Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]12[CH2:35][CH2:34][C@:33]3([CH3:36])[C:28](=[C:29]([CH3:37])[CH2:30][CH2:31][CH2:32]3)[C@@H:3]1[O:4][C:5](=[O:27])[CH:6]2[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:16]=2[CH2:25][OH:26])[CH2:10][CH2:9]1.[C:38](OC(=O)C)(=[O:40])[CH3:39].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:38]([O:26][CH2:25][C:16]1[C:17]([O:23][CH3:24])=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][N:8]([CH2:7][CH:6]2[C:5](=[O:27])[O:4][C@H:3]3[C:28]4[C@@:33]([CH3:36])([CH2:34][CH2:35][C:2]23[OH:1])[CH2:32][CH2:31][CH2:30][C:29]=4[CH3:37])[CH2:9][CH2:10]1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(CN2CCN(CC3C(=O)O[C@H]4C5=C(C)CCC[C@]5(C)CCC34O)CC2)c(CO)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1cc(CN2CCN(CC3C(=O)O[C@H]4C5=C(C)CCC[C@]5(C)CCC34O)CC2)c(COC(C)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound of example 38 (200.0 mg, 0.39 mmol) was dissolved in DCM (10 mL). To it was added acetic anhydride (43.86 mg, 0.43 mmol), pyridine (61.70 mg, 0.78 mmol) and DMAP (2 mg) and reaction mixture was stirred at room temperature (25° C.) for 2 hours. Reaction mixture was diluted with water and extracted with DCM (3×50 mL). The crude product was purified by column chromatography (silica gel, 40% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13]3[C:19]4[C:20]([NH:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]6[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=6)=[C:27]([Cl:40])[CH:26]=5)=[N:21][CH:22]=[N:23][C:18]=4[S:17][C:14]=32)=[N:9]1)(=O)=O.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(N(C(C)C)CC)(C)C>CC#N>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]3[S:17][C:14]4[C:15]5[C:10]([CH2:11][CH2:12][C:13]=4[C:19]=23)=[N:9][N:8]([CH2:7][CH2:6][N:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)[CH:16]=5)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To 250 mL CH3CN were sequentially added 2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]ethyl methanesulfonate (5.80 g, 9.67 mmol), 1-methylpiperazine (3.22 mL, 29.0 mmol), and diisopropylethylamine (3.37 mL, 19.3 mmol). The opaque white suspension was stirred with heating to reflux, upon which the contents turn brown and homogeneous. After 15 h the mixture was removed from heating, and allowed to cool to rt. The contents were concentrated under reduced pressure to 10% volume, diluted with CH2Cl2 (150 mL), and washed with aq NH4Cl (50 mL). The aqueous layer was separated and extracted with CH2Cl2 (50 mL), and the combined organic layers then washed with sat. NaHCO3 (2×100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The solid product was triturated from methanol and then recrystallized from ethanol to afford the final product (3.22 g, 55%) as an off-white solid. 1H-NMR (CD2Cl2) δ 1.98 (s, 3H), 2.30-2.50 (broad m, 8H), 2.68 (t, 2H), 2.98 (t, 2H), 3.25 (t, 2H), 4.08 (t, 2H), 5.07 (s, 2H), 6.93-7.00 (m, 3H), 7.14-7.20 (m, 2H), 7.25-7.39 (m, 2H), 7.75 (s, 1H), 8.31 (s, 1H); LCMS RT=3.15 min; [M+H]+=604.3.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]2[CH2:17][CH2:16][CH2:15][S:14][C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][Cl:31]>CN(C)C=O>[CH2:1]([C:8]1[C:9](=[O:19])[N:10]([CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])[C:11](=[O:18])[N:12]2[CH2:17][CH2:16][CH2:15][S:14][C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)n2c(c1Cc1ccccc1)SCCC2
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(Cc2ccccc2)c2n(c(=O)n1CCCCCl)CCCS2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.11 g (15 mmol) of 9-benzyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 3.32 g (24 mmol) of potassium carbonate in 70 ml of N,N-dimethylformamide, 3.46 ml (60 mmol) of 1-bromo-4-chlorobutane was added at room temperature, followed by stirring at 60° C. for 2 hours and then at 100° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane-water; the organic layer was washed with water and dried. The oily substance obtained by distilling off the solvent was purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→2/1) to yield 4.96 g (90.6%, light yellow oily substance) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([O:10][CH3:11])[CH:6]=2)[N:1]=[C:14]([CH3:16])[C:13]=1[C:12]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(N)c(C#N)c1
Product: CCOC(=O)c1c(C)nc2ccc(OC)cc2c1N

Procedure:
Prepared as in Example 2a from 2-amino-5-methoxybenzonitrile (Campbell, J. B. et al. Synth. Commun. 1989, 19, 2255-2263.) and ethyl acetoacetate as an off-white solid (92%). 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=6.8 Hz, 3H), 2.57 (s, 3H), 3.86 (s, 3H), 4.33 (q, J=6.8 Hz, 2H), 7.28 (dd, J=2.8, 9.2 Hz, 1H), 7.59 (d, J=9.2 Hz, 1H), 7.60 (bs, 2H), 7.63 (d, J=2.8 Hz, 1H). MS 261 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]([CH:38]([CH3:40])[CH3:39])=[CH:26][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]([CH:38]([CH3:40])[CH3:39])=[CH:26][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=[S:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)c1cc(C(=O)Nc2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1cc(C(=S)Nc2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 161.3 %

Procedure:
2,4-bis-benzyloxy-5-isopropyl-N-[4-(morpholin-4-yl)phenyl]benzamide (F370-IM2, 2.45 g, 4.60 mmol) was suspended in toluene (50 mL), mixed with Lawesson's reagent (2.05 g, 5.06 mmol) and the mixture was heated at 110° C. for 1 hour. As the reaction proceeded, the suspension changed to a yellow solution. The reaction mixture was cooled to room temperature, mixed with 5% aqueous sodium hydrogencarbonate (50 mL), and the organic layer was separated. The organic layer thus obtained was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure. To the residue were added toluene (20 mL) and hexane (10 mL), and the resulting suspension was stirred at room temperature for 1 hour, crystals (F370-IM3) were collected by filtration. The mother liquor was concentrated and purified by silica gel column chromatography (ethyl acetate:hexane 2:1), to afford F370-IM3. The combined title compound (F370-IM3, about 4.1 g) was subjected to the next reaction.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CCO>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: C1COCCN1
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCOCC1)OC2

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), morpholine (0.50 ml, 5.7 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 313 (M+, 1), 101 (6), 100 (bp), 77 (4), 56 (6).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8]C(C)C.ClC1C=C(C2ON=C(C3C=CC(OC(C)C)=C(I)C=3)N=2)C=CC=1OCCC>>[I:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15](/[CH:17]=[CH:18]/[C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1ccc(/C=C/c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1
Agent: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Product: Cc1ccc(/C=C/c2nc(-c3ccc(O)c(I)c3)no2)cc1
Yield: 53 %

Procedure:
When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 53% yield, as colourless solid. 1H-NMR (CDCl3) 8.44 (d, 1H, J=1.95 Hz); 8.0 (dd, 1H, J=8.49, 2.01 Hz); 7.84 (d, 1H, J=16.35 Hz); 7.49 (d, 1H, J=8.16 Hz); 7.07 (d, 1H, J=8.49 Hz); 6.98 (d, 1H, J=16.83 Hz); 5.61 (s, 1H).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9]>CN1CCCC1=O>[C:1]([S:3][C@@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: O=C(O)[C@H](Cl)Cc1ccccc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(=O)S[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 24 h
Yield: 94.4 %

Procedure:
Potassium thioacetate (93 mg, 0.81 mmol) was added to a solution of 100 mg (0.54 mmol) of (2R)-2-chloro-3-phenylpropionic acid in 2 ml of N-methyl-2-pyrrolidone at room temperature, and the mixture was stirred for 24 hours. The work-up procedure in the same manner as in Example 18 of the reaction mixture was followed to give 114 mg (0.51 mmol, yield 94%) of the desired (2S)-2-acetylthio-3-phenylpropionic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=4[S:24][C:23]=3[NH:31][C:32]([C:34]3[CH:35]=[C:36]([S:40]([N:43]([CH3:55])[CH2:44][C@@H:45]([C@H:47]([C@@H:49]([C@@H:51]([CH2:53][OH:54])[OH:52])[OH:50])[OH:48])[OH:46])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=3)=[O:33])=[O:21])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+:57]>C(O)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]3[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=4[S:24][C:23]=3[NH:31][C:32]([C:34]3[CH:35]=[C:36]([S:40]([N:43]([CH3:55])[CH2:44][C@@H:45]([C@H:47]([C@@H:49]([C@@H:51]([CH2:53][OH:54])[OH:52])[OH:50])[OH:48])[OH:46])(=[O:41])=[O:42])[CH:37]=[CH:38][CH:39]=3)=[O:33])=[O:21])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)([O-:4])=[O:2].[Na+:57]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)c4)sc4c3CCCC4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)[O-])cc4)cc2)CCCC3)c1

Procedure:
A mixture of 250 mg of 1-deoxy-1-[{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)phenyl]sulfonyl}(methyl)amino]-D-glucitol, 1.5 mL of a 1.0 M aqueous sodium hydroxide solution, and 2.5 mL of ethanol was heated and refluxed overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by ODS silica gel column chromatography (acetonitrile-water). The product was lyophilized to obtain 33 mg of sodium 1-{[(3-{[3-({4-[2-(4-carboxylatophenyl)ethyl]phenyl}carbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]carbamoyl}phenyl)sulfonyl](methyl)amino}-1-deoxy-D-glucitol as a yellow foamed solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH:11]([NH2:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[BrH:19]>CC(O)=O>[NH2:18][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1.[BrH:19]
Reactant: COc1cccc(CCC(N)c2ccccc2)c1
Agent: Br
Solvent: CC(=O)O
Product: NC(CCc1cccc(O)c1)c1ccccc1
Reaction time: 2.5 h

Procedure:
A mixture of the product from Step C (920 mg), HOAc (2 mL) and 48% HBr (3 mL) was stirred while heating at reflux. After 2-3 hours, the solution was concentrated in vacuo to provide a pale beige sticky solid which was triturated with Et2O. Removal of residual solvents in vacuo provided the titled product hydrobromide as a pale beige froth.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:11]=1[C:12]#[N:13].[C:19](=[O:21])=[O:20].O>C1COCC1.CCOCC>[C:12]([C:11]1[C:14]([Cl:18])=[C:15]([CH:16]=[CH:17][C:10]=1[Cl:9])[C:19]([OH:21])=[O:20])#[N:13]
Reactant: N#Cc1c(Cl)cccc1Cl
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: N#Cc1c(Cl)ccc(C(=O)O)c1Cl
Reaction time: 1.5 h

Procedure:
A solution of lithium di-isopropylamide (2M in heptane, 25 ml) was added to a solution of 2,6-dichlorobenzonitrile (8.6 g) in THF while maintaining the temperature below -70° C. The mixture was stirred for 1.5 hours then poured onto solid carbon dioxide. It was stirred for 1 hour then diluted with ether. Water was added and the mixture was acidified to pH1. It was extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 3-cyano-2,4-dichlorobenzoic acid (9.4 g) as a white solid mp 230°-232° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([CH3:25])[CH:3]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32](B(O)O)[CH:33]=2)[CH:28]=[CH:27]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:32]5[CH:33]=[C:34]6[C:29]([CH:28]=[CH:27][NH:26]6)=[CH:30][CH:31]=5)=[CH:3][C:4]=4[CH3:25])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: Cc1cc(Br)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc3cc[nH]c3c2)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Temperature: 150 °C
Yield: 49 %

Procedure:
A microwave vial was charged with 4-(4-bromo-2-methylphenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (105 mg, 0.259 mmol), 1H-indol-6-ylboronic acid (41.7 mg, 0.259 mmol), PdCl2(dppf) (9.48 mg, 0.013 mmol), K2CO3 (90 mg, 0.648 mmol), 1,4-dioxane (3 mL) and water (1 mL). The reaction was purged with nitrogen, sealed and heated in a microwave reactor at 150° C. for 30 min (LCMS indicated complete conversion of starting material to desired product). The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMSO, filtered through a syringe filter and purified by reverse phase HPLC (Gilson, YMC-Pack ODS-A C18 5 μm 75×30 mm column, 10-90% MeCN/water+0.1% TFA, 3×1 mL injections). The appropriate fractions were concentrated to remove a majority of the MeCN, leaving an aqueous suspension of product. The precipitate was collected by filtration, rinsed with minimal water and dried to constant weight under vacuum to provide the title product (56 mg, 0.127 mmol, 49.0% yield) as a white solid. MS(ES)+ m/e 442.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.74 (d, J=3.79 Hz, 1H), 11.24 (s, 1H), 7.74 (br. s., 1H), 7.70 (s, 1H), 7.64 (d, J=8.34 Hz, 2H), 7.31-7.44 (m, 3H), 6.47 (d, J=2.27 Hz, 1H), 3.63-3.85 (m, 1H), 2.87-3.57 (m, 3H), 2.30-2.47 (m, 3H), 2.13-2.21 (m, 3H), 2.08 (s, 1H), 1.44-1.76 (m, 2H), 0.61-0.78 (m, 4H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][CH:19]=[C:20]([C:26](OCC)=[O:27])[C:21]=2[O:22][CH2:23][O:24][CH3:25])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[Cl-].[NH4+]>C1COCC1>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][CH:19]=[C:20]([CH2:26][OH:27])[C:21]=2[O:22][CH2:23][O:24][CH3:25])=[CH:13][CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CCOC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1OCOC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COCOc1c(CO)csc1-c1ccc(C(C)(C)C)cc1
Yield: 47.3 %

Procedure:
To lithium aluminium hydride (27 mg, 0.72 mmol) in THF (0.86 mL), 2-(4-t-butylphenyl)-3-methoxymethyloxy-4-ethoxycarbonylthiophene (0.21 g, 0.60 mmol) in THF (0.86 mL) was added dropwise under cooling with ice, and the reaction solution was stirred under cooling with ice for 1 hour. After addition of saturated aqueous ammonium chloride, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to give the desired product as a colorless oil (87 mg, yield 47%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C@@H:11]([CH3:24])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:23])[C:20]=2[Br:22])[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(C)=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:23][C:19]1[C:20]([Br:22])=[C:21]2[C:16]([CH:15]=[N:14][N:13]2[CH2:12][C@@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:25])[CH3:24])=[CH:17][CH:18]=1)[CH3:38]
Reactant: C[C@@H](Cn1ncc2ccc(O)c(Br)c21)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc2cnn(C[C@H](C)NC(=O)OCc3ccccc3)c2c1Br
Yield: 84.1 %

Procedure:
To a mixture of the compound from Step A (0.90 g, 2.23 mmol), potassium carbonate (0.40 g, 2.90 mmol) in acetone (80 mL) was added ethyl bromoacetate (0.484 g, 0.32 mL, 2.90 mmol) with stirring. The mixture was heated at reflux temperature for 3 h and evaporated to dryness. The residue was mixed with water (100 mL) and extracted with EtOAc (3×60 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated to dryness. Chromatography on silica eluting with a gradient of 10% to 30% EtOAc/hexane gave a solid (0.92 g, 84%): mp 89-90° C.; LCMS (+APCI) 490, 492 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[C:16]([C:21](O)=[O:22])[C:17]([F:20])=[C:18]([F:19])[C:12]=2[N:11]=1.[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>C(OCC)(=O)C.C(#N)C>[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:21]([C:16]2[C:17]([F:20])=[C:18]([F:19])[C:12]3[N:11]=[C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[NH:14][C:13]=3[CH:15]=2)=[O:22])=[CH:27][CH:26]=1
Reactant: O=C(O)c1cc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c(F)c1F
Reactant: Nc1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Nc1ccc(Br)cc1)c1cc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c(F)c1F

Procedure:
2-(2,6-Dichlorophenylamino)-4,5-difluoro-1H-benzimidazole-6-carboxylic acid (150 mg 0.42 mmol), TEA (0.15 mL, 1.05 mmol), 4-bromoaniline (70 mg, 0.42 mmol) and 50% solution of PPA (0.3 mL 0.5 mmol) in ethyl acetate in 10 mL acetonitrile was stirred for a weekend at ambient temperature. Then the solvent was removed i.vac. The residue was purified by HPLC.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:17][CH2:18][CH2:19][CH3:20])[CH:3]=[CH:4][C:5]([CH:7]1[CH:14]2[CH:10]([O:11][C:12](=[O:15])[CH2:13]2)[CH2:9][CH:8]1[CH3:16])=[O:6].C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].[OH-].[Na+].OO>C1COCC1>[OH:6][CH:5]([CH:7]1[CH:14]2[CH:10]([O:11][C:12](=[O:15])[CH2:13]2)[CH2:9][CH:8]1[CH3:16])[CH:4]=[CH:3][C:2]([CH3:1])([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(C)(C)C=CC(=O)C1C(C)CC2OC(=O)CC21
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCC(C)(C)C=CC(O)C1C(C)CC2OC(=O)CC21
Reaction time: 1 h

Procedure:
The crude racemic (3aR,4S,5R,6aS)-[S*,R*(E)]-rac-4-(4,4-Dimethyl-1-oxo-2-octenyl)hexahydro-5-methyl-2H-cyclopenta[b]furan-2-one (12.9 g, 0.044 mole) in THF (60 mL) solution was cooled to -77° and treated dropwise with a 1M solution of potassium tri-sec-butyl-borohydride in THF (Aldrich "K-Selectride") (56 mL, 0.056 mole). Stirring at -77° was continued for 11/2 hours after the addition was completed. An aqueous solution of 10% NaOH (30 mL) was then added and the mixture allowed to warm to -20°. Aqueous 30% H2O2 (30 mL) was then added dropwise while keeping the temperature in the -5° to +5° range. After 1 hour, the cooling bath was removed and 3N HCL (90 mL) was added. Following 2 hours more of stirring, most of the solvent was stripped off and the product was taken up in ethyl acetate (200 mL). This solution was washed with aqueous NaHCO3, brine, and dried over Na2SO4. The volume was reduced to 100 mL by evaporation and this solution of crude [3aR-[3a alpha,4alpha-(1S*,2E),5beta,6a alpha]]-4-[1-(hydroxy)-4,4-dimethyl-2-octenyl]hexahydro-5-methyl-2H-cyclopenta[b]furan-2-one was used directly in Example VII.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[N:14]=1)[N:11]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10](=[O:27])[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:8]2)=O.[OH-].[Na+].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH3:52][O:53][C:54](=[O:58])[CH2:55][CH2:56][NH2:57].CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1.CO>[CH3:52][O:53][C:54](=[O:58])[CH2:55][CH2:56][NH:57][C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[N:14]=1)[N:11]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10](=[O:27])[C:9]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[CH:8]2)=[O:2]
Reactant: COC(=O)c1nc(-c2nccs2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: COC(=O)CCN
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)CCNC(=O)c1nc(-c2nccs2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-thiazol-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (64 mg, 0.14 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. overnight. The mixture was concentrated to approximately one-third of its original volume, and then acidified to pH about 3 with 1 M HCl. The resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. To the residue were then added HOBt (30 mg, 0.22 mmol), CH2Cl2 (3 mL), and EDC (47 mg, 0.25 mmol), and the resulting mixture was stirred for 10 min. β-Alanine methyl ester HCl salt (31 mg, 0.22 mmol) and Hunig's base (0.1 mL, 0.49 mmol) were added, and the mixture was stirred for 16 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH) to give 28 mg of the title compound. MS: (+) m/z 541.31 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24]Br>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: Clc1cc(Cl)cc(CBr)c1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cc(Cl)cc(Cl)c2)c(=O)[nH]c1=O
Yield: 67.1 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dichlorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (292 mg, yield: 67.1%).