Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][C:23]([O:26][CH3:27])=[CH:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:35])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:35])[NH:12][C:11]([C:21]2[S:22][C:23]([O:26][CH3:27])=[CH:24][N:25]=2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2ncc(OC)s2)=NC1c1ccc(F)cc1Br
Solvent: ClCCl
Product: CCOC(=O)C1=C(CBr)NC(c2ncc(OC)s2)=NC1c1ccc(F)cc1Br
Yield: 34.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(5-methoxythiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (2 g, 4.4 mmol) was reacted with NBS (0.78 g, 4.4 mmol) in DCM (50 mL) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.80 g, 34%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1](Br)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[OH:10][C:11]1[CH:22]=[CH:21][C:14](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:12]=1[O:23][CH2:24][CH2:25][CH3:26]>CC(=O)CC>[CH2:1]([O:10][C:11]1[CH:22]=[CH:21][C:14](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:12]=1[O:23][CH2:24][CH2:25][CH3:26])[CH3:2]
Reactant: CCCOc1cc(/C=C/C(=O)OC)ccc1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1cc(/C=C/C(=O)OC)ccc1OCC
Temperature: 25 °C

Procedure:
0.49 ml (6.60 mmol) of ethyl bromide and 1.37 g (9.9 mmol) of potassium carbonate are added to a mixture of 780 mg (3.30 mmol) of methyl (E)-4-hydroxy-3-propoxycinnamate and 10 ml of 2-butanone and then refluxed for 2 hours. Thereafter, the reaction mixture is cooled to room temperature and is partitioned between ethyl acetate and water, and the organic phase is washed several times with water, dried over magnesium sulfate, filtered and evaporated down. Chromatography of the residue over silica gel using 9:1 cyclohexane/ethyl acetate gives methyl 3(E)-[4-ethoxy-3-propoxyphenyl]acrylate.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22]>CCOCC>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:21](=[O:22])[C:20]1[CH:19]=[C:18]([O:17][CH3:16])[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=1)#[N:5]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: N#Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COc1cc(C(=O)Nc2ccccc2C#N)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-L 3-necked round-bottom flask, was placed 2-aminobenzonitrile (20 g, 169.30 mmol, 1.00 equiv), ether (500 mL) and potassium carbonate (75 g, 542.65 mmol, 3.21 equiv). This was followed by the addition of 3,4,5-trimethoxybenzoyl chloride (40 g, 173.43 mmol, 1.02 equiv) in several batches at reflux. The mixture was stirred overnight at reflux. The resulting solution was cooled to room temperature. The reaction was then quenched by the addition of 500 mL of water. The solids were collected by filtration. This resulted in 22 g (42%) of N-(2-cyanophenyl)-3,4,5-trimethoxybenzamide as a yellow solid. MS (ESI) m/z 313 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[NH:3]1.[N+:14]([O-])([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([CH3:12])[CH:8]=2)[NH:3]1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c(c1)CCC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc2c(cc1[N+](=O)[O-])NC(C)(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,2,6-trimethyl-1,2,3,4-tetrahydroquinoline (0.66 g, 3.8 mmol) in 10 mL of concentrated sulfuric acid was cooled to 0° C. in an ice bath. To this solution was added dropwise 1.0 mL 90% fuming nitric acid. The resulting mixture was stirred at 0° C. for 30 min, poured onto 150 mL of ice-water, neutralized to pH=7 with K2CO3 and extracted with CH2Cl2 (3×200 mL). The combined organic layers were washed with water (2×300 mL), saturated aqueous NaHCO3 (300 mL) and brine (300 mL) The solution was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Silica gel, 15 to 20% ethyl acetate/hexane gradient elution) to give 2,2,6-trimethyl-7-nitro-1,2,3,4-tetrahydroquinoline. 1H NMR (500 MHz, CDCl3): 8.03 (s, 1H), 7.05 (s, 1H), 2.85 (td, J=6.6, 1.1 Hz, 2H), 2.17 (s, 3H), 1.76 (t, J=6.6 Hz, 2H), 1.35 (s, 6H).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][C:29](=O)[CH2:28][CH2:27]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([F:23])[CH:25]=3)[CH2:30]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: O=C1CCc2cc(F)ccc2C1
Product: CCCC(NC1CCc2cc(F)ccc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6-Fluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 19.6, 24.3, 26.6, 28.1, 28.3, 29.2, 30.1, 35.9, 36.5, 36.6, 36.7, 53.2, 53.4, 56.0, 59.1, 60.4, 60.7, 67.3, 104.7, 104.8, 112.9, 113.1, 114.8, 114.9, 115.0, 115.1, 130.2, 130.7, 130.8, 130.8, 131.1, 137.3, 137.8, 138.1, 160.1, 162.5, 172.5; MS m/z 456.4 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:8]=2[CH:17]=1.Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].Cl>CN(C=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][C:9]([C:13]([O:15][CH3:16])=[O:14])([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:8]=2[CH:17]=1
Reactant: COC(=O)C1CCOc2ccc(F)cc21
Reactant: COC(=O)CCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCC1(C(=O)OC)CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 8.81 g (0.183 mol) 50% NaH in 300 ml of DMF was added, dropwise, a solution of 27.5 g (0.131 mol) of methyl 6-fluoro-2,3-dihydro-4H-benzopyran-4-carboxylate in 100 ml of DMF. After stirring at room temperature for 1 hour, a solution of 33 g (0.183 mol) of methyl 4-bromobutyrate in 25 ml of DMF was added. The resultant homogeneous solution was stirred at room temperature for 16 hours and then poured onto ice/H2O and acidified to pH 3.0 with concentrated HCl. The aqueous was extracted twice with CH2Cl2 and the combined extracts were dried (NaSO4) and filtered. The filtrate was evaporated in vacuo to an oil (44 g) which was purified by column chromatography on 2 Kg of silica gel, eluting with CH2Cl2 /Et2O.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:19][CH2:18][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)([OH:20])[CH2:16][CH2:15]3)=[O:13])[CH2:7][C:6]=2[CH:31]=1.[N+:32]([C:35]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:38][C:36]=1[NH2:37])([O-:34])=[O:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[NH2:37][C:36]1[CH:38]=[CH:39][C:40]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]([C:12]([N:14]4[CH2:19][CH2:18][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=5)([OH:20])[CH2:16][CH2:15]4)=[O:13])[CH2:7][C:6]=3[CH:31]=2)=[CH:41][C:35]=1[N+:32]([O-:34])=[O:33]
Reactant: O=C(N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)N1CCOc2ccc(Br)cc2C1
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2ccc3c(c2)CN(C(=O)N2CCC(O)(c4cccc(C(F)(F)F)c4)CC2)CCO3)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 26 %

Procedure:
To a solution of 1-[(7-bromo-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl)carbonyl]-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol (0.688 g, 1.38 mmol) and 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.365 g, 1.38 mmol) in dioxane (24 mL) and water (3.00 ml) was added tribasic potassium phosphate (0.413 g, 1.79 mmol). The solution was sparged with N2(g) for ten minutes before the addition of dichloro[1,1-bis-(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.023 g, 10 mol %). The resulting suspension was heated at 90° C. for 2 hours in a sealed tube vessel. On cooling to room temperature the mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL) and then dried over anhydrous sodium sulfate. Filtration and concentration afforded a crude orange oil that was purified by silica gel chromatography (7:3 hexanes/ethyl acetate) to provide 1-{[7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol (0.200 g, 26% yield) as an orange oil. MS (EI) for C28H27F3N4O5: 557 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2.O.[OH-].[Na+].Cl>CO>[N:11]1[C:12]2[C:7](=[CH:6][C:5]([CH2:4][C:3]([OH:15])=[O:2])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc2ncccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc2ncccc2c1
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
Sulphuric acid (67.5 ml) was added to 4-Aminophenylacetic acid (45 g, 297 mmol), glycerol (61.7 g, 67 mmol), and iodine (1.14 g, 4 mmol) drop-wise at rt. The mixture was heated to 140° C. for 24 h. After that reaction mixture cooled to rt and pH adjusted to 5 using 10% sodium hydroxide solution. To this methanol (350 ml) and sulphuric acid (3 ml) was added and heated to 100° C. for 24 h. Reaction mixture filtered through celite and filtrate was evaporated on rotavapour to obtain the residue. pH of the residue was adjusted to 5 using 4% NaOH solution and extracted with EtOAc. EtOAc layer was dried on anhydrous Na2SO4 and EtOAc removed on rotavapour to obtain the crude. Crude was purified by column using EtOAc and Petether as eluent to obtain methyl-2-(quinolin-6-yl)acetate (11.2 g). Methyl-2-(quinolin-6-yl)acetate (11.2 g) was dissolved in Methanol (8 ml) and water (8 ml) and added sodium hydroxide (3.3 g, 82 mmol). This mixture stirred for 30 mins and methanol removed on rotavapour to obtain the residue. Residue was acidified to pH 5 using 0.8 N HCl to obtain the solid. Solid was filtered and dried to obtain the title compound (8.2 g).
Reaction SMILES: Cl.C([N:9]1[CH2:29][CH2:28][C@H:12]2[N:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][C:19]=3[C@@H:11]2[CH2:10]1)C1C=CC=CC=1.ClC(OCC)=O>>[F:20][C:17]1[CH:16]=[CH:15][C:14]2[N:13]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C@@H:12]3[CH2:28][CH2:29][NH:9][CH2:10][C@H:11]3[C:19]=2[CH:18]=1
Reactant: Fc1ccc(N2c3ccc(F)cc3[C@@H]3CN(Cc4ccccc4)CC[C@H]32)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Product: Fc1ccc(N2c3ccc(F)cc3[C@@H]3CNCC[C@H]32)cc1

Procedure:
Alternately, dl-trans-2-benzyl-8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole hydrochloride is refluxed in the presence of excess ethyl chloroformate or the corresponding methyl, isopropyl or n-butyl chloroformate esters, then hydrolyzed and worked up by the procedure described above to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[S:22])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: c1ccncc1
Product: O=C1CC(=S)Nc2ccc(Cl)cc2N1c1ccccc1
Reaction time: 0.67 h

Procedure:
A solution of 28.6 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione and 23.3 g of phosphorus pentasulfide in 250 ml of pyridine is refluxed, with stirring, for 40 minutes under argon. The solvent is evaporated in vacuo.
Reaction SMILES: [C:1]1([N:7]=[C:8]=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:10]>>[C:1]1([NH:7][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C=Nc1ccccc1
Reactant: O
Product: O=C(Nc1ccccc1)Nc1ccccc1

Procedure:
Isothiocyanates may be converted to ureas and thus phenyl isothiocyanate, on oxidation with a telluroxide in the presence of water (e.g. of formula (I) as hereinbefore defined), gives 1,3-diphenylurea.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:26][CH3:27])=[C:10](/[C:13](/[CH3:25])=[CH:14]\[CH:15]=[CH:16]\[C:17](\[CH3:24])=[CH:18]\[C:19]([O:21]CC)=[O:20])[CH:11]=2)[O:6][C:5]([CH3:29])([CH3:28])[CH:4]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:26][CH3:27])=[C:10](/[C:13](/[CH3:25])=[CH:14]\[CH:15]=[CH:16]\[C:17](\[CH3:24])=[CH:18]\[C:19]([OH:21])=[O:20])[CH:11]=2)[O:6][C:5]([CH3:28])([CH3:29])[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC1=CC(C)(C)Oc2cc(OC)c(/C(C)=C\C=C\C(C)=C\C(=O)O)cc21
Temperature: 60 °C

Procedure:
To a solution of ethyl 7-(4-ethyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)3-methyl-octa-2E,4E,6Z-trienoate (Compound 32, 50 mg, 0.13 mmol) in ethanol (5 mL) and THF (2 mL) was added 1M NaOH (1.0 mL, 1.0 mmol). The mixture was heated to 60° C. for 5 h and was cooled to room temperature, acidified with 1M HCl, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 30% ethyl acetate in hexanes) followed by recrystallization from acetonitrile to give the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3].[OH:10]O.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10])[CH2:2][CH3:3]
Reactant: CCCc1ccccn1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCc1cccc[n+]1[O-]
Temperature: 65 °C
Reaction time: 3 h

Procedure:
20 ml of 2-n-propylpyridine were dissolved in 60 ml of glacial acetic acid, mixed with 40 ml of H2O2 (30%) and stirred for 16 hours at room temperature and 3 hours at 65° C. The acetic acid was then partly rotated out, the residue was adjusted to pH 8 with NaOH (20%), extracted with dichloromethane and the organic phase rotated in to dryness. 20 g of crude 2-propylpyridine-N-oxide were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[C:29]4[CH2:30][CH2:31][CH2:32][CH2:33][C:28]=4[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]3[C:29]4[CH2:30][CH2:31][CH2:32][CH2:33][C:28]=4[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c4c(sc3n2)CCCC4)cc1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: COC(=O)c1ccc(-c2nc(NCc3cccc([N+](=O)[O-])c3)c3c4c(sc3n2)CCCC4)cc1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-5,6,7,8,-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:27])[CH:17]=3)[CH2:13][CH:12]([C:28]([OH:30])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:32]=[C:33]([CH:35]1[CH2:37][CH2:36]1)[NH2:34]>>[CH:35]1([C:33]2[N:34]=[C:28]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[C:18]([CH3:27])[CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:30][N:32]=2)[CH2:37][CH2:36]1
Reactant: NC(=NO)C1CC1
Reactant: Cc1cc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)ccc1OC(F)(F)F
Product: Cc1cc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCC(O)CC3)C2)ccc1OC(F)(F)F

Procedure:
100 mg (0.22 mmol) of the compound from Example 170A and 33 mg (0.331 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 41 mg (37% of theory)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#N.[OH2:27]>C(O)=O.[Pt](=O)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:27]
Reactant: CN1CCC(OC(c2cccc(C#N)c2)c2nc3ccccc3[nH]2)CC1
Reactant: O
Agent: O=[Pt]=O
Solvent: O=CO
Product: CN1CCC(OC(c2cccc(C=O)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-benzonitrile (example 172, 740 mg) in 80% aqueous formic acid (3 mL) is added platinum(IV) oxide (48 mg). The reaction mixture is heated at 60° C. for 7 h, then at room temperature for 2 days. As the reaction is not complete, 80% aqueous formic acid (3 mL) and platinum (IV) oxide (48 mg) are added and the reaction mixture is heated at 60° C. overnight. Water is added and the reaction mixture is filtered on celite. The phase is basified by adding a solution of 1N sodium hydroxide and extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated to give 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde. 1H NMR: 9.99 (s, 1H), 9.67 (sl, 1H), 8.01 (s, 1H), 7.85-7.65 (m, 2H), 7.60-7.40 (m, 2H), 7.32-7.15 (m, 3H), 5.95 (s, 1H), 3.65-3.50 (m, 1H), 2.82-2.65 (m, 2H), 2.26 (s, 3H), 2.20-1.65 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])[C:7]3[N:8]([CH3:21])[C:9]([C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:11]=3[CH2:12][S:13][C:4]=2[CH:3]=1.N1C=CN=C1.S>N1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])[C:7]3[N:8]([CH3:21])[C:9]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:11]=3[CH2:12][S:13][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(=O)c1cc2c(n1C)C(=O)c1ccc(Cl)cc1SC2
Agent: S
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cc2c(n1C)C(=O)c1ccc(Cl)cc1SC2
Yield: 90.7 %

Procedure:
Ethyl 7-chloro-4,10-dihydro-10,α-dioxo-1-methyl-1H-[1]benzothiepino[4,3-b]pyrrole-2-acetate (87 mg, 0.23 mmol) is dissolved in pyridine (2 ml) and placed in a resealable pressure tube along with imidazole (100 mg) and a small stirring bar. The tube and its contents are cooled to -78° and hydrogen sulfide (0.5 ml) is conducted inside it. The tube is then sealed and allowed to come to room temperature with stirring. The mixture is stirred for three hours, then cooled again to -78° and the tube is opened. The tube is allowed to warm and the hydrogen sulfide evaporates. When bubbling ceases, the tube contents are poured into 1.2 N aqueous HCl (30 ml), and the resulting heterogeneous mixture is extracted with ether (2×50 ml). The combined ether layers are washed with 10% aqueous sodium carbonate (3×15 ml), saturated aqueous brine (15 ml), and dried with sodium sulfate. The solvent is removed to give a white solid smelling like garlic. This material is purified by preparative TLC (1/1 EtoAc/Hex, silica gel 0.70) to give 73 mg of ethyl 7-chloro-4,10-dihydro-1-methyl-10-oxo-1H-[1]benzothiepino[4,3-b]pyrrole-2-acetate (88%).
Reaction SMILES: C([O:4][C:5]1[C:6]([O:26][CH3:27])=[CH:7][C:8]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[C:9]([CH:16]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[OH:4][C:5]1[C:6]([O:26][CH3:27])=[CH:7][C:8]([CH2:17][O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21])=[C:9]([CH:16]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCc1cc(OC(C)=O)c(OC)cc1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)CCc1cc(O)c(OC)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 18 h

Procedure:
A mixture of methyl 5-acetoxy-2-tert-butyldimethylsilyloxymethyl-4-methoxyhydrocinnamate (4.64 g) and potassium carbonate (0.16 g) in anhydrous methanol (50 ml) is stirred at 0°-5° C. for about 18 hours, diluted with water, and the pH adjusted to 5 with dilute HCl. The mixture is extracted with ether and the ether solution is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by HPLC, eluting with 20% ethyl acetate in hexanes to give the desired product.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:26]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:34](=[O:42])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[CH3:43])[N:27]=1)[NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][NH:21]2)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:26]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:34](=[O:42])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[CH3:43])[N:27]=1)[NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][NH:21]2
Reactant: [H][H]
Reactant: Cc1cccc2nc(C(CCCCNC(=O)OCc3ccccc3)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc2nc(C(CCCCN)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12

Procedure:
A mixture of compound 49 (28.5 mg) and palladium on carbon (10 mg, 10% Pd) in ethanol (2 mL) was shaken with hydrogen (40 psi) for 48 h. The mixture was filtered through CELITE® and the filtrate was concentrated to afford the product 54. ESI-MS m/z 455 (MH+). Compound 54 is shown below.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[O:27][CH3:28])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:29][C:30]1[CH:31]=[C:32]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:15]([N:39]1[CH2:40][CH2:41][N:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[CH:31]=3)[CH2:37][CH2:38]1)[N:16]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:27][CH3:28])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: COC(=O)/C=C/c1cccc(F)c1N=C=Nc1cc(C(F)(F)F)ccc1OC
Solvent: ClCCl
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(C)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
11.5 g (29.16 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A), 5.14 g (29.16 mmol) of 1-(3-methylphenyl)piperazine and a spatula tip of silica gel are stirred in 300 ml of dichloromethane at room temperature for 1 hour and then under reflux for 20 hours. The product is obtained after chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1, 5:1).