Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1.Cl[CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[S:18][CH:19]=1>C1OCCOCCOCCOCCOC1.C1COCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([C:17]2[S:18][CH:19]=[C:15]([CH2:14][O:3][CH2:4][CH2:5][C:6]3[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=3)[N:16]=2)=[CH:25][CH:24]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: Nc1cccc(CCO)c1
Reactant: CC(C)(C)c1ccc(-c2nc(CCl)cs2)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(COCCc3cccc(N)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.1 %

Procedure:
To a solution of 0.027 g (1 mmol) of 95% sodium hydride and 0.5 drop of 15-crown-5 in 20 mL of THF was added dropwise a solution of 0.139 g (1 mmol) of 3-(2-hydroxy ethyl)phenyl amine at 0° C. After stirring for 0.5 hr 0.28 g (1.1 mmol) of 4-chloromethyl-2-(4-tert-butyl phenyl)thiazole was added in one portion. The mixture was stirred at room temperature for 5 hr. At the end of this time, the solution was concentrated and the residue washed with 10 ml of saturated ammonium chloride and extracted 2 times with 30 mL of ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated to recover an oil, which was purified by column chromatography on SiO2 with 30% ethyl acetate:hexane elution to provide 0.125 g of product as an oil, used in the next step without further purification. NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=8 Hz, 2H, ArH), 7.50 (d, J=8 Hz, 2H, ArH), 7.45 (s, 1H, N═CH) 7.08 (t, J=8 Hz, 1H, H5), 6.63 (d, J=8 Hz, 1H, H4), 6.54 (s, 1H, H2), 6.51 (d, J=8 Hz, 1H, H6) 4.59 (s, 2H, OCH2), 3.71 (t, J=7 Hz, 2H, OCH2), 2.87 (t, J=7 Hz, 2H, ArCH2), 1.30 (s, 9H, t-bu).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][CH2:3]1.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:47].Cl>>[ClH:47].[ClH:47].[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]4[C:13]5=[C:14]([F:22])[CH:15]=[N:16][C:17]6[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=65)[CH2:10]4)[CH2:4][CH2:3]3)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(F)c2c43)CC1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=c1ccc2ncc(F)c3c2n1C[C@H]3CN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Yield: 71 %

Procedure:
The title compound was prepared from (4R)-4-[(4-amino-1-piperidinyl)methyl]-3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one Enantiomer 1 and 2,3-dihydro-1,4-benzodioxin-6-carboxaldehyde (Aldrich) according to the general method of Example 2(h) (except that the dihydrochloride was prepared) in 71% yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25](O)=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C([O:44][CH:45]1[CH2:48][NH:47][CH2:46]1)C1C=CC=CC=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([N:47]4[CH2:48][CH:45]([OH:44])[CH2:46]4)=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(COC2CNC2)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)O)cc32)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)N4CC(O)C4)cc32)cc1

Procedure:
6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carboxylic acid (intermediate 58, 14 mg, 0.0277 mmol) was treated with 3-benzyloxyazetidine hydrochloride (6 mg, 0.03 mmol) and PyBOP according to the procedure described in Example 13, Step A. The desired product was obtained by column chromatography on silica gel. LC/MS: m/e 651.1 (M+H)+.
Reaction SMILES: [C:1]1(=[O:32])[N:5]([C@H:6]2[C@@H:9](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8](C3C=CC(OC)=CC=3)[C:7]2=[O:26])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.[NH4+].[N+]([O-])([O-])=O.[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O1CCCC1.O>[C:4]1(=[O:27])[N:5]([C@H:6]2[C@@H:9](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:8][C:7]2=[O:26])[C:1](=[O:32])[C:2]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:3]12
Reactant: COc1ccc(N2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2/C=C/c2ccccc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1N[C@H](/C=C/c2ccccc2)[C@@H]1N1C(=O)c2ccccc2C1=O

Procedure:
In 25 ml of tetrahydrofuran is dissolved 1 g of cis-3-phthalimido-4-(E)-styryl-1-(p-methoxyphenyl)-2-oxoazetidine and under stirring at -5° C. to -10° C., solution of ammonium, cerium (IV) nitrate (3 g) in 10 ml of water is added dropwise over a period of 5 minutes. Then, the mixture is stirred at -5° C. to 0° C. for 20 minutes. The tetrahydrofuran is distilled off under reduced pressure and the residue is shaken with ethyl acetate and water. The ethyl acetate layer is taken, washed with aqueous sodium sulfite and aqueous sodium chloride in this order and dried over anhydrous sodium sulfate. The solvent is then distilled off and the residue is purified by silica gel column chromatography [eluent:chloroform-ethyl acetate (7:3)] and crystallized from ethyl acetate-ether to give cis-3phthalimido-4-(E)-styryl-2-oxoazetidine, melting at 168°-170° C.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=O)[CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[CH2:16]([NH:23][CH:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc2C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reaction time: 5 h

Procedure:
Under nitrogen, to a solution of 3-nitro-5,7,8,9-tetrahydrobenzocyclohepten-6-one (300 mg) in 1,2-dichloroethane (10 ml) were added benzylamine (0.24 ml), sodium triacetoxyborohydride (460 mg) and acetic acid (0.17 ml) at room temperature, and the mixture was stirred at the same temperature for 5 hours. The resulting mixture was poured into aqueous 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 to 1:5) to give N-benzyl-(3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (342 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:14](=O)([O-])[O-:15].[K+].[K+]>CO.O>[CH3:14][O:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(I)cc(CBr)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COCc1cc(I)cc(C(=O)OC)c1
Temperature: 55 °C
Yield: 96.5 %

Procedure:
A mixture of methyl 3-(bromomethyl)-5-iodobenzoate (400 mg, 1.1 mmol) and potassium carbonate (311 mg, 2.3 mmol) in methanol/tetrathydrofuran (5 mL/5 mL) was heated at 55° C. for 1 hour. After cooling, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. After drying in vacuo, 325 mg (94%) of methyl 3-(methoxymethyl)-5-iodobenzoate was isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:18]#[N:19])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1.[N+:20]([O-])([OH:22])=[O:21].O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:18]#[N:19])=[CH:11][C:12]2[N:13]([C:15]([N+:20]([O-:22])=[O:21])=[CH:16][N:17]=2)[CH:14]=1
Reactant: O=[N+]([O-])O
Reactant: N#Cc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1cc2ncc([N+](=O)[O-])n2cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (3.07 g, 6.10 mmol, prepared according to Example 3, Step 2.3) in concentrated H2SO4 (55 mL) was added a freshly prepared mixture of fuming HNO3 in H2SO4 (1:2, v/v, 2.55 mL) at RT. The reaction mixture was stirred at RT for 2 h then cautiously added to cold water (300 mL) and extracted with DCM (5×). The combined organic fractions were dried over Na2SO4, filtered, and evaporated to dryness to give the crude 6-(2,4-dichloro-phenyl)-3-nitro-imidazo[1,2-a]pyridine-7-carbonitrile as a brown solid (533 mg). MS: 333 [M+1]+; HPLC: AtRet=1.57.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1.Cl.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-:27].[Na+]>O>[CH3:1][C:2]([CH3:17])([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[NH2:4])[CH:3]=[O:27].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [OH-]
Reactant: CC(C)C1CCCCCCCCC(C)(C)C=N1
Agent: Cl
Agent: [Na+]
Solvent: NCc1ccccc1
Solvent: O
Product: CC(C)C(N)CCCCCCCCC(C)(C)C=O
Yield: 56.4 %

Procedure:
The procedure described in Example 2(b) is repeated, except that 68.5 g (0.5 mol) of 3,3-dimethyl-12-isopropyl-1-aza-cyclododecene, 50 g of 37% hydrochloric acid, 54 g (0.5 mol) of benzylamine and 200 ml of water are used. After neutralisation with 22 g (0.55 mol) of solid sodium hydroxide, 97 g (0.282 mol) of 2,2-dimethyl-11-isopropyl-11-amino-undecanal-benzylamine are obtained; yield 56.4% of theory.
Reaction SMILES: C([O:4][C:5]([C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:9][N:8]=1)=O)(C)C.[NH3:18]>CO>[CH2:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([C:5]([NH2:18])=[O:4])=[N:8][CH:9]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: Cc1cc(C(=O)OC(C)C)ncc1CC(C)C
Reactant: N
Solvent: CO
Product: Cc1cc(C(N)=O)ncc1CC(C)C
Temperature: 75 °C
Reaction time: 72 h

Procedure:
A solution of 5-isobutyl-4-methyl-pyridine-2-carboxylic acid isopropyl ester (655 mg, 2.78 mmol, prepared in analogy to the corresponding ethyl ester) in 7 N NH3 in methanol (40 mL) is stirred in a sealed vial at 75° C. for 72 h. The solvent is removed in vacuo and the residue is dissolved again in 7 N NH3 in methanol. The resulting solution is again stirred at 75° C. for 24 h. The solvent is evaporated to give crude 5-isobutyl-4-methyl-pyridine-2-carboxylic amide (535 mg); LC-MS: tR=0.80 min; [M+1]+=193.01. This material is dissolved in DCM (20 mL) and pyridine (1.08 g, 11.13 mmol) is added. The mixture is stirred at rt for 5 min before trifluoroacetic acid anhydride (1.75 g, 1.18 mmol) is added dropwise. The mixture is stirred at rt for 16 h. The mixture is diluted with DCM (100 mL), washed with sat. aq. NaHCO3 solution (3×50 mL) and brine (50 mL). The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with a gradient of EA in heptane to give 5-isobutyl-4-methyl-pyridine-2-carbonitrile (106 mg) as a pale yellow oil; LC-MS: tR=0.96 min; [M+1]+=175.03.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][S:6][C:7]1[C:16]([CH3:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([CH3:19])=[C:12]([CH3:18])[CH:13]=2)[N:8]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:24][N:2]([CH3:1])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][S:6]([C:7]1[C:16]([CH3:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([CH3:19])=[C:12]([CH3:18])[CH:13]=2)[N:8]=1)=[O:33]
Reactant: Cc1cc2nc(C)c(SCc3ccccc3N(C)C)nc2cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc2nc(C)c(S(=O)Cc3ccccc3N(C)C)nc2cc1C
Yield: 28.8 %

Procedure:
In a mixture of 35 ml of chloroform and 3 ml of methanol was dissolved 3.71 g of 2-(2-dimethylaminobenzylthio)-3,6,7-trimethylquinoxaline. To the chilled solution kept at a temperature of lower than 0° C. (temperature of solution) was slowly added 2.45 g of m-chloroperbenzoic acid (purity: 80%). After the reaction was complete, chloroform and saturated aqueous NaHCO3 solution were added to the reaction mixture. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (acetone/hexane). The eluate was concentrated and the resulting residue was crystallized from ether/hexane to give 1.12 g of 2-(2-dimethylaminobenzylsulfinyl)-3,6,7-trimethylquinoxaline as a yellow crystalline powder, m.p. 83°-88° C. (decompn.).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[N:8]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:9]([S:12][CH2:13][C:14]([OH:16])=[O:15])=[N:10][N:11]=1.[OH:30][CH:31]1[O:37][C@H:36]([C@@H:38]([CH2:40]O)[OH:39])[C@H:34]([OH:35])[C@H:32]1[OH:33]>N1C=CC=CC=1>[Br:6][C:7]1[N:8]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:9]([S:12][CH2:13][C:14]([O:16][CH2:40][CH:38]([OH:39])[CH:36]2[CH:34]([OH:35])[CH:32]([OH:33])[CH:31]([OH:30])[O:37]2)=[O:15])=[N:10][N:11]=1
Reactant: OC[C@@H](O)[C@H]1OC(O)[C@H](O)[C@H]1O
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)OCC(O)C1OC(O)C(O)C1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (2.4 mmol) is added dropwise over 5 mins to a solution of 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (810 mg, 2.0 mmol) in pyridine (20 mL) at 0° C. The mixture is stirred at 0° C. for a further 1 hour and then 1,2-O-isopropilydene-□-D-glucofuranose (440 mg, 2.0 mmol) dissolved in pyridine (5 mL) is added dropwise over 5 mins. The mixture is stirred at 0° C. for a further 3 hours and 1 hour at 20° C. and then quenched by addition of water (1 mL). Volatile solvents are removed in vacuo and DCM (200 mL) added. The organic phase is washed with water (1×50 mL), saturated sodium carbonate solution (1×50 mL) and brine (1×50 mL), dried over Na2SO4 and concentrated to dryness. Ethanol and water are added to produce a solid which is collected by filtration. Additional product is recovered by extraction of the filtrate with DCM. Combined product is concentrated, dried and purified by column chromatography (acetone/DCM eluent). The combined solids are dissolved in acetic acid (25 mL) and water (5 mL) mixture, heated at 60° C. for 3 hours. Volatile solvents are removed in vacuo. Ethanol and water are added to produce a solid which is collected by filtration.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]1=[O:33].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>C1(C)C=CC=CC=1>[NH:38]1[C:27]([CH2:26][CH2:25][CH2:24][S:23][C:9]2[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]3[C:6]=2[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:33])[N:4]3[CH2:29][CH:30]([CH3:31])[CH3:32])=[N:28][N:40]=[N:39]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC#N)n(Cc3cccc4ccccc34)cc21
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCc3nnn[nH]3)n(Cc3cccc4ccccc34)cc21
Yield: 28 %

Procedure:
The compound of Example 18, 4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1 H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanenitrile (98 mg) was dissolved in toluene (20 ml) and trimethyltin azide (100 mg) was added. The solution was heated under reflux for 110 hours, then the solvent was evaporated and the residue was chromatographed, eluting with ethanol:dichloromethan(1:19), to give the title compound (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Oc1cncc(Cl)c1
Reactant: COc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2cncc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To a solution of 3-chloro-5-hydroxypyridine (2.0 g, 17.0 mmol), 4-methoxybenzyl alcohol (2.85 g, 25.5 mmol) and triphenylphosphine (6.68 g, 25.5 mmol) in dry THF (100 ml) DEAD (4.44 g, 25.5 mmol) was added dropwise. The resulting solution was stirred 3 hours at room temperature. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed (brine), dried (Na2SO4), filtered and concentrated under vacumm. Purification on silica gel with 20% ethyl acetate/hexane to provide the title compound (1.9 g, 53%). MS (DCI/NH3) m/e 250 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+].CC(O)C>O>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:3]2[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)C1CCNCC1
Reactant: Clc1nccnc1OC1CCN(c2ccc3ccccc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C1CCN(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 160 °C
Yield: 27 %

Procedure:
To a mixture of 2-[4-(3-chloro-pyrazin-2-yloxy)-piperidin-1-yl]-quinoline (see PREPARATION P2.1; 0.34 g, 1.0 mmol) and methyl piperidine-4-carboxylate (0.14 g, 1.0 mmol) and K2CO3 (0.27 g, 2.0 mmol) was added i-PrOH (2 mL) and water (0.5 ml). The solution was heated to 160° C. under microwave for 5 hours. Then the mixture was concentrated and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in petroleum ether) to give the title product (0.12 g, 0.27 mmol, 27% yield) as white solid. ESI-MS (M+1): 448 calc. for C25H29N5O3 447.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([O:24]C)=[O:23].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([OH:24])=[O:23]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1)CCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1)CCC3
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a solution of methyl [2-methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl]pentanoate (0.049 g; 0.118 mmol) in methanol (2.5 mL) and ethanol (2.6 mL) was added a 5% sodium hydroxide solution (3.3 mL; 4.125 mmol). The reaction mixture was heated under reflux for 4.5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.029 g (61%) of the title compound as a white powder.
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][CH2:44][NH2:45]>C1COCC1>[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)=[O:26]
Reactant: CN(C)CCCCN
Reactant: O=C(O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCCCNC(=O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1

Procedure:
4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (4-dimethylamino-butyl)-amide was prepared as described in example 1. 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.8 g, 2.19 mmol, 1 eq.) in THF was treated with 1,1′-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.). The resulting acyl imidazole was then treated with 4-dimethylaminobutylamine (0.28 g, 2.41 mmol, 1.1 eq.). When complete, the reaction was worked up to leave a yellow oil (0.72 g, 71% yield) which solidified on standing. The free base was converted to the oxalate as described in example 3 to give 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (4-dimethylamino-butyl)-amide oxalate (0.61 g) as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])[N:3]=1.Cl.[OH2:24]>>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([CH2:14][S:13][C:4]2[N:3]=[C:2]([NH:10][C@H:11]([CH3:2])[CH2:6][OH:24])[C:11]3[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=3[N:5]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O
Reactant: O=c1cnc2c(Br)nc(SCc3cccc(Cl)c3F)nc2[nH]1
Agent: Cl
Product: C[C@H](CO)Nc1nc(SCc2cccc(Cl)c2F)nc2[nH]c(=O)cnc12

Procedure:
The titled compound was prepared by the method of Example 2, step (f) using the product from example 6, step (e) (75 mg). The reaction mixture was poured into water and acidified with conc. HCl. The suspended solid was removed by filtration, dried in air and recrystallized from acetonitrile to give a yellow solid (37 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:19][S:20]([O:18][CH2:17][C:14]1[CH:13]=[N:12][C:11]([NH:10][C:4]2[C:5](=[O:9])[N:6]([CH3:8])[N:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:16][CH:15]=1)(=[O:22])=[O:21]
Reactant: Cn1nc(Cl)cc(Nc2ccc(CO)cn2)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc(Cl)cc(Nc2ccc(COS(C)(=O)=O)cn2)c1=O

Procedure:
Intermediate 180b was treated with methanesulfonyl chloride and diisopropylethylamine in methylene chloride at 0° C. to give 180c.