Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C(Br)=C[C:5]([O:9]C)=C(Br)N=1.BrC1C(O)=CC=CN=1.[Br:20][C:21]1[C:26](OC)=[CH:25][CH:24]=[C:23]([N+:29]([O-:31])=[O:30])[N:22]=1>C(O)C>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([O:9][CH3:5])=[C:23]([N+:29]([O-:31])=[O:30])[N:22]=1
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Reactant: COc1cc(Br)c(N)nc1Br
Agent: Oc1cccnc1Br
Solvent: CCO
Product: COc1ccc(Br)nc1[N+](=O)[O-]

Procedure:
Starting material -2-amino-6-bromo-5-methoxybromo-pyridine, was prepared in following manner: 2-bromopyridin-3-ol (Aldrich) was converted to 2-bromo-3-methoxy-6-nitropyridine as described in J. Med. Chem. 1981, 24, 39-42. Hydrogenation of 2-bromo-6-nitro-5-methoxypyridine in ethanol (Pt on C, 1 atm) gave the starting material as a reddish oil. This product was then condensed with cis/trans mixture of 2-(2-chloro-3-ethoxy-6-fluorophenyl)cyclopropyliso-cyanates, described in Example 53, in a manner analogous to the method n Example 7 to provide cis/trans (50:50) mixture of N-2-(2-Chloro-3-ethoxy-6-fluorophenyl)-cyclopropyl-N′-(6-bromo-5-hydroxypyrid-2-yl)-ureas. 1H NMR (250 MHz, CDCl3) δ 7.62-7.43 (m, 1H), 7.29-7.12 (m, 1H), 6.91-6.67 (m, 2H), 4.10-3.94 (m, 2H), 3.90 and 3.84 (2 s, 3H),3.38-3.02 (m, 1H) 2.18-2.00 (m, 1H), 1.55-1.30 H (m, 5H), 1.43 (t, 3H), 0.92-0.80 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH2:27]([OH:30])[C:28]#[CH:29]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=[C:16]2[O:30][CH2:27][C:28]#[CH:29])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Reactant: C#CCO
Solvent: c1ccncc1
Product: C#CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-5-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and propargyl alcohol with pyridine there is obtained isopropyl 2-chloro-4-fluoro-5-[6-oxo-2-(2-propynyloxy)-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoate, m.p. 117°-119° C.;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([CH2:12][CH2:13][C:14](Cl)=[O:15])([O:10][CH3:11])=[O:9].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14](=[O:15])[CH2:13][CH2:12][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: COC(=O)CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(Br)cc1

Procedure:
In a manner similar to Example 2, Step (a), bromobenzene (10.0 mL, 0.0950 mol) was allowed to react with 3-carbomethoxypropionyl chloride (12.9 mL, 0.105 mol) in the presence of aluminum chloride (26.9 g, 0.202 mol) in dichloromethane to give, after chromatography on silica gel (435 g, 230-400 mesh), eluting with hexanes-acetone (9:1, 10×400 mL; 8:1, 7×400 mL), 21.2 g of 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester as an off-white solid; mp 49-51° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](I)[CH2:25][CH2:26][CH3:27]>[Ag]=O.CN(C)C=O>[CH2:24]([N:13]1[CH2:14][C@@H:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:23])[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: CCCCI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CCCCN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Yield: 89.1 %

Procedure:
6.4 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 8.6 g of silver oxide, 18.4 g of n-butyl iodide and 100 ml of dimethylformamide are treated in the same manner as described in Example 1-(2). 6.7 g of tert.-butyl (4S)-1-n-butyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless syrup.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:17]1N2CN3CN(C2)C[N:18]1C3.Cl.[C-]#N.[Na+]>C(O)(=O)C.C(Cl)Cl>[C:17]([CH:6]([OH:7])[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1)#[N:18]
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#CC(O)c1ccc(F)c(Oc2ccccc2)c1

Procedure:
For example, 4-fluoro-3-phenoxy-toluene, when reacted with N-bromosuccinimide in the presence of a radical initiator, for example azodiisobutyronitrile, optionally using a diluent, for example carbon tetrachloride, optionally using a diluent, and 100° C., gives 4-fluoro-3-phenoxy-benzyl bromide. From this, 4-fluoro-3-phenoxy-benzaldehyde can be prepared in a Sommelet reaction, that is to say by reaction with hexamethylenetetramine in the presence of a diluent, for example methylene chloride, at temperatures between 0° and 50° C., followed by reaction with aqueous acetic acid and thereafter with hydrochloric acid, at temperatures between 80° and 120° C. The reaction of 4-fluoro-3-phenoxy-benzaldehyde with sodium cyanide in aqueous acetic acid at 20° C. gives α-cyano-4-fluoro-3-phenoxy-benzyl alcohol. The reaction sequence described above is outlined in the following equations: ##STR11##
Reaction SMILES: C(O[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5][C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]=1)C.F[B-](F)(F)F.C1(N)CCCCC1.C1(C(NC2CCCCC2)=[CH:37][C:38]2CC[CH2:41][CH2:40][N:39]=2)C=CC=CC=1.CS([O-])(=O)=O>C(NCC)C>[C:12]1([C:4]([N:39]([CH2:40][CH3:41])[CH2:38][CH3:37])=[CH:5][C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C(=C(NC1CCCCC1)c1ccccc1)C1=NCCCC1
Reactant: CCOC(=CC1=NCCCC1)c1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCNCC
Solvent: NC1CCCCC1
Product: CCN(CC)C(=CC1=NCCCC1)c1ccccc1

Procedure:
Analogously to Example 1, there is obtained, starting with 9.5 of 2-(2-ethoxy-2-phenyl-ethenyl)-3,4,5,6-tetrahydropyridine-tetrafluoroborate and 30 ml of cyclohexylamine, 2-[(2-phenyl-2-(cyclohexylamino)-ethenyl]-3,4,5,6-tetrahydropyridine, and from this its (1:1)-methanesulphonate, m.p. 172°-173°; and starting with 9.5 g of 2-(2-ethoxy-2-phenyl-ethenyl)-3,4,5,6-tetrahydropyridine-tetrafluoroborate and 30 ml of diethylamine, is obtained 2-[2-phenyl-2-(diethylamino)-ethenyl]-3,4,5,6-tetrahydropyridine, and from this its (1:1)-fumarate, m.p. 169°-170° (from isopropanol).
Reaction SMILES: [N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8](=O)[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])=[N+:2]=[N-:3].C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO>[N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([NH2:30])[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1c2cccnc2C(=O)CC[C@H]1c1cccc(F)c1F
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](N)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (5S,6S)-5-azido-6-(2,3-difluorophenyl)-5,6,7,8-tetrahydro-9H-cyclohepta[b]pyridin-9-one (190 mg, 0.60 mmol), and ammonium acetate (2.3 g, 30 mmol) in MeOH (10 mL) was added sodium cyanoborohydride (27 mg, 0.42 mmol) and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (20 mL) and aqueous 1 N NaOH solution (5 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc:MeOH:Et3N-100:0:0 to 85:10:5, to give the title compound as a mixture of diastereomers. MS: m/z=316.2 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[H][H].CCOCC>C(O)(=O)C.[Pd]>[Br:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CBr)C2
Yield: 78.2 %

Procedure:
2-Bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (4.0 g, 13.6 mmol) was dissolved in acetic acid (100 ml). To the resultant solution, 10% palladium-on-carbon (4 g) was added, followed by stirring at 70° C. for 7 hours in the stream of hydrogen. The palladium-on-carbon was filtered off, and the filtrate was condensed under reduced pressure. Ether was added to the residue, obtaining 3.15 g of the title compound as a colorless solid (78.2%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20]([F:27])[CH:19]=1)(O)O.C([O-])([O-])=O.[Na+].[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.COCCOC>[NH2:14][C:3]1[C:2]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20]([F:27])[CH:19]=2)=[CH:7][C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][N:4]=1
Reactant: Nc1ncc(C2CCOCC2)cc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1F
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: COCCOC
Product: Nc1ncc(C2CCOCC2)cc1-c1ccc(C(=O)O)c(F)c1
Temperature: 125 °C
Reaction time: 0.67 h
Yield: 136.9 %

Procedure:
To a microwave vial were charged with 3-bromo-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (500 mg, 1.95 mmol), 4-borono-2-fluorobenzoic acid (1.07 g, 5.83 mmol), aqueous Na2CO3 (2 M, 4.86 mL) and DME (10 mL). The mixture was purged with argon, then followed by addition of Pd(PPh3)4 (225 mg, 0.194 mmol). The mixture was purged with argon, sealed and heated via microwave reactor at 125° C. for 20 min, and then at 130° C. for another 40 min. The DME layer of the reaction mixture was collected, and the solid precipitates were triturated with methanol (2×10 mL). Methanol supernatants were combined with DME layer, and concentrated. The obtained residue was stirred with Et2O (2×60 mL), and the Et2O supernatants were discarded. The solid residue was partitioned between EtOAc (20 mL) and aq. HCl (1 N, 20 mL). The EtOAc layer was stripped with 1N HCl (2×5 mL), and the aqueous layers were combined. The aqueous layer was concentrated under reduced pressure, and the obtained light yellow solid was triturated with methanol (8 mL). The supernant was isolated via filtration and concentrated. 4-(2-Amino-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluorobenzoic acid (0.844 g, 2.67 mmol, 137% yield) was obtained as light yellow foam. LCMS (m/z) 317.2 (MH+) 0.46 min.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH2:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[CH:23]1([CH2:26][O:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[CH2:25][CH2:24]1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:21][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH:23]2[CH2:24][CH2:25]2)=[CH:36][CH:35]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(OCC2CC2)cc1
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(C(F)(F)F)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)NC(=O)c1ccc(OCC2CC2)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(trifluoromethyl)phenyl]propanoyl}amino)ethyl acetate and 4-(cyclopropylmethoxy)benzoic acid prepared in Example 18 (18a) to give the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19](OS(C)(=O)=O)[CH2:18][CH2:17]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CN(C=O)C>[C:8]([O:12][C:13](=[O:14])[NH:15][C@H:16]1[CH2:17][CH2:18][C@@H:19]([N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH2:20][CH2:21]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](n2cncn2)CC1
Temperature: 65 °C
Yield: 48.8 %

Procedure:
Sodium hydride (104 mg of a 60% dispersion in mineral oil, 2.60 mmol) was added portionwise to a solution of 1,2,4-triazole (194 mg, 2.80 mmol) in DMF (5 mL). After 5 minutes trans methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohexyl ester (587 mg, 2.00 mmol) was added. The reaction mixture was then heated at 65° C. for 3 days. The cooled mix was poured into ice-cold water (75 mL) which was then extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (75 mL), dried over sodium sulfate and concentrated under vacuum to give the crude product. This was purified by chromatography on silica gel (eluting with 0-5% methanol in ethyl acetate) to afford 260 mg (49%) of cis (4-[1,2,4]triazol-1-yl-cyclohexyl)-carbamic acid tert-butyl ester a white solid. LCMS (Method H, ESI): RT=2.60 min M+H=267.0; 1H NMR (400 MHz, DMSO): δ 8.55 (s, 1H), 7.95 (s, 1H), 6.89 (br s, 1H), 4.32-4.22 (m, 1H), 3.58 (br s, 1H), 2.20-2.07 (m, 2H), 1.88-1.77 (m, 2H), 1.69-1.56 (m, 4H), 1.39 (s, 9H).
Reaction SMILES: [CH:1]([C:4]([CH3:22])([N:7]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]3[CH:19]=[CH:18][N:17]([CH3:20])[C:16]=3[C:9]=2[C:8]1=[O:21])[C:5]#[N:6])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:24]>C(Cl)Cl>[CH:1]([C:4]([CH3:22])([N:7]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]3[CH:19]=[CH:18][N:17]([CH3:20])[C:16]=3[C:9]=2[C:8]1=[O:21])[C:5]([NH2:6])=[O:24])([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C#N)N1C(=O)c2ccc3ccn(C)c3c2C1=O
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)C(C)(C(N)=O)N1C(=O)c2ccc3ccn(C)c3c2C1=O
Reaction time: 8 h
Yield: 23.2 %

Procedure:
A solution of 6,8-dihydro-α-isopropyl-α,1-dimethyl-6,8-dioxobenzo[2,1-b:3,4-c']dipyrrole-7(1H)acetonitrile (5.30 g, 18.0 mmol) in methylene chloride is added dropwise to concentrated sulfuric acid at 5°-10° C. with rapid stirring. The ice bath is removed and the reaction mixture is stirred overnight at ambient temperatures, poured over crushed ice, diluted with methylene chloride, treated with 50% sodium hydroxide solution with ice bath cooling to pH 3-4 and separated. The aqueous layer is extracted with methylene chloride. The combined organic layers are dried (MgSO4) and concentrated in vacuo to give an orange foam residue, which is recrystallized from methylene chloride to afford the title product as yellow crystals (1.30 g, 23.2%), mp 184°-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:49])[CH:5]=[C:6]([Cl:48])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][NH:29][CH:30]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:31](=[O:41])[O:32][C@@H:33]2[CH:38]3[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]3)[CH2:34]2)=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[CH:50](=O)[CH3:51].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C(F)(F)F>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:49])[CH:5]=[C:6]([Cl:48])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][N:29]([CH2:50][CH3:51])[CH:30]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:31](=[O:41])[O:32][C@@H:33]2[CH:38]3[CH2:37][CH2:36][N:35]([CH2:40][CH2:39]3)[CH2:34]2)=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNC(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)s2)cc1OC
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: CC(=O)O
Product: CCN(Cc1ccc(C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC)c(OC)c2)s1)C(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 40 °C
Yield: 25.4 %

Procedure:
A suspension of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[[[2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]methyl]thiophene-2-carboxylate (Example 42, 100 mg, 0.12 mmol) in trifluoroethanol (0.5 mL) was heated at 40 C for 5 min. Acetaldehyde (11 μL, 0.19 mmol) was added followed by acetic acid (7 μL, 0.12 mmol) and the reaction mixture was heated at 40° C. for 18 h. Sodium triacetoxyborohydride (52 mg, 0.25 mmol) was added and the mixture was heated at 40° C. for 2 h. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (1 mL) and water (1 mL). 0.2N aqueous HCl was added to adjust pH=1. The acidic aqueous phase was washed with ethyl acetate (3×1 mL), sodium chloride (1 g) was added to the aqueous phase that was extracted with chloroform (3×1 mL), the combined chloroform extracts were filtered through a phase separator and the solvent was removed in vacuo. The combined ethyl acetate washes were extracted with 0.2N HCl (1 mL), water (1 mL). The aqueous phases were combined, saturated with solid sodium chloride and extracted with chloroform (3×1 mL). The crude product from both extractions was combined and purification by preparative HPLC gave the title compound as an off-white solid (23 mg, 24%).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C1COCC1>[Cl:20][CH2:21][CH2:22][CH2:23][C:24]([N:17]1[CH2:18][CH2:19][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15][CH2:16]1)=[O:25]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(Cl)CCCCl
Solvent: C1CCOC1
Product: O=C(CCCCl)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
25 g (99 mmol) benzhydrylpiperazine and 15.2 ml (109 mmol) TEA are present in 200 ml absolute THF and cooled to ca. 0° C. under moisture exclusion. 14 g (99 mmol) 4-chlorobutyric chloride are dissolved in 40 ml absolute THF and added dropwise. The mixture is stirred an additional three hours at RT and subsequently filtered. The filtrate is concentrated under vacuum, the residue is taken up in acetic acid ethyl ester and washed with saturated NaCl solution. The organic phase is dried over sodium sulfate and concentrated under vacuum until dry. The resin is further processed without further purification: yield 35.1 g (99%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:20]#[N:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].Cl.[NH2:23][OH:24].C(N(CC)CC)C>CO>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4](=[N:3][O:2][CH3:1])[C:20](=[N:23][OH:24])[NH2:21]
Reactant: CON=C(C#N)c1ccccc1COc1ccccc1C
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=C(C(N)=NO)c1ccccc1COc1ccccc1C
Yield: 67 %

Procedure:
A mixture of part of the sample of isomer 1 of 2-(2-methylphenoxymethyl) benzoyl cyanide O-methyloxime (280 mg), hydroxylamine hydrochloride (80 mg) and triethylamine (110 mg) in methanol (5 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated and the residue, dissolved in ethyl acetate, was washed with water, dried, concentrated, and chromatographed using ethyl acetate:hexane (1:1) as eluant to give two stereoisomers of 2-[2-(2-methylphenoxymethyl)phenyl]-2-methoxyimino acetamide oxime. Isomer I (200 mg, 67% yield), eluted first, was a white solid, mp 140° C., 1H NMR (CDCl3): δ 2.3 (3H,s), 4.0 (3H,s) and 5.05 (2H,s) ppm. Isomer II (100 mg, 33% yield), was also a white solid, mp 110°-2° C., 1H NMR (CDCl3): δ 2.3 (3H,s), 4.0 (3H,s) and 5.2 (2H,s) ppm.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[C:9]([CH3:19])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:19][C:9]1[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:3]=2[C:10]=1[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]
Reactant: C1COCCN1
Reactant: Cc1c(-c2cccc(C#N)c2)c2c(Cl)ncnc2n1COCC[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1c(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc2n1COCC[Si](C)(C)C
Temperature: 100 °C

Procedure:
To a solution of 3-(4-chloro-6-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C7) (140 mg, 0.351 mmol) in n-butanol (5 mL) was added morpholine (30.6 mg, 0.351 mmol) and N,N-diisopropylethylamine (90.9 mg, 0.703 mmol). The reaction mixture was heated at 100° C. for 18 hours, then concentrated in vacuo to provide the product as a yellow solid. Yield: 125 mg, 0.278 mmol, 79%. LCMS m/z 450.3 [M+H+].
Reaction SMILES: C([O-])(C)(C)C.[K+].[C:7]([NH:9][CH:10]=[N:11][CH:12]1[C:19]2[CH:18]=[CH:17][S:16][C:15]=2[CH2:14][C:13]1([CH3:21])[CH3:20])#[N:8].[CH3:22][O:23][C:24](=[O:27])[CH2:25]Br>CS(C)=O>[CH3:22][O:23][C:24]([C:25]1[N:11]([CH:12]2[C:19]3[CH:18]=[CH:17][S:16][C:15]=3[CH2:14][C:13]2([CH3:21])[CH3:20])[CH:10]=[N:9][C:7]=1[NH2:8])=[O:27]
Reactant: CC1(C)Cc2sccc2C1N=CNC#N
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1c(N)ncn1C1c2ccsc2CC1(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3.3 g of potassium tert.-butanolate are added to a mixture of 6.2 g of N-cyano-N'-(5,6-dihydro-5,5-dimethyl-4H-cyclopenta[b]thiophen-4-yl)-formamidine and 5 ml of dimethyl sulfoxide. After the mixture has been stirred for 15 hours at room temperature, 3.1 ml of bromoacetic acid methyl ester are added dropwise thereto. After 2 hours, ice-water is added to the reaction mixture. Extraction with ether, drying of the organic phase with sodium sulfate and evaporation of the solvent yield 8.4 g of N-cyano-N'-(5,6-dihydro-5,5-dimethyl-4H-cyclopenta[b]thiophen-4-yl)-N'-methoxycarbonylmethylformamidine in the form of a yellowish-brown oil. The oil is placed in 8 ml of methanol and, after the addition of 2.6 ml of 30% methanolic sodium methanolate solution, is heated at boiling for 16 hours. After cooling, the reaction solution is poured onto an ice-water/ether mixture. The organic phase is separated off, extracted with water and dried over sodium sulfate. Filtration and evaporation yield 5.1 g of brown crystals which are purified by chromatography on silica gel (eluant: ethyl acetate/hexane 1:1). 3.7 g of 4-amino-1-(5,6-dihydro-5,5-dimethyl-4H-cyclopenta[b]thiophen-4-yl)-5-imidazolecarboxylic acid methyl ester are obtained in the form of beige crystals having a melting point of 161°-162° C.
Reaction SMILES: [OH:1][C:2]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=12.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[C:25]([O:1][C:2]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=12)(=[O:27])[CH3:26]
Reactant: CCOC(=O)c1c(O)c2ccccc2c2nc3ccccc3nc12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1c(OC(C)=O)c2ccccc2c2nc3ccccc3nc12
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A mixture of 640 mg ethyl 5-hydroxybenzo[a]phenazine-6-carboxylate, 6 ml of acetic anhydride and two drops of pyridine was stirred overnight and poured into water. The precipitated solid was collected by filtration and recrystallized from ethanol to give 600 mg (91.1% yield) of ethyl 5-acetoxybenzo[a]phenazine-6-carboxylate as orange needles, m.p. 195°-196° C., Anal. Calcd. (%) for C21H16N2O4 : C, 69.99; H, 4.48; N, 7.77; Found: C, 70.12; H, 4.45; N, 7.63