Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[O:30]1[CH2:33][CH:32]([N:34]2[CH2:41][C:38]3([CH2:40][CH2:39]3)[NH:37][CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:36][CH2:35][N:34]([CH:32]5[CH2:33][O:30][CH2:31]5)[CH2:41][C:38]54[CH2:39][CH2:40]5)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: C1CN(C2COC2)CC2(CC2)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4COC4)CC34CC4)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (183 mg, 0.47 mmol), 7-oxetan-3-yl-4,7-diazaspiro[2.5]octane (90 mg, 0.54 mmol) and 4 Å powdered molecular sieves (1.0 g) in DCE (10 mL) was allowed to stir at r.t. for 6 h before the addition of sodium triacetoxyborohydride (144 mg, 0.68 mmol). The resulting mixture was allowed to stir for 16 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 5% then MeOH:DCM, 1-5%) followed by recrystallisation from Et2O affording 744 (156 mg, 61%). LCMS (method I): RT 2.53 min [M+H]+ 544.2. 1H NMR (DMSO, 400 MHz): δ 8.00-7.99 (1 H, m), 7.65-7.61 (1 H, m), 7.24-7.23 (2 H, m), 4.53 (2 H, t, J=6.46 Hz), 4.42 (2 H, t, J=6.05 Hz), 4.24 (4 H, brd s), 4.07 (2 H, s), 3.77 (4 H, t, J=4.61 Hz), 3.73 (3 H, s), 3.50-3.42 (1 H, m), 3.26 (2 H, q, J=7.44 Hz), 2.85-2.75 (2 H, m), 2.32 (2 H, t, J=4.72 Hz), 2.17 (2 H, brd s), 1.33 (3 H, t, J=7.44 Hz), 0.72-0.65 (2 H, m), 0.52-0.51 (2 H, m)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]([C:20]([F:23])([F:22])[F:21])=[C:10]2[C:24]#[N:25])=[C:5]([O:26][CH3:27])[CH:4]=1)#[N:2].F[B-](F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34].ClCCl>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:33][CH3:34])[NH:12][C:11]([C:20]([F:23])([F:22])[F:21])=[C:10]2[C:24]#[N:25])=[C:5]([O:26][CH3:27])[CH:4]=1)#[N:2]
Reactant: CC[O+](CC)CC
Reactant: COc1cc(C#N)ccc1C1C(C#N)=C(C(F)(F)F)Nc2cc[nH]c(=O)c21
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C#N)=C(C(F)(F)F)N2

Procedure:
390 mg (1.05 mmol) of 4-(4-cyano-2-methoxyphenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonitrile and 398 mg of triethyloxonium tetrafluoroborate (2.1 mmol) are mixed under a dry argon atmosphere. After addition of dichloromethane (32 ml), the suspension is stirred until a solution is obtained (about 2 h), and then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 250 mg (59% of theory) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:37][CH2:38][CH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=O)[CH:21]=2)[NH:16][C:15]=1[C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[CH:30]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:48]12[NH:54][CH:51]([CH2:52][CH2:53]1)[CH2:50][CH2:49]2.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.CO.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([CH3:28])([CH3:27])[C:24]([N:54]3[CH:48]4[CH2:53][CH2:52][CH:51]3[CH2:50][CH2:49]4)=[O:26])[CH:21]=2)[NH:16][C:15]=1[C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[CH:30]=1)[CH2:37][CH2:38][CH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2CCN(CCCCc2cccnc2)C(=O)OCc2ccccc2)c1
Reactant: C1CC2CCC1N2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN(CCCCc2cccnc2)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of of 92.7 mg (0.15 mmol) of 2-[3-[2-[benzyloxycarbonyl-[4-(pyridin-3-yl)butyl]amino]ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid, 80.2 mg (0.6 mmol) of 7-azabicyclo[2.2.1]heptane hydrochloride, 83.2 mg (0.16 mmol) of PyBOP reagent, 0.107 mL (77.8 mg; 0.77 mmol) of triethylamine, and 0.75 mL of dry methylene chloride was stirred at room temperature in a stoppered flask for 48 hours. The solution was then partitioned between 10 mL of ethyl acetate and 10 mL of 0.5 N hydrochloric acid. The organic phase was washed with 10 mL of saturated aqueous sodium bicarbonate solution and then with 5 mL of saturated aqueous sodium chloride solution. The ethyl acetate phase was then dried (magnesium sulfate), filtered, and concentrated in vacuo at room temperature. The residue was purified by preparative TLC on 6 Analtech tapered silica gel plates (20×20 cm), which were developed in 95:5 CH2Cl2-MeOH. The product band from each plate was isolated, combined, and extracted with 95:5 CH2Cl2-MeOH. Concentration of the extracts in vacuo yielded 85.9 mg (82%) of a very pale yellow glass; virtually homogeneous by TLC in 95:5 CH2Cl2-MeOH. 506 MHz 1H NMR (CDCl3) was complex, owing to rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e=697.6 (M+H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:29][C:30]([C@@H:32]([NH:43][C:44](=[O:53])[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:33][CH2:34][C:35](=[O:42])[N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:31])[C@H:9]([OH:28])[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[ClH:60]>>[ClH:60].[C:44]([NH:43][C@H:32]([CH2:33][CH2:34][C:35](=[O:42])[N:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)[C:30]([NH:29][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]([OH:28])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:31])([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:53]
Reactant: COc1cccc(CN(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CCC(=O)N2CCCCC2)NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](CCC(=O)N2CCCCC2)NC(=O)OCc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
A 50 ml round bottom flask was charged with 1-benzyl (1S)-1-[({(1S,2R)-1-benzyl-3-[(tert-butoxycarbonyl)(3-methoxybenzyl)amino]-2-hydroxypropyl}amino)carbonyl]-4-oxo-4-(1-piperidinyl)butylcarbamate (XXXVI, EXAMPLE 3, 100 mg) in dioxane/hydrochloric acid (4 N, 4 ml). The reaction is stirred 15 minutes when HPLC analysis indicates complete de-protection. The reaction mixture is concentrated under reduced pressure. The crude product is chased with acetonitrile (5 ml) then methylene chloride (5 ml). The resulting hydrochloride salt is dried under reduced pressure, to give the title compound, M+H=631.
Reaction SMILES: [I:1]N1C(C)(C)C(=O)N(I)C1=O.[CH3:12][C:13]([NH:19][C:20]([C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:21])([CH3:18])[CH2:14][S:15]([CH3:17])=[O:16].CN1CCCC1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[I:1][C:31]1[C:22]([C:20]([NH:19][C:13]([CH3:12])([CH3:18])[CH2:14][S:15]([CH3:17])=[O:16])=[O:21])=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccccc1C(=O)NC(C)(C)CS(C)=O
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccc(I)c1C(=O)NC(C)(C)CS(C)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 137.3 %

Procedure:
Into the same reactor as in Example 1 were charged 1.5 mg of palladium acetate, 0.83 g of 1,3-diiodo-5,5-dimethylhydantoin, 1.0 g of methyl 2-(1,1-dimethyl-2-methylsulfinylethylaminocarbonyl)benzoate and 5 ml of N-methylpyrrolidone. The mixture thus obtained was heated with stirring at 90° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into water, and the objective product was extracted with ethyl acetate. The organic layer was washed successively with aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, a crude product was obtained. Purification of the crude product by silica gel column chromatography (ethyl acetate/n-hexane=1/3) gave 1.27 g of methyl 3-iodo-2-(1,1-dimethyl-2-methylsulfinylethylaminocarbonyl)-benzoate (yield 89.1%, melting point 150.7–151.8° C.).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:25]=[CH:24][NH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:25]=[CH:24][NH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2nc(-c3cc[nH]c3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc[nH]c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a solution of methyl 3-[(2S)-2-methylpyrrolidin-1-yl]-2-(1H-pyrrol-3-yl)quinoxaline-6-carboxylate (100 mg, 0.30 mmol) in methanol (30 ml) and water (2.0 ml) was added sodium hydroxide (48 mg, 1.20 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL1) and adjusted to pH 4 with HCl (3 N). The solids were collected by filtration to afford 3-[(2S)-2-methylpyrrolidin-1-yl]-2-(1H-pyrrol-3-yl)quinoxaline-6-carboxylic acid as a light yellow solid (70 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:10][NH:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[Br:1])[CH3:14])[CH3:18]
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1cccc(NN)c1Br
Product: CCOC(=O)C(C)=NNc1cccc(C)c1Br

Procedure:
The title compound, ISP-MS: m/e=299.3 and 301.3 (M+H+), was prepared in accordance with the general method of example 25b) from (2-bromo-3-methyl-phenyl)-hydrazine and ethyl pyruvate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.CCCCCC.C([Li])CCC.[C:24](=[O:26])=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:12][O:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:24]([OH:26])=[O:25])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: COc1cc(Br)c2[nH]ccc2c1
Reactant: O=C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c2[nH]ccc2c1
Temperature: -78 °C
Yield: 59.1 %

Procedure:
A mixture of 7-bromo-5-methoxy-1H-indole (1.2 g) and THF (12 mL) was stirred at −78° C. under an argon atmosphere. To the reaction mixture was added dropwise an n-butyllithium n-hexane solution (1.65 M, 9.6 mL) at −50° C. or lower. The reaction mixture was stirred for 0.5 hour under ice-cooling. The reaction mixture was cooled to −78° C., and dry ice (10 g) was added thereto, followed by slowly warming to room temperature. The reaction mixture was poured into a 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (THF/hexane=20→60%) to obtain 5-methoxy-1H-indole-7-carboxylic acid (0.60 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:33]=[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:30][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:14]([CH:24]=1)[C:15]([NH:17][CH2:18][C:19]([O:21]CC)=[O:20])=[O:16])=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].O.Cl>C(O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:33]=[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:30][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:14]([CH:24]=1)[C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CNC(=O)c1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(C(=O)NCC(=O)O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
In 7 ml of ethanol is dissolved 0.64 g of ethyl 2-{[5-(2,4-diisobutoxybenzoyl)-2-isobutoxybenzoyl]amino}acetate, to which is added 0.73 ml of 5 mol/L solution of sodium hydroxide. The mixture thus obtained is stirred at ambient temperature for one hour. Water and ethyl acetate are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; chloroform:ethanol=20:1) to obtain 0.25 g of 2-{[5-(2,4-diisobutoxybenzoyl)-2-isobutoxybenzoyl]amino}-acetic acid as a white solid product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)(=[O:11])=[O:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:45]1[NH:50][CH2:49][CH2:48][N:47]2[CH2:51][CH2:52][CH2:53][C@H:46]12>CN(C)C(=O)C.CC1CCCO1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([N:50]2[CH2:49][CH2:48][N:47]3[CH2:51][CH2:52][CH2:53][C@@H:46]3[CH2:45]2)=[O:17])[CH:13]=1)(=[O:10])=[O:11]
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccccc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CC1CCCO1
Product: O=C(c1cccc(S(=O)(=O)Nc2ccccc2F)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (800 mg, 2.71 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1133 mg, 2.98 mmol) in N,N-dimethylacetamide (6.5 mL) and 2-methyltetrahydrofuran (19.5 mL) was added (R)-octahydropyrrolo[1,2-α]pyrazine (479 mg, 3.79 mmol). The reaction was stirred at room temperature for 3 hours, diluted with 2-methyltetrahydrofuran (5 mL), and washed with saturated bicarbonate (2×25 mL). The combined aqueous layers were adjusted to pH 7 with buffer and re-extracted with 2-methyltetrahydrofuran (3×15 mL). The combined organic layers were concentrated under reduced pressure. The residue was taken up in ethanol (25 mL) and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Cc1ccc2ncccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ncccc2c1
Yield: 54 %

Procedure:
To a solution of 6-methylquinoline (2.15 g, 15.0 mmol) in CCl4 (30 mL) was added NBS (2.92 g, 16.5 mmol) and benzoyl peroxide (BP, 0.36 g, 1.5 mmol) at room temperature. The mixture was heated at reflux for 2 hours. After cooling, the mixture was evaporated under vacuum to give a yellow solid, which was extracted with Petroleum Ether (30 mL×5). The extracts were concentrated under vacuum to give crude 6-bromomethylquinoline (1.8 g), which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.CN([CH:31]=[O:32])C>C1COCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: Clc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: O=Cc1cnccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
A solution of 4-chloropyridine (2.89 g, 25.5 mmol) in THF (15 ml) at -78° C. was added to a stirred solution of lithium di-isopropylamide prepared by addition of n-butyl lithium (10.2 ml of 2.5 M, 25.5 mmol) to a solution of di-isopropylamine (2.58 g, 25.5 mmol) in dry tetrahydrofuran at -78° C. After 2 hours a solution of DMF (2.05 g, 28.1 mmol) in THF (25 ml) at -78° C. was added. After a further 1 hour at -78° C. the reaction mixture was allowed to warm slowly to room temperature (16 hours). The resulting solution was poured into saturated brine (200 ml) and extracted with ether (3×100 ml). The combined ether extracts were washed with saturated brine and then the solvent was evaporated. Flash chromatography (eluent petrol-ether) of the resulting residue gave 4-chloro-3-pyridine carboxaldehyde (2.86 g) as a solid; melting point 53-54° C.; infrared max (nujol) 1580, 1695 cm-1 ; 1H NMR delta (CDCl3) 7.45 (1H,d), 8.70 (1H,d), 9.07 (1H,s), 10.50 (1H,s).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:4][C:5]3[CH:6]=[C:7]4[C:11](=[C:12]([CH:26]=3)[CH2:13][CH2:14][C:15]3[CH:25]=[C:19]([NH:20][C:21]([N:24]=2)=[N:22][CH:23]=1)[CH:18]=[CH:17][CH:16]=3)[O:10][C:9](=[O:27])[N:8]4[CH2:28][C:29]([O:31]C)=[O:30].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:3]2[NH:4][C:5]3[CH:6]=[C:7]4[C:11](=[C:12]([CH:26]=3)[CH2:13][CH2:14][C:15]3[CH:25]=[C:19]([NH:20][C:21]([N:24]=2)=[N:22][CH:23]=1)[CH:18]=[CH:17][CH:16]=3)[O:10][C:9](=[O:27])[N:8]4[CH2:28][C:29]([OH:31])=[O:30]
Reactant: COC(=O)Cn1c(=O)oc2c3cc(cc21)Nc1nc(ncc1Cl)Nc1cccc(c1)CC3
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)Cn1c(=O)oc2c3cc(cc21)Nc1nc(ncc1Cl)Nc1cccc(c1)CC3
Temperature: 20 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
A solution of methyl [4-chloro-19-oxo-18-oxa-2,6,8,20,25-pentaazapentacyclo[14.6.1.1(3,7).1(9,13).0(17,21)]pentacosa-1(23),3(25),4,6,9(24),10,12,16,21-nonaen-20-yl]acetate (0.23 g, 0.51 mmol) in dichloromethane (15 mL) at −78° C. was treated with 1 M of boron tribromide in dichloromethane (1.5 mL, 1.5 mmol) and stirred at 20° C. for 16 h. The reaction mixture was cooled to 0° C., treated with additional 1 M of boron tribromide in dichloromethane (1.5 mL, 1.5 mmol), and stirred at 20° C. for 6 h. The reaction mixture was cooled to 0° C., quenched with 0.5 M HCl (10 mL) dropwise, concentrated and filtered. The brown solid that was collected was washed with water and dried. This material was diluted with dichloromethane (20 mL), cooled to 0° C., treated with 1 M of boron tribromide in dichloromethane (1.5 mL, 1.5 mmol), and stirred at 20° C. for 24 h. The reaction mixture was cooled to 0° C., quenched with 0.5 M HCl (10 mL) dropwise, concentrated and filtered. The brown solid that was collected was washed with water and dried to give the desired product (0.15 g, 67%) as a tan solid. LCMS for C21H17ClN5O4 (M+H)+: m/z=438.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[OH:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]>CC(C)=O.[O-2].[O-2].[Mn+4]>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]([C:5]1[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: COc1cc(C(O)c2cccs2)cc([N+](=O)[O-])c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: COc1cc(C(=O)c2cccs2)cc([N+](=O)[O-])c1OC

Procedure:
9.9 g of α-(3,4-dimethoxy-5-nitrophenyl)-2-thiophenemethanol dissolved in 300 ml of acetone are treated with 90 g of manganese dioxide and heated under reflux for 4 hours. The manganese dioxide is removed by suction filtration and the filtrate is evaporated. There is obtained 3,4-dimethoxy-5-nitrophenyl 2-thienyl ketone of m.p. 102°-104° (from methylene chloride/hexane).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([C:17]4([C:20]5[CH:21]=[C:22]6[C:27](=[CH:28][CH:29]=5)[N:26]=[CH:25][CH:24]=[CH:23]6)[CH2:19][CH2:18]4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.[I-].[Na+].CN[C@H]1CCCC[C@@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[N:30]1([C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[N:10][C:11]4[N:12]([C:14]([C:17]5([C:20]6[CH:21]=[C:22]7[C:27](=[CH:28][CH:29]=6)[N:26]=[CH:25][CH:24]=[CH:23]7)[CH2:19][CH2:18]5)=[N:15][N:16]=4)[N:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: Brc1cccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)c1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: c1cc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc(-n2ccnc2)c1
Temperature: 120 °C
Yield: 46.5 %

Procedure:
To a solution of 6-{1-[6-(3-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline (20 mg, 0.04 mmol) in 1,4-dioxane (1 mL) was added 1H-imidazole (4.61 mg, 0.0677 mmol), sodium iodide (14 mg, 0.090 mmol), (1S,2S)-N,N′-dimethylcyclohexane-1,2-diamine (1 mg, 0.009 mmol), copper(I) iodide (0.8 mg, 0.004 mmol), and cesium carbonate (31 mg, 0.095 mmol), then the mixture was heated at 120° C. overnight. The reaction mixture was cooled to RT and filtered. The filtrate was diluted with MeOH and purified by RP-HPLC (pH=10) to afford the desired compound 8 mg (40%) LCMS: (M+H)+=431.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[CH:12]([S:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:18]([C:17]1[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=1[S:15][CH:12]([CH3:14])[CH3:13])=[O:19])[CH2:6][CH2:5]2
Reactant: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1ccc2c(c1)CCNC2
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(Cl)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [33537-99-4]) and 2-isopropylsulfanyl-5-methanesulfonyl-benzoic acid (example 2.7). MS (m/e): 424.1 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>CS(C)=O.O>[S:19]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=[C:11]1[C:8]1[N:6]2[N:7]=[C:2]([NH:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1ccc2ncc(-c3cc4cccnc4s3)n2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: O[C@H]1CC[C@H](Nc2ccc3ncc(-c4cc5cccnc5s4)n3n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-3-(thieno[2,3-b]pyridin-2-yl)imidazo[1,2-b]pyridazine (45 mg, 0.157 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (22 mg, 0.157 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.784 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 40 mg of the yellow solid, 70%.