Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:12](=[O:13])[C@@H:11]([NH:14]C(OC(C)(C)C)=O)[CH2:10][NH:9][C:8]2[CH:22]=[CH:23][CH:24]=[CH:25][C:7]1=2>C(OCC)(=O)C>[ClH:1].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:12](=[O:13])[C@@H:11]([NH2:14])[CH2:10][NH:9][C:8]2[CH:22]=[CH:23][CH:24]=[CH:25][C:7]1=2
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)[C@@H](N)CNc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Anhydrous hydrogen chloride was bubbled into a solution of (3(S)-tert-butoxycarbonylamino-2-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)acetic acid methyl ester (103, 1 g, 2.86 mmol) in 25 ml of ethyl acetate for 2 minutes then stirred for 1 hour at room temperature. The reaction was evaporated to give 2-oxo-3(S)-amino-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl acetic acid methyl ester hydrochloride as a white solid. The hydrochloride salt was suspended into 20 ml of dichloromethane and cooled to 0° C. Triethylamine (1.6 ml, 11.5 mmol) was added to the suspension followed by the dropwise addition of dihydrocinnamoyl chloride (0.9 ml, 6 mmol). The mixture was warmed to room temperature and stirred for 18 hours. The mixture was diluted with 25 ml of dichloromethane and washed twice with 50 ml of water and once with 50 ml of brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give a viscous, yellow oil that was purified by flash chromatography eluting with 1:1 ethyl acetate/dichloromethane to afford 1.35 g (92%) of the title product as a white solid. 1H NMR (CDCl3) δ 7.45-7.02 (14 H, m), 6.37-6.32 (1H, d), 4.78-4.72 (1H, m), 4.52-4.3 (3H, m), 3.82-3.77 (1H,m), 3.74 (3H, s), 3.03-2.87 (4H, m), 2.58-2.45 (2H, m), 2.45-2.35 (1H, m), 2.25-2.16 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:24][C@H:13]23)=[O:7])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Cc1ccc(C(=O)O)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1N
Yield: 63 %

Procedure:
The title compound is prepared from 3-amino-4-methyl-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 63% of theory; LC (method 4): tR=1.81 min; Mass spectrum (ESI+): m/z=307 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][N:18]1[CH2:27][CH:28]([OH:46])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][N:18]1[CH2:27][CH:28]([OH:46])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[CH:8][N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:6]=3[CH:16]=2)[CH:32]=1
Reactant: Brc1ccc2ncn(-c3ccccc3)c2c1
Reactant: CC1(C)OB(c2cccc(OCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: OC(COc1cccc(-c2ccc3ncn(-c4ccccc4)c3c2)c1)CN1CCc2ccccc2C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
A mixture of 6-bromo-1-phenyl-1H-benzo[d]imidazole (200 mg, 0.73 mmol), 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (330 mg, 0.81 mmol), K2CO3 (303 mg, 2.19 mmol) and Pd(dppf)Cl2 (50 mg) in a solution of dioxane (8 mL) and H2O (2 mL) was stirred at 100° C. for 16 h. The catalyst was filtered, and the filtrate concentrated. The residue was purified by prep-HPLC to give the desired title compound (152 mg, 43.8%). 1HNMR(CH3OD, 400 MHz) δ: 8.42 (s, 1H), 8.37 (br, 1H), 8.22-8.20 (m, 1H), 7.70-7.52 (m, 7H), 7.49-7.18 (m, 7H), 6.96-6.93 (m, 1H), 4.53-4.38 (m, 3H), 4.02-3.96 (m, 2H), 3.61-3.55 (m, 2H), 3.48-3.36 (m, 2H), 3.25-3.13 (m, 2H). LCMS (m/z): 476.2 [M+H]+
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12](Cl)[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cu](C#N)[C:22]#[N:23].CN1CCCC1=O.O.N>S([O-])([O-])(=O)=O.[Cu+2].O>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([C:22]#[N:23])[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: FC(F)(F)c1ccc2c(c1)CCc1c(Cl)cccc1S2
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cccc2c1CCc1cc(C(F)(F)F)ccc1S2
Reaction time: 18.5 h
Yield: 14.7 %

Procedure:
The mixture of 450 mg of 2-trifluoromethyl-9-chloro-10,11-dihydrodibenzo[b,f]thiepin, 0.4 g of copper cyanide, 0.05 g of anhydrous copper sulfate and 10 ml of N-methylpyrrolidone was stirred at 180° to 210° C. for 18.5 hrs. while preventing the moisture. After cooling, to the mixture was added 2.5 ml of conc. ammonia water and 35 ml of water and the resulting mixture was filtered with the use of celite. The thus obtained solution was extracted with benzene and the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 0.3 g of a brown oily substance, which was chromatographed on a silica gel, eluted with n-hexane, and there was obtained 64 mg of the desired product. This was recrystallized from n-hexane to afford 2-trifluoromethyl-9-cyano-10,11 -dihydrodibenzo[b,f]thiepin having a melting point of 113° to 114.5° C. as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]=O)[CH2:3][CH2:2]1.[CH3:7][C:8]1([CH3:28])[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:1]1([CH2:4][CH2:5][N:25]2[CH2:26][CH2:27][N:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH:10]3[CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:8]([CH3:28])([CH3:7])[CH2:9]3)[CH2:23][CH2:24]2)[CH2:3][CH2:2]1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: O=CCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccccc2N2CCN(CCC3CC3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of cyclopropylacetaldehyde in 1,2-dichloroethane (0.29 M, 5 mL) were added 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (25 mg, 0.0832 mmol) produced in Example (8b), sodium triacetoxyborohydride (22.9 mg, 0.108 mmol) and acetic acid (0.009 mL, 0.158 mmol), followed by stirring for 20 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed twice with ethyl acetate. The organic layer was concentrated and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 20.9 mg of 1-(2-cyclopropylethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=O)[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:19]=1.N>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C@H:11]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:22]=2)[C@@H:14]2[CH2:15][CH2:16][CH2:17][N:13]2[CH2:12]1
Reactant: COc1ccc(C(=O)CN2CCCC2c2cccc(OCCCN3CCCCC3)c2)c(OC)c1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c(OC)c1
Yield: 78 %

Procedure:
1. 1-(2,4-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.28 g (78%) of the desired product as a pale yellow oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C28H38N2O4, 466.3; m/z found, 467.5 [M+H]+. 1H NMR (MeOH-d4): 7.16 (m, 1H), 7.10 (d, J=3.2, 1H), 6.97 (dd, J=3.2, 9.0, 1H), 6.93 (d, J=1.6, 1H), 6.87 (m, 2H), 6.76 (m, 1H), 4.04 (m, 1H), 3.91 (m, 2H), 3.69 (s, 3H), 3.63 (s, 3H), 3.43 (m, 3H), 2.39 (m, 6H), 2.30 (m, 1H), 2.11 (m, 1H), 1.92 (m, 3H), 1.82 (m, 1H), 1.75 (m, 1H), 1.55 (m, 4H), 1.42 (m, 2H).
Reaction SMILES: [C:1]([O:8]C([O-])=O)(=O)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH3:12][C:13]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[C:30]([CH3:37])[C:14]=1[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.O1CCCC1.C(#N)C>[C:3]([O:2][C:1]([N:21]1[C:22]2[C:18](=[CH:17][C:16]([O:15][C:14]3[C:30]([CH3:37])=[CH:31][C:32]([N+:34]([O-:36])=[O:35])=[CH:33][C:13]=3[CH3:12])=[CH:24][CH:23]=2)[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:20]1)=[O:8])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCCCCc1n[nH]c2ccc(Oc3c(C)cc([N+](=O)[O-])cc3C)cc12
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCc1nn(C(=O)OC(C)(C)C)c2ccc(Oc3c(C)cc([N+](=O)[O-])cc3C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102 %

Procedure:
889 mg (4.074 mmol) of tert-butyl pyrocarbonate are added at 0° C. to a suspension of 1.20 g (3.395 mmol) of 5(2,6-dimethyl-4-nitrophenoxy)-3-pentyl-1H-indazole (Example XX), 378 mg (3.735 mmol) of triethylamine and 41 mg (0.340 mmol) of 4-dimethylaminopyridine in 5 ml of tetrahydrofuran and 5 ml of acetonitrile and the mixture is stirred at room temperature for 30 min. The reaction mixture is then freed from the solvent in vacuo, taken up with ethyl acetate, and the organic phase is washed once each with 1N hydrochloric acid, satd sodium hydrogencarbonate solution and satd. sodium chloride solution, dried over sodium sulphate, freed from the solvent in vacuo and purified on silica gel using methylene chloride. 1.57 g (92% of theory) of 1-tert-butoxycarbonyl-5-(2,6-dimethyl-4-nitrophenoxy)-3-pentyl-1H-indazole are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]3[O:21][CH2:20][CH2:19][C:18]=3[CH:22]=1)[C:6]([C:23]([OH:25])=[O:24])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CO.[H][H]>[C].[Pd].C1COCC1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([CH2:13][N:7]3[C:6]([C:23]([OH:25])=[O:24])=[C:5]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:4]4[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=4)[C:8]3=[O:12])=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: [H][H]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1ccc2c(c1)CCO2
Yield: 65.1 %

Procedure:
A mixture of 6-bromo-2-(2,3-dihydrobenzofuran-5-ylmethyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (350 mg), 10% palladium carbon (150 mg), methanol (5 ml) and THF (5 ml) was stirred at room temperature under 1 atm hydrogen pressure for 12 hrs. Palladium carbon was filtered off, and the filtrate was concentrated. The obtained crystals were washed with diethyl ether to give the title compound (190 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([NH:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:31])[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.[ClH:43]>CO.O1CCCC1>[ClH:43].[ClH:43].[NH2:35][CH2:34][CH2:33][NH:32][C:30]([CH:27]1[CH2:26][CH2:25][N:24]([C:21]2[N:20]=[C:19]([N:16]3[CH2:17][CH2:18][N:13]([C:11]([NH:10][C:3]4[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][N:2]=4)=[O:12])[CH2:14][CH2:15]3)[S:23][N:22]=2)[CH2:29][CH2:28]1)=[O:31]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCCNC(=O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Yield: 91 %

Procedure:
A solution of tert-butyl [2-({[1-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperidin-4-yl]carbonyl}amino)ethyl]carbamate (70.0 mg, 0.117 mmol) and a solution of 2 N hydrogen chloride in methanol (10 ml) in tetrahydrofuran (10 ml) was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of methanol and diethyl ether to give 61.0 mg (91.0%) of the desired product as a solid.
Reaction SMILES: [N:1]([C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[C:5]([O:7]C)=O)=[C:2]=[S:3].[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17].CC(C)([O-])C.[K+].O>O1CCCC1.C(O)(=O)C>[CH3:9][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:1][C:2](=[S:3])[N:17]([NH:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:5]1=[O:7]
Reactant: COC(=O)C(C)(N=C=S)c1ccccc1
Reactant: NNc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(c2ccccc2)NC(=S)N(Nc2ccccn2)C1=O
Temperature: 5 °C
Yield: 59.6 %

Procedure:
2 g (9 mmol) of methyl 2-isothiocyanato-2-phenylpropionate are dissolved in 30 ml of tetrahydrofuran. A solution containing 0.99 g of 2-hydrazinopyridine and 10 ml of tetrahydrofuran is added: the temperature of the mixture rises from 20 to 30° C. and a solid precipitates. The mixture is allowed to react for 0.5 hour at 30° C. and then is cooled to 5° C. A solution containing 1 g of potassium tert-butoxide and 10 ml of tetrahydrofuran is then added: the mixture becomes violet in color. The mixture is left to return to room temperature and is left to react for 2 hours. The mixture is poured into 150 ml of water. The mixture is neutralized with acetic acid. The product is extracted with 150 ml of ethyl acetate. The solution is washed with water, dried over magnesium sulfate and then treated with active charcoal. The solution is concentrated and the product is crystallized from 20 ml of diethyl ether. The above-mentioned product is filtered and is dried under vacuum. 1.6 g (yield: 60%) of 5-methyl-5-phenyl-3-(2-pyridylamino)-2-thiohydantoin is obtained as a pale-yellow solid melting at 80° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[F:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: COc1cccc(B(O)O)c1F
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Product: COc1cccc(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)c1F
Yield: 77.3 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 2-fluoro-3-methoxyphenylboronic acid (158 mg, 0.94 mmol) were reacted. After purification the title compound (128 mg, 78% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.04(d, J=4.9 Hz, 1H), 8.48 (dd, J=2.6, 7.2 Hz, 1H), 7.79 (m, 2H), 7.23 (m, 2H), 7.02 (m, 1H), 3.90 (s, 3H), 2.95 (m, 1H), 0.67 (m, 4H). MS APCI, m/z=353.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=2[C:43](O)=[O:44])[CH:36]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>>[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=2[C:43]([N:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:1]([N:8]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:7]3)[CH2:2]2)=[O:44])[CH:36]=1
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Reactant: O=C(O)c1ccccc1-c1cccnc1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: O=C(c1ccccc1-c1cccnc1)N1CC[C@H]2CN(c3cnc4ccccc4n3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)quinoxaline (Intermediate 3) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-pyridin-3-yl-benzoic acid for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C26H23N5O, 421.49; m/z found, 422.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.79-8.44 (m, 2H), 8.27-8.26 (m, 9H), 6.83-6.13 (m, 2H), 4.78-3.77 (m, 4H), 3.73-3.32 (m, 2H), 3.18-2.58 (m, 2H), 2.00-1.47 (m, 2H).
Reaction SMILES: [N:1]([C:4]1[N:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)=[N+]=[N-].O.O.Cl[Sn]Cl.Cl.C([O-])(O)=O.[Na+]>CO>[N:9]1[C:10]2[CH:11]=[CH:12][N:13]=[C:4]([NH2:1])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=Nc1nccc2ncccc12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Product: Nc1nccc2ncccc12
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of 5-azido-1,6-naphthyridine (3.2 g, 18.7 mmol) in MeOH (30 mL) was stirred at room temperature. SnCl2.2H2O (21 g, 93.6 mmol) was added to the mixture, followed by the addition of concentrated HCl (10 mL), then the mixture was refluxed for 5 h. The mixture was cooled to room temperature, and neutralized with sat. NaHCO3 to adjust the pH to 7-8. The mixture was filtered, and the aqueous phase was extracted with EtOAc (5×30 mL). The combined organic layers were dried with Na2SO4, filtered, and the solvent was removed under reduced pressure to yield 1,6-naphthyridin-5-amine as a pale yellow solid, which was used in the next step without further purification (2.20 g, yield 81%). ESI MS: m/z 146 [M+11]+. 1H NMR (400 MHz, CDCl3) δ 8.91 (dd, 1J=1.6 Hz, 2J=4.8 Hz, 1H), 8.62 (d, J=8.0 Hz, 1H), 8.00 (d, J=6.0 Hz, 1H), 7.47 (dd, 1J=4.8 Hz, 2J=8.0 Hz, 1H), 7.09 (br, 2H), 6.98 (d, J=6.0 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[O:13][C:12](=[O:22])[NH:11]2)[C:6]([F:9])=[N:7][CH:8]=1)#[CH:2].Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([F:30])[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C(N(CC)CC)C.[Cu]I.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>[F:9][C:6]1[C:5]([C@@H:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[O:13][C:12](=[O:22])[NH:11]2)=[CH:4][C:3]([C:1]#[C:2][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([F:30])[CH:25]=2)=[CH:8][N:7]=1
Reactant: Fc1cc(Br)ccn1
Reactant: C#Cc1cnc(F)c([C@H]2NC(=O)O[C@@H]2c2cccc(F)c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2cc(C#Cc3ccnc(F)c3)cnc2F)[C@@H](c2cccc(F)c2)O1
Temperature: 90 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a 15 ml sealable vial was added (4R,5R)-4-(5-ethynyl-2-fluoropyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (20 mg, 0.067 mmol) in triethylamine (2 mL). To this suspension was added 4-bromo-2-fluoropyridine (15.24 mg, 0.087 mmol), triphenylphosphine (5.24 mg, 0.020 mmol) and copper(I) iodide (0.254 mg, 1.332 μmol). The solution was degassed with nitrogen for 20 min, then bis(triphenylphosphine)palladium(II) chloride (0.935 mg, 1.332 μmol) was quickly added and the vial was sealed, heated to 90° C., and allowed to stir overnight. The next day the suspension had turned homogeneous and the reaction was cooled to room temperature and the solvent was evaporated in vacuo. The crude residue was purified by silica gel chromotagraphy eluting first with 100% CH2Cl2 then 1% MeOH/99% CH2Cl2 affording (4R,5R)-4-(2-fluoro-5-((2-fluoropyridin-4-yl)ethynyl)pyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (9.1 mg, 0.021 mmol, 31.4% yield) as a light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.63 (s, 1H), 8.51 (d, J=4.0, 1H), 8.45 (s, 1H), 8.14 (dd, J=8.0, 4.0, 1H), 7.69-7.64 (m, 1H), 7.60-7.54 (m, 1H), 7.50-7.43 (m, 1H), 7.21-7.13 (m, 2H), 6.05 (brs, 1H), 5.39 (d, J=4.0, 1H), 5.04 (d, J=4.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=2.01 min. Mass=396.20 (MH)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3]Cl.[CH3:14][C@H:15]1[O:20][C@@H:19]([CH3:21])[CH2:18][NH:17][CH2:16]1>C(Cl)Cl>[CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][N:17]1[CH2:16][C@H:15]([CH3:14])[O:20][C@H:19]([CH3:21])[CH2:18]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC(CCl)CCCc1ccccc1
Solvent: ClCCl
Product: CC(CCCc1ccccc1)CN1C[C@@H](C)O[C@@H](C)C1
Yield: 64.3 %

Procedure:
20 g of 2-methyl-5-phenylpentyl chloride and 35 g of 2,6-cis-dimethylmorpholine are heated at 150° C. for 10 hours, after which the mixture is left to cool, taken up with CH2Cl2, washed with water, dilute NaOH and once again with water, dried over Na2SO4 and evaporated down, and the residue is distilled to give 18 g of a product of boiling point 130°-132° C./0.4 mbar.
Reaction SMILES: C([O:5][C:6]1[C:7](=[O:37])[C:8](=[O:36])[C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[NH:18][C:19]([CH3:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:36][C:8]1[C:7](=[O:37])[C:6](=[O:5])[C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[NH:18][C:19]([CH3:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[CH:12]=1
Reactant: COc1ccc(C(NC(C)(C)c2ccccc2)c2cccc(Nc3c(OC(C)(C)C)c(=O)c3=O)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(NC(C)(C)c2ccccc2)c2cccc(Nc3c(O)c(=O)c3=O)c2)cc1
Yield: 99.8 %

Procedure:
Following a similar procedure to that described in Example (55b), 1.40 g of 3-t-butoxy-4-{3-[(4-methoxyphenyl )-(1-methyl-1-phenylethylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione [prepared as described in step (c) above], 10 ml of trifluoroacetic acid and 35 ml of dichloromethane were reacted, to obtain 1.24 g of the title compound as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH2:15])=[C:10]([CH3:16])[CH:9]=1.[C:17](OCC)(=[O:20])[C:18]#[CH:19]>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:19]=[CH:18][C:17]([OH:20])=[N:15]2)=[C:10]([CH3:16])[CH:9]=1
Reactant: C#CC(=O)OCC
Reactant: Cc1cc(Br)ccc1NN
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(Br)ccc1-n1ccc(O)n1
Yield: 24.3 %

Procedure:
Potassium tert-butoxide (20 ml, 1M in tert-butanol, 20.0 mmol) was added to 1-(4-bromo-2-methylphenyl)hydrazine (J. Chem. Soc. 109; 1916; 582)(2.01 g, 10.0 mmol) to give a dark brown suspension. Ethyl propiolate (1.02 ml, 10 mmol) was then added dropwise over 10 minutes, with cooling, and once addition was complete, the reaction was heated under reflux for 4 hours. The reaction was diluted with water (200 ml) and this mixture washed with dichloromethane (2×50 ml). The aqueous phase was acidified using hydrochloric acid (2N), extracted with dichloromethane (5×100 ml), these combined organic extracts dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (98:2) as eluant, and triturated with ether/di-isopropyl ether to give the title compound (615 mg, 24%) as a solid.