Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Li])CCC.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([F:8])[C:5]([S:15]([CH3:14])(=[O:17])=[O:16])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1cccc(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Cl)nc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-6-fluoropyridine (500 mg, 3.8 mmol) was taken up in tetrahydrofuran (19 mL) and cooled to −78° C. n-Butyllithium (2.4 mL, 3.8 mmol) was added dropwise over 10 minutes. The solution was stirred for 30 minutes and methanesulfonyl chloride (0.3 mL, 3.8 mmol) was added dropwise over 15 minutes. The resulting mixture was stirred at −78° C. for 2 hours and then warmed to 0° C. and stirred for 2 hours followed by an additional 2 hours at room temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica, 0-75% ethyl acetate/hexanes) to afford the title compound as a light yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]4[C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.[OH-].[Na+]>C(Cl)Cl.CO.O1CCOCC1>[C:27]1([C:26]2[N:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:20]3=[N:19][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncccn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4ncccn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.3 %

Procedure:
To a mixture of crude {1-[4-(3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (390 mg) in DCM (0.9 mL) and methanol (0.57 mL) was added a solution of 4 M hydrogen chloride in dioxane (1.77 mL) and the mixture was stirred overnight at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted three times with a mixture of DCM/methanol. The combined organic phases were washed with brine, dried and concentrated in vacuo to give the crude title compound as a yellow oil. Purification was achieved by chromatography [amino phase silica; gradient elution: hexane to EtOAc], followed by trituration with diisopropylether at 0° C. to give the title compound (21.9 mg).
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:29])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]C(OCC)=O)=[C:17]([O:27][CH3:28])[CH:16]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([NH:11][C:12](=[O:29])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:27][CH3:28])[CH:16]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: CCOC(=O)Oc1ccc(C=CC(=O)NC/C=C(\C)CCC=C(C)C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C=CC(=O)NC/C=C(\C)CCC=C(C)C)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a solution of 1.44 g of 4-ethoxycarbonyloxy-3-methoxycinnamic acid geranylamide in 25 ml of methanol is added 10 ml of 2N aqueous solution of sodium hydroxide. The mixture is stirred at room temperature for one hour. The reaction mixture, after acidified with 1N hydrochloric acid, is extracted with chloroform. The organic layer is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to column chromatography on silica gel. From the fraction eluted with chloroform is obtained 0.70 g of 4-hydroxy-3-methoxycinnamic acid geranylamide (14). Spectroscopic data of the product support the structure of the formula (14) below.
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11](O)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2].C(N(CCCC)CCCC)CCC.S(Cl)([Cl:31])=O.C(C(CC)CC1(C(OC(C2(CC(CC)CC)CCCCC2)=O)=O)CCCCC1)C>CCCCCCC>[CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11]([Cl:31])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2]
Reactant: CCC(CC)CC1(C(=O)O)CCCCC1
Reactant: O=S(Cl)Cl
Agent: CCC(CC)CC1(C(=O)OC(=O)C2(CC(CC)CC)CCCCC2)CCCCC1
Solvent: CCCCCCC
Solvent: CCCCN(CCCC)CCCC
Product: CCC(CC)CC1(C(=O)Cl)CCCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A mixture of 6.0 kg (28.3 mol) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 20.6 mL tributylamine (0.085 mmol) in 10 L heptane was warmed to 50° C. 2.5 L (34.5 mol) of thionyl chloride was added during 40 minutes at a temperature of 40-50° C. (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 53-55° C. An IPC-control after 60 minutes indicated complete conversion (0.04% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and no 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components under reduced pressure (70° C. bath, 13-8 mbar) 6.86 kg of the residue was obtained (assay 92.5% 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 97.2%)
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:14]=[CH:15][C:16]3[CH2:22][N:21]([CH3:23])[CH2:20][CH2:19][C:17]=3[N:18]=2)[CH2:9]1)(C)(C)C.[ClH:25]>CO.O1CCOCC1>[ClH:25].[ClH:25].[ClH:25].[CH3:23][N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([N:10]3[CH2:11][CH2:12][C@@H:8]([NH2:7])[CH2:9]3)[N:14]=[CH:15][C:16]=2[CH2:22]1
Reactant: CN1CCc2nc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ncc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCc2nc(N3CC[C@@H](N)C3)ncc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
tert-Butyl[(3R)-1-(6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)pyrrolidin-3-yl]carbamate (10.0 g, 30.0 mmol) was dissolved in methanol (40 mL) and cooled to 0° C. To this was added a solution of 4 N hydrochloric acid in dioxane (80 mL). The mixture was allowed to warm to room temperature and then stirred at room temperature for 1 hour and then evaporated to dryness. The residue was boiled with ethanol (100 mL) then cooled to 0° C. and the resulting precipitate was filtered off. This gave the title compound (6.99 g, yield 69%) as a pale pink hygroscopic solid. LCMS (ES+) M+H 234. 1H NMR (DMSO-d6) 2.12 (m, 1H) 2.30 (m, 1H) 2.86-2.94 (s+m, 4H) 3.14-3.24 (m, 1H) 3.37-3.46 (m, 1H) 3.56-3.77 (br m, 6H) 3.78 (br m, 1H) 4.13 (dd, J=14.6, 8.3 Hz, 1H) 4.35 (d, J=14.0 Hz, 1H) 8.28 (s, 1H) 8.52 (br s, 3H) 11.71 (br s, 1H). LRMS M+H 234.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:16][C:2]1[N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=[N:17][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: Nc1ccccn1
Product: Cc1c(-c2ccc3c(c2)NC(=O)CO3)nc2ccccn12
Yield: 38.1 %

Procedure:
6-(3-Methylimidazo[1,2-a]pyridin-2-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.75 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.0 g) and 2-aminopyridine (1.8 g). mp. 280°-282° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH2:23])[C:19]([NH2:22])=[CH:20][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][C:18]=1[NH:23][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][N:9]=1)=[O:13]
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Reactant: COc1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N)c(NC(=O)c2n[nH]c3ncc(Br)cc23)c1
Temperature: 45 °C

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid Compound 1c (200 mg, 0.826 mmol), 4-methoxy-benzene-1,2-diamine Compound 19a (114 mg, 0.826 mmol), HATU (314 mg, 0.826 mmol) and DIPEA (213 mg, 1.652 mmol) in DMF (10 mL) was stirred and heated to 45° C. overnight. The mixture was diluted with AcOEt (60 mL) and washed with water. The organic layer was separated, dried and evaporated to give a brown solid residue. The residue was recrystallized with AcOEt/hexane mixture to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (2-amino-5-methoxy-phenyl)-amide Compound 19b (221 mg, 74% yield) as a light brown powder. MS m/z 362 (M+).
Reaction SMILES: II.[Mg].[CH2:4]([O:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11](I)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)[CH3:5].C1([Mg]Cl)C=CC=CC=1.[Li+].[Cl-].[C:29]1([CH2:35][C:36](=[O:38])[CH3:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[OH:38][C:36]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([O:6][CH2:4][CH3:5])=[O:18])=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16])([CH3:37])[CH2:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: CCOC(=O)c1ccc(I)c([N+](=O)[O-])c1
Agent: Cl[Mg]c1ccccc1
Agent: II
Agent: [Cl-]
Product: CCOC(=O)c1ccc(C(C)(O)Cc2ccccc2)c([N+](=O)[O-])c1
Yield: 70.1 %

Procedure:
According to Example 2, the Grignard reagent 1e (freshly prepared via iodine-magnesium exchange[6] from ethyl-4-iodo-3-nitrobenzoate (353 mg, 1.10 mmol; 1.10 equiv) and PhMgCl.LiCl (0.95 M in THF; 1.13 mL, 1.07 mmol, 1.07 equiv) at −50° C.) was reacted with 1-phenyl-propan-2-one (201 mg; 1.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 3.03 mL, 1.00 mmol, 1.00 equiv). The crude product was purified by flash column chromatography (silica; pentane:Et2O, 19:1) to give the desired product as yellow oil (231 mg, 73%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[O:11]([C:9]1[S:10][C:6]([CH2:4][OH:3])=[CH:7][N:8]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cnc(Oc2ccccc2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cnc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
2-Phenoxy-thiazole-5-carboxylic acid ethyl ester described in Preparation Example 114 (384 mg, 1.54 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (292 mg, 7.70 mmol) was added at 0° C. The solution was stirred at room temperature for 1 hour, then, at 0° C., water (292 μl), an aqueous solution of 5N sodium hydroxide (292 μl) and water (876 μl) were sequentially added thereto. The reaction solution was filtered through Celite pad, then, the filtrate was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4), and the title compound (270 mg, 1.30 mmol, 85%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)=[CH:12][N:11]=2)[CH2:5]1.[BH4-].[Na+]>CO.O>[OH:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([C:13]2[CH:14]=[CH:15][C:10]([N:6]3[CH2:5][CH:4]([CH2:3][O:2][CH3:1])[O:8][C:7]3=[O:9])=[N:11][CH:12]=2)[CH2:17][CH2:18]1
Reactant: COCC1CN(c2ccc(C3CCC(=O)CC3)cn2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC1CN(c2ccc([C@H]3CC[C@H](O)CC3)cn2)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.4 g of (RS)-5-methoxymethyl-3-[5-(4-oxo-cyclohexyl)-pyridin-2-yl]-oxazolidin-2-one in 25 ml of methanol and 2.5 ml of water was treated with 0.2 g of sodium borohydride and stirred at room temperature for 16 h. Then, the mixture was concentrated and the residue was taken up in methylene chloride and washed with water. The aqueous phase was extracted with methylene chloride and the organic phases were combined, dried with magnesium sulfate and concentrated. The residue (0.4 g) was recrystallized from ethyl acetate and there was obtained 0.2 g of (RS)-3-[5-(trans-4-hydroxy-cyclohexyl)-pyridin-2-yl]-5-methoxymethyl-oxazolidin-2-one. M.p.: 142°-143°.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:27][C:25]1[NH:24][N:23]=[C:22]([NH:21][C:13]2[N:12]=[C:11]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OCCN1CCOCC1
Product: Cc1cc(Nc2cc3ccccc3c(OCCN3CCOCC3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-morpholin-4-yl-ethanol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-[1-(2-morpholin-4-yl-ethoxy)-isoquinolin-3-yl]-amine. LC-MS m/e 354(MH+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].C(O)C.[OH-].[K+].Cl>O>[F:1][C:2]1[CH:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1

Procedure:
A mixture of 3.5 g of methyl 2-fluoro-4-hexadecylaminobenzoate, 40 ml of ethanol, 60 ml of water, and 3.8 g of potassium hydroxide is heated on a steam bath for 14 hours. The hot solution is acidified with concentrated hydrochloric acid. The reaction mixture is cooled and filtered. The colorless residue is recrystallized from chloroform-hexane to yield 2-fluoro-4-(hexadecylamino)benzoic acid as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:57]=[CH:56][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:42][C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])[NH:14][CH2:15][C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]([C@@H:26]3[CH2:30][C@H:29]([S:31]CC4C=CC(OC)=CC=4)[CH2:28][N:27]3[CH3:41])=[O:25])[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)S(O)(=O)=O.CCOCC>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[N+:1]([C:4]1[CH:57]=[CH:56][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:42][C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])[NH:14][CH2:15][C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]([C@@H:26]3[CH2:30][C@H:29]([SH:31])[CH2:28][N:27]3[CH3:41])=[O:25])[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](NC(=O)CNC(=NC(=O)OCc4ccc([N+](=O)[O-])cc4)NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](NC(=O)CNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 63.7 %

Procedure:
2.99 g of (2S,4S)-2-[(3S)-3-[2-[2,3-bis(4-nitrobenzyloxycarbonyl)guanidino]acetylanino]pyrrolidin-1-ylcarbonyl]-4-(4-methoxybenzylthio)-1-methylpyrrolidine [prepared as described in step (1) above] were dissolved in a mixture of 21 ml of trifluoroacetic acid and 4.1 ml of anisole, and then 1.15 ml of trifluoromethanesulfonic acid were added dropwise, whilst stirring and ice-cooling, to the resulting solution. The reaction mixture was stirred for 20 minutes at room temperature, after which the mixture was poured into ether. The resulting precipitate was collected by filtration and the precipitate was dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated sodium hydrogencarbonate, with water and with brine and dried over anhydrous sodium sulfate. The ethyl acetate solution was concentrated by evaporation under reduced pressure to obtain 1.62 g of (2S,4S)-2-[(3S)-3-[2-[2,3-bis(4-nitrobenzyloxycarbonyl)guanidino]acetylamino]pyrrolidin-1-ylcarbonyl]-4-mercapto-1-methylpyrrolidine, in the form of an amorphous powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH2:13][C:14]1[C:15]([C:32]#[C:33][C:34]2[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=2)=[N:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:18][N:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:13][C:14]1[C:15]([C:32]#[C:33][C:34]2[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=2)[O:40][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[N:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])=[CH:24][CH:25]=2)=[CH:18][N:19]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3cccc(O)c3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3cccc(OCCCNC(=O)OC(C)(C)C)c3)n2)cc1
Temperature: 65 °C
Reaction time: 0.08 h

Procedure:
tert-Butyl N-(3-bromopropyl)carbamate (40.86 mg, 0.1716 mmol) was added to a stirred solution of 3-[2-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]ethynyl]phenol (45 mg, 0.1144 mmol) and K2CO3 (39.53 mg, 0.2860 mmol) in DMF (1 mL) and the reaction mixture warmed to 65° C. for 16 hours. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3 and stirred for 5 minutes. The layers were separated by filtration through a phase separation cartridge and the aqueous layer retained was washed with DCM (×2). The combined organics were concentrated in vacuo and used directly in the next step.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:14][CH3:15])[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11](Cl)=[O:12])[NH:7][CH:8]=1.C(Cl)Cl.[OH-].[NH4+:21]>>[CH3:1][C:2]([CH3:16])([CH2:14][CH3:15])[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]([NH2:21])=[O:12])[NH:7][CH:8]=1
Reactant: CCC(C)(C)Cc1c[nH]c(CCC(=O)Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC(C)(C)Cc1c[nH]c(CCC(N)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]propanoyl chloride in methylene chloride (0.3 M) (7.8 mL, 2.3 mmol) was added to a rapidly stirred solution of concentrated aqueous ammonium hydroxide (2.5 mL) at 0° C. After stirring at rt for 1 h, the volatiles were removed to afford the title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:3]=1.COC1C=CC(CS[C:19]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=CC=1>O1CCCC1>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][S:31]/[C:19](/[CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:8](/[C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)\[CH2:9][CH3:10])=[CH:38][CH:37]=1
Reactant: CCOC(=O)C(C(=O)OCC)=C(SCc1ccc(OC)cc1)SCc1ccc(OC)cc1
Reactant: CCCc1cc(Cl)ccn1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)/C(SCc1ccc(OC)cc1)=C(/CC)c1cc(Cl)ccn1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Lithium diisopropylamide (LDA) is formed by dropwise addition of n-butyllithium (1.6 M in hexanes, 10.1 mL, 16.2 mmol) to a stirred solution of diisopropylamine (2.3 mL, 16.4 mmol) in tetrahydrofuran (25.0 mL) at −78° C. The resulting solution is stirred at −78° C. for 5 min, stirred at 0° C. for 15 min, and then re-cooled to −78° C. A solution of 4-chloro-2-propylpyridine (2, 2.29 g, 14.7 mmol) in tetrahydrofuran (25.0 mL) is added dropwise to this solution over a period of 30 min. The resulting deep red suspension is stirred at −78° C. for 1 h. A solution of diethyl 2-[bis(4-methoxybenzylsulfanyl)methylene]malonate (1, 7.03 g, 14.8 mmol) in tetrahydrofuran (40.0 mL) is then added dropwise over a period of 15 min. The resulting yellow solution is stirred at −78° C. for 1.5 h, −15° C. for 1.5 h, and room temperature for 30 min. to give a dark orange solution. The reaction mixture is quenched with a saturated aqueous solution of ammonium chloride (100 mL) and extracted with diethyl ether (2×100 mL). The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure to give an orange oil. The product is purified by flash column chromatography (eluting with 5% ethyl acetate in methylene chloride; Rf0.50) to give 3 as an orange oil. 1H NMR (DMSO-d6): δ0.76 (t, J=7.5 Hz, 3H, CH2CH3), 1.17 (t, J=7.0 Hz, 6H, 2×CO2CH2CH3), 2.81 (q, J=7.5 Hz, 2H, CH2CH3), 3.74 (s, 3H, OCH3), 4.01 (s, 2H, SCH2), 4.10 (q, J=7.0 Hz, 4H, 2×CO2CH2CH3), 4.41 (s, 1H, CH(CO2CH2CH3)2), 6.90 (m, 2H, benzylic H-3/H-5), 7.28 (m, 2H, benzylic H-2/H-6), 7.44 (d, J=2.0 Hz, 1H, pyridyl H-3), 7.52 (dd, J=5.5 Hz, 2.0 Hz, 1H, pyridyl H-5), 8.56 (d, J=5.5 Hz, 1H, pyridyl H-6). 13C{1H} NMR (DMSO-d6): δ12.4 (CH2CH3), 13.9 (CH(CO2CH2CH3)2), 28.3 (CH2CH3), 39.5 (SCH2), 55.0 (OCH3), 58.5 (CH(CO2CH2CH3)2), 61.1 (CH(CO2CH2CH3)2), 113.9 (benzylic C-3/C-5), 122.9 (pyridyl C-5), 123.0 (pyridyl C-3), 125.7 (═C(SAr)(CH(CO2CH2CH3)2)), 129.3 (benzylic C-1), 130.2 (benzylic C-2/C-6), 143.4 (pyridyl C-4, C—Cl), 150.6 (pyridyl C-6), 153.3 (═C(CH2CH3)(pyridyl)), 158.4 (benzylic C-4, C—OCH3), 159.1 (pyridyl C-1), 167.2 (CH(CO2CH2CH3)2). LCMS m/z calcd for C24H28ClNO5S 477 ([M+]); found 478 ([M+H]+).
Reaction SMILES: [CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:25])=[N:19][C:20]([CH:23]=[O:24])=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[O-:27]Cl=O.[Na+]>CC(O)(C)C>[CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:25])=[N:19][C:20]([C:23]([OH:27])=[O:24])=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ncc(C(=O)NC(c2ccccc2)c2ccccc2)c(O)n1
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1ncc(C(=O)NC(c2ccccc2)c2ccccc2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of step G product (2-h, 0.7 g) in t-BuOH (35 mL) was added NaH2PO4.12H2O (0.6 g, 1.7 mmol) followed by H2O (6 mL) and NaClO2 (0.95 g, 10.5 mmol). After being allowed to stir at the ambient temperature overnight, the reaction mixture was evaporated under vacuum to remove t-BuOH, diluted with H2O, treated with aq. HCl to pH 2 and the solid was filtered and the cake was washed with water and dried under vacuum to afford compound 2-i as a crude (0.35 g), which was directly used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>CS(C)=O>[CH3:1][C:2]1[C:7]2[C:8](=[O:10])[N:14]3[CH2:21][CH2:20][CH2:19][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: Cc1cccc2c1C(=O)N1CCC[C@H]1C(=O)N2

Procedure:
A solution of 13.6 g (0.0768 mol) of 6-methylisatoic acid anhydride and 8.8 g (0.0768 mol) of L-proline is heated at 110° C. for 1 hour in 75 ml of dimethyl sulphoxide. Subsequently, the mixture is evaporated to dryness in a high vacuum and the residue is recrystallised from ethyl acetate with the addition of active carbon. There is obtained (S)-1,2,3,11a-tetrahydro-6-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 212°-214° C.