Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1.O.[C:23](OCC(Cl)(Cl)Cl)(=[O:26])[CH2:24][CH3:25]>N1C=CC=CC=1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][O:19][C:23](=[O:26])[CH2:24][CH3:25])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1
Reactant: CCC(=O)OCC(Cl)(Cl)Cl
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)OC[C@H]1O[C@@H](n2cnc3c(OC)nc(N)nc32)[C@@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 23 h

Procedure:
2-Amino-6-methoxy-9-(β-D-arabinofuranosyl)-9H-purine (1.0 g, 3.3 mmol) (prepared as described in European Patent Application No. 294 114) was suspended in 40 ml of pyridine that contained 300 μL of H2O and 2 ml of trichloroethyl propionate (Trichloroethyl propionate was synthesized by addition of 19 ml of propionyl chloride (Aldrich) over 30 minutes to 19.1 ml of trichlorethanol (Aldrich) in 40 ml of pyridine at 0° C.). The product was purified by successive washing with 2×100 ml aliquots of H2O, 5% NaHCO3, and H2O. 1H-NMR (200 MHz, CDCl3, 4.74 (s, 2H, Cl3CH2-), 2.49 (q, 2H, J=7.6 Hz, CH3CH2CO2-), 1.21 (t, 3H, J=7.6 Hz, CH3CH2 CO2-). The reaction was initiated with 0.100 g of subtilisin (Sigma Chemical Co., St. Louis, Mo., P-5380, lot No. 38F-0356), which had been activated by dissolving 1 g of the enzyme in 20 ml of 0.1M potassium phosphate at pH 7.8 and lyophilizing to dryness. After stirring for 23 hours at 40° C., the reaction was quenched by filtering off the enzyme and the solvent was removed in vacuo. The crude product was purified by chromatography on a 4.5×25 cm silica gel column with CH2Cl2 :CH3OH (9:1) as eluant. Product fractions were pooled and lyophilized from water to yield 0.76 g of the desired product as a white powder: m.p. 124° C.; TLC Rf =0.43 (silica gel; CH2Cl2 :CH3OH (9:1); UVλmax (ε, mM-1 cm-1) at pH 7.0, 278 nm (9.5).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[SH:8][CH2:9][CH2:10][CH2:11][OH:12].[NH2:13][C:14]1[N:22]=[C:21](Cl)[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cl-].[Na+].O>[NH2:13][C:14]1[N:22]=[C:21]([S:8][CH2:9][CH2:10][CH2:11][OH:12])[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: OCCCS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(SCCCO)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
Sodium hydride (600 mg, 15 mmol 60% in mineral oil) were added DMF (10 ml), 3-mercapto-1-propanol (1 ml, 12 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred at 100° C. for 2 hours. After addition of saturated brine the reaction mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (30 mg, yield 12%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:13][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:20](Cl)(Cl)=[O:21]>ClC1C=CC=CC=1>[N:1]([C:2]1[CH:3]=[C:4]([C:8]2[O:13][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[C:20]=[O:21]
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc(-c2nc3ccccc3c(=O)o2)c1
Agent: Cl
Solvent: Clc1ccccc1
Product: O=C=Nc1cccc(-c2nc3ccccc3c(=O)o2)c1

Procedure:
40 Parts by weight of 2-(m-aminophenyl)-3,1-benzoxazin-4-one are suspended in 300 parts by volume of chlorobenzene and the suspension is treated with hydrogen chloride gas until saturated therewith, and then with phosgene gas for 4 hours at 110° C. The clear solution is concentrated under reduced pressure and the residue is then washed with ether and petroleum ether, giving 39 parts by weight of 2-(m-isocyanatophenyl)-3,1-benzoxazin-4-one of melting point 115°-121° C.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[NH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][N:32]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[C:35]([C:34]1[CH:37]=[CH:38][C:31]([NH:30][C:20]([C:19]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2/[CH:11]=[CH:10]/[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:1])[F:29])[C:5]=2[O:23][CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:21])=[N:32][CH:33]=1)#[N:36]
Reactant: N#Cc1ccc(N)nc1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2ccc(C#N)cn2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (80 mg, 0.189 mmol) with 6-aminonicotinonitrile (27 mg, 0.226 mmol) in the presence of EDCI hydrochloride (72 mg, 0.378 mmol), DMAP (22 mg, 0.189 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 25 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 9H), 3.56 (s, 2H), 7.17 (t, J=74.1 Hz, 1H), 7.19-7.25 (m, 2H), 7.42-7.50 (m, 2H), 7.55-7.62 (m, 1H), 7.82 (d, J=15.6 Hz, 1H), 8.02-8.08 (m, 1H), 8.18-8.24 (m, 1H), 8.28-8.35 (m, 1H), 8.83-8.90 (m, 1H), 11.39 (br s, 1H); APCI-MS (m/z) 524.25 (MH)+.
Reaction SMILES: [F:1][C:2]([CH3:34])([CH3:33])[CH2:3][CH2:4][CH:5]([CH2:9][CH:10]([OH:32])[CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([OH:8])=[O:7].[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].N1C=CN=C1>CN(C)C=O>[C:38]([Si:35]([CH3:37])([CH3:36])[O:32][CH:10]([CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH:5]([CH2:4][CH2:3][C:2]([F:1])([CH3:34])[CH3:33])[C:6]([OH:8])=[O:7])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)O
Reaction time: 96 h
Yield: 38.6 %

Procedure:
To a solution of 2-(3-fluoro-3-methyl-butyl)-4-hydroxy-6-phenyl-5-[(quinoxaline-2-carbonyl)-amino]-hexanoic acid (1.63 g, 3.49 mmol) in dimethylformamide (10 mL) was added t-butyldimethylsilyl choride (3.2 g, 20.9 mmol) and imidazole (2.9 g, 41.9 mmol). The reaction was stirred for 4 days then quenched with methanol and stirred another 0.5 hours. The solution was diluted with ether and water. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. Chromatography on silica gel gave the title compound (784 mg, 39%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:9]=2)[CH:5]=[C:4]([CH2:19]O)[CH:3]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:22][CH2:19][C:4]1[CH:3]=[C:2]([CH3:1])[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:9]=2)[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(CO)cc2cn(COCC[Si](C)(C)C)nc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1cc(CBr)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)methanol (138 mg, 0.472 mmol) and carbon tetrabromide (235 mg, 0.708 mmol) in tetrahydrofuran (1 mL) at 0° C. was added triphenylphosphine (186 mg, 0.708 mmol). The resulting solution was stirred at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (5→12% EtOAc/Hex) to give 114 mg (68%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.48 (s, 1H), 7.06 (s, 1H), 5.68 (s, 2H), 4.55 (s, 2H), 3.61 (m, 2H), 2.59 (s, 3H), 0.91 (m, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 148.8, 131.6, 129.0, 126.6, 123.3, 121.6, 118.1, 81.7, 67.3, 35.4, 17.7, 17.1, −1.5.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C[O:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])[C:22]=1[OH:35].Cl>O1CCCC1.O>[OH:35][C:22]1[C:21]([C:20](=[O:19])[CH2:2][C:1]([N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[O:3])=[CH:26][CH:25]=[CH:24][C:23]=1[O:27][S:28]([C:31]([F:34])([F:32])[F:33])(=[O:30])=[O:29]
Reactant: COC(=O)c1cccc(OS(=O)(=O)C(F)(F)F)c1O
Reactant: CC(=O)N1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(=O)N1CCOCC1)c1cccc(OS(=O)(=O)C(F)(F)F)c1O
Reaction time: 1 h

Procedure:
A solution of N-acetylmorpholine (1.72 g, 13.3 mmol, 2 eq) in 30 ml dry tetrahydrofuran under nitrogen was cooled in an acetone/dry ice bath (−78° C.) and treated with LDA (10 ml, 2M solution in THF, 3 eq). The reaction mixture was stirred for 60 minutes then 2-hydroxy-3-trifluoromethanesulfonyloxy-benzoic acid methyl ester [α] (2 g, 6.6 mmol, 1 eq as a solution in 10 ml dry THF) was added. The reaction mixture was allowed to warm from −78° C. to room temperature and stirred over night. The reaction was diluted with water (4 ml) followed by 2M hydrochloric acid (40 ml), then extracted three times with dichloromethane. The extracts were combined, washed with brine, dried with magnesium sulphate, filtered and evaporated. The crude product was purified by flash chromatography eluting with ethyl acetate to afford trifluoro-methanesulfonic acid 2-hydroxy-3-(3-morpholin-4-yl-3-oxo-propionyl)-phenyl ester [D]. Yield 1.06 g, 40%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][O:18][C:17]3=[O:22])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:23][NH2:24]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:22])[O:18][CH2:19][C:20]([NH:24][CH3:23])=[O:21])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1COC(=O)N1CCCc1cc(-c2ccc(Cl)cc2)no1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCCc1cc(-c2ccc(Cl)cc2)no1
Yield: 74.9 %

Procedure:
0.6 g (1.87 mmol) of 3-{3-[3-(4-chlorophenyl)isoxazol-5-yl]propyl}-1,3-oxazolidine-2,4-dione, prepared in stage 4.2., is dissolved in a mixture of 8 ml of tetrahydrofuran and of 15 ml of methanol. 2.8 ml of a 2M solution of methylamine (5.6 mmol) in tetrahydrofuran are added. Reaction is allowed to take place at ambient temperature overnight and then the mixture is evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a 98/2 and then 95/5 and 90/10 mixture of dichloromethane and of methanol. The product is recrystallized from a mixture of ethyl acetate and of methanol to produce 0.49 g (1.4 mmol) of white crystals.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH2:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][NH:7]1.C(N(CC)CC)C.C([O:31][C:32](=O)[C:33](OCC)=[O:34])C>C(Cl)(Cl)Cl>[CH3:3][N:4]1[C:32](=[O:31])[C:33](=[O:34])[N:7]2[CH2:8][C@@H:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[C:15]([C@@H:6]2[CH2:5]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CCOC(=O)C(=O)OCC
Reactant: CNC[C@@H]1NC[C@H](c2ccccc2)c2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1C[C@H]2c3ccccc3[C@H](c3ccccc3)CN2C(=O)C1=O
Yield: 77.4 %

Procedure:
To a stirred solution of cis-1,2,3,4-tetrahydro-1-methylaminomethyl-4-phenylisoquinoline dihydrochloride (30.6 g, 0.094 m) in chloroform (500 ml) maintained under nitrogen at ambient temperature was added triethylamine (42.6 g, 0.42 m) and then in one portion diethyloxalate (30.1 g, 0.206 m) and the mixture heated to reflux for 4 hours. The mixture was cooled and washed with 10% HCl (3×150 ml) and water (150 ml), then dried over MgSO4. The solvent was evaporated to give 22.3 g of cis-1,3,4,6,7,11b-hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline-3,4-dione as a pale yellow solid. An analytical sample, recrystallized from isopropanol, had m.p. 193°-194°.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)=[O:6])[CH3:3].[CH3:12][C:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])[CH:19]=1)([CH3:17])[C:14](O)=[O:15].CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[CH2:2]([O:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:14](=[O:15])[C:13]([CH3:12])([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:29][C:30]=2[CH3:31])[CH:19]=1)[CH3:17])=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@H]1CCCN1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(C(C)(C)C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCCN1C(=O)C(C)(C)c1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Reaction time: 48 h

Procedure:
To a stirred solution of (R)-pyrrolidine-2-carboxylic acid ethyl ester hydrochloride (1.7 g, 9.4 mmot), TEA (1.0 g, 10.3 mmol) and the title C compound, 2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid (3.0 g, 8.55 mmol) in DCM (50 mL) is added EDCl (2.0 g, 10.3 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt, 1.2 g, 8.55 mmol) at RT. The reaction mixture is stirred for 48 h. The reaction mixture is diluted with ethyl acetate, washed with 2 N aqueous HCl, water, 2 N aqueous sodium hydroxide, water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 35% ethyl acetate in hexane to yield (R)-1-{2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionyl}-pyrrolidine-2-carboxylic acid ethyl ester as a clear oil.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]1[O:9][C:8]([CH2:10][N:11]2[C:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:19][C:15]=3[C:14](=[O:26])[N:13]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:12]2=[O:33])=[N:7][N:6]=1.[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:13]5[C:14](=[O:26])[C:15]6[S:19][C:18]([C:20]7[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=7)=[CH:17][C:16]=6[N:11]([CH2:10][C:8]6[O:9][C:5]([CH2:4][O:3][CH3:2])=[N:6][N:7]=6)[C:12]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: COCc1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnc(COC)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-{[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]methyl}-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (250 mg; compound B33) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (223 mg; compound C10) and HBTU (232 mg) in DCM (15 ml) in the presence of DIPEA (0.36 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 1/0 to 3/2 (v/v)] and preparative HPLC as a solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:18]([NH2:20])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C@H:9]([C:11]([NH:13][C@H:14]([C:18]([NH2:20])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH3:10]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)[C@H](C)N)C(N)=O
Yield: 23 %

Procedure:
N-(tert-butoxycarbonyl)-L-alanyl-L-valinamide (0.5 g, 1.74 mmol) is stirred with 3 mL of TFA in 6 mL of dichloromethane for 1 h. It is then concentrated, neutralized with 3.5 mL of 1N NaHCO3 and 3.5 mL of 1N Na2CO3, and extracted into 60 mL of ethyl ether containing several mL of methanol. The aqueous phase is extracted with 100 mL of dichloromethane and 10 mL of methanol. The aqueous layer is evaporated and the solids are extracted with methanol. This is concentrated to 180 mg (0.96 mmol, 55%) of an 85:15 mixture of the title compound and a minor diastereomer. The combined organic phases are concentrated to afford 74 mg (0.4 mmol, 23%) of the title compound as a white solid. HRMS (ESI) calcd for C8H17N3O2+H1 188.1399, found 188.1408.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([O:8][C:9]([NH:11][C@@H:12]([CH3:19])[CH2:13]OS(C)(=O)=O)=[O:10])([CH3:7])([CH3:6])[CH3:5]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[C:4]([O:8][C:9](=[O:10])[NH:11][C@@H:12]([CH3:19])[CH2:13][C:1]#[N:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](CC#N)NC(=O)OC(C)(C)C
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Sodium cyanide (48.92 g, 0.421 mol) was added to dimethylformamide (DMF) (420 mL) and the mixture was stirred at 35° C. for 30 minutes. Tetrabutylammonium bromide (5.22 g, 0.016 mol) was added and the reaction mixture was stirred for an additional 2 h at 35° C. Methanesulfonic acid 2-(S)-tert-butoxycarbonylamino-propyl ester (82.03 g, 0.324 mol) was added and the reaction mixture was stirred at 35° C. overnight. Add an additional 5.22 g of tetrabutylammonium bromide (0.016 mol) was added and stirred overnight at 35° C. The mixture was then partitioned between 1200 mL water and 1600 mL of ethyl acetate. The resulting organic and aqueous phases were separated and extracted sequentially 2 times with 800 mL of ethyl acetate. The combined extracts were washed 3 times with 500 mL of water and a saturated solution of sodium chloride in water. The organic layer was dried over magnesium sulfate, filtered and concentrated to afford a solid in 84% of (S)-(2-cyano-1-methyl-ethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: NC1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]2)=[O:10])[CH2:4]C1.C(OC([N:24]1CC[C@@H](N)C1)=O)(C)(C)C>>[NH:24]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]2)=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: NC1CCC(NC(=O)N2CC[C@@H](N)C2)CC1
Product: N[C@@H]1CCN(C(=O)N[C@@H]2CCNC2)C1

Procedure:
(R)-3-Amino-pyrrolidine-1-carboxylic acid (R)-pyrrolidin-3-ylamide is prepared analogously to (R)-3-amino-pyrrolidine-1-carboxylic acid (4-amino-cyclohexyl)-amide (Intermediate IF) by replacing (4-amino-cyclohexyl)-carbamic acid tert-butyl ester with (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:15][C:16]([OH:18])=[O:17])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
4-methoxy-3-nitro-benzaldehyde (compound of Example 5; 1.05 g, 5.79 mmol) and malonic acid (1.32 g, 1.27 mmol) were dissolved in pyridine (20 mL) under stirring and piperidine (1 mL) was added to the pyridine solution. The reaction mixture was heated at 75° C. to 80° C. for 3 h, after which the temperature was further increased to 120° C. and maintained at this temperature for 6 h. At the end of the reaction, pyridine was evaporated, followed by addition of aqueous HCl (1:1) to obtain pH ˜4. The solid obtained was filtered, washed with cold water and dried.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][C:19]([O:21]C)=O)=[C:13]([CH3:23])[CH:12]=1.[Si]([O:31][C:32]([O:34][CH3:35])=[CH2:33])(C(C)(C)C)(C)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[C:13]([CH3:23])[C:14]([CH2:18][CH:19]([OH:21])[CH2:33][C:32]([O:34][CH3:35])=[O:31])=[C:15]([CH3:17])[CH:16]=1
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Reactant: COC(=O)Cc1c(C)cc(Br)cc1C
Agent: CC(C)C[AlH]CC(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CC(O)Cc1c(C)cc(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
DIBAL-H (8.66 mL, 12.99 mmol) was added dropwise to a solution of methyl 2-(4-bromo-2,6-dimethylphenyl)acetate (3.18 g, 12.37 mmol) in CH2Cl2 (60 mL) at −78° C. and stirred for 1 h. 1-(tert-Butyldimethylsilyloxy)-1-methoxyethene (4.05 mL, 18.55 mmol) followed by BF3.OEt2 (1.959 mL, 15.46 mmol) were added. The reaction was stirred at −78° C. for 20 min and then allowed to warm to rt. The reaction was quenched by the addition of 10 mL of 1.0 M HCl, extracted with dichloromethane. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (loading in chloroform, 0% to 50% ethyl acetate in hexane over 15 min using a 40 g silica gel cartridge) to yield 2A (2.5 g, 8.30 mmol, 67.1% yield) as a clear oil. 1H NMR (500 MHz, chloroform-d) δ ppm 7.18 (2H, s), 4.20-4.28 (1H, m), 3.72 (3H, s), 2.91 (1H, dd, J=14.03, 8.25 Hz), 2.72-2.78 (2H, m), 2.53-2.57 (2H, m), 2.55 (2H, dd, J=40.03, 6.19 Hz), 2.33 (6H, s), 1.58 (2H, br. s.).
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([OH:13])[N:7]2[N:6]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:20]O>>[OH:13][C:12]1[N:7]2[N:6]=[C:5]([CH2:4][C:1]([O:3][CH3:20])=[O:2])[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=1
Reactant: Cc1cc(O)n2nc(CC(=O)O)nc2n1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1nc2nc(C)cc(O)n2n1

Procedure:
A solution of the product obtained in Step 2 (1.5 g) in 50 ml of methanol was cooled to 0° C., 24 ml of thionyl chloride was added by dropwise to this solution at that temperature, and the mixture was refluxed for 1.5 hours. After removing the solvent by distillation under reduced pressure, the residue was recrystallized from ethyl acetate/ether, giving 1.5 g of the objective compounds.