Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]([CH3:43])[C:39]([SH:42])=[N:40][N:41]=2)=[CH:33][CH:32]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]5[N:38]([CH3:43])[C:39]([SH:42])=[N:40][N:41]=5)=[CH:35][CH:36]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: Cn1c(S)nnc1-c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(-c5nnc(S)n5C)cc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (50 mg, 0.12 mmol) and 5-(4-aminophenyl)-4-methyl-4H-1,2,4-triazole-3-thiol (25 mg, 0.12 mmol) in pyridine (10 mL) was added POCl3 (0.3 mL, 3.29 mmol) at 0° C., the reaction mixture was stirred at room temperature for 8 hours, a sat. NaHCO3 solution (15 mL) was added slowly, the solvent was removed in vacuo, dichloromethane (40 mL) was added and filtrated, the filtrate was collected, concentrated and purified by a silica column chromatography (silica gel 200-300 mesh, eluting with dichloromethane:methanol=50:1) to afford 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)piperidine-3-carboxamide (24.0 mg, 33.1%) as a white solid. 1H NMR (300 MHz, DMSO): δ 13.88 (s, 1H), 10.34 (s, 1H), 9.68 (s, 1H), 8.87 (s, 1H), 7.82-7.66 (m, 5H), 7.38-7.35 (m, 1H), 6.83 (brs, 1H), 4.83 (d, 1H, J=12.0 Hz), 4.68 (d, 1H, J=11.7 Hz), 3.71 (s, 3H), 3.63 (s, 3H), 3.58 (s, 3H), 3.15-3.07 (m, 1H), 3.00-2.93 (m, 1H), 2.62-2.58 (m, 1H), 2.07-2.03 (m, 1H), 1.83-1.71 (m, 2H), 1.51-1.47 (m, 1H). LC-MS: 604 [M+H]+, tR=1.50 min. HPLC: 99.39% at 214 nm, 99.39% at 254 nm, tR=5.36 min.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([NH2:11])=[CH:9][N:8]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[CH:31]([S:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)(=[O:36])=[O:35])([CH3:33])[CH3:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:31]([S:34]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[N:3]=[C:4]3[C:10]([NH2:11])=[CH:9][N:8]([C:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:5]3=[N:6][CH:7]=2)=[CH:39][CH:38]=1)(=[O:35])=[O:36])([CH3:33])[CH3:32]
Reactant: Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
2-bromo-5-trityl-pyrrolo[2,3-b]pyrazin-7-amine (300 mg, 0.6588 mmol), (4-isopropylsulfonylphenyl)boronic acid (180.3 mg, 0.7906 mmol) and Na2CO3 (988.0 μL of 2 M, 1.976 mmol) combined in dioxane (3 mL) in a microwave tube and the mixture de-gassed (×2 vacuum-N2 cycles). Pd (tBu3P)2 (33.67 mg, 0.06588 mmol) added and the mixture de-gassed (×2 cycles) then heated at 65° C. (block temp), sealing tube with a crimp-top and left to stir for 1 hour. Reaction mixture cooled to ambient temperature and the mixture partitioned between DCM and water. Aqueous phase extracted with DCM and combined organics dried and concentrated. Residue purified by chromatography eluting with 0-30% MeOH-DCM. Brown/yellow solid obtained (332 mg, 90%). 1H NMR (400.0 MHz, DMSO) δ 8.67 (s, 1H), 8.35 (d, J=8.5 Hz, 2H), 7.91 (d, J=8.5 Hz, 2H), 7.35-7.25 (m, 15H), 7.01 (s, 1H), 4.59 (s, 2H), 3.57 (s, 1H), 3.49-3.40 (m, 1H), 1.29 (d, J=12.1 Hz, 2H) and 1.17 (d, J=6.8 Hz, 6H) ppm; MS (ES+) 559.17
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:18])([F:17])[C:7]1[CH:8]=[C:9]([OH:16])[C:10](=[CH:14][CH:15]=1)[C:11](O)=[O:12].[NH3:19].Cl>C1(C)C=CC=CC=1.CN(C)C=O>[OH:16][C:9]1[CH:8]=[C:7]([C:6]([F:18])([F:17])[F:5])[CH:15]=[CH:14][C:10]=1[C:11]([NH2:19])=[O:12]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Reactant: N
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(C(F)(F)F)cc1O
Reaction time: 0.17 h

Procedure:
Thionyl chloride (2.7 mL) and N,N-dimethylformamide (0.1 mL) were added to a toluene (50.0 mL) solution of 4-trifluoromethylsalicylic acid (5.0 g), and the reaction mixture was refluxed for 30 minutes. The reaction mixture was left to cool. The reaction mixture was then added dropwise to aqueous ammonia (50.0 mL) under ice cooling, and the reaction mixture was stirred at the same temperature for 10 minutes. The pH of the reaction mixture was adjusted to 3 with concentrated hydrochloric acid, and the reaction mixture was then extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 50:50). The title compound (1.84 g) was obtained as pale beige crystals.
Reaction SMILES: [CH:1]1([C@H:4]([NH:8]C(=O)[O-])[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1.C(Cl)(Cl)[Cl:13].Cl>CCO.O1CCOCC1.[Pd]>[ClH:13].[CH:1]1([C@H:4]([NH2:8])[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1
Reactant: ClC(Cl)Cl
Reactant: COC[C@@H](NC(=O)[O-])C1CC1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COC[C@@H](N)C1CC1
Yield: 100 %

Procedure:
To a solution of (S)-1-cyclopropyl-2-methoxyethylcarbamate (4.36 g, 17.5 mmol) from Part D in EtOH (80 mL) and CHCl3 (3 mL) in a Parr bottle was added 4 N HCl in dioxane (5 mL) and Pd/C (476 mg, 10%, wet, Degussa type). The mixture was placed on a Parr shaker under H2 atm at 45 psi for 16 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated then reconcentrated from hexanes (2×) to afford (S)-1-cyclopropyl-2-methoxyethanamine hydrochloride (2.65 g, 100% yield) as a white solid: mp 190-192° C.; [α]25D +14.3 (c 0.446, MeOH); 1H NMR (400 MHz, CDCl3) δ 8.41 (s br, 3H), 3.68 (d, J=5.6 Hz, 2H), 3.39 (s, 3H), 2.64-2.60 (m, 1H), 1.20-1.13 (m, 1H), 0.71-0.58 (m, 3H), 0.32-0.28 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 72.1, 59.2, 57.5, 10.7, 4.2, 4.1; LRMS (ESI) m/e 231.2 [(2M+H)+, calcd for C12H27N2O2 231.2].
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]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)=[N:10]1.Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH:31]([CH2:35][C:36]([OH:38])=[O:37])[CH2:30]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[NH:12][C:13]([CH2:20][N:29]2[CH2:34][CH2:33][O:32][CH:31]([CH2:35][C:36]([OH:38])=[O:37])[CH2:30]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)CC1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Yield: 41.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1-methyl-1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.36 g, 2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.47 g, 42%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH2:27](O)[CH3:28]>>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:27][CH3:28])=[O:14])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CCCc1c(OCCCCC(=O)O)ccc(C(C)=O)c1O
Agent: O=S(=O)(O)O
Product: CCCc1c(OCCCCC(=O)OCC)ccc(C(C)=O)c1O

Procedure:
Eleven grams of 5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid were dissolved in 200 ml. of absolute ethanol. With stirring, 1 ml. of sulfuric acid was added and the reaction was stirred overnight. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and dilute potassium carbonate solution. The ethyl acetate was separated, dried, and evaporated to give 9.9 g. of the title product, M+ =322.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N:14]2[CH2:15][CH:16]([CH2:17][OH:18])[O:19][CH:20]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(CC(C)NCC(O)CO)cc1OC
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(CC(C)N2CC(CO)OC2c2ccccc2)cc1OC

Procedure:
A mixture of 3-[3-(3,4-dimethoxyphenyl)-2-propylamino]-1,2-propanediol (14.3 g., 0.053 m.), benzaldehyde (12.7 g., 0.12 m.) and benzoic acid (0.3 g.) in toluene (45 ml.) is refluxed for 3 hours, collecting the water formed in a Dean-Stark trap. After washing with saturated NaHCO3 solution and with H2O (2x), the solvent is distilled under reduced pressure. Excess benzaldehyde is distilled at 100° C. at 0.1 mm. The residue, (II) (16.88 g., 89%) is used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]=[O:13])[C:5]([O:7][CH3:8])=[O:6].[CH2:14]=[CH:15][CH:16]=[CH2:17]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH:16]=[CH:15][CH2:14][O:13]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=CC=C
Reactant: COC(=O)c1ccc(N=O)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(N2CC=CCO2)c(Cl)c1
Temperature: 0 °C

Procedure:
1.00 g (5.01 mmol) methyl 3-chloro-4-nitroso-benzoate are placed in 10 ml chloroform and a freshly prepared solution of 1.10 g (20.3 mmol) butadiene in 6 ml chloroform is added dropwise with stirring at 0° C. The reaction mixture is stirred for 30 minutes at 0-10° C. and for 16 hours at ambient temperature, evaporated down i. vac. and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=19:1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(O)CO.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:27]4[CH2:28][CH2:29][CH2:30][N:24]([CH3:23])[CH2:25][CH2:26]4)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cnn(-c2ccc(I)cc2)c1)c1ccc(Cl)s1
Reactant: CN1CCCNCC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CN1CCCN(c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)cn3)cc2)CC1
Temperature: 85 °C
Yield: 5.2 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide (100 mg, 0.225 mmol), 1-methylhomopiperazine (0.100 mL, 0.81 mmol), ethylene glycol (0.025 mL, 0.45 mmol) and K3PO4 (100 mg, 0.47 mmol) in isopropanol (1 mL) was degassed with Argon before being charged with CuI (20 mg, 0.11 mmol). The mixture in a sealed tube was heated at 85° C. overnight. It was then purified by HPLC to give the title compound (5 mg). MS 430.0 and 432.0 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[C:7](/C(/C)=C/C(=O)C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][CH:21]([O-:23])[CH3:22].[CH3:24][CH:25]([O-])C.CC([O-])C.[Al+3].C(O)(C)C>>[Cl:1][C:2]1[CH:7]=[C:6](/[C:24](/[CH3:25])=[CH:20]/[CH:21]([OH:23])[CH3:22])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)/C=C(\C)c1cccc(-c2ccccc2)c1Cl
Reactant: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: C/C(=C\C(C)O)c1ccc(-c2ccccc2)c(Cl)c1
Reaction time: 5 h

Procedure:
80.0 Gm (0.296 mol) of (E)-4-(2-chloro-biphenylyl)-3-pentene-2-one were gently refluxed with 68.0 gm (0.333 mol) of aluminum isopropylate and 300 ml (3.92 mols) of isopropanol in a dry distillation apparatus with a 60-cm-Vigreux-column, such that only about 5 drops were distilled off per minute. After about 5 hours no acetone was found to be present in the distillate (using hydrochloric acid 2,4-dinitrophenyl-hydrazine solution) and in the reaction mixture no unreacted starting material could be found (by thin-layer-chromatography). The isopropanol was distilled off in a weak vacuum. The residue was hydrolyzed by addition of 300 gm of crushed ice. The ethereal (upper) phase, was decanted, and the aluminum hydrozide slurry was carefully washed with ether several times. The combined extracts were washed with water, with aqueous 5% sodium hydroxide and again with water, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized once from petroleum ether/ethyl acetate (ratio by volume = 4:1). Yield: 64.0 gm (79% of theory) of colorless crystals, m.p. 86°C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[N:8]=[C:9]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][C:18]2=O)=[O:15])[NH:10][C:11]=1[CH2:12][CH3:13].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1.CO>[Cl:6][C:7]1[N:8]=[C:9]([C:14]([NH:16][C@@H:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][C@H:18]2[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:15])[NH:10][C:11]=1[CH2:12][CH3:13]
Reactant: C1CCNC1
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2N2CCCC2)nc1Cl
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Pyrrolidine (45 μL, 0.539 mmol) and 3 Å molecular sieves (100 mg) were added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (100 mg, 0.270 mmol) in tetrahydrofuran (3 mL), and the mixture was heated at 50° C. for four hours. Methanol (3 mL), pyrrolidine (45.0 μL, 0.539 mmol), sodium cyanoborohydride (51 mg, 0.809 mmol) and acetic acid (154 μL, 2.70 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain two isomers of the title compound, 21 mg of the cis isomer (18%) and 9 mg of the trans isomer (8%), as pale yellow oily substances.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]1([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3([C:32]4[NH:33][CH2:34][CH2:35][N:36]=4)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[N:11]1([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3([C:32]4[NH:36][CH:35]=[CH:34][N:33]=4)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: c1cc(C2(C3=NCCN3)CCOCC2)ccc1OCCCN1CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: c1c[nH]c(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
Dimethylsulphoxide (0.156 mL, 2.19 mmol) and dichloromethane (15 mL) were combined and cooled to −78° C. under nitrogen, oxalyl chloride (0.191 mL, 2.19 mmol) was added and the reaction mixture was stirred at −78° C. under nitrogen for 1 hour. A solution of 2-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}4,5-dihydro-1H-imidazole (0.314 g, 0.88 mol) in dichloromethane (15 mL) was added slowly. The reaction was stirred at −78° C. for 1 hour. Triethylamine (0.611 mL, 4.4 mmol) was then added and the reaction was stirred for a further hour. The reaction mixture allowed to warm to room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (100 mL) and washed with an aqueous ammonia solution (20 mL). The organic was dried over sodium sulphate, filtered and concentrated in vacuo to provide a yellow oil. This was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 to 90:10:1) to provide a yellow oil, which was triturated with diethyl ether. A cream solid was filtered to provide the title compound (0.07 g, 22%). 1H NMR (400 MHz, CDCl3) δ 1.80 (m, 4H), 2.05 (m, 2H), 2.30 (m, 2H), 2.50 (m, 2H), 2.60-2.78 (m, 6H), 3.73 (m, 2H), 3.83 (m, 2H) (4.0 (t, 2H), 6.85 (d, 2H), 6.95 (s, 2H), 7.15 (d, 2H). HRMS ESI+ m/z 356.2327 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.[CH2:15]([N:17]([CH2:30][CH3:31])[C:18]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:19]=1[C:20](O)=[O:21])[CH3:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:9]3[CH2:10][N:11]([C:20]([C:19]4[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:18]=4[N:17]([CH2:30][CH3:31])[CH2:15][CH3:16])=[O:21])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1
Reactant: Clc1ccc2sc3c(c2c1)CCNC3
Reactant: CCN(CC)c1ccc([N+](=O)[O-])cc1C(=O)O
Product: CCN(CC)c1ccc([N+](=O)[O-])cc1C(=O)N1CCc2c(sc3ccc(Cl)cc23)C1

Procedure:
The title compound was prepared in analogy to Example 1 using 6-chloro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-c]pyridine [29078-50-0] and 2-(diethylamino)-5-nitro-benzoic acid [727718-14-1]. MS (m/e): 444.1 (M+H+).
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]1.[C:18]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([N:26]=[C:27]=[O:28])=[O:25])=[CH:22][CH:21]=1)#[N:19].C(#N)C>C(N(CC)CC)C>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:26][C:27]([N:5]2[CH2:6][CH2:7][CH:8]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:10]2)=[O:28])=[O:25])=[CH:29][CH:30]=1)#[N:19]
Reactant: CCOC(=O)COC1CCNCC1
Reactant: N#Cc1ccc(C(=O)N=C=O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOC(=O)COC1CCN(C(=O)NC(=O)c2ccc(C#N)cc2)CC1
Yield: 54 %

Procedure:
In a similar manner to Example 1, starting material step (a), the product from step (b) (1.7 g), 4-cyanobenzoyl isocyanate (1.1 g), acetonitrile (100 ml total) and triethylamine (2.1 ml) were stirred at ambient temperature overnight. The mixture was evaporated and the residue was purified by column chromatography on silica eluting with 5% ethanol/dichloromethane to give ethyl N-[N-(4-cyanobenzoyl)carbamoyl]piperidin-4-yloxyacetate (1.24 g) as a pale yellow oil: NMR Spectrum (DMSO-d6) 1.21 (3H, t), 1.50 (2H, m), 1.87 (2H, m), 3.20 (2H, m), 3.67 (3H, m), 4.12 (2H, q), 4.15 (2H, s), 7.97 (4H, s), 10.40 (1H, br s); Mass Spectrum m/Z 360 (M+H)+.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:13][C:12]([F:14])([F:15])[C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][NH2:1])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])C=Cc1ccc(C(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCCc1ccc(C(F)(F)F)cc1

Procedure:
In close analogy to the procedure described above, 1-(2-Nitro-vinyl)-4-trifluoromethyl-benzene is reacted with lithium aluminium hydride to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[H-].[Na+].[N+]([C:15]1[CH:16]=[C:17]([CH3:22])[N+:18]([O-:21])=[CH:19][CH:20]=1)([O-])=O>CN1CCCC1=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[CH:19][N+:18]([O-:21])=[C:17]([CH3:22])[CH:16]=2)=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(Br)c(F)c2)cc[n+]1[O-]
Temperature: 180 °C
Yield: 38.6 %

Procedure:
To a room temperature solution of 4-bromo-3-fluorophenol (6 g, 31.41 mmol) in N-methylpyrrolidone (20 ml) was added sodium hydride (1.34 g, 56 mmol, 60% in mineral oil) portionwise. After stirring for 10 minutes 4-nitro-2-picoline N-oxide (5.6 g, 36.12 mmol) was added. The reaction mixture was heated at 180° C. for 60 minutes under microwave irradiation. After cooling to room temperature the mixture was diluted with EtOAc (250 ml) and washed with water (250 ml). The solution was then extracted with additional EtOAc (2×150 ml) The combined organic extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM to DCM/MeOH(NH3) up to 2% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 13 (3.61 g, 39%).
Reaction SMILES: Cl[C:2]1[CH:33]=[CH:32][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([N:17]3[CH2:22][CH:21]4[CH:19]([CH:20]4[C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH2:18]3)=[O:16])[CH:12]=[CH:11][C:10]=2[CH3:31])=[O:7])=[CH:4][N:3]=1.[CH:34]([NH2:37])([CH3:36])[CH3:35].C([O-])(O)=O.[Na+]>CS(C)=O>[CH:34]([NH:37][C:2]1[CH:33]=[CH:32][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([N:17]3[CH2:18][CH:19]4[CH:21]([CH:20]4[C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH2:22]3)=[O:16])[CH:12]=[CH:11][C:10]=2[CH3:31])=[O:7])=[CH:4][N:3]=1)([CH3:36])[CH3:35]
Reactant: CC(C)N
Reactant: COc1ccc(C2C3CN(C(=O)c4ccc(C)c(NC(=O)c5ccc(Cl)nc5)c4)CC32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C2C3CN(C(=O)c4ccc(C)c(NC(=O)c5ccc(NC(C)C)nc5)c4)CC32)cc1
Temperature: 120 °C
Yield: 36 %

Procedure:
A mixture of 6-chloro-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide (compound 118.11, 0.107 g, 0.23 mmol) and isopropylamine (1.5 mL) in DMSO (1.5 mL) was heated at 120° C. in a sealed pressure tube overnight. After cooling to room temperature, the reaction mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc (3×). The combined organic extract was dried over MgSO4, filtered and concentrated. The residue was triturated with hexane to give the title compound as a white powder (40 mg, 36% yield). MS [M+H]+: 485. 1H-NMR (DMSO-d6, 400 Hz) δ 9.63 (s, 1H), 8.69 (d, J=3 Hz, 1H), 7.95-7.90 (m, 1H), 7.55-7.51 (m, 1H), 7.39-7.30 (m, 2H), 7.10-7.03 (m, 3H), 6.84 (d, J=9.2 Hz, 2H), 6.52 (d, J=9.2 Hz, 1H), 4.17-4.07 (m, 2H), 3.85-3.77 (m, 1H), 3.74 (s, 3H), 3.65-3.51 (m, 2H), 2.30 (s, 3H), 1.87 (s, 2H), 1.69 (t, J=3.7 Hz, 1H), 1.20 (d, J=7.2 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[C:12]([OH:13])=[CH:11][CH:10]=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[Br:14]Br>C(O)(=O)C>[Br:14][C:11]1[CH:10]=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]2=[C:2]([OH:1])[C:12]=1[OH:13])=[O:6]
Reactant: O=C1NC(=O)c2c1ccc(O)c2O
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1NC(=O)c2c1cc(Br)c(O)c2O

Procedure:
3,4-Dihydroxyphthalimide (Example 4e) was heated with bromine in acetic acid for about 6 hours to give 5-bromo-3,4-dihydroxyphthalimide which was subsequently treated in a manner similar to Example 1f)-h).