Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl.Cl[CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH3:30][C:27]1[S:28][CH:29]=[C:25]([CH2:24][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:26]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2csc(C)n2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
A mixture of 2.9 parts of ethyl 4-[(1H-benzimidazol-2-yl)amino]-1-piperidinecarboxylate, 1.8 parts of 4-(chloromethyl)-2-methylthiazole monohydrochloride, 2.12 pans of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at 70° C. The reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.5 parts (37.5%) of ethyl 4-[[1-[(2-methyl-4-thiazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 160° C. (comp. 12).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:23]([O:25][CH3:26])=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.[CH3:27][O-:28].[Na+].CO>[Cu]I.CN(C)C=O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[N:11]1[C:8]2=[N:9][C:10]3[C:6](=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:4]=[CH:3][C:2]=3[O:28][CH3:27])[N:7]2[CH2:14][CH2:13][CH2:12]1
Reactant: C[O-]
Reactant: COC(=O)c1ccc(Br)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Cu]I
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 30.5 %

Procedure:
A mixture of methyl 9-bromo-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (200 mg, 0.439 mmol), sodium methoxide (237 mg, 4.39 mmol), copper(I) iodide (100 mg, 0.525 mmol), methanol (1.8 mL) and N,N-dimethylformamide (2.6 mL) was stirred at 100° C. for 4 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (54.4 mg, 0.134 mmol, 31%).
Reaction SMILES: [Na].[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]=[CH:13]2)[N:4]=1.[C:29]1([CH3:55])[CH:34]=[CH:33][C:32]([C:35]([O:37][C@@H:38]2[C@@H:42]([CH2:43][O:44][C:45]([C:47]3[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=3)=[O:46])[O:41][C@H:40](Cl)[CH2:39]2)=[O:36])=[CH:31][CH:30]=1>CC#N.C(Cl)Cl>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:40]2[O:41][C@H:42]([CH2:43][O:44][C:45]([C:47]3[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=3)=[O:46])[C@@H:38]([O:37][C:35]([C:32]3[CH:31]=[CH:30][C:29]([CH3:55])=[CH:34][CH:33]=3)=[O:36])[CH2:39]2)=[C:5]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:14]=[CH:13]2)[N:4]=1
Reactant: Clc1nc(-n2cnc(-c3ccccc3)c2-c2ccccc2)c2[nH]cnc2n1
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cnc4c(-n5cnc(-c6ccccc6)c5-c5ccccc5)nc(Cl)nc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1

Procedure:
The sodium salt of 2-chloro-6-(4,5-diphenylimidazol-1-yl)purine (94 mg, 0.25 mmol) in dried CH3CN (10 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.334 g, 0.86 mmol) in CH2Cl2 (10 mL) by general method 2. Sampling of the reaction mixture showed no α-nucleoside by 1H NMR (500 MHz). Volatiles were evaporated in vacuo, and the residue was chromatographed (25 g silica gel, EtOAc/hexanes, 3:7→1:1) to give the β-anomer (quantitative). Recrystallization (EtOAc/hexanes) gave 2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(4,5-diphenylimidazol-1-yl)purine: UV (MeOH) max 240, 275 nm (∈ 53 400, 19 300), min 223, 270 nm (∈ 42 000, 19 100); 1H NMR (500 MHz, CDCl3) δ 8.97 (s, 1H), 8.25 (s, 1H), 7.97 (d, J=7.9 Hz, 2H), 7.86 (d, J=7.9 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.19-7.40 (m, 13H), 6.56 (t, J=7.0 Hz, 1H), 5.77-5.78 (m, 1H), 4.76-4.79 (m, 1H), 4.65-4.69 (m, 2H), 2.92-2.96 (m, 2H), 2.45 (s, 3H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.06, 165.94, 154.03, 153.17, 147.13, 144.71, 144.45, 142.81, 140.38, 139.24, 133.50, 131.02, 129.85, 129.55, 129.37, 129.34, 128.25, 128.17, 127.47, 127.17, 126.41, 126.18, 124.00, 85.11, 83.52, 74.85, 63.84, 38.57, 21.78, 21.71; HRMS m/z 747.2100 (MNa+[C41H33ClN6O5Na]=747.2099).
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C:17](=O)[C@:18]5([OH:28])[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.[OH:30]/[N:31]=C1\C[C@@H]2[C@@H]([C@]3(C)C\1CC(=O)CC3)CC[C@@]1(C)[C@H]2CCC1=O>>[CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:31]\[OH:30])/[C@:18]5([OH:28])[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC(=O)[C@@]4(O)CCCC[C@]34C)[C@@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CC[C@H]3[C@@H](C/C(=N\O)[C@@]4(O)CCCC[C@]34C)[C@@H]1CC13OCCOC12OCCO3
Yield: 85 %

Procedure:
17,17-Bis(ethylendioxy)-5α-hydroxy-6-(E)-hydroxyimino-androstane was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-5α-hydroxyandrostan-6-one (Prepn. 26) by the procedure described above for the preparation of 6-(E)-hydroxyiminoandrostane-3,17-dione (II-ah, Prepn. 18). The crude was purified by flash chromatography (SiO2, cyclohexane/acetone/CH2Cl2 70/15/15). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 10.45 (1H, s), 4.33 (1H, s), 3.96-3.69 (8H, m), 2.96 (1H, dd), 2.02-1.08 (18H, m), 0.74 (3H, s), 0.71 (3H, s).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]2=[O:25])=[N:6][C:5]=1[CH3:26])(=[O:3])[CH3:2].CO[C:29](OC)([N:31]([CH3:33])[CH3:32])[CH3:30]>CN(C)C(=O)C>[CH3:32][N:31]([CH3:33])/[C:29](/[CH3:30])=[CH:2]/[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)[C:10]2=[O:25])=[N:6][C:5]=1[CH3:26])=[O:3]
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Reactant: COC(C)(OC)N(C)C
Solvent: CC(=O)N(C)C
Product: C/C(=C\C(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C)N(C)C
Temperature: 110 °C
Yield: 90 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)-imidazolidin-2-one (1.00 g, 2.60 mmol) in N,N-dimethylacetamide (10 mL) was added N,N-dimethylacetamide dimethyl acetal (1.0 mL, 6.15 mmol). The reaction mixture was heated for 20 hours at 110° C. The solvent was removed in vacuo, and the residue was washed with water to afford the title compound as a colorless solid in 90% yield (1.07 g): 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 5.23 (s, 1H), 4.49 (s, 2H), 3.99-3.91 (m, 2H), 3.48-3.40 (m, 2H), 2.98 (s, 6H), 2.49-2.43 (m, 6H): MS (ES+) m/z 453.1 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH2:14][C@@H:15]([OH:19])[C:16]([OH:18])=[O:17])[CH:10]=[CH:11][C:12]=1[OH:13].[CH3:20]O>>[Br:6][C:7]1[CH:8]=[C:9]([CH2:14][C@@H:15]([OH:19])[C:16]([O:18][CH3:20])=[O:17])[CH:10]=[CH:11][C:12]=1[OH:13]
Reactant: CO
Reactant: O=C(O)[C@H](O)Cc1ccc(O)c(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H](O)Cc1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.5 mL concentrated sulphuric acid were added to a solution of 53.6 g (154 mmol) (R)-3-(3-bromo-4-hydroxy-phenyl)-2-hydroxy-propionic acid in 250 mL MeOH and the reaction mixture was stirred for 4 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 250 mL EtOAc, the organic phase was washed twice with 100 mL saturated NaHCO3 solution and saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was further reacted without purification.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([C:46](=[O:48])[CH3:47])[CH:43]=[CH:44][CH:45]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[O:48])[CH3:47])[CH:41]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 22.5 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (6.22 g), 3′-bromoacetophenone (2.30 g) and tetrakis(triphenylphosphine)palladium(0) (0.210 g), the title compound (1.50 g) was obtained as colorless powder crystals.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[C:2]1=[O:3])[CH2:4][CH2:6][CH3:7]
Reactant: NNC(=O)c1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Product: CCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccccc21
Yield: 65.3 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 5 and benzhydrazide according to the synthetic method D. The resulting solid was washed with ethanol. Yield: 65.3%. 1H NMR (DMSO-d6): δ 0.95 (t, J=7.5 Hz, 3H), 1.36-1.41 (m, 2H), 1.64-1.69 (m, 2H), 3.78 (t, J=7.2 Hz, 2H), 7.19 (t, Hz, J=7.5 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.49 (td, J=1.2 Hz, J=7.8 Hz, 1H), 7.60-7.73 (m, 4H), 7.90-7.92 (m, 2H), 13.90 (br s, 1H). 13C NMR (DMSO-d6): δ 14.06 (CH3), 20.04 (CH2), 29.56 (CH2), 39.49 (CH2), 110.69 (CH), 119.66 (C), 121.26 (CH), 123.69 (CH), 127.88 (CH), 129.67 (CH), 132.22 (CH), 132.43 (C), 133.40 (CH), 137.40 (C), 143.43 (C═N), 161.58 (C═O), 163.34 (C═O). HRMS (ES+) calcd for C19H20N3O2 (M+H+), m/e, 322.1548. found, 322.1550.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[O:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>>[CH3:1][C:2]1[CH:11]=[C:10]([O:12][CH2:22][CH:21]=[CH2:20])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[O:7]2
Reactant: C=CCBr
Reactant: Cc1cc(O)cc2oc(=O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1cc(C)c2ccc(=O)oc2c1

Procedure:
A Me2CO (250 ml) solution of 5-methyl-7-hydroxycoumarin (I; 15.0 g) was reacted with allyl bromide (20 ml) in the presence of K2CO3 (5.0 g) by refluxing the mixture for 5 hours. After chilling the K2CO3 is filtered off and washed with fresh Me2CO. The pooled filtrate and acetonic washings were concentrated to dryness and the residue crystallized from cyclohexane giving 5-methyl-7-allyloxycoumarin (IV; 13.8 g; m.p. 83° ). ##STR7##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=[CH:6][C:5]=1[OH:25].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=[CH:6][C:5]=1[O:25][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCOc1ccc(O)c(C(=O)OC)c1
Product: CCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Yield: 82 %

Procedure:
The reaction of 2-(hydroxy-5-(tetradecyloxy)benzoic acid methyl ester with benzyl bromide under conditions described in Example 59 gave 2-(phenylmethoxy)-5-(tetradecyloxy)benzoic acid methyl ester (82% yield, mp 43°-46°).
Reaction SMILES: C(O[C:6]1[C:7](=[O:25])[C:8](=[O:24])[C:9]=1[NH:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=2[CH:16]=1)CCC.[C:26]([NH2:31])([CH2:29][CH3:30])([CH3:28])[CH3:27]>C(O)C>[CH3:27][C:26]([NH:31][C:6]1[C:7](=[O:25])[C:8](=[O:24])[C:9]=1[NH:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=2[CH:16]=1)([CH3:28])[CH2:29][CH3:30]
Reactant: CCC(C)(C)N
Reactant: CCCCOc1c(NCc2cc3cc([N+](=O)[O-])ccc3o2)c(=O)c1=O
Solvent: CCO
Product: CCC(C)(C)Nc1c(NCc2cc3cc([N+](=O)[O-])ccc3o2)c(=O)c1=O
Temperature: 70 °C
Reaction time: 18 h
Yield: 84.7 %

Procedure:
To 3-butoxy-4-[(5-nitro-benzofuran-2-ylmethyl)-amino]-cyclobut-3-ene-1,2-dione (0.25 g, 0.727 mmol), as prepared in Example 8, in ethanol (5 mL) was added tert-amylamine (0.53 mL, 4.54 mmol). The reaction was stirred at 70° C. for 18 hours and then at room temperature for 48 hours. The precipitated product was filtered and washed with ethyl acetate, diethyl ether, and petroleum ether to afford 0.22 g (85%) of 3-(1,1-dimethyl-propylamino)-4-[(5-nitro-benzofuran-2-ylmethyl)-amino]-cyclobut-3-ene-1,2-dione as an off-white solid: mp 283.5°-287.5° C. (dec); 1H NMR (DMSO-d6): δ 8.61 (d, 1H), 8.18 (dd, 1H), 7.96 (br t, 1H), 7.81 (d, 1H), 7.46 (br s, 1H), 7.07 (s, 1H), 4.99 (d, 2H), 1.66 (q, 2H), 1.30 (s, 6H), 0.82 (t, 3H). IR (KBr): 3220, 2950, 1800 cm-1 ; MS (m/z) 357 (M+).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[N:13]([CH3:21])[C:12]2[CH:22]=[C:23]([CH2:26][NH2:27])[CH:24]=[CH:25][C:11]1=2)[CH3:9].[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38])([O-:30])=[O:29].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([N:10]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[N:13]([CH3:21])[C:12]2[CH:22]=[C:23]([CH2:26][NH:27][S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N+:28]([O-:30])=[O:29])(=[O:38])=[O:39])[CH:24]=[CH:25][C:11]1=2)[CH3:9]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNS(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.6 ml) was added to a dichloromethane solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-aminomethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.0 g). The mixture was cooled with ice. 2-Nitrobenzenesulphonyl chloride (0.80 g) was added, and the mixture was stirred at room temperature overnight. A saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction using dichloromethane.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:30]([O:32][CH3:33])=[O:31])#[N:2].[CH3:34][C:35]1[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:23]=[C:24]([C:36]4[CH:37]=[CH:38][CH:39]=[C:40]([CH3:41])[C:35]=4[CH3:34])[CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:30]([O:32][CH3:33])=[O:31])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(I)c4)cc3)c(C#N)cc21
Reactant: Cc1cccc(B(O)O)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5cccc(C)c5C)c4)cc3)c(C#N)cc21
Temperature: 100 °C
Reaction time: 17 h
Yield: 64 %

Procedure:
In a vial were placed methyl 6-cyano-7-(4-(3-iodophenylcarbamoyl)phenoxy)chroman-4-carboxylate (Preparation 3) (56 mg, 0.101 mmol), 2,3-dimethylphenylboronic acid (19.70 mg, 0.131 mmol), Na2CO3 (32.12 mg, 0.303 mmol), toluene (1 ml), and water (0.1 ml). The mixture was degassed with Argon for few minutes. Tetrakis(triphenylphosphine)palladium(0) (5.836 mg, 0.0050 mmol) was added and the vial was sealed. The mixture was stirred for 17 hours at 100° C. The crude mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 34.4 mg of the title compound as a thin film (64%).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC#N>[CH2:30]([O:29][C:27]([NH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1)=[O:28])[CH3:31]
Reactant: NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Reactant: CCOC(=O)Cl
Solvent: CC#N
Product: CCOC(=O)NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21

Procedure:
[7-[(4-Oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acid ethyl ester (482) was synthesized following the general scheme above, from amine (273-I) and ethyl chloroformate. Overall yield (18%). HPLC ret. time 2.84 min, 10-99% CH3CN, 5 min run; ESI-MS 406.5 m/z (MH+).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[C:15](OC(=O)C)(=[O:17])[CH3:16].Cl>O>[C:15]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)O

Procedure:
To a stirred solution of 20.0 parts of D-phenylalanine in 121 parts of water, cooled to about 1° -2°, is added, portionwise, an aqueous 50% sodium hydroxide solution until pH 12 is reached. Then 37 parts of acetic anhydride is added, while continuously adding aqueous 50% sodium hydroxide to keep the pH at about 12 and cooling the solution to keep the temperature at between about 10° to 30°. After about 20 minutes the mixture is acidified to pH 1 with concentrated hydrochloric acid and filtered. The recovered solid is recrystallized from water to afford N-acetyl-D-phenylalanine, melting at about 170°-172°.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]=2[O:27][CH3:28])=[O:7])=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1.CCOC(C)=O>[C:23]([C:11]1[C:10]([O:27][CH3:28])=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:3][CH:4]=2)[CH:14]=[C:13]([C:15]2[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncccc1-c1cc(NC(=O)c2ccc(N)cc2)c(OC)c(C(C)(C)C)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1cc(NC(=O)c2ccc(NS(C)(=O)=O)cc2)c(OC)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
step 5—To a solution of 104 (0.10 g, 0.25 mmol) in pyridine (2 mL) at 0° C. was added methanesulfonyl chloride (0.034 g, 0.30 mmol). Stirring was continued at 0° C. for two h, then at RT for an additional two h. The reaction mixture was diluted with EtOAc, washed sequentially with aqueous CuSO4 and 2N HCl, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography (EtOAc/hexane) to afford 0.12 g of N-[3-tert-butyl-2-methoxy-5-(2-methoxypyridin-3-yl)phenyl]-4-methanesulfonylaminobenzamide (106) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[K].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>CC(CC)=O>[CH2:2]([N:11]1[C:7](=[O:17])[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:12])[CH2:3][CH:4]=[CH2:5]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCBr
Agent: [K]
Solvent: CCC(C)=O
Product: C=CCCN1C(=O)c2ccccc2C1=O

Procedure:
50 g (370 mmol) 4-bromo-1-butene and 68.5 g (370 mmol) phthalimide potassium salt are suspended in 800 ml ethyl methyl ketone and heated under reflux for 14 hours. After cooling, the mixture is filtrated and the filtrate is concentrated under vacuum. The residue is taken up in acetic acid ethyl ester and washed with water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum: yield 50 g (67%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=2)=[O:8])=[CH:5][N:6]=1.[OH:29][CH2:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][NH:9][C:7]([C:4]3[S:3][C:2]([N:34]4[CH2:35][CH2:36][CH:31]([CH2:30][OH:29])[CH2:32][CH2:33]4)=[N:6][CH:5]=3)=[O:8])=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: OCC1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(N2CCC(CO)CC2)s1

Procedure:
2-(4-Hydroxymethyl-piperidin-1-yl)-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate F and 4-hydroxymethyl piperidine. MS calcd. for C26H25ClN4O3S [(M+H)+] 509.1, obsd. 509.