Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:18][CH2:17][C:5]2=[N:6][C:7]3[CH:8]=[N:9][C:10]4[C:15]([C:16]=3[N:4]2[N:3]=1)=[CH:14][CH:13]=[CH:12][CH:11]=4.[BH4-].[Na+]>CO>[CH3:1][CH:2]1[CH2:18][CH2:17][C:5]2=[N:6][C:7]3[CH:8]=[N:9][C:10]4[C:15]([C:16]=3[N:4]2[NH:3]1)=[CH:14][CH:13]=[CH:12][CH:11]=4
Reactant: CC1=Nn2c(nc3cnc4ccccc4c32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1CCc2nc3cnc4ccccc4c3n2N1
Reaction time: 3 h
Yield: 78.9 %

Procedure:
A solution of 10-methyl-8,9-dihydropyridazino[1′,6′:1,2]imidazo[4,5-c]quinoline (1.96 g, 8.30 mmol) in methanol (50 mL) was cooled to 0° C. The solution was treated with NaBH4 (1.26 g, 33.2 mmol) over 3 min. The reaction was allowed to come to ambient temperature over 3 h. The reaction was quenched with slow addition of saturated NH4Cl aqueous solution (20 mL) and then concentrated under reduced pressure to remove the methanol. The residual material was partitioned between chloroform (75 mL) and 10% Na2CO3 aqueous solution (25 mL) and then separated. The organic portion was washed with water (25 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a tan solid. Purification by column chromatography (100 g silica gel eluted with 95:5 chloroform:methanol) yielded 1.56 g of 10-methyl-8,9,10,11-tetrahydropyridazino[1′,6′:1,2]imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH:32]([OH:34])[CH3:33])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(O)CN
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)CNCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-amino-2-propanol (0.015 mL, 0.19 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(2-hydroxypropylaminomethyl)indol-2-yl]isoindolinone.
Reaction SMILES: C(OC[N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16])C1C=CC=CC=1.C(O)(=O)C.Cl>O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:11]2[NH:12][CH:13]=[CH:14][N:10]=2)[OH:16])=[CH:28][CH:27]=1
Reactant: OC(c1ccccc1)(c1ccc(Cl)cc1)c1nccn1COCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: OC(c1ccccc1)(c1ccc(Cl)cc1)c1ncc[nH]1

Procedure:
About 17 g. (0.042 mol) of 1-[(benzyloxy)methyl]-α-(p-chlorophenyl)-α-phenylimidazole-2-methanol was boiled under reflux in a mixture of 85 ml. of glacial acetic acid, 8.5 ml. of water and 8.5 ml. of concentrated hydrochloric acid solution. Acetic acid was removed by evaporation and the base was liberated by addition of 2 N sodium hydroxide solution. It was crystallised from isopropyl alcohol. Melting point of the product was 162°-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:17])[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].[CH3:20][S:21]([CH:24]=[CH2:25])(=[O:23])=[O:22]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:17][CH2:25][CH2:24][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH2:10]2)[C:6]=1[CH3:7]
Reactant: C=CS(C)(=O)=O
Reactant: Cc1c(Br)cnn1CC1(O)CCCC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Br)cnn1CC1(OCCS(C)(=O)=O)CCCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of EXAMPLE 157B (0.218 g) in tetrahydrofuran (2.5 mL) was added sodium hydride (0.027 g) and the reaction mixture was stirred for 15 minutes at room temperature. Methylsulfonylethene (0.095 mL) was added and the reaction was stirred at room temperature overnight. The reaction was cooled and diluted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 1-20% ethyl acetate in hexanes provided the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=O)[C:14]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[N:13]([CH:23]3[CH2:25][CH2:24]3)[C:12]2=[O:26])=[CH:7][CH:6]=1)[CH3:2].[BH4-].[Na+]>C1COCC1.CO>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C:14]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[N:13]([CH:23]3[CH2:25][CH2:24]3)[C:12]2=[O:26])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2C(=O)N(C3CC3)C3(CCCCCC3)C2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CC3(CCCCCC3)N(C3CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
To 228 mg (0.61 mmol) of 4-(1-Cyclopropyl-2,4-dioxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid ethyl ester dissolved in 4 ml THF/Methanol 1:1 was added under ice-cooling 70 mg (1.84 mmol) of sodium borohydride. The reaction mixture was stirred for 2 h at RT and then additional 70 mg of sodium borohydride was added and the stirring was continued over night. The whole was concentrated under reduced pressure to dryness and the residue was dissolved in 2 ml of trifluoroacetic acid. To this ice-chilled solution was added again 70 mg of sodium borohydride. The reaction mixture was stirred for 1 h at RT and then the trifluoroacetic acid was removed under reduced pressure. The residue was taken up in EtOAc and washed with sodium bicarbonate solution and water. The crude product was purified by chromatography over silica gel with DCM/EtOAc 9:1 to give 103 mg of pure 4-(1-Cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid ethyl ester. MS (ESI): 357.3 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].CO[CH:16](OC)[CH2:17]Cl.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[S:3]1[CH:17]=[CH:16][N:2]=[C:1]1[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(CCl)OC
Reactant: COC(=O)c1cccc(C(N)=S)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(-c2nccs2)c1
Temperature: 100 °C
Yield: 76 %

Procedure:
Preparation H11, Step 3: A solution of 0.6 g (0.003 mol) of methyl 3-carbamothioylbenzoate in 6 ml of acetic acid was charged with 1.15 g (0.009 mol) of chloroacetaldehyde dimethyl acetal and a catalytic amount of PTSA. The RM was heated to 100° C. over night. Acetic acid was removed under vacuum and the crude product was purified by 60-120 silica gel column using 5% of ethyl acetate in pet ether as eluent to provide methyl 3-(thiazol-2-yl)benzoate (0.5 g) as a white solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]=12.C1C(=O)N([Br:24])C(=O)C1>C1C=CC=CC=1>[Br:24][C:3]1[N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCn2ccnc2C1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCn2c(Br)cnc2C1

Procedure:
A mixture of tert-butyl 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (2.23 g, 10 mmol) and NBS (1.78 g, 10 mmol) in benzene (10 mL) is heated at reflux for one hr. The solvent is evaporated and the residue is purified by column with 5% MeOH in DCM to give the title compound. 1H NMR (CDCl3) δ 6.98 (s, 1H), 4.65 (s, 2H), 3.86 (s, 4H), 1.47 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]([S:17][CH2:18][CH2:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=1>C(OCC)(=O)C.[O-2].[Mn+2]>[CH:2]([C:3]1[CH:4]=[C:5]([CH:9]([S:17][CH2:18][CH2:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(CO)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (-)-methyl 5-(3-(hydroxymethyl)phenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoate (step 6) (679 mg) in ethyl acetate (30 mL) was added activated manganese oxide (1.3 g). The suspension was stirred overnight at room temperature. The suspension was filtered on a pad of silica gel and washed with EtOAc. The solvent was evaporated, affording the title compound.
Reaction SMILES: [N+](=C)=[N-].C[O:5][C:6](=[O:13])[C@H:7]([CH3:12])[NH:8][C:9](=[O:11])[CH3:10]>>[C:9]([NH:8][C@@H:7]([C:6]([OH:13])=[O:5])[CH3:12])(=[O:11])[CH3:10]
Reactant: COC(=O)[C@H](C)NC(C)=O
Agent: C=[N+]=[N-]
Product: CC(=O)N[C@H](C)C(=O)O

Procedure:
A sample was treated with diazomethane to make the methyl ester before analysis. See Example 14 (N-acetyl alanine methyl ester) for analytical details.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1([S:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[C:12]([CH3:18])[C:11]=2[CH3:19])[CH2:8][CH2:7][CH2:6]1.O.Cl>[OH-].[Na+].CO>[OH:17][C:13]1[C:14]([CH3:16])=[C:15]2[C:10](=[C:11]([CH3:19])[C:12]=1[CH3:18])[S:9][C:5]1([CH2:6][CH2:7][CH2:8]1)[CH2:4][C:3]2=[O:2]
Reactant: COC(=O)CC1(Sc2cc(C)c(O)c(C)c2C)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)C(=O)CC1(CCC1)S2
Reaction time: 1 h
Yield: 87.1 %

Procedure:
[1-(4-Hydroxy-2,3,5-trimethyl-phenylsulfanyl)-cyclobutyl]-acetic acid methyl ester (1.16 g) was suspended in 50 mL of 1N NaOH in MeOH and water (1:1, v/v), and the mixture was allowed to stir for 1 hour. The mixture was then acidified with 1 N HCl and extracted 3 times with ethyl acetate. The organic layer was washed with water and dried over anhydrous MgSO4, and concentrated in vacuo. The resulting acid was dissolved in 50 mL of concentrated sulfuric acid to form a homogeneous dark red solution. After 1 hour at room temperature the solution was poured into crushed ice. The resulting green mixture was extracted 3 times with ethyl acetate. The organic layer was washed with water and dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with 10% ethyl acetate in hexane to give 0.9 g of 6′-hydroxy-5′,7′,8′-trimethylspiro[cyclobutane-1,2′-thiochromen]-4′(3′H)-one as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.ClC1C(C2C=CC=CC=2)=NN=[C:30]2[N:40]([CH2:49][C:50]([NH:52][CH3:53])=O)N=C(C3C=CC=CC=3)[C:29]=12.CN1CCNCC1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:40]3[CH2:30][CH2:29][N:52]([CH3:53])[CH2:50][CH2:49]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: CNC(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN1CCNCC1
Product: CN1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1

Procedure:
Compound 1 was synthesised from 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid following a similar procedure outlined in Example 16 (Compound 5), using N-methylpiperazine instead of methylamine hydrochloride in the final step. The residue in the final step was purified by preparative HPLC, followed by column chromatography (silica gel, gradient 0 to 5% triethylamine/acetone), yielding the Compound 1 as an off-white solid (6 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:12].Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[OH:12]
Reactant: COc1ccc(C(=O)C(CCOC2CCCCO2)c2ccccc2)cc1
Reactant: Brc1ccccc1
Product: COc1ccc(C(O)(c2ccccc2)C(CCOC2CCCCO2)c2ccccc2)cc1

Procedure:
The (RS,SR)-isomers are prepared from the evaporation residue obtained in step (a) and 23.6 g of bromobenzene in the same manner as (RR,SS)-isomers above.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:25][CH:24]=2)=[O:21])=[CH:14][CH:13]=1)C1C=CC=CC=1>[Pd].CO.C(OCC)(=O)C>[C:43]([C:40]1[CH:39]=[CH:38][C:37]([CH:19]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:13][CH:14]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:25][CH:24]=2)=[O:21])=[CH:42][CH:41]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)c1ccc(C(Cc2ccc(OCCOCc3ccccc3)cc2)C(=O)Nc2ccc(OCC3CCCCC3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1ccc(C(Cc2ccc(OCCO)cc2)C(=O)Nc2ccc(OCC3CCCCC3)cc2)cc1
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A mixture of 3-[4-(2-Benzyloxyethoxy)-phenyl]-2-(4-tert-butylphenyl)-N-(4-cyclohexylmethoxyphenyl)-propionamide (200 mg, 0.32 mmol) and 10% Pd/C (20 mg) in a solution of methanol/ethyl acetate (60 mL, 4:1) was stirred under an atmosphere of H2 overnight. The mixture was filtered through celite and concentrated under vacuum. The crude was purified by chromatography on silica gel (ISCO cartridge, 40 g), eluting with dichloromethane over 20 minutes to afford 2-(4-tert-Butylphenyl)-N-(4-cyclohexylmethoxyphenyl)-3-[4-(2-hydroxy ethoxy)-phenyl]-propionamide (126 mg, 74%). LC-MS m/z/z=530 [C34H43NO4+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:29])=[C:8](C(OC(C)(C)C)=O)[NH:9][C:10]=1[CH2:11][CH2:12][C:13](=[O:21])[NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[O:5])[CH3:2].Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:29])=[CH:8][NH:9][C:10]=1[CH2:11][CH2:12][C:13](=[O:21])[NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCC(=O)NCCNC(C)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(C)c[nH]c1CCC(=O)NCCNC(C)=O
Temperature: 60 °C
Yield: 97 %

Procedure:
5-[2-(2-Acetylamino-ethylcarbamoyl)-ethyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 62a (818 mg, 2 mmol) was dissolved in 5 ml of ethanol under stirring, and added with hydrochloric acid solution (5 ml, 12 mol/L) to the solution at room temperature. Upon completion of the addition, the reaction mixture was heated at 60° C. in an oil bath for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure to evaporate ethanol, adjusted to about pH 12 with aqueous sodium hydroxide solution (10%) and extracted with ethyl acetate (20 ml×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 2-[2-(2-acetylamino-ethylcarbamoyl)-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 62b (600 mg, yield 97%) as a white solid.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([C@@:13]1([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([OH:23])=[C:15]([C:24]2[NH:29][C:28]3[CH:30]=[CH:31][C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][C:27]=3[S:26](=[O:40])(=[O:39])[N:25]=2)[C:14]1=[O:41])=[O:12])(=O)C.C([O-])([O-])=O.[K+].[K+].Cl>CO>[OH:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@:13]([C:11]([N:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[CH2:5][OH:4])=[O:12])([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[C:14](=[O:41])[C:15]=1[C:24]1[NH:29][C:28]2[CH:30]=[CH:31][C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][C:27]=2[S:26](=[O:40])(=[O:39])[N:25]=1
Reactant: CC(=O)OC[C@H]1CCCN1C(=O)[C@]1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)CC[C@@]1(C(=O)N2CCC[C@@H]2CO)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 171G (0.15 g, 0.22 mmol) in methanol (2 mL) was added K2CO3 (68 mg, 0.5 mmol). The resulting mixture was stirred at r.t. for 3 hrs, and then poured into N HCl (10 mL), extracted with ethyl acetate (3×10 mL), and the combined organic layers were dried over Na2SO4. The crude product was purified by column chromatography on silica gel using 5% methanol in chloroform, and the title compound was obtained as a lt. yellow solid (0.134 g, 97%). 1H NMR (300 MHz, DMSO-d6): δ 0.45 (m, 1 H), 0.63 (d, J=6.62 Hz, 3 H), 0.69 (d, J=6.62 Hz, 3 H), 0.94 (m, 1 H), 1.27 (m, 1 H), 1.61 (m, 3 H), 1.99 (m, 1 H), 2.23 (m, 2 H), 2.89 (m, 1 H), 3.03 (s, 3 H), 3.20 (m, 1 H), 3.65 (dd, J=9.93, 3.68 Hz, 1 H), 3.98 (m, 1 H), 7.13 (m, 1 H), 7.52 (m, 5 H), 8.11 (m, 1 H), 10.07 (br s, 1 H), 14.18 (br s, 1 H); MS (ESI) m/z=631 [M+H].
Reaction SMILES: [Br:1][C:2]([C@H:5]1[C@H:9]([OH:10])[O:8][C:7](=[O:11])[CH2:6]1)([CH3:4])[CH3:3].[CH:12](O)([CH3:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]([C@H:5]1[C@H:9]([O:10][CH:12]([CH3:14])[CH3:13])[O:8][C:7](=[O:11])[CH2:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)O
Reactant: CC(C)(Br)[C@@H]1CC(=O)O[C@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)O[C@@H]1OC(=O)C[C@H]1C(C)(C)Br
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 1.95 g of dl trans 4-(2-bromo-prop-2-yl)-5-hydroxy-tetrahydrofuran-2-one, 2 ml of isopropanol, 100 mg of p-toluene sulfonic acid and 30 ml of benzene was stirred at room temperature for 60 hours and was then washed with aqueous sodium bicarbonate solution. The mixture was extracted with benzene and the organic phase was dried and evaporated to dryness under reduced pressure to obtain 2 g of dl trans 4-(2-bromo-prop-2-yl)-5-isopropyloxy-tetrahydrofuran-2-one as an oily product which was used as is for the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](=[S:25])[NH2:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].Br[CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]3[S:25][CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:24]=3)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(N)=S)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1csc(C2CC(c3ccc(CC)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
850 mg of the compound from Example 140A and 550 mg (2.82 mmol) of ethyl 3-bromo-oxopropanoate were reacted according to the General Method 3. Yield: 150 mg (12% of theory).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:11]=[CH:10][S:9][CH:8]=1>C(Cl)Cl>[Br:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Brc1ccsc1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1sccc1Br
Reaction time: 1 h
Yield: 30.6 %

Procedure:
Chlorosulfonic acid (20 ml, 300 mmol) was added to a solution of 3-bromothiophene (8.15 g, 50 mmol) in methylene chloride (50 ml) at −78° C. over a 20 min. period. After the completion of addition, the cold bath was removed and stirring continued at ambient temperature for 1 hr. The reaction mixture was carefully added, dropwise, to crushed ice (100 g). The mixture was extracted with methylene chloride (2×100 ml). The combined organic layers was dried over MgSO4 and evaporated. The crude product was purified by flash chromatography on silica gel using hexane as the eluent resulting in 3-bromothiophene-2-sulfonyl chloride (4 g, 30% yield) and 4-bromothiophene-2-sulfonyl chloride (200mg, ≦1%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20](=O)[CH2:21]Cl)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]([NH2:27])=[S:26].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:27][C:25]1[S:26][CH:21]=[C:20]([C:14](=[N:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:24]=1
Reactant: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)c1csc(N)n1
Temperature: 40 °C
Yield: 29.2 %

Procedure:
A mixture of ethyl 2-(2-benzoyloxyethoxyimino)-4-chloro-3-oxobutyrate (syn isomer, 29 g.), thiourea (7.76 g.), sodium acetate (8.37 g.), water (75 ml.) and ethanol was stirred at 40° C. for an hour. The reaction mixture was treated in a conventional manner to give ethyl 2-(2-aminothiazol-4-yl)-2-(2-benzoyloxyethoxyimino)acetate (syn isomer, 9 g.).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:25]=1>>[CH3:19][O:18][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:24]3[N:25]=[C:21]([CH3:20])[S:22][CH:23]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cncc1OC
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Product: COc1cncc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.54 min.; [M+H]+: 423.76 g/mol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[CH:5]2.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[CH:5]2
Reactant: Cc1cc2ncncc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cncnc4cc3C)c2cc1OC
Temperature: 150 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
6-Hydroxy-7-methyl-quinazoline (38 mg), 4-chloro-6,7-dimethoxyquinoline (159 mg), and 4-dimethylaminopyridine (87 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 150° C. overnight. The reaction solution was cooled to room temperature, water was then added to the solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (71 mg, yield 86%).