Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:66]([CH3:69])([CH3:68])[CH3:67])[C:3]([N:5]1[C@H:9]([C:10](=[O:22])[NH:11][C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH2:8][C@H:7]([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][C@@H:28]([C:53](=[O:65])[NH:54][C@H:55]4[C:64]5[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=5)[CH2:58][CH2:57][CH2:56]4)[N:29]([C:33](=[O:52])[C@@H:34]([NH:44]C(OC(C)(C)C)=O)[C:35]([S:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])([CH3:37])[CH3:36])[CH2:30]3)=[CH:25][CH:24]=2)[CH2:6]1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:44][C@H:34]([C:33]([N:29]1[C@H:28]([C:53](=[O:65])[NH:54][C@H:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH2:58][CH2:57][CH2:56]2)[CH2:27][C:26]2[C:31](=[CH:32][C:23]([C@H:7]3[CH2:8][C@@H:9]([C:10](=[O:22])[NH:11][C@H:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:15][CH2:14][CH2:13]4)[N:5]([C:3](=[O:4])[C@@H:2]([NH2:1])[C:66]([CH3:69])([CH3:68])[CH3:67])[CH2:6]3)=[CH:24][CH:25]=2)[CH2:30]1)=[O:52])[C:35]([S:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])([CH3:37])[CH3:36]
Reactant: COC(=O)CSC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](N)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CSC(C)(C)[C@H](N)C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](N)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.1 %

Procedure:
To a solution of methyl 2-(((R)-4-((S)-7-((3R,5S)-1-((S)-2-amino-3,3-dimethylbutanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-((tert-butoxycarbonyl)amino)-2-methyl-4-oxobutan-2-yl)thio)acetate (0.34 g, 0.35 mmol) in DCM (6 mL) was added TFA (1.2 mL, 15.6 mmol) slowly. The reaction mixture was stirred at rt for 40 min and concentrated in vacuo. The residue was basified with sat. aq. NaHCO3 solution to adjust the pH to 8-9. The resulting mixture was extracted with EtOAc (2×). The organic layers were combined and washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the title compound as a white solid (0.30 g, 100%). MS (ESI+) m/z 865.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[C:6]([NH:8][N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]1[CH2:15][CH2:16][CH3:17])=[O:7])[CH3:2].[Br:22]Br.O.C(O)C>C(O)(=O)C.CC(C)=O>[Br:22][C:13]1[N:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[O:3][CH2:1][CH3:2])[C:10]([CH2:15][CH2:16][CH3:17])=[N:11][C:12]=1[CH3:14]
Reactant: BrBr
Reactant: CCCc1nc(C)cn1NC(=O)c1ccccc1OCC
Solvent: CCO
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCCc1nc(C)c(Br)n1NC(=O)c1ccccc1OCC
Temperature: 25 °C

Procedure:
2-Ethoxy-N-(4-methyl-2-propylimidazol-1-yl)benzamide from Example D (50 g, 174 mmol) is introduced into acetic acid. Bromine (12.5 ml, 243.6 mmol) dissolved in acetic acid is added dropwise at room temperature. The mixture is then stirred at room temperature until conversion is complete (up to 3 hours). For working up, water and ethanol (or optionally acetone) are added to the mixture. The product is precipitated by neutralizing with sodium hydroxide solution. The crystals are isolated, washed and dried in vacuo.
Reaction SMILES: [CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:37][O:38][CH3:39])[C:11]([NH:13][CH:14]2[C:35](=[O:36])[N:16]3[C:17]([C:22]([O:24]CC4C=CC([N+]([O-])=O)=CC=4)=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2].CO>[Pd].O1CCCC1>[CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:37][O:38][CH3:39])[C:11]([NH:13][CH:14]2[C:35](=[O:36])[N:16]3[C:17]([C:22]([OH:24])=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1cccc(NC=O)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1cccc(NC=O)n1
Reaction time: 4 h
Yield: 62.2 %

Procedure:
A mixture of 4-nitrobenzyl 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer)(1.43 g.), 10% palladium on carbon (0.8 g.), methanol (30 ml.) and tetrahydrofuran (60 ml.) was subjected to catalytic reduction at ambient temperature under ordinary pressure for 4 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue, and the aqueous layer was separated. The aqueous layer was adjusted to pH 6, washed with ethyl acetate, and then adjusted to pH 1 to 2. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. Diethyl ether (30 ml.) was added to the residue, stirred for one hour, and then the precipitates were collected by filtration to give 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer)(680 mg.), brownish yellow powder, mp. 200° to 204° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C1(C)C=CC=CC=1.[CH2:22]([N:25]([CH2:31][CH:32]=O)[C:26](=[O:30])[O:27][CH2:28][CH3:29])[CH:23]=[CH2:24]>O>[CH2:7]([N:6]1[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:24][CH:23]2[CH:32]1[CH2:31][N:25]([C:26]([O:27][CH2:28][CH3:29])=[O:30])[CH2:22]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CC2CN(C(=O)OCC)CC2N1Cc1ccccc1

Procedure:
50 g (0.25 mol) of N-benzylglycine ethyl ester in 1 1 of toluene are heated under reflux in a water separator and 43 g (0.25 mol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are added dropwise during the course of two hours. The mixture is heated under reflux until water no longer separates and concentrated, and the residue is distilled.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[N:5]([C:13]([CH3:18])([CH3:17])[C:14]([O-:16])=O)=[N:6][C:7]([CH3:12])([CH3:11])[C:8]([O-:10])=O.C[O-].[Na+].O>CO>[N:6]([C:7]([CH3:11])([CH3:12])[C:8]([NH:4][CH2:1][CH2:2][CH3:3])=[O:10])=[N:5][C:13]([CH3:18])([CH3:17])[C:14]([NH:4][CH2:1][CH2:2][CH3:3])=[O:16]
Reactant: CCCN
Reactant: CC(C)(N=NC(C)(C)C(=O)[O-])C(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCCC
Temperature: 5 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
28.3 Grams of propylamine is mixed with 50 g of 2,2'-azobis (2-methyl propionate), and 10 g of 28% sodium methoxide solution in methanol and 10 ml of methanol are added thereto with stirring, followed by conducting a reaction at room temperature with stirring for 6 hours and keeping standing overnight. 100 Milliliter of water is added to the reaction solution and cooled to 5° C. to precipitate crystals. The crystals are recovered by filtration and dried to give 54.0 g (yield: 87%) of 2,2'-azobis(N-propyl-2-methyl propionamide) as pale yellow crystal. The solubility is shown in Table 1.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](=O)[CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[S:36][C:10]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(C(=O)CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)s1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)s2)s1
Yield: 50.8 %

Procedure:
In a manner similar to Example 1, the reaction of N-[2-(5-methylthienyl)-2-oxoethyl]-3,5-bis(trifluoromethyl)benzamide (4.0 g, 0.01 mole) in toluene (100 ml) with a suspension of Lawesson's Reagent (2.0 g, 0.005 mole) in toluene (100 ml) yielded 1.0 g of 5-(5-methylthien-2-yl)-2-[3,5-bis(trifluoromethyl)phenyl]thiazole as a solid, m.p. 119.5°-121° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.[CH2:23](I)[CH3:24]>>[CH2:23]([N:19]1[CH:20]=[CH:21][C:16]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[N:6]=[C:2]2[CH3:1])=[CH:17][C:18]1=[O:22])[CH3:24]
Reactant: Cc1cccc(C#Cc2cn(-c3cc[nH]c(=O)c3)c(C)n2)c1
Reactant: CCI
Product: CCn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O

Procedure:
The title compound, light brown solid, MS: m/e=318.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-(2-Methyl-4-m-tolylethynyl-imidazol-1-yl)-1H-pyridin-2-one and ethyl iodide.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[C:23]([O-])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([C:7]2[NH:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:3][C:4]=3[N:8]=2)=[CH:10][CH:11]=1
Reactant: O=C([O-])c1ccccc1
Reactant: Nc1ccc2[nH]c(-c3ccc(-c4ccccn4)cc3)nc2c1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(-c4ccccn4)cc3)nc2c1)c1ccccc1

Procedure:
Compound 479 was prepared from 5-amino-2-(4-(pyridin-2-yl)phenyl)-1H-benzimidazole and benzoate by standard conditions. [M+H]+ calcd for C25H18N4O: 391.16; found: 390.91.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[Cl:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[CH:43]=[CH:44][CH:45]=[C:46]([F:47])[C:41]=2[Cl:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1cccc(F)c1Cl
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(F)c3Cl)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-3-fluorophenyl)boronic acid gave 337. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.20-8.12 (m, 1H), 7.84 (s, 1H), 7.52 (s, 2H), 7.50-7.39 (m, 2H), 4.82 (dd, J=10.7, 3.6 Hz, 1H), 4.53-4.36 (m, 1H), 4.33-4.20 (m, 1H), 4.14-3.98 (m, 1H), 3.76 (s, 3H), 2.09-2.01 (m, 1H), 1.88-1.66 (m, 4H). LCMS (ES+) m/z 483 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)#[N:2].Br[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:19]=[CH:18][CH:17]=[C:15]([NH2:16])[CH:14]=1)#[N:2]
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1ccccc1B(O)O
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: N#Cc1ccccc1-c1cccc(N)c1
Temperature: 25 °C
Yield: 79 %

Procedure:
2-cyanophenyl boronic acid (0.102 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.071 g in 79% yield.
Reaction SMILES: [Li][CH2:2]CCC.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH2:2])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1
Reactant: O=Cc1cc(F)cc(C(F)(F)F)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=Cc1cc(F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask is added methyltriphenylphosphonium bromide (2.79 g, 7.8 mmol) and anhydrous ethyl ether (40 mL). The suspension is then cooled down to −78° C. and BuLi (6.77 mmol, 4.23 mL 1.6 M solution in hexane) is added dropwise. After the addition, the bright yellow mixture is warmed up to 0° C. and stirred for 30 min and cooled down to −78° C. again. To this mixture, a solution of 3-fluoro-5-trifluoromethyl-benzaldehyde (1 g, 5.2 mmol) in anhydrous ethyl ether (6 mL) is added drop by drop. After the addition, the mixture is slowly warmed up to room temperature and stirred for 14 hr. The precipitate is removed by filtration and washed with ethyl ether (2×5 mL). The filtrate is concentrated by distilling off ethyl ether at ˜60° C. bath temperature. The resulted higher boiling point liquid is purified by pass through a short column (silica gel) with hexane. After removing the hexane under vacuum (˜150 mmHg), the resulted crude 1-fluoro-3-trifluoromethyl-5-vinyl-benzene is used directly for next step.
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]CC)=[CH:6][C:5]=1[NH:13][C:14](=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])C.C(OC1C=CC(OCC)=CC=1N)C.C(Cl)(=O)CCCCCCCCCCCCCCC.B(Br)(Br)Br>C(Cl)(Cl)Cl.O>[C:14]([NH:13][C:5]1[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=1[OH:3])(=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1cc(OCC)ccc1OCC
Agent: BrB(Br)Br
Agent: CCCCCCCCCCCCCCCC(=O)Cl
Agent: CCOc1ccc(OCC)c(N)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)Nc1cc(O)ccc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 107.3 %

Procedure:
83.8 g (0.2 mol) of 1,4-diethoxy-2-hexadecanoylaminobenzene prepared from 2,5-diethoxyaniline and hexadecanoyl chloride was dissolved in 500 ml of chloroform and to the solution was added dropwise 100 g of boron tribromide at a temperature range between 5° C. and 10° C. After stirring at room temperature for 6 hours, 50 g of ice and 100 ml of water were added to the mixture and chloroform was distilled off under a reduced pressure. To the residue was added 100 ml of methanol, the resulting precipitate was collected by filtration to obtain 78 g of 2-hexadecanoylaminohydroquinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C@:13]([NH2:22])([CH3:21])[C:14]([F:20])([F:19])[CH2:15][O:16][C:17]#[N:18])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+].ClCCl>CO>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C@:13]3([CH3:21])[C:14]([F:20])([F:19])[CH2:15][O:16][C:17]([NH2:18])=[N:22]3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@](N)(c1cnn(-c2cccc(Br)c2)c1)C(F)(F)COC#N
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: C[C@]1(c2cnn(-c3cccc(Br)c3)c2)N=C(N)OCC1(F)F
Yield: 66.7 %

Procedure:
In a sealed tube a solution of (R)-1-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-3-cyanato-2,2-difluoro-1-methylpropylamine (3.0 g, 8.08 mmol) and ammonium hydroxide (25% in water, 7 ml) in methanol (10 ml) was heated to 60° C. for 16 hours. For the workup, the solution was evaporated at reduced pressure. The crude material thus obtained was purified by column chromatography on silica gel using a 95:5-mixture of dichloromethane and methanol as the eluent to give the (R)-4-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (2.0 g, 54% yield) as a white solid. MS (ISP): m/z=371.2 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.Br[C:24]1C=CC([N+]([O-])=O)=CC=1C(OC)=O.COC1C=CC(C)=CC=1B(O)O>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>[CH3:22][O:21][C:5]1[CH:4]=[CH:3][C:2]([CH3:24])=[CH:7][C:6]=1[C:8]1[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(C)cc1B(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(C)ccc1OC
Yield: 98 %

Procedure:
This compound was prepared in a manner similar to that of methyl 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylate (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (1.80 g, 6.92 mmol), (PPh3)4Pd (0.33 g, 0.28 mmol), and 2-methoxy-5-methylphenylboronic acid (1.58 g, 9.51 mmol) to afford 2.03 g (98%) of methyl 2'-methoxy-5'-methyl-4-nitro-2-biphenylcarboxylate as a white solid. Data for methyl (2'-methoxy-5'-methyl-4-nitro-2-biphenylcarboxylate): 1H NMR (400 MHz, CDCl3) 8.69 (d, J=2.5, 1H), 8.36 (dd, J=8.4, 2.5, 1H), 7.51 (d, J=8.5, 1H), 7.20 (m, 1H), 7.07 (d, J=2.1, 1H), 6.81 (d, J=8.4, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[N+](=[CH2:21])=[N-]>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:9]([C:14]([O:16][CH3:21])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(c1ccc(F)cc1)c1cccnc1C(=O)O
Product: COC(=O)c1ncccc1C(=O)c1ccc(F)cc1

Procedure:
Treatment of 3-(4-fluorobenzoyl)pyridine-2-carboxylic acid with diazomethane, followed by silica gel chromotography (using hexanes-EtOAc (3:2) as the eluent), gives pure 3-(4-fluorobenzoyl)-2-carbomethoxypyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:17]2[C:12]([CH2:13][CH:14]([CH2:18][CH3:19])[CH2:15][CH:16]=2)=[CH:11][C:10]1=[O:20]>[Pd].C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][CH3:19])=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:20]
Reactant: CCC1CC=C2C(=CC(=O)N2c2c(C)cccc2Cl)C1
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CCc1ccc2c(c1)CC(=O)N2c1c(C)cccc1Cl

Procedure:
1-(2-Chloro-6-methyl-phenyl)-5-ethyl-1,4,5,6-tetrahydro-indol-2-one can be oxidized by classical methods, e.g. with 10% Pd—C in refluxing xylene to yield N-(2-Chloro-6-methyl-phenyl)-5-ethyl-oxindole.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])=[N:2]1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[F:25][C:21]1[N:20]=[C:19]([CH2:18][N:1]2[CH:5]=[CH:4][C:3]([N:6]3[C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])=[N:2]2)[CH:24]=[CH:23][CH:22]=1
Reactant: Fc1cccc(CCl)n1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1c1ccn(Cc2cccc(F)n2)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 31.1 %

Procedure:
A mixture of Intermediate 44 (200 mg, 0.938 mmol), 2-(chloromethyl)-6-fluoropyridine (ALLICHEM, 137 mg, 0.938 mmol) and potassium carbonate (ALDRICH, 157 mg, 0.938 mmol) dissolved in acetonitrile (10 mL) was stirred at 80° C. for 6 h. 0.2 eq. of 2-(chloromethyl)-6-fluoropyridine (ALLICHEM, 27.3 mg, 0.188 mmol) and 5 mL of dry acetonitrile were added. Reaction was stirred at 80° C. overnight. Reaction was diluted with DCM and filtered. Solvent was evaporated to dryness. Residue was purified by silica column chromatography using a linear gradient of hexane/EtOAc to yield the title compound (94 mg, 0.292 mmol, 31% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.02-7.88 (m, 6H), 7.11 (m, 2H), 6.43 (d, 1H), 5.45 (s, 2H). [ES+MS] m/z 323 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[H-].[Na+].[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][CH2:36][O:37][C:32]=2[C:31]([C:38](O)=[O:39])=[CH:30][C:29]=1[Cl:41].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1.C(#N)C>[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][CH2:36][O:37][C:32]=2[C:31]([C:38]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:6][CH2:7]2)=[O:39])=[CH:30][C:29]=1[Cl:41]
Reactant: COc1cc(C(=O)CCCN2CCC(O)CC2)cc(OC)c1OC
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1CCCO2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1cc(C(=O)CCCN2CCC(OC(=O)c3cc(Cl)c(N)c4c3OCCC4)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
4-(4-hydroxy-1-piperidinyl)-1-(3,4,5-trimethoxyphenyl)-1-butanone (3.3 g) was added to a solution of sodium hydride (0.4 g) in tetrahydrofuran (100 ml) (solution I) under a N2 flow. A mixture of 5-amino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxylic acid (2.14 g) and 1,1'-carbonylbis-1H-imidazole (2 g) in acetonitril (100 ml) was stirred for 2 hours at room temperature and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (100 ml) (solution II). At room temperature, solution (II) was poured out into solution (I) and the reaction mixture was stirred for 4 hours at room temperature. The solvent was evaporated. The residue was diluted with water and extracted twice with CH2Cl2. The separated organic layer was washed with water, dried over MgSO4, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /hexane/(CH3OH/NH3) 50/42/3). The desired fractions were collected and the solvent was evaporated. The residue (2.3 g) was purified by high-performance liquid chromatography over silica gel (eluent: CH2Cl2 /CH3OH 90/10). The pure fractions were collected and the solvent was evaporated. The residue (1.2 g) was crystallized from diisopropyl ether. The precipitate was filtered off and dried, yielding 0.93 g of 1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl]-4-piperidinyl 5-amino-6-chloro-3,4-dihydro-2H-benzopyran-8-carboxylate (17%); mp. 112.7° C. (compound 8).
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[N:8][C:7]=1[OH:13].[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:10]1[C:9]([OH:12])=[N:8][C:7]([OH:13])=[N:6][CH:11]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc(O)n1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnc(O)nc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 3-necked roundbottom flask was charged with sulfuric acid (5400 ml) and the solution was cooled to 0° C. Pyrimidine-2,4-diol (1.0 kg, 8.93 mol) was added in several batches. The resulting solution was allowed to react, with stirring, for 30 minutes. To the above was added nitric acid (1800 ml) dropwise with stirring, while the temperature was maintained at 0° C. The resulting solution was allowed to react, with stirring, for 2 hours. The reaction mixture was then quenched by adding ice water and a precipitate formed. The solid was collected by filtration and dried in an oven under reduced pressure to afford the title compound.