Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([O:16][CH2:17][C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](OC(C)(C)C)=O)[CH:12]=[N:13][C:14]=2[Cl:15])=[CH:3][CH:2]=1.C=O>C(O)=O>[ClH:15].[ClH:15].[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([O:16][CH2:17][C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH3:23])[CH:12]=[N:13][C:14]=2[Cl:15])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Agent: C=O
Solvent: O=CO
Product: CN1CCC[C@@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Product: Cl
Temperature: 100 °C
Yield: 135.3 %

Procedure:
To 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 81a (760 mg, 1.8 mmol) was added formalin (37%, 20 mL) and formic acid (10 mL), and the mixture was heated at 100° C. for 1 hours. The solvent was concentrated, and saturated aqueous NaHCO3 was added to the residue. At pH 8 the mixture was extracted with methylene chloride, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 100:2-100:15 to afford to give the free base of the title compound (327 mg, 55% yield). MS (DCI/NH3) m/z 330 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.80 (m, 3H), 2.07 (m, 1H), 2.35 (m, 1H), 2.52 (s, 3H), 2.72 (m, 1H), 3.16 (m, 1H), 4.00 (m, 1H), 4.07 (m, 1H), 7.0 (m, 1H), 7.40 (m, 2H), 7.53 (m, 2H), 8.06 (m, 1H), 8.63 (m, 2H). The base was converted to the salt by treatment with HCl in ether to give the title compound. mp 220°-222° C. (dec). MS (DCI/NH3) m/z 330 (M+H)+. 1 H NMR (D2O, 300 MHz) δ: 2.06-2.37 (m, 3H), 2.44 (m, 1H), 3.07 (s, 3H), 3.30 (m, 1H), 3.78 (m, 1H), 3.98 (m, 1H), 4.42 (dd, J=6.1, 11.2 Hz, 1H), 4.58 (dd, J=3.0, 11.2 Hz, 1H), 7.35 (d, J=16.3 Hz, 1H), 7.82 (d, J=16.6 Hz, 1H), 7.87 (d, J=3.1 Hz, 1H), 8.03 (d, J=6.8 Hz, 2H), 8.11 (d, J=2.7 Hz, 1H), 8.63 (d, J=6.8 Hz, 2H). Anal. Calcd for C18H20N3OCl·2.2 HCl: C, 52.73; H, 5.46; N, 10.23. Found: C, 52.98; H, 5.56; N, 9.90. [α]25D =+11.48° (c 0.30, MeOH).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]([NH:13][C:14]3C=CC=CC=3O)=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:31](N1C=CN=C1)(N1C=CN=C1)=S.[NH2+]1C2C=CC=CC=2N=N1.F[B-](F)(F)F.CNC>ClCCl.O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:25])[CH3:26])[C:11]([N:13]([CH3:14])[CH3:31])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)Nc1ccccc1O)c1ccc2occc2c1
Agent: CNC
Agent: F[B-](F)(F)F
Agent: c1ccc2c(c1)N=N[NH2+]2
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(C(=O)N(C)C)c1ccc2occc2c1
Reaction time: 18 h
Yield: 40.5 %

Procedure:
A solution of methyl N-{(1R)-1-(benzofuran-5-yl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (410 mg) and 1,1′-thiocarbonyldiimidazole (196 mg) in dichloromethane (5 ml) was left to stand for 18 hours. Water (20 l) was added to the reaction mixture and this was then stirred rapidly for 30 minutes. After this, 1H-Benzotriazolium, 1-[bis(dimethylamino)methylene]-, tetrafluoroborate (1-), 3-oxide (TBTU, 710 mg) and a solution of dimethylamine in tetrahydrofuran (3 ml of 2M solution) were added. The reaction mixture was stirred for a further 18 hours and was then passed down an SPE (5 g, silica) eluting with a gradient (3:1 to 1:2 cyclohexane:ethyl acetate). The required fractions were combined and evaporated to furnish methyl N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (140 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH:10]=O)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH2:10][CH:8]([OH:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=CC(=O)c1cccc(Cl)c1
Reactant: Cc1ccc(CCN)cc1
Product: Cc1ccc(CCNCC(O)c2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9 using 3-chlorophenylglyoxal and 2-(4-methylphenyl)ethanamine. Recrystallization of the chromatographed material from cyclohexane gave the title compound m.p. 85-88 (analysed as the hemi-hydrate). τ(CDCl3) 7.7 (3H, s), 7.0-7.5 (6H, m, +2H disappears with D2O), 5.4 (1H, dd), 2.9 (4H, s), 2.6-2.8 (4H, m).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH2:10].[CH3:11][O:12][CH2:13][CH2:14][Br:15]>>[BrH:15].[CH3:11][O:12][CH2:13][CH2:14][N:3]1[C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[S:1][C:2]1=[NH:10]
Reactant: Nc1nc2c(s1)CCCC2
Reactant: COCCBr
Product: Br
Product: COCCn1c2c(sc1=N)CCCC2

Procedure:
A mixture of 4,5,6,7-tetrahydro-benzothiazol-2-ylamine (300 mg, 1.94 mmol) and 2-bromoethyl methyl ether (600 μL, 6.40 mmol) was processed according to the method of Example 2A to afford the title compound: MS (LC/MS) m/z 213 (M+H)+.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][C@H:14]1[CH2:28][C@@H:27]2[C@@H:17]([CH2:18][C:19]3[C:29]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]2=4)[NH:21][CH:20]=3)[N:16]([CH3:30])[CH2:15]1>C(#N)C>[CH3:30][N:16]1[C@H:17]2[C@H:27]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:29]=3[C:19]([CH2:18]2)=[CH:20][NH:21]4)[CH2:28][C@H:14]([CH2:13][NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[CH2:15]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CN1C[C@@H](CN)C[C@H]2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: CC#N
Product: CN1C[C@@H](CNC(=S)NC(=O)c2ccccc2)C[C@H]2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
1.05 ml of benzoyl isothiocyanate were added to a suspension of 2 g of 8α-aminomethyl-6-methyl-10β-ergoline in 22 ml of acetonitrile at 80° C. under shaking. The solution was refluxed for thirty minutes and then evaporated in vacuo to dryness. The residue was chromatographed on silica gel (eluant chloroform with 2% methanol) to give 2.2 g of the title compound, m.p. 153°-155° C., after crystallization from diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]=[CH:23]N(C)C)=[CH:17][C:16]=1[N:28]([CH3:32])[C:29](=[O:31])[CH3:30].C(OCC)(=O)C>C(O)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[N:28]([CH3:32])[C:29](=[O:31])[CH3:30]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1Cl
Yield: 78.7 %

Procedure:
A mixture of 0.083 g (0.43 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.12 g (0.43 mmol) of N-[2-chloro-5-(3-dimethylamino-acryloyl)-phenyl]-N-methyl-acetamide in 12 ml of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 139 mg of N-{2-chloro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 79%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][C:11]([O:13]CC2C=CC=CC=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH2:7][CH2:8][N:9]([C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:10][C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(CN(CCc1ccccc1)C(=O)CCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CN(CCc1ccccc1)C(=O)CCc1ccccc1
Yield: 99.1 %

Procedure:
A methanol solution (20 mL) of benzyl N-[(2-phenyl)ethyl]-N-[(3-phenyl)propionyl]glycinate (1.3 g, 3.24 mmol) and palladium on carbon (10%, 180 mg) was stirred under 1 atmosphere of hydrogen gas for 18 hours. The reaction was purged with nitrogen and filtered through a pad of diatomaceous earth and evaporated to give N-[(2-phenyl)ethyl]-N-[(3-phenyl)propionyl]glycine (1.0 g) in quantitative yield. LRMS: (M+NH3)+ =326.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH:8]([N:10]=[CH:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[NH2:9].[OH-].[K+]>C(O)=O>[CH:5]([N:15]1[CH2:16][CH2:17][N:12]([CH:11]=[N:10][NH:8][NH2:9])[CH2:13][CH2:14]1)=[O:7]
Reactant: NNN=CN1CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Product: NNN=CN1CCN(C=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
12.7 ml of acetic acid anhydride are added dropwise to 42 ml of ice-cooled formic acid, the mixture is stirred for ca. 1 hour and 16 g of the benzylidene derivative of 1-(hydrazinoimino-methyl) piperazine in 42 ml of formic acid are added dropwise. The mixture is left for ca. 2 hours at 0° and the solvent is evaporated off. The residue is treated with water and the pH of the mixture obtained is adjusted to pH 11 by addition of 10N KOH. The mixture is extracted with dichloromethane, the dichloromethane phase is dried and the solvent is evaporated off. The benzylidene derivative of 1-formyl4-(hydrazinoiminomethyl)piperazine is obtained in the form of a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1.CCN(C(C)C)C(C)C.[F:19][C:20]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[C:21]=1[C:22](Cl)=[O:23]>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[C:21]=1[C:22]([NH:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1)=[O:23]
Reactant: COc1cc(N)ccn1
Reactant: O=C(Cl)c1c(F)cc(C(F)(F)F)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)c2c(F)cc(C(F)(F)F)cc2C(F)(F)F)ccn1
Reaction time: 2 h
Yield: 61.7 %

Procedure:
2-Methoxypyridin-4-amine (632.1 mg, 5.09 mmol) and DIEA (1.8 mL, 10.18 mmol) were dissolved in DMF (15 mL) and treated dropwise with a solution of 2-fluoro-4,6-bis(trifluoromethyl)benzoyl chloride (1500 mg, 5.09 mmol) in DMF (2 mL). After 2 hours, the reaction was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The solution was dried over anhydrous Na2SO4, filtered, and dried down to a purple residue. Silica gel chromatography using a gradient of ethyl acetate/hexane (10-99%) provided 2-fluoro-N-(2-methoxypyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide (1.2 g, 67%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.42 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.13 (dd, J=5.4, 0.9 Hz, 1H), 7.14-7.10 (m, 2H), 3.85 (s, 3H) ppm. ESI-MS m/z calc. 382.05. found 383.1 (M+1)+; Retention time: 1.48 minutes (3 minutes run).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[CH2:9][CH2:10][CH2:11][OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:48][C:49]1[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=1)[O:52][C:53]1[C:58](O)=[CH:57][CH:56]=[CH:55][N:54]=1>C1COCC1>[Br:48][C:49]1[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=1)[O:52][C:53]1[C:58]([O:12][CH2:11][CH2:10][CH2:9][C:8]2[C:3]([O:2][CH3:1])=[CH:4][N:5]=[CH:6][C:7]=2[O:13][CH3:14])=[CH:57][CH:56]=[CH:55][N:54]=1
Reactant: COc1cncc(OC)c1CCCO
Reactant: Oc1cccnc1Oc1cccc(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cncc(OC)c1CCCOc1cccnc1Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(3,5-Dimethoxypyridin-4-yl)-1-propanol (0.60 g, 3.0 mmol) obtained in Example 1 and triphenylphosphine (1.18 g, 4.5 mmol) are dissolved in THF (30 ml), and thereto are successively added with stirring diisopropyl azodicarboxylate (0.78 g, 3.9 mmol) and 2-(3-bromophenoxy)-3-pyridinol (1.04 g, 3.9 mmol) obtained in Reference Example 11 under ice-cooling. The mixture is stirred at room temperature for 30 minutes, and the reaction solution is concentrated under reduced pressure. To the residue is added ethyl acetate (50 ml), and the mixture is extracted with a 10% aqueous hydrochloric acid solution (50 ml×2). The pH value of the aqueous layer is adjusted to pH 12 with potassium carbonate, and the mixture is extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give 2-(3-bromophenoxy)-3-[3-(3,5-dimethoxypyridin-4-yl)propoxyl]pyridine, which is further treated with fumaric acid to give the title compound (1.26 g), m.p. 106-154° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)[N:9]=1.[Br:23][CH:24]([CH3:28])[C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[Br:23][CH:24]([CH3:28])[C:25]([NH:7][C:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[N:9]=1)=[O:26]
Reactant: CC(Br)C(=O)Cl
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)NC1=NN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
To 100 ml. of chloroform with stirring is added 2.75 g. of potassium carbonate and 5.3 g. of 3-amino-1-(α,α,α-trifluoro-m-tolyl)-2-pyrazoline, then 5.0 g. of α-bromopropionylchloride is added dropwise. After the addition is complete the reaction mixture is refluxed on a steam bath for 4 hours. Then the solvent is removed in vacuo and water is added to give a gum. The gum is extracted with dichloromethane. The extracts are combined and dried over anhydrous magnesium sulfate. The solution is passed through a short column of a hydrous magnesium silicate, then is evaporated leaving a gummy solid. The solid is triturated with ether to give 1.13 g. of a yellow solid. The solid is recrystallized from acetone-hexane to give the desired product as yellow crystals, m.p. 54°-56° C.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]3[N:34]=[N:35][N:36]=[C:26]3[C:25]=2[NH2:37])[CH:12]=1>ClCCCl.C(=O)(O)[O-].[Na+]>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:23]2[C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]4[N:34]=[N:35][N:36]=[C:26]4[C:25]=3[N:37]=[CH:1]2)[CH:12]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1c(NCCOCCCc2cccnc2)c2ccccc2n2nnnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: c1cncc(CCCOCCn2cnc3c2c2ccccc2n2nnnc32)c1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
Triethyl orthoformate (21.1 ml, 127 mmol) was added to a solution of N5-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinoline-4,5-diamine (30.8 g, 84.7 mmol) in 1,2-dichloroethane (750 ml) and the reaction was heated to reflux for 3 hours. The reaction was cooled to room temperature and diluted with saturated sodium bicarbonate (200 ml). The phases were separated and the aqueous layer was extracted with dichloromethane (3×75 ml). The combined organic fractions were washed with brine (200 ml), dried (Na2SO4) and concentrated to provide an orange solid. The solid was triturated with diethyl ether and then filtered to yield 28.7 g of 6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a tan/orange solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][C@:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:3]1[CH2:4][CH2:5][C@H:6]2[O:23][C@H:24]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[CH3:25].[CH2:40](OC(OCC)OCC)C.[N-:50]=[N+:51]=[N-:52].[Na+]>C(O)(=O)C>[CH2:10]([N:9]1[C@@H:3]2[C@H:2]([N:1]3[CH:40]=[N:52][N:51]=[N:50]3)[CH2:8][C@@:7]1([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C@H:6]([O:23][C@H:24]([C:26]1[CH:27]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH3:25])[CH2:5][CH2:4]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](O[C@@H]1CC[C@H]2[C@H](N)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@H](O[C@@H]1CC[C@H]2[C@H](n3cnnn3)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
(1R*,2R*,5S*,6R*)-6-Amino-8-benzyl-2-{(1S*)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 132; 150 mg, 0.27 mmol) in glacial acetic acid (2 ml) with triethylorthoformate (3 ml) was heated to 90° C. Sodium azide (178 mg, 2.74 mmol) was then added and the mixture stirred at 90° C. overnight. The reaction mixture was cooled and partitioned between saturated sodium hydrogen carbonate solution and dichloromethane and the organics dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil (158 mg, 95%).
Reaction SMILES: [CH3:1][N:2]([CH2:4]N(C)C)[CH3:3].[F:8][C:9]([F:22])([F:21])[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH2:15][CH2:14]2.C([Cl:26])(=O)C>C(#N)C>[ClH:26].[CH3:1][N:2]([CH2:4][CH:15]1[CH2:14][C:13]2[C:17](=[CH:18][CH:19]=[C:11]([O:10][C:9]([F:22])([F:8])[F:21])[CH:12]=2)[C:16]1=[O:20])[CH3:3]
Reactant: O=C1CCc2cc(OC(F)(F)F)ccc21
Reactant: CN(C)CN(C)C
Reactant: CC(=O)Cl
Solvent: CC#N
Product: CN(C)CC1Cc2cc(OC(F)(F)F)ccc2C1=O
Product: Cl
Reaction time: 3 h

Procedure:
6.4 ml of bis-(dimethylamino)-methane were added to a solution of 10.1 g of the product from step 2 in 37 ml of acetonitrile; 3.3 ml of acetic acid chloride were added dropwise at from 0 to 10° C., a further 25 ml of acetonitrile were added, and stirring was carried out for 3 hours at 50° C. and then for 18 hours at room temperature. The resulting solid was filtered off with suction, washed twice with diethyl ether and dried in vacuo (yield 12.4 g).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][CH2:7][CH2:8][NH2:9].[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]=1[CH2:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=1.O>O1CCOCC1>[CH3:5][O:6][CH2:7][CH2:8][NH:9][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([O:23][CH2:22][C:12]2[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:14][O:15][C:11]=2[CH3:10])=[N:25][CH:26]=1
Reactant: COCCN
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: COCCNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 2.0 mL, 4.0 mmol) was added dropwise (exothermic) to a solution of 2-methoxyethylamine (300 mg, 4.0 mmol) in dioxane (3 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (310 mg, 1.0 mmol) in dioxane (3 mL) was added. The resulting mixture was then heated at 85-95° C. for 4 days and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 9:1) afforded the title compound (280 mg, 76%) which was obtained as a colourless oil. MS: m/e=368.1 [M+H]|.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[N+:12]([C:15]1[S:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(O)(=O)C.CCO>[N+:12]([C:15]1[S:19][C:18]([CH:20]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(NN=Cc1ccc([N+](=O)[O-])s1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 5-nitro-2-thiophenecarboxaldehyde (0.28 g, 0.002 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.55 g, in 95% yield, mp: 194.5° C. 1H NMR (DMSO-d6) δ 11.99 (s, 1H), 10.18 (s, 1H), 8.63 (s, 1H), 8.11 (d, 2H), 7.78 (d, 2H), 7.53 (d, 1H), 6.86 (d, 2H). 13C NMR (DMSO-d6) δ 164.9, 162.9, 152.5, 149.0, 142.0, 132.4, 131.8, 131.1, 125.1, 117.0. Anal. Calcd for C12H9N3O4S : C, 49.48; H, 3.11; N, 14.43. Found: C, 49.55; H, 3.09; N, 14.36.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH2:13])[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: C[C@H](N)c1nc2c(Cl)cccc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2c(Cl)cccc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 18.4 %

Procedure:
A mixture of (S)-1-(4-chloro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 9 (250 mg, 0.92 mmol), 6-chloro-9H-purine (200 mg, 1.29 mmol) and DIPEA (0.29 mL, 1.66 mmol) in n-butanol (2 mL) was stirred in a sealed tube for 16 h at 120° C. Additional amounts of 6-chloro-9H-purine (100 mg, 0.64 mmol) and DIPEA (0.14 mL, 0.802 mmol) were added and the stirring was continued at 120° C. for 24 h. After cooling to RT, the crude reaction mixture was partitioned between DCM and water. The aqueous phase was further extracted with DCM (×3) and then the combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) and then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 60 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) affording 120 (66 mg, 42%). LCMS: RT 3.69 min [M+H]+ 390.0. 1H NMR (CDCl3, 400 MHz): δ 12.90 (1H, bs), 8.28-7.90 (3H, m), 7.71-7.41 (5H, m), 7.32 (1H, d, J=7.75 Hz), 7.19 (1H, t, J=7.90 Hz), 7.03 (1H, d, J=8.10 Hz), 5.46 (1H, br), 1.67-1.53 (3H, m)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[O:29].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[C:12](=[O:15])[CH2:13][CH2:14][C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)=[O:29])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=Cc1ccccn1
Reactant: C=CC(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)CCC(=O)c2ccccn2)cc1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
To a solution of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydrofuran-3-yl)pent-1-en-3-one (229 mg) in ethanol (3.6 mL) were added pyridine-2-carbaldehyde (84.8 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (22.0 mg) and triethylamine (44.5 μL), and the mixture was stirred with heating under reflux for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (43.5 mg, yield 14%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio).