Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[C:56]([O:61][Si](C(C)(C)C)(C)C)[CH:57]=4)[CH:52]=3)[CH:46]([OH:69])[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[C:56]([OH:61])[CH:57]=4)[CH:52]=3)[CH:46]([OH:69])[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O[Si](C)(C)C(C)(C)C)ccc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O)ccc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 48 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (39.8 mg) in CH2Cl2 (1.5 mL.) at 0° C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL. of a 10% w/v solution). The mixture was stirred 1.25 h at 0° C. and then 1.75 h at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted 2× with 2:1 hexanes/acetone) affording 17 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6' "-hydroxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral analysis were consistent with the desired structure).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: Cc1ccc(F)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C(=O)Cl

Procedure:
A suspension of 5-fluoro-2-methyl benzoic acid (2.31 g, 15.0 mmol) in dichloromethane (30 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (1.6 mL, 18.3 mmol). After gas evolution subsided, the reaction mixture was refluxed for an additional 10 minutes, and then evaporated to dryness. The crude acid chloride was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][C:13](=[O:17])[CH:14](Br)[CH3:15])([CH3:11])([CH3:10])[CH3:9].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:8]([O:12][C:13](=[O:17])[C@H:14]([CH3:15])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CC(Br)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ccccc1)C(=O)OC(C)(C)C
Yield: 81.3 %

Procedure:
A mixture of aniline (9.30 g, 0.10 mol), 2-bromopropionate t-butyl ester 20.9 g, 0.10 mol), Hunig's base (12.90 g, 0.10 mol) and toluene (200 mL) were stirred at reflux for 16 hours. The salt that formed was removed by filtration and the filtrate concentrated in vacuo to an oil (20 g). The oil was distilled. Pure N-phenylalanine t-butyl ester (18.0 g, 81% yield) was collected at 105-115 C (0.08 mm Hg).
Reaction SMILES: O.[F:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[CH:12][C:13](=[O:32])[N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)[N:15]=2)[CH:6]=[C:7]([F:9])[CH:8]=1.Br[C:34]1[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.C(=O)([O-])O.[Na+]>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.C(#N)C>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[CH2:16][N:14]2[C:13](=[O:32])[CH:12]=[CH:11][C:10]([C:5]3[CH:4]=[C:3]([F:2])[CH:8]=[C:7]([F:9])[CH:6]=3)=[N:15]2)=[N:35][CH:36]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CC1(C)OB(c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1cnc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)cn1
Temperature: 80 °C

Procedure:
5 ml of water and 5 ml of acetonitrile are added to 150 mg (0.35 mmol) of 6-(3,5-difluorophenyl)-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl]-2H-pyridazin-3-one, 63 mg (0.35 mmol) of 5-bromopyrazin-2-ylamine and 167 mg (1.99 mmol) of sodium hydrogencarbonate, and the mixture is degassed a number of times. Under an argon atmosphere, 20 mg (0.017 mmol) of tetrakis(triphenylphosphine)palladium(0) are added, and the mixture is subsequently heated at 80° C. for 15 h with stirring. A further 20 mg (0.017 mmol) of tetrakis(triphenylphosphine)palladium(0) are subsequently added, and the mixture is stirred at 80° C. for a further 24 h. The hot suspension is filtered. The filtrate is concentrated to half. After cooling to room temperature, the resultant precipitate is filtered off with suction and washed with a little water. The residue is purified by means of preparative HPLC; yield: 21 mg of “A280”; HPLC: Rt=2.68 min (method C); LC-MS: 392 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[S:20][C:18]=2[N:19]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1OC

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dimethoxybenzylamine with 2,4dichloro-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[NH2:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:27]
Reactant: NCc1cccnc1
Reactant: COc1cccc(CC2NCCc3cc(OC)c(OC)cc32)c1
Reactant: O=C(Br)CBr
Product: COc1cccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2cccnc2)c1

Procedure:
prepared by reaction of 1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with 3-aminomethyl-pyridine
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.[CH3:32][O:33][CH2:34][CH2:35][N:36]1[C:40]([CH3:41])=[C:39]([C:42]([OH:44])=O)[N:38]=[N:37]1.[CH3:45][NH:46][C:47]1[CH:52]=[CH:51][N:50]=[N:49][CH:48]=1>CN(C=O)C>[CH3:32][O:33][CH2:34][CH2:35][N:36]1[C:40]([CH3:41])=[C:39]([C:42]([N:46]([CH3:45])[C:47]2[CH:52]=[CH:51][N:50]=[N:49][CH:48]=2)=[O:44])[N:38]=[N:37]1
Reactant: CNc1ccnnc1
Reactant: COCCn1nnc(C(=O)O)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCn1nnc(C(=O)N(C)c2ccnnc2)c1C
Temperature: 25 °C
Reaction time: 96 h
Yield: 67 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphat (HATU; 1.23 g, 3.24 mmol, 3.00 eq) and N-methylmorpholine (0.71 ml, 0.66 g, 6.5 mmol, 6.0 eq) was added to a solution of 1-(2-methoxyethyl)-5-methyltriazole-4-carboxylic acid (200 mg, 1.08 mmol) and N-methylpyridazin-4-amine (118 mg, 1.08 mmol, 1.00 eq) in DMF (2.5 ml) and the mixture was stirred at room temperature for 4 d. After removal of the solvent, the residue was dissolved in dichloromethane, washed twice with sat. aq. NaHCO3 sol. and once with brine and dried over Na2SO4. Removal of the solvent under vacuum and chromatographic purification (CH:EtOAc) gave the title compound as a brown oil (200 mg, 64%, 95% purity).
Reaction SMILES: O.[O:2]1[CH2:7][CH:6]=[C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[N:11]=[C:10]([N:23]3[CH:28]4[CH2:29][CH2:30][CH:24]3[CH2:25][O:26][CH2:27]4)[N:9]=2)[CH2:4][CH2:3]1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[CH:24]12[N:23]([C:10]3[N:9]=[C:8]([C:5]4[CH2:6][CH2:7][O:2][CH2:3][CH:4]=4)[N:13]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=4)[N:11]=3)[CH:28]([CH2:29][CH2:30]1)[CH2:27][O:26][CH2:25]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(C3=CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc(C3=CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A mixture of iron powder (0.071 g, 1.27 mmoles) in acetic acid (2 ml) was heated to 55° C. for 15 minutes. Water (2 ml) was then added and oil bath was turned off. A solution of 8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.100 g, 0.253 mmol) in ethyl acetate (2 ml) was then added to this warm solution over 5 minutes. The mixture was cooled to RT and allowed to stir for 16 hours. The mixture was extracted with ethyl acetate by decantation (4×) into a sep. funnel containing saturated aqueous sodium carbonate. The combined organic extracts were washed with water, brine, dried, and concentrated to provide 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline (0.068 g, 74%), which was used in the next step without purification. (M+H) 366.4.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:3]=1.[H][H]>C1COCC1.CCO.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc([N+](=O)[O-])c3)n2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(N)c3)n2)n1
Yield: 80.5 %

Procedure:
A mixture of the above prepared 6-methyl-6′-(3-nitro-phenyl)-4-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl (3.4 g, 7.81 mmol) in THF-EtOH 1:1 (100 mL) and 10% palladium on carbon (1 mol %) was hydrogenated (1 bar hydrogen) at 23° C. for 2 h. The catalyst was filtered off, washed with EtOH and the filtrate was completely evaporated totally to leave a crude product, which was purified by silica gel column chromatography with heptane/EtOAc, followed by trituration with diethyl ether to give the title compound as a white solid (2.55 g, 80%). MS (ISP) 406.3 [(M+H)+]; mp 167° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:28][CH:29]([F:43])[O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][CH:40]([F:42])[F:41])[CH:34]=O>C1COCC1>[F:41][CH:40]([F:42])[O:39][C:38]1[CH:37]=[CH:36][C:33]([CH:34]=[CH2:1])=[CH:32][C:31]=1[O:30][CH:29]([F:43])[F:28]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(OC(F)F)c(OC(F)F)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(OC(F)F)c(OC(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Potassium tert-butoxide (6.7 g, 0.0683 mol) was taken in dry THF (25 mL) and stirred at 0° C. under a nitrogen atmosphere for 15 min. Methyl triphenylphosphonium iodide (27.6 g, 0.0683 mol; see step (ii) above) was then added, followed by 3,4-bis(difluoromethoxy)benzaldehyde (8 g, 0.034 mol; see step (i) above). The reaction mixture was then stirred for 1 h at RT, before being quenched with water. The organic solvents were evaporated under reduced pressure and the aqueous layer extracted with dichloromethane. Evaporation of the solvents followed, by chromatography of the residue over silica gel (using petroleum ether in ethyl acetate as eluent) afforded the sub-title compound as a pale yellow liquid. Yield: 6.5 g
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH3:18]>CN(C=O)C>[CH2:17]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1)[CH3:18]
Reactant: CCI
Reactant: OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 2-(4-piperidinyl)ethanol (1 g, 7.74 mmol) and potassium carbonate (2.67 g, 19.35 mmol) in dry DMF (10 ml) was added iodoethane (0.687 ml, 8.51 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours. The solvent was partially removed in vacuo and the residue partitioned between water (20 ml) and ethyl acetate (20 ml). The aqueous was washed with further ethyl acetate and the combined organics dried (hydrophobic frit) and concentrated in vacuo to give the title compound as a mixture with residual DMF as a clear oil, 1.55 g
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].C(N(CC)CC)C>C1C=CC=CC=1>[CH:1]1([NH:7][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccccc1C(=O)NC1CCCCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
9.9 PARTS OF CYCLOHEXYLAMINE IS DISSOLVED IN 100 PARTS OF BENZENE AND THE MIXTURE IS REACTED WITH 15.5 PARTS OF 2-METHYLBENZOYL CHLORIDE IN THE PRESENCE OF 12 PARTS OF TRIETHYLAMINE AT 10°C. The whole is stirred for 3 hours at 60°C and then cooled; the precipitated triethylamine chloride is filtered, the filtrate is concentrated under vacuum and the residue is recrystallized from a mixture of methanol and water.
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH2:9]([C:11]1[S:44][C:14]2[N:15]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)[C:16](=[O:28])[C:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([CH3:19])[C:13]=2[CH:12]=1)[CH3:10].[N:45]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH2:9]([C:11]1[S:44][C:14]2[N:15]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:45][C:4](=[O:7])[O:5][N:43]=4)=[CH:34][CH:35]=3)[C:16](=[O:28])[C:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([CH3:19])[C:13]=2[CH:12]=1)[CH3:10]
Reactant: CCc1cc2c(C)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCc1cc2c(C)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A mixture of hydroxylammonium chloride (1.62 g), sodium hydrogencarbonate (2.36 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[2-ethyl-4-methyl-6-oxo-5-(2-phenylethyl)thieno[2,3-b]pyridin-7(6H)-yl]methyl}biphenyl-2-carbonitrile (0.69 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (50 mL), N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.28 g, 67%).
Reaction SMILES: [S:1]([CH:5]([CH2:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])([OH:4])(=[O:3])=[O:2].[Na].C(O)(C)C.[OH-].[Cu+2:35].[OH-]>O>[S:1]([CH:5]([CH2:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])([OH:4])(=[O:3])=[O:2].[Cu:35]
Reactant: [Cu+2]
Agent: CCCCCCCCOC(=O)CC(C(=O)OCCCCCCCC)S(=O)(=O)O
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: [Cu]

Procedure:
Into a fritted column was added: 12 g (12 meq H+) ion exchange resin (Amberlite® IR 120 brand). Resin beads were washed with 100 ml deionized water. Into a 50 ml beaker were added: 7 g (10 meq) sodium dioctyl sulfosuccinate (Triton® GR-5M brand), 7 g water, and 7 g isopropanol. The surfactant solution was run through the column and collected in a 100 ml beaker containing: 0.5 g (10 meq Cu) copper hydroxide and 20 g water. The effluent/copper hydroxide mixture was swirl mixed while collecting the effluent. A 10 g water rinse of the column was added to the copper mixture. Extraction of the beaker's contents was done with 2×25 ml toluene, the toluene solubles were dried with molecular sieve, rotary evaporator stripping removed the toluene, and the resulting solids were vacuum dried overnight at room temperature.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)[OH:6].N[C:11]1[C:20]2[C:19]3[CH:21]=[CH:22][C:23]([Br:25])=[CH:24][C:18]=3[CH2:17][CH2:16][C:15]=2[N:14]=[C:13]([NH2:26])[N:12]=1>>[NH2:26][C:13]1[NH:12][C:11](=[O:6])[C:20]2[C:19]3[CH:21]=[C:22]([N+:1]([O-:4])=[O:2])[C:23]([Br:25])=[CH:24][C:18]=3[CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: Nc1nc(N)c2c(n1)CCc1cc(Br)ccc1-2
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(O)O
Product: Nc1nc2ccc3cc(Br)c([N+](=O)[O-])cc3c2c(=O)[nH]1
Reaction time: 0.75 h

Procedure:
To a mixture of fuming nitric acid (7 ml) and sulphuric acid (6 ml) at 0° C. was added 1,3-diamino-8-bromo-5,6-dihydrobenzo[f]quinazoline (1.0 g, 3.4 mmoles) in a single portion. The reaction mixture was stirred at 0°-5° C. for 45 minutes, and then slowly poured onto ice (15 g). The resulting precipitate was filtered, washed with water (10 ml) and ether (10 ml), and resuspended in boiling 1N HCl (100 ml) for 1 hour. After cooling, the solid was filtered, triturated with hot ethanol, filtered again, washed with ethanol and ether, and dried to give 3-amino-8-bromo-9-nitrobenzo[f]quinazolin-1(2H)-one as a pale yellow solid. (0.59 g, 45%) 1H NMR(DMSO-d6, 80 MHz) δ: 7.62-7.71(d, J=7 Hz, 1H, Ar); 7.77(s, 3H, NH3+); 8.23-8.34(d, J=9 Hz, 1H, Ar); 8.59(s, 1H, Ar); 10.08(s, 1H, Ar). Anal. Calculated for C12H7BrN4O3.1 /2HNO3.H2O C, 37.47; H, 2.49; N, 16.39. Found C, 37.20; H, 2.24; N, 16.00.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=O)#[N:10]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][CH2:20][C:11]=2[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: N#CC1CCc2ccccc2C1=O
Product: N#CC1=C(Nc2ccc(F)cc2)c2ccccc2CC1
Temperature: 150 °C

Procedure:
4-Fluoro-aniline (Aldrich Chemicals) (1.11 g, 10 mmol) and 2-cyano-3 ,4-dihydro-1 (2H) -naphthalenone (synthesised according to the method of Johnson. W. S. and Shelberg W. E. J. Amer. Chem. Soc., (1945), 67 p.1745.) (91.71 g 10 mmol) were heated together at 150° C. for 1 hour. After cooling, chromatography on silica with chloroform as the eluent followed by Kugelrohr distillation (175° C., 0.2 mmHg) gave the product as pale brown crystals.
Reaction SMILES: [Cl:1][Si](C)(C)C.O.[CH3:7][N:8]([CH3:32])[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:17])[CH2:11][CH2:10]1>CC(CC)=O>[ClH:1].[CH3:32][N:8]([CH3:7])[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[O:17])[CH2:13][CH2:14]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)Nc2ccc(F)cc2)CC1
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 18 h

Procedure:
Chlorotrimethylsilane (0.122 ml) and water (9 μl) were added to a solution of the more polar diastereoisomer of 2-(4-dimethylamino-4-phenyl-cyclohexyl)-N-(4-fluoro-phenyl)-acetamide (310 mg, 0.9 mmol) in ethyl methyl ketone (2 ml). After 18 h it was possible to isolate the hydrochloride as a solid in a yield of 64% (220 mg; 0.6 mmol) (Example 58).
Reaction SMILES: CO.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[CH2:14][C@H:13]2[C:15]([O:17][CH3:18])=[O:16])=[CH:8][CH:7]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:3][C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]2[CH2:14][C@H:13]2[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Reaction time: 5 h
Yield: 33 %

Procedure:
To a 1000 mL parr hydrogenater flask with methanol (70 mL) and ethyl acetate (70 mL), was added methyl (1R,2R)-2-(4-nitrophenyl)cyclo propane carboxylate (14 g, 63.3 mmol) and 10% Pd/C (2 g) under N2 atmosphere. The RM was hydrogenated at 40 psi for 5 h. RM was diluted with ethyl acetate (100 mL), filtered through celite bed to remove Pd/C and evaporated to dryness under reduced pressure. The crude was purified by flash column chromatography on silica gel (230/400 mesh), to give the product (4 g, yield: 33.1%). MS (ESI, 120 eV): m/z=192.1 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 6.83-6.86 (d, 2H), 6.58-6.61 (d, 2H), 3.63 (s, 3H), 2.36-2.39 (m, 1H), 1.69-1.75 (m, 1H), 1.42-1.49 (m, 1H), 1.14-1.20 (m, 1H).