Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][C@H:6]1[CH2:24][OH:25])(=[O:4])=[O:3].[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>N1C=CC=CC=1>[CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][C@H:6]1[CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1C[C@@H](P(=O)(C2CCCCC2)C2CCCCC2)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@@H]1C[C@H](P(=O)(C2CCCCC2)C2CCCCC2)CN1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
In 20 ml of pyridine was dissolved 1.4 g (3.6 m-mol) of (2S,4S)-N-methanesulfonyl-4-dicyclohexylphosphinyl-2-hydroxymethylpyrrolidine [VIII], and 0.82 g (7.2 m-xol) of methanesulfonyl chloride was added dropwise to the solution under ice-cooling. After stirring the mixture at 0° C. for 3 hours and then at room temperature overnight, 70 ml of 10% hydrochloric acid was added to the mixture under ice-cooling. The mixture was extracted three times with 80 ml of ethyl acetate, and the extract was washed with 30 ml of a saturated solution of sodium hydrogen carbonate and with 30 ml of water and dried over magnesium sulfate. The extract was concentrated under reduced pressure to obtain 1.24 g (yield: 74%) of (2S,4S)-N-methanesulfonyl-4-dicyclohexylphosphinyl-2-methanesulfonyloxymethylpyrrolidine as white crystals. Besides this, 1.88 g (8.52 m-mol) of chlorodiphenylphosphine and 392 mg (17.04 m-mol) of metallic sodium were added to 20 ml of dioxane and the mixture was refluxed in nitrogen atmosphere for 3 hours. After allowing the mixture to stand for cooling, 20 ml of tetrahydrofuran was added to the mixture, and a solution of the previously obtained crystals in 20 ml of dimethylformamide was added dropwise to the mixture at -20° C. to -30° C. lest any air should enter in the reaction system. The mixture was stirred overnight at -20° C. to -30° C. in nitrogen atmosphere, separated from insoluble matters and concentrated under reduced pressure. The residue was extracted three times with 50 ml of ethyl acetate and the extract was washed with 50 ml of water and concentrated under reduced pressure. Using 2.45 g (7.2 m-mol) of 10% hydrogen peroxide, the operation was carried out in the same manner as described in Example 1(e) whereby the title compound was obtained as crystals. Yield 982 mg (80%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](Cl)=[O:15])[CH:5]=[CH:4][C:3]1=2.Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>C(COC)OC.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.[Zn]>[C:24]([C:23]1[CH:28]=[CH:29][C:20]([CH2:19][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[O:15])=[CH:21][CH:22]=1)([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: COCCOC
Product: COC(=O)c1ccc(CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
A solution of 4 g (16 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carbonyl chloride and 4 g (16 mmol) of methyl 4-bromomethylbenzoate in 20 ml of dimethoxyethane was added dropwise to a solution or suspension of 0.56 g of bis(triphenylphosphine)palladium(II) dichloride and 2.1 g of zinc powder in 40 ml of dimethoxyethane at room temperature. The reaction mixture was then refluxed for 6 h. After cooling, solids were filtered off and the filtrate was heated with active carbon and filtered hot. The filtrate was concentrated and yielded after recrystallization 3× from methanol and finally from isopropanol 0.9 g of the title compound of melting point 103°-104° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[C:18]([NH2:20])=[O:19])[C:8]2=O)=[CH:4][CH:3]=1.CO>Cl>[Cl:11][C:10]1[C:9]2[C:8]3[NH:20][C:18](=[O:19])[C:14]4[N:13]([CH:17]=[CH:16][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: NC(=O)c1nccn1C1Cc2ccc(Cl)c(Cl)c2C1=O
Agent: Cl
Solvent: CO
Product: O=c1[nH]c2c(n3ccnc13)Cc1ccc(Cl)c(Cl)c1-2
Yield: 39.6 %

Procedure:
The procedure is carried out as in Example 14 but starting with 0.26 g of 1-(6,7-dichloro-1-oxo-2-indanyl)imidazole-2-carboxamide, 80 ml of methanol and 20 ml of hydrochloric acid (12N). 97 mg of 6,7-dichloro-5H, 10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained in hydrochloride form which melt at a temperature greater than 260° C. (analysis: % calculated C: 49.35, H: 2.44, Cl: 29.88, N: 13.28, % found C: 49.40, H: 2.10, Cl: 29.90, N: 13.10).
Reaction SMILES: [C:1](O)([C:3]([F:6])([F:5])[F:4])=[O:2].[O:8]=[C:9]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:11]2([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:10]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.CN(C1C=CN=CC=1)C>[F:4][C:3]([F:6])([F:5])[C:1]([N:14]1[CH2:15][CH2:16][C:11]2([C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9](=[O:8])[CH2:10]2)[CH2:12][CH2:13]1)=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1CC2(CCN(C(=O)C(F)(F)F)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
TFA (25 mL) was added to a solution of commercially available tert-butyl 3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (5.0 g, 16.6 mmol) in dichloromethane (25 mL) at 0° C. The reaction was then allowed to warm to rt for 30 min. The reaction was evaporated and dried under high vacuum for 30 min. The crude amine was dissolved in dichloromethane (25 mL) and triethylamine (6.9 mL, 49.8 mmol), trifluoroacetic anhydride (2.6 mL, 18.3 mmol) and DMAP (20 mg, 0.17 mmol) were added in that order. The reaction was stirred at rt for 2 h and then diluted in dichloromethane and washed with water, sat. NH4Cl solution and brine. The organics were then dried (MgSO4), filtered and evaporated to give 19a as a light yellow solid (4.55 g, 92%). (M+H)+=298. 1H NMR (400 MHz, CDCl3) δ ppm 7.75 (d, J=7.6 Hz, 1H); 7.66 (t, J=7.0 Hz, 1H); 7.48 (d, J=7.9 Hz, 1H); 7.44 (t, J=7.5 Hz, 1H); 4.69 (d, J=15.9 Hz, 1H); 4.13 (d, J=14.1 Hz, 1H); 3.30 (t, J=11.8 Hz, 1H); 2.90 (t, J=13.4 Hz, 1H); 2.68 (m, 2H); 2.05 (dt, J=13.6, 3.8 Hz, 2H); 1.66 (d, J=13.9 Hz, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]4)[C:16]3=[O:27])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.[CH3:33][N:34]([CH2:36][CH2:37]Cl)[CH3:35]>O>[CH:3]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([O:26][CH2:37][CH2:36][N:34]([CH3:35])[CH3:33])[CH2:22][CH2:21]4)[C:16]3=[O:27])=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CN(C)CCCl
Reactant: O=c1n(-c2ccc(OC3CCCC3)cc2)ccn1[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCO[C@H]1CC[C@H](n2ccn(-c3ccc(OC4CCCC4)cc3)c2=O)CC1
Reaction time: 8 h

Procedure:
Sodium hydride (42 mg) was added to a mixture of trans-1-(4-cyclopentyloxy-phenyl)-3-(4-hydroxycyclohexyl)-1,3-dihydroimidazol-2-one (0.30 g) and DMF (10 ml) and, after gas evolution ceased, dimethylaminoethyl chloride (94 mg) was added. After eight hours, the reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 413.56 (C24H35N3O3) was obtained in this way; MS (ESI): 414 ([M+H]+).
Reaction SMILES: [NH2:1][C:2](=[N:22][OH:23])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[CH3:24][O:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33](O)=O)[CH:30]=[CH:29][C:28]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42]>>[CH3:18][O:17][CH2:16][CH2:15][N:7]([CH2:6][C:5]1[CH:19]=[CH:20][CH:21]=[C:3]([C:2]2[N:1]=[C:33]([C:31]3[CH:30]=[CH:29][C:28]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])=[C:27]([CH2:26][O:25][CH3:24])[CH:32]=3)[O:23][N:22]=2)[CH:4]=1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COCCN(Cc1cccc(C(N)=NO)c1)C(=O)OC(C)(C)C
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCCN(Cc1cccc(-c2noc(-c3ccc(-c4ccccc4C)c(COC)c3)n2)c1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared following procedure described for example 141, step 1, but starting from Intermediate 70 (194.03 mg; 0.60 mmol) and Intermediate 28 (161.47 mg; 0.63 mmol), the crude mixture was purified by flash chromatography (C-hex/(DCM/EtOAc 1:1) to afford the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 8.45 (d, J=1.4 Hz, 1H), 8.17 (dd, J=7.8, 1.7 Hz, 1H), 8.11-8.08 (m, 2H), 7.48 (t, J=7.7 Hz, 1H), 7.41-7.23 (m, 5H), 7.13 (d, J=7.3 Hz, 1H), 4.63-4.60 (m, 2H), 4.23 (s, 2H), 3.54-3.33 (m, 10H), 2.08 (s, 3H), 1.49 (br s, 9H).). LC/MS (Method B): 544.5 (M+H)+. HPLC (Method A) Rt 6.61 min (Purity: 99.5%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH3:22])[CH2:17][CH2:16]2)=[CH:10][N:9]=1)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[CH2:21]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=2)[CH2:20][CH2:19]1)[CH3:22]
Reactant: CCN1CCN(Cc2ccc(NC(=O)OC(C)(C)C)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCN1CCN(Cc2ccc(N)nc2)CC1

Procedure:
A mixture of [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]carbamic acid tert-butyl ester (Step 26.2) (0.75 g, 2.8 mmol) and a 4 N solution of HCl in dioxane (20 mL) was stirred for 72 h at rt and concentrated to afford 660 mg of the title compound as a white solid: ESI-MS: 221.1 [M+H]+; tR=0.80 min (System 1).
Reaction SMILES: [SH:1][NH:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].Cl.C(OC(=O)CN[C:32](=O)[C@H:33]([CH2:35]C1C=CC=CC=1)N)C.Cl.C(OC(=O)CNC(=O)[C@H](CC(C)C)N)C>>[SH:1][NH:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH2:12][C:13]1[CH:15]=[CH:35][CH:33]=[CH:32][CH:14]=1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CCOC(=O)CNC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NS
Agent: CCOC(=O)CNC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NS

Procedure:
This mercaptopeptidyl ester was prepared substantially similarly as HS-Leu-Leu-Gly-OC2H5, above, except that an equivalent amount of L-phenylalanylglycine ethyl ester hydrochloride was used in the coupling reaction instead of L-leucylglycine ethyl ester hydrochloride.
Reaction SMILES: [F:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]3[N:15]([CH3:16])[C:14]4[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:13]=4[N:12]=3)=[N:7][C:6]=2[CH:24]=1.CN(C(O[N:34]1N=N[C:36]2C=CC=C[C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(N)C>[CH2:35]([NH:34][C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([NH:10][C:8]3[S:9][C:5]4[CH:4]=[C:3]([F:25])[C:2]([F:1])=[CH:24][C:6]=4[N:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:22])[CH3:36]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(Nc2nc3cc(F)c(F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)c(F)cc3s1)n2C
Yield: 56.8 %

Procedure:
2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid ethylamide (55 mg) was prepared by following General Procedure F starting from 2-(5,6-difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (90 mg), ethylamine (2 M in THF, 250 uL), HBTU (114 mg), and DIEA (65 uL). LC/MS: m/z 388.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.34 (bs, 1H), 8.42 (s, 1H), 8.04 (s, 1H), 7.95 (dd, 1H), 7.74 (d, 1H), 7.55 (s, 1H), 7.45 (d, 1H), 3.62 (s, 3H), 3.30 (q, 2H), 1.13 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16](=[O:18])[NH2:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:26]1([CH2:32]Br)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.N>CO.C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:11]([C:16](=[O:18])[NH2:17])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(O)c(C(N)=O)c1
Agent: C
Agent: N
Agent: O=C([O-])[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(OCC2CCCCC2)c(C(N)=O)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of (3-Carbamoyl-4-hydroxy-benzyl)-carbamic acid tert-butyl ester (2.0 g, 7.5 mmol) in 15 mL methanol at room temperature was added cesium carbonate (2.7 g, 8.3 mmol). The reaction was stirred overnight. The reaction was then concentrated under reduced pressure. N,N-dimethylformamide (50 mL) was then added, and the reaction was then reconcentrated under reduced pressure to remove any remaining methanol. The residue was then suspended in N,N-dimethylformamide (15 mL) and cyclohexylmethyl bromide (1.1 mL, 8.3 mmol) was then added, and the reaction was heated at 65° C. for 4 hours. The reaction was then concentrated under reduced pressure. The residue was diluted with ethyl acetate and 5% citric acid. The organic layer was washed with 5% citric acid (2×50 mL), 1N sodium hydroxide (2×50 mL), 5% citric acid (2×50 mL), and saturated sodium chloride (1×50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a pale yellow powder. The powder was collected and washed with ether, followed by drying under reduced pressure to yield (1.5 g, 57%). 1H NMR (400 MHz, DMSO): δ 7.68 (bs, 1H), 7.52 (d, 2H), 7.36 (t, 1H), 7.27 (d, 2H), 7.05 (d, 1H), 4.04 (d, 2H), 3.88 (d, 2H), 1.76-1.61 (m, 6H), 1.36 (s, 9H), 1.28-1.02 (m, 5H); Mass Spectrum (Chemical Ionization, 1% NH3 in CH4) m/z 363 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:4][CH:3]=1.O[C:20]1C=CC=C[C:21]=1[C:22](CCC(O)=O)=[O:23].N1CCCCC1.[OH-].[Na+]>ClCCl>[O:23]1[CH2:22][CH:21]1[CH2:20][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccccc1O
Reactant: O=C1CCC(c2ccc(O)c3ccccc23)=NN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C1CCC(c2ccc(OCC3CO3)c3ccccc23)=NN1
Yield: 71.7 %

Procedure:
A mixture of 6-(4-hydroxy-1-naphthyl)-4,5-dihydro-3(2H)-pyridazinone (0.5 g, 0.002 mole), epichlorohydrin (2g, 0.02 mole), and piperidine (0.02 g) was heated on a steam bath for 1.5 hours. Evaporation under reduced pressure gave an oil which was dissolved in dichloromethane and shaken with dilute sodium hydroxide (5 ml). The organic phase was washed with water, dried and evaporated to an oil which with ethanol-ether gave crystalline 6[4-(2,3-epoxy-propoxy)-1-naphthyl]-4,5-dihydro-3(2H)-pyridazinone (0.425 g, 69%, m.p. 151°-155° C). Crystallisation from ethanol gave the pure epoxide, m.p. 153.5°-155.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5]2.[Br:14]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(C#N)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc2cc(CBr)ccc2c1
Yield: 78.6 %

Procedure:
6.11 g of 6-methyl-2-naphthalenecarbonitrile was dissolved in 100 ml of carbon tetrachloride, and the solution was mixed with 6.63 g of N-bromosuccinimide and 30 mg of 2,2-azobis-iso-butylonitrile. After refluxing under heating for 4 hours, the resulting reaction solution was mixed with chloroform, washed with water, and then dried. By distilling off the solvent, 7.07 g of colorless 6-bromomethyl-2-naphthalenecarbonitrile was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[CH3:8].[N:23]1([CH2:29][CH2:30][NH2:31])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:31][CH2:30][CH2:29][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NCCN1CCOCC1
Reactant: Cc1ccc(Nc2c(C#N)cnc3cnc(F)cc23)cc1Br
Product: Cc1ccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)cc1Br
Yield: 18 %

Procedure:
Following the procedure described above in Example 1, 4-[(3-bromo-4-methylphenyl)amino]-6-fluoro-[1,7]naphthyridine-3-carbonitrile (300 mg, 1.1 mmol, 1 eq) was reacted with 2-morpholin-4-yl-1-ethylamine (3 mL, 20 eq). The crude product was purified via preparative HPLC to obtain 67 mg product (18% yield):
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([CH3:16])[CH2:7]P(OCC)(OCC)=O)[CH3:2].[Li]CCCC.[CH:23]([C:26]1[C:27]([O:41][CH2:42][CH2:43][CH3:44])=[C:28]([C:35]([CH2:39][CH3:40])=[CH:36][CH:37]=O)[CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=1)([CH3:25])[CH3:24]>CN1CCCN(C)C1=O.C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([CH3:16])[CH:7]=[CH:37][CH:36]=[C:35]([C:28]1[CH:29]=[C:30]([CH:32]([CH3:33])[CH3:34])[CH:31]=[C:26]([CH:23]([CH3:25])[CH3:24])[C:27]=1[O:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH3:40])[CH3:2]
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Reactant: CCCOc1c(C(=CC=O)CC)cc(C(C)C)cc1C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCCOc1c(C(=CC=CC(C)=CC(=O)OCC)CC)cc(C(C)C)cc1C(C)C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
To a solution of 4-(diethoxy-phosphoryl)-3-methyl-but-2-enoic acid ethyl ester (10.6 mL, 43.6 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 20 mL) and THF (80 mL) at −78° C. was added n-BuLi dropwise (1.6 M in hexanes, 27.2 mL, 43.6 mmol). After 10 min, 3-(3,5-diisopropyl-2-propoxy-phenyl)-pent-2-enal (Intermediate 6, 8.77 g, 29.0 mmol) in THF (15 mL and 5 mL rinse) was added slowly to the reaction. The mixture was stirred at −78° C. for 2h, was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was separated, washed successively with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2.5% EtOAc-hexanes) to yield the title compound as a yellow syrup (11.4 g, 95%).
Reaction SMILES: Cl.ClC1C=CC(NN)=CC=1.BrCCC1CCC(C)(C)C1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH2:30][CH2:31][CH:32]2[CH2:36][CH2:35][C:34]([CH3:38])([CH3:37])[CH2:33]2)N)=[CH:24][CH:23]=1.C(OC(OCC)CCCNC)C.ClC1C=C2[C:58](=CC=1)[N:57]([CH2:61][CH2:62][CH:63]1[CH2:67][CH2:66]C(C)(C)C1)C=C2CCNC.C=O.C(O)(C(F)(F)F)=O>C(#N)C.C(N(CC)CC)C>[Cl:21][C:22]1[CH:27]=[C:26]2[C:25](=[CH:24][CH:23]=1)[N:28]([CH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][C:34]([CH3:38])([CH3:37])[CH2:33]1)[C:67]1[CH2:66][N:57]([CH3:58])[CH2:61][CH2:62][C:63]2=1
Reactant: CC1(C)CCC(CCN(N)c2ccc(Cl)cc2)C1
Reactant: CNCCc1cn(CCC2CCC(C)(C)C2)c2ccc(Cl)cc12
Agent: C=O
Agent: CC1(C)CCC(CCBr)C1
Agent: CCOC(CCCNC)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCc2c(n(CCC3CCC(C)(C)C3)c3ccc(Cl)cc23)C1

Procedure:
The title compound is prepared by following General Methods 1, 3 and 4 using 4-chlorophenylhydrazine hydrochloride, 3-(2-bromoethyl)-1,1-dimethylcyclopentane, and triethylamine (General Method 1), 1-(4-chlorophenyl)-1-(2-(3,3-dimethylcyclopentyl)ethyl)hydrazine and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and 2-(5-chloro-1-(2-(3,3-dimethylcyclopentyl)ethyl)-1H-indol-3-yl)-N-methylethanamine (Example 14), formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)CN
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COC(=O)CNCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
To a mixture of glycine methyl ester hydrochloride (2.07 g, 16.5 mmol) and 4-benzyloxybenzaldehyde (3.18 g, 15.0 mmol) in CH2Cl2 (50 mL) at 0° C. was added sodium triacetoxyborohydride (3.81 g, 18.0 mmol). The mixture was allowed to warm to room temperature and stirred for 4 hours. Aqueous NaHCO3 was added, and the mixture was stirred for 30 minutes. The aqueous layer was extracted three times with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSo4, and concentrated. Flash chromatography (75% ethyl acetate/hexane) gave 1.98 g (46%) of the title compound as a white solid; mp 57-58° C.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+]>[Ag]=O.CCOCC>[C:1]([C:5]1[C:6](=[O:7])[CH:8]=[CH:9][C:10](=[O:12])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(O)ccc1O
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)C1=CC(=O)C=CC1=O
Reaction time: 0.33 h

Procedure:
30 g. of tert-butylhydroquinone (Eastman-Kodak) were dissolved in 200 ml. of anhydrous ether and 30 g. of anhydrous sodium sulfate were added. To this mixture was added 60 g. of silver oxide in small increments. An exothermic reaction ensued. After shaking for 20 minutes, the reaction mixture was filtered and the filtrate evaporated under the hood. Yellow crystals of tert-butyl-p-benzoquinone were obtained melting at 55°-60° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH2:12])=[CH:7][C:6]=1[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH3:2].[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=1[N:29]=[C:30]=[S:31]>C(#N)C>[NH2:12][C:8]1[C:9]([NH:11][C:30]([NH:29][C:22]2[C:23]([F:28])=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=2[Cl:20])=[S:31])=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:19])=[C:6]([O:13][CH2:14][C:15]([F:16])([F:18])[F:17])[CH:7]=1
Reactant: CCOC(=O)c1cc(N)c(N)cc1OCC(F)(F)F
Reactant: Fc1ccc(Cl)c(Cl)c1N=C=S
Solvent: CC#N
Product: CCOC(=O)c1cc(NC(=S)Nc2c(F)ccc(Cl)c2Cl)c(N)cc1OCC(F)(F)F

Procedure:
Prepared analogously to example 583h from ethyl-4,5-diamino-2-(2,2,2-trifluoro-ethoxy)-benzoate (synthesis described at example 575) and 2,3-dichloro-6-fluoro-1-isothiocyanato-benzene in acetonitrile.