Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.CN([CH:28]=[O:29])C>>[CH2:6]([N:13]1[C:19]2[CH:20]=[CH:21][C:22]([CH:28]=[O:29])=[CH:23][C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: C1=Cc2ccccc2N(Cc2ccccc2)C=C1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)C=CC=CN2Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (1.9 ml, 20.4 retool) was added to DMF (10 ml) at ambient temperature and the mixture was stirred for 30 minutes under nitrogen atmosphere. To the mixture was added crude 1-benzyl-1H-1-benzazepine (3.23 g, 13.6 mmol) in DMF (5 ml) at ambient temperature. The mixture was stirred at ambient temperature for 1 hour and at 70° C. for 2 hours. Water (35 ml) was added and the mixture was stirred for 10 minutes. The mixture was extracted with EtOAc (2×100 ml) and the combined extracts were washed with H2O (2×50 ml), saturated NaHCO3 solution (50 ml) and brine (50 ml). The solution was dried over MgSO4 and concentrated in vacuo affording the title compound as a brown oil (3.42 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=[O:13])[N:9]=1)(=[O:3])[CH3:2].[H][H]>CN(C)C=O.[Pd]>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[O:13])[N:9]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1nc(C=CC=O)cs1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CCC=O)cs1
Reaction time: 4.5 h
Yield: 91 %

Procedure:
To a solution of 2-acetylamino-4-(2-formylvinyl)thiazole (2.24 g) in N,N-dimethylformamide was added 10% palladium on carbon (11.2 g) and hydrogen gas was bubbled thereinto for 4.5 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (10:1 V/V) to give 2-acetylamino-4-(2-formylethyl)thiazole (2.06 g).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:6][C:5]=1[CH3:15].Cl[CH2:17][CH2:18][OH:19].Cl>O>[OH:19][CH2:18][CH2:17][O:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:6][C:5]=1[CH3:15]
Reactant: OCCCl
Reactant: Cc1cc(C(O)C(=O)O)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(O)C(=O)O)ccc1OCCO
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of 8.0 g (200 mmol) of sodium hydroxide in 15 ml of water is added dropwise over a period of one hour to a solution of 18.2 g (100 mmol) of 4-hydroxy-3-methylmandelic acid (Example 13), 4.0 g (100 mmol) of sodium hydroxide and 13.4 ml (200 mmol) of 2-chloroethanol in 60 ml water heated to 70° C. Another 6.7 ml (100 mmol) of 2-chloroethanol and 4.0 g (100 mmol) of sodium hydroxide in 10 ml of water are then added. After another 15 minutes, the reaction mixture is acidified with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organic phases are washed with water, combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. This gives 23.0 g (about 100%) of 4-(2-hydroxyethoxy)-3-methylmandelic acid as a yellowish resin (compound (203), Table 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]([N:14]1[CH2:15][CH2:16][N:17]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:21])=[O:22])[CH2:18][CH2:19]1)=[O:13]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(COc1ccc(Cl)cc1Cl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 85.9 %

Procedure:
2,4-dichloro phenol (138 mg, 0.85 mmol), 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) and anhydrous potassium carbonate (0.293 g, 2.125 mmol) were stirred for over night in dry acetonitrile (20 mL). The mixture was poured into a large volume of water and the solution extracted with diethyl ether. Un-reacted phenol was removed with cold 1N NaOH solution. The ether extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (350 mg, 87.5% yield) as an off-white solid.
Reaction SMILES: [CH:1](=[N:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:14]([CH2:17]Cl)[CH2:15][S:16][C@H:11]12)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:37]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I-].[Na+].C(O)(C)C>CN(C)C=O>[CH:1](=[N:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:14]([CH:17]=[CH2:37])[CH2:15][S:16][C@H:11]12)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(N=Cc3ccccc3O)C(=O)N12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N=Cc3ccccc3O)[C@H]2SC1
Yield: 78.4 %

Procedure:
To a cooled solution of benzhydryl 7-salicylideneamino-3-chloromethyl-3-cephem-4-carboxylate (4 g) in dimethylformamide (10 ml) were added triphenylphosphine (2.2 g) and sodium iodide with stirring. After stirring for 2 hours at ambient temperature, the reaction mixture was poured into isopropyl alcohol (250 ml), and the precipitated solids (6.7 g) were collected by filtration. To a stirred solution of the above solids in methylene chloride (10 ml) and water (5 ml) was added 36% formaldehyde solution (17.4 ml). Then the reaction mixture was adjusted to pH 9.0 with a saturated aqueous sodium bicarbonate. After stirring for an hour at ambient temperature, the separated organic layer was washed with water and an aqueous sodium chloride, followed by drying over magnesium sulfate. The solution was evaporated under reduced pressure to give benzhydryl 7-salicylideneamino-3-vinyl-3-cephem-4-carboxylate (3 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][NH2:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][C:14](=[O:15])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[NH:35][CH2:34][CH2:33][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCNC(=O)CCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)CCCCCNC(=O)CCNC(=O)OCc1ccccc1
Yield: 72.5 %

Procedure:
The compound 37 was prepared using General Procedure B with the acid 36 2.23 g, 6.63 mmol), 2-t-butoxycarbonylamino-ethylamine (1.27 g, 7.95 mmol), 1-hydrobenzotriazole (HOBt) (1.25 g, 9.28 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.79 g, 9.28 mmol) in DMF (20 mL). Recrystallization of the crude product from EtOAc afforded 2.30 g (73%) of the desired product (37) as a white solid. 1H NMR (CDCl3): δ 7.32 (m, 5H, ArH), 6.44 (s, 1H, NH), 6.23 (s, 1H, NH), 5.67 (s, 1H, NH), 5.19 (s, 1H, NH), 5.06 (s, 2H, OCH2Ar), 3.45 (dt, J=6.4, 12.4 Hz, 2H, CH2NHCO), 3.31 (dt, J=5.2, 10.4 Hz, 2H, CH2NHCO), 3.21 (m, 4H, CH2NHCO), 2.39 (dt, J=6.0, 6.4 Hz, 2H, CH2CO), 2.14 (dt, J=7.0, 7.2 Hz, 2H, CH2CO), 1.60 (m, 2H, CH2), 1.47 (m, 2H, CH2), 1.41 (s, 9H, t-Bu), 1.30 (m, 2H, CH2); ESI-MS m/z 513[N+Cl]−; 501[M+Na]+, 479[M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6]C(=O)OC(C)(C)C)[CH2:2]1.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.[ClH:23].O1CCOCC1>C(Cl)(Cl)Cl>[ClH:23].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:1]2[CH2:5][CH2:4][C@@H:3]([NH2:6])[CH2:2]2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: N[C@@H]1CCN(Cc2ccc(F)cc2)C1

Procedure:
To a chloroform solution (2 mL) of tert-butyl (R)-pyrrolidin-3-yl-carbamate (500 mg, 2.68 mmol), 4-fluorobenzyl bromide (329 μL, 2.68 mmol) was added and the resultant solution was stirred at room temperature for 1 day. Subsequently, 4 M hydrogen chloride/1,4-dioxane solution (2 mL) was added to the reaction solution and the resultant mixture was stirred for 1 day. After completion of the reaction, solidified product was collected by filtration and dried under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][C:5](OC)=[C:4](OCC2CCN(C)CC2)[CH:3]=1.C(O)(=O)C.[CH:28](N)=[NH:29]>COCCO>[N:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8](=[O:10])[NH:29][CH:28]=1
Reactant: N=CN
Reactant: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1N
Solvent: CC(=O)O
Solvent: COCCO
Product: O=c1[nH]cnc2ccccc12
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 173.8 %

Procedure:
A solution of ethyl 6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (16.1 g, 50 mmol) in 2-methoxyethanol (160 ml) containing formamidine acetate (5.2 g, 50 mmol) was heated at 115° C. for 2 hours. Formamidine acetate (10.4 g, 100 mmol) was added in portions every 30 minutes during 4 hours. Heating was prolonged for 30 minutes after the last addition. After cooling, the volatiles were removed under vacuum. The solid was dissolved in ethanol (100 ml) and methylene chloride (50 ml). The precipitate was removed by filtration and the filtrate was concentrated to a final volume of 100 ml. The suspension was cooled to 5° C. and the solid was collected by filtration, washed with cold ethanol followed by ether and dried under vacuum overnight at 60° C. to give 6-methoxy-74(1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (12.7 g, 70%).
Reaction SMILES: OC[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[C:18]([O:27][CH3:28])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O-:25])=[O:24].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:18]([O:27][CH3:28])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:24]
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: CN(OCCOCCCO)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)OCCOCCON(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 2-(3-hydroxypropoxy)ethoxy(methyl)carbamate (152 mg, 0.646 mmol) and monomethyl adipate (104 mg, 0.646 mmol) in CH2Cl2 (4 mL) were added DCC (146 mg, 0.711 mmol) and DMAP (16 mg, 0.129 mmol). The reaction mixture was stirred at room temperature for 16 h and filtered. The solvent was removed under reduced pressure. The crude product was purified by silica gel flash column chromatography using 27% EtOAc/hexanes as eluent. The desired product was obtained as colorless oil (152 mg, 0.403 mmol, 62%). 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.41 (s, 9H), 1.56-1.60 (m, 4H), 2.25-2.27 (m, 4H), 3.03 (s, 3H), 3.58 (s, 3H), 3.59-3.63 (m, 4H), 3.91-3.94 (m, 2H), 4.14-4.16 (m, 2H).
Reaction SMILES: [CH:1]1[N:5]([CH:6]2[O:10][CH:9]([CH2:11][OH:12])[CH:8]([OH:13])[CH:7]2[OH:14])[C:4]2[N:15]=[C:16]([Cl:20])[N:17]=[C:18]([NH2:19])[C:3]=2[C:2]=1[C:21]#[N:22].[NH2:23][OH:24]>C(O)C>[NH2:19][C:18]1[C:3]2[C:2]([C:21](=[N:23][OH:24])[NH2:22])=[CH:1][N:5]([C@@H:6]3[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]3[OH:14])[C:4]=2[N:15]=[C:16]([Cl:20])[N:17]=1
Reactant: NO
Reactant: N#Cc1cn(C2OC(CO)C(O)C2O)c2nc(Cl)nc(N)c12
Solvent: CCO
Product: NC(=NO)c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(Cl)nc(N)c12
Reaction time: 24 h
Yield: 72.6 %

Procedure:
2-Chlorotoyocamycin (6, 250 mg) and solid hydroxylamine (250 mg) were added to 20 ml of absolute ethanol and the mixture was heated at reflux temperature for 30 min. The solution was allowed to stand at -10° for 24 hr and the solid was collected by filtration, washed with 10 ml of ice cold ethanol and recrystallized from water to yield 200 mg (76%) of 10, mp 170° dec.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][NH:20][C:21](=O)[CH:22]([CH3:24])[CH3:23])=[N:17][CH:18]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.O.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[CH:22]([C:21]1[N:17]2[CH:18]=[C:13]([C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:14]=[CH:15][C:16]2=[N:19][N:20]=1)([CH3:24])[CH3:23]
Reactant: Cc1nc(-c2ccccc2)c(-c2ccc(NNC(=O)C(C)C)nc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2ccccc2)c(-c2ccc3nnc(C(C)C)n3c2)o1
Temperature: 60 °C
Yield: 64.3 %

Procedure:
A mixture of 23 mg of isobutyric acid N′-[5-(2-methyl-4-phenyl-oxazol-5-yl)-pyridin-2-yl]-hydrazide in 0.68 mL of phosphorous oxychloride was heated at 60° C. for 16 hours. The mixture was cooled to 22° C. and carefully added to 25 mL of water. The aqueous mixture was made basic with 3 N sodium hydroxide and extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried (sodium sulfate), filtered, and the filtrate was concentrated to a dark yellow oil. This oil was purified by flash chromatography (eluting with 97:3 ethyl acetate/methanol) to give 14 mg of 3-isopropyl-6-(2-methyl-4-phenyl-oxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine as a light yellow solid. LCMS (m/z) 319 M+1. 1H NMR (400 MHz, CDCl3 δ8.18 (s, 1 H), 7.85 (d, 1 H, J=9.8 Hz), 7.60-7.62 (m, 2 H), 7.42-7.49 (m, 4 H), 3.32-3.34 (m, 1 H), 2.63 (s, 3 H), 1.51 (d, 6 H, J=6.7 Hz).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][S:22]C3C=CC=CC=3C(OC)=O)[C@@H:18]([OH:33])[C@H:17]2[OH:34])[CH2:2]1.S[C:36]1[O:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1.C(C1C=CC=CC=1S)(OC)=O>>[O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:17]([OH:34])[C@H:18]([OH:33])[C@@H:19]([CH2:21][S:22][C:36]3[O:37][C:38]4[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=4[N:40]=3)[O:20]2)[CH2:2]1
Reactant: Sc1nc2ccccc2o1
Reactant: COC(=O)c1ccccc1SC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Agent: COC(=O)c1ccccc1S
Product: O[C@@H]1[C@H](O)[C@@H](CSc2nc3ccccc3o2)O[C@H]1n1cnc2c(N[C@@H]3CCOC3)ncnc21

Procedure:
This compound was prepared in a manner similar to that of 23 substituting 2-mercaptobenzoxazole for 2-carbmethoxy thiophenol (M+1)=471.4.
Reaction SMILES: [CH:1]([C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([CH3:3])[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH:1]([C:4]1[C:5]([CH:6]=[CH:17][N+:14]([O-:16])=[O:15])=[CH:8][CH:9]=[CH:10][C:11]=1[O:12][CH3:13])([CH3:3])[CH3:2]
Reactant: COc1cccc(C=O)c1C(C)C
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cccc(C=C[N+](=O)[O-])c1C(C)C
Yield: 88.6 %

Procedure:
Using a method similar to Example 659, Step 1, using 2-isopropyl-3-methoxy-benzaldehyde (3.56 g, 20.0 mmol), nitromethane (3.25 ml, 60.0 mmol), ammonium acetate (2.00 g, 26.0 mmol) and acetic acid (25 ml) gave 2-isopropyl-1-methoxy-3-(2-nitro-vinyl)-benzene (3.92 g) as a viscous oil. 1H NMR (CDCl3): 8.48 (d, 1H), 7.38 (d, 1H), 7.20 (t, 1H), 7.02-6.96 (m, 2H), 3.84 (s, 3H), 3.41 (m, 1H), 1.36 (d, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH2:15])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:18])[F:17])=[N:3]1.C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:33])[CH:30]=[CH:31][CH3:32]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:29](=[O:33])[CH:30]=[CH:31][CH3:32])[NH2:15])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[N:3]1
Reactant: CC=CC(=O)Cl
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cccc(CN)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC=CC(=O)C(N)c1cccc(Oc2cc(C(F)(F)F)nn2C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.100 g (0.368 mmol) of 2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-6-(aminomethyl)-pyridine was introduced in 5 ml of methylene chloride together with 71.1 mg (0.55 mmol) of diisopropylethylamine, at room temperature 46.1 mg (0.44 mmol) of but-2-enoyl chloride were added and the mixture was stirred at room temperature for 3 h. The crude product was concentrated, subjected to extraction with 1 N HCl and ethyl acetate and then filtered over a silica gel bed. The filtrate was concentrated. The residue was crystalline.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][C:32](OC)=[O:33])(=[O:30])=[O:29])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[BH4-].[Na+].CO>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][CH2:32][OH:33])(=[O:29])=[O:30])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)CS(=O)(=O)N[C@H]1CCc2c(-c3cnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@@H]4NS(=O)(=O)CCO)s2)cc1C#N
Temperature: 75 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
Prepared using General Procedure 17: To a stirred solution of (S)-methyl 2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate (20 mg, 0.04 mmol) in THF (0.5 mL) was added sodium borohydride (3.6 mg, 0.09 mmol) at room temperature. The reaction was heated to 75° C. and methanol (0.06 mL, 1.4 mmol) was added dropwise. After 1 h, the reaction was cooled and concentrated. Purification of the crude material by preparative HPLC gave 12.2 mg (64%) of (S)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide 165. LCMS-ESI (m/z) calculated for C24H25N3O4S2: 483.1; found 484.2 [M+H]+, tR=3.45 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:8]([CH3:20])[C:7]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24].C(OC(=O)[C@H](C(COC(=O)C)C1C=CC(NC(OC(C)(C)C)=O)=C(C)C=1)CC(OCC)=O)C>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])=[C:8]([CH3:20])[C:7]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24]
Reactant: COC(=O)C(=Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1COC(C)=O)NC(=O)OCc1ccccc1
Agent: CCOC(=O)C[C@H](C(=O)OCC)C(COC(C)=O)c1ccc(NC(=O)OC(C)(C)C)c(C)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H](Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1COC(C)=O)NC(=O)OCc1ccccc1
Yield: 97 %

Procedure:
A solution of 3-(2-acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-benzyloxycarbonylamino-acrylic acid methyl ester (2.51 g, 4.9 mmol) in methanol (50 mL) and ethyl acetate (15 mL) was reacted in a manner similar to the preparation of 2-(S)-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinic acid diethyl ester. Title compound was obtained as an off-white solid in 97% yield. 1H NMR (300 MHz, CDCl3): δ=7.66 (d, J=7.9, 1H), 7.31 (m, 5H), 6.99 (d, J=8.5, 1H), 6.21 (s, 1H), 5.31 (d, J=7.6, 1H), 5.17 (d, J=3.7, 2H), 5.04 (d, J=5.80, 2H), 4.56 (m, 1H), 3.71 (s, 3H), 3.23 (dd, J1=5.80, J2=14.7, 1H), 3.07 (dd, J1=7.8, J=14.2, 1H), 2.21 (s, 3H), 2.00 (s, 3H), 1.50 (s, 9H). MS m/e (M−H)−=513.0.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([F:20])[C:13]=1B(O)O>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].C(Cl)Cl>[F:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([F:20])[C:13]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Reactant: O=C(O)c1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: COc1cc(F)c(-c2cccc(C(=O)O)n2)c(F)c1
Yield: 42 %

Procedure:
Method 1 was followed using 6-bromopicolinic acid (1.0 equiv.) and 2,6-difluoro-4-methoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 6-(2,6-difluoro-4-methoxyphenyl)picolinic acid in 42% yield. LC/MS=266.1 (M+H), Rt=0.75 min.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([C:30]1[CH:35]=[CH:34][C:33](Br)=[CH:32][N:31]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[OH2:69]>CS(C)=O.C(OCC)(=O)C>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[C:30]1[N:31]=[CH:32][C:33]([OH:69])=[CH:34][CH:35]=1
Reactant: O
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(Br)cn1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(O)cn1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyridin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (475 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium methylene chloride complex (55 mg), potassium acetate (198 mg) and bis(pinacolato)diboron (256 mg) are dissolved in dimethylsulfoxide (2 ml), and the mixture is heated to 80° C. under nitrogen atmosphere and stirred for 1 hour. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (10 ml), and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (0.75 ml) under ice-cooling. The reaction solution is stirred at room temperature overnight, and thereto is added a saturated aqueous sodium thiosulfate solution under ice-cooling to consume the excess hydrogen peroxide, followed by an addition of water and diethylether, and the mixture is separated. The organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give 6-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-ol (141 mg). MS (m/z): 643 [M+H]+