Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH:15]=O)[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:17][C:18]([S:21]([NH2:23])=[O:22])([CH3:20])[CH3:19].O>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH:1]1([CH2:4][C:5]2([CH:15]=[N:23][S:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH2:6][CH2:7][C:8]3([O:9][CH2:10][CH2:11][O:12]3)[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=CC1(CC2CC2)CCC2(CC1)OCCO2
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)N=CC1(CC2CC2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The crude aldehyde was dissolved in tetrahydrofuran (40 mL) and 2-methyl-2-propanesulfinamide (1.81 g, 14.9 mmol, 1.1 eq.) and titanium(IV) ethoxide (4.27 mL, 20.3 mmol, 1.5 eq.) were added. The resulting mixture was stirred for 5 h under reflux and 16 h at room temperature, before being treated with water (10 mL) and filtered through celite. The filter cake was washed with ethyl acetate, the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0%→100% ethyl acetate in heptane) to yield 1.90 g of the title compound (19). Rt=1.58 min (Method B). Detected mass: 328.3 (M+H+).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[N:5]=1.Cl.C(=O)(O)[O-].[Na+]>>[CH3:11][S:10][C:6]1[N:5]=[C:4]([CH:3]=[O:2])[CH:9]=[CH:8][N:7]=1
Reactant: COC(OC)c1ccnc(SC)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CSc1nccc(C=O)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3) (53.7 g, 268 mmol) was added carefully to 1.2 N aqueous HCl (300 mL, 268 mmol, 1.0 equiv.) and stirred at 60° C. for 3 hours. The reaction mixture was then cooled to room temperature and neutralized by the slow addition of solid sodium bicarbonate. The crude mixture was extracted with diethyl ether (3×150 mL) and the combined organic layer was concentrated under reduced pressure to afford 2-(methylthio)pyrimidine-4-carbaldehyde (4) as a yellow solid (14.2 g, 41.5 g theoretical, 34%). LC-MS m/z 155 (M+1). Reference: WO 2006/009734 A1, pg 67.
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[S:27])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16](O)=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[CH:38]([O:41][CH2:42][CH2:43][CH2:44][NH2:45])([CH3:40])[CH3:39]>O1CCCC1>[F:2][C:3]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[S:27])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([NH:45][CH2:44][CH2:43][CH2:42][O:41][CH:38]([CH3:40])[CH3:39])=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)O
Reactant: CC(C)OCCCN
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)NCCCOC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Compound 1e (13.2 mg), 3-isopropoxypropylamine (9.11 μL), and 4-(5,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride n-hydrate (hereinafter referred to as DMTMM•n-hydrate) (8.67 mg) were dissolved in tetrahydrofuran (1 mL), followed by stirring at room temperature for 2 hours. The reaction mixture was distilled under reduced pressure, and water was added to the residue. The precipitate was filtrated, to thereby yield the titled compound 1 (11.6 mg, yield: 79%).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][CH:30]([C:33]4[N:34]=[C:35]([C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5C(OCC5C=CC=CC=5)=O)[NH:36][CH:37]=4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[NH:19][CH:20]=1)=O)C1C=CC=CC=1.C(Cl)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.C(OCC)(=O)C>[NH:39]1[CH2:40][CH2:41][CH2:42][C@H:38]1[C:35]1[NH:36][CH:37]=[C:33]([CH:30]2[CH2:31][CH2:32][CH:27]([C:24]3[CH:25]=[CH:26][C:21]([C:18]4[NH:19][CH:20]=[C:16]([C@@H:12]5[CH2:13][CH2:14][CH2:15][NH:11]5)[N:17]=4)=[CH:22][CH:23]=3)[CH2:28][CH2:29]2)[N:34]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1c[nH]c(-c2ccc(C3CCC(c4c[nH]c([C@@H]5CCCN5C(=O)OCc5ccccc5)n4)CC3)cc2)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: c1cc(C2CCC(c3c[nH]c([C@@H]4CCCN4)n3)CC2)ccc1-c1nc([C@@H]2CCCN2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 202.9 %

Procedure:
To a solution of A5 (19.2 g) in dichloromethane (500 mL) at −20° C. was added acetyl chloride (16.8 mL), followed by aluminum chloride (43 g). The reaction was allowed to warm up to rt. After overnight stirring, the reaction was poured into a mixture of ethyl acetate (800 mL), 1M HCl (800 mL) along with some ice. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, H2O, dried over Na2SO4, filtered, and concentrated to afford A6 (24 g), which was used for next reaction without further purification.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Br:13][C:14]1[CH:22]=[C:18]([C:19]([OH:21])=O)[C:17]([OH:23])=[CH:16][CH:15]=1.[NH2:24][CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:35])[CH:31]=2)[CH2:26]1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([OH:23])=[C:18]([CH:22]=1)[C:19]([NH:24][CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:34]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[O:35])[CH:31]=2)[CH2:26]1)=[O:21]
Reactant: NC1Cc2ccc(C(=O)N3CCOCC3)cc2C1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NC1Cc2ccc(C(=O)N3CCOCC3)cc2C1)c1cc(Br)ccc1O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 11.7 %

Procedure:
WSC•HCl (96 mg, 0.5 mmol) was added to a solution of 5-bromosalicylic acid (109 mg, 0.5 mmol), 2-amino-5-(morpholino)carbonylindan (refer to Chem. Pharm. Bull., 2000, 48, 131; 141 mg, 0.5 mmol) and triethylamine (70 μL, 0.5 mmol) in dichloromethane (5 mL), and the mixture was stirred at 40° C. for 1.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 2 N hydrochloric acid, water and brine one after another, dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=19:1) to give the title compound (26 mg, 11.9%) as a white crystal.
Reaction SMILES: [CH:1]([CH2:4][C:5](C)(C)[CH3:6])([CH3:3])[CH3:2].[C:9]1([C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](O)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:24]([O:27]CC)(=[O:26])[CH3:25].ClCCl>>[CH3:3][C:1]1[CH:2]=[C:16]([C:20]2[CH:21]=[CH:22][CH:23]=[C:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:25]=2[C:24]([OH:27])=[O:26])[CH:17]=[C:5]([CH3:6])[CH:4]=1
Reactant: CCOC(C)=O
Reactant: CC(C)CC(C)(C)C
Reactant: O=C(O)c1ccccc1-c1ccccc1
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2cccc(-c3ccccc3)c2C(=O)O)c1

Procedure:
Palladium acetate (5.6 mg, 0.025 mmol), 2-phenylbenzoic acid (99 mg, 0.5 mmol) and 3,5-dimethylchlorobenzene (211 mg, 1.5 mmol), butyldi-1-adamantylphosphine (19.2 mg, 0.05 mmol), Cs2CO3 (358 mg, 1.1 mmol), molecular sieves 3 Å (155 mg and anhydrous DMF (2.5 mL). After flash chromatography and preparative HPLC 101 mg (67%) of a white solid was obtained, mp 198-200° C. (isooctane). Rf-0.79 (1/9 ethyl acetate-dichloromethane). 1H NMR (300 MHz, CDCl3) δ 2.30 (s, 6H), 7.00 (s, 1H), 7.03 (s, 2H), 7.33-7.38 (m, 7H), 7.46-7.52 (m, 1H), 9.6 (br s, 1H). 1C NMR (75 MHz, CDCl3) δ 21.7, 122.5, 126.9, 128.1, 128.8, 129.0, 129.3, 129.5, 129.8, 130.0, 132.0, 138.3, 140.7, 141.0, 141.2, 174.2. FT-IR (neat, cm1) υ 1688, 1295. Anal. calcd for C21H18O2 (302.37 g/mol): C, 83.42; H, 6.00. Found: C, 83.13; H, 6.05. The 1H NMR spectrum of 2-phenylbenzoic acid is shown in FIG. 41. The 1H NMR and 13C NMR spectra of the product are shown in FIGS. 42A&E, respectively.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Na+].[Na+].B(O)(O)[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
Nitrogen was bubbled through a solution of 2-bromobenzonitrile (309.4 g, 1.70 mol) in dimethoxyethane (4.2 L) for 30 minutes then the following reagents added in succession: tetrakis(triphenylphosphine)palladium(0), (95 g, 0.082 mol); 2M aqueous sodium carbonate solution (1785 mL, 3.57 mol); and p-tolylboronic acid (239.1 g, 1.76 mol). The reaction mixture was heated under an atmosphere of nitrogen at 70° to 78° C. for 19 hours. The two-phase mixture was cooled to room temperature and the layers separated. The organic layer was evaporated to dryness under reduced pressure. The aqueous layer was extracted with ether (3×1.2 L) and the extracts added to the organic residue. The insoluble material was filtered off and washed with ether. The filtrate was dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue was filtered to remove the solids and the filtrate distilled under high vacuum (0.1-0.2 torr) collecting the fraction boiling between 135° to 140° C. to afford 325 g of 2-cyano-4'-methylbiphenyl. MS (DEI) 193 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5](O)=[O:6].O.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)O)cc1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)cc1Cl
Temperature: 76 °C
Yield: 91.8 %

Procedure:
To a solution of 3-chloro-4-(methoxycarbonyl)benzoic acid (400 mg, 1.9 mmol) in anhydrous THF (15 mL) was added Borane methyl sulfide complex (10 M, 0.56 mL, 5.6 mmol). The resulting solution was heated at 76° C. for 6 hours. After being cooled, the mixture was slowly poured into water (40 mL) at −10° C., then followed a standard aqueous/EtOAc workup procedure to give crude product (350 mg, yield 94%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH3:6])=O.[CH3:7]CO.P(OC[C@H]1O[C@@H](N2C=C(C3C=[CH:37][C:36]([O:39]C)=[CH:35]C=3)C(=O)NC2=O)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O>C1CCCCC1.CCOC(C)=O>[CH2:2]([O:3][CH2:4][CH3:6])[CH3:1].[CH3:35][C:36]([OH:39])([CH3:7])[CH3:37]
Reactant: CCOC(C)=O
Reactant: COc1ccc(-c2cn([C@@H]3O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]3O)c(=O)[nH]c2=O)cc1
Reactant: CCO
Solvent: C1CCCCC1
Product: CC(C)(C)O
Product: CCOCC

Procedure:
Under a nitrogen atmosphere, a solution of 4 (274 mg, 0.67 mmol), n-Bu3SnCl (57 μL, 0.21 mmol, 0.3 equiv.), NaBH3CN (95% grade, 65 mg, 1.04 mmol, 1.5 equiv.), diethyl vinylphosphonate (1.1 mL, 6.91 mmol, 10 equiv.), ABCN (110 mg, 0.45 mmol, 0.67 equiv.), and tert-butanol (0.65 mL, 6.91 mmol, 10 equiv.) in diethylether (5 mL) was stirred at reflux temperature (35° C.). After 4 days, TLC (cyclohexane/EtOAc 1:1) showed complete consumption of the starting material and the formation of two new species, the desired diethyl 2-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-ethylphosphonate 5a (Rf 0.1) and side product 2,3,4,6-tetra-O-acetyl-β-D-glucopyranose 5b (Rf 0.47). The reaction was concentrated in vacuo, and the oily residue was dissolved in CH2Cl2 (30 mL). The organic solution was washed with water (3×30 mL), dried over MgSO4, and reduced to dryness. The residue was purified by chromatography on a silica gel column, which was eluted first with cyclohexane/EtOAc (1:1) and then with EtOAc/EtOH (20:1), to afford 5a as a syrup (257 mg, 71%): Rf 0.5 (EtOAc/EtOH 20:1); δH (400 MHz, CDCl3) 5.37 (dd, 1H, J5,6 3.0 Hz, J6,7 2.8 Hz, H-6), 5.24 (dd, 1H, J3,4 5.2 Hz, J4,5 9.3 Hz, H-4), 5.14 (dd, 1H, J5,6 3.3 Hz, J4,5 9.5 Hz, H-5), 4.22-4.00 (m, 7H, H-3, H-8a, H-8b, 2 OCH2CH3), 3.97 (m, 1H, H-7), 2.09, 2.04, 2.01, 1.98 (all s, 12H, 4×C(O)CH3), 2.98-1.56 (m, 4H, H-1a, H-1b, H-2a, H-2b), 1.29 (dt, 6H, 4JH,P 2.8 Hz, JH,H 7.0 Hz, 2 OCH2CH3); δC (100 MHz, CDCl3) 170.4, 170.0, 169.9, 169.8 (4×C═O), 72.9 (d, JC,P 17.0 Hz, C-3), 68.3 (C-7), 68.2 (C-4), 67.9 (C-5), 67.6 (C-6), 61.8 (d, 2JC,P 6.0 Hz, OCH2CH3), 61.7 (d, 2JC,P 5.0 Hz, OCH2CH3), 61.5 (C-8), 22.1 (C-1), 20.7 (4×C(O)CH3), 19.3 (C-2), 16.4 (d, JC,P 6.0 Hz, 2×OCH2CH3); δP (161.9 MHz, CDCl3) 32.0. m/z (ESI) 497.1772 [M+H]+, C20H33O12P requires 497.1782. 5b: Rf 0.47 (cyclohexane/EtOAc 1:1); δH (400 MHz, CDCl3) 5.35 (dd, 1H, J3,4 3.4 Hz, J6,7<1.0 Hz, H-4), 5.11 (dd, 1H, J1a,2 5.5 Hz, J1b,2 10.3 Hz, J2,3 10.3 Hz, H-2), 4.95 (dd, 1H, H-3), 4.10 (dd, 1H, J1a,1b 11.1 Hz, H-1a), 4.00 (d, 2H, J5,6 6.4 Hz, H-6a, H-6b), 3.74 (t, 1H, H-5), 3.20 (dd, 1H, H-1b), 2.06, 1.97, 1.96, 1.91 (all s, 12H, 4×C(O)CH3); δC (100 MHz, CDCl3) 170.6, 170.4, 170.3, 170.1 (4×C═O), 75.0 (C-5), 71.6 (C-3), 67.9 (C-4), 67.2 (C-1), 66.5 (C-2), 62.2 (C-6), 20.9, 20.8 (4×C(O)CH3). m/z (ESI) 350.1445 [M+NH4]+, C14H2O9 requires 350.1446.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:27])[CH2:10][CH2:9][C:8]2[C:11]([CH3:26])=[C:12]([O:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4].[I-:28].[Na+].CC(C)=O.O>CCOCC>[CH3:1][O:2][C:3]([C:5]1([CH3:27])[CH2:10][CH2:9][C:8]2[C:11]([CH3:26])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][I:28])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4]
Reactant: [I-]
Reactant: COC(=O)C1(C)CCc2c(C)c(OCCCOS(C)(=O)=O)c(C)c(C)c2O1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)C1(C)CCc2c(C)c(OCCCI)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 43.5 h
Yield: 75.9 %

Procedure:
A mixture of the crude methanesulfonate from Example 14 (about 0.932 mmole), 595 mg of sodium iodide, and 5 ml of acetone was stirred at room temperature for 43.5 hours then treated with water and worked-up with ether in the usual manner (the ether extracts were additionally washed with dilute sodium bisulfite solution). The oily product (390 mg) was chromatographed on 20 g of silica gel. Elution with 19:1 and 9:1 hexane-ethyl acetate afforded 306 mg (76.0%) of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(3-iodopropoxy)-2H-1-benzopyran-2-carboxylic acid methyl ester as a colorless oil. In another experiment, iodide prepared in this way crystallized to a solid, mp 73°-75.5° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([C:28]#[CH:29])=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[OH:30]S(O)(=O)=O>CC(C)=O.S([O-])([O-])(=O)=O.[Hg+2]>[C:28]([C:9]1[CH:10]=[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][CH:8]=1)(=[O:30])[CH3:29]
Reactant: C#Cc1cnc(OCCCC)c(-c2nc3c(CC)n(CCOC)nc3c(=O)[nH]2)c1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Solvent: CC(C)=O
Product: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1

Procedure:
The title compound of Example 15 (2.4 g, 6 mmol) and mercury sulfate (100 mg, 0.34 mmol) were stirred together in a mixture of 1N H2SO4 (5 mL) and acetone (35 mL). After 2 h a further portion of mercury sulfate (100 mg) was added and a third portion (100 mg in 5 mL 1N H2SO4) was added 2 h later. The crude reaction mixture was concentrated and the black residue partitioned between dichloromethane and water. The organic phase was separated and washed with saturated sodium bicarbonate solution and brine, dried (MgSO4) and evaporated. Purification by flash column chromatography (gradient elution from 30% ethyl acetate: pentane to 100% ethyl acetate) gave 780 mg product.
Reaction SMILES: [Na].Br[C:3]1[N:8]=[CH:7][C:6]([C:9]2([C:17]#[N:18])[CH2:14][CH2:13][C:12]([F:16])([F:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:3]1[N:8]=[CH:7][C:6]([C:9]2([C:17]#[N:18])[CH2:14][CH2:13][C:12]([F:16])([F:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:20]
Reactant: CCO
Reactant: N#CC1(c2ccc(Br)nc2)CCC(F)(F)CC1
Agent: [Na]
Product: CCOc1ccc(C2(C#N)CCC(F)(F)CC2)cn1
Temperature: 70 °C
Yield: 49 %

Procedure:
Sodium metal (229 mg, 9.96 mmol) was added to ethanol (5 mL) at room temperature. To this solution was added 1-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (300 mg, 1.00 mmol) and the reaction was heated at 70° C. for 6 hours. After cooling to room temperature the volatiles were removed under reduced pressure. The residue was diluted with water and extracted with AcOEt (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford 1-(6-ethoxy-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (130 mg, 49%). LC-MS (m/z) 241.4 (MH+). 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=2.7 Hz, 1 H), 7.66 (dd, J=8.8, 2.7 Hz, 1 H), 6.78 (d, J=8.8, Hz, 1 H), 4.38 (q, J=7.1, Hz, 2 H), 2.07-2.42 (m, 8 H), 1.41 (t, J=7.1, Hz, 3 H).
Reaction SMILES: C(Cl)Cl.Cl[CH:5]1[NH:10][CH:9]=[CH:8][N:7]2[C:11]([CH:30]3[CH2:33][CH2:32][CH2:31]3)=[N:12][C:13]([C:14]3[CH:23]=[C:22]4[C:17]([N:18]=[CH:19][C:20]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:21]4)=[CH:16][CH:15]=3)=[C:6]12.[N:34]#N.N>CC(O)C>[CH:30]1([C:11]2[N:7]3[CH:8]=[CH:9][N:10]=[C:5]([NH2:34])[C:6]3=[C:13]([C:14]3[CH:23]=[C:22]4[C:17](=[CH:16][CH:15]=3)[N:18]=[CH:19][C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:21]4)[N:12]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: N#N
Reactant: ClC1NC=Cn2c(C3CCC3)nc(-c3ccc4ncc(-c5ccccc5)nc4c3)c21
Agent: N
Solvent: ClCCl
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4ncc(-c5ccccc5)nc4c3)c12
Temperature: 100 °C

Procedure:
DCM solution of 7-(8-chloro-3-cyclobutyl-7,8-dihydroimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoxaline (61 mg, 0.15 mmol) was evaporated to dryness by passing a stream of N2. The residue was suspended in anh. i-PrOH (4 mL) and the suspension was saturated with gaseous NH3 at 0° C. (2 min). The reaction vessel was sealed and heated to 100° C. (external temperature) for 63 h. Then the reaction was cooled to rt, concentrated under reduced pressure and purified by flash chromatography (silica gel, 0-5% MeOH in DCM) and then preparative TLC (4% MeOH in CH3CN) to afford the title compound as a light yellow solid; 1H NMR (400 MHz, CDCl3) δ 9.36 (d, J=4Hz, 1H), 8.43 (s, 1H), 8.30-8.25 (m, 4H), 7.65-7.50 (m, 3H), 7.15 (m, 2H), 5.26 (br, 2H), 3.86 (quintet, J=8 Hz, 1H), 2.75-2.60 (m, 2H), 2.60-2.45 (m, 2H), 2.20 (q, J=8 Hz, 1H), 2.07 (br, 1H). MS (ES+): m/z 393.1 (100) [MH+]; HPLC: tR=2.30 min (OpenLynx, polar—5 min).
Reaction SMILES: P(Cl)(Cl)Cl.[C:5]([O:9][C:10](=[O:31])[C@H:11]([CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)([CH3:8])([CH3:7])[CH3:6].[CH2:32]([NH:50][C:51]([O:53][CH:54]([CH2:62][O:63][C:64](=[O:84])[NH:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[CH2:55][S:56][CH2:57][CH2:58][C:59](O)=[O:60])=[O:52])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>N1C=CC=CC=1>[C:5]([O:9][C:10](=[O:31])[C@H:11]([CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:59](=[O:60])[CH2:58][CH2:57][S:56][CH2:55][CH:54]([O:53][C:51](=[O:52])[NH:50][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:62][O:63][C:64](=[O:84])[NH:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])=[CH:16][CH:15]=1)([CH3:7])([CH3:8])[CH3:6]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)O)OC(=O)NCCCCCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)NCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of phosphorus trichloride (19 mg) in pyridine (4 ml), 4-aminobenzoyl-glutamic acid di-t-butyl ester (106 mg) was added, followed by stirring at room temperature for 1 hour. To this mixture, 6,7-bis(octadecylcarbamoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 10 (216 mg) was added, followed by stirring at 50° C. for 1 hour. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel preparative TLC (dichloromethane:methanol=50:1×3) to yield the title compound (102 mg, yield 32%) as a colorless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]1[C:19]([OH:21])=[O:20])=[O:11].Br[C:23]1[S:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:27]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][N:16]([C:23]2[S:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:27]=2)[CH2:15][C@H:14]1[C:19]([OH:21])=[O:20])=[O:11]
Reactant: Cc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2C(=O)O)c(Cl)c1Cl
Reactant: COC(=O)c1cnc(Br)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](C(=O)O)C2)s1
Temperature: 55 °C

Procedure:
Cis(±)4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-3-carboxylic acid hydrochloride (Intermediate 79; 1.84 g) was dissolved in anhydrous DMF (20 ml) under an argon atmosphere in a 100-ml round bottom flask. Methyl 2-bromothiazole-5-carboxylate (1.43 g) was added followed by N,N-diisopropylethylamine (3.6 ml) at room temperature. The reaction was heated to 55° C. for 14 h cooled to room temperature. The reaction mixture was diluted with EtOAc (250 ml) and washed with a saturated aqueous ammonium chloride solution (125 ml), followed by a saturated aqueous sodium chloride solution (100 ml). The EtOAc solution was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography using 0-10% CH3OH in DCM. The recovered product was recrystallised from EtOAc to further enhance the diastereomeric excess, increasing it from a 90:10 cis:trans mixture to a 96:4 cis:trans mixture (by HPLC analysis). The recrystallised product was carried on to the next reaction (2 g). MS (ES−(M+H)+): 461, 463 for C17H18Cl2N4O5S; NMR: 1.71 (m, 1H), 1.91 (m, 1H), 2.16 (s, 3H), 2.81 (dt, 1H), 3.42 (m, 2H), 3.74 (s, 3H), 3.86 (m, 1H), 4.34 (m, 2H), 7.43 (d, 1H), 7.88 (s, 1H), 8.50 (brs, 1H), 12.06 (s, 1H).