Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH:17]([C:19]1[O:20][C:21]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:22][C:23](=[O:36])[C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=O.C(O)(=O)C>C1COCC1>[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])/[CH:5]=[CH:17]/[C:19]1[O:20][C:21]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])=[CH:22][C:23](=[O:36])[C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: CCOC(=O)CCCCCOc1c(C=O)oc(COC(=O)C(C)(C)C)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCC(=O)/C=C/c1oc(COC(=O)C(C)(C)C)cc(=O)c1OCCCCCC(=O)OCC
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a solution, under nitrogen, of 0.206 g (4.3 mmole) of sodium hydride (50% dispersion in mineral oil) in 15 ml of dry THF was added dropwise 1.04 g (4.69 mmole) of dimethyl (2-oxoheptyl)-phosphonate. The heterogeneous mixture was stirred for 1.0 hour then a solution of 1.55 g (3.9 mmole) of 2-formyl-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone in 5 ml of THF was added. The mixture was stirred for 15 min then was neutralized to pH 7 with glacial acetic acid. The neutralized solution was concentrated by rotary evaporation and the residue dissolved in methylene chloride. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. Removal of the solvent left an oil which was purified by chromatography on silica gel using ether as the eluent. Concentration of the fractions containing product furnished 0.425 g (22%) of pure 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone as an oil. NMR (CDCl3): δ0.88 (3H, t, J=5 Hz); 1.25 (9H, s), 2.27 (2H, t, J=6.5 Hz); 2.60 (2H, t, J=6.5 Hz); 4.91 (2H, s).
Reaction SMILES: Br[C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[O:7]1[CH2:10][CH:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:8]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:5][C:2]([N:14]1[CH2:15][CH2:16][N:11]([CH:9]2[CH2:10][O:7][CH2:8]2)[CH2:12][CH2:13]1)([CH3:6])[CH:3]=[O:4]
Reactant: C1CN(C2COC2)CCN1
Reactant: CC(C)(Br)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C=O)N1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromo-2-methyl-propanal (696.6 mg, 4.61 mmol) in DCM (10 mL) was cooled with an ice bath and 1-(oxetan-3-yl)piperazine (328 mg, 2.31 mmol), diluted with 5-10 mL of DCM, was slowly added via addition funnel over a 15 min period. Next, Hunig's base (0.4 mL, 2.31 mmol) was added and then the cooling bath was removed. The reaction mixture was stirred at room temperature overnight and the DCM layer was washed three times with 0.5N HCl. The combined aqueous layer was neutralized with NaOH to pH 10-11 and extracted with DCM. The combined organic layer was washed with brine and dried over Na2SO4. Filtration and removal of solvent afforded 2-methyl-2-[4-(oxetan-3-yl)piperazin-1-yl]propanal as a light yellow liquid, which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]([CH:10]3[CH2:15][NH:14][CH2:13][CH2:12][NH:11]3)=[C:8]([CH3:9])[C:4]=2[CH:3]=1.Cl[C:19]1[CH:28]=[C:27]2[C:22]([C:23](=[O:34])[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]2[CH2:29][CH3:30])=[CH:21][C:20]=1[F:35]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]([CH:10]3[NH:11][CH2:12][CH2:13][N:14]([C:19]4[CH:28]=[C:27]5[C:22]([C:23](=[O:34])[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]5[CH2:29][CH3:30])=[CH:21][C:20]=4[F:35])[CH2:15]3)=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: Cc1c(C2CNCCN2)sc2ccc(Cl)cc12
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4sc5ccc(Cl)cc5c4C)C3)cc21

Procedure:
A 3.0 g portion of 2-(5-chloro-3-methylbenzo[b]-thien-2-yl)piperazine was added to 5 ml of pyridine. A 1.01 g portion of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and the mixture was heated in a pressure bottle, under argon at 130°-135° C. for 18 hours, then cooled and placed in an ice bath. The resulting crystals were collected, washed with cold pyridine, dichloromethane and ether and recrystallized from dimethylformamide, giving 401 mg of the desired product, mp 300°-305° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][C@@H:26]2[CH2:28][C@H:23]1[CH2:24][NH:25]2)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([O:19][C:20]([N:22]1[CH2:27][C@@H:26]2[CH2:28][C@H:23]1[CH2:24][N:25]2[S:2]([CH3:1])(=[O:4])=[O:3])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2S(C)(=O)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Methanesulfonyl chloride (120 μL, 1.55 mmol) and DIPEA (187 μL, 1.07 mmol) were added to a solution of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) in DCM (20 mL) and the reaction mixture stirred at ambient temperature for 17 h, then partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo to give (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester. TFA (3 mL) was added to a solution of (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g); the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a white solid (170 mg, 96%). 1H NMR (CDCl3, 400 MHz) δ 4.37 (d, J=2.0 Hz, 1H); 3.83 (d, J=2.0 Hz, 1H); 3.41 (dd, J=9.2, 2.19 Hz, 1H); 3.25 (d, J=9.2 Hz, 1H); 3.20 (d, J=10.3 Hz, 1H); 3.01 (dd, J=10.3, 2.14 Hz, 1H); 2.89 (s, 3H); and 1.79 (bs, 2H)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].F[C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26].ClC1C=CC(SC)=CC=1[N+]([O-])=O>CN(C=O)C.O>[CH3:3][O:4][N:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26]
Reactant: CONS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1ccc(F)c([N+](=O)[O-])c1
Agent: CSc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc(SC)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1

Procedure:
To a suspension of sodium hydride (60%, 0.33 g (8.17 mmol)) in DMF (10.0 ml), N-methoxy-p-toluenesulfonamide (1.63 g (8.17 mmol)) was added with stirring under cooling with ice. To the resulting mixture, after 15 minutes' stirring at room temperature, a 3:2 mixture of 2-fluoro-5-(methylthio)nitrobenzene and 2-chloro-5-(methylthio)nitrobenzene (1.39 g) was added. The mixture was stirred overnight at room temperature, poured into water and extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:6 to 1:4) as eluent. The eluted substance was recrystallized from ethyl acetate-hexane to give 0.60 g of the title compound as yellow crystals.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:22]([O-])([OH:24])=[O:23].O.[OH-].[Na+]>CCOCC>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([N+:22]([O-:24])=[O:23])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)cc1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
Ethyl α -hydroxy-γ-(4-cyclohexylphenyl)butyrate 0.066 mole is added to ice-cold concentrated sulfuric acid (18 ml.) and stirred with cooling for 5 minutes. Concentrated nitric acid (Sp. G. 1.51) (2.5 ml.) is added dropwise, maintaining the temperature between 30° and 40° by water cooling if necessary. After addition of the nitric acid is complete, the mixture is stirred for 1/2 hour, then poured into water. The mixture is made alkaline with sodium hydroxide, then ex-racted with ether. The ether extract is washed, dried over sodium sulfate, evaporated and the residue is fractionally distilled to obtain ethyl α-hydroxy-γ-(3-nitro-4-cyclohexylphenyl)butyrate.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[CH:14]=[N:15][OH:16].O>CN(C=O)C>[Cl:1][C:13]1([CH:14]=[N:15][OH:16])[CH:17]=[CH:18][CH:19]=[C:11]([O:10][CH3:9])[CH2:12]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc(C=NO)c1
Solvent: O
Solvent: CN(C)C=O
Product: COC1=CC=CC(Cl)(C=NO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-chlorosuccinimide (32.2 g, 241 mmol) was added to a solution of 3-methoxybenzaldehyde oxime (30.4 g, 201 mmol) in DMF (200 ml) at RT, causing the temperature to rise briefly to 50° C. The reaction mixture was cooled in an ice bath, stirred overnight at RT, mixed with water (250 ml) while being cooled with ice and the precipitate formed was removed by suction-filtration. The filtrate was extracted with ether (3×400 ml) and the combined organic phases were washed with water (300 ml) and sat. aq. NaCl solution (300 ml), dried and the solvent was removed under vacuum. The desired product 1-chloro-1-hydroxyiminomethyl-3-methoxybenzene was obtained as a yellowish solid (32.86 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([F:23])[CH:15]=2)[C@H:10]([CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([Li])CCC.IC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][C:20]([CH3:25])=[CH:19][C:18]=3[CH:17]=[C:16]([F:23])[CH:15]=2)[C@H:10]([CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cc(F)cc2ccoc12
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2cc(F)cc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3C)c2o1
Reaction time: 0.08 h

Procedure:
A solution of 0.100 gm (0.3 mMol) (−)-cis-1-(tert-butoxycarbonyl)-3-methyl-4-(5-fluorobenzofur-7-yl)piperidine in 2 mL tetrahydrofuran was cooled to −78° C. To this solution were added 0.38 mL (0.6 mMol) n-butyllithium (1.6 M in hexane) dropwise. After stirring for 5 minutes, 0.02 mL (0.33 mMol) iodomethane were added and the reaction mixture was stirred at −78° C. for 3 hours. The solution was treated with an additional 0.06 mL (0.1 mMol) n-butyllithium (1.6 M in hexane) followed by 0.02 mL (0.33 mMol) iodomethane. After stirring for 1 hour at −78° C., an additional 0.06 mL (0.1 mMol) n-butyllithium (1.6 M in hexane) followed by 0.02 mL (0.33 mMol) iodomethane were added to the reaction mixture. The mixture was then stirred at room temperature for 14 hours and was then partitioned between 5 mL deionized water and 40 mL ethyl acetate. The organic phase was washed sequentially with 20 mL portions of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic phase was then dried over magnesium sulfate and concentrated under reduced pressure to provide (−)-cis-1-(tert-butoxycarbonyl)-3-methyl-4-(2-methyl-5-fluorobenzofur-7-yl)piperidine.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH:29]1[CH3:41])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:38][CH:39]=2)[CH2:30][CH:29]1[CH3:41])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Product: CC1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1C(=O)OC(C)(C)C
Yield: 97.7 %

Procedure:
Using Buchwald Procedure A, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethyl amide (0.142 g, 0.485 mmol) and (+/−)-4-(6-amino-pyridin-3-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.156 g, 0.533 mmol) gave 4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (260 mg, 97%) (following SiO2 chromatography, eluting with 0-3% MeOH/dichloromethane). MS (ESI) m/z 549.3 (M+H)+
Reaction SMILES: [CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=O)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:17])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CC1CCc2ccccc21
Reactant: C1CCNC1
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C([C@@H]1CCCN1C(=O)CC1CCc2ccccc21)N1CCCC1
Yield: 62 %

Procedure:
A colorless oil of 1-[1-(2-indanylacetyl)-L-prolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(2-indanylacetyl)-L-proline and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 62%).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.Br[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C(OCC)(=O)C>C1COCC1>[O:3]1[CH2:8][CH2:7][CH:6]([O:9][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:5][CH2:4]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(COC2CCOCC2)cc1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil; 490 mg, 12.2 mmol) in THF (10 mL) was added a solution of tetrahydro-2H-pyran-4-ol (1.20 g, 12.2 mmol) in THF (2 mL) at rt. The reaction mixture was stirred at it for several minutes and then heated to reflux for 15 min. After cooling to rt, 4-(bromomethyl)benzonitrile (2.00 g, 10.2 mmol) was added, and the reaction mixture was stirred at it over night. Ethyl acetate was added and the mixture was washed with water. The organic layer was dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 7:3) to afford the title compound (1.57 g, 71%): 1H NMR (400 MHz, CDCl3) δ 7.53 (d, 2H), 7.45 (d, 2H), 4.61 (s, 2H), 4.00-3.92 (m, 2H), 3.65-3.58 (m, 1H), 3.49-3.41 (m, 2H), 1.99-1.92 (m, 2H), 1.72-1.62 (m, 2H); ES-MS m/z 218, HPLC RT (Method D) 1.86 min.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.[OH:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]([O:27]CC)=[O:26])[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:30]1([C:22]2[C:23]([C:25]([OH:27])=[O:26])=[CH:24][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:2][C:3]4[N:4]=[C:5]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[S:6][CH:7]=4)=[CH:37][CH:36]=3)[N:21]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A mixture of 4-chloromethyl-2-phenylthiazole (1.19 g), ethyl 1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-carboxylate (1.65 g), potassium carbonate (1.18 g) and N,N-dimethylformamide (25 ml) was stirred overnight at 80° C. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. A mixture of the residue, potassium hydroxide (0.93 g) and ethanol (50 ml) was refluxed for 5 hours. After the reaction solvent was removed under reduced pressure, water was added to the reaction mixture, then the mixture was acidified with 1N hydrochloric acid. The crystals obtained were collected by filtration to yield 3-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-carboxylic acid (1.82 g, yield: 76%). This was recrystallized from acetone-hexane. Melting point: 119–120° C.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:15][N:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[C:19]([CH3:30])[CH:18]=[N:17]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:15][N:16]1[C:20]([C:2]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:19]([CH3:30])[CH:18]=[N:17]1
Reactant: CCOC(=O)c1c(Br)cccc1OC
Reactant: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
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
Solvent: O
Product: CCOC(=O)c1c(OC)cccc1-c1c(C)cnn1C
Temperature: 100 °C
Yield: 95.2 %

Procedure:
In a microwave vial was dissolved ethyl 2-bromo-6-methoxybenzoate (500 mg, 1.54 mmol) and 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (377 mg, 1.70 mmol) in DME (10 mL) and water (2 mL). Na2CO3 (259 mg, 3.09 mmol) was then added followed by Pd(PPh3)4 (89 mg, 0.077 mmol) and the reaction mixture was degassed with N2 for 10 minutes. The reaction mixture was then heated at 100° C. for 1 h in the microwave. The mixture was cooled to room temperature, filtered through Celite and washed with EtOAc and DCM. The crude solution was concentrated in vacuo and directly purified via silica gel chromatography (10-80% EtOAc in hexanes) to afford the title compound (402 mg, 95%). MS (ESI) mass calcd. for C15H18N2O3, 274.1; m/z found 275.2 [M+H]+. 1H NMR (400 MHz, Chloroform-d) 7.45 (dd, J=8.4, 7.6 Hz, 1H), 7.29 (s, 1H), 7.04 (dd, J=8.5, 0.9 Hz, 1H), 6.84 (dd, J=7.6, 0.9 Hz, 1H), 4.07 (qd, J=7.2, 1.5 Hz, 2H), 3.90 (s, 3H), 3.61 (s, 3H), 1.86 (s, 3H), 1.01 (t, J=7.1 Hz, 3H).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].N1C=CC=CC=1.[C:11]([O:15][C:16](=[O:29])[NH:17][C:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[N:23]=1)([CH3:21])[CH2:19][OH:20])([CH3:14])([CH3:13])[CH3:12].Cl>C(Cl)Cl>[C:11]([O:15][C:16]([N:17]1[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[N:23]=2)([CH3:21])[CH2:19][O:20][S:1]1=[O:2])=[O:29])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1cccc(Br)n1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1S(=O)OCC1(C)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an at 0° C. precooled solution of thionyl chloride (3.42 ml, 5.57 g, 46.8 mmol) in pyridine (9.46 ml, 9.25 g, 117.0 mmol) was added dropwise a solution of [1-(6-bromo-pyridin-2-yl)-2-hydroxy-1-methyl-ethyl]-carbamic acid tert-butyl ester (see Example 1 step d), 7.75 g, 23.4 mmol) in DCM (230 ml). The reaction mixture was allowed to stir for 1 h at rt, then 0.5 N aq. HCl and DCM were added, the phases were separated and the aq. phase was twice reextracted with DCM. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated to leave the title compound (mixture of diastereomers) as an orange solid. HPLC RtH4=1.16, 1.20 min (diastereomers); ESIMS: 377, 379 [(M+H)+].
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][C:7]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:17][C:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]=1[CH2:27][NH:28][CH3:29]>>[Cl:17][C:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]=1[CH2:27][N:28]([CH3:29])[C:14](=[O:16])/[CH:13]=[CH:12]/[C:7]1[CH:8]=[N:9][C:10]2[NH:11][C:2](=[O:1])[CH2:3][CH2:4][C:5]=2[CH:6]=1
Reactant: O=C(O)C=Cc1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1oc2ccccc2c1Cl
Product: CN(Cc1oc2ccccc2c1Cl)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 56 %

Procedure:
According to the method of example 43d, 3-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-acrylic acid (203 mg, 0.8 mmol) and (3-chloro-benzofuran-2-ylmethyl)methylamine (172 mg, 0.88 mmol) were coupled to yield the title compound (176, 56%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.21-7.64 (m, 6H), 4.84-5.08 (rotamers, 2s, 2H), 3.22 (s, 3H), 2.91-2.96 (m, 2H), 2.52-2.59 (m, 2H); MS (ESI) m/e 396 (C21H18ClN3O3+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(C(F)(F)F)c2)n1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccc(C(F)(F)F)c2)n1
Yield: 34.7 %

Procedure:
Following the procedure in Example 118A, 3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (344 mg, 1.21 mmol) and phenyl chloroformate (0.25 mL, 1.82 mmol) were reacted to give phenyl 3-tert -butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-ylcarbamate (119 mg, 0.42 mmol, 35%). 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 7.62-7.50 (m, 3H), 7.58-7.43 (m, 3H), 7.23 (t, 1H), 7.12 (br s, 2H), 6.39 (s, 1H), 1.29 (s, 9H); LC-MS (ESI) m/z 404 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].B.CSC>C1COCC1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: O=[N+]([O-])c1ccc2c(c1)C(O)CCC2
Temperature: 0 °C
Yield: 99.2 %

Procedure:
7-Nitro-3,4-dihydro-1(2H)-naphthalenone (5.0 g, 26.1 mmol) was stirred with 2M borane-dimethylsulfide in THF (14.4 mL, 28.8 mmol) in THF (200 mL) at rt for 15 h. The reaction was cooled to 0° C. and quenched with MeOH. The solvent and reaction byproducts were removed under vacuum and afforded 5.0 g (99%) of the desired alcohol as a brown powder. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=2.6 Hz, 1 H), 7.98 (dd, J=8.5, 2.6 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 5.55 (d, J=5.7 Hz, 1H), 4.63 (m, 1H), 2.87-2.73 (m, 2H), 2.00-1.83 (m, 2H), 1.75-1.60 (m, 2H).