Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[O:12]=[CH:13][C@@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[OH:17])O.O>C(O)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C@@H:22]1[O:23][C@H:14]([CH2:13][OH:12])[C@@H:16]([OH:17])[C@H:18]([OH:19])[C@H:20]1[OH:21]
Reactant: Fc1ccc2c(c1Cl)CCN2
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Solvent: O
Product: OC[C@H]1O[C@@H](N2CCc3c2ccc(F)c3Cl)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 94.2 %

Procedure:
A mixture of 4-chloro-5-fluoroindoline (584 mg) and D-glucose (1.04 g) in ethyl alcohol (20 ml)-H2O (3 ml) was refluxed for 1.5 days. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-85:15) to give 4-chloro-5-fluoro-1-(β-D-glucopyranosyl)indoline (1.07 g) as a colorless foam. APCI-Mass m/Z 334/336 (M+H). 1H-NMR (DMSO-d6) δ 3.02 (m, 3H), 3.20-3.45 (m, 4H), 3.57 (m, 2H), 3.71 (m, 1H), 4.35 (t, J=5.8 Hz, —H), 4.60 (d, J=8.3 Hz, 1H), 4.93 (d, J=5.1 Hz, 1H), 5.04 (d, J=4.0 Hz, 1H), 5.07 (d, J=4.3 Hz, 1H), 6.51 (dd, J=8.6, 3.6 Hz, 1H), 7.00 (t, J=9.1 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:41])[NH:5][C:6](=[O:40])[N:7]([CH:39]=1)[C@@H:8]1[O:38][C@H:16]([CH2:17][O:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:10](OS(C)(=O)=O)[CH2:9]1)[CH3:2].[I-:42].[Na+]>COCCOC>[I:42][C@@H:10]1[C@@H:16]([CH2:17][O:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:38][C@@H:8]([N:7]2[CH:39]=[C:3]([CH2:1][CH3:2])[C:4](=[O:41])[NH:5][C:6]2=[O:40])[CH2:9]1
Reactant: CCc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Reactant: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1cn([C@H]2C[C@H](I)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O

Procedure:
A mixture of 5-ethyl-3'-O-methanesulfonyl-5'-O-trityl-2'-deoxyuridine (13.2 g, 5.6 mmole) and sodium iodide (15.0 g, 100 mmole) in 1,2-dimethoxyethane is refluxed for 18 hr.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C@@H:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15](=[O:21])[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36].O>CN(C)C=O>[CH2:36]([N:13]([C@@H:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15](=[O:21])[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])[CH:35]=[CH2:34]
Reactant: C=CCBr
Reactant: O=C([C@@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1ccccc1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN([C@H](C(=O)N1CCCC1)c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
To a stirred solution of 2-nitro-N-(2-oxo-1-(S)-phenyl-2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (62.4 g, 160 mmol) in anhydrous dimethylformamide (300 cm3) was added potassium carbonate (44.3 g, 320 mmol). The mixture was stirred at ambient temperature for 10 minutes and allyl bromide (18.0 cm3, 208 mmol) was added dropwise over 10 minutes. The mixture was stirred for 16 hours at ambient temperature and poured into water (2000 cm3) to afford a white precipitate. The mixture was vacuum filtered, washed with water (3×200 cm3) and vacuum dried at 50° C. to constant weight to afford the title compound as a white solid (66.2 g, 96.2%) with a positive ion ESI (M−H)+430.2.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[OH:8][C:7]1[C:4]([O:5][CH3:6])=[CH:3][C:2]([C:1]([OH:12])=[O:11])=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O

Procedure:
A suspension of vanillic acid (68.8 kg) in acetic acid (720 kg) is cooled to 17° C. before an excess of a 65% nitric acid (44.0 kg) is added. After complete dosage of nitric acid the suspension is stirred for 2 hours. The suspension is filtered off and the wet cake is successively washed with acetic acid (80.0 kg), acetic acid/water (1:2 w/w—105 kg) and finally water (80 kg—if necessary repeat). The solid is dried at 52° C. for NMT 12 hours prior going to next step.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:43]([CH3:45])=[CH2:44])[C:7]([O:30][C@@H:31]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(=[O:3])[NH2:2].C(O)C>[Pd].O1CCCC1>[C:1]([C:4]1[N:5]=[C:6]([CH:43]([CH3:45])[CH3:44])[C:7]([O:30][C@@H:31]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:32]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:21][CH2:22]2)=[CH:13][CH:12]=1)(=[O:3])[NH2:2]
Reactant: C=C(C)c1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a mixture of tert-butyl (3R)-3-{[5-carbamoyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-3-(prop-1-en-2-yl)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (300 mg), ethanol (6 mL), and tetrahydrofuran (6 mL) was added 10% palladium-supported carbon (50% wet product) (260 mg), followed by stirring at room temperature overnight under a hydrogen gas atmosphere (4 atm). The reaction mixture was filtered through celite, and then the solvent was evaporated under reduced pressure and washed with diisopropyl ether to obtain tert-butyl (3R)-3-{[5-carbamoyl-3-isopropyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (253 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19]C(=O)CC4C=CC=CC=4)[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:30][Cl:31])=[O:10])=[CH:5][CH:4]=1.CN1CCOCC1.[C:41]([O:45][C:46]([NH:48][C:49]1[S:50][CH:51]=[C:52]([C:54](=[N:58][O:59][C:60]([C:63]([O:65][CH:66]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[O:64])([CH3:62])[CH3:61])[C:55](O)=[O:56])[N:53]=1)=[O:47])([CH3:44])([CH3:43])[CH3:42].C1C=CC(OP(Cl)(Cl)=O)=CC=1>ClCCl.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:55](=[O:56])[C:54]([C:52]4[N:53]=[C:49]([NH:48][C:46]([O:45][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:47])[S:50][CH:51]=4)=[N:58][O:59][C:60]([C:63]([O:65][CH:66]([C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)[C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)=[O:64])([CH3:61])[CH3:62])[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:30][Cl:31])=[O:10])=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=NOC(C)(C)C(=O)OC(c2ccccc2)c2ccccc2)C(=O)O)cs1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)C(=NOC(C)(C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Yield: 108.4 %

Procedure:
To a suspension of 7β-amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (1) hydrochloride (72.1 g; 171 mMol.) in dichloromethane (1200 ml) are added N-methylmorpholin (18.8 ml; 1 Eq.) and 2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-1-methylethoxyimino)acetic acid (95.5 g; 1.3 Eq.) at 0° C. and then phenylphosphoric acid dichloride (33.2 ml; 1.3 Eq.) and N-methylmorpholin (56.4 ml; 3 Eq.) at -40° C., and the mixture is stirred at -40° to -25° C. for 50 minutes. The reaction mixture is diluted with water. The formed dichloromethane layer is taken, washed with hydrochloric acid, water, aqueous sodium hydrogen carbonate, and water, dried, and concentrated under reduced pressure to give 7β-[2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-(1-diphenylmethoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (2) (165 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1)#[CH:2].[N-:21]=[N+:22]=[N-:23].[Na+].CN(C=O)C>O>[N:21]1[CH:2]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:10][N:11]=3)[N:8]=2)[NH:23][N:22]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C#Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1nnc2ccc(-c3cnn[nH]3)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (6-ethynyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.109 g, 0.399 mmol) and sodium azide (0.0285 g, 0.439 mmol) were dissolved DMF (2 mL) at RT. The reaction mixture was stirred overnight at RT then at 70° C. for 3 h. Water was added at RT and the aqueous layer was extracted with EtOAc and 1-butanol. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Used without further purification.
Reaction SMILES: [F:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>C1COCC1.C(Cl)Cl>[Cl:10][C:9]1[C:2]([F:1])=[C:3]([CH2:4][OH:5])[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccc(Cl)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-fluoro-3-chloro-benzaldehyde (4.74 g, 30 mmol) in THF (20 mL) was added NaBH4 (1.48 g, 40 mmol). The resulting mixture was stirred at room temperature for 30 min before diluting with DCM. The organic layer was washed with water and brine. The combined organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to give desired product without further purification (4.8 g, 100%). MS: 161.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:15]([NH2:18])[CH2:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH2:15]([NH:18][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])=[CH:9][C:2]=1[OH:1])[CH2:16][CH3:17]
Reactant: CCCN
Reactant: O=Cc1ccc(C(Cl)=C(Cl)Cl)cc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCNCc1ccc(C(Cl)=C(Cl)Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.211 g (0.84 mmol) of the product of Step A and 0.177 g (2.94 mmol) of n-propylamine dissolved in 8 mL of CH2Cl2 was added 0.5 g of finely powdered 4 Å molecular sieves. The reaction mixture was stirred under a nitrogen atmosphere at room temperature overnight, then 0.445 g (2.1 mmol) of sodium triacetoxyborohydride was added. The reaction was then stirred an addition 8 h at room temperature, then diluted with CH2Cl2 and MeOH. The mixture was filtered through a pad of Celite filter aid eluted with CH2Cl2, and the filtrate was washed with saturated aqueous NaHCO3. The organic layer was the separated, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted first with CH2Cl2-MeOH—NH4OH (96:3:1) followed by CH2Cl2-MeOH—NH4OH (94:5:1). Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[CH:27]=O)[N:20]=2)[N:10]=[N:9]1.[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[CH2:27][NH:36][CH2:35][CH2:34][O:33][CH3:32])[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1cccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)c1
Reactant: COCCN
Product: COCCNCc1cccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)c1

Procedure:
The title compound was prepared following the procedure described for Example 94, starting from 3-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (100 mg; 0.24 mmol) and 2-methoxyethanamine (36.4 mg; 0.48 mmol) to give Example 147 as a yellow solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.62, 1.58 Hz), 8.05 (1H, s), 7.95-7.85 (2H, m), 7.76-7.69 (1H, m), 7.64-7.49 (6H, m), 3.90 (2H, s), 3.47 (2H, t, J=5.6 Hz), 3.29 (3H, s), 2.76 (2H, t, J=5.6 Hz). LC/MS (Method C): 472 (M+H)+. HPLC (Method E) Rt 2.18 min (Purity: 94.9%).
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1>>[CH3:27][C:23]1[N:22]=[C:21]([NH:20][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(Cl)c2)cc(C)n1
Reactant: Cc1cccc(N)n1
Product: Cc1cccc(NC(=O)c2cc(-c3ccnc(Cl)c3)cc(C)n2)n1

Procedure:
The title compound, was prepared from 2′-Chloro-6-methyl-[4,4′]bipyridinyl-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 2-amino-6methylpyridine instead of 3-chloroaniline to yield the final compound as a white crystalline, MS (ISP): m/e=339.2, 341.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH:11](O)[CH3:12])[CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[C:14]([O:19]C)(=[O:18])[C:15]([CH3:17])=[CH2:16]>>[CH2:3]([N:2]([CH3:1])[CH2:11][CH2:12][O:19][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=C(C)C(=O)OC
Reactant: C=CCCCC=CCN(C)C(C)O
Product: C=CCCC/C=C/CN(C)CCOC(=O)C(=C)C

Procedure:
The resulting (methyl(octa-2,7-dienyl)amino)ethanol was subsequently reacted with methyl methacrylate to give 2-[((2-E)octa-2,7-dienyl)methylamino]ethyl-2-methylprop-2-enoate.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([N:17]([CH3:19])[CH3:18])[N:11]=2)[CH:5]=1.[H-].[Na+].Cl.CNC(N)=N.O=C(C)CC(C1C=[C:36](C=CC=1)[C:37]([OH:39])=[O:38])=O>CC(O)C.O>[C:4]([O:39][C:37](=[O:38])[CH2:36][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([N:17]([CH3:18])[CH3:19])[N:11]=2)[CH:5]=1)=[O:20])([CH3:9])([CH3:5])[CH3:3]
Reactant: CC(=O)CC(=O)c1cccc(C(=O)O)c1
Reactant: COC(=O)c1cccc(-c2cc(C)nc(N(C)C)n2)c1
Agent: CNC(=N)N
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc(N(C)C)n1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared from 3-(2-dimethylamino-6-methyl-pyrimidin-4-yl)-benzoic acid methyl ester [prepared by the following procedure: A mixture of NaH (50% dispersion in mineral oil, 1.56 g, 32.5 mmol) in 2-propanol (45 ml) was stirred at 50° C. for 10 min. N-methylguanidine hydrochloride (3.3 g, 30 mmol) was added and stirring was continued for 10 min. After the addition of 3-(3-oxo-butyryl)-benzoic acid (3.1 g, 15 mmol), the mixture was stirred at 80° C. for 48 h. After cooling to RT, H2O (100 ml) was added and the mixture was concentrated in vacuum to a volume of ca. 80 ml. The pH was set to 2.5 with 25% HCl and the precipitate was collected, dried and then esterified by stirring in 1N HCl-MeOH (30 ml) for 60 h at RT The crude product was purified by chromatography (silica gel, AcOEt) to give the methyl ester as light yellow solid (0.27 g).] (0.26 g, 1 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a light yellow oil (0.38 g, crude product).
Reaction SMILES: C([C:3]1[CH:11]=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[N:15]=[C:14]([CH:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)[CH:13]=2)[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6])C.C(Cl)(=O)C([Cl:38])=O>C(Cl)Cl.CN(C=O)C>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:16]1[C:12]([C:10]2[CH:11]=[CH:3][C:4]([C:5]([Cl:38])=[O:6])=[CH:8][CH:9]=2)=[CH:13][C:14]([CH:25]2[CH2:30][C:29]([CH3:31])([CH3:32])[O:28][C:27]([CH3:33])([CH3:34])[CH2:26]2)=[N:15]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cc(-c2cc(C3CC(C)(C)OC(C)(C)C3)nn2-c2ccccc2OC)ccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 4-[1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-benzoic acid (Example 46) (177 mg, 0.41 mmol) in 4 mL of DCM was added oxalyl chloride (0.043 mL, 0.49 mmol) and 1 drop of DMF and the mixture stirred for 3 hrs at RT The mixture was concentrated and used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccncc3)c(N(C)C(C)C)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (150 mg, 0.51 mmol, 1.00 equiv), pyridin-4-ylboronic acid (124.5 mg, 1.02 mmol, 1.99 equiv), Pd(PPh3)4 (59 mg, 0.05 mmol, 0.10 equiv), K3PO4 (433 mg, 2.04 mmol), 1,4-dioxane (4 mL). The resulting solution was stirred for overnight at 50° C. in an oil bath under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with EA/PE (1:40). This resulted in 50 mg (29%) of methyl 3-(isopropyl(methyl)amino)-2-(pyridin-4-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([OH:13])[CH2:5][C:6](=[O:12])[CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH3:11].C(B(CC)CC)C.[BH4-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.CO>[OH:1][CH2:2][CH2:3][C@@H:4]([OH:13])[CH2:5][C@@H:6]([OH:12])[CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH3:11]
Reactant: C/C=C/CCC(=O)C[C@H](O)CCO
Agent: CCB(CC)CC
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: C/C=C/CC[C@H](O)C[C@H](O)CCO
Temperature: -70 °C
Reaction time: 3 h

Procedure:
1 g (5.4 mmol) of compound 2b from Example 10 is stirred at room temperature in 50 ml of tetrahydrofuran with 8.6 ml of a 1 molar triethylborane solution in tetrahydrofuran (8.6 mmol) for 15 min. After cooling to -70° C., 4.3 ml of methanol and 0.4 g (10.7 mmol) of sodium borohydride are added and the reaction mixture is stirred at this temperature for a further 3 h. For working-up, 30 ml of a saturated sodium hydrogen carbonate solution are added to the mixture and it is extracted three times using 100 ml of ethyl acetate in each case. The ester phase is dried over sodium sulfate After filtering off, the solvent is removed by distillation in vacuo and an oily product is obtained. This is treated with methanol a further five times and distilled in vacuo so that excess borane is removed The residue which remains is purified on silica gel using acetone:hexane (2:3) and gives the compound 3c in a yield of 0.84 g (83%) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:30][CH3:31])=[C:7](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)[CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:33]CC(Cl)=O>>[C:1]([C:5]1[C:6]([O:30][CH3:31])=[C:7](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)[CH:8]=[C:9]([N:11]2[CH2:33][CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(Cl)CCBr
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(N2CCCC2=O)cc1C(C)(C)C
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(N2CCCCC2=O)cc1C(C)(C)C

Procedure:
N-(4-{(E)-2-[3-tert-Butyl-2-methoxy-5-(2-oxo-pyrrolidin-1-yl)-phenyl]-vinyl}-phenyl)-methanesulfonamide can be prepared analogously except in step 2,4-bromo-butyryl chloride is replaced with 3-bromo-propionyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:16]1[O:20][CH:19]=[N:18][CH:17]=1)=[O:15].[C:21]1(I)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(=O)([O-])[O-].[Ag+2].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:16]1[O:20][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:18][CH:17]=1)=[O:15]
Reactant: Ic1ccccc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cnco1
Agent: Cl[Pd]Cl
Agent: [Ag+2]
Agent: [Fe+2]
Solvent: ClCCl
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cnc(-c2ccccc2)o1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Water (5 mL) was added to a pre-stirred mixture of N-(2-(5-chloro-1H-indol-3-yl)ethyl)oxazole-5-carboxamide intermediate 173 (0.107 g; 0.369 mmol), phenyl iodide (0.050 mL; 0.443 mmol), (1,1′-bis(diphenylphosphino) ferrocene)-dichloropalladium(II), complex with dichloromethane (0.015 g; 0.019 mmol), silver carbonate (0.204 g; 0.738 mmol) and triphenylphosphine (0.010 g; 0.037 mmol). The resulting mixture was stirred at 70° C. for 24 hours and after cooling down the mixture was partitioned between brine and dichloromethane. The two phases were separated and the aqueous layer was extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.025 (19%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:13])([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O>[C:20]([O:13][C:8]([C:6]1[CH:5]=[CH:4][C:3]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:2]([F:1])[CH:7]=1)([CH3:12])[C:9]([OH:11])=[O:10])(=[O:22])[CH3:21]
Reactant: CC(O)(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OC(C)(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(+)-2-(2-Fluoro-4-biphenylyl)-2-hydroxypropionic acid (1 g.) from Example 42 was added to acetic anhydride (10 g.) and the mixture stirred overnight at room temperature. The mixture was added to water (40 ml.) and allowed to stand for two hours. The product was collected and recrystallised from a mixture of ether and light petroleum (b.p. 62°-68° C.) to give (-)-2-acetoxy-2-(2-fluoro-4-biphenylyl)propionic acid, m.p. 125°-127° C. and [α]D20 -33.0°.