Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:9]([O:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)[CH3:10].[Br:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][CH:26]=[CH:25]2>C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][CH:26]=[C:25]2[C:15](=[O:17])[CH2:14][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:18]
Reactant: Brc1cccc2cc[nH]c12
Reactant: CCOC(=O)CCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)c1c[nH]c2c(Br)cccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a dichloromethane (50 mL) solution of aluminum chloride (6.80 g), succinic acid monoethyl ester chloride (8.39 g) was added under ice cooling and the mixture was stirred for 30 minutes. To the mixture, 7-bromoindole (5.0 g) was added, followed by stirring at room temperature for 5 hours. To the reaction mixture, ice water and ethyl acetate were added, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was washed with diisopropyl ether to obtain the titled compound having the following physical properties (6.04 g).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([CH2:23]O)=[CH:18][N:17]=1.Cl>C(O)(=O)C>[CH2:1]([C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([CH2:23][C:19]2[C:20]([NH2:22])=[N:21][C:16]([NH2:15])=[N:17][CH:18]=2)[CH:5]=1)[CH:2]=[CH2:3]
Reactant: Nc1ncc(CO)c(N)n1
Reactant: C=CCc1ccc2cccnc2c1O
Agent: Cl
Solvent: CC(=O)O
Product: C=CCc1cc(Cc2cnc(N)nc2N)c2cccnc2c1O
Yield: 28.2 %

Procedure:
7-Allyl-8-hydroxyquinoline [H. Fiedler, Arc. Pharm., 297, 108 (1964)] (33.0 g, 0.227 mol), 2,4-diamino-5-hydroxymethylpyrimidine (32.97 g, 0.227 mole), glacial acetic acid (300 mL) and concentrated HCl (31.5 mL) were refluxed for 5 hr. The resulting precipitate was filtered off and then slurried with H2O (250 mL) and sufficient NH4OH to give a pH of 8. The undissolved solid was filtered off, washed with H2O and dried to give the title compound as yellow powder (19.7 g, 28%), mp 229°-231° dec., structure confirmed by NMR. Anal. Calcd for C17H17N5O: C, 66.43; H, 5.58; N, 22.79. Found: C, 66.41; H, 5.59; N, 22.78. Additional product (5.0 g, 7%) was obtained by evaporation of filtrates and chromatography to separate unreacted starting materials.
Reaction SMILES: [OH-].[Na+].[C:3]([CH:8]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH2:15][C:16]([O:18]CC)=[O:17])C(OCC)=O)([O:5]CC)=[O:4]>O.C(O)C>[F:27][C:23]1[CH:22]=[C:21]([CH:14]([CH2:8][C:3]([OH:5])=[O:4])[CH2:15][C:16]([OH:18])=[O:17])[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CC(c1cccc(F)c1)C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC(CC(=O)O)c1cccc(F)c1
Yield: 77.3 %

Procedure:
To a hot solution of sodium hydroxide (19.15 g, 0.479 mol) in water (50 ml) was added a solution of diethyl 2-carbethoxy-3-(3-fluorophenyl)glutarate (18.8 g, 0.0532 mol) in ethanol (36 ml). The resulting slurry was refluxed for 5 hrs. The mixture was poured into icewater and the ethanol was removed by spin evaporation in vacuo. The residual aqueous solution was acidified with concentrated hydrochloric acid (12N) and the solution (200 ml) was extracted with ethyl acetate (3×300 ml). The ethyl acetate layers were combined, washed with water (50 ml) and the volatiles were removed by spin evaporation in vacuo to give a solid that was recrystallized from dichloromethane and hexanes to give 9.3 g (77%) of 3-(3-fluorophenyl)glutaric acid a white solid; m.p., 126°-127.5° C.;
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[NH2:5][N:6]1[C:11](=[O:12])[CH:10]([Cl:13])[N:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:8]=[C:7]1[SH:18].[OH-].[Na+].C1(C)C=CC=CC=1>O.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCC>[NH2:5][N:6]1[C:11](=[O:12])[CH:10]([Cl:13])[N:9]([C:14]([CH3:15])([CH3:17])[CH3:16])[N:8]=[C:7]1[S:18][CH2:3][C:2]#[CH:1]
Reactant: CC(C)(C)N1N=C(S)N(N)C(=O)C1Cl
Reactant: C#CCBr
Agent: CCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C#CCSC1=NN(C(C)(C)C)C(Cl)C(=O)N1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.2 %

Procedure:
18.6 g (80% stength solution in toluene=0.125 mol) of propargyl bromide and 0.5 g of pentyltributylphosphonium bromide were added to a solution of 23.5 g (0.1 mol) of 4-amino-6-chloro-tert.-butyl-3-mercapto-1,2,4-triazin-5-one and 4.4 g of sodium hydroxide in 40 ml of water. The reaction mixture was stirred for about 20 hours at room temperature, 100 ml of toluene were then added, and the mixture was filtered. The filtrate was washed with 100 ml of water, with 100 ml of 1 N sodium hydroxide solution and again with water. The organic phase was dried over sodium sulphate, filtered and concentrated. The oily residue was brought to crystallization by trituration in diisopropyl ether, and the product was recrystallized from ethyl acetate/petroleum ether. 13.8 g (57.5% of theory) of 4-amino-6-chloro-tert.-butyl-3-propargylthio-1,2,4-triazin-5-one of melting point 107°-108° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccnc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.2 %

Procedure:
A solution of 2-chloronicotinic acid (2.0 g, 12.6 mmol) in THF (15 mL) at 0° C. was treated dropwise with 1M LAH in THF (15 mL, 15.0 mmol), warmed to room temperature, stirred for 5 hours, treated sequentially with water (0.5 mL), 40% NaOH solution (0.5 mL) and water (1.5 mL), stirred for 2 hours, filtered through a pad of diatomaceous earth (Celite®), and extracted with dichloromethane. The combined extracts were dried (MgSO4), filtered, and concentrated to provide 1.56 g (87%) of the desired product of sufficient purity for subsequent use. MS (DCI/NH3) m/z 144 (M+H)+; 1H NMR (CDCl3) δ 8.34 (dd, 1H), 7.90 (m, 1H), 7.29 (dd, 1H), 4.80 (s, 2H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12]1.[S:22]1[C:26]2[CH:27]=[C:28]([C:31](Cl)=[O:32])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1.O>C1COCC1>[S:22]1[C:26]2[CH:27]=[C:28]([C:31]([CH:18]3[C:17](=[O:20])[CH2:16][CH2:15][C:14]4([O:13][CH2:12][CH2:11][O:21]4)[CH2:19]3)=[O:32])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=C(Cl)c1ccc2ncsc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC2(CC1C(=O)c1ccc3ncsc3c1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35.6 %

Procedure:
Under a nitrogen atmosphere, lithium hexamethyldisilazide (2.4 mL, 2.4 mmol) was mixed with THF (5 mL). The reaction was cooled to −78° C. 1,4-cyclohexane-dione monoethylene acetal (374 mg, 2.4 mmol), dissolved in THF (2 mL) was slowly added via dropping funnel. The reaction was stirred for 20 min at −78° C. It was then cannulated to a flask, cooled at −78° C., containing benzothiazole-6-carbonyl chloride (498 mg, 2.52 mmol) dissolved in THF (5 mL). After the addition, the reaction was stirred at −78° C. for 1 hr, and then allowed to warm to room temperature. After 12 h, water (30 mL) was added and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 10% citric acid (20 mL), water (20 mL), bicarb (20 mL), and brine (20 mL). It was then dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column (1:1 EtOAc/Hexanes) to yield 7-(Benzothiazole-6-carbonyl)-1,4-dioxa-spiro[4.5]decan-8-one (271 mg, 35%, light yellow solid).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:22])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:19][CH:20]=[CH2:21])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:23][C:24]1[N:25]=[CH:26][N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:28]=1[C:29](O)=[O:30].CCN(C(C)C)C(C)C.C(Cl)CCl>C1COCC1>[Cl:23][C:24]1[N:25]=[CH:26][N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:28]=1[C:29]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH2:19][CH:20]=[CH2:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:22])=[O:30]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(2-propen-1-yl)benzonitrile (0.113 g, 0.358 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.099 g, 0.358 mmol), and DIEA (0.125 mL, 0.715 mmol) were combined in THF (4 mL) and stirred at 25° C. overnight. Additional 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.049 g, 0.179 mmol), EDC (0.069 g, 0.358 mmol) and THF (4.00 mL) were added to the reaction mixture and stirred at 50° C. overnight. The reaction mixture was concentrated to dryness and partitioned between DCM and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 20 to 70% EtOAc/hexanes to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(2-propen-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.088 g, 0.153 mmol, 42.7% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (t, J=5.81 Hz, 1H), 8.00 (s, 1H), 7.36-7.52 (m, 3H), 7.20 (s, 1H), 7.17 (s, 1H), 5.86-6.01 (m, 1H), 5.51 (s, 2H), 5.10 (d, J=5.49 Hz, 1H), 5.07 (s, 1H), 4.50 (d, J=5.77 Hz, 2H), 3.40 (m, 4H), 0.77 (t, J=8.10 Hz, 2H), −0.07 (s, 9 H). LC-MS (ES−) m/z 573.22, 575.17 [M−1]. LC-MS (ES+) m/z 575.15, 577.16 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([OH:14])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([O:14][C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CNC(=O)N(O)c1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNC(=O)N(OC(=O)Oc1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-hydroxy-3-methylurea (6 grams; 0.025 mol) in diethyl ether (200 ml), and triethylamine (4 ml) were charged into a glass reaction flask equipped with a mechanical stirrer. Phenyl chloroformate (4.2 grams; 0.027 mol) was added thereto. The reaction mixture was stirred, at room temperature, for a period of about one-half hour resulting in the formation of a precipitate. The precipitate was recovered by filtration, was washed with water, dried, and was recrystallized from a methylene chloride-pentane mixture to yield 1-(3,4-dichlorophenyl)-1-phenoxycarbonyloxy-3-methylurea melting at 93°C with decomposition and having the following elemental analysis as calculated for C15H12Cl2N2O4 :
Reaction SMILES: [CH2:1]1[S:9](=[O:11])(=[O:10])[O:8][CH2:7][CH2:6][O:5][S:2]1(=[O:4])=[O:3].[H-].[Na+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:24])(=O)=O)=CC=1.C(Cl)Cl>C1COCC1.CC#N.C1CCCCC1>[F:24][CH:1]1[S:2](=[O:3])(=[O:4])[O:5][CH2:6][CH2:7][O:8][S:9]1(=[O:11])=[O:10]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=S1(=O)CS(=O)(=O)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CC#N
Product: O=S1(=O)OCCOS(=O)(=O)C1F
Yield: 15.3 %

Procedure:
To a solution of 2.4 g of ethylene methanedisulfonate in 20 mL of THF and 0.35 g of NaH was added 3.8 g of N-fluorobenzene sulfonimide in 25 mL of CH3CN. The product was isolated by crystallization from CH2Cl2 and cyclohexane to give 0.4 g of ethylene fluoromethane disulfonate which was brominated in H2O to give ethylene fluorobromomethanedisulfonate, m.p. 82-90° C. (93-3).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3]1.C(N(CC)CC)C.[CH2:31]([O:38][CH2:39][C:40](Cl)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:31]([O:38][CH2:39][C:40]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3][C:2]3=[O:1])=[CH:8][CH:9]=2)[CH2:18][CH2:17]1)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)cc2)C(=O)O1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)COCc4ccccc4)CC3)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 17, 300 mg) and triethylamine (0.20 mL) in dry methylene chloride (19 mL) at 0° C. under N2 is treated with benzyloxyacetyl chloride (0.18 mL), and the resulting solution is stirred at 0° C. for one hour and at ambient temperature for one hour. The reaction mixture is then washed with water (2×10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 45 g), eluting with a gradient of methanol/methylene chloride (1/99-2/98). Pooling and concentration of those fractions with an Rf =0.28 by TLC (methanol/chloroform, 5/95) gives the title compound, NMR (CDCl3, 400 MHz) 7.45, 7.35, 7.18, 6.26, 4.75, 4.63, 4.22, 4.04, 3.78, 3.70, 3.60, 3.09, 2.70, 2.02, 1.85, 1.60 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1.[CH3:25][S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27].CS(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:20][CH2:21][N:22]([CH2:30][CH2:29][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:23][CH2:24]2)[CH2:15][CH2:14]1
Reactant: C=CS(C)(=O)=O
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)c(Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
1-{1-[2-Chloro-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (Example 112, step D) (0.050 g, 1.41 mmol) was taken up in THF (10 mL) and methylvinylsulfone (0.371 mL, 4.23 mmol) was added. DMSO was added to solubilize the starting material. Reaction was stirred overnight at rt. Reaction was not complete and over the next 3 days, 30 equivalents more methylvinylsulfone were added. Reaction was then stirred over the weekend. Poured reaction mixture onto prepackaged silica gel cartridge, dried by vacuum suction of air through cartridge and then flash chromatographed to give the title compound of step A (0.370 g, 57%). MS (M+H, ES+) 461.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:25][CH2:24][C:23]4[C:22]5[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=5[CH2:20][CH2:19][C:18]=4[CH2:17]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[OH:2][CH2:1][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:25][CH2:24][C:23]4[C:22]5[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=5[CH2:20][CH2:19][C:18]=4[CH2:17]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc2c(CCCCN3CCC4=C(CCc5ccccc54)C3)c[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(CCCCN3CCC4=C(CCc5ccccc54)C3)c[nH]c2c1
Reaction time: 1 h

Procedure:
A solution of 3.84 g of 3-[4-(6-formyl-3-indolyl)butyl]-1,2,3,4,5,6-hexahydrobenzo[f]isoquinoline in 40 ml of THF is added dropwise to a stirred suspension of 0.57 g of lithium aluminium hydride in 20 ml of THF under N2. The mixture is then stirred at 20° for 1 hour, and decomposition is carried out with dilute sodium hydroxide solution and then with water, and the mixture is filtered and the usual working up is carried out, and 3-[4-(6-hydroxymethyl-3-indolyl)butyl]-1,2,3,4,5,6-hexahydrobenzo[f]isoquinoline is obtained.
Reaction SMILES: O1C2C=CC(C(Cl)=O)=CC=2OC1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1)[NH2:17].[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:44][C:39]=2[O:38][CH2:37]1>C1(C)C=CC=CC=1.C(O)C>[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:44][C:39]=2[O:38][CH2:37]1.[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C:45]([NH:47][C:48]([NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:21][C:22]4[C:31]5[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=5)[N:25]=[CH:24][CH:23]=4)=[C:14]([Cl:13])[CH:15]=3)=[S:49])=[O:46])=[CH:44][C:39]=2[O:38][CH2:37]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Agent: O=C(N=C=S)c1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc5c(c4)OCO5)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
1,3-Benzodioxole-5-carbonyl isothiocyanate was prepared using commercially available 1,3-benzodioxole-5-carbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 1,3-benzodioxole-5-carbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (47 mg, yield 58%).
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2C(=CC=CC=2)C=[CH:3][N:2]=1.C(N(CC)C(C)C)(C)C.[CH:23]1[CH:24]=[CH:25][C:26]2N(O)N=N[C:27]=2[CH:28]=1.C(Cl)CCl.N1C2C=CC=CC=2N=C1CN(C1C2N=CC=CC=2CCC1)CCCN>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O.O>[CH:3]1[C:26]2[C:27](=[CH:28][CH:23]=[CH:24][CH:25]=2)[CH:10]=[C:1]([C:11]([OH:13])=[O:12])[N:2]=1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: On1nnc2ccccc21
Agent: NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc2ccccc2cn1
Yield: 152.5 %

Procedure:
To a stirred solution of 1-isoquinolinecarboxylic acid (51.6 mg, 0.30 mmol) in anhydrous DMF (3 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.6 mmol), HOBT (48.3 mg, 0.36 mmol), EDC (68.6 mg, 0.36 mmol) and N1-(1H-Benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (100 mg, 0.30 mmol). The resultant solution was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (40 mL), brine (15 mL) and H2O (5 mL) and the two layers mixed vigorously for 15 minutes. The layers were separated and the organic layer washed with brine (5×15 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude material by radial chromatography on a 1 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 50:1:1) gave the free base of the title compound (79.2 mg, 54%) as a white foam.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:20]=[N+:21]=[N-:22].[CH3:23][C:24]1[CH:29]=[C:28]([OH:30])[C:27]2[O:31][C:32]3[C:37]([C:38]([O:40][CH2:41][C:26]=2[CH:25]=1)=[O:39])=[C:36]([O:42][CH3:43])[C:35]([C@@H:44](O)[CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:34][CH:33]=3.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1.C(Cl)Cl>[N:20]([CH:44]([C:35]1[CH:34]=[CH:33][C:32]2[O:31][C:27]3[C:28]([OH:30])=[CH:29][C:24]([CH3:23])=[CH:25][C:26]=3[CH2:41][O:40][C:38](=[O:39])[C:37]=2[C:36]=1[O:42][CH3:43])[CH2:45][CH:46]([CH3:48])[CH3:47])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=N
Reactant: COc1c([C@@H](O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1c(C(CC(C)C)N=[N+]=[N-])ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4.6 g (17.6 mmol) of triphenylphosphine and 29.3 ml of a freshly prepared 0.6 N solution of hydrazoic acid in toluene are added to 6 g (16.1 mmol) of penicillide (1b) in 100 ml of tetrahydrofuran. 2.7 ml (17.6 mmol) of diethyl azodicarboxylate are added dropwise to this mixture at 0° C. under argon. The mixture is then stirred at 25° C. for 12 h. After diluting with methylene chloride, the mixture is washed with aqueous bicarbonate, dried and evaporated. Chromatography on silica gel Si60 in diethyl ether/petroleum ether =2:1 yields 5.6 g (88% of theory) of colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:25])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[CH3:28]I.O>CN(C=O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([F:24])([F:22])[F:23])[CH:19]=[CH:20][C:15]=3[N:14]([CH3:28])[C:13]2=[O:25])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](Cn2c(=O)[nH]c3ccc(C(F)(F)F)cc32)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](Cn2c(=O)n(C)c3ccc(C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
trans-4-(2-Oxo-6-trifluoromethyl-2,3-dihydro-benzoimidazol-1-ylmethyl)-cyclohexanecarboxylic acid methyl ester (0.87 mg, 2.44 mmol) was dissolved in anhydrous DMF. NaH (1.95 g, 4.9 mmol, 60% in mineral oil) and MeI (0.30 ml, 4.9 mmol) were added and the mixture was stirred at room temperature for two days. H2O was added and the solvents were evaporated. The crude was dissolved in DCM (15 ml) and washed with H2O (10 ml). The organic layer was dried over Na2SO4, filtered and the solvent removed to give 0.93 g (yield quantitative) of the titled compound.
Reaction SMILES: [C:1]12([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([OH:30])[CH2:19][O:20][C:21]4[CH:29]=[CH:28][C:24]([CH2:25][C:26]#[N:27])=[CH:23][CH:22]=4)[CH2:13][CH2:12]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:31]([C:33]1[C:34]([NH2:41])=[N:35][C:36]([NH2:40])=[N:37][C:38]=1[NH2:39])=O.C(OCC[O-])C.[Na+].O>C(OCCO)C>[C:1]12([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([OH:30])[CH2:19][O:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]5[N:31]=[C:33]6[C:34](=[N:41][C:26]=5[NH2:27])[N:35]=[C:36]([NH2:40])[N:37]=[C:38]6[NH2:39])=[CH:28][CH:29]=4)[CH2:13][CH2:12]3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: N#CCc1ccc(OCC(O)CN2CCN(C34CC5CC(CC(C5)C3)C4)CC2)cc1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Agent: CCOCC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCCO
Product: Nc1nc(N)c2nc(-c3ccc(OCC(O)CN4CCN(C56CC7CC(CC(C7)C5)C6)CC4)cc3)c(N)nc2n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
A mixture of 4-[3-[4-(1-adamantyl)-1-piperazinyl]-2-hydroxypropoxy]benzylcyanide (3.44 g, 8.4 mmol), 5-nitroso-2,4,6-triamino-pyrimidine (1.08 g, 7.0 mmol) and 0.2N sodium-(2-ethoxyethoxide) in 2-ethoxyethanol (35 ml) was stirred at 120° C. for 30 minutes. After cooling to about 90° C. 100 ml of water was added and the mixture was cooled to room temperature followed by stirring in an ice-water bath for 30 minutes. The precipitate was collected, washed with water and acetonitrile to give the title compound (3.23 g) as a yellow powder, mp. 287°-289° C. (dec.), yield: 84.6%.