Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH:8]([C:11]2[C:16]([Br:17])=[CH:15][C:14]([CH2:18]OC3CCCCO3)=[CH:13][C:12]=2[Br:26])C#N)=[CH:4][C:3]=1[CH:27]([CH3:29])[CH3:28].C([O-])(=[O:32])C.[Na+].[ClH:35]>C(O)(=O)C.C(OCC)(=O)C>[Br:26][C:12]1[CH:13]=[C:14]([CH2:18][Cl:35])[CH:15]=[C:16]([Br:17])[C:11]=1[CH2:8][C:5]1[CH:4]=[C:3]([CH:27]([CH3:29])[CH3:28])[C:2](=[O:32])[NH:7][N:6]=1
Reactant: CC(=O)[O-]
Reactant: Cl
Reactant: CC(C)c1cc(C(C#N)c2c(Br)cc(COC3CCCCO3)cc2Br)nnc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)c1cc(Cc2c(Br)cc(CCl)cc2Br)n[nH]c1=O
Temperature: 25 °C
Yield: 36 %

Procedure:
A mixture of (6-chloro-5-isopropyl-pyridazin-3-yl)-[2,6-dibromo-4-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-acetonitrile (61) (332.8 mg, 0.61 mmol) and sodium acetate (103.8 mg, 1.26 mmol) in glacial acetic acid (2.7 mL) was heated to reflux for 2.5 h. The reaction was then treated with concentrated hydrochloric acid (2.0 mL) and heated to reflux for 18 h. At this time, the reaction was treated with more concentrated hydrochloric acid (6.0 mL) and additional glacial acetic acid (3.0 mL) and heated to reflux for an additional 24 h. The reaction was then cooled to 25° C. and diluted with ethyl acetate (150 mL). This solution was washed with a saturated aqueous sodium chloride solution (2×50 mL) and a saturated aqueous sodium carbonate solution (1×100 mL), dried with magnesium sulfate, filtered, and concentrated under vacuum. The resulting brown oil was treated with glacial acetic acid (1.0 mL) and concentrated hydrochloric acid (6.0 mL) and was heated to reflux for 3 d. At this time, the reaction was cooled to 25° C. and diluted with ethyl acetate (150 mL). This solution was washed with a saturated aqueous sodium chloride solution (2×50 mL) and a saturated aqueous sodium carbonate solution (1×100 mL), dried with magnesium sulfate, filtered, and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 6-(2,6-dibromo-4-chloromethyl-benzyl)-4-isopropyl-pyridazin-3-one (62) (96.3 mg, 36%) as an off-white solid; LRMS for C15H15Br2ClN2O (M+H) at m/z=433. Molecular Weight=434.5606; Exact Mass=431.9240
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2].[CH2:11](O)[CH2:12][OH:13].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([C:6]1([CH3:7])[O:13][CH2:12][CH2:11][O:8]1)[CH3:9])[CH3:2]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C)C1(C)OCCO1
Yield: 72.1 %

Procedure:
A mixture of 2-methyl-3-oxo-butyric acid ethyl ester (50 g, 0.347 mol), ethylene glycol (65 g, 1.05 mol) and p-toluenesulfonic acid monohydrate (0.2 g) in anhydrous toluene (200 mL) was refluxed using a Dean-Stark trap until the theoretical amount of water (6.3 mL) was collected. After cooling, the mixture was extracted with saturated bicarbonate solution (100 mL), water (100 mL×5), and brine (100 mL×2). After drying with sodium sulfate, filtration, and concentration on a rotary evaporator, the product was purified by distillation (fraction with b.p. 74-76° C./2 mm Hg) to yield 47.12 g (72%) of 2-(2-methyl-[1,3]dioxolan-2-yl)-propionic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20]#[N:21])=[CH:13][CH:14]=2)[C:9]1([CH2:24][CH3:25])[CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].C([OH:29])C.CN(C=O)C>O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:29])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH2:22][CH3:23])[CH2:24][CH3:25])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC1(CC)c2cc(C#N)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Reactant: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a mixture of trans-(7-cyano-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (33.0 g, 92 mmol), ethanol (45 mL), DMF (25 mL) and water (7.5 mL) was added hydrido(dimethylphosphoniousacid-kP) [hydrogen bis(dimethylphosphinito-kP)]platinum(II) (0.25 g, 0.58 mmol) and the reaction mixture was heated at 80° C. for 24 h. The reaction was cooled to room temperature and concentrated to dryness under vacuum to give the title compound (36.3 g) which was used without further purification. (m/z): [M+H]+ calcd for C21H32N2O4 377.24. Found 377.8. 1H NMR (d6-DMSO, 400 mHz) δ (ppm): 7.92 (s, 1H), 7.64 (m, 2H), 7.26 (s, 1H), 7.14 (d, J=7.9 Hz, 1H), 6.64 (d, J=9.4 Hz) 3.81 (t, J=10.0 Hz), 3.58 (m, 1H), 3.30 (s, 3H), 2.58 (dd, J=16.9 Hz, 9.4 Hz, 1H), 1.82 (m, 1H), 1.56-1.45 (m, 4H), 1.41 (s, 9H), 0.58 (m, 6H).
Reaction SMILES: O=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:24]2[C:3]([C:4]3[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=3)[C:7]#[N:8])=[C:2]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:36][C:34](=[O:35])[NH:33]2)[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH3:19]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: N#Cc1cccc(CC(=O)c2ccccc2)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2cccc(C#N)c2)cc([N+](=O)[O-])c1O
Yield: 13.4 %

Procedure:
To a solution of 3-(2-oxo-2-phenylethyl)benzonitrile (Intermediate 11) (80 mg, 0.36 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (76 mg, 0.36 mmol), and urea (50 mg, 1.08 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl solution, and the mixture was stirred at reflux for 2 days. After the solvent was removed under reduced pressure, the residue was purified by thin layer chromatography (PE:EtOAc=1:2) to give Compound 29 (22 mg, yield 2.5%). 1H NMR (CD3OD 400 MHz): δ 7.45 (s, 1H), 7.27 (d, J=7.2 Hz, 1H), 7.21-7.18 (m, 5H), 7.12-7.05 (m, 3H), 6.98 (s, 1H), 5.20 (s, 1H), 3.97-3.94 (m, 2H), 1.30 (t, J=6.8 Hz, 3H); MS (ESI): m/z 457.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].[CH3:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]2([NH2:44])[CH2:43][CH2:42]2)[N:36]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:37]3[N:36]=[C:35]([CH3:34])[CH:40]=[CH:39][N:38]=3)[CH2:43][CH2:42]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: Cc1ccnc(C2(N)CC2)n1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nccc(C)n5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.089 mmol, 1 eq), 1-(4-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.06 g, 0.11 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.027 g, 0.26 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.022 g (42%). 1H NMR (400 MHz, CD3OD): δ 8.54 (d, J=5.6 Hz, 1H), 7.97-7.94 (m, 2H), 7.90 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 4H), 7.19 (s, 1H), 4.10 (s, 3H), 2.96 (s, 3H), 2.55 (s, 3H), 2.31 (s, 3H), 1.89-1.86 (m, 2H), 1.59-1.56 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ−77.65 (TFA), −112.33, −122.77 LCMS: (ES+) m/z=583.2 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][NH:6]C=O.C([NH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](=[O:21])[CH2:19][Cl:20])=[CH:16][CH:15]=1)(=O)C>O>[Cl-:20].[CH3:1][N+:2]([CH3:9])([CH2:19][C:18]([C:17]1[CH:16]=[CH:15][C:14]([NH2:13])=[CH:23][CH:22]=1)=[O:21])[CH2:3][CH2:4][CH2:5][NH2:6]
Reactant: CN(C)CCCNC=O
Reactant: CC(=O)Nc1ccc(C(=O)CCl)cc1
Solvent: O
Product: C[N+](C)(CCCN)CC(=O)c1ccc(N)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 143.5 parts of N-(3-dimethylaminopropyl)formamide and 700 parts of water is added 249 parts of p-acetamidophenacyl chloride. The mixture is stirred at room temperature for 16 hours and then at 60°-65° C. for 2 hours. Insoluble material is removed by filtration. The filtrate is combined with one-half its volume of concentrated hydrochloric acid (36% by weight) and the resulting solution is heated at the boil for 2 hours. The aqueous solution of N,N-dimethyl-N-(p-aminophenacyl)-N-3-aminopropylammonium chloride is used as such in the preparation of dyes.
Reaction SMILES: C(O[C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)C1C=CC=CC=1.C(O[C:31]1[C:40]([N+:41]([O-:43])=[O:42])=[C:39](Cl)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][N:37]=2)[N:32]=1)C1C=CC=CC=1.C([NH2:49])(C)(C)C>>[N+:19]([C:18]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH2:32])=[CH:15][CH:14]=[CH:13][CH:12]=2)([O-:21])=[O:20].[N+:41]([C:40]1[CH:31]=[N:32][C:33]2[C:38]([C:39]=1[NH2:49])=[N:37][CH:36]=[CH:35][CH:34]=2)([O-:43])=[O:42]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1c(OCc2ccccc2)nc2cccnc2c1Cl
Reactant: O=[N+]([O-])c1c(OCc2ccccc2)nc2ccccc2c1Cl
Product: Nc1c([N+](=O)[O-])cnc2ccccc12
Product: Nc1c([N+](=O)[O-])cnc2cccnc12

Procedure:
Compounds of the invention can also be prepared according to Reaction Scheme V, wherein Bn, E, R, R3-1, and n are as defined above; P is an amino protecting group; and Da is —(CH2)1-4—. In step (1) of Reaction Scheme V, a benzyloxy-4-chloro-3-nitroquinoline or benzyloxy-4-chloro-3-nitro[1,5]naphthyridine of Formula XLI is reacted with tert-butylamine in the presence of base, and the tert-butyl group is subsequently removed under acidic conditions to provide a 3-nitroquinolin-4-amine or 3-nitro[1,5]naphthyridin-4-amine of Formula XLII, which is reduced in step (2) to provide a quinoline-3,4-diamine or [1,5]naphthyridine-3,4-diamine of Formula XLIII. In step (3) of Reaction Scheme V, a. quinoline-3,4-diamine or [1,5]naphthyridine-3,4-diamine of Formula XLIII is reacted with acetic acid or acetyl chloride to provide a 2-methyl-1H-imidazo[4,5-c]quinoline or a 2-methyl-1H-imidazo[4,5-c][1,5]naphthyridine of Formula XLIV, which undergoes protection at the 1-position in step (4) with a suitable protecting group. In step (5) of Reaction Scheme V, the 2-methyl group of a 1H-imidazo[4,5-c]quinoline or 1H-imidazo[4,5-c][1,5]naphthyridine of Formula XLV is deprotonated with n-butyllithium and subsequently reacted with an alkylating agent of formula Br—CH2-Da-CH2—Cl, and the product of Formula XLVI is then deprotected using conventional methods to provide a 1H-imidazo[4,5-c]quinoline or 1H-imidazo[4,5-c][1,5]naphthyridine of Formula XLVII. The compound of Formula XLVII is then cyclized to provide a compound of Formula XLVIII. Steps (1) through (7) of Reaction Scheme V can be carried out using the conditions described in U.S. Pat. No. 5,482,936 (Lindstrom).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH:5]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][N:9]=1)[C:6]#[N:7].[C:22](OC(=O)C)(=[O:24])[CH3:23]>C1C=CC=CC=1>[C:22]([O:1][CH2:2][CH2:3][S:4][CH:5]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][N:9]=1)[C:6]#[N:7])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1OC)C(C(C#N)SCCO)=NCC2
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(C(C#N)SCCOC(C)=O)=NCC2

Procedure:
To 1.0 g. of α-(2-hydroxyethylmercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile 5 ml. of acetic anhydride and 15 ml. of benzene are added and the reaction mixture is refluxed for 4 hours. The mixture is then evaporated to dryness and to the residue carbon tetrachloride is added. 0.6 g. of α-(2-acetoxyethyl-mercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile are obtained, melting at 157° C. after recrystallization from butanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CC[N:25]([CH:29]([CH3:31])C)[CH:26]([CH3:28])C.CO.C(Cl)Cl>C(OCCO)C>[C:19]([O:18][C:16]([NH:15][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]2[C:28]3[C:31](=[CH:29][N:25]=[CH:26][CH:28]=3)[CH:31]=[CH:29][N:25]=2)=[CH:7][CH:6]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Solvent: CCOCCO
Product: CCOC(=O)[C@H](Cc1ccc(Nc2nccc3cnccc23)cc1)NC(=O)OC(C)(C)C
Yield: 77.4 %

Procedure:
Ethyl (S)-3-(4-aminophenyl)-2-[N-(t-butyloxycarbonyl)amino]propanoate (600 mg, 1.95 mmol), Intermediate 21 (350 mg, 2.13 mmol) and DIPEA (276 mg, 372 μl, 2.13 mmol) in 2-ethoxyethanol (0.5 ml) were stirred at 130° under N2 for several hours. The reaction was partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (30 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic extracts were washed with brine (10 ml), dried (MgSO4) and evaporated in vacuo to afford a dark oil. Chromatography (SiO2; 3% MeOH/DCM) gave the title compound as a dull orange foam (360 mg, 42%). δH (CDCl3) 9.19 (1H, s), 8.67 (1H, d, J 5.9 Hz), 8.24 (1H, d, J 5.8 Hz), 7.66 (1H, d, J 5.9 Hz), 7.65 (2H, d, J 8.5 Hz), 7.21 (1H, d, J 5.8 Hz), 7.16 (2H, d, J 8.5 Hz), 7.15 (1H, obscured s), 5.05-4.97 (1H, m), 4.60-4.51 (1H, m), 4.19 (2H, q, J 7.1 Hz), 3.17-3.04 (2H, m), 1.44 (9H, s), 1.27 (3H, t J 7.1 Hz); m/z (ES+, 70V) 459 (MNa+), 437 (MH+).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)=[CH:8][CH:7]=1)CCC.B(Br)(Br)Br.O>ClCCl>[CH2:22]([C@H:19]1[CH2:18][CH2:17][C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][C:9]2[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=2)[CH2:21][CH2:20]1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC[C@H]1CC[C@H](CCCCc2ccc(OCCCC)cc2)CC1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CCCCc2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of 16 g of 1-butyloxy-4-[4-(trans-4-pentylcyclohexyl)-1-butyl]benzene and 100 ml of absolute dichloromethane was treated at 0° C. and while gassing with nitrogen with 50 ml of a 1M solution of boron tribromide in dichloromethane. After completion of the addition the reaction mixture was stirred at room temperature for a further 2 hours and then treated cautiously with 200 ml of water. The organic phase was separated and the aqueous phase was back-extracted three times with 100 ml of dichloromethane each time. The combined organic phases were washed in succession with 1000 ml of water, 500 ml of dilute potassium carbonate solution and again with 1000 ml of water, dried over magnesium sulfate, filtered and subsequently concentrated. Recrystallization of the residue from hexane gave 11 g of pure 4-[4-(trans-4-pentylcyclohexyl)-1-butyl]phenol with m.p. 86° C.
Reaction SMILES: OC1CC(O)C(CC=CCCCC(OC)=O)C1COC(=O)NC1C=CC=CC=1.[CH2:29]([NH:36][C:37]([O:39][CH2:40][CH:41]1[CH:45]([O:46]C2CCCCO2)[CH2:44][CH:43]([O:53]C2CCCCO2)[CH:42]1[CH2:60][CH:61]=[CH:62][CH2:63][CH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67])=[S:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[CH2:29]([NH:36][C:37]([O:39][CH2:40][CH:41]1[CH:45]([OH:46])[CH2:44][CH:43]([OH:53])[CH:42]1[CH2:60][CH:61]=[CH:62][CH2:63][CH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67])=[S:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)CCCC=CCC1C(OC2CCCCO2)CC(OC2CCCCO2)C1COC(=S)NCc1ccccc1
Agent: COC(=O)CCCC=CCC1C(O)CC(O)C1COC(=O)Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: COC(=O)CCCC=CCC1C(O)CC(O)C1COC(=S)NCc1ccccc1
Yield: 89.9 %

Procedure:
According to the procedures described for 3a the reaction of bis-THP ether 2c (3 80.3 mg, 0.65 mmol) and pyridinium p-toluenesulfonate (200 mg, 0.78 mmol) afforded 246.4 mg (91%) of the title compound after purification by flash column chromatography (silica gel, 1:1 hexane/EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:15]>ClC1C=CC=CC=1Cl>[CH2:19]([O:18][C:16]([C:14]1[S:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:15]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C#N
Reactant: O=c1oc(-c2ccc(Cl)cc2)ns1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)ns1
Temperature: 150 °C
Yield: 84.8 %

Procedure:
To a solution of 5-(4-chlorophenyl)-[1,3,4]oxathiazol-2-one (1.35 g, 6.32 mmol) in 1,2-dichlorobenzene (5 ml) was added ethyl cyanoformate (2.50 ml, 25.27 mmol). The resulting reaction mixture was refluxed for 24 h at 150° C. After the completion of the reaction (TLC monitoring), added ice-cold water and extracted with ethyl acetate (3×100 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum, to get the desired product (1.44 g, 85%).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:27])=[C:9]([CH:19]([CH2:24][CH2:25][CH3:26])[C:20]([O:22]C)=[O:21])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:4]=1[CH3:28])[CH3:2].[OH-].[Na+]>CO.C(O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:27])=[C:9]([CH:19]([CH2:24][CH2:25][CH3:26])[C:20]([OH:22])=[O:21])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:4]=1[CH3:28])[CH3:2]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc(C)c(CC)c2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2sc(C)c(CC)c2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
To a solution of methyl 2-(3-ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.130 g; 0.329 mmol) in methanol (7 mL) and ethanol (3.5 mL) was added a 5% sodium hydroxide solution (9 mL; 11.25 mmol). The reaction mixture was heated under reflux for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.068 g (54%) of the title compound as a white powder.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][NH:13][C:14](=[O:26])[CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.ClCCl.[NH2:42][C@H:43]([C:50]([NH:52][C@H:53]([CH:58]=[N:59][NH:60][C:61]([NH2:63])=[O:62])[CH2:54][CH:55]([CH3:57])[CH3:56])=[O:51])[CH2:44][C:45]1[N:49]=[CH:48][NH:47][CH:46]=1>CN(C)C=O.C(N(CC)CC)C>[CH2:1]([CH:8]([CH2:12][NH:13][C:14](=[O:26])[CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:9]([NH:42][C@H:43]([C:50]([NH:52][C@H:53]([CH:58]=[N:59][NH:60][C:61]([NH2:63])=[O:62])[CH2:54][CH:55]([CH3:57])[CH3:56])=[O:51])[CH2:44][C:45]1[N:49]=[CH:48][NH:47][CH:46]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccc2ccccc12)NCC(Cc1ccccc1)C(=O)O
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CNC(=O)Cc1cccc2ccccc12)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.7 %

Procedure:
A mixture of 139 mg of (±)-2-benzyl-3-(1-naphthylacetamido)propionic acid and 65 mg of 1,1'-carbonyldiimidazole was added to 5 ml of dry dichloromethane, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was added to a solution of 261 mg of L-histidyl-L-leucinal semicarbazone.2p-toluenesulfonic acid salt and 0.11 ml of triethylamine in 3 ml of dry N,N-dimethylformamide, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: lower layer of chloroform/methanol/water=8/3/1 by volume) to obtain 30 mg of N-[(±)-2-benzyl-3-(1-naphthylacetamido)propionyl]-L-histidyl-L-leucinal semicarbazone as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].[CH2:12]([NH2:16])[CH2:13][CH2:14][NH2:15]>C1COCC1>[ClH:1].[Cl:8][C:6]1[C:5]([Cl:9])=[C:4]([NH:15][CH2:14][CH2:13][CH2:12][NH2:16])[C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: NCCCN
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Solvent: C1CCOC1
Product: Cl
Product: NCCCNc1c(Cl)c(Cl)nc(Cl)c1Cl
Yield: 57 %

Procedure:
Using the same procedure as in Example 2, 25.1 g. (0.1 mole) of pentachloropyridine in 200 ml. of THF was caused to react with 22.3 g. (0.3 mole) of 1,3-propanediamine in 200 ml. of THF to give 18.6 g. (57%) of the title compound, melting at 248°-9°.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1([C:23]2[N:33]=[C:26]3[C:27]([O:31][CH3:32])=[CH:28][CH:29]=[CH:30][N:25]3[N:24]=2)[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[CH3:32][O:31][C:27]1[C:26]2[N:25]([N:24]=[C:23]([C:20]3([CH2:19][OH:18])[CH2:22][CH2:21]3)[N:33]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccn2nc(C3(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC3)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccn2nc(C3(CO)CC3)nc12
Reaction time: 16 h
Yield: 78.8 %

Procedure:
To a solution of 2-(1-((tert-butyldiphenylsilyloxy)methyl)cyclopropyl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (4.5 g, 9.84 mmol) in dry THF (40 ml) was added TBAF (38.38 mmol, 1M in THF) at RT and the mixture was stirred further. After 16 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic phase was dried over anhyd. Na2SO4 and concentrated under reduced pressure. The residue obtained was purified by column chromatography to afford (1-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropyl)methanol (1.7 g, 79%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[Br:13]N1C(=O)CCC1=O>ClCCl.N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Br:13])=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(C)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClCCl
Product: COc1ccc(CBr)cc1[N+](=O)[O-]
Yield: 78.2 %

Procedure:
To a solution of 4-methoxy-3-nitrotoluene (5.02 g) and N-bromosuccinimide (5.51 g) in dichloromethane (50 mL) was added 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (463 mg). The mixture was heated under reflux for 8 hours. The solution was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with n-hexane-ethyl acetate (20:1) to give 4-methoxy-3-nitrobenzyl bromide as a pale yellow powder (5.78 g).