Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[O:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)c(Cl)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)cc3Cl)c2cc1OC
Temperature: 160 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (0.89 g), 2-chloro-4-methylphenol (1.0 g), and 4-dimethylaminopyridine (1 g) were suspended in o-dichlorobenzene (10 ml), and the mixture was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, and water was then added thereto. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine, and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (0.92 g, yield 70%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>ClCCl>[CH3:15][O:14][C:13]1[C:12]([O:16][CH3:17])=[CH:11][CH:10]=[C:9]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[C:8]=1[O:7][CH2:6][C:3]1([CH2:2][O:1][C:38](=[O:39])[NH:37][CH2:35][CH3:36])[CH2:4][CH2:5]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)CC2)c1OC
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)OCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)CC1
Temperature: 50 °C

Procedure:
To a stirring solution of 4-[2-(1-Hydroxymethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 177) (150 mg, 0.407 mmol) in dichloromethane (15 mL), were added triethylamine (123 mg, 1.22 mmol) and ethyl isocyanate (86 mg, 1.22 mmol) and the resultant reaction mixture was heated to 50° C. for 16 h. The reaction mixture was quenched with sodium bicarbonate solution and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-30% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[I:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(I)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(I)cc2)c1
Temperature: 25 °C

Procedure:
A mixture of 6.69 g (E)-3-[1-(4-Iodo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester in 180 ml dichloromethane and 18.1 ml TFA is stirred at ambient temperature over the weekend. The reaction mixture is evaporated and the crude product is washed with toluene and dried in vacuo.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20]([C:22]1[O:23][CH:24]=[CH:25][C:26]=1[CH2:27][O:28]C(=O)C)=[O:21])(=[O:3])[CH3:2].[OH-].[Na+].[Cl-].[NH4+]>C(O)C.O>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20]([C:22]1[O:23][CH:24]=[CH:25][C:26]=1[CH2:27][OH:28])=[O:21])(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2occc2COC(C)=O)c(NC(C)=O)c2ccc(Cl)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1c(C(=O)c2occc2CO)[nH]c2cc(Cl)ccc12
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
To a solution of 3-acetylamino-6-chloro-1-ethoxycarbonyl-2-(3-acetoxymethyl-2-furoyl) indole (step 3, 180 mg, 0.4 mmol) in a mixture of ethanol (10 ml) and water (5 ml) was added 2N aqueous sodium hydroxide (2 ml) at room temperture. After stirring for 1.5 h, the mixture was poured into saturated aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1/1), and the product recrystalized from acetone/hexane to give 98 mg (73%) of the titled compound as a yellow crystalline solid. m.p.: 196-198° C. 1H-NMR (CDCl3) δ: 10.6 (1H, br s), 9.52 (1H, br s), 8.33 (1H, d, J=9.2 Hz), 7.66 (1H, br s), 7.30 (1H,br s), 7.01 (1H, d, J=9.2 Hz), 6.66 (1H, br s), 4.81 (2H, s), 2.32 (3H, s). The signal due to H of OH was not observed.
Reaction SMILES: NC1C=CC(CO)=CC=1.N([O-])=O.[Na+].Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.CC([O-])=O.[Na+].[OH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[N:38]C2C=CC(O)=CC=2)=[CH:33][CH:32]=1>CCO.O.CCO>[OH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[N:38][C:22]2[CH:21]=[CH:20][C:19]([OH:23])=[CH:18][C:17]=2[O:16][CH3:15])=[CH:33][CH:32]=1
Reactant: OCc1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: COc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: Nc1ccc(CO)cc1
Solvent: CCO
Solvent: O
Product: COc1cc(O)ccc1N=Nc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Aminobenzyl alcohol (0.275 g, 2.24 mmol) and NaNO2 (0.16 g, 2.35 mmol) were dissolved in 7.5 mL EtOH:water (1.5:1) and added to 2 N HCl solution (4.5 mL) and reaction mixture stirred at 0° C. for 1 hour. 3-methoxyphenol (0.25 g, 2.01 mmol) in EtOH was added, followed by addition of NaOAc (0.15 g) at 0° C. and remaining procedure followed as described for compound 1 to obtain compound 2. Yield: 0.435 g (84%). 1H NMR (500 MHz, CD3SOCD3) δ 3.34 (bs, 4H, OMe, —OH), 4.55 (bs, 2H, Hf), 5.31 (s, 1H, phenol-OH), 6.43-6.46 (m, 1H, Hb), 6.57-6.60 (m, 1H, He), 7.44-7.48 (m, 2H, He), 7.53-7.57 (m, 1H, Ha), 7.69-7.74 (m, 2H, Hd). 13C NMR (125 MHz, CD3SOCD3) δ 55.7 (OMe), 62.5 (Cf), 99.9 (Cc), 107.9 (Cb), 117.4 (Ci), 121.9 (Cd), 127.0 (Ce), 134.8 (Ca), 144.7 (Ck), 151.5 (Cj), 158.9 (Ch), 162.6 (Cg). ESI-MS: [M+H]+ C14H15N2O3 calcd 259.1083, obsd 259.10.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[O:30][C:31]1[O:35][C:34]([C:36](Cl)=[O:37])=[CH:33][CH:32]=1>C1COCC1>[Cl:26][C:27]1[CH:28]=[C:29]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[O:30][C:31]1[O:35][C:34]([C:36]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:15]=3)[CH2:10][CH2:9]2)=[O:37])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(Oc2cc(Cl)cc(Cl)c2)o1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)c3ccc(Oc4cc(Cl)cc(Cl)c4)o3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-(3,5-dichlorophenoxy)-2-furoyl chloride: ESMS m/e: 600.2 (M+H)+.
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([CH2:15][N+:16]([CH3:19])([CH3:18])C)=[N:3]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][C:27]1[CH2:28]CNC[CH:32]=1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][C:27]1[CH2:28][CH2:19][N:16]([CH2:15][C:4]2[C:5]3[CH2:6][CH2:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[C:10]=3[NH:2][N:3]=2)[CH2:18][CH:32]=1
Reactant: C[N+](C)(C)Cc1n[nH]c2c1CCc1ccccc1-2
Reactant: C1=C(CCc2ccco2)CCNC1
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C1=C(CCc2ccco2)CCN(Cc2n[nH]c3c2CCc2ccccc2-3)C1

Procedure:
A solution of (4,5-dihydro-1H-benzo[g]indazol-3-ylmethyl)-trimethylammonium iodide (0.42 g), 4-(2-furan-2-ylethyl)-1,2,3,6-tetrahydropyridine (0.20 g) and diisopropylethylamine (0.20 cm3) in DMF (10 cm3) was heated under argon at 90° C. for 24 hours. The mixture was cooled, poured into water (50 cm3) and extracted with 10% ethyl acetate-diethyl ether (2×25 cm3). The extracts were dried (MgSO4), filtered and concentrated to give a brown oil. Preparative thin layer chromatography on silica, eluting with 10% methanol-dichloromethane+1% ammonia, gave the title compound as a brown off, which was recrystallised as its half-oxalate salt from ethanol-hexane (0.083 g; 18%), m.p. 205°-208° C. (from EtOH-hexane); Found: C, 70.85; H, 6.5; N, 10.05. C23H25N3O.0.5(CO2H)2.0.2(H2O) requires C, 70.6; H, 6.5; N, 10.3%. δH (360 MHz; d6 -DMSO) 2.16 (2H, broad s, NCH2CH2), 2.27 (2H, t, J 7.7, --CH2 --), 2.67-2.73 (4H, m, 2 x --CH2 --), 2.86-2.90 (4H, m, 2 x --CH2 --), 3.22 (2H, broad s, NCH2CH=C), 3.88 (2H, broad s, --CH2N), 5.42 (1H, broad s, NCH2CH=C), 6.1 (1H, d, J 3, furyl-H3), 6.33 (1H, dd, J 3 and 2, furyl-H4), 7.18-7.29 (3H, m, 3 of ArH), 7.48 (1H, d, J 2, furyl-H5) and 7.64 (1H, d, J 6.6, 1 of ArH); m/z (CI+ ; NH3) 360 (MH+ ; 30%), 204 (50) and 174 (100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:24]([CH3:37])=[C:25]([CH3:36])[C:26]4[O:30][C:29]([CH3:32])([CH3:31])[C:28](=[O:33])[C:27]=4[C:34]=3[CH3:35])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>CCCCCC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2([OH:33])[C:27]3[C:34]([CH3:35])=[C:23]([N:20]4[CH2:21][CH2:22][N:17]([C:14]5[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=5)[CH2:18][CH2:19]4)[C:24]([CH3:37])=[C:25]([CH3:36])[C:26]=3[O:30][C:29]2([CH3:31])[CH3:32])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Solvent: CCCCCC
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(F)cc3)C(C)(C)O4)CC2)cc1
Yield: 84 %

Procedure:
Using 1-bromo-4-fluorobenzene and 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine obtained in Reference Example 13, the title compound was synthesized in the same manner as in Example 33. Yield 84%. mp. 142–144° C. (hexane).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])[CH2:2][C:3]#[CH:4].O1CCCC1.Br[C:22]1[N:23]=[CH:24][S:25][CH:26]=1>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.[Cu](I)I.C(N(CC)CC)C>[S:25]1[CH:26]=[CH:22][N:23]=[C:24]1[C:4]#[C:3][CH2:2][CH2:1][N:5]1[C:9](=[O:10])[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:15]
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: Brc1cscn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1nccs1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To 1184 mg of dichlorobis(triphenylphosphine)palladium, 322 mg of copper iodide, and 6.64 g of N-(3-butynyl)phthalimide were added 78 ml of tetrahydrofuran, 5.49 g of 4-bromothiazole, and 20.3 ml of triethylamine in a nitrogen atmosphere, and the mixture was stirred under reflux for 5 hours. After the stirring, the reaction mixture was cooled to room temperature and the solids were filtered. After concentrating the filtrate, the residue was purified by column chromatography (Wakogel C-200; toluene:ethyl acetate=4:1) to give 6.35 g of a phthalimide compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8].[O-2].[Ca+2:21]>O>[OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([NH:9][C@H:10]([C:16]([O-:18])=[O:17])[CH2:11][CH2:12][C:13]([O-:15])=[O:14])=[O:8].[Ca+2:21]
Reactant: O=C(O)CC[C@H](NC(=O)c1cncc(O)c1)C(=O)O
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Product: O=C([O-])CC[C@H](NC(=O)c1cncc(O)c1)C(=O)[O-]

Procedure:
Heat suspension of 2.68 g (0.01M) of N-(5-hydroxynicotinoyl)-L-glutamic acid in 50 ml of water up to 60-70° C. and add 0.68 g (0.012M) of calcium oxide in small portions. The sediment gradually dissolves. Heat the suspension for complete dissolution. Evaporate aquatic solution to 20 ml. Add resultant solution dropwise to 200 ml of ethanol. Mix formed precipitate for 0.5 hour and leave it for 12 hours at room temperature. Filter the precipitate, wash with alcohol and dry at 100° C. for constant weight (3 hours). Calcium N-(5-hydroxynicotinoyl)-L-glutamate (I) is obtained, recovery is 2.7 g (83%), [α]D20+11° (c 1, water).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9]([C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2].[NH:23]1[CH2:27][CH2:26][C@@H:25]([N:28]2[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]2)[CH2:24]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9]([C:14]3[C:15]([N:23]4[CH2:27][CH2:26][CH:25]([N:28]5[CH2:29][CH2:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33]5)[CH2:24]4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2]
Reactant: O=S1(=O)CCN([C@@H]2CCNC2)CC1
Reactant: CCc1cc(OC)cc2nc(-c3cccnc3F)oc(=O)c12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(OC)cc2nc(-c3cccnc3N3CCC(N4CCS(=O)(=O)CC4)C3)oc(=O)c12

Procedure:
To 5-ethyl-2-(2-fluoropyridin-3-yl)-7-methoxy-4H-benz[d][1,3]oxazin-4-one (50.0 mg, 0.17 mmol) in anhydrous 1,4-dioxane (850 μL) was added compound Z (52.9 mg, 0.22 mmol) and diisopropylethyl amine (120 μL, 0.85 mmol) at room temperature under N2 overnight. The solution was concentrated, and the resulting residue was purified on a Biotage 40M amine column using a gradient of 20-75% ethyl acetate/hexanes to obtain the title compound. The fractions containing the title compound were combined and concentrated by speedvac to afford the title compound as a yellow oil (19.2 mg, 23% yield). 1H NMR (CDCl3, 400 MHz) δ: 8.33 (dd, 1H, J=1.0 Hz), 8.1 (d, 1H, J=7.0 Hz), 6.92 (dd, 2H, J=2.5 Hz), 6.83 (m, 1H), 3.93 (s, 3H), 3.83 (m, 1H), 3.62 (m, 2H), 3.39 (m, 1H), 3.26 (m, 1H), 3.22 (m, 4H), 3.17 (m, 6H), 2.16 (m, 1H), 1.94 (m, 1H), 1.29 (t, 3H, J=7.5 Hz); ESMS m/z 485.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH:10]=[N:9][CH:8]=[CH:7]3)[CH2:3][CH2:2]1.[In].[NH4+].[Cl-]>CCO>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][NH:9][CH2:8][CH2:7]3)[CH2:3][CH2:2]1
Reactant: c1cc2cc(C3CC3)ccc2cn1
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CCO
Product: c1cc2c(cc1C1CC1)CCNC2
Yield: 57.7 %

Procedure:
To a solution of 6-cyclopropylisoquinoline (0.500 g, 0.003 mol) in EtOH (15 mL) was added indium powder (3 g) and saturated aqueous NH4Cl (5 mL). The reaction mixture was heated at reflux for 36 h while stirring. After completion, the reaction mixture was filtered through Celite® (diatomaceous earth) and the filtrate concentrated at reduced pressure to afford crude 6-cyclopropyl-1,2,3,4-tetrahydro-isoquinoline. Purification was done by silica gel column chromatography eluting with MeOH in CH2Cl2 (0-10%) to afford pure 6-cyclopropyl-1,2,3,4-tetrahydro-isoquinoline (0.300 g, 58%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][CH2:28][NH:27][C:26]4=[O:30])=[CH:21][C:18]=3[C:19]#[N:20])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][CH2:28][N:27]([CH2:32][CH2:33][O:34][CH3:35])[C:26]4=[O:30])=[CH:21][C:18]=3[C:19]#[N:20])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3C#N)CC2)c(C)c1
Reactant: COCCBr
Product: COCCN1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(C#N)c2)C1=O
Yield: 73.9 %

Procedure:
Using 2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxoimidazolidin-1-yl)benzonitrile (399 mg) described in Example 434 and 1-bromo-2-methoxyethane (165 mg) and by the reaction and treatment in the same manner as in Example 36, the title compound (337 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([N:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]2=[O:34])=[N:24][C:23]=1[CH3:35])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[S:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][O:33][C:30]1[CH:31]=[CH:32][N:27]([C:25]2[S:26][C:22]([C:20]([NH:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:21])=[C:23]([CH3:35])[N:24]=2)[C:28](=[O:34])[CH:29]=1
Reactant: BrCc1nc2ccccc2s1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc(OCc3nc4ccccc4s3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 14 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 2-(bromomethyl)benzo[d]thiazole in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 14% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.79 (t, J=5.9 Hz, 1H), 8.66 (d, J=8.1 Hz, 1H), 8.13-8.11 (m, 1H), 8.03-8.00 (m, 1H), 7.55-7.42 (m, 2H), 7.34-7.18 (m, 5H), 6.48 (dd, J=8.1, 2.7 Hz, 1H), 6.34 (d, J=2.7 Hz, 1H), 5.68 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 489.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([CH2:22][O:23][CH2:24][CH3:25])([OH:21])[CH:6]([N+:18]([O-])=O)[CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1)[CH3:2]>[Ni]>[CH2:24]([O:23][CH2:22][C:5]([CH2:4][O:3][CH2:1][CH3:2])([OH:21])[CH:6]([NH2:18])[CH2:7][C:8]1[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)[CH3:25]
Reactant: CCOCC(O)(COCC)C(Cc1cc(OC)cc(OC)c1)[N+](=O)[O-]
Agent: [Ni]
Product: CCOCC(O)(COCC)C(N)Cc1cc(OC)cc(OC)c1
Yield: 76.6 %

Procedure:
α,α-Diethoxymethyl-β-nitro-3,5-dimethoxybenzenepropanol (3.39 g) was hydrogenated in isoproipanol (50 ml) over Raney nickel at atmospheric pressure and room temperature. When hydrogen absorption was complete, the reaction mixture was degased for 15 minutes under vacuum and the catalyst was filtered on celite. The solvent was evaporated under vacuum to yield the title compound as an oil (2.38 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][CH:14]([C:29]1[N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:31]=[C:32]([CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37])[N:33]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)=[CH:18][CH:17]=1>>[CH3:38][C:35]([CH3:39])([CH2:36][CH3:37])[CH2:34][C:32]1[N:33]=[C:29]([CH:14]([NH:13][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)=[CH:18][CH:17]=2)[N:30]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH:31]=1
Reactant: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(N)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(Cc2ccc(-c3ccc(F)cn3)cc2)NS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (22 μL, 0.16 mmol) followed by methanesulfonyl chloride (10 μL, 0.1 mmol) were added to an ambient temperature solution of tert-butyl 2-{1-amino-2-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}-4-(2,2-dimethylbutyl)-1H-imidazole-1-carboxylate (for synthesis see Example 39) (24 mg, 0.05 mmol). After stirring at ambient temperature for 1 h, the reaction mixture was quenched with water and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Preparatory plate chromatography eluting with 20% ethyl acetate/hexane afforded tert-butyl 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-[(methylsulfonyl)amino]ethyl}-1H-imidazole-1-carboxylate.
Reaction SMILES: [CH3:1][S:2][CH3:3].ClN1C(=O)CCC1=O.[CH3:12][O:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19](C=[CH:21][NH:22]2)=[CH:18][CH:17]=1)=[O:15]>ClCCl>[CH3:1][S:2][C:3]1[C:19]2[C:23](=[CH:24][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][CH:18]=2)[NH:22][CH:21]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(SC)c[nH]c2c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Dimethyl sulfide (0.54 mL, 7.42 mmol) was added dropwise at 0° C. to a suspension of N-chlorosuccinimide (0.99 g, 7.42 mmol) in dichloromethane (10 mL). The reaction mixture was cooled to −20° C. and a solution of 1H-indole-6-carboxylic acid methyl ester (1.0 g, 5.71 mmol) in dichloromethane (10 mL) was added. The reaction mixture was warmed to room temperature and stirred for 1 h. The solvent was evaporated and the residue and xylene (50 mL) were refluxed at 140-150° C. for 1 h. The xylene was removed under vacuum and the remnant purified by column chromatography [100-200 mesh silica; dichloromethane/hexane=1:1]. Light brown solid. Yield: 0.9 g (71% of theory). HPLC-MS (method 5): Rt=3.26 min; m/z [M+H]+=222
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[C:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>CO>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]#[C:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1csc(C#Cc2cc(OC)c(OC)c(OC)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C#Cc2nc(C(=O)O)cs2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 2-(3,4,5-trimethoxyphenylethynyl)thiazole-4-carboxylate (200 mg) was suspended in methanol (2 mL), to the suspension a 4 M solution (1 mL) of sodium hydroxide was added, and the mixture was stirred at room temperature for 4 hours. Concentrated hydrochloric acid was added dropwise to the reaction mixture at 0° C. to weakly acidify the reaction mixture. Crystals formed were collected by filtration, washed with water and dried to obtain the title compound.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.Cl.[NH2:14][C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27](=[O:40])[C@@H:28]([CH2:30][CH2:31][CH2:32][NH:33][C:34]([NH2:39])=[N:35][N+:36]([O-:38])=[O:37])[NH2:29])=[CH:21][CH:20]=1)=[O:16].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:14][C:15]([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH:26][C:27](=[O:40])[C@@H:28]([CH2:30][CH2:31][CH2:32][NH:33][C:34]([NH2:39])=[N:35][N+:36]([O-:38])=[O:37])[NH:29][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)=[O:12])=[CH:23][CH:24]=1)=[O:16]
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: NC(=O)NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)c2cccc3[nH]ccc23)cc1
Yield: 82 %

Procedure:
Prepared analogously to Example 69a) from 1H-indole-4-carboxylic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamide-hydrochloride and TBTU in a yield of 82% of theory.