Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: OCC(F)(F)F
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(OCC(F)(F)F)n4)cc3)cc12

Procedure:
Using trifluoroethanol and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 466 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:29]12([C:39](=[O:42])[CH2:40]Br)[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[C:29]12([C:39](=[O:42])[CH2:40][N:9]3[C:10](=[O:11])[C:5]4[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=4[N:7]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([C:20]5[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=5)=[CH:16][CH:15]=4)[C:8]3=[O:12])[CH2:36][CH:35]3[CH2:34][CH:33]([CH2:32][CH:31]([CH2:37]3)[CH2:30]1)[CH2:38]2
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)C34CC5CC(CC(C5)C3)C4)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.7 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 1-(1-adamantyl)-2-bromoethanone (1.0 g) and N,N-dimethylformamide (8 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with ethyl acetate, successively washed with water and saturated brine and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.68 g, 47%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:13](=[O:15])[N:11]([CH3:12])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[CH:6]1.Cl[CH2:19][CH:20]([OH:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[O:22]([CH2:21][CH:20]([OH:29])[CH2:19][NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:13](=[O:15])[N:11]([CH3:12])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[CH:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cn1c(=O)c2c(ncn2CCCN)n(C)c1=O
Reactant: OC(CCl)COc1ccccc1
Solvent: CCO
Product: Cn1c(=O)c2c(ncn2CCCNCC(O)COc2ccccc2)n(C)c1=O
Reaction time: 8 h

Procedure:
A mixture of 75 g of 7-(3-aminopropyl)-theophylline and 27.4 g of 1-chloro-3-phenoxy-2-propanol is heated for 8 hours at 130° to 140° C. After the melt has been cooled to 70°-90° C., ethanol is added to it, followed by brief boiling under reflux. After standing overnight, the untreated and precipitated aminopropyl theophylline hydrochloride is filtered off under suction, the filtrate is acidified with alcoholic hydrochloric acid, heavily concentrated and acetone added until crystallisation begins. The reaction product then separates and is recrystallised from methanol. Yield 30.2 g. Melting point of the hydrochloride: 183°-186° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[CH2:13][C:14]#[C:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[O:17][CH2:16][C:15]#[C:14][CH2:13][CH:11]1[CH2:12][CH:10]1[CH2:9][OH:8]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC1CC#CCOC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCC1CC1CC#CCOC1CCCCO1
Reaction time: 1 h
Yield: 111.5 %

Procedure:
The 2-(4-tetrahydropyranyloxy-2-butynyl)cyclopropylmethyl t-butyldimethylsilyl ether (5.8 g, 17.2 mmol) was dissolved in tetrahydrofuran (50 ml), and a tetrabutyl ammonium fluoride (factor=1.0) tetrahydrofuran solution (33 ml, 33 mmol) was added thereto at 0° C. The mixture was stirred for one hour. The product was purified by column chromatography to obtain 2-(4-tetrahydropyranyloxy-2-butynyl)cyclopropylmethanol (4.3 g).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([S:7]([OH:10])(=[O:9])=[O:8])[CH:4]=[C:3]([NH2:11])[CH:2]=1.[CH2:12]([O:14][C:15](=[O:29])[CH:16]([CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17](=O)[CH3:18])[CH3:13].[OH-].[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:20]=[C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:11]([C:3]2[CH:2]=[CH:1][CH:6]=[C:5]([S:7]([OH:10])(=[O:8])=[O:9])[CH:4]=2)[C:17]=1[CH3:18])=[O:29])[CH3:13]
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(S(=O)(=O)O)c2)c1C

Procedure:
Metanilic acid (5 mmol, 0.9 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), sodium hydroxide (5 mmol, 0.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The unreacted metanilic acid was precipitated on ice and filtered from the reaction mixture. The filtrate was evaporated to yield an oil, which was purified over silica gel. After standing, the named product solidified as purple crystals (m.p. 94° C.-96° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH:19]=O.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CN(C)C(=O)C>[NH2:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:19]([C:18]1[CH:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:16]([O:15][CH3:14])[CH:17]=1)[NH:6][C:4]2=[O:5]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)cc(-c2nc3ccc(N)cc3c(=O)[nH]2)c1
Temperature: 150 °C
Reaction time: 17 h

Procedure:
A mixture of 2-amino-5-nitro-benzamide (1.81 g, 10.0 mmol), 3,5-dimethoxy-benzaldehyde (1.83 g, 11.0 mmol), sodium hydrogen sulfite (58.5 wt %, 3.94 g, 22.0 mmol), and p-toluenesulfonic acid monohydrate (0.38 g, 2.00 mmol) in N,N-dimethylacetamide (20 mL) was stirred at 150° C. for 17 hours under nitrogen and then cooled to room temperature. Saturated aqueous NaHCO3 (approximately 1 mL) was added. The mixture was stirred at room temperature for 2 hours, then concentrated to dryness. Water (80 mL) was added, stirred for 0.5 hours, and filtered. The solid was air dried. The crude compound was purified by column chromatography (silica gel 230-400 mesh; ethyl acetate as eluent) to give 6-amino-2-(3,5-dimethoxy-phenyl)-3H-quinazolin-4-one as a yellow solid. Yield: 1.50 g (50%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CCCCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Product: CCCCCCCCCCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.087 g, 0.313 mmol) was reacted with N-(2-azidoethyl)palmitamide (0.102 g, 0.313 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-palmitamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.29 (s, 1H), δ 6.78 (t, 1H), δ 6.41 (s, 1H), δ 6.19 (s, 2H), δ 4.39 (t, 2H), δ 3.67 (q, 2H), δ 2.61 (t, 2H), δ 2.12 (t, 2H), δ 2.07 (t, 2H), δ 1.42 (m, 13H), δ 1.42 (m, 2H), δ 1.32 (m, 22H), 0.81 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 176.8, 174.3, 173.9, 149.5, 148.3, 121.9, 106.4, 85.0, 67.2, 51.1, 49.5, 39.5, 39.1, 38.1, 36.8, 36.7, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 29.3, 28.9, 28.3, 28.2, 27.9, 25.9, 25.6, 22.9, 14.3 ppm; HRMS (ESI) calcd for C33H59N7O3(M+) 601.4679, found 601.4671, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)palmitamide hydrochloride (0.155 g, 92% yield). 1H NMR (300 MHz, CD3OD) δ 8.59 (s, 1H), δ 6.53 (s, 1H), δ 4.72 (s, 2H), δ 3.75 (S, 2H), δ 2.90 (s, 2H), δ 2.54 (s, 2H), δ 2.16 (t, 2H), δ 1.80 (s, 2H), δ 1.69 (s, 2H), δ 1.51 (s, 4H), δ 1.28 (bs, 24H), δ 0.71 (t, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 175.7, 147.2, 145.6, 128.4, 127.6, 108.6, 67.2, 52.7, 37.4, 36.5, 35.8, 31.9, 29.7, 29.5, 29.4, 29.2, 28.0, 27.9, 27.8, 27.7, 25.8, 24.1, 23.6, 23.2, 22.6 ppm; HRMS (ESI) calcd for C28H51N7O (M+) 501.4155, found 501.4143.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:26])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[CH:18]=3)=[N:13]2)=[O:8])[N:6]=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>N1C=CC=CC=1>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([NH:31][CH2:30][CH2:29][O:28][CH3:27])[S:3][CH:4]=3)=[O:8])[CH3:26])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: COCCN
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(Br)n1
Solvent: c1ccncc1
Product: COCCNc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Temperature: 120 °C
Yield: 47.8 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide (0.2 g, 0.444 mmol) and dry pyridine were added into a microwave vial under nitrogen atmosphere. 2-methoxyethylamine (0.193 ml, 2.219 mmol) was added and the mixture was heated with microwaves at 120° C. for 10 h. Afterwards a total of 0.232 ml of 2-methoxyethylamine was added and the mixture was heated for another 10 h. The product was purified by Flash-chromatography. Yield 47.8%. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 3.41 (s, 3H), 3.44 (m, 2H), 3.57 (m, 2H), 4.29 (dd, 1H), 4.40 (dd, 1H), 4.54 (m, 1H), 5.39 (t, 1H), 6.62 (d, 1H), 7.33 (d, 1H), 7.49 (d, 1H), 7.68 (dd, 1H), 7.69 (d, 1H), 7.83 (dd, 1H), 7.98 (dd, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH3:34])[CH:29]=[CH:28]3)[C:22]([OH:35])=[C:21]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:47]>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH3:34])[CH:29]=[CH:28]3)[C:22]([O:35][CH3:47])=[C:21]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccc2cc(-c3nc(OCc4ccccc4)c(C(=O)OCc4ccccc4)c(OCc4ccccc4)c3O)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(-c2ccc3c(ccn3C)c2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
Into a solution of benzyl 2,4-bis(benzyloxy)-5-hydroxy-6-(1-methyl-1H-indol-5-yl)nicotinate (80 mg, 0.14 mmol) in DMF (0.3 mL) was added 60% NaH (7.3 mg, 0.18 mmol). After 15 min, iodomethane (13 μL, 0.20 mmol) was added. The mixture was stirred at room temperature for another 30 min and then loaded directly onto a silica column and chromatographed to give benzyl 2,4-bis(benzyloxy)-5-methoxy-6-(1-methyl-1H-indol-5-yl)nicotinate (73 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:12](=O)[CH2:11][S:10](=[O:16])(=[O:15])[CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>O1CCOCC1.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:12](=[S:28])[CH2:11][S:10](=[O:16])(=[O:15])[CH2:9]2)[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)CC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)CC(=S)N1
Temperature: 80 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
To a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1λ6-thio morpholin-3-one (3.11 g, 9.25 mmol, Eq: 1.00) in dioxane (72.3 ml) was added Lawesson's reagent (2.99 g, 7.4 mmol, Eq: 0.8) at 23° C. The mixture was stirred for 2 hours at 80° C. Diluted with sat. NaHCO3-sol., extracted with ethyl acetate, washed with brine, dried over Na2SO4 and filtered off. Removal of solvent in vacuum left a yellow oil (5.8 g), which was purified by flash chromatography on 50 g silica gel with 0-50% ethyl acetate in heptane to give the (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1λ6-thio morpholin-3-thione (2.7 g, 7.67 mmol, 82.9% yield) as a light yellow foam. MS (ISN): m/z=350.1 [M−H]− and 352.2 [M+2−H]−.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[CH2:15][CH:16]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: C1=C(c2nc3ccccc3s2)CCNC1
Agent: Cl
Product: N#Cc1ccc(CN2CC=C(c3nc4ccccc4s3)CC2)cc1
Yield: 60.3 %

Procedure:
4-(Benzothiazol-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (300 mg, 1.2 mmol) was reacted with α-bromo-p-tolunitrile (280 mg, 1.44 mmol) as exemplified in Example 1. The crude product was purified by flash chromatography eluting with 25% ethyl acetate in petroleum spirit to give a solid. Recrystallisation of this solid from ethyl acetate yielded the title compound as a yellow solid (240 mg, 60%) mp. 165°-166° C. (Found: C, 72.00; H, 4.92; N, 12.61. C20H17N3S requires C, 72.48; H, 5.17; N, 12.68%). δH (CDCl3), 2.76 (2H, m, NCH2CH2), 2.83 (2H, m, NCH2CH2), 3.24 (2H, m, NCH2CH2), 3.72 (2H, s, NCH2Ar), 6.68 (1H, m, NCH2CH), 7.41 (4H, m, ArH), 7.51 (1H, d, J 8.4Hz, ArH), 7.64 (1H, d, J 8.4Hz, ArH), 7.83 (1H, d, J 7.0Hz, ArH), 8.00 (1H, d, J 8.3Hz, ArH). m/z (ES+) 332 (M+1)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8])(=[O:3])[CH3:2].Br[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:36]=[CH:35][C:28]2[C:29](=[O:34])[CH:30]=[C:31]([CH3:33])[O:32][C:27]=2[CH:26]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:36]=[CH:35][C:28]3[C:29](=[O:34])[CH:30]=[C:31]([CH3:33])[O:32][C:27]=3[CH:26]=2)[CH2:12][CH2:11]1)=[O:8])(=[O:3])[CH3:2]
Reactant: Cc1cc(=O)c2ccc(OCCCBr)cc2o1
Reactant: CC(=O)Oc1ccccc1C(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1ccccc1C(=O)NC1CCN(CCCOc2ccc3c(=O)cc(C)oc3c2)CC1

Procedure:
A mixture of 4.9 g. (0.02 mol) 4-(2-acetoxybenzamido)-piperidine, 5.6 g. (0.02 mol) 7-(3-bromopropoxy)-2-methyl-4H-1-benzopyran-4-one, 13.9 ml. (0.10 mol) triethylamine and 100 ml. tetrahydrofuran is heated under reflux for 10 hours and then evaporated. The 7-{3-[4-(2-acetoxybenzamido)-piperidino]-propoxy}-2-methyl-4H-1-benzopyran-4-one obtained as a crude product is mixed with 100 ml. 1 N aqueous sodium hydroxide solution, stirred for 1 hour, filtered, washed with ethyl acetate and the aqueous phase then neutralised. The precipitate obtained is taken up in acetone, mixed with excess ethereal hydrochloric acid and the dihydrochloride of the desired end product isolated; m.p. 169°-170° C. The yield is 4.6 g. (45% of theory).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])=O.[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[NH2:22]>CO>[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[O:23][CH:2]=[C:3]([C:5]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=2[O:12][CH3:13])[N:22]=1
Reactant: COC(=O)CCCCC(N)=O
Reactant: COc1ccc(Cl)cc1C(=O)CBr
Solvent: CO
Product: COC(=O)CCCCc1nc(-c2cc(Cl)ccc2OC)co1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine 2-bromo-1-(5-chloro-2-methoxy-phenyl)-ethanone (12.0 g, 46 mmol) with 5-carbamoyl-pentanoic acid methyl ester (12.7 g, 79.9 mmol) and heat the neat mixture in a sealed vessel at 120-140° C. for about 6 h. Cool the mixture and add methanol and allow the mixture to stir overnight at room temperature. Concentrate the mixture and partition the residue between aq NaHCO3 and EtOAc. Dry the combined extracts over Na2SO4 and concentrate. Chromatography over silica gel (CHCl3) allows for recovery of 5-[4-(5-chloro-2-methoxy-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (5.5 g, 37%). MS (ES): (M+1)+ 324.1, 326.1 m/z.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([Br:14])=[CH:16][CH:17]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: Nc1ccc(Br)cc1
Solvent: CO
Product: COc1cc(C=Nc2ccc(Br)cc2)cc(OC)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
3,5-Dimethoxy-4-hydroxybenzaldehyde (1 g, 5.46 mmol) was dissolved in methanol (50 ml) and 4-bromoaniline (939 mg, 5.46 mmol) was added. The resultant reaction solution was stirred overnight at room temperature under nitrogen to give a precipitate that was collected by filtration to yield light yellow fine crystals (860 mg) of the title product: 1H NMR (300 MHz, CDCl3); δ 8.30 (S, 1H), 7.49 (d, J=9 Hz, 2H), 7.16 (S, 2H), 7.07 (d, J=9 Hz, 2H), 5.86 (S, 1H), 3.98 (S, 6H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][C:23]4(OCC(C)(C)C[O:26]4)[CH2:22]3)[C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.Cl>CC(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)[C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH2:2][CH2:3]1
Reactant: CC1(C)COC2(CC[C@H](C[C@@H](C(=O)O)c3ccc(S(=O)(=O)C4CC4)c(C4CC4)c3)C2)OC1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CC[C@H](C[C@@H](C(=O)O)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Yield: 100 %

Procedure:
A mixture of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R)-8,8-dimethyl-6,10-dioxaspiro[4.5]dec-2-yl]propionic acid (22 g), 4 M hydrochloric acid (22 mL), and acetone (88 mL) was stirred under heating and reflux for 2 hours. The solvent was evaporated under reduced pressure, and then to the residue were added ethyl acetate/water (1/3, 300 mL) and sodium hydroxide (5.7 g) under ice-cooling. To the aqueous layer was added concentrated hydrochloric acid under ice-cooling to adjust the pH to 1, and chloroform was added thereto. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propionic acid (17.9 g) as a colorless amorphous substance.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=3)[S:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=3)[S:9][C:5]=2[CH:4]=1
Reactant: COc1cccc(-c2nc3ccc(OC)cc3s2)c1
Agent: BrB(Br)Br
Product: Oc1cccc(-c2nc3ccc(O)cc3s2)c1
Yield: 31 %

Procedure:
6-Methoxy-2-(3-methoxy-phenyl)-benzothiazole (54 mg, 0.199 mmol) was treated with boron tribromide under standard condition to give 6-hydroxy-2-(3-hydroxy-phenyl)-benzothiazole (15 mg, 31% yield) as a yellow solid. Mass spec: MH+=244.
Reaction SMILES: [BH4-].[Na+].[I-].[Cl:4][C:5]1[CH:27]=[CH:26][C:8]2[C:9]3[C:10](=[CH:22][N:23]([CH3:25])[CH:24]=3)[CH2:11][N+:12]([CH3:21])=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]=2[CH:6]=1>CO>[Cl:4][C:5]1[CH:27]=[CH:26][C:8]2[C:9]3[C:10](=[CH:22][N:23]([CH3:25])[CH:24]=3)[CH2:11][N:12]([CH3:21])[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]=2[CH:6]=1
Reactant: Cn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+](C)C2
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CN1Cc2cn(C)cc2-c2ccc(Cl)cc2C1c1ccccc1Cl
Reaction time: 0.33 h

Procedure:
Portionwise 0.2 g (52 mmol) of sodium borohydride was added to a solution of 3.0 g (6.3 mmol) of 8-chloro-6-(2-chlorophenyl)-2,5-dimethyl-2H,4H-pyrrolo[3,4-d][2]benzazepin-5-ium iodide in 50 ml of methanol which was cooled to 0°. The mixture was stirred at 0° for 20 min followed by the removal of the methanol at reduced pressure. The residue was partitioned between methylene chloride and water. The methylene chloride solution was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a pale yellow oil. Crystallization from ether gave colorless crystals, mp 154°-155°.
Reaction SMILES: [CH:1](=[C:11]1/[C:12](=[O:17])[NH:13][C:14](=[O:16])[S:15]/1)\[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH:1](=[C:11]1/[C:12](=[O:17])[N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](=[O:16])[S:15]/1)\[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)CBr
Reactant: CCCCCCCCC/C=C1\SC(=O)NC1=O
Product: CCCCCCCCC/C=C1\SC(=O)N(CC(=O)OCC)C1=O

Procedure:
TZD10EA was prepared according to General Procedure A2 presented hereinabove using (Z)-5-decylidenethiazolidine-2,4-dione and ethyl 2-bromoacetate as reactants.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.B(O)(O)[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1>>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=[C:2]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:7]2[N:8]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Product: Cc1ccc(-c2cc(N)nc3cc(C)nn23)cc1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that 7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J) and p-tolylboronic acid were used as starting materials.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[N:3]=[CH:2]1>C(Cl)Cl.O=[Mn]=O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCc1ccc2scnc2c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ccc2scnc2c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of benzothiazol-5-yl-methanol (1 eq.) in DCM was added MnO2 (10 eq.). The dark suspension was stirred at 20° C. for 15 h, filtered through a pad of celite and the solvent removed under reduced pressure to afford benzothiazole-5-carbaldehyde which was used as such without further purification.