Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34]([NH:36][CH3:37])=[O:35])=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C1COCC1.CCO>[CH:40]1([C:39]2[C:20]([N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:21][C:22]3[O:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=3[CH:38]=2)[CH2:42][CH2:41]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCc4ccccc4)cc3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(O)cc3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 97.7 %

Procedure:
A solution of 6-(N-(4-(benzyloxy)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.174 g, 0.298 mmol) in 3:1 THF/EtOH (20 mL) was subjected to hydrogenation at 40 psi in the presence of 5% palladium on charcoal (20 mg). After 3 hours the reaction vessel was purged with nitrogen, catalyst removed by filtration through Celite and the filtrate concentrated to dryness at reduced pressure. The residue was triturated with DCM/hexane. The resulting solid was collected by filtration and dried in vacuo to afford the title compound (144 mg, 98%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (br. s., 1H) 8.44 (q, J=4.4 Hz, 1H) 8.13 (s, 1H) 7.97 (dd, J=8.9, 5.4 Hz, 2H) 7.46 (d, J=8.9 Hz, 2H) 7.40 (t, J=8.9 Hz, 2H) 7.12 (s, 1H) 6.77 (d, J=8.9 Hz, 2H) 3.27 (s, 3H) 2.83 (d, J=4.6 Hz, 3H) 2.28-2.39 (m, 1H) 0.76-1.11 (m, 3H) 0.47 (br. s., 1H). LCMS (m/z, ES+)=495 (M+H+).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]2[N:19]=[C:20]([N:28]3[CH2:33][CH2:32][C@H:31]([NH:34][C:35]([C:37]4[NH:38][C:39]([CH3:44])=[C:40]([Cl:43])[C:41]=4[Cl:42])=[O:36])[C@H:30]([O:45][CH3:46])[CH2:29]3)[S:21][C:22]=2[C:23]([O:25]CC)=[O:24])=[N:16][CH:17]=1.Cl>O1CCCC1.C(#N)C>[Cl:42][C:41]1[C:40]([Cl:43])=[C:39]([CH3:44])[NH:38][C:37]=1[C:35]([NH:34][C@@H:31]1[CH2:32][CH2:33][N:28]([C:20]2[S:21][C:22]([C:23]([OH:25])=[O:24])=[C:18]([C:15]3[CH:14]=[N:13][C:12]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:17][N:16]=3)[N:19]=2)[CH2:29][C@@H:30]1[O:45][CH3:46])=[O:36]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1-c1cnc(Cl)cn1
Reactant: OCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CO[C@H]1CN(c2nc(-c3cnc(OCCN4CCCC4)cn3)c(C(=O)O)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 44.1 %

Procedure:
To a stirred solution of 2-(pyrrolidine-1-yl)ethanol (0.102 mL, 0.872 mmol) in dry tetrahydrofuran (20 mL) was added sodium hydride (70 mg, 1.771 mmol) at 0° C. The reaction mixture was heated to 80° C. After 10 min, ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 59, 250 mg, 0.436 mmol) was added to the reaction mixture at 80° C. and further maintained at 80° C. for 10 min. After the completion of the reaction, the reaction mixture was cooled and carefully quenched by adding ice pieces. The aqueous layer was extracted with ethyl acetate (2×50 mL) to get rid of any organic impurities and discarded. The aqueous layer was acidified to pH=2 using 2N HCl solution and was extracted with 10% methanol/dichloromethane (2×100 mL). The organic layer was dried and concentrated under reduced pressure to yield the product. The obtained product was stirred in acetonitrile (10 mL). The solid was filtered and dried to obtain 120 mg (45%) of 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-{5-[2-(pyrrolidin-1-yl)ethoxy]pyrazin-2-yl}-1,3-thiazole-5-carboxylic acid as yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]=[C:11]([NH:14][CH2:15][C:16]3[O:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(#N)C>[CH3:21][C:18]1[O:17][C:16]([CH2:15][NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)[CH:23]=[CH:22][C:9]=3[N:10]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(CNC2=Nc3ccc(NC(=O)CCl)cc3CO2)o1
Reactant: CN1CCNCC1
Solvent: CC#N
Product: Cc1ccc(CNC2=Nc3ccc(NC(=O)CN4CCN(C)CC4)cc3CO2)o1
Yield: 71.3 %

Procedure:
Prepared from the above described 2-chloro-N-{2-[(5-methyl-furan-2-ylmethyl)-amino]-4H-benzo[d][1,3]oxazin-6-yl}-acetamide (100 mg, 0.300 mmol) and 1-methylpiperazine (0.333 ml 2.996 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as an off-white foam (85 mg, 71%), MS (ISP) m/e=398.2 [(M+H)+].
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][C:49]=1[NH2:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:50][C:49]4[CH:51]=[C:52]([CH3:55])[CH:53]=[CH:54][C:48]=4[F:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1ccc(F)c(N)c1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cc(C)ccc2F)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-fluoro-5-methylaniline (Aldrich) to give the title product. LC-MS (ES+) 772 [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[CH2:10][CH2:11][C:12]#[CH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1>>[CH2:1]([O:8][C:9](=[O:14])[CH2:10][CH2:11][C:12]#[C:13][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#CCCC(=O)OCc1ccccc1
Product: O=C(CCC#Cc1ccc(C(F)(F)F)cc1)OCc1ccccc1

Procedure:
In analogy to the procedure described for example 8 a], pent-4-ynoic acid benzyl ester (Rosowsky, Andre; Forsch, Ronald A.; Queener, Sherry F., Journal of Medicinal Chemistry (2003), 46(9), 1726-1736) was reacted with 4-iodobenzotrifluoride in the presence of PdCl2(Ph3P)2 and cuprous iodide to give the title compound as yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Yield: 53.3 %

Procedure:
To a solution of (2R)-2-methyl-piperizine (4.5 g, 45 mmol) in ethanol (80 mL) was added 4-fluorobenzyl chloride (5.38 mL, 45.0 mmol) and sodium hydrogen carbonate (11.3 g, 135 mmol). The reaction was refluxed overnight, cooled and concentrated. The remaining residue was diluted with dichloromethane and washed with water. The organic layer was separated and concentrated to give a clear oil. Chromatography on silica gel gave the title compound (5.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][CH:15]=[C:14]([CH3:20])[C:13]=3[NH:12][C:11]([CH3:21])=[C:10]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2].C(OCC)(OCC)O[CH2:33][CH3:34]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:20])[CH:15]=[N:16][C:17]=3[O:19][CH2:33][CH3:34])[NH:12][C:11]([CH3:21])=[C:10]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2]
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(C#N)ccc1C1C(C(=O)OCCC#N)=C(C)Nc2c(C)c[nH]c(=O)c21
Agent: O=S(=O)(O)O
Product: CCOc1ncc(C)c2c1C(c1ccc(C#N)cc1OC)C(C(=O)OCCC#N)=C(C)N2
Temperature: 130 °C
Reaction time: 8 h

Procedure:
2.22 g (5.44 mmol) of the compound from Example 28A are suspended in 100 ml of triethyl orthoformate and heated to 130° C. Then, over a total period of 8 hours, 10 drops of concentrated sulfuric acid are added each hour to the reaction mixture. It is then stirred at the same temperature overnight. After cooling, excess orthoester is removed in a rotary evaporator, and the crude product is purified by column chromatography (silica gel; mobile phase: initially dichloromethane then isohexane/ethyl acetate 1:1). The product fractions are combined, the solvent is removed, and the residue is crystallized from ethyl acetate/diethyl ether. The precipitate is filtered off and dried under high vacuum. 1.80 g (77% of theory) of the title compound are obtained.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[NH:11][C:10]2([CH3:18])[CH3:17].O>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[NH:11][C:10]2([CH3:18])[CH3:17]
Reactant: COc1ccc2c(c1)C(C)(C)NC2=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC1(C)NC(=O)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
A 1 M solution of BBr3 in CH2Cl2 (88.0 mL, 88.0 mmol) is dissolved in dry CH2Cl2 under N2. A solution of lactam 57 (7.65 g, 40.0 mmol) in CH2Cl2 (50 mL) is added to the BBr3 solution dropwise over 10 min. The resulting mixture is stirred at rt overnight. The reaction mixture is poured into water and extracted with EtOAc (3×). The organic phase is dried (MgSO4), filtered, and evaporated, leaving the product 62 as a white solid (4.03 g, 57%), mp 231-233° C., which requires no purification. 1H NMR (DMSO-d6, 2.50 ppm) 8.18 (s, 1), 7.28 (d, 1, J=8.5), 6.75 (d, 1, J=1.6), 6.67 (dd, 1, J=8.5, 1.6), 1.25 (s, 6); 13C NMR (CDCl3 +DMSO-d6) 169.30, 161.06, 155.40, 124.68, 121.53, 115.39, 107.26, 57.98, 27.47; MS (MW=177.2, EI, eE=70 eV) m/z 177 (M+), 163, 162 (base peak).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]#[N:21])=[CH:14][CH:13]=1)[CH2:6][CH2:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[C:29](OC(=O)C)(=[O:31])[CH3:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][NH:21][C:29](=[O:31])[CH3:30])=[CH:16][CH:17]=1)[CH2:6][CH2:5]2
Reactant: CC(=O)OC(C)=O
Reactant: N#CCCc1ccc(OC2CCc3cc(Cl)ccc32)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCCCc1ccc(OC2CCc3cc(Cl)ccc32)cc1
Reaction time: 3 h
Yield: 33.7 %

Procedure:
To a solution of 4-[(5-chloro-2,3-dihydro-1H-inden-1-yl)oxy]benzenepropanenitrile (0.50 g, 1.7 mmol) in tetrahydrofuran (25 mL) was added lithium aluminum hydride (77 mg, 2.0 mmol) under ice-cooling, and the mixture was stirred in an ice bath for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The obtained oil was dissolved in pyridine (20 mL), acetic anhydride (0.18 mL, 0.95 mmol) was added, and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.11 g, yield 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CC1C=CC(S(O[CH2:38][CH2:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH:43]=[CH:42]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:38][CH2:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH:43]=[CH:42]2)=[CH:24][CH:25]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCCOC2C=CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOC4C=CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (30 mg) in anhydrous DMF were added 2-(cyclohex-2-enyloxy)ethyl 4-methylbenzenesulfonate (intermediate BV) (1.5 eq) and Cs2CO3 (2 eq). The mixture was stirred at room temperature for 16 h, after which LC-MS showed the reaction was complete. The reaction mixture was poured into water, extracted with EA, washed with water and brine, and then dried with anhydrous Na2SO4 and concentrated to an oil. The crude oil was purified by preparative-HPLC to obtain compound BW (17.1 mg). 1H NMR (CD3OD, 400 MHz): δ 7.32 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.87˜5.76 (s, 2H), 4.59 (s, 1H), 4.11˜3.89 (m, 6H), 3.89˜3.76 (m, 3H), 3.72˜3.68 (m, 1H), 3.49˜3.40 (m, 3H), 2.03˜1.98 (m, 2H), 1.89˜1.84 (m, 1H), 1.80˜1.62 (m, 2H), 1.79˜1.51 (m, 1H); MS ESI (m/z) 506 (M+H)+, calc. 505.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[O-]S([O-])(=O)=O.[Na+].[Na+]>[C:16]1([CH:15]([OH:22])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)c1ccccc1
Temperature: -10 °C

Procedure:
To 100 mL (0.10 mol) of 1.0 M BnMgBr in THF 9.50 g (90 mmol) of benzaldehyde (2) was added with vigorous stirring at −10° C. This mixture was slowly warmed to room temperature and then stirred for 2 hr at this temperature. The mixture was added to 300 mL of saturated aqueous Na2SO4. The organic layer was separated and washed with saturated aqueous NH4Cl. The aqueous layer was extracted with 2×100 mL of diethyl ether. The combined organic extracts were evaporated to dryness, and the residue was dissolved in 100 mL of dichloromethane. The obtained solution was dried over Na2SO4 and evaporated to dryness. This crude product was further used without an additional purification. Yield 12.0 g (67%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:22]([O:26][C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][C:33]([CH2:39][CH2:40]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][C:33]([CH2:39][CH2:40][N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]3=[O:15])=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ccc(OCc4ccccc4)cc3=O)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 450 mg (2.24 mmol) 4-benzyloxy-1H-pyridin-2-one in 2.2 mL DMF at 0° C. is added 1.46 g (4.47 mmol) cesium carbonate and after 15 min 1.00 g (2.32 mmol) 7-[2-(toluene-4-sulfonyloxy)ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7). The reaction mixture is stirred overnight at RT, filtered and is directly transferred to reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.CO[C:13](=O)[C@@H:14]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1.S(=O)(=O)(O)O>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[C:13]([C@H:14]2[NH:15][C:16](=[O:19])[CH2:17][CH2:18]2)[O:5][N:4]=1
Reactant: CC(C)=NO
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([C@@H]2CCC(=O)N2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a cooled (0°-5° C.) solution of acetone oxime (11.74 g, 160.8 mmol) in THF (200 mL) was slowly added n-butyl lithium (128.6 mL, 2.5M, 321.6 mmol) in hexanes. After being stirred at 0°-5° C. for one hour, a solution of pyroglutamic methyl ester (10.0 g, ~69.9 mmol, the product of step 13a)in THF (50 mL) was added. After stirring for 4 hr, the solution was allowed to slowly warm up to room temperature, and the stirring was continued for 16 hr. Sulfuric acid (35 g, 98%) was slowly added with cooling, followed by the addition of water (35 mL). The resulting mixture was refluxed for one hour. The organic layer was decanted and the slurry was washed with ethyl acetate (5×50 mL). To the mixture was added ethyl acetate (400 mL) and sodium carbonate until basic. Again, the organic layer was decanted and the slurry was washed with ethyl acetate (4×20 mL). The combined organics were then dried over magnesium sulfate. Evaporation of the solvents gave the title product (5.33 g, 46%), which was taken directly to the next step. HPLC (analytical Chiralark AD column) analysis indicated >99.6% ee.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([Cl:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:21](O)(=O)C.C(N)=N>CCO.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:6]([Cl:12])[C:7]2[N:11]=[CH:21][NH:10][C:8]=2[CH:9]=1)=[O:20]
Reactant: COC(=O)c1cc(N)c(N)c(Cl)c1Nc1ccccc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1cc2[nH]cnc2c(Cl)c1Nc1ccccc1
Temperature: 80 °C
Reaction time: 44 h
Yield: 100.3 %

Procedure:
4,5-Diamino-3-chloro-2-phenylamino-benzoic acid methyl ester 6b (0.32 g, 1.09 mmol) and formamidine acetate (72 mg, 1.64 mmol) in EtOH (36 mL) are heated, with stirring, to 80° C. After 44 hours, the reaction mixture is cooled to room temperature and diluted with EtOAc and washed with water (3×), saturated NaHCO3, and brine. The combined organic extracts are diluted (Na2SO4) and concentrated under reduced pressure to give 0.33 g (99%) clean desired product as a solid. MS APCI (+) m/z 320.3 (M+1) detected.
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)([CH2:9][N+:10]([O-])=O)[CH2:3][C:4](OCC)=O.C1(C)C=CC=CC=1.C([OH:28])C>[Ni]>[CH3:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3](=[O:28])[CH2:4][NH:10][CH2:9]1
Reactant: CCO
Reactant: CCOC(=O)CC(C)(C[N+](=O)[O-])c1ccccn1
Agent: [Ni]
Solvent: Cc1ccccc1
Product: CC1(c2ccccn2)CNCC1=O

Procedure:
A solution of 5.9 g of the compound obtained in Step 2 in 150 ml of ethanol was hydrogenated for 12 hours in the presence of 0.6 g of Raney nickel (10% w/w) under a hydrogen gas pressure of 60 psi. After the reaction was completed, the reaction solution was filtered with Celite® 545 and the filtrate was concentrated under reduced pressure. To the residue thus obtained was added 150 ml of toluene, and the resulting mixture was heated to reflux for 2 hours. The reaction product solution was concentrated under reduced pressure, and the residue thus obtained was purified by a silica gel column chromatography using a mixture of ethyl acetate and methanol of 9:1 to obtain 3.35 g of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([CH3:16])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:19]([O:18][C:13]([C:14]1([CH3:16])[C:9]2=[CH:10][CH:11]=[CH:12][N:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1)=[O:17])[CH3:20]
Reactant: Oc1ccccc1-n1cccc1
Reactant: CCOC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1(C)Oc2ccccc2-n2cccc21
Reaction time: 18 h

Procedure:
A solution of the compound of formula 2, N-(2-hydroxyphenyl)pyrrole (18 g), described in Example 1, ethyl pyruvate (13 g) and p-toluenesulfonic acid (1.8 g) in benzene (1.2 1) is stirred and heated at reflux with a Dean-Stark water trap for 30 min. The reaction mixture is allowed to cool and stand at room temperature for 18 hr. The mixture is filtered and the filtrate is washed with 5% NaHCO3, water, saturated brine solution, and then dried (MgSO4). The solvent is evaporated and the remaining material is adsorbed on a silica gel column. Elution with chloroform gives 4-methyl-4H-pyrrolo[2,1-c][1,4]benzoxazine-4-carboxylic acid ethyl ester, νmaxCHCl3 1,735, 1,605, 1,510, 1,345, 1,125, 1,095 cm-1.
Reaction SMILES: [N:1]1([C:6]2[CH:36]=[CH:35][C:9]([CH2:10][N:11]3[C:19]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:18]4[C:13]([N:14]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:15](=[O:29])[N:16]([CH3:28])[C:17]4=S)=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[NH3:37]>CO.Cl[Hg]Cl>[N:1]1([C:6]2[CH:36]=[CH:35][C:9]([CH2:10][N:11]3[C:19]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:18]4[C:13]([N:14]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:15](=[O:29])[N:16]([CH3:28])[C:17]4=[NH:37])=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: N
Reactant: Cn1c(=S)c2c(Nc3ccccc3)n(Cc3ccc(-n4cncn4)cc3)nc2n(CC(C)(C)C)c1=O
Agent: Cl[Hg]Cl
Solvent: CO
Product: Cn1c(=N)c2c(Nc3ccccc3)n(Cc3ccc(-n4cncn4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 110 °C
Yield: 90 %

Procedure:
2-(4-(1H-1,2,4-triazol-1-yl)benzyl)-5-methyl-7-neopentyl-3-(phenylamino)-4-thioxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one (60 mg, 0.12 mmol) and HgCl2 (65 mg, 0.24 mmol) are suspended in 2 mL of 7N NH3 in methanol. The reaction mixture is heated in a Biotage microwave at 110° C. for 3 hours. After routine workup, the mixture is purified by a semi-preparative HPLC to give 52 mg of pure product as off-white solids (yield: 90%). MS (ESI) m/z 484.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][NH:17][C:16](=O)[CH2:15]1)=[O:13].F[B-](F)(F)F.C([O+](CC)CC)C.[S:33]1[C:37]([C:38]([NH:40][NH2:41])=O)=[N:36][CH:35]=[N:34]1>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[C:38]([C:37]3[S:33][N:34]=[CH:35][N:36]=3)=[N:40][N:41]=[C:16]2[CH2:15]1)=[O:13]
Reactant: O=C1CN(C(=O)c2cccc(C(F)(F)F)c2Cl)CCN1
Reactant: NNC(=O)c1ncns1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2-c2ncns2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-piperazinone (I1) (0.307 g, 1 mmol) in dry Dichloromethane (DCM) (3 ml) was added triethyloxonium tetrafluoroborate (0.209 g, 1.100 mmol). The solution was then stirred at room temperature and under argon for 30 minutes. 1,2,4-Thiadiazole-5-carbohydrazide (I80) (0.144 g, 1.000 mmol) was then added and the solution was stirred for 1 hour, before the solvent was concentrated and n-BuOH (3.00 ml) was added. The solution was then stirred under argon and reflux for a further 3 hours. The solution was then allowed to cool to room temperature before the solvent was evaporated in vacuo.