Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:39]([C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)[CH2:40][CH2:41][CH2:42][CH3:43]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:39]([C@H:44]1[CH2:45][CH2:46][C@H:47]([C:50]([O:23][C:20]2[CH:19]=[CH:18][C:17]([C:4]3[N:3]=[C:2]([F:1])[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=3)=[CH:22][CH:21]=2)=[O:51])[CH2:48][CH2:49]1)[CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)nc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)[C@H]3CC[C@H](CCCCC)CC3)cc2)nc1F

Procedure:
1.11 g (3.50 mmol) of 2-fluoro-6-(4-hydroxyphenyl)-3-octyloxypyridine, 0.72 g (3.50 mmol) of dicyclohexylcarbodiimide, 0.69 g (3.50 mmol) of trans-4-pentylcyclohexanecarboxylic acid and 0.02 g of 4-(N,N-dimethylamino)pyridine are stirred in 20 ml of dichloromethane at room temperature for 3 hours. After filtration of the mixture, evaporation of the filtrate to dryness, purification of the residue by chromatography (silica gel, 8:2 hexane/ethyl acetate) and recrystallization from n-hexane, 1.00 g of 4-(2-fluoro-3-octyloxypyridine-6-yl)phenyl trans-4-pentylcyclohexanecarboxylate is obtained. ##STR48##
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[N-:9]=[N+:10]=[N-:11].[Na+]>CS(C)=O.O>[N:9]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCCC1Br
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NC1CCCCC1=O
Reaction time: 2 h
Yield: 92 %

Procedure:
2-Bromocyclohexan-1-one (K. Tanemura, T. Suzuki, Y. Nishida, K. Satsumabayashi, T. Horaguchi, Chem. Commun. 2004, 470-471) (0.55 g, 3.11 mmol) was dissolved in DMSO (3 mL). Sodium azide (1.00 g, 15.5 mmol) was added, and the resulting mixture was stirred for 2 h. The solution was then diluted with water (50 mL) and extracted with diethyl ether (2×20 mL). The organic layers were combined, washed with water (2×20 mL), dried over Na2SO4(s), filtered, and concentrated under reduced pressure. The resulting oil was found to be pure by NMR analysis and was used without further purification (0.40 g, 2.87 mmol, 92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([CH:14]=[N:15][N:16]=3)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:16]([N:15]=[CH:14][N:10]=3)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cncn3cnnc23)cc1
Solvent: CO
Product: Clc1ccc(-c2cncn3ncnc23)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.76 g. of 8-(4-chlorophenyl)-1,2,4-triazolo[4,3-c]pyrimidine and 25 ml. of methanol is heated at the reflux temperature for 18 hours. The reaction mixture is cooled to room temperature to separate a crystalline material which is collected by filtration to give 1.53 g. (83%) of the product of the example, m.p. 154°-155° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]3[C:15]4[C:16]([O:20][CH2:21][CH2:22][C:23]5[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=5)=[N:17][CH:18]=[N:19][C:14]=4[S:13][C:10]=32)=[N:5]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(#N)C>[CH3:40][N:41]1[CH2:46][CH2:45][N:44]([CH2:2][CH2:3][N:4]2[CH:12]=[C:11]3[C:6]([CH2:7][CH2:8][C:9]4[C:15]5[C:16]([O:20][CH2:21][CH2:22][C:23]6[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=6)=[N:17][CH:18]=[N:19][C:14]=5[S:13][C:10]=43)=[N:5]2)[CH2:43][CH2:42]1
Reactant: O=[N+]([O-])c1ccc(CCOc2ncnc3sc4c(c23)CCc2nn(CCBr)cc2-4)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(OCCc4ccc([N+](=O)[O-])cc4)c23)CC1
Temperature: 80 °C
Yield: 99.7 %

Procedure:
To a suspension of 2-(2-bromoethyl)-6-[2-(4-nitrophenyl)ethoxy]-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazole (4.0 g, 7.99 mmol), K2CO3 (2.21 g, 15.99 mmol), and NaI (1.20 g, 7.99 mmol) in acetonitrile (300 mL) was added N-methyl piperazine (3.20 g, 31.98 mmol). Resulting mixture was heated at 80° C. for 4.5 h after which time analytical HPLC showed no more starting material present and a new major peak appeared. Solvents were evaporated and the residue was dissolved in water and CH2Cl2. The organic layer was separated, dried (Na2SO4), and concentrated to afford a light yellow solid. The solid material was further washed with ether, air-dried to afford a pale solid (4.14 g, 95%) as the desired product. 1H-NMR (DMSO-d6) δ 8.52 (s, 1H), 8.19 (d, 2H), 7.95 (s, 1H), 7.63 (d, 2H), 4.78 (t, 2H), 4.14 (t, 2H), 3.28 (t, 2H), 3.01 (t, 2H), 2.78 (t, 2H), 2.67 (t, 2H), 2.40 (broad, 4H), 2.26 (broad, 4H), 2.11 (s, 3H); LCMS RT=2.42 min; [M+H]+=520.2.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:23][C:19]1[C:18](/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH3:28])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:29]
Reactant: CCC/C=C\c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC/C=C\c1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
The mixture of 2-[3-methyl-2-((Z)-pent-1-enyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (124) (69 mg, 0.18 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (8 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 5 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜4. The precipitate is filtered to give a pure product (125) as white solid (42 mg, 64%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=1)#[CH:2].[N:15]1([C:20]2[CH:21]=[C:22]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[C:34](I)[CH:33]=3)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[CH:19]=[CH:18][N:17]=[CH:16]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.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.[Cu]I>[N:15]1([C:20]2[CH:21]=[C:22]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([C:2]#[C:1][C:3]4[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][N:10]5[CH2:14][CH2:13][CH2:12][CH2:11]5)[CH:8]=4)[CH:33]=3)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cncc(CN2CCCC2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cncc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-Ethynyl-5-(pyrrolidin-1-ylmethyl)pyridine (0.52 mmol), 0.245 g (0.52 mmol) of N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide (as prepared above), 0.030 g (0.026 mmol) of Pd(PPh3)4, 0.007 g (0.039 mmol) of CuI, and 0.14 mL (0.78 mmol) of diisopropylethylamine in 3.0 mL of DMF is stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture is concentrated and the crude product is purified by silica gel flash chromatography (eluted with 10% EtOAc/hexanes, then 100% EtOAc, then 10% MeOH/EtOAc) to provide the title product.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[N:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO>C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[N:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(NS(=O)(=O)c2ccccc2)Cc2nc(-c3ccccc3)ccc2N1Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(NC1Cc2nc(-c3ccccc3)ccc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a suspension of 2C (45 mg, 0.096 mmol) in THF (1 mL) at RT under argon was added borane-tetrahydrofuran complex (1 M solution in THF, 0.48 mL, 0.48 mmol) dropwise. After the addition, the reaction became a clear solution. The reaction was allowed to stir at RT under argon for 1 h. After this time, no starting material was detected by LC-MS. MeOH (1 mL) was added carefully to the reaction and the mixture was stirred at RT for 60 min, then concentrated under reduced pressure. The resulting residue was partitioned between CH2Cl2 (30 mL) and saturated aqueous NaHCO3. The layers were separated. The aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic layer were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The resultant residue was dissolved in boiling CH3CN (2 μL) and EtOAc (2 mL), and then hexane (10 mL) was added. After cooling to RT. White precipitates foamed. The product was collected by filtration and washed with hexane to give the title compound as a white solid (33 mg, 76%). HPLC (method B): 99% at 5.62 min. MS (ES): m/z 456 [M+H]+. 1H NMR (DMSO6, 400 MHz): δ 8.13 (d, J=6.2 Hz, 1H), 7.92-7.96 (m, 4H), 7.64-7.76 (m, 3H), 7.59 (d, J=8.6 Hz, 1H), 7.29-7.46 (m, 4H), 7.28-7.34 (m, 4H), 7.00 (d, J=8.6 Hz, 1H), 4.54 (dd, J1=48.9 Hz, J2=16.5 Hz, 2H), 3.40-3.45 (m, 1H), 3.36-3.40(m, 1H), 3.25-3.29 (m, 1H), 2.90-3.01(m, 2H).
Reaction SMILES: [BH4-].[Na+].[I-:3].[CH3:4][NH+:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[N:6]1[CH3:23].I>C(O)(C)C.O>[IH:3].[CH3:4][N:5]1[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[N:6]1[CH3:23]
Reactant: CN1C(c2cccc(F)c2)=CC(c2ccccc2)[NH+]1C
Reactant: [I-]
Agent: I
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CN1C(c2ccccc2)CC(c2cccc(F)c2)N1C
Reaction time: 24 h

Procedure:
Sodium borohydride (76 g, 0.02 mole) is added to a slurry of 1,2-dimethyl-3-(m-fluorophenyl)-5-phenylpyrazolinium iodide (4 g, 0.01 mole) in isopropanol (125 ml). After becoming homogeneous, the reaction mixture is stirred for 24 hours. Water (10 ml) is then slowly added. Isopropanol is removed on a rotary evaporator and resultant residue is slurried in water (50 ml) and extracted with chloroform. Evaporation of the organic layer yields an oil, which is slurried in water. Aqueous hydriodic acid (5 ml, 46-50%) is next added. After stirring for one hour, resulting solid is filtered and dried to give 3,3 g, 83%; melting point 187°-189° C.
Reaction SMILES: [I:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].F[C:13]1[C:18]2[CH:19]=[C:20]([C:22]#[N:23])[S:21][C:17]=2[C:16](O)=[CH:15][CH:14]=1>C1COCC1>[I:1][CH2:2][CH2:3][C@@H:4]([O:5][C:13]1[C:18]2[CH:19]=[C:20]([C:22]#[N:23])[S:21][C:17]=2[CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1cc2c(F)ccc(O)c2s1
Reactant: O[C@@H](CCI)c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1cc2c(O[C@H](CCI)c3ccccc3)cccc2s1
Reaction time: 18 h
Yield: 96.8 %

Procedure:
4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenyl phosphonium (498 mg, 1.12 mmol) was added in one portion to a stirred solution of (S)-3-iodo-1-phenyl-1-propanol (Molander, Gary A.; Shakya, Sagar R.; J. Org. Chem.; 1994, 59; 12; 1994; 3445–3452) (237 mg, 0.84 mmol) and 4-fluoro-7-hydroxy-benzothiophene-2-carbonitrile (144 mg, 0.70 mmol) in dry THF (12 mL) under an inert atmosphere on nitrogen. The resulting suspension was allowed to stir for a further 18 hrs before the solvent was removed in vacuo. The residue was purified by flash chromatography with a gradient of 0–4% diethyl ether in hexane to give the title compound as a colourless oil (284 mg, 72%); δH (300 MHz, CDCl3) 7.83 (1H, s, 3-ArH), 7.36–7.12 (5H, m, ArH), 6.85–6.75 (1H, m, ArH), 6.65–6.57 (1H, m, ArH), 5.40–5.30 (1H, m, CHO), 3.47–3.28 (1H, m, CH2CHHI), 3.23–3.12 (1H, m, CH2CHHI), 2.60–2.42 (1H, m, CHHCH2I) and 2.34–2.19 (1H, m, CHHCH2I).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH:34]=[O:35])[N:31]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH3:16].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH:34]([C:2]3[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[OH:35])[N:31]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH3:16]
Reactant: CCOc1ccc(-c2nc(CCC=O)cs2)cc1OCC
Reactant: COc1cccnc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(CCC(O)c3ncccc3OC)cs2)cc1OCC
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 25.8 %

Procedure:
A solution of 2-bromo-3-methoxypyridine (1.65 g, 8.78 mmol) in THF was cooled to −78° C., and 5.23 ml (8.16 mmol) of a 1.57 N solution of n-butyllithium in n-hexane was added dropwise. The resulting mixture was stirred at the same temperature for 45 minutes, and a solution (15 ml) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionaldehyde (1.34 g, 4.39 mmol) in THF was added dropwise. After stirring at the same temperature for 30 minutes, the temperature of the mixture was raised to −30° C. over a period of 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated salt solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). The solvent was distilled off under reduced pressure, to thereby obtain 470 mg (yield: 26%) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanol as a yellow oil.
Reaction SMILES: C(NC1C=CC=CC=1)=O.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23](Cl)=[CH:22][CH:21]=1)([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[CH:14]1[CH:15]=[CH:16][C:11]([NH:10][C:23]2[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=CNc1ccccc1
Agent: [K+]
Solvent: O=CO
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1

Procedure:
formanilide method, where formic acid and aniline are used as starting materials to prepare formanilide, which in turn reacts with p-nitro-chlorobenzene in the presence of an acid-binding agent such as potassium carbonate, to produce 4-nitrodiphenylamine, and then, 4-nitrodiphenylamine is reduced by sodium sulfide to form 4-aminodiphenylamine;
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[C:20]1([CH:30]=O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[C:20]1([CH2:30][N:3]2[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]3/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/3)[CH2:5][CH2:4]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2cccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added triethylamine (0.35 mL) and naphthalene-1-carbaldehyde (0.09 mL). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (554 mg) was added. The reaction mixture was stirred at room temperature for 3 hr, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (104 mg).
Reaction SMILES: [CH:1]([N:3]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[C@@H:4]([CH3:13])[C@@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)=[O:2].C(P(=O)(OCC)OCC)#N.CN1CCOCC1.Cl.[S:39]1[CH:43]=[CH:42][N:41]=[C:40]1[NH:44][C:45](=[O:59])[C@@H:46]([NH2:58])[C@H:47]([CH3:57])[CH2:48][CH2:49][NH:50][CH2:51][N:52]=[N:53][N+:54]([O-:56])=[O:55].[Cl-].[Na+]>CN(C=O)C>[CH3:57][C@H:47]([CH2:48][CH2:49][NH:50][CH2:51][N:52]=[N:53][N+:54]([O-:56])=[O:55])[C@H:46]([NH:58][C:6](=[O:8])[C@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@@H:4]([N:3]([CH:1]=[O:2])[O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH3:13])[C:45](=[O:59])[NH:44][C:40]1[S:39][CH:43]=[CH:42][N:41]=1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C)N(C=O)OC1CCCCO1
Reactant: C[C@H](CCNCN=N[N+](=O)[O-])[C@H](N)C(=O)Nc1nccs1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@@H](C(=O)N[C@H](C(=O)Nc1nccs1)[C@H](C)CCNCN=N[N+](=O)[O-])[C@H](C)N(C=O)OC1CCCCO1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To a 0° C. solution of (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(2-methyl-1-propyl)butanoic acid (34 mg, 0.12 mmol) in 1 mL anhydrous DMF is added diethyl cyanophosphonate (19 mg, 0.119 mmol) followed by NMM (12 mg). Stirring is continued for 30 min at 0° C. (2S,3R)-2-Amino-3-methyl-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide hydrochloride (42 mg, 0.119 mmol) is added followed by additional NMM (36 mg). The mixture is heated at 40° C. for 16 h then allowed to cool to 25° C. The reaction mixture is added to half-saturated aqueous sodium chloride and extracted with 1:1 EtOAc-ether. The combined organic layers are washed with pH 4.3 phosphate buffer, 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, and dried over magnesium sulfate. Concentration and chromatography on silica gel (elution with 5% methanol in dichloromethane) provides 35 mg of (2R,3S)-3-(formyl-tetrahydropyranyloxyamino)-2-(2-methyl-1-propyl)butanoic acid [(1S,2R)-2-methyl-4-(nitroimino-amino)methylamino-1-(1,3-thiazol-2-ylcarbamoyl)-1-butyl]amide as a foam.
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[F:7][C:8]([F:24])([F:23])[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][CH2:20][CH2:21]O)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>O>[F:7][C:8]([F:24])([F:23])[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][CH2:20][CH2:21][Br:1])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: OCCNc1ccnc2cc(C(F)(F)F)ccc12
Reactant: Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc2c(NCCBr)ccnc2c1
Temperature: 165 °C
Yield: 58 %

Procedure:
Hydrobromic acid (0.88 ml, 16.2 mmol) and then sulphuric acid (0.29 ml, 5.5 mmol) are added dropwise to the 7-trifluoromethyl-4-(β-hydroxyethylamino)quinoline 10 (0.67 g, 2.6 mmol), the reaction medium being refrigerated using a bath of cold water. The reaction medium is then heated at 165° C. for 3 h 30 min, and then poured into 10 ml of cold water. The pH is then adjusted by adding NaHCO3 (pH approximately 9) and the medium is then extracted at the reflux of toluene (10 ml) for 15 min. The organic phase is then collected and the product 11 is obtained by crystallization at −18° C. overnight, filtration, and then drying under vacuum: 0.48 g (yield=58%). Mp: 106° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)Cl.O>[CH2:59]([NH:66][C:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])[CH2:19][CH2:20]1)=[O:25])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1ccccc1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (200 mg, 0.500 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (115 mg, 0.600 mmol), and 1-Hydroxybenzotriazole (81 mg, 0.600 mmol) were dissolved in 10.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (131 μL, 0.750 mmol) and benzylamine (82 μL, 0.750 mmol) were added. The reaction was allowed to stir overnight. The reaction was diluted with water and dichloromethane. The layers were separated and the organic layer was washed with water, saturated ammonium chloride, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified using 10 gram silica Biotage column, with the gradient 30% ethyl acetate: hexanes to 100% ethyl acetate. After purification, pure white solid was obtained. Yield: 105 mg (White solid)
Reaction SMILES: Br.[Cl:2][C:3]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:7]=2[CH:6]=[C:5]([OH:21])[C:4]=1[OH:22].[C:23]([Br:26])(=[O:25])[CH3:24]>FC(F)(F)C(O)=O>[BrH:26].[Cl:2][C:3]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:23](=[O:25])[CH3:24])=[CH:18][CH:19]=3)[C:7]=2[CH:6]=[C:5]([O:21][C:17](=[O:20])[CH3:16])[C:4]=1[O:22][C:5](=[O:21])[CH3:4]
Reactant: CC(=O)Br
Reactant: Oc1ccc(C2CNCCc3c2cc(O)c(O)c3Cl)cc1
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc(C2CNCCc3c2cc(OC(C)=O)c(OC(C)=O)c3Cl)cc1
Reaction time: 2 h

Procedure:
6-Chloro-7,8-dihydroxyl-1-p-hydroxyphenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (Example 2, 1.0 g) was slurried in 200 ml of trifluoroacetic acid, then 1.29 ml of acetyl bromide was added. The mixture was heated at reflux for 2 hours then stirred for 2 hours. After evaporation to dryness the residue was taken up in benzene and concentrated to give a solid which was recrystallized from ethylacetatehexane to give 6-chloro-7,8-diacetoxy-1-(p-acetoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; m.p. 214.5-217°, 0.77 g.