Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[Cl:12][CH2:13][CH2:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]=[C:28]=[O:29])(=[O:26])=[O:25])=[O:17]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:28]([NH:27][S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:16]([O:15][CH2:14][CH2:13][Cl:12])=[O:17])(=[O:25])=[O:26])=[O:29])[N:7]=1
Reactant: COc1nc(N)nc(OC)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1C(=O)OCCCl
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OCCCl)nc(OC)n1
Temperature: 25 °C

Procedure:
To 0.7 g of 2-amino-4,6-dimethoxy-1,3,5-triazine in 10 ml anhydrous methylene chloride solvent was added 1.45 g 2-(β-chloroethoxycarbonyl)benzenesulfonyl isocyanate. After stirring at ambient temperature for sixteen hours the solvent was removed under reduced pressure, the residue triturated with ether and the solid product filtered off, yield 1.21 g m.p. 171°-174° C. The solid showed infrared absorption peaks at 1705 and 1715 cm-1, consistent for N-[(4,6-dimethoxy-1,3,5-triazin-2-yl)aminocarbonyl]-2-(2-chloroethoxycarbonyl)benzenesulfonamide.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](Cl)=[O:36])=[CH:29][CH:28]=1>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:35](=[O:36])[CH2:34][CH2:33][C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCc1ccc(Cl)cc1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)CCc2ccc(Cl)cc2)N(c2nnc(C(C)(C)C)s2)C1=O

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. β-(4-Chlorophenyl)propionyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl- 1,3,4-thiadiazol-2-yl)-3-methyl-6-[β-(4-chlorophenyl)propionyloxy] -2 (1H)-pyrimidinone as the residue.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][C:2]1[N:3]([S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])[C:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c(C)[nH]c(-c2ccccc2)c1C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(C)c(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1C
Yield: 37 %

Procedure:
Using ethyl 2,4-dimethyl-5-phenyl-1H-pyrrole-3-carboxylate (3.0 g), sodium hydride (60% in oil, 596 mg) and benzenesulfonyl chloride (1.92 mL), a procedure as in Reference Example 4 was performed to give the title compound as a brown oil (yield 506 mg, 37%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3](=[O:21])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=1)([CH3:7])[CH3:6].[CH2:24]1[CH2:28]OC[CH2:25]1>C(OCC)C>[CH3:20][S:17]([C:10]1[CH:9]=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3]([C:2]([F:1])([F:22])[F:23])([OH:21])[CH2:28][C:24]#[CH:25])[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=1)(=[O:18])=[O:19]
Reactant: C1CCOC1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(S(C)(=O)=O)cc2c1OCC2
Solvent: CCOCC
Product: C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of 1,1,1-trifluoro-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methylpentan-2-one (5.4 g, 15.4 mmol) in a mixture of 10 mL of anhydrous diethyl ether and 10 mL of anhydrous THF was treated with the organoaluminum reagent at −78° C. After 1 hour at −78° C. and 1 hour at room temperature, the reaction mixture was quenched with saturated ammonium chloride solution and diluted with water. The aqueous layer was extracted with three 100 mL portions of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 6.3 g of the title product as a solid, which was used without further purification (quantitative yield).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26].N12CCN(CC1)CC2.Cl>O.CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:23]4[CH2:24][CH2:25][NH:20][C:21](=[O:26])[CH2:22]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: O=C1CNCCN1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Yield: 72.4 %

Procedure:
5.3 g (20 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are initially introduced into 50 ml of DMSO and heated with 2.4 g (24 mmol) of 2-piperazinone and 4.4 g (40 mmol) of 1,4-diazabicyclo[2.2.2]octane at 130° C. for 1 hour. After cooling, the suspension is adjusted to pH 5 with 2 N hydrochloric acid, 50 ml of water are added, and the precipitate is filtered off with suction, washed with water and methanol, and then boiled in 50 ml of methanol. 5 g (72% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-oxo-1-piperazinyl)-3-quinolinecarboxylic acid of melting point 342°-348° C. (decomposition) and purity 97% (HPLC) are isolated. Mass spectrum: m/e 345 (M+), 301 (94%, M+--CO2), 231 (M+--C 3 H4NO), 202, 44 (100%, CO2). NMR (CF3COOH)=δ1.45 and 1.7 broad (4H in the cyclopropyl radical), 3.9 and 4.0 broad (5H, N--CH in the cyclopropyl radical, N--CH2CH2 --N), 4.6 broad (2H, CO--CH2 --N), 7.85 d (1H, on C-8), 8.28 d (1H, on C-5), 9.3 s (1H, on C-2).
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][O:9][C:10](=[O:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([CH3:28])[C:25]([CH3:29])=[CH:24][C:22]=2[N:23]=1.Cl[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>O>[CH3:8][O:9][C:10](=[O:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[N:20]([CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[C:21]2[CH:27]=[C:26]([CH3:28])[C:25]([CH3:29])=[CH:24][C:22]=2[N:23]=1
Reactant: ClCc1cccc2ccccc12
Reactant: COC(=O)c1ccccc1CSc1nc2cc(C)c(C)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccccc1CSc1nc2cc(C)c(C)cc2n1Cc1cccc2ccccc12
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
Sodium hydride (1.1 mg, 0.306 mmol) and 2 ml of tetrahydrofuran was added to a previously dried reaction vessel. To the mixture were added 2-((5,6-dimethylbenzimidazole-2-ylthio)methyl)benzoic acid methyl ester (50 mg, 0.153 mmol) and 1-chloromethylnaphthalene (69 μl, 0.459 mmol), which was then stirred at 60° C. for 45 minutes. Water was added thereto, followed by extraction with ethyl acetate. After drying the ethyl acetate phase with anhydrous sodium sulfate, it was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 2-((5,6-dimethyl-1-(1-naphthylmethyl)benzimidazole-2-ylthio)methyl)benzoic acid methyl ester (yield 32%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5](O)=[O:6].Cl.C[N:14](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>C(#N)C.O>[F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5]([NH2:14])=[O:6]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(CC(=O)O)C(F)(F)F
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)(CC(N)=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
Treat a 0° C. solution of 4,4,4-trifluoro-3,3-dimethylbutanoic acid [See: US2010/0240663] (17 g, 100 mmol) in acetonitrile (200 mL) with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23 g, 120 mmol) and 1-hydroxybenzotriazole (16.2 g, 120 mmol), stir at 0° C. for 2 h, treat with concentrated ammonia in water (25 wt %, 15 mL), allow to warm to RT and stir overnight. Remove the organics under reduced pressure, dissolve the residue in EtOAc, and wash with saturated. NaHCO3, then brine, dry over MgSO4, and concentrate to dryness. Treat the material with pet ether, collect the solid via filtration and dry to afford the title compound (13 g, 77% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.46 (s, 1H), 6.93 (s, 1H), 2.19 (s, 2H), 1.18 (s, 6H).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH2:21][CH3:22])[C:19]#[N:20]>C(O)C>[C:19]([CH2:18][CH2:21][CH2:22][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])#[N:20]
Reactant: O=C(O)c1cccc(S)c1
Reactant: CCC(Br)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#CCCCSc1cccc(C(=O)O)c1
Yield: 54.7 %

Procedure:
To solution of 3-mercaptobenzoic acid (250 mg, 1.62 mmole) in ethanol (10 ml), anhydrous potassium carbonate (896 mg, 6.48 mmole) was added followed by bromobutyronitrile (239.97 mg, 1.62 mmole). The reaction mixture was refluxed overnight. The ethanol was evaporated and water added. The basic solution was extracted with ethyl acetate. The aqueous layer was acidified and the resulting precipitate filtered and dried to yield 196 mg product. M.S. m/s 220 (M−1)+. 1H NMR (DMSO) δ 1.79 (2H, m, —CH2-), 2.37 (2H, t, —CH2-), 3.02 (2H, t, CH2), 7.56 (1H, d, 1×ArH), 7.74 (1H, d, 1×ArH), 7.83 (1H, bs, 1H, 1×ArH).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].Cl>O.CO>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)c1ccc(N)cc1
Yield: 88.8 %

Procedure:
A solution of 4-acetylamino-N-tert-butylbenzenesulfonamide (8.0 g, 29.6 mmol), KOH (8.30 g, 148 mmol), H2O (6 mL) and MeOH (24 mL) is heated at 100° C. for 2 h. H2O (24 mL) is added and the mixture is heated for two more hours. It is allowed to cool, H2O is added and it is brought to pH 8 with 1N HCl. It is then extracted with EtOAc, dried over Na2SO4 and the solvent is removed, to give 6.0 g of the product as a white solid (yield: 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]([CH3:16])[CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:17]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]([CH3:16])[CH3:15])[CH3:17])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC(C)C)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N(C)C(C)C)c1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 5-bromo-3-(isopropylamino)-2-methylbenzoate (0.5 g, 1.75 mmol) in acetonitrile (10 mL), Cs2CO3 (1.02 g, 2.63 mmol) and methyl iodide (1.45 g, 3.5 mmol) were added to it. The resulting reaction mixture was stirred at 80° C. for 4 h. Upon completion, the solvent was removed under reduced pressure and residue dissolved in water and extracted with ethyl acetate. Crude material obtained was purified by column chromatography over silica gel affording the desired compound product without further purification (0.39 g)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][N:25]1[C:29]([C:30](O)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:30]([C:29]3[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=3)=[O:31])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1cc(C(=O)O)n(C)n1
Product: Cc1cc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)n(C)n1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2,5-dimethyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.75 min; [M+H]+=455.2.
Reaction SMILES: [NH2:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:8]([F:13])[CH:9]=2)[N:4]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:3]=1.[CH2:26]([O:28][C:29](=[O:35])[CH2:30][CH2:31][C:32](O)=[O:33])[CH3:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH:15]1([NH:14][C:7]2[CH:6]=[C:5]3[C:10]([C:11](=[O:12])[C:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:35])=[CH:3][N:4]3[CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:9][C:8]=2[F:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: CCOC(=O)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(=O)Nc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
250 mg of 3-amino-7-(cyclohexylamino)-1-cyclopentyl-6-fluoroquinoline-4(1H)-one and 127 mg of 4-ethoxy-4-oxobutanoic acid were dissolved in 20 ml of DMF, and 170 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 160 mg of 1-hydroxybenzotriazole were added, followed by overnight stirring at room temperature. By adding water to the reaction mixture and collecting the insoluble materials by filtration, 220 mg of ethyl 4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}-4-oxobutanoate was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)([CH:10]([CH3:12])[CH3:11])[C:6]([O:8][CH3:9])=[O:7].[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:5]([C:6]([O:8][CH3:9])=[O:7])([CH:10]([CH3:12])[CH3:11])[CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COC(=O)C(CCCCl)(c1ccc(OC)c(OC)c1)C(C)C
Reactant: CNCCc1ccc(C(=O)OC)cc1
Product: COC(=O)c1ccc(CCN(C)CCCC(C(=O)OC)(c2ccc(OC)c(OC)c2)C(C)C)cc1

Procedure:
Reaction of 1e with 2b produced 3h. MS found M+H=486. The oxalate salt of 3h was recrystallized from ethyl acetate; mp 129-131° C.
Reaction SMILES: BrC1C=CC([C:8]2[C:13]3[O:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)=CC=1.Br[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Br:32])[CH:28]=2)[CH:23]=1>>[Br:32][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C:18]1[CH:19]=[CH:20][C:15]3[O:14][C:13]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:16]=3[CH:17]=1)[CH:31]=[CH:30]2
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: Brc1ccc(-c2cccc3c2oc2ccccc23)cc1
Product: Brc1ccc2cc(-c3ccc4oc5ccccc5c4c3)ccc2c1

Procedure:
2-(6-bromonaphthalen-2-yl)dibenzofuran was synthesized in the same manner as in the synthesis of 4-(4-bromophenyl)dibenzofuran except that 2,6-dibromonaphthalene was used instead of 4-bromoiodobenzene.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:15]([CH3:17])[CH3:16])[C:10]([O:12][CH2:13]Cl)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[I-:19]>CC(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:15]([CH3:17])[CH3:16])[C:10]([O:12][CH2:13][I:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCI
Yield: 49.4 %

Procedure:
To a solution of (S)-chloromethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (4.53 g, 17 mmol) in acetone (50 mL) was added NaI (7.67 g, 51 mmol). The mixture was heated to reflux for 12 h. The solution was diluted with H2O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel, eluted with PE:EA=100:1 to 50:1, to give (S)-iodomethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (3 g, 49%) as a white solid. 1H NMR (400 MHz, CDCl3): δ ppm 6.06-6.05-7.30 (d, J=2.2, 1H), 5.86-5.85 (d, J=2.0, 1H), 4.97-4.95 (d, J=4.0, 1H), 4.25-4.22 (m, 1H), 2.20-2.18 (m, 1H), 1.46 (s, 9H), 1.01-1.00 (d, J=3.6, 3H), 0.94-0.93 (d, J=3.4, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:27]=[CH:26][C:25]([N+]([O-])=O)=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:37]([OH:40])[CH2:38][OH:39]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:27]=[CH:26][C:25]([O:39][CH2:38][CH2:37][OH:40])=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: OCCO
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccccc3F)nc3ncccc23)c2ccncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: OCCOc1ccc(-c2cc(-c3ccccc3F)nc3ncccc23)c2ccncc12
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A slurry of 198 mg (0.50 mmol) 2-(2-fluoro-phenyl)-4-(8-nitro-isoquinolin-5-yl)-[1,8]naphthyridine (synthesis see example 6) in 1 ml ethane-1,2-diol was treated with 326 mg (1.00 mmol) cesium carbonate. The resulting slurry was stirred at 80° C. for two days. The reaction mixture was cooled to room temperature and diluted with water. The resulting precipitate was filtered off, washed with water and chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 2-{5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-isoquinolin-8-yloxy}-ethanol as colourless crystals; HPLC/MS: 1.53 min, [M+H] 412.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)C(C)C)C>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1nc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1nc(Cl)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a stirred solution of 2,4-dichloro-6-methoxy-1,3,5-triazine (10.0 g, 55.6 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (11.4 g, 55.6 mmol, 1.0 equiv) in acetonitrile (300 mL) was added drop by drop N-ethyl diisopropylamine (48.5 mL, 36.6 g, 278 mmol, 5.0 equiv) keeping the temperature below 25° C. After stirring the reaction mixture at rt for 16 h, the heterogeneous mixture was poured onto ice water and extracted three times with ethyl acetate. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 11.4 g (60%) of the title compound as a off-white foam. MS (ISP): 344.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:18](O)[CH3:19]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH2:18][CH3:19])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1n[nH]c2cc(Br)ccc12
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1n[nH]c2cc(Br)ccc12
Temperature: 25 °C

Procedure:
To a stirred solution of 6-bromo-1H-indazole-3-carboxylic acid (5 g, 21 mmol) in ethanol (160 Ml), thionyl chloride (8 Ml, 104 mmol; SOCl2) was added. The mixture was refluxed for 3 h, cooled to room temperature, and concentrated under reduced pressure. Ethyl acetate was added. The organic layer was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, DCM:MeOH=9:1) to give ethyl 6-bromo-1H-indazole-3-carboxylate (2.8 g).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:5]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[NH2:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[CH2:7][C@@H:6]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:5]1
Reactant: [H][H]
Reactant: COc1ccc2c(c1OC)CC(C1CCCCC1)C=C2CN
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1OC)C[C@@H](C1CCCCC1)C[C@H]2CN
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
1-Aminomethyl-3-cyclohexyl-5,6-dimethoxy-3,4-dihydronaphthalene hydrochloride (1 g, 3.3 mmol), from Step 2 of Example 36, was dissolved in 20 mL of ethanol and 0.25 g of 10% palladium on carbon was added to the ethanol solution. The reaction mixture was sealed under one atmosphere of hydrogen and shaken at ambient temperature for 24 h. The reaction mixture was filtered to remove the catalyst and concentrated to give 1 g (100% yield) of the title compound. m.p. 282°-283° C.; 1H NMR (d6 -DMSO) δ: 1.0-1.5 (m, 8H), 1.5-1.9 (m, 5H), 2.0-2.2 (m, 2H), 2.7-3.1 (m, 3H), 3.3-3.4 (m, 1H), 3.8 (s, 3H), 3.9 (s, 3H), 6.4-6.8 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(O)(C)(C)C>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=3)[N:5]=[CH:4][C:3]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cnc2ccc(Cl)nc2c1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.7 %

Procedure:
Ethyl 4,6-dichloro-1,5-naphthyridine-3-carboxylate (0.5 g, 1.85 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (0.45 g, 2.22 mmol) were dissolved in the mixture of DCM (5 mL) and tert-butyl alcohol (5 mL). Potassium carbonate (0.612 g, 4.43 mmol) was added to the solution. The reaction mixture was stirred at ambient temperature for 24 h and filtrated under reduced pressure. The solid was washed by DCM. The filtrate was concentrated under reduced pressure. The residue was recrystallized in diethyl ether to give a faint yellow solid (0.73 g, 90.9% yield).