:2]1)[CH3:32]
Reactant: CC(C)=O
Reactant: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
A solution of 1′-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-2′(1′H)-one (0.29 g, 0.77 mmol), acetone (0.10 mL, 1.4 mmol), sodium cyanoborohydride (0.10 g, 1.51 mmol) and acetic acid (6 drops) in methanol (4 mL), sealed in a well-stoppered round-bottomed flask, was stirred at 60° C. for 16 h. The reaction was cooled, diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with dichloromethane (3×25 mL). The organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/methanol (14:1) afforded 1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.21 g, 64%) as a colorless foam: 1H NMR (300 MHz, CD3OD) δ 7.33 (ddd, J=7.8, 7.5, 0.9 Hz, 1H), 7.14-7.05 (m, 3H), 6.44 (s, 1H), 6.32 (s, 1H), 4.81 (d, J=9.2 Hz, 1H), 4.65 (d, J=9.2 Hz, 1H), 4.99 (t, J=8.7 Hz, 2H), 3.74 (dd, J=14.0, 7.2 Hz, 1H), 3.65 (dd, J=14.0, 7.1 Hz, 1H), 3.02-2.91 (m, 4H), 2.77 (septet, J=6.6 Hz, 1H), 2.30-2.18 (m, 2H), 2.00-1.84 (m, 1H), 1.81-1.71 (m, 2H), 1.50-1.34 (m, 2H), 1.08 (d, J=6.6 Hz, 6H); 13C NMR (75 MHz, CD3OD) δ180.3, 163.2, 162.9, 144.1, 134.1, 123.0, 124.8, 124.6, 121.6, 121.4, 120.0, 110.5, 93.7, 81.7, 73.5, 59.2, 56.2, 49.5, 49.4, 46.6, 36.0, 30.7 (2C), 29.9, 18.3, 18.3; MS (ES+) m/z 419.2 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]([O:24][CH3:25])=[O:23])[CH:16]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.[OH-].[Na+].CN(C)[CH:31]=[O:32]>C(O)(=O)C>[CH:31]([C:21]1[C:20]2[C:15](=[CH:16][C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=2)[NH:14][C:13]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:32]
Reactant: CCCCCCCc1cc2ccc(C(=O)OC)cc2[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCCCCCc1[nH]c2cc(C(=O)OC)ccc2c1C=O
Reaction time: 2 h

Procedure:
A solution of phosphorus oxychloride (35 ml) in dimethylformamide (150 ml) was added to a solution of methyl 2-(n-heptyl)indole-6-carboxylate (67.5 g) in dimethylformamide (250 ml) and the resulting solution was stirred at between 70° and 85° C. for 2 hours. The mixture was then stirred for 30 minutes while the temperature dropped to 50° C. and was then poured into water (2 liters). Ice was added to reduce the temperature to 25° C. and a 50% w/v aqueous sodium hydroxide solution was added until the pH reached 11. After stirring for 10 minutes, acetic acid was added to pH 5 and the mixture was stirred until the product has solidified. Recrystallisation from methanol yielded methyl 3-formyl-2-(n-heptyl)indole-6-carboxylate (65.0 g) in the form of colourless, lustrous needles, m.p. 177°-180° C.
Reaction SMILES: O=[C:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CCN(CC)CC.Cl.[NH2:24][OH:25]>C1COCC1>[OH:25][N:24]=[C:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCOCC(=O)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC(=NO)C1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
A solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate 38.2 (1.23 g, 5.74 mmol) in 1,4-dioxane (20 mL) and H2O (20 mL) was treated with sodium periodate (2.46 g, 11.49 mmol) and a solution of 2.5% OsO4 in t-BuOH (0.36 mL, 0.028 mmol). The reaction mixture was stirred at room temperature for 18 hrs. The resulting yellow-white suspension was diluted with H2O and extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide a brown oil (1.30 g) that was used immediately without further purification. The crude tert-Butyl 6-oxo-1,4-oxazepane-4-carboxylate (4.4 g, 20.4 mmol) was dissolved in THF (100 mL) and treated with Et3N (11.4 mL, 81.8 mmol) and hydroxylamine hydrochloride (3.1 g, 45.0 mmol). The mixture was stirred at room temperature over the weekend. The mixture was concentrated in vacuo to dryness and the residue was suspended between EtOAc and water. The aqueous layer was extracted with EtOAc. The organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (4.8 g) of a semisolid product 38.3. LCMS m/z=253.1 [M+Na], 461.3 [2M] with two equal peaks observed (oxyme stereoisomers presumably). Used without further purification.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([CH3:28])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:29][CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[C:20]([CH3:28])[N:19]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:35]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[CH3:29])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC1COCCC1=O
Reactant: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](N)C3)CC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](NC4CCOCC4C)C3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-(4-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine (120 mg, 0.30 mmol), 3-methyltetrahydro-4H-pyran-4-one (100 mg, 0.90 mmol), and triethylamine (0.12 mL, 0.90 mmol) in methylene chloride (20 mL) was added sodium triacetoxyborohydride (0.19 g, 0.90 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography to provide the desired product as a mixture of four isomers. LCMS calculated for C26H39F3N4O2: (M+1) 497.3; found 497.2 for four isomers.
Reaction SMILES: Br[C:2]1[C:28]([F:29])=[CH:27][C:5]2[O:6][C:7]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:8]=3[C@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[C:30]([Cu])#[N:31].CN1C(=O)CCC1.O>C(OCC)(=O)C.[Cu]I>[C:30]([C:2]1[C:28]([F:29])=[CH:27][C:5]2[O:6][C:7]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:8]=3[C@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1)#[N:31]
Reactant: N#C[Cu]
Reactant: O=C(N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12)C(F)(F)F
Agent: [Cu]I
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1cc2c(cc1F)Oc1cc(F)ccc1[C@H]1[C@H](NC(=O)C(F)(F)F)CCCN21
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
A mixture of 2.74 g (5.74 mmol) of (−)-(cis)-N-(7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide, CuCN (1.3 g, 14.3 mmol), CuI (0.123 g, 0.57 mmol) and NMP (25 mL) was stirred in a microwave for 20 min. at 180° C., 300 Watt with cooling. After cooling down, the reaction mixture was poured into water (500 mL). The precipitate, containing product and salts, was redissolved in ethyl acetate and the salts were filtered off. The organic layer was washed with NH4OH-solution, water, and brine, dried, and concentrated to give the crude compound which was crystallized to give the title compound (1.45 g, 59%). 1H-NMR (400 MHz, DMSO) 1.60-1.86 (m, 3H), 2.01 (m, 1H), 3.15 (m, 1H), 3.86 (m, 1H), 4.133 (d, J=10.0, 1H), 4.35 (m, 1H), 7.00 (m, 1H), 7.03 (m, 1H), 7.44 (d, J=7.7, 1H), 7.6 (d, J=6.3, 1H), 9.23 (br-d, J=7.8, 1H). (m/z)=424 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:15].O[CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)C>[ClH:15].[C:9]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC1CCNCC1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1

Procedure:
The starting material is prepared as follows: The mixture 268 of diphenylmethanol, 200 g of 4-hydroxypiperidine hydrochloride and 28.8 g of p-toulenesulfonic acid monohydrate is stirred and heated to 160° while reducing the pressure to 0.2 mm Hg with a vacuum pump for 3 hours. It is cooled to 80°, dissolved in 500 ml of ethanol and the solution cooled to 10°. The resulting suspension is filtered, the residue washed with isopropanol and dried at 60°, to yield the 4-diphenylmethoxy-piperidine hydrochloride. It is suspended in 1,800 ml of water, converted into the free base with 125 ml of aqueous ammonia and extracted with diethyl ether and the extract evaporated.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH2:17][O:18][CH3:19])[C:3]=1[CH:4]=[O:5].CCN(CC)CC.[O:27](S(C(F)(F)F)(=O)=O)[S:28]([C:31]([F:34])([F:33])[F:32])(=O)=[O:29]>ClCCl.O>[CH:4]([C:3]1[C:6]([CH2:17][O:18][CH3:19])=[CH:7][C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:9][C:2]=1[O:1][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:27])=[O:5]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COCc1cc(OC2CCCCO2)cc(O)c1C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COCc1cc(OC2CCCCO2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of 2-hydroxy-6-methoxymethyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (3.09 g, 11.62 mmol) and Et3N (6.47 mL, 46.48 mmol) in dichloromethane (50 mL) was added Tf2O (4.30 mL, 25.56 mmol) at −78° C. The mixture was stirred at −78° C. for 1 hour. The mixture was diluted with H2O and extracted with dichloromethane. The organic extracts were washed with brine, dried and concentrated in vacuo. The residue was dissolved in Hexane-EtOAc(4:1), filtered through a plug of silica gel and filtrate was concentrated to give trifluoro-methanesulfonic acid 2-formyl-3-methoxymethyl-5-(tetrahydro-pyran-2-yloxy)-phenyl ester (2.60 g, 72%). 1H NMR (400 MHz, CDCl3) δ 10.30 (s, 1H), 7.44 (s, 1H), 7.00 (s, 1H), 5.60 (s, 1H), 4.80 (s, 2H), 3.80 (m, 1H), 3.65 (m, 1H), 3.50 (s, 3H), 2.00-1.50 (m, 6H).
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH:15]1([CH2:14][O:8][C:7]2[C:2]([I:1])=[N:3][C:4]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:5][CH:6]=2)[CH2:17][CH2:16]1
Reactant: CS(=O)(=O)c1ccc(O)c(I)n1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(I)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
A mixture of 2-iodo-6-methylsulfonylpyridin-3-ol (500.0 mg, 1.67 mmol), bromomethylcyclopropane (248.4 mg, 1.84 mmol) and K2CO3 (461.3 mg, 33.4 mmol) in ACN (15 mL) was stirred at 80° C. for 4 hrs. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the title compound (500.0 mg, 84.8%). 1H NMR (CDCl3, 400 MHz) δ 7.96 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 4.09 (d, J=6.8 Hz, 2H), 3.22 (s, 3H), 1.36-1.22 (m, 1H), 0.69-0.57 (m, 2H), 0.43-0.37 (m, 2H). LCMS: 354.0 (M+1)+
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[CH2:15]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1)[CH3:16].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:22]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([CH2:15][CH3:16])=[CH:18][CH:19]=1)[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Reactant: CCc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1ccc(CN2Cc3cc(Br)cc(Cl)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (1.06 g, 3.00 mmol), 4-ethyl-benzylamine (0.575 mL, 4.0 mmol), and K2CO3 (0.967 g, 7.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-ethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.442 g, 41%). GC-MS: m/z 364 (M)+, 336 (M−28)+. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.24 (t, 3H), 2.64 (q, 2H) 4.20 (s, 2H), 4.73 (s, 2H), 7.21 (m, 4H), 7.44 (s, 1H), 7.58 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][NH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1.[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:4]([CH2:3][CH:2]([CH3:17])[CH3:1])[C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6]1
Reactant: CC(C)CN[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CN(Cc1cccc(Cl)c1Cl)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 16 h

Procedure:
To a solution of 1,1-dimethylethyl (3S)-3-(2-methylpropyl amino)-pyrrolidine-1-carboxylate (see Example 197(a)) (0.363 g, 1.5 mmol) in 1,2-dichloroethane (10 mL) was added 2,3-dichloro-benzaldehyde (1.05 g, 6.0 mmol), followed by sodium triacetoxyborohydride (0.95 g, 4.5 mmol), and the mixture left to stir for 16 h. The reaction mixture was quenched with water (5 mL) and 2N sodium hydroxide (5 mL), and the organic layer separated by passing through a hydrophobic frit. The organic solution was diluted with methanol (5 mL) and absorbed onto an Isolute™ SCX-2 ion exchange cartridge (5 g), washed with methanol (15 mL) and the product eluted with 2M ammonia in methanol solution (15 mL). The solvent was removed in vacuo to give 1,1-dimethylethyl (3S)-3-{[(2,3-dichlorophenyl)methyl](2-methylpropyl)amino}pyrrolidine-1-carboxylate as a colourless oil. This was taken up in dichloromethane (2 mL), trifluoroacetic acid (1.4 mL, 18.3 mmol) added, and the mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue diluted with methanol (5 mL) and absorbed onto an Isolute™ SCX-2 ion exchange cartridge (5 g). The column was washed with methanol (15 mL) and the product eluted with 2M ammonia in methanol solution (15 mL). The solvent was removed in vacuo and the residue purified by mass guided preparative LCMS. The residue was diluted with methanol (5 mL) and again absorbed onto an Isolute™ SCX-2 ion exchange cartridge (5 g). The column was washed with methanol (15 mL), the product eluted with 2M ammonia in methanol solution (15 mL) and the solvent removed in vacuo. The desired compound product was taken up in cyclohexane (15 mL) and a hot solution of L-tartaric acid (1 equiv.) in isopropanol (1 mL) was added. The solvent was removed in vacuo and the residue taken up in 40% acetonitrile/water and freeze dried to give the tile compound as a white solid.
Reaction SMILES: CO[CH:3]1[N:7]([C:8]([O:10][CH3:11])=[O:9])[C@H:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:4]1.C[Si]([C:20]#[C:21][CH3:22])(C)C.[Sn](Cl)(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:20]([C@@H:3]1[N:7]([C:8]([O:10][CH3:11])=[O:9])[C@H:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:4]1)#[C:21][CH3:22]
Reactant: CC#C[Si](C)(C)C
Reactant: COC(=O)[C@@H]1CCC(OC)N1C(=O)OC
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC#C[C@H]1CC[C@@H](C(=O)OC)N1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cold −45° C. solution of dimethyl(2S)-5-methoxypyrrolidine-1,2-dicarboxylate (10 g, 46.08 mmol, Example 1B) and trimethylsilylpropyne (14.24 ml, 92.16 mmol, 2.0 equiv) in methylene chloride (180 mL) was added a solution of tin (IV) chloride (1 M in methylene chloride, 60.0 mL, 60.0 mmol, 1.3 equiv) dropwise via an addition funnel over 30 minutes. To the dark yellow solution was added solid aluminum chloride (8.58 g, 64.52 mmol, 1.4 equiv) in one portion. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 48 hours. The reaction mixture was carefully quenched by saturated aqueous NH4OH (100 mL) with ice cooling. A white precipitate formed and was removed by filtration. The crude product was obtained after concentration. The residue was chromatographed on a Biotage flash 40 M eluting with 70% hexane/30% ethyl acetate to afford the titled compound. MS (DCI/NH3) m/e 226 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.NC1C2C(=CC=CC=2)N=C(C)C=1C(=O)C.BrC1C=CC(CBr)=C([F:48])C=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[C:22]([F:48])[CH:23]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Agent: CC(=O)c1c(C)nc2ccccc2c1N
Product: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1F

Procedure:
1-(4-(4-Bromo-2-fluorobenzylamino)-2-methylquinolin-3-yl)ethanone was synthesized by the same process as described for 1-(4-(4-bromobenzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from 1-(4-amino-2-methylquinolin-3-yl)ethanone and 4-bromo-2-fluorobenzyl bromide. MS(ES+): 387/389.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33].ClC(OCC)=O>>[C:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:23][CH2:24][N:25]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27]3)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)Cl
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Agent: CCOC(=O)Cl
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)Nc3ccccc3)c3ccccc23)CC1

Procedure:
The title compound was prepared according to the general procedure in Scheme 11, substituting 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid phenylamide for 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide, and butyryl chloride for ethyl chloroformate. 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.67 (m, 1H), 8.36 (m, 2H), 8.25 (d, 1H), 8.08 (m, 2H), 7.87 (d, 1H), 7.78 (d, 1H), 7.70 (m, 1H), 7.63 (m, 1H), 5.50 (d, 1H), 3.95 (m, 1H), 3.55 (m, 1H), 3.26 (m, 1H), 2.88 (m, 1H), 2.48 (m, 1H), 2.13 (m, 2H), 1.66 (m, 2H), 1.48 (m, 3H), 1.19 (m, 1H), 0.88 (t, 3H); LC/MS m/z 480 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH:18]([CH3:20])[CH3:19].[Br:24]Br.N.CO>O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]2[C:9]=1[N:10]=[C:11]([Br:24])[N:12]2[CH:18]([CH3:20])[CH3:19]
Reactant: COc1cccc(CNc2nc(Cl)nc3c2ncn3C(C)C)c1
Reactant: BrBr
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(CNc2nc(Cl)nc3c2nc(Br)n3C(C)C)c1
Yield: 88 %

Procedure:
1 mmol of 6-(3-methoxybenzylamino)-2-chloro-9-isopropylpurine was brominated with 1.1 mmol of bromine as described in Example 1. The crude 2,8-dihalogeno derivative prepared was alkalinized with NH3/MeOH and extacted between water-EtOAc. The product crystallizes after partial evaporation of ethylacetate. M.p.123-125° C., yield 88%. MS-ESI(+)m/z 409.5, 411.4, 413.3 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:15]=[N:14][C:5]2[N:6]=[CH:7][C:8](=[O:13])[N:9]([CH2:10][CH:11]=C)[C:4]=2[CH:3]=1.I([O-])(=O)(=O)=[O:17].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[CH:15]=[N:14][C:5]2[N:6]=[CH:7][C:8](=[O:13])[N:9]([CH2:10][CH:11]=[O:17])[C:4]=2[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)cnc2ncc(Br)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CCn1c(=O)cnc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-Bromo-1-(2-propen-1-yl)pyrido[2,3-b]pyrazin-2(1H)-one (278 mg, 1.045 mmol) was dissolved in 1,4-dioxane (10 ml) and water (10 ml). Sodium periodate (559 mg, 2.613 mmol) was added, followed by osmium tetroxide (0.22 ml of 4% aqueous solution). The mixture stirred at rt for 1 h, water 40 ml was added the mixture was stirred for a further 1 h. The reaction was concentrated to about 50 ml and extracted with 20% MeOH/DCM (3×100 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give (7-bromo-2-oxopyrido[2,3-b]pyrazin-1(2H)-yl)acetaldehyde (existing mostly as the hydrate) as an impure brown oil (423 mg, 107%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17])=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:51][O:52][C:53](=[O:68])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[CH3:51][O:52][C:53](=[O:68])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([N:62]1[CH2:63][CH2:64][N:65]([C:20](=[O:22])[CH2:19][NH:18][C:16]([C:13]2[CH:12]=[CH:11][C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[O:17])[CH2:66][CH2:67]1)=[O:61]
Reactant: COC(=O)c1ccccc1C(=O)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
DIPEA (233 mg, 1.80 mmol) was added to a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (161 mg, 0.63 mmol) in DMF (5 mL), HOBt (85.6 mg, 0.63 mmol) and EDCI.HCl (276 mg, 1.44 mmol) at room temperature. After 2 minutes 2-(piperazine-1-carbonyl)-benzoic acid methyl ester (143 mg, 0.58 mmol) was and the resulting mixture was stirred at room temperature overnight. The mixture was then diluted with cold water and the product extracted with ethyl acetate. The organic layer was separated, washed with 10% HCl solution, NaHCO3 solution, and brine, dried over sodium sulphate and concentrated to afford 106 mg (37.9% yield) of 2-(4-{2-[(biphenyl-4-carbonyl)-amino]-acetyl}-piperazine-1-carbonyl)-benzoic acid methylester, LC-MS purity: 98.96%, 1H NMR: (DMSO) δ 8.6 (bs, 1H), 7.9 (d, 3H), 7.8-7.6 (m, 5H), 7.54 (t, 1H), 7.54-7.46 (t, 2H), 7.44-7.36 (t, 2H), 4.1 (d, 1H), 3.8 (s, 3H), 3.6 (d, 4H), 3.4 (bs, 2H), 3.1 (bd, 2H).