Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][S:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[S:19][CH3:18]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: CSc1ccccc1N
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3ccccc3SC)c2cc1OC
Yield: 52.4 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.139 g of 2-(methylmercapto)aniline, 20 mg of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrogen chloride to adjust pH to 7. The product was collected, washed with water, and dried to give 0.184 g of 6,7-dimethoxy-4-(2-methylsulfanyl-phenylamino)-quinoline-3-carbonitrile as a solid, mp 245-247° C.; mass spectrum (EI, m/e): M 351.1051.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+].Cl>CN(C)C=O>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:8][CH:9]=1
Reactant: OCCCCCCCCBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCCCCCCOc1ccc(OC(F)(F)F)cc1
Temperature: 80 °C

Procedure:
A mixture of 5.0 g of 4-(trifluoromethoxy)phenol, 5.87 g of 8-bromo-1-octanol, and 7.76 g of K2CO3 in 56 ml of anhydrous dimethylformamide is stirred and heated at 80° C. for 16 hours. The reaction mixture is poured into dilute HCl solution and the mixture is extracted three times with ethyl acetate. The combined extracts are washed with brine and dried over MgSO4. After filtration and concentration, the crude product is purified by flash chromatography on silica gel, eluting with a 4:1 hexane/ethyl acetate mixture to give the title compound 8-(4-(trifluoromethoxy)-phenoxy)-1-octanol.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[C:8]([NH:32][C:33](=[O:36])[CH2:34]Cl)=[C:9]([C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:16]=3)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH3:4]>CN(C=O)C>[C:3]([NH:6][C:7]1[C:8]2[NH:32][C:33](=[O:36])[CH2:34][N:14]3[C:15]4[CH:16]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:18]=[CH:19][C:20]=4[C:21]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[C:13]3[C:9]=2[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc(NC(C)=O)c3NC(=O)CCl)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Nc1c(NC(C)=O)cccc1-3
Reaction time: 1 h
Yield: 94 %

Procedure:
NaH (60% dispersion in mineral oil) (1.7 eq) was added to a stirred solution of methyl 2-{3-(acetylamino)-2-[(chloroacetyl)amino]phenyl}-3-cyclohexyl-1H-indole-6-carboxylate in anhydrous DMF (0.02 M) at RT under N2. The reaction was stirred vigorously for 1 h before quenching with 1N HCl (aq) and extracting into EtOAc. The aqueous phase was extracted a second time with EtOAc and the combined organics washed well with 1N HCl (aq), water and brine before being dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a brown glass (94%). The material was taken on in the subsequent step without further purification. MS (ES+) m/z 446 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[S:26]([CH2:30][CH2:31][NH2:32])[CH2:27][CH2:28][NH2:29]>>[NH2:29][CH2:28][CH2:27][S:26][CH2:30][CH2:31][NH:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: NCCSCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCSCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2′-sulfanediyldiethanamine. MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (dd, J=7.83, 1.26 Hz, 1 H), 7.84 (d, J=7.33 Hz, 1 H), 7.65 (td, J=7.58, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.51-7.39 (m, 2 H), 7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.03 (s, 1 H), 5.14 (s, 2 H), 3.65-3.50 (m, 4 H), 2.92-2.79 (m, 4 H), 2.78-2.68 (m, 2 H), 2.42 (s, 3 H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[N:4]1.[I-].[Na+].Cl[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[C:32]([CH3:42])=[N:33][N:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:35]=4)[CH2:26][CH2:25]3)=[N:20][CH:21]=[CH:22][N:23]=2)=[CH:14][CH:13]=1>CN(C=O)C>[CH3:42][C:32]1[C:31]([CH2:30][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[C:18]([C:15]4[CH:16]=[CH:17][C:12]([CH2:11][N:4]5[N:5]=[CH:6][CH:7]=[N:3]5)=[CH:13][CH:14]=4)=[N:23][CH:22]=[CH:21][N:20]=3)[CH2:29][CH2:28]2)=[CH:35][N:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:33]=1
Reactant: c1c[nH]nn1
Reactant: Cc1nn(-c2ccccc2)cc1CN1CCN(c2nccnc2-c2ccc(CCl)cc2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)cc1CN1CCN(c2nccnc2-c2ccc(Cn3nccn3)cc2)CC1
Reaction time: 1 h
Yield: 18.5 %

Procedure:
Add sodium hydride (173 mg, 4.33 mmol) to a solution of 1H-1,2,3-triazole (308 mg, 4.33 mmol) in DMF (3 mL). Maintain stirring under nitrogen for 1 hr then add sodium iodide (162 mg, 1.08 mmol) and a solution of 3′-(4-Chloromethyl-phenyl)-4-(3-methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (495 mg, 1.08 mmol) in DMF (8 mL). Maintain stirring under nitrogen for 20 hr. Quench by adding water (10 mL), wash with DCM (3×10 mL) and discard the aq. phase. Concentrate to dryness to give a mixture of 4-(3-Methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3′-(4-[1,2,3]triazol-1-ylmethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl and 4-(3-Methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3′-(4-[1,2,3]triazol-2-ylmethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl. Purify first by preparative HPLC then by SCX-2® ion exchange chromatography, eluting with 2 M NH3 in MeOH. to give 4-(3-methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3′-(4-[1,2,3]triazol-2-ylmethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (98 mg). MS (ES): m/z=492 [M+H]+ 2 min.
Reaction SMILES: [SH:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[O-]CC.[Na+].[CH3:19][N:20]([CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl>CN(C)C=O>[CH3:19][N:20]([CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(C)CCCCCCCl
Reactant: O=C(c1cccs1)c1cccnc1S
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCCCCSc1ncccc1C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50 ml of dimethylformamide are added 4.4 g of 2-mercapto-3-(2-thenoyl)pyridine and 1.5 g of sodium ethoxide The mixture is stirred at room temperature for 30 minutes. Thereto, 4.0 g of 6-dimethylaminohexyl chloride is added, and the mixture is stirred at room temperature for 24 hours. The mixture is poured into ice-water, followed by extraction with toluene. The extract is washed with water, and the solvent is distilled. The residue is subjected to silica gel column chromatography with chloroform as the eluent, and recrystallized from isopropyl ether to give 2-(6-dimethylaminohexylthio)-3-(2-thenoyl)pyridine, m.p. 69°-71° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1.CC1C=CC=CC=1OCC(Cl)=O>>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1)=[O:8]
Reactant: Cc1ccccc1OCC(=O)O
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: Cc1ccccc1OCC(=O)Cl
Product: Cc1ccccc1OCC(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 47.5 %

Procedure:
(2-Methylphenoxy)acetic acid (32 mg, 0.193 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, and (2-methylphenoxy)acetic acid chloride mentioned above, the title compound (21 mg, yield 48%) was obtained in the same manner as that of Example 1.
Reaction SMILES: C(OC(=O)C(OC1C=CC(OCCC2N=C(C3C=CC=CC=3)OC=2C)=CC=1CBr)(C)C)C.C1C(O)=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+].C([O:49][C:50](=[O:85])[C:51]([CH3:84])([O:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH2:61][CH2:62][C:63]2[N:64]=[C:65]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[O:66][C:67]=2[CH3:68])=[CH:56][C:55]=1[CH2:75][O:76][C:77]1[CH:78]=[C:79]([CH3:83])[CH:80]=[CH:81][CH:82]=1)[CH3:52])C.[OH-].[Na+]>C(O)C>[CH3:84][C:51]([O:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH2:61][CH2:62][C:63]2[N:64]=[C:65]([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)[O:66][C:67]=2[CH3:68])=[CH:56][C:55]=1[CH2:75][O:76][C:77]1[CH:78]=[C:79]([CH3:83])[CH:80]=[CH:81][CH:82]=1)([CH3:52])[C:50]([OH:85])=[O:49]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1COc1cccc(C)c1
Agent: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1cccc(O)c1
Solvent: CCO
Product: Cc1cccc(OCc2cc(OCCc3nc(-c4ccccc4)oc3C)ccc2OC(C)(C)C(=O)O)c1
Temperature: 80 °C
Yield: 38 %

Procedure:
General procedure for the parallel synthesis of analogs using the DynaVac Carousel apparatus: A 50 mL glass tube with screw cap and nitrogen inlet was charged with 2-{2-bromomethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methyl-propionic acid ethyl ester (0.040 g, 0.080 mmol), m-cresol (0.012 mL, 0.12 mmol), absolute ethanol (1 mL), and then potassium carbonate (0.022 g, 0.16 mmol; 325 mesh). The mixture was heated to 80° C. for 4 h. MS analysis of the reaction indicated that 2-methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-m-tolyloxymethylphenoxy}-propionic acid ethyl ester: MS (ES) m/e 530 (M+1) had formed. The reaction mixture was treated with 2N NaOH (0.4 mL), heated at 55° C. for 3 h, cooled, and concentrated. The residue was treated with 5N HCl (0.75 mL) and CH2Cl2 (1 mL) and was poured onto a 3-mL ChemElute cartridge to remove the aqueous layer. The cartridge was washed with CH2Cl2, and the solvent was removed in vacuo. The crude residue was purified by mass-directed reverse phase HPLC to provide the title compound (0.032 g, 38%). MS (ES) m/e 502 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[N:11]=2)=[CH:4][CH:3]=1.[CH:15]1([N:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:21]=3[CH2:20][CH2:19]2)[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.C(O)(=O)C.CN(C=O)C>[CH:15]1([N:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[C:26]([NH:29][C:9]([C:10]([NH:11][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])([CH3:13])[CH3:12])=[O:14])[CH:27]=[CH:28][C:21]=3[CH2:20][CH2:19]2)[CH2:16][CH2:17]1
Reactant: CC1(C)N=C(c2ccc(Cl)s2)OC1=O
Reactant: Nc1ccc2c(c1)CCN(C1CC1)CC2
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(NC(=O)c1ccc(Cl)s1)C(=O)Nc1ccc2c(c1)CCN(C1CC1)CC2
Temperature: 80 °C
Reaction time: 48 h

Procedure:
200.0 μl (10.0 μmol) of a 0.05 molar 2-(5-chloro-thiophen-2-yl)-4,4-dimethyl-4H-oxazol-5-one solution in toluene/acetic acid 9:1 are combined with 200.0 μl (10.0 μmol) of a 0.05-molar 3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine solution in DMF and 1.7 μl (10.0 μmol) DIPEA, heated to 80° C. overnight and left to stand for 2 days at room temperature. The reaction solution is filtered through basic aluminium oxide and the filtrate is evaporated down i. vac.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[N:22]1([CH2:27][C:28](O)=[O:29])[CH:26]=[N:25][N:24]=[N:23]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:28](=[O:29])[CH2:27][N:22]3[CH:26]=[N:25][N:24]=[N:23]3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: O=C(O)Cn1cnnn1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1cnnn1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 57.4 %

Procedure:
Preparation of example 12 from the title compound of Example 7 (15 mg, 0.054 mmol), tetrazol-1-yl-acetic acid (8 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in N,N-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Additional tetrazol-1-yl-acetic acid (1.0 mg, 0.008 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.0 mg, 0.008 mmol) were added after c.a. 18 hours to drive the reaction to completion. Filtration, concentration and recrystallization afforded the title compound (12 mg, 0.031 mmol) as a yellow powder in 58% yield.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][C:24]=1[NH:30][C:31](=[O:42])[C:32]1[CH:37]=[C:36]([CH3:38])[C:35]([O:39][CH3:40])=[C:34]([CH3:41])[CH:33]=1>O1CCCC1.[Cu]I>[Cl:29][C:27]1[N:26]=[CH:25][C:24]2[N:30]=[C:31]([C:32]3[CH:37]=[C:36]([CH3:38])[C:35]([O:39][CH3:40])=[C:34]([CH3:41])[CH:33]=3)[O:42][C:23]=2[CH:28]=1
Reactant: COc1c(C)cc(C(=O)Nc2cnc(Cl)cc2Cl)cc1C
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2nc3cnc(Cl)cc3o2)cc1C
Temperature: 180 °C

Procedure:
In a microwaveable vessel, 0.98 g of N-(4,6-dichloropyridin-3-yl)-4-methoxy-3,5-dimethylbenzamide were dissolved in 15 ml of dry tetrahydrofuran, and 29 mg of copper(I) iodide, 54 mg of 1,10-phenanthroline and 1.47 g of cesium carbonate were added. In a microwave sunthesizer, the reaction mixture was then heated at 180° C. for 3 h. For work-up, the mixture was added to 12 ml of a 0.5 M aqueous hydrochloric acid solution. The precipitated solid was filtered off with suction and the mother liquor was extracted twice with ethyl acetate. The collected organic phases were combined with the suction-filtered solid and the solvent was removed under reduced pressure. This gave 0.79 g (91%) of the product, which was reacted further without any further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O)=[O:9].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:8]=[O:9])[CH:3]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: Cc1cc(Br)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(-c2ccccc2C=O)cs1
Temperature: 150 °C
Yield: 80.9 %

Procedure:
In a microwave vial, 4-bromo-2-methyl-thiophene (653 mg, 3.69 mmol), 2-formyl phenylboronic acid (500 mg, 3.36 mmol) and 7 ml of actonitrile were mixed. 6.7 ml of 1N aqueous sodium carbonate was added to above solution, followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, 50 ml of ethyl acetate was added, the organic layer was separated, washed with water, dried with sodium sulfate, the organic solvent was evaporated and the residue was purified by ISCO to give 550 mg of 2-(5-methyl-thiophen-3-yl)benzaldehyde, yield 81%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=[O:19])[C:6]=2[CH:20]=1.C(=O)(O)[O-].[Na+].[BH4-].[Na+].Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH2:8][CH:7]([OH:19])[C:6]=2[CH:20]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C(=O)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Product: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C(O)C2
Temperature: 50 °C

Procedure:
Suspend 15.5 gm of the crude 10-keto compound of Step B in 750 ml of water and add 10 gm of sodium bicarbonate. Stir the mixture and warm to 50° C. for 15-20 minutes. Stop heating and slowly add 5 gm of sodium borohydride. Acidify the mixture with 10% aqueous hydrochloric acid, separate the solids by filtration, wash with water and air-dry. The residue may be used as such in the next step. (m.p. 204°-210° C., subsequent gassing)
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[O:4][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:20])[C:2]=1[S:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=C(Br)C(=O)O1
Reactant: Sc1ccccc1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)CCC1(c2ccccc2)CC(O)=C(Sc2ccccc2)C(=O)O1

Procedure:
The title compound was prepared as described in General Method 6 from 1.5 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (prepared in example CCC), 1.6 mmol of benzenethiol, and 1.6 mmol of piperidine in 20 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound, (m.p. 154°-155° C.). 1H NMR (DMSO-d6) δ0.80 (m, 6H), 0.97 (m, 1H), 1.16 (m, 2H), 1.42 (m, 1H), 1.91 (m, 2H), 3.40 (2H+H2O), 6.45 (m, 2H), 6.93 (m, 3H), 7.37 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][C@@H:13]([NH:15][C:16]([C:18]2[NH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][C:23]([Cl:27])=[CH:22][CH:21]=3)=[O:17])[C@H:12]([NH2:28])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][C:33]2[N:36]=[C:37]([C:39]([O-])=[O:40])[S:38][C:32]=2[CH2:31]1.[Li+].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][C@@H:13]([NH:15][C:16]([C:18]2[NH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][C:23]([Cl:27])=[CH:22][CH:21]=3)=[O:17])[C@H:12]([NH:28][C:39]([C:37]2[S:38][C:32]3[CH2:31][N:30]([CH3:29])[CH2:35][CH2:34][C:33]=3[N:36]=2)=[O:40])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1CC(COCc2ccccc2)C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2nc(C(=O)N[C@@H]3CC(COCc4ccccc4)C[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
(1R*,2R*)-4-Benzyloxymethyl-N1-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine (794 mg) was dissolved in N,N-dimethylformamide (150 ml), and lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (694 mg), 1-hydroxybenzotriazole monohydrate (61 mg) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.15 g) were added to stir the mixture overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue to conduct extraction with dichloromethane. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (dichloromethane:acetone=2:1) to obtain Stereoisomer A (378 mg) and Stereoisomer B (354 mg) of (1R*,2R*)-4-benzyloxymethyl-N1-[(5-chloroindol-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[O:11][N:10]=2)[CH2:3]1.[O:21]1[CH2:23][C@H:22]1[CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[CH:35]=1>C(O)(CC)(C)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[O:11][N:10]=[C:9]([CH2:8][N:4]2[CH2:5][CH2:6][N:7]([CH2:23][C@H:22]([OH:21])[CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]4[S:33][C:32]([CH3:34])=[N:31][C:30]=4[CH:35]=3)[C@@H:2]([CH3:1])[CH2:3]2)[CH:13]=1
Reactant: C[C@H]1CN(Cc2cc(-c3ccccc3F)on2)CCN1
Reactant: Cc1nc2cc(OC[C@@H]3CO3)ccc2s1
Solvent: CCC(C)(C)O
Product: Cc1nc2cc(OC[C@@H](O)CN3CCN(Cc4cc(-c5ccccc5F)on4)C[C@@H]3C)ccc2s1
Temperature: 95 °C
Reaction time: 24 h
Yield: 38.3 %

Procedure:
To a stirred solution of (2S)-methylpiperazine (40 mg, 0.40 mmol) in ethanol (5 mL) was added 3-chloromethyl-5-(2-fluorophenyl)isoxazole (42 mg, 0.20 mmol) and triethylamine (60μL, 0.43 mmol). The resulting mixture was stirred at 80° C. for 8 hours. It was then cooled, concentrated, and purified by preparative chromatography (1:9 methanol:methylene chloride) to yield 3-[((3S)-3-methylpiperazinyl)methyl]-5-(2-fluorophenyl)isoxazole (30 mg, M+1=276.14). B. To a solution of 3-[((3S)-3-methylpiperazinyl)methyl]-5-(2-fluorophenyl)isoxazole (28 mg, 0.10 mmol) in tert-amylalcohol (5 mL) was added 5-[((2S)oxiran-2-yl)methoxy]-2-methylbenzothiazole (22 mg, 0.10 mmol). The reaction mixture was stirred at 95° C. for 1 day. It was then cooled, concentrated, and purified by preparative chromatography (1:19 methanol:methylene chloride) to afford (2S)-3-((2S)-4-{[5-(2-fluorophenyl)isoxazol-3-yl]methyl}-2-methylpiperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol (19 mg, M+1=497.27).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][NH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)Cc1cccc(Br)c1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(CN)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 19 h
Yield: 75.4 %

Procedure:
To an ice-cold mixture of crude 3-(3-bromophenyl)-2,2-dimethylpropanenitrile (28) (3.0 g, 12.6 mmol) in anhydrous THF (20 mL) was added BH3-THF (20 mL of a 1M solution in THF, 20 mmol) slowly. The reaction was allowed to warm slowly and stirred for 19 h. The reaction was quenched with the dropwise addition of 6 M HCl then stirred for 1.5 h. Volatiles were removed under reduced pressure. The aqueous layer was extracted with diethyl ether twice then EtOAc was added and the mixture was made basic with 5 M aqueous KOH. The layers were separated and the aqueous layer was extracted with EtOAc twice. The combined organics were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give 3-(3-bromophenyl)-2,2-dimethylpropan-1-amine as a light yellow oil (2.3 g). This material was taken on to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.32-7.35 (m, 1H), 7.30 (t, J=1.7 Hz, 1H), 7.13 (t, J=7.7 Hz, 1H), 7.06 (dd, J=7.6, 1.2 Hz, 1H), 2.50 (s, 2H), 2.47 (s, 2H), 0.84 (s, 6H).