Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[N:13]C#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCNC1=N)C1C=CC=CC=1.[CH2:29]([NH:36][C:37]([C:39]1[S:43][C:42](Br)=[N:41][C:40]=1[CH3:45])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:37]([C:39]1[S:43][C:42]([N:10]2[CH2:11][CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]2=[NH:13])=[N:41][C:40]=1[CH3:45])=[O:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: N#CN=C1NCCN1Cc1ccccc1
Agent: N=C1NCCN1Cc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=N)sc1C(=O)NCc1ccccc1
Yield: 4 %

Procedure:
Following the procedure as described in Example 27, making variations as required to replace N-(1-benzylimidazolidin-2-ylidene)cyanamide with 1-benzylimidazolidin-2-imine to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 4% yield: mp 125-126° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.37-7.26 (m, 10H), 5.89 (t, J=5.5 Hz, 1H), 5.56 (br s, 1H), 4.54 (d, J=5.5 Hz, 2H), 4.33 (s, 2H), 4.15-4.01 (m, 2H), 3.44 (t, J=7.7 Hz, 2H), 2.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.4, 138.0, 128.9, 128.7, 128.0, 127.9, 127.6, 127.5, 105.6, 53.4, 49.3, 44.0, 43.8, 17.3; MS (ES+) m/z 406.4 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:50]3[CH2:49][CH2:48][N:47]([CH2:46][CH2:45][CH2:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH2:52][CH2:51]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(F)cc2)C(C)(c2ccc(F)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(F)cc2)[C@@](C)(c2ccc(F)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C38H49N4O4SF2 [(M+H)+] 695.3437, observed 695.3433.
Reaction SMILES: [CH:1]([C:3]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:6]2[N:7]([CH3:16])[C:8](=[O:15])[C:9]3[C:14]([C:5]=2[CH:4]=1)=[CH:13][CH:12]=[N:11][CH:10]=3)=[O:2].C([O-])([O-])=O.[K+].[K+].CC1C=CC(S([CH2:50][N+:51]#[C-:52])(=O)=O)=CC=1>CO>[CH3:24][CH:23]([CH3:25])[CH2:22][C@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:20][O:19][C:18]1[C:3]([C:1]2[O:2][CH:52]=[N:51][CH:50]=2)=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1C=O)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)C[C@@H](COc1cc2c(cc1-c1cnco1)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 24.5 %

Procedure:
A mixture of (S)-tert-butyl (1-((9-formyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (100 mg, 0.220 mmol), K2CO3 (33.5 mg, 0.243 mmol) and TOSMIC (47.4 mg, 0.243 mmol) in MeOH (5 mL) was heated at 60° C. for 2 h. After cooling, the MeOH was removed under reduced pressure and residue was taken up in ethyl acetate. The organic layer was washed with H2O, followed by saturated NaHCO3, dried over Na2SO4 and concentrated under reduced pressure to afford (S)-tert-butyl (4-methyl-1-((6-methyl-9-(oxazol-5-yl)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (50 mg, 0.054 mmol, 24% crude yield) as a gum. The material was carried on without further purification. LC/MS (ESI) m/e 493.4, [(M+H)+, calcd for C27H33N4O5, 493.6]; LC/MS retention time (method E): tR=1.08 min.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14]>CCOCC.CCCCCC>[CH3:12][Si:13]([CH3:15])([CH3:14])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: Brc1nccs1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(C)c1nccs1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 8.28 g of 2-bromothiazole in 100 ml of ether at -78° C., under argon, was added 21.7 ml of n-butyl lithium in hexane. The mixture was stirred at -78° C. for 45 minutes then 6.8 ml of trimethylsilyl chloride was added. This mixture was stirred at -78° C. for 1 hour, warmed to -30° C. over 1 hour, then 0° C. over 1/2 hour and kept at 0° C. for 1 hour. The reaction was quenched with 50 ml of 50% saturated sodium bicarbonate and then diluted with 50 ml of ether. The ether solution was washed with 50 ml of brine, dried, filtered and evaporated, giving 10.81 g of 2-trimethylsilylthiazole as an amber colored oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH2:28][CH2:27][NH:26][CH2:25][C:24]=5[C:29]([NH2:31])=[O:30])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.CO>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([C:23]5[CH:24]([C:29]([NH2:31])=[O:30])[CH2:25][N:26]([CH3:34])[CH2:27][CH:28]=5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(N)=O)CNCC3)cc1OCC2
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=CCN(C)CC3C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[2-(2-isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid amide from Example 414 (0.15 g, 0.35 mmol) in DCM (16 mL) and methanol (8 mL) was added formaldehyde (0.053 mL, 37% aq., 0.7 mmol), sodium triacetoxyborohydride (0.11 g, 0.52 mmol) and acetic acid (24 μL, 0.42 mmol). The reaction mixture was stirred at RT for 16 h. Sodium hydrogen carbonate (aqueous) and 10% methanol in DCM were added to the mixture and the organic fraction separated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give the title compound. The product was triturated with diethyl ether, filtered and dried to give the title compound (24 mg, 16%). LCMS: RT=2.39 min, [M+H]+=434. 1H NMR 400 MHz (DMSO-d6) δ: 8.33 (1 H, d, J=8.48 Hz), 7.92 (1 H, s), 7.91 (1 H, s), 7.32 (1 H, br, s), 7.27 (1 H, dd, J=8.51, 1.92 Hz), 7.11 (1 H, d, J=1.86 Hz), 6.90 (1 H, br, s), 6.35 (1 H, d, J=3.82 Hz), 5.90-5.89 (1 H, m), 4.51-4.49 (4 H, m), 3.53 (1 H, s), 3.31 (1 H, m), 2.97 (1 H, m), 2.85 (1 H, m), 2.64 (1 H, m), 2.33 (3 H, s), 1.48 (6 H, dd, J=6.60, 3.70 Hz)
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22]>C(Cl)Cl>[C:1]([NH:9][N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
Benzoyl-2-tert-butylhydrazine (4.8 g, 0.25 mole) is stirred vigorously in a two-phase system of 50 mL of methylene chloride and 25 mL of 10% aqueous sodium hydroxide (2.5 g, 0.063 mole) until all dissolves. To this solution is added a solution of 3,4-dichlorobenzoyl chloride (7.3 g, 0.025 mole) in methylene chloride. After stirring the two-phase mixture several hours at ambient temperature, the solid is removed and washed with water and methylene chloride. Recrystallization from 2-propanol gives 7.1 g (78%) of product with mp 234°-235° C.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3].C1COCC1.C([Li])CCC.[P:18](Cl)(=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CCCCCC>[CH2:6]([O:5][S:2]([CH2:1][P:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:25])(=[O:4])=[O:3])[CH3:7]
Reactant: CCOS(C)(=O)=O
Reactant: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOP(=O)(CS(=O)(=O)OCC)OCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of methanesulfonic acid, ethyl ester (11.00 mL, 0.1068 mol) in THF (200.0 mL, 2.466 mol) at −78° C. was added 2.500 M of n-butyllithium in hexane (50.00 mL) over 15 minutes and the mixture was stirred for 20 minutes. Phosphorochloridic acid, diethyl ester (10.0 mL, 0.0694 mol) was added to the mixture at −78° C. The mixture was stirred for 3.5 hours, allowing to warm to 0° C. The reaction was quenched with 5M ammonium chloride in water (100 mL) and the mixture was concentrated in vacuo to remove THF. The aqueous was extracted with EtOAc (2×150 mL) and the organics were combined and concentrated in vacuo. The product was purified by flash chromatography (0 to 100% EtOAc/Hexanes) to yield the product as an oil (9.07 g, 50%+10.4 g of a mixed fraction).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C@H:29]([CH:33]([CH3:35])[CH3:34])[C:30](O)=[O:31]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[C@H:29]([OH:28])[CH:33]([CH3:35])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CC(C)[C@@H](O)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CC(C)[C@@H](O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (12.1 mg, 34.4%), MS (ISP) m/z=432.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and (R)-2-hydroxy-3-methylbutanoic acid.
Reaction SMILES: [OH:1][CH:2]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]([OH:5])=O.[NH2:11][C@H:12]([C:14]([C:16]1([NH2:35])[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]([CH3:33])[C:17]1=[O:34])=[O:15])[CH3:13]>>[CH:6]1([CH:2]([OH:1])[C:3]([NH:11][C@H:12]([C:14]([C:16]2([NH2:35])[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=3[N:18]([CH3:33])[C:17]2=[O:34])=[O:15])[CH3:13])=[O:5])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(O)C(O)C1CCCC1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O
Product: C[C@H](NC(=O)C(O)C1CCCC1)C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using (±)-α-hydroxy-cyclopentylacetic acid (Example P) and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-1H-1,4-benzodiazepin-2-one (Example 8-B), the title compound was prepared as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].Cl>C(O)C>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1

Procedure:
Benzyl ethers may conveniently be used to protect --YH groups. For example, methyl 4-hydroxyphenylacetate (0.2 mol) is heated at reflux with 25 g benzyl chloride (0.2 mol) and 25 g K2CO3 (0.2 mol) in 100 mL ethanol. The product is added to dilute aqueous HCl, extracted with ether, and purified by silica gel chromatography to yield methyl 4-benzyloxyphenylacetate (7).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[C:9]([O:49][CH3:50])=[C:10]([NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([CH3:48])=[C:25]([CH:47]=2)[O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)[CH:28]=2)=[O:20])[CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1.C(N(CC)CC)C.O>ClCCl>[C:14]([C:12]1[CH:13]=[C:8]([NH:7][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[C:9]([O:49][CH3:50])=[C:10]([NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([CH3:48])=[C:25]([CH:47]=2)[O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][CH:34]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:38][CH2:39]3)[CH:28]=2)=[O:20])[CH:11]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: O=C(Cl)C1CC1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NC(=O)c1ccc(C)c(Oc2ccnc(CC3CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(NC(=O)c2ccc(C)c(Oc3ccnc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)cc(C(C)(C)C)cc1NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At ambient temperature 36 μl cyclopropanecarboxylic acid chloride are added to a solution of 160 mg tert-butyl 4-{4-[5-(3-amino-5-tert-butyl-2-methoxy-phenylcarbamoyl)-2-methyl-phenoxy]-pyridin-2-ylmethyl}-piperidine-1-carboxylate and 70 μl triethylamine in 2 ml dichloromethane. The solution is stirred overnight at ambient temperature and then mixed with water. The mixture is extracted with dichloromethane, and the combined extracts are washed with water and saturated aqueous saline solution, dried (MgSO4) and evaporated down. The residue is chromatographed on silica gel with cyclohexane/ethyl acetate (50:50→0:100) as eluant.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][S:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=3)[N:17]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:16]=2)=[O:14])[S:10][CH:11]=1)C.[OH-].[Na+].Cl>CCO>[CH:26]1([CH2:25][N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:15]([C:13]([NH:12][C:9]3[S:10][CH:11]=[C:7]([S:6][CH2:5][C:4]([OH:29])=[O:3])[N:8]=3)=[O:14])=[CH:16]2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)CSc1csc(NC(=O)c2cn(CC3CC3)c3cc(F)ccc23)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CSc1csc(NC(=O)c2cn(CC3CC3)c3cc(F)ccc23)n1
Temperature: 80 °C
Yield: 83.9 %

Procedure:
Following general procedure A using 6-fluoroindole and R5X=cyclopropyl-methylbromide {2-[(1-Cyclopropylmethyl-6-fluoro-1H-indole-3-carbonyl)-amino]-thiazol-4-ylsulfanyl}-acetic acid ethyl ester was obtained. Ester hydrolysis: 110 mg (0.25 mmol) {2-[(1-cyclopropylmethyl-6-fluoro-1H-indole-3-carbonyl)-amino]-thiazol-4-ylsulfanyl}-acetic acid ethyl ester was dissolved in EtOH (3 mL) and NaOH (254 μL, 4N) was introduced. The mixture was heated to 80° C. for 1 hour before it was cooled to room temperature and pH was adjusted to 2 using 1 N HCl, where-upon a white precipitate was formed. The product was filtered off and dried to give 85 mg {2-[(1-Cyclopropylmethyl-6-fluoro-1H-indole-3-carbonyl)-amino]-thiazol-4-ylsulfanyl}-acetic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].C([O-])([O-])=[O:14].[Ca+2]>>[CH2:11]([OH:12])[C@H:9]([OH:10])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C:3]([C:2]([OH:14])=[O:1])=[O:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Temperature: 30 °C
Reaction time: 48 h

Procedure:
The colonies treated with the mutagen on the complete medium plate were streaked onto a fresh complete medium plate over a length of about 2 cm at the rate of 12 strains per plate. After incubation at 28° C. for 2 days, one loopful of the grown cells were transferred to a test tube containing 3 ml of a medium (pH 6.5) composed of 7.0% of L-sorbose (separately sterilized), 1.0% of dried yeast 10% of peptone, 0 1% of ferrous chloride and 3.0% of CaCO3 and incubated with shaking at 30° C. for 4 days. Among the tested mutant strains, the strain TH14-86 was found to produce 2-keto-L-gulonic acid twice as much as the parental strain K591s under the above conditions. This strain TH14-86 (IFO 14466; FERM BP-1128) was chosen as an oxidative strain with an augmented ability to oxidize L-sorbose.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]=[CH:17][N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C:19]2[CH:24]=[C:23]([C:25](=[O:30])[NH:26][CH:27]3[CH2:29][CH2:28]3)[CH:22]=[CH:21][C:20]=2[CH3:31])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O1CCCC1.CO.O>[CH:27]1([NH:26][C:25]([C:23]2[CH:22]=[CH:21][C:20]([CH3:31])=[C:19]([N:14]3[CH:13]=[N:12][C:11]4[C:15]3=[N:16][CH:17]=[N:18][C:10]=4[C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:32])=[O:2])=[CH:9][CH:8]=3)[CH:24]=2)=[O:30])[CH2:29][CH2:28]1
Reactant: COC(=O)c1ccc(-c2ncnc3c2ncn3-c2cc(C(=O)NC3CC3)ccc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(C(=O)O)cc3)ncnc21
Reaction time: 5 h
Yield: 13.9 %

Procedure:
To a solution of the 4-[9-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-9H-purin-6-yl]-benzoic acid methyl ester (65 mg, 0.87 mmol) in 2 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of water was added sodium hydroxide (2M, 0.15 mL, 0.3 mmol) at 20° C. The reaction mixture was stirred at that temperature for 5 hours and then the clear solution was neutralized by dropwise addition of 2N aqueous hydrochloric acid to give a solid. The product was collected by filtration to give a colorless solid (50 mg, 80%). HPLC tR=2.01 min; MS m/z 414 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C1COCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:15](=[O:16])[C:14]2[CH:18]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=[CH:21][C:13]=2[F:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cc(C(F)(F)F)ccc1F
Reaction time: 16 h

Procedure:
5-Amino-2-chloro-benzoic acid (0.4 g, 2.32 mmol) was diluted with THF (12 mL), treated with 2-fluoro-5-trifluoromethyl-benzoyl chloride (0.388 g, 2.56 mmol) and stirred for 16 h. Solvents were then removed and resulting solids were triturated with DCM. After filtration, the title compound was obtained as a white solid (0.5 g, 60%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:11][CH:10]=2)O1.Br[C:25]1[CH:26]=[C:27]([C:32]2[N:33]=[N:34][N:35]([CH:37]([CH3:39])[CH3:38])[CH:36]=2)[C:28]([NH2:31])=[N:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].N#N>O1CCOCC1.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.O>[CH:37]([N:35]1[CH:36]=[C:32]([C:27]2[C:28]([NH2:31])=[N:29][CH:30]=[C:25]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[CH:13][CH:14]=3)[CH:26]=2)[N:33]=[N:34]1)([CH3:39])[CH3:38]
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Reactant: CC1(C)OB(c2ccc(CCN3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1cc(-c2cc(-c3ccc(CCN4CCOCC4)cc3)cnc2N)nn1
Temperature: 100 °C
Reaction time: 16 h
Yield: 53.4 %

Procedure:
To a solution of 4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-morpholine (can be prepared as described in US2002026052) (101 mg, 0.31 mmol) and 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (90 mg, 0.31 mmol) in 1,4-dioxane (7.0 mL)/water (3.0 mL) was added Cs2CO3 (251 mg, 0.70 mmol) at RT. N2 was purged through the reaction mixture for 10 min. Pd(PPh3)4 (18 mg, 0.015 mmol) was added and through the reaction mixture N2 was purged for 10 min and stirred at 100° C. for 16 h. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford crude compound (GVK-B1319-120A1). Crude compound was purified by column using 100-200 mesh silica gel and eluted with 2-3% MeOH in DCM to afford 65 mg of a brown semisolid. Further purification of Prep-HPLC furnished 14 mg of the title compound as an off-white solid.
Reaction SMILES: [O:1]=[C:2]([CH:8]=[CH:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]>CO.[OH-].[Pd+2].[OH-]>[O:1]=[C:2]([CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)C=Cc1nccs1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CC(=O)CCc1nccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
A mixture of methyl 3-oxo-5-(1,3-thiazole-2-yl)-4-pentenoate (132.0 g) and palladium hydroxide, 20 wt % on carbon (13 g) in MeOH (2600 ml) was stirred under hydrogen atmosphere by balloon at room temperature for 4 h. Catalyst was removed by filtration and the filtrate evaporated to give 130.0 g of methyl 3-oxo-5-(1,3-thiazole-2-yl)pentanoate as a brown liquid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[OH:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.CN(C=O)C.C(N(CC)CC)C>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:13])[CH:19]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(Br)cnc1N
Reactant: OB(O)c1cccc(O)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(-c2cccc(O)c2)cnc1N
Temperature: 95 °C
Yield: 71.3 %

Procedure:
3-Amino-6-bromo-N-methylpyrazine-2-carboxamide (1.34 g, 5.8 mmol) and 3-hydroxyphenylboronic acid (1.2 g, 8.7 mmol) were taken into DMF (10 mL) followed by addition of [1,1′-bis(diphenylphosphinoferrocene]dichloropalladium (II) dichloromethane complex (440 mg, 0.54 mmol) and triethylamine (4.8 mL, 35 mmol). The mixture was heated to 95° C. for 12 hours then cooled to room temperature and diluted with an excess of ethyl acetate. The organic solution was washed with 0.5 M aqueous hydrochloric acid (1×), water (3×) then brine and dried over anhydrous magnesium sulfate. The mixture was then filtered and the organic solution concentrated and the residue purified by silica gel flash chromatography using ethyl acetate:hexanes (3:1) eluent. The pure fractions were combined and concentrated then dried in vacuo to give 3-amino-6-(3-hydroxyphenyl)-N-methylpyrazine-2-carboxamide (1.01 g, 71% yield) as a yellow solid: MS (EI) for C12H13N4O2: 245 (MH+).