Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:11]=3[O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([N:22]([C:30]4[N:31]=[CH:32][S:33][CH:34]=4)C(=O)OC(C)(C)C)(=[O:21])=[O:20])=[CH:15][C:14]=3[C:35]#[N:36])=[CH:8][CH:7]=[N:6]2)[CH2:2]1>Cl.O1CCOCC1>[NH:1]1[CH2:2][CH:3]([N:5]2[C:9]([C:10]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:11]=3[O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:30]4[N:31]=[CH:32][S:33][CH:34]=4)(=[O:21])=[O:20])=[CH:15][C:14]=3[C:35]#[N:36])=[CH:8][CH:7]=[N:6]2)[CH2:4]1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(Oc2ccc(Cl)cc2-c2ccnn2C2CNC2)c(C#N)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1ccc(Cl)cc1-c1ccnn1C1CNC1
Yield: 38.9 %

Procedure:
tert-butyl ({4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-3-cyanophenyl}sulfonyl)1,3-thiazol-4-ylcarbamate (Preparation 679, 200 mg, 0.326 mmol) was stirred in 4M hydrogen chloride solution in 1,4-dioxan (10 ml) at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between methyl-t-butyl ether (80 ml) and water (40 ml). The aqueous layer was neutralized to pH=7 by adding sodium hydrogen carbonate and was then concentrated in vacuo. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.880 aqueous ammonia, 90:10:1 to 70:30:3. This gave a buff powder (65 mg) which was triturated with methyl tert-butyl ether to give the title compound as a buff powder, 55 mg.
Reaction SMILES: CN(C)[CH:3]=[CH:4][N+:5]([O-:7])=[O:6].C(O)(C(F)(F)F)=O.[CH3:16][S:17]([C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[CH:25][NH:26]2)=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[N+:5]([CH:4]=[CH:3][C:24]1[C:23]2[C:27](=[CH:28][C:20]([S:17]([CH3:16])(=[O:19])=[O:18])=[CH:21][CH:22]=2)[NH:26][CH:25]=1)([O-:7])=[O:6]
Reactant: CS(=O)(=O)c1ccc2cc[nH]c2c1
Reactant: CN(C)C=C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc2c(C=C[N+](=O)[O-])c[nH]c2c1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Combine 1-dimethylamino-2-nitroethylene (892.1 mg, 7.68 mmol) and TFA (9.0 ml) and stir until dissolved. Add 6-methanesulfonyl-1H-indole (1.5 g, 7.68 mmol) and stir at ambient temperature. After 24 hours, pour the reaction mixture into ice/water, extract with ethyl acetate, then wash ethyl acetate with brine and saturated sodium bicarbonate. Filter, wash, and dry the precipitate to give the title compound as a yellow powder: mp>250° C. MS (ACPI): m/e 267.0 (M+1). Analysis for C11H10N2O4S: Calcd: C, 49.62; H, 3.79; N, 10.52. found: C, 49.86; H, 3.97; N, 10.25.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6](=[O:25])[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[CH3:4].C(O)(=O)C>C(O)C>[CH2:3]([O:5][C:6](=[O:25])[CH:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[CH3:4]
Reactant: CCOC(=O)C(=Cc1ccc(NC)cc1[N+](=O)[O-])C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(NC)cc1[N+](=O)[O-])C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
Sodium borohydride (NaBH4) (0.2 g, 5.8 mmol) was added to a slurry of the cinnamic ester (2) (3.4 g, 10.5 mmol) in 100 mL of absolute ethanol and the reaction allowed to stir at room temperature for 1.5 hours. Acetic acid (0.5 mL) was added and the mixture concentrated. The residue was dissolved in 250 mL of CHCl3 and was washed with 100 mL of saturated sodium bicarbonate (NaHCO3) solution, and H2O (100 mL). The organic phase was separated, dried (Na2SO4) and concentrated to produce 3.1 g of an orange solid. An analytical sample was obtained by crystallization from methanol(MeOH)-water, m.p. 75°-77° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.[Li]CCCC.[Si:21]([O:28][C:29]1[CH:30]=[C:31]([CH:38]=[CH:39][C:40]=1[F:41])[C:32](N(OC)C)=[O:33])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].Cl>CCOCC>[Si:21]([O:28][C:29]1[CH:30]=[C:31]([C:32]([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=2)=[O:33])[CH:38]=[CH:39][C:40]=1[F:41])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Reactant: CON(C)C(=O)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reaction time: 1 h
Yield: 71 %

Procedure:
At −78° C. under argon, to a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (2.04 g, 7.01 mmol) in anhydrous ether (20 mL) was added nBuLi (3.5 mL, 2.0 M in cyclohexane, 7.0 mmol) dropwise and the reaction mixture was stirred for 1 h. 3-(Tert-butyldimethylsilyloxy)-4-fluoro-N-methoxy-N-methylbenzamide (2.00 g, 6.38 mmol) was added in one portion and the reaction mixture was stirred at −78° C. for 1.5 h. The pale yellow solution was poured into a 1 N HCl aqueous solution (30 mL) and ether (30 mL) was used to rinse the reaction flask. The aqueous phase was separated and extracted with diethyl ether (20 mL). The combined ether portions were dried over Na2SO4, filtered and concentrated. The resulting oil was purified by ISCO chromatography (120 g column) using hexanes/EtOAc (0-100% over 30 min) to give (3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone at a retention time of 7 min (2.11 g, 71% yield). LCMS: RT=2.41 min [M+H] 465.19 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.33 ppm, 3H, m; 7.28 ppm, 1H, m; 7.11 ppm, 2H, m; 5.86 ppm, 1H, t, J=53.39 Hz; 0.95 ppm, 9H, s; 0.15 ppm, 6H, s.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][CH:28]1[CH2:31][CH2:30][CH2:29]1>>[CH:28]1([CH2:27][O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]3[CH:9]=[N:10][C:11]4[C:6]([CH:7]=3)=[C:5]3[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]3=[N:3][C:2]=4[NH2:1])=[CH:19][CH:18]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: BrCC1CCC1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCC4CCC4)cc3)cc12

Procedure:
2-(4-(Cyclobutylmethoxy)phenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 136, but using (bromomethyl)cyclobutane. 1H NMR (Acetone-d6): δ 8.79 (s, 1H), 8.73 (s, 1H), 8.33 (d, 1H), 7.47 (s, 1H), 7.26 (d, 1H), 7.16 (d, 2H), 6.82 (d, 2H), 3.90 (d, 2H), 3.23 (t, 2H), 3.06 (t, 2H), 2.68-2.79 (m, 1H), 2.49 (s, 3H), 2.05-2.14 (m, 2H), 1.80-1.98 (m, 4H). LRMS [M+H]=398.2
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6](O)=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O>COCCOC>[C:9]([NH:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:4])[CH3:5])([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CC(C)[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.02 h
Yield: 86.5 %

Procedure:
In 5 ml of 1,2-dimethoxyethane (DME), 1.086 g of Boc-Val-OH was dissolved and 550 μl of N-methylmorpholine and 650 μl of isobutyl chloroformate were successively added dropwise at −15° C. After stirring for 1 min, N-methylmorpholine hydrochloride was filtered off and washed twice with 2.5 ml each of DME. The filtrate and washings were combined and a solution of 284 mg of sodium borohydride in 2.5 ml of water was added in one portion. After 30 sec, 125 ml of water was added and the mixture was extracted with 25 ml of ethyl acetate and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure to give 879 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([I:11])=[C:4]([N+:8]([O-])=O)[CH:5]=[CH:6][CH:7]=1.C(O)C.[ClH:15].C(=O)([O-])[O-].[Na+].[Na+]>[Fe].C(OCC)(=O)C>[ClH:15].[F:1][C:2]1[C:3]([I:11])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cccc(F)c1I
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccc(F)c1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 18.4 %

Procedure:
To a 1 L, 3 necked round bottom flask fitted with a mechanical stirrer was added 3-fluoro-2-iodonitrobenzene (3B Medical, 47.7 g, 179 mmol) and 500 mL absolute ethanol. To this stirred solution was added iron powder (325 mesh, Aldrich, 30 g, 537 mmol) followed by dropwise addition of concentrated HCl (30 mL, 360 mmol). The internal temperature rose from 23 to ˜60° C. over the addition. The flask was fitted with a heating mantle and heated with vigorous stirring for 90 minutes. After cooling to room temperature, 1 N sodium carbonate (300 mL) was added followed by ethyl acetate (200 mL). The mixture was stirred for 30 minutes and then filtered through a pad of celite. The celite was washed with ethyl acetate (3×150 mL). The filtrates were placed in a separatory funnel and the water layer was removed. The organic layer was concentrated under reduced pressure to a volume of ˜200 mL, placed in a separatory funnel, diluted with ethyl acetate (400 mL), washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was taken up in ether (300 mL) and made acidic to pH 1 with 2M hydrochloric acid/ether (Aldrich). After 1 hour, the tan solid was isolated by filtration (39.2 g, 80%). The above aqueous layers were extracted with diethyl ether (300 mL), dried over sodium sulfate, combined with the filtrate of the 1st crop, made acidic to pH 1, and isolated as above to give additional tan solid (9.0 g, 18%) for an overall yield of 98%. 1H NMR (300 MHz, CDCl3) δ 7.06 (m, 1H), 6.58 (m, 1H), 6.39 (m, 1H), 5.73 (bm, 1H). MS APCI, m/z=238 (M+H). HPLC 2.19 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([Cl:20])=[C:18]([C:21]([F:24])([F:23])[F:22])[N:17]([CH3:25])[N:16]=2)=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7].C(Cl)(=O)C(Cl)=O.[CH3:32][CH:33]([CH3:37])[CH2:34][CH2:35]O>C(Cl)Cl.CN(C=O)C.O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([Cl:20])=[C:18]([C:21]([F:23])([F:24])[F:22])[N:17]([CH3:25])[N:16]=2)=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([O:8][CH2:35][CH2:34][CH:33]([CH3:37])[CH3:32])=[O:7]
Reactant: CC(C)CCO
Reactant: CC(Oc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCOC(=O)C(C)Oc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Yield: 95 %

Procedure:
To a solution of 1.9 g (5.0 mmole) of 2-(2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluorophenoxy)-propanoic acid in 50 mL methylene chloride was added 1.3 mL (15.0 mmole) oxalyl chloride over 5 minutes, causing the evolution of gas. When this evolution ceased, one drop of DMF was added and the solution stirred until the gas evolution ceased. The solution was stripped to dryness in vacuo. The acid chloride was dissolved in 40 mL of 3-methyl-1-butanol and heated to reflux for one hour. The reaction mixture was cooled, diluted with 100 mL cold water and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified chromatographically using 25% ethyl acetate in hexane as the eluent to give 2.17 g (95%) of 2-(2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluorophenoxy)-propanoic acid, 3-methylbutyl ester as a white solid; mp 128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:22](=[O:23])[C:10]3[N:11]=[C:12]([CH3:21])[N:13]([CH2:14][CH2:15][C:16]4[N:17]=[CH:18][NH:19][CH:20]=4)[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:24]=1.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:22]([OH:23])[C:10]3[N:11]=[C:12]([CH3:21])[N:13]([CH2:14][CH2:15][C:16]4[N:17]=[CH:18][NH:19][CH:20]=4)[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:24]=1
Reactant: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2n1CCc1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1nc2c(n1CCc1c[nH]cn1)C=Cc1cc(Cl)ccc1C2O

Procedure:
The subtitle product was prepared from the product of step (i) (0.966 g) and sodium borohydride (0.215 g) according the method of example 71 step (ii). Used directly in the next step.
Reaction SMILES: ClC1C=CC(OCC(N2C3C=CC=CC=3CN3C=CC=C3C2)=O)=CC=1.[Cl:26][C:27]([Cl:57])([Cl:56])[C:28]([C:30]1[N:39]2[C:33]([CH2:34][N:35]([C:44](=[O:55])[CH2:45][O:46][C:47]3[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][C:48]=3C)[C:36]3[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=3[CH2:38]2)=[CH:32][CH:31]=1)=[O:29]>>[Cl:57][C:27]([Cl:26])([Cl:56])[C:28]([C:30]1[N:39]2[C:33]([CH2:34][N:35]([C:44](=[O:55])[CH2:45][O:46][C:47]3[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=3)[C:36]3[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=3[CH2:38]2)=[CH:32][CH:31]=1)=[O:29]
Reactant: Cc1cc(Cl)ccc1OCC(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Agent: O=C(COc1ccc(Cl)cc1)N1Cc2cccn2Cc2ccccc21
Product: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21

Procedure:
The title compound was prepared from 10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A in the same manner as the preparation of 2,2,2-trichloro-1-{10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 139, Step C, m.p. 165-167° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:15][N:16]([CH3:18])O.Cl.CN(C)O>CN(C)C=O.O.N1C=CC=CC=1.C(N(CC)CC)C.ClCCl.C(Cl)(Cl)Cl>[OH:1][C:2]1[C:3]([C:8]([O:10][N:16]([CH3:18])[CH3:15])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1O
Reactant: CN(C)O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)OC(=O)c1ncccc1O
Reaction time: 0.5 h

Procedure:
7.0 Grams of 3-hydroxypicolinic acid was dissolved in 10 ml of N,N-dimethylformamide, and the resulting solution was cooled to 0° to 5° C. 5.9 Grams of thionyl chloride was then added dropwise to the solution which was then stirred at 0° to 5° C. for further 30 minutes. Thereafter, 30 ml of chloroform was added to the solution which was then stirred at 0° to 5° C. for further 15 minutes. To the resulting mixed solution was added dropwise a dichloromethane solution of N,N-dimethylhydroxylamine prepared from 7.4 g of N,N-dimethylhydroxylamine hydrochloride and 7.6 g of triethylamine. After stirring at 0° to 5° C. for 30 minutes, 7.9 g of pyridine was added, and stirring was continued at 0° to 5° C. for further 1 hour. After stirring at room temperature for 8 hours, the reaction solution was poured into water, and insoluble matters were removed by filtration on celite. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to chromatography to obtain 1.0 g of 3-hydroxy-2-(N,N-dimethylaminooxycarbonyl)pyridine.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[C:18]2[C:14](=[CH:15][N:16]([CH3:19])[N:17]=2)[C:13](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:12][CH:11]=1.O>CS(C)=O>[F:9][C:10]1[C:18]2[C:14](=[CH:15][N:16]([CH3:19])[N:17]=2)[C:13]([CH:20]2[CH2:4][CH:21]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C/c1ccc(F)c2nn(C)cc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1ccc(F)c2nn(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (290 mg, 7.25 mmol) in dimethyl sulfoxide (45 mL) was added trimethylsulfoxonium iodide (1.73 g, 7.86 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(7-fluoro-2-methyl-2H-indazol-4-yl)acrylate (1.50 g, 6.04 mmol) in dimethyl sulfoxide (15 mL) at 0° C., and the mixture was stirred at 70° C. for 27 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=15/85-+50/50) to give the title compound (1.20 g, yield 76%).
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([O:11]CC)=[O:10])[CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C.O>[O:1]=[C:2]([CH3:14])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1
Reactant: CCOC(=O)c1cc(CC(C)=O)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: CC(=O)Cc1cc(C(=O)O)no1
Temperature: 25 °C
Reaction time: 7 h
Yield: 36.4 %

Procedure:
Ethyl 5-(2-oxopropyl)isoxazole-3-carboxylate (0.65 g, 3.30 mmol) was dissolved in ethanol (10 ml). A solution of cesium carbonate (1.611 g, 4.94 mmol) in water (5 ml) was added to the reaction mixture and it was stirred for 7 h at RT. The reaction mixture was concentrated, diluted with water and pH was adjusted to 2 with citric acid. The aqueous phase was extracted with ethyl acetate, dried with Na2SO4 and evaporated to dryness afforded 0.203 g (36%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ, 2.21 (s, 3H), 4.20 (s, 2H), 6.67 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=O)[CH:3]=1.C(O)C.N1C=CC=CC=1.Cl.[NH2:28][OH:29]>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:28][OH:29])[CH:3]=1
Reactant: NO
Reactant: O=C(Cc1cc(Br)ccn1)c1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: ON=C(Cc1cc(Br)ccn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.3 %

Procedure:
7.5 g (24.26 mmol) of 2-(4-bromopyridin-2-yl)-1-(4-fluorophenyl)ethanone are placed in a round-bottomed flask containing 100 ml of absolute ethanol. 20 ml (247.78 mmol) of pyridine and 7.08 g (101.88 mmol) of hydroxylamine monohydrochloride are added before leaving the medium to stir at ambient temperature for 3 h. The ethanol is subsequently evaporated under vacuum and the residue obtained is taken up in 250 ml of water and 250 ml of ethyl acetate. The organic phase is separated and then the aqueous phase is extracted 5 times with 150 ml of ethyl acetate. The organic phases are subsequently combined, dried over sodium sulphate and concentrated under vacuum. 7.82 g of compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:25])[N:15]4[CH2:23][CH:22]([OH:24])[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:28]1COCC1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:25])[N:15]4[CH2:23][CH:22]([O:24][CH3:28])[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=c1c2ccc(C#Cc3cccc(F)c3)cc2nc2n1CC(O)CC2
Agent: [H-]
Agent: [Na+]
Product: COC1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-((3-fluorophenyl)ethynyl)-8-hydroxy-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one (0.2 g, 0.6 mmol, 1 equiv) in THF (15 mL) was added NaH (57.6 mg, 2.4 mmol, 4 equiv) in portions. After stirring at rt for 1 h, the reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified using silica gel chromatography to give the desired product. MS (ESI): 349 (M+H+); 1H NMR (300 MHz, CDCl3) δ 8.27-8.24 (d, J=8.46 Hz, 1H), 8.01 (s, 1H), 7.62-7.50 (d, J=8.19 Hz, 1H), 7.37-7.35 (m, 2H), 7.30-7.28 (m, 1H), 7.14-7.09 (m, 1H), 4.58-4.57 (m, 1H), 4.02-4.00 (m, 1H), 3.87-3.81 (m, 1H), 3.42 (s, 3H), 3.33-3.20 (m, 2H), 2.26-2.15 (m, 2H). mGluR5 PAM EC50: +++++. Fold shift at 10 μM: +.
Reaction SMILES: OC1C=C(C=C(N2CCCC2=O)C=1)C(O)=O.[CH2:17]([C@H:24]([NH:41][C:42](=[O:59])[C:43]1[CH:48]=[C:47]([N:49]2[CH2:53][CH2:52][CH2:51][C:50]2=[O:54])[CH:46]=[C:45]([O:55][CH:56]([CH3:58])[CH3:57])[CH:44]=1)[C@@H:25]([OH:40])[CH2:26][C@H:27]([C:29](=[O:39])[NH:30][CH2:31][CH2:32][C:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=1)[CH3:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([C@H:24]([NH:41][C:42](=[O:59])[C:43]1[CH:48]=[C:47]([N:49]2[CH2:53][CH2:52][CH2:51][C:50]2=[O:54])[CH:46]=[C:45]([O:55][CH:56]([CH3:58])[CH3:57])[CH:44]=1)[C@@H:25]([OH:40])[CH2:26][C@H:27]([C:29](=[O:39])[NH:30][CH2:31][CH2:32][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[CH3:28])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCCC2=CCCCC2)cc(N2CCCC2=O)c1
Agent: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Product: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCCC2CCCCC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D6 (hydrogenation stage) from N-[(1S,2S,4R)-1-benzyl-4-(cyclohex-1-enylethylcarbamoyl)-2-hydroxypentyl]-3-isopropoxy-5-(2-oxopyrrolidin-1-yl)benzamide (D51).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[N:12]=1)=[N+:8]=[N-:9].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+].[O-]S([O-])(=O)=O.[Cu+2].O>[Br:17][C:13]1[N:12]=[C:11]([CH2:10][N:7]2[CH:3]=[C:2]([C:1]([O:5][CH3:6])=[O:4])[N:9]=[N:8]2)[CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NCc1cccc(Br)n1
Reactant: C#CC(=O)OC
Agent: [Cu+2]
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1cn(Cc2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl propiolate (641 μL, 7.63 mmol) and 2-(azidomethyl)-6-bromopyridine (1.25 g, 5.87 mmol) were combined in t-BuOH (9.0 mL) and water (5.0 mL). A solution of CuSO4.H2O (73 mg, 0.29 mmol) in water (2.0 mL) was added, followed by sodium ascorbate (232 mg, 1.17 mmol) in water (2.0 mL). The reaction was stirred at room temperature for 18 h, during which time it became a yellow suspension. The suspension was diluted with saturated NaHCO3 and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated to dryness. The crude solid was purified by flash chromatography (40-100% ethyl acetate/hexanes) to afford the title compound as a colorless solid. LRMS (APCI) calc'd for C10H10BrN4O2 [M+H]+: 297, Found: 297.
Reaction SMILES: [CH2:1]([C:15]1C=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:22]([O:21][CH2:17][CH2:18][CH2:19][CH2:20][CH2:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:24])[CH3:23]
Reactant: CCCCCCCCCCCCCCc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCOC(C)=O
Reaction time: 16 h

Procedure:
A mixture of 18.85 g of 3-tetradecylphenol, 20 ml of acetic anhydride and 60 ml of pyridine was stirred for 16 hours, then diluted with chloroform, washed with aqueous sodium bicarbonate, dried and the solvent removed by evaporation with toluene, giving 21 g of the desired compound.