Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](S(C2C=CC=CC=2)(=O)=O)[N:20]=1>C1COCC1>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[N:20]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc([Mg]Br)cc1
Reactant: O=S(=O)(c1ccccc1)c1cccc(F)n1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2cccc(F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.06 mol of 4-octyloxyphenylmagnesium bromide (prepared from 0.06 mol of 4-octyloxybromobenzene and 0.06 mol of 4-octyloxybromobenzene and 0.06 mol of magnesium) and 25 ml of THF is added at 30°-40° C. to a mixture of 0.05 mol of 2A and 15 ml of THF. The mixture is stirred at room temperature for 2 hours and subjected to customary work-up. The unpurified product is processed further in accordance with 2C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=O)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:20]1([CH:26]([CH3:35])[CH2:27][S:28][C:29]2[S:33][C:32]([NH2:34])=[N:31][N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C(Cl)Cl>[C:20]1([CH:26]([CH3:35])[CH2:27][S:28][C:29]2[S:33][C:32]([NH:34][C:14](=[O:16])[CH:13]([NH:12][C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:17][CH2:18][CH3:19])=[N:31][N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC(CSc1nnc(N)s1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(SCC(C)c2ccccc2)s1
Temperature: 25 °C

Procedure:
A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid (25.4 mg, 0.2 mmol), 5-(2-phenyl-propylsulfanyl)-[1,3,4]thiadiazol-2-ylamine (50 mg, 0.2 mmol), HBOT (29 mg, 0.21 mmol), EDC HCl (46 mg, 0.24 mmol.) and triethylamine (0.12 ml) in methylene chloride was stirred at room temperature until product formation or disappearance of starting material. The mixture was quenched with water and extracted with methylene chloride. The organic layer was separated, washed with dilute HCl, brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide the title compound as a cude oil. The oil was purified by Shimadzu HPLC to provide the title compound as a light yellow solid (26 mg), LC-MS M+1=505.0
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([CH2:17][CH3:18])[CH:12]([OH:16])[CH2:13][O:14][CH3:15].CN1CCOCC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:17][CH3:18])[CH:12]([OH:16])[CH2:13][O:14][CH3:15])=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(c1ccc(Cl)cc1)(C(O)COC)n1ccc2c(N)cccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(c1ccc(Cl)cc1)(C(O)COC)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the mixture of the product from Step B (39 mg, 0.108 mmol) and NMM (22 mg, 0.216 mmol) in DCM (8 mL) was added methylsulfonyl chloride (18 mg, 0.163 mmol) dropwise. Then the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (10 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by PREP-TLC eluting with PE/EA (1/1, v/v) to get the title compound as a colorless amorphous solid. LC/MS m/z=437.1[M+H]+.
Reaction SMILES: [S:1]1[C:5]([C:6]2([OH:16])[CH2:15][CH2:14][C:9]3(OCC[O:10]3)[CH2:8][CH2:7]2)=[CH:4][N:3]=[CH:2]1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[OH:16][C:6]1([C:5]2[S:1][CH:2]=[N:3][CH:4]=2)[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]1
Reactant: OC1(c2cncs2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2cncs2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of 8-(1,3-thiazol-5-yl)-1,4-dioxaspiro[4.5]decan-8-ol (0.95 g, 4.14 mmol) in THF (20 mL) was added an aqueous solution of 3 N HCl (10 mL). The mixture was stirred for 1 h at 50° C. After cooling to room temperature, the solution was treated with Na2CO3 to pH 8 and extracted with EtOAc three times. The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated to give 0.78 g (98%) of the desired product. MS (M+H)+=198.2.
Reaction SMILES: [Br-].[C:2]1([P+:8]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:14][C:13]3[CH:15]=[CH:16][C:17]4[C:22]([C:12]=3[C:11]3[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=5[CH:29]=[CH:30][C:10]=3[CH2:9]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:37].[Na+]>C(O)C>[C:2]1([P:8]([CH2:9][C:10]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:11]=2[C:12]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:13]=2[CH3:14])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: c1ccc([P+]2(c3ccccc3)Cc3ccc4ccccc4c3-c3c(ccc4ccccc34)C2)cc1
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2ccccc2c1-c1c(CP(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Reaction time: 4 h

Procedure:
4 g (7.3 mmol) of 4,4-diphenyl-4,5-dihydro-3H-dinaphtho-[2,1-c:1',2'-e]phosphepinium bromide are suspended in a mixture of 80 ml of 2N sodium hydroxide solution and 30 ml of ethanol and heated to boiling for 4 hours. The reaction solution is subsequently evaporated to dryness at 12 torr/40° C. The residue is taken up in 80 ml of dichloromethane and extracted twice with 30 ml of water each time. The organic phase is dried over sodium sulfate and evaporated to dryness at 12 torr/40° C. This gives colorless crystals (melting point: 199.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH2:16][OH:17])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(CO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 75C (2.8 g) in dichloromethane (50 mL) was added Dess-Martin Periodinane (5.68 g). The reaction mixture was stirred at room temperature for 3 hours and diluted with ether and washed with 5% NaOH and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography using 20% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH2:10])[CH2:7][CH:8]=[CH2:9].C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][C:3]([NH:10][CH2:6][CH2:7][CH:8]=[CH2:9])=[O:4]
Reactant: O=C(Br)CBr
Reactant: C=CCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCNC(=O)CBr
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
A solution of bromoacetyl bromide (5.21 g, 25.8 mmol) in dichloromethane (5 ml) was added dropwise at −78° C. to a solution of 3-butene-1-amine (2.00 g, 25.8 mmol) and triethylamine (2.56 g, 25.8 mmol) in dichloromethane (20 ml). After 10 min at −78° C., the reaction mixture was allowed to reach room temperature over 2 h, then washed with water. The organic layer was washed with brine, dried (MgSO4), and evaporated to produce the title compound (4.59 g, 94%). Yellow liquid, 1H-NMR (300 MHz, CDCl3): 6.53 (br. s, 1H), 5.85-5.7 (m, 1H), 5.2-5.1 (m, 2H), 3.89 (s, 2H), 3.38 (q, J=6.3, 2H), 2.31 (q, J=6.3, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:25][C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:40][CH2:41][CH3:42]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]([CH2:40][CH2:41][CH3:42])[C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(C(=O)O)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
(5-Benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (0.09 g, 0.23 mmol) in THF (1.2 ml) was added dropwise to a solution of LHMDS in hexanes (0.49 ml, 0.49 mmol, 1.0M) at −15° C. After 30 min iodopropane (0.08 ml, 0.82 mmol) in THF (0.3 ml) was added and the mixture was stirred for a further 30 min at −15° C. The mixture was then quenched by pouring onto a mixture of ice and HCl solution (2M aq). This was then extracted with EtOAc (×2), washed with NaHSO3 solution (10% aq) and the organics were dried (MgSO4) and then concentrated in vacuo to afford a yellow oil. The oil was purified by flash column chromatography (EtOAc:petroleum ether) to afford 2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid (0.016 g, 0.04 mmol) in 18% yield. 1H NMR (CDCl3) δ 7.69-7-63 (m, 4H), 7.47-7.42 (m, 2H), 7.40 (t, 2H), 7.35-7.31 (m, 1H), 7.13-7.09 (m, 2H), 7.01-6.99 (m, 1H), 5.11 (s, 2H), 3.63-3.59 (m, 1H), 2.11-2.03 (m, 1H), 1.84-1.75 (m, 1H), 1.36-1.26 (m, 2H) 0.92 (t, 3H); LCMS method (A), (M-H−) 385, RT=4.9 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([F:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[O:18]=[C:16]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([F:14])[CH:7]=2)[NH:1]1
Reactant: NC(=O)c1cc(F)c([N+](=O)[O-])cc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2cc(F)c([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
3.1 g (15.6 mmol) of 2-amino-5-fluoro-4-nitro-benzamide were dissolved in 130 ml of tetrahydrofuran and treated at 0° C. with 3.1 g (10.4 mmol) of triphosgene. The mixture was left to warm to room temperature and stirred for a further 1.5 hrs. Then, the solution was concentrated and triturated with water. The precipitate was filtered off under suction and dried. 2.09 g (60%) of 2,4-dioxo-6-fluoro-7-nitro-1,2,3,4-tetrahydroquinazoline were obtained as yellowish crystals;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]23[O:16][C:15](=[O:17])[CH:14]2[CH2:13][CH2:12][CH2:11][CH2:10]3)=[O:8])=[CH:5][CH:4]=1.[NH:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23].C(N(CC)C(C)C)(C)C.Cl>C(Cl)Cl>[OH:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][OH:26])[C:15]([CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1([OH:16])[C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17]
Reactant: OCCNCCO
Reactant: COc1ccc(C(=O)C23CCCCC2C(=O)O3)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)C2(O)CCCCC2C(=O)N(CCO)CCO)cc1

Procedure:
A solution of 26.03 g (0.100 mol) of 6-(4-methoxy-benzoyl)-7-oxa-bicyclo[4.2.0]octan-8-one in 200 ml of methylene chloride is added to 10.5 g (0.100 mol) of diethanolamine and 32 ml of N,N-diisopropylethylamine. The reaction mixture is heated at reflux for several hours and monitored by thin layer chromatography. Upon completion of the reaction, the mixture is cooled and poured into 1N hydrochloric acid solution. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17](=O)[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH3:24])=[O:5])[CH3:2].C(Cl)([Cl:27])=O.C1(C)C=CC=CC=1>CN(C=O)C>[Cl:27][C:17]1[C:8]2[N:9]([C:23]([CH3:24])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1C
Reactant: O=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc2c(Cl)nc3cc(C(F)(F)F)ccc3n2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a suspension of 2-ethoxycarbonyl-1-methyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 1) (88 g, 259 mmol) in DMF (1.5 l) was dropwise added a solution of 28% phosgene in toluene (0.5 l, 960 mmol). The mixture was stirred at 50° C. for 1 h and overnight at 25° C. followed by evaporation in vacuo. The residue was stirred with ice-cooled water. The solid was collected by filtration and washed with water to yield 83,4 g (95%) of 4-chloro-2-ethoxycarbonyl-1-methyl-7trifluoromethylimidazo[1,2-a]quinoxaline. M.p. 182°-183° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:12]1([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:23])=[CH:25][CH:26]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: Nc1ccc2cccnc2c1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(C2CCCCC2)cc1

Procedure:
Using the procedure outlined in Example 45, the title compound was prepared from 7-aminoquinoline (D55) (30 mg, 21 mmol) and 4-cyclohexylbenzoic acid (51 mg, 0.25 mmol) as a yellow solid. MS(ES): MH+ 331, M-H+ 329
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16])(C)(C)C.[ClH:26]>C(O)C>[ClH:26].[ClH:26].[S:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])([C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=1)(=[O:16])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)NCCCCCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NCCCCCCN)cc1

Procedure:
Batch size: 13.0 g (<35 mmol) N-[6-(tosyl-amino)-hexyl]-carbamic acid tert-butyl ester and 7.7 ml (93 mmol) concentrated hydrochloric acid in 100 ml ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH:17]=[CH2:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[S:19]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]O)=[CH:20]1.C(P(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:24][C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH:17]=[CH2:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: OCCc1ccsc1
Reactant: C=CCOc1ccc2[nH]c(C(=O)OCC)cc2c1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: C=CCOc1ccc2c(c1)cc(C(=O)OCC)n2CCc1ccsc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.8 %

Procedure:
To solution of 5-allyloxyindole-2-carboxylic acid ethyl ester (1.0 g, 4.08 mmol) in THF (10 mL) was added azodicarboxylic acid bis[dimethylamide] (TMAD; 1.4 g, 8.15 mmol). After stirring at room temperature for 20 min, 2-(3-thienyl)ethanol (0.78 g, 6.12 mmol) was added followed by the addition of tributyl phosphine (1.65 g, 8.15 mmol). After stirring at room temperature for 18 h, the reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over Na2SO4. Purification by flash colunmn chromatography (silica gel, EtOAc/hexanes) yielded the desired product as an oil (1.36 g, 94%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:26]2[C:32]([C:33](O)=[O:34])=[C:31]([CH3:36])[N:30]=[C:27]2[S:28][CH:29]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[N:26]3[C:27]([S:28][CH:29]=[C:25]3[CH3:24])=[N:30][C:31]=2[CH3:36])=[O:34])=[O:10])[N:12]=1
Reactant: Cc1nc2scc(C)n2c1C(=O)O
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3scc(C)n23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,6-Dimethyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=506.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[NH2:10])[C:5]#[N:6].[I:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH:21]=O.II>CO>[I:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[C:14]=1[C:21]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([CH3:11])[C:9]=2[N:10]=1
Reactant: Cc1cc(C#N)cc(N)c1N
Reactant: COc1nccc(I)c1C=O
Agent: II
Solvent: CO
Product: COc1nccc(I)c1-c1nc2c(C)cc(C#N)cc2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a solution of 3,4-diamino-5-methyl-benzonitrile (2.00 g, 13.6 mmol) in MeOH (40 mL) was added 4-iodo-2-methoxy-pyridine-3-carbaldehyde (3.6 g, 13.6 mmol) in MeOH (20 mL) at 0° C. The resulting slurry was stirred at 0° C. for 1 h. Iodine (1.73 g, 8.8 mmol) in MeOH (10 mL) was added dropwise via a dropping funnel to the reaction mixture at 0° C. The reaction mixture was stirred at room temperature for 14 h. After removal of MeOH, the residue was diluted with saturated Na2S2O3 and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4. The crude product was purified by flash column chromatography (3% MeOH/CH2Cl2) to yield the title compound (1.81 g, 46%). 1H NMR (300 MHz, CDCl3) δ 7.90 (1H, s), 7.49 (1H, d, J=5.4 Hz), 7.46 (1H, s), 7.41 (1H, d, J=5.3 Hz), 3.78 (3H, s), 2.68 (3H, s). LCMS (M+H)+ m/z 391 (t=1.27 min.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[H-].[Na+].[CH3:15][O:16][CH2:17]Cl.O>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH2:15][O:16][CH3:17]
Reactant: Oc1cccc2c(Br)cccc12
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cccc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6.0 g of 5-bromo-1-naphthol was dissolved in 50 ml of N,N-dimethylformamide, to which 1.2 g of 60% sodium hydride was added. After stirring at a room temperature for 10 min, it was cooled to 0° C., to which 3.5 ml of chloromethyl methyl ether was added and stirred for 10 min. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then the solvent was distilled off. When the resultant residue was purified on silica gel column chromatography (10% ethyl acetate/hexane), 7.2 g of the above-captioned compound was obtained as red acicular crystals.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O-]CC.[Na+].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:17]>C(O)C.C(O)C.C1(C)C=CC=CC=1>[C:3]([CH:2]([CH2:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(=O)c1ccc(Cl)cc1Cl)C(C)=O
Reaction time: 0.25 h

Procedure:
To a solution of 3.26 ml of ethyl acetoacetate in ethanol (20 ml) is added dropwise 0.5 ml of a sodium ethoxide solution (21% in EtOH) at 0° C. The mixture is stirred for 15 minutes and 5.82 g de 2-bromo-1-(2,4-dichlorophenyl)ethanone predissolved in 30 ml of an ethanol/toluene mixture (2/1; v/v) is then added. The mixture is stirred for 4 hours at RT and then concentrated to dryness. The residue is purified by chromatography on silica gel to give 3.8 g of liquid corresponding to the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].C1(C)C=CC=CC=1.OS(O)(=O)=O.[C:33](=O)([O-])[O-:34].[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:34][CH3:33])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 90 °C

Procedure:
5 g of (+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was dissolved in 45 ml methanol, followed by 15 mL of toluene. 5 mL (0.28 mol) of conc. H2SO4 was instantly added and another 10 mL of conc. H2SO4 was slowly added later, while maintaining the temperature at 90° C. After that, the reaction mixture was refluxed at 90° C. for 13 hrs. The solvent was distilled off under reduced pressure. To the residue, 50 mL of water was added and the pH of reaction mixture was adjusted between 9 to 10 using aq. sodium carbonate. The residue was extracted with 100 mL ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and evaporated under vacuum. The combined eluent was evaporated at reduced pressure to yield 2.8 g of crude product purified by column chromatography, using hexane:ethyl acetate (9:1) as eluent.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].O1CCCC1.Cl[C:24]1[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.[H-].[Na+]>CCOCC>[Cl:30][C:29]1[C:24]([O:1][CH2:2][C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[CH:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[CH:9]=2)[O:6][CH3:7])=[N:25][CH:26]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:28]=1
Reactant: COC(c1cc(C)no1)c1ccccc1CO
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(c1cc(C)no1)c1ccccc1COc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a mixture of 0.21 g (0.9 mmol) of 5-(2-hydroxymethyl-α-methoxybenzyl)-3-methylisoxazole, 3 ml of tetrahydrofuran and 0.29 g (1.35 mmol) of 2,3-dichloro-5-trifluoromethylpyridine was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at room temperature for 2 hours. After completion of the reaction, 100 ml of ether was added and washed with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[2-(3-chloro-5-trifluoromethyl-2-pyridyloxymethyl)-α-methoxybenzyl]-3-methylisoxazole (0.32 g, 86.1%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1ccc(F)c(F)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccc(F)c(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(3,4-difluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):