Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=[CH2:31].C(O)(=O)C>CO>[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:30][CH2:31][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:6]=2)[CH2:1]1
Reactant: C=Cc1ccccn1
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(Nc1ccc2c(c1)CCN(CCc1ccccn1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
Compound (II) (300 mg, 0.76 mmole), 2-vinylpyridine (95 mg, 0.91 mmole) and glacial acetic acid (24 mg, 0.40 mmole) were combined in 15 mL of methanol and heated to reflux for 24 hrs. The solvent was removed under vacuum and the residue was purified using silica gel chromatography with a gradient of 0 to 3% methanol in ethyl acetate as the eluent.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5].[Cl:21][CH2:22][CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O)(=O)C>C(O)C>[Cl:21][CH2:22][CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]2[N:6]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)[C:4](=[O:5])[C:3]3[C:2](=[C:18]([O:19][CH3:20])[CH:17]=[CH:16][CH:15]=3)[NH:1]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(NC(=O)c2cccc(OC)c2N)cc1
Reactant: O=Cc1ccc(OCCCl)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(N2C(=O)c3cccc(OC)c3NC2c2ccc(OCCCl)cc2)cc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a solution of 20.05 g (0.0736 mol) of 2-amino-N-(4-methoxy-phenyl)-3-methoxy-benzamide in 400 mL of ethanol was added 13.6 g (0.0736 mol) of p-(2-chloro-ethoxy)-benzaldehyde (Frinton Labs), and 10 mL of acetic acid. The reaction mixture was stirred and heated to a mild reflux overnight. After cooling to room temperature, the solvent was evaporated in a rotary evaporator. The residue was dissolved in 300 mL of ethyl acetate and washed with water (4×100 mL). The organic phase was removed, dried over magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. The residual oil was placed under the vacuum pump, which yielded 26.0 g (mp 122-124° C.) of product.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[N:7]/[NH:8][C:9]([NH2:11])=[O:10])=[C:4]([F:14])[CH:3]=1.BrBr.CCOCC>CC(O)=O>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]2[NH:11][C:9](=[O:10])[NH:8][N:7]=2)=[C:4]([F:14])[CH:3]=1
Reactant: NC(=O)N/N=C/c1ccc(Br)cc1F
Agent: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=c1[nH]nc(-c2ccc(Br)cc2F)[nH]1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A solution of compound 59a (7.2 g, 28 mmol) in AcOH (30 mL) was treated with Br2 (8.8 g, 55 mmol). The resulting solution was stirred at 95° C. for 2 h. The resulting solution was allowed to cool to rt and treated with Et2O (50 mL). The solids formed were collected by filtration to obtain compound 59b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C8H5BrFN3O: 258.0 (M+H). Found: 258.0.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH2:5]([O:7][C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[O:9])[CH3:6]>O1CCOCC1>[CH3:1][NH:2][C:3]([NH:13][C:11]([NH:10][C:8]([O:7][CH2:5][CH3:6])=[O:9])=[NH:12])=[O:4]
Reactant: CN=C=O
Reactant: CCOC(=O)NC(=N)N
Solvent: C1COCCO1
Product: CCOC(=O)NC(=N)NC(=O)NC

Procedure:
5.1 parts by weight of methylisocyanate were added to a suspension of 10 parts by weight of ethoxycarbonylguanidine (manufactured according to Isr. J. Chem. 8, 651 [1970] ) in 60 parts by volume of anhydrous dioxane, in the course of which the temperature rose to 45°C and the precipitate dissolved. After a short time, a crystalline precipitate separated out again, which was filtered off after cooling and washed with ether. It was dried in vacuo over P2O5 and paraffin chips.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:22]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:22])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a solution of diethyl 2-(4-bromophenyl)malonate (1.5 g, 4.8 mmol) in dry THF (5 mL) at 0° C. was added sodium hydride (380 mg, 9.5 mmol). After stirring for 30 minutes at 0° C., iodomethane (600 μL, 9.5 mmol) was added and the reaction was allowed to warm to room temperature. After stirring for 12 h at room temperature, the reaction was quenched with water (3 mL). The mixture was partitioned between 1 N HCl (10 mL) and dichloromethane (10 mL), and the organic layer was separated. The organic layer was washed with 1 N HCl (10 mL), dried over Na2SO4 and evaporated. The crude material was purified by silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes, to give diethyl 2-(4-bromophenyl)-2-methylmalonate (850 mg, 55%) 1H NMR (400 MHz, DMSO-d6) δ 7.59-7.55 (m, 2H), 7.31-7.27 (m, 2H), 4.21-4.14 (m, 4H), 1.75 (s, 3H), 1.19-1.16 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:14])([F:13])[O:7][C:8]2([F:12])[F:11])=[CH:4][C:3]=1[OH:15].[F:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[F:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[OH:15])[C:6]([F:14])([F:13])[O:7][C:8]2([F:11])[F:12])=[O:20]
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1cc2c(cc1O)C(F)(F)OC2(F)F
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1F
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A mixture of 1.5 g of 6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 0.95 g of 3-fluoroisonicotinic acid, 1.68 g of WSC and 13 ml of pyridine was stirred while heating at 80° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.46 g of 3-fluoro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide.
Reaction SMILES: [CH2:1]=[C:2]([CH2:15][CH2:16][CH3:17])[CH:3]([O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].[CH2:18]([SnH:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>>[CH2:1]=[C:2]([CH2:15][CH2:16][CH3:17])[CH:3]([O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH2:4][CH:5]=[CH:6][Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCC(O[Si](CC)(CC)CC)C(=C)CCC
Reactant: CCCC[SnH](CCCC)CCCC
Product: C=C(CCC)C(CC=C[Sn](CCCC)(CCCC)CCCC)O[Si](CC)(CC)CC
Temperature: 150 °C

Procedure:
A mixture of 20 g. of 5-methylene-4-triethylsilyloxy-1-octyne, 25.36 g. of tri-n-butylstannane and 0.1 g. of azobisisobutyrylnitrile is placed in an oil bath at 100° C. After 10 minutes an exotherm raises the temperature to 150° C. The mixture is then heated at 130°-140° C. for 1.5 hours. The excess tri-n-butylstannane is distilled off at 130° C. (1 mm.) and the residue is distilled in a Kugelrohr at 120°-140° C., 0.15-0.05 mm., giving the product as a colorless liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:36]([O:37][CH3:38])=[CH:35][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:36]([O:37][CH3:38])=[CH:35][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(CCO)CC2
Yield: 61 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol. Product was isolated as a white foam (58 mg, 61%). MS (ESI+): 546.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.23 (s, 1H), 8.58 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.02 (s, 1H), 7.95 (d, J=8 Hz, 1H), 7.62 (t, J=7 Hz, 1H), 7.52 (s, 1H), 6.68 (s, 1H), 3.90 (s, 3H), 3.65 (t, J=5 Hz, 2H), 3.28 (m, 1H), 2.89 (m, 2H), 2.73-2.67 (m, 8H), 1.34 (d, J=7 Hz, 6H).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[CH:17][CH:16]=3)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].[CH3:30][N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=O>>[CH3:29][O:28][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:9]1[CH2:10][CH2:5][CH:30]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:7][CH2:8]1)[N:9]=[CH:8][C:7]([C:12]#[N:13])=[C:6]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:17][CH:16]=1
Reactant: CN1CCCC1=O
Reactant: COc1cc2c(Nc3ccc(Sc4ccccn4)cc3)c(C#N)cnc2cc1F
Product: COc1cc2c(Nc3ccc(Sc4ccccn4)cc3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.37 mmol) of 7-fluoro-6-methoxy-4-[4-(pyridin-2-ylsulfanyl)-phenylamino]-quinoline-3-carbonitrile, 287 mg (1.86 mmol) of 4-(1-pyrrolidinylpiperidine) are refluxed in 1-methyl 2-pyrrolidinone (1 mL) at 105° C. for 12 hours to yield the crude product. Purification by silica gel chromatography (95:5 methylene chloride/methanol) gives 107 mg of 6-methoxy-4-[4-(pyridin-2-ylsulfanyl)-phenylamino]-7-(4-pyrrolidin-1-yl-piperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 182-184° C.
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]2[CH2:17][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:5]1[CH:6]=[CH:7]2)(=[O:3])[CH3:2].F>>[C:1]([N:4]1[CH:9]2[CH:8]3[CH:7]([CH2:6][CH:5]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17]3)[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1CC2C=CC1N(C(C)=O)C2Cc1ccccc1
Agent: F
Product: CCOC(=O)C1CC2C3CC1N(C(C)=O)C2Cc1ccccc13

Procedure:
Cyclization of ethyl 2-acetyl-3-benzyl-2-azabicyclo-[2.2.2]oct-5-ene-7-carboxylate, described in Example 1BQ, in the presence of hydrofluoric acid at 0°-15° C. using a procedure similar to that described in Example 2A affords ethyl 1-acetyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C1(C)C=CC(S(O[CH2:25][C@H:26]2[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[O:27]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:31][C:28]1([CH3:32])[O:27][C@@H:26]([CH2:25][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:30][O:29]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)O1
Temperature: 25 °C

Procedure:
A solution of 4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (9.24 g, 47.6 mmol), (R)-(−)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl p-toluenesulfonate (15.00 g, 52.38 mmol) and CsHCO3 (23.3 g, 71.4 mmol) in anhydrous DMF (236 mL) was heated to 100° C. for 16 h. The reaction mixture was allowed to cool to rt and partitioned between EtOAc and H2O and separated. The aqueous was re-extracted with EtOAc (3×) and the combined organic fractions were washed with H2O (2×) and brine (2×), dried over Na2SO4, filtered and concentrated in vacuo resulting in the title compound as an orange oil. It was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.31 (s, 12H), 1.33 (s, 3H), 1.39 (s, 3H), 3.78 (dd, J=8.8, 5.9 Hz, 1H), 4.07 (dd, J=8.8, 6.2 Hz, 1H), 4.23-4.35 (m, 2H), 4.47 (quint, J=5.8 Hz, 1H), 7.78 (s, 1H), 7.81 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][C:16]([C:20]([O:22]C)=[O:21])([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][C:16]([C:20]([OH:22])=[O:21])([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C12CCCC(NC(=O)OCc3ccccc3)(CC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC12CCCC(C(=O)O)(CC1)C2)OCc1ccccc1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
To a solution of methyl 5-(benzyloxycarbonylamino)bicyclo-[3.2.1]octane-1-carboxylate (25 g, crude product) in methanol (200 mL) was added NaOH (5N, 50 mL) and the reaction mixture was refluxed for two hours. After cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with diethyl ether (3×100 mL) to remove the organic impurities. The aqueous phase was adjusted to pH 1˜2 with 2N aq. HCl, and extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 8.5 g (49%, steps 5 and 6) of 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic acid as a yellow oil. ESI-MS m/z: 304 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=O)[CH:10]([CH3:12])[CH3:11].[Cl:14][CH2:15][C:16]#[N:17]>O1CCOCC1>[Cl:14][CH2:15][C:16]1[N:17]=[C:9]([CH:10]([CH3:12])[CH3:11])[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:2]=1
Reactant: CC(C)C(=O)c1ccccc1N
Reactant: N#CCCl
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1nc(CCl)nc2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dry hydrogen chloride gas is piped through a solution of 2.86 g of 1-(2-amino-phenyl)-2-methyl-propan-1-one and 1.33 ml of chloroacetonitrile in 14 ml dioxane with stirring at ambient temperature for approx. five hours. Then the dioxane is largely distilled off in a water jet vacuum. The honey-like residue is combined with ice water and the resulting suspension is made alkaline with saturated potassium carbonate solution while cooling with an ice bath. The precipitate is suction filtered, washed with water and dried. The crude product is purified by chromatography over a silica gel column with petroleum ether/methylene chloride (8:2 to 0:1) as eluant.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[N:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:20][N:19]=4)[CH:13]=3)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1>COCCOC.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>[CH3:44][N:45]1[CH:49]=[C:48]([C:2]2[N:7]=[C:6]3[N:8]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]5[N:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]6[CH2:28][CH2:29][O:30][CH2:31][CH2:32]6)=[CH:22][N:23]=5)[CH:13]=4)[N:9]=[N:10][C:5]3=[N:4][CH:3]=2)[CH:47]=[N:46]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc2nnn(Cc3cccc(-c4ncc(OCCN5CCOCC5)cn4)c3)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2cnc3nnn(Cc4cccc(-c5ncc(OCCN6CCOCC6)cn5)c4)c3n2)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.1 %

Procedure:
Under an argon atmosphere, 225 mg (0.24 mmol) of 6-bromo-1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-1H-1,2,3-triazolo[4,5-b]pyrazine are dissolved in 5 ml of ethylene glycol dimethyl ether, and 102 mg (0.48 mmol) of tripotassium phosphate trihydrate and 55 mg (0.26 mmol) of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole are added. The reaction mixture is evacuated and flushed with argon twice. 14 mg (0.02 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, the mixture is again evacuated and flushed argon. The reaction mixture is stirred at 80° C. for 16 hours. 10 ml of water are added to the reaction mixture, during which an oil precipitates out. This is extracted with dichloromethane and with dichloromethane comprising about 10% of MeOH, the aqueous phase is adjusted to pH 14 using 32% NaOH and again extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and purified by means of preparative HPLC, giving 42 mg of 6-(1-methyl-1H-pyrazol-4-yl)-1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-1H-1,2,3-triazolo[4,5-b]-pyrazine (“A2”); the product is in the form of the TFA salt; Rt.=2.26 (method A), LCMS: 499 (M+H);
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4].[CH:28]([NH2:31])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[O:6][C:7]2[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=2[C:9]=1[S:10]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]([OH:23])[CH2:22][NH:31][CH:28]([CH3:30])[CH3:29])=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)N
Reactant: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(OCC2CO2)cc1
Solvent: ClC(Cl)Cl
Product: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(OCC(O)CNC(C)C)cc1

Procedure:
2-n-Butyl-3-[4-(2,3-epoxypropoxy)phenylsulfonyl]benzofuran (1.9 g.) was dissolved in 30 ml. of freshly distilled isopropylamine and the solution was heated at 100° for 2 hours. After cooling, the solvent was evaporated to give a residue which was dissolved in chloroform. Evaporation of the solvent gave the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([C:5]1[CH:17]=[C:16]([O:18]CC2C=CC=CC=2)[C:8]2[N:9]=[C:10]([CH3:15])[N:11]([CH2:12][O:13][CH3:14])[C:7]=2[CH:6]=1)=[O:4].C(O)(=O)C>C(O)C.[Pd]>[CH3:26][N:2]([CH3:1])[C:3]([C:5]1[CH:17]=[C:16]([OH:18])[C:8]2[N:9]=[C:10]([CH3:15])[N:11]([CH2:12][O:13][CH3:14])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COCn1c(C)nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COCn1c(C)nc2c(O)cc(C(=O)N(C)C)cc21
Yield: 60.8 %

Procedure:
A solution of 1.8 g (5.0 mmol) 7-benzyloxy-3-methoxymethyl-2-methyl-3H-benzimidazole-5-carboxylic acid dimethylamide and 270 μl acetic acid in 150 ml ethanol was hydrogenated over 240 mg 10% Pd/C in autoclave (5 bar H2) at 50° C. for 18 h. The catalyst was filtered off and the filtrate was concentrated in vacuo and crystallized from ethyl acetate-petroleum ether to afford 0.8 g (62%) of the title compound as a white solid. m.p. 173°-183° C.
Reaction SMILES: C([Li])CCC.Br.[CH2:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17])[CH3:8].[CH2:18]([N:20]([C:29]#[N:30])[C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])[CH3:19].C1COCC1>CCCCCC>[CH3:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[N:9]([CH2:7][CH3:8])[C:29]([N:20]([C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])[CH2:18][CH3:19])=[NH:30]
Reactant: CCN(C#N)c1c(C)cccc1C
Reactant: CCNc1c(C)cccc1C
Agent: Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(C(=N)N(CC)c1c(C)cccc1C)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (20.5 mL, 1.6 M in hexane, 32.8 mmol) was added dropwise to a stirred suspension of N-ethyl-2,6-dimethylaniline hydrobromide (3.8 g, 16.5 mmol) in hexane (40 mL) at 0° C. The reaction mixture was stirred for 1 h at room temperature and cooled subsequently to −80° C. N-Ethyl-N-cyano-2,6-dimethylaniline (2.92 g, 16.8 mmol) was added drop wise at −80° C. after which the reaction mixture was allowed to slowly warm up to room temperature. The resulting reaction mixture was stirred for 2 h at room temperature, during which hexane (60 mL) and THF (20 mL) were added to form a homogeneous solution. The reaction mixture was quenched and washed with water (100 mL). The organic layer was separated, the aqueous layer was extracted with diethyl ether (100 mL) and the combined organic layers were dried with Na2SO4. Filtration and rotatory evaporation of the volatiles yielded the desired guanidine as a yellow waxy material. Yield: 5.3 g (99%).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:18])[CH2:12][CH2:13][C@H:14]([NH2:17])[CH2:15][F:16].[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:19]([NH:17][C@H:14]([CH2:15][F:16])[CH2:13][CH2:12][C:11]([O:10][CH3:9])=[O:18])(=[O:21])[CH3:20]
Reactant: COC(=O)CC[C@H](N)CF
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@@H](CF)NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.26 ml of triethylamine and 2 ml of glacial acetic acid were mixed with 0.34 g of 4. The mixture was cooled to 0° C. and 0.21 ml of acetic anhydride was added drop-by-drop to the stirred mixture. The mixture was allowed to warm to room temperature and stirred for 30 minutes. The solvents were evaporated under reduced pressure, the residue was triturated with a mixture of ethyl acetate and ether and filtered. The filtrate was eluted through a florisil pad, using ethyl acetate as eluent. The solvent was evaporated under reduced pressure to give 6, as a brown solid.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH:34]=[O:35])[N:31]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH3:16].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH:34]([C:2]3[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[OH:35])[N:31]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH3:16]
Reactant: COc1cccnc1Br
Reactant: CCOc1ccc(-c2nc(CCC=O)cs2)cc1OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(CCC(O)c3ncccc3OC)cs2)cc1OCC
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 25.8 %

Procedure:
A solution of 2-bromo-3-methoxypyridine (1.65 g, 8.78 mmol) in THF was cooled to −78° C., and 5.23 ml (8.16 mmol) of a 1.57 N solution of n-butyllithium in n-hexane was added dropwise. The resulting mixture was stirred at the same temperature for 45 minutes, and a solution (15 ml) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionaldehyde (1.34 g, 4.39 mmol) in THF was added dropwise. After stirring at the same temperature for 30 minutes, the temperature of the mixture was raised to −30° C. over a period of 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated salt solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). The solvent was distilled off under reduced pressure, to thereby obtain 470 mg (yield: 26%) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanol as a yellow oil.