Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([C@H](N)C(O)=O)CC(N[C@H](C(NCC(O)=O)=O)CS)=O.[CH3:29][CH2:30][CH2:31][CH2:32][CH2:33][C@H:34]([OH:53])/[CH:35]=[CH:36]/[C@@H:37]1[C@@H:41]([CH2:42]/[CH:43]=[CH:44]\[CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[C@H:40]2[O:51][O:52][C@@H:38]1[CH2:39]2.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>CS(C)=O.C(#N)C>[CH3:29][CH2:30][CH2:31][CH2:32][CH2:33][C@H:34]([OH:53])/[CH:35]=[CH:36]/[C@@H:37]1[C@@H:41]([CH2:42]/[CH:43]=[CH:44]\[CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[C:40](=[O:51])[CH2:39][C@H:38]1[OH:52]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H]2C[C@H]1OO2
Agent: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: CS(C)=O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Reaction time: 0.02 h

Procedure:
The typical reaction conditions of the enzymatic reaction were thus: Test compound: ranging from 60 μM to 0.002 μM, or zero in positive and negative controls; potassium phosphate buffer pH 6.8: 50 mM; GSH: 2.5 mM; mPGES-1-containing microsomes: 2 μg/mL (sample and positive controls) or 0 μg/mL (negative control); PGH2: 10.8 μM; Acetonitrile: 7.7% (v/v); DMSO: 0.6% (v/v). The reaction was stopped after one minute by adding an acidic solution (pH 1.9) of ferric chloride and citrate (final concentrations 7 mM and 47 mM respectively), by which the PGH2 was sequestered (the PGH2 is reduced to mainly 12-hydroxy heptadecatrineoic acid (12-HHT) which is not detected by the subsequent PGE2 detection step). The resulting solution was then pH neutralized by addition of potassium phosphate buffer, prior to diluting an aliquot of the resulting solution in a weak potassium phosphate buffer (50 mM, pH 6.8) containing 0.2% BSA (w/v). [Adapted from Jacobsson et al., Proc. Natl. Acad. Sci. USA, 1999, vol. 96, pp. 7220-7225] The PGE2 formed was quantified by use of a commercial HTRF based kit (catalogue #62PG2PEC or #62P2APEC from Cisbio International). 100% activity was defined as the PGE2 production in positive controls subtracted by the PGE2 production in the negative controls. IC50 values were then determined using standard procedures.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=1)=[O:5])[CH3:2].[Br:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>ClCCl>[CH2:14]([O:13][C:11]([C:9]1[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:16])[CH:22]=2)[N:8]=1)=[O:12])[CH3:15]
Reactant: OB(O)c1cccc(Br)c1
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)OCC)n(-c2cccc(Br)c2)n1
Reaction time: 36 h
Yield: 83.8 %

Procedure:
A mixture of diethyl-3,5-pyrazoledicarboxylate (1.0 g, 4.71 mmol), 3-bromophenylboronicacid (1.89 g, 9.42 mmol) and di-Micron-hydroxo-bis[(N,N,N′,N′-tetramethylethylenediamine)copper(II)]chloride (0.21 g, 0.47 mmol) in dichloromethane (22 mL) was stirred under air for 36 hours under air. It was filtered over a short silica gel pad, concentrated and purified by column chromatography (hexanes:ethyl acetate; 90:10) to yield 1.45 g (85%) of the product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20].Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]([CH:30]([CH:37]2[CH2:39][CH2:38]2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=1.[H-].[Na+].Cl>C1COCC1>[CH:37]1([CH:30]([C:26]2[CH:25]=[C:24]([O:17][CH2:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=3)[N:29]=[CH:28][N:27]=2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:39][CH2:38]1
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
Under a nitrogen atmosphere, to a solution of (6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)methanol (379 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (382 mg) in THF (5.0 mL) was added 60% sodium hydride (65 mg) at 0° C., and the mixture was stirred at room temperature for 5 hr. 1N Hydrochloric acid was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (489 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C@:9]1([CH:33]=[CH2:34])[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@@H:10]1[OH:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[CH2:1]([O:8][C@:9]1([CH:33]=[CH2:34])[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@@H:10]1[O:32][S:36]([CH3:35])(=[O:38])=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O
Solvent: c1ccncc1
Product: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
Nucleoside 24 (2.57 g, 5.53 mmol) was dissolved in anhydrous pyridine (18 cm3) and cooled to 0° C. Methanesulfonyl chloride (1.28 cm3, 16.6 mmol) was added dropwise and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water (5 cm3) and the resulting mixture was extracted with dichloromethane (3×80 cm3). The combined extract was washed with saturated aqueous sodium hydrogencarbonate (3×120 cm3) and dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give nucleoside 25 as a yellow foam (2.53 g, 84%). δH (CDCl3) 8.92 (1H, br s, NH), 7.71 (1H, d, J 1.4, 6-H), 7.41-7.28 (10H, m, Bn), 6.57 (1H, d, J 7.8, 1′-H), 5.99-5.61 (4H, m, 2′-H, 1″-H and 2″-Ha, 2″-Hb), 4.86-4.50 (4H, m, Bn), 4.37 (1H, dd, J 1.5, 2.4, 4′-H), 8.82 (1H, dd, J 2.6, 11.0, 5′-Ha), 3.55 (1H, dd, J 1.2, 11.0, 5′-Hb), 3.02 (3H, s, CH3), 1.47 (3H, d, J 1.1, CH3). δC (CDCl3) 163.7 (C-4), 151.5 (C-2), 138.7, 136.7 (Bn), 135.7 (C-6), 130.9 (C-1″), 128.8, 128.5, 128.4, 127.6, 127.0 (Bn), 121.8 (C-2″), 111.9 (C-5), 85.1 (C-1′), 84.5 (C-3′), 84.0 (C-4′), 80.7 (C-2′), 73.7 (C-5′), 69.2, 67.7 (Bn), 38.9 (CH3), 11.8 (CH3).
Reaction SMILES: CS(O[CH2:6][C:7]1([C:10]#[N:11])[CH2:9][CH2:8]1)(=O)=O.CN(C=O)C.[CH2:17]([N:24]1[CH:29]=[C:28]([CH3:30])[C:27](=[O:31])[NH:26][C:25]1=[O:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+]>O.[Cl-].[NH4+]>[CH2:17]([N:24]1[CH:29]=[C:28]([CH3:30])[C:27](=[O:31])[N:26]([CH2:6][C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[C:25]1=[O:32])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)OCC1(C#N)CC1
Reactant: Cc1cn(Cc2ccccc2)c(=O)[nH]c1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(Cc2ccccc2)c(=O)n(CC2(C#N)CC2)c1=O

Procedure:
A mixture of the 1-cyanocycloprop-1-ylmethyl methanesulfonate and DMF (78 mL) was added to a mixture of 1-benzyl-5-methyl-2,4(1H,3H)-pyrimidinedione (9.1 g, 42.2 mmol), 60% sodium hydride (1.95 g, 48.8 mmol) and DMF (117 mL) at 0° to 5° C. The mixture was heated 20 hours at 45° to 55° C., then diluted with water (20 mL) and saturated ammonium chloride (20 mL) and extracted with ethyl acetate. The extract was washed with water and then brine, dried (MgSO4) and concentrated to dryness. The residue was purified by flash chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to give 1-benzyl-3-(1-cyanocycloprop-1-ylmethyl)-5-methyl-2,4(1H,3H)-pyrimidinedione (10.4 g, 35.2 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>[Fe].C(O)C>[NH2:10][C:4]1[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Cn1cc(Br)cc([N+](=O)[O-])c1=O
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1cc(Br)cc(N)c1=O
Temperature: 60 °C
Yield: 77 %

Procedure:
A 1-L three-neck round-bottomed flask equipped with a mechanical stirrer and reflux condenser was purged with nitrogen and charged with 41 (21.7 g, 93.3 mmol), ethanol (305 mL), iron powder (−325 mesh, 52.1 g, 933 mmol) and 2N hydrochloric acid (50 mL, 100 mmol), and the mixture was heated for 2 h at 60° C. After this time, the reaction was cooled to room temperature, and potassium carbonate was added to pH 8 as determined by a pH paper. The resulting suspension was filtered and the filter cake washed with ethanol (4×100 mL). The filtrate was concentrated under reduced pressure to yield a brown solid. This solid was purified by column chromatography on silica gel to afford 42 in 77% yield (14.5 g) as an off-white powder: mp 104-105° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.15 (d, 1H, J=2.5 Hz), 6.46 (d, 1H, J=2.5 Hz), 5.45 (bs, 2H), 3.40 (s, 3H); MS (ESI+) m/z 203 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][C:17](=[O:37])[CH2:18][O:19][C:20]1[C:25]([C:26](=[O:28])[CH3:27])=[CH:24][CH:23]=[C:22]([O:29][CH2:30][CH2:31][CH2:32]Br)[C:21]=1[CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:15][O:16][C:17](=[O:37])[CH2:18][O:19][C:20]1[C:25]([C:26](=[O:28])[CH3:27])=[CH:24][CH:23]=[C:22]([O:29][CH2:30][CH2:31][CH2:32][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:21]=1[CH2:34][CH2:35][CH3:36]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1OCC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc(C(C)=O)c(OCC(=O)OC)c2CCC)ccc(C(C)=O)c1O
Yield: 32.7 %

Procedure:
A mixture of 1.72 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 3.43 g of [6-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl ester, 2.44 g of anhydrous potassium carbonate in 50 ml of anhydrous acetone and 25 ml of anhydrous dimethylformamide was stirred at reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by high pressure liquid chromatography to give 1.45 g (33%) of [6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid methyl ester as an oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([OH:53])=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH:54]([C:56](=[O:69])[CH2:57][CH:58]1[CH2:61][N:60]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:59]1)[NH2:55]>C(Cl)Cl>[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([NH:55][NH:54][C:56](=[O:69])[CH2:57][CH:58]1[CH2:61][N:60]([C:62]([O:64][C:65]([CH3:67])([CH3:66])[CH3:68])=[O:63])[CH2:59]1)=[O:53])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)NN)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
HATU (19.6 g, 52.2 mmol) and DIPEA (16.6 g, 130.5 mmol) were added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (12.0 g, 43.5 mmol), tert-butyl 3-(2-hydrazinyl-2-oxoethyl)azetidine-1-carboxylate (11.3 g, 49.8 mmol) in CH2Cl2 (360 mL). The mixture was allowed to warm to rt then the mixture was stirred at rt for 12 hrs. The mixture was then diluted with CH2Cl2 (300 mL), washed with water (2×) and saturated sodium chloride (2×), dried and concentrated. The residue was purified by silica gel column chromatography (0-20% gradient elution EtOAc/petroleum ether) to afford tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)azetidine-1-carboxylate (19.3 g, 93%) as a white solid. ESI-MS (EI+, m/z): 488 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11]>C(O)C.CCOC(C)=O.O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:2][CH3:1])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CNS(=O)(=O)c1ccccc1F
Temperature: 0 °C
Yield: 93.4 %

Procedure:
A RBF was charged with methylamine (0.5 mL, 40%, 14 mmol) in ethanol (2 mL). The mixture was chilled to 0° C. in an ice bath while being stirred under an inert atmosphere. 2-Fluorobenzenesulfonyl chloride (0.6 mL, 3 mmol) was added dropwise into the mixture. The resulting mixture was allowed to stir at 0° C. for 30 minutes. The mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc three times, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 2-fluoro-N-methylbenzenesulfonamide (0.530 g, 99% yield) as a colorless oil. MS (ESI pos. ion) m/z: 190 (MH+). Calculated exact mass for C7H8FNO2S: 189.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][N:23]=1)[C:15](N(OC)C)=[O:16].C1([Mg]Cl)C=CC=CC=1.Cl.[OH-].[Na+]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:21]=[CH:22][N:23]=1
Reactant: CON(C)C(=O)c1ccnc(Br)c1
Reactant: Cl[Mg]CCc1ccccc1
Agent: Cl
Agent: Cl[Mg]c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)c1ccnc(Br)c1
Temperature: 25 °C

Procedure:
1.0 mL of 1.0 N phenyethylmagnesium chloride in THF was added dropwise to a −78° C. solution of 200 mg of 2-bromo-N-methoxy-N-methylisonicotinamide in 6 mL of THF. The solution was allowed to warm to 25° C. After 10 minutes the solution was cooled back to −78° C. and an additional 1.0 mL of 1.0 N phenylmagnesium chloride in THF was added. The mixture was warmed to 25° C. and after 10 minutes 10 mL of 1.0 N hydrochloric acid was added. The solution was then made basic with excess aqueous sodium hydroxide solution and the mixture was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate and the combined organic extracts were dried over sodium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel to give 168 mg of product.
Reaction SMILES: [F:1][CH:2]1[CH:7]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=3[NH:10][C:9]2=[O:21])[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([C:29]([C:31]2[CH:41]=[C:40]([CH3:42])[C:34]3[N:35]([CH3:39])[C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:24]=1.CO>CN(C=O)C>[CH3:39][N:35]1[C:34]2[C:40]([CH3:42])=[CH:41][C:31]([C:29]([C:25]3[N:26]=[CH:27][N:28]=[C:23]([N:4]4[CH2:5][CH2:6][CH:7]([N:8]5[CH2:14][CH2:13][C:12]6[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=6[NH:10][C:9]5=[O:21])[CH:2]([F:1])[CH2:3]4)[CH:24]=3)=[O:30])=[CH:32][C:33]=2[O:37][C:36]1=[O:38]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1F)C(=O)N2
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1F)C(=O)N2

Procedure:
60 mg (0.21 mmol) 3-(3-fluoro-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one, 60 mg (0.20 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.040 mL (0.30 mmol) TEA were stirred overnight in 1 mL DMF at RT. The reaction mixture was combined with 2 mL MeOH and the precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried.
Reaction SMILES: [CH3:1][C:2]12[CH2:25][CH:6]([N:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18]4)=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:27])([CH3:26])[CH2:3]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>C1COCC1>[N:58]1([C:22]([CH:19]2[CH2:20][CH2:21][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:9]([N:7]4[CH2:27][C:4]5([CH3:26])[CH2:5][CH:6]4[CH2:25][C:2]([CH3:1])([CH3:8])[CH2:3]5)=[O:10])=[CH:16][CH:15]=3)[CH2:18]2)=[O:23])[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N3CCC(C(=O)O)C3)cc2)C1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N3CCC(C(=O)N4CCOCC4)C3)cc2)C1
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
To a mixture of 1-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-pyrrolidine-3-carboxylic acid (300 mg, 0.81 mmol, prepared as described in ex-ample 1) and HOBT (131 mg, 0.97 mmol) in dry THF (20 ml) was added EDAC (186 mg, 0.97 mmol). The resulting mixture was stirred for 10 min followed by addition of a mixture of DIPEA (219 μl, 1.22 mmol) and morpholine (85 μl, 0.97 mmol). The reaction mixture was stirred for an additional 16 hrs. and evaporated to dryness. The resulting residue was purified by preparative HPLC (Gilson) and pure fractions were collected and evaporated to dryness and dried in vacuo at 50° C. affording 250 mg (70%) of the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([OH:22])=[O:21]>O1CCCC1>[CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([O-:22])=[O:21]
Reactant: O=CO
Agent: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Solvent: C1CCOC1
Product: O=C[O-]
Temperature: 50 °C

Procedure:
To a stirred solution of O-desmethylvenlafaxine (13.17 g, 0.050 mol.) in tetrahydrofuran (300 mL) at 62–65° C., under a nitrogen atmosphere, was added 96 wt % formic acid (2.20 mL, d=1.22, 0.056 mol., 1.2 molar excess) in tetrahydrofuran (30 mL) dropwise over a period of 2 minutes, while maintaining the temperature in the range 62° C.–64° C. The solution was filtered through a pad of Celite filter aid (prewashed with tetrahydrofuran) and the filter pad was washed with hot (60–65° C.) tetrahydrofuran (2×20 mL). The filtrate and washings (temperature ˜35° C.) were warmed to 50° C. under a nitrogen atmosphere and allowed to cool. At 48° C. the stirred solution was seeded with crystals of O-desmethylvenlafaxine formate. Crystallization ensued immediately. When the slurry of crystals had cooled to 22° C. it was chilled to −5° C. to −10° C. The crystals were collected on a filter and washed with chilled (−5 to −10° C.) tetrahydrofuran (2×30 mL). After drying in a vacuum oven at room temperature under oil pump vacuum for 23 hours the product, O-desmethylvenlafaxine formate, weighed 13.79 g, (89% yield) and it had mp=149–150° C. It was characterized by DSC (sharp endotherm at 151.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH:16]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)=[O:14])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH+:15]([O-:32])[CH:16]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)=[O:14])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: O=C1COc2c(cc(Cl)cc2C(=O)NC2CN3CCC2CC3)N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C1COc2c(cc(Cl)cc2C(=O)[NH+]([O-])C2CN3CCC2CC3)N1
Reaction time: 0.5 h

Procedure:
To a solution of 4.8 g of 6-chloro-3,4-dihydro-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide in 150 ml of chloroform is added portionwise 3.7 g of metachloroperbenzoic acid under cooling and stirring. After 0.5 hour, ammonia gas is bubbled through the reaction solution under stirring and the precipitate is filtered off. The mother liquor is distilled off under reduced pressure followed by recrystallizing the residue from ethanol-isopropyl ether to give 6-chloro-3,4-dihydro-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide N-oxide.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]2)[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1
Reactant: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1cnc(Cl)nc1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C#N)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)methanone and 2-chloropyrimidine-5-carbonitrile. ESI-MS (m/z): 430 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:20]=[C:19]([C:21](OCC)=[O:22])[S:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:20]=[C:19]([CH2:21][OH:22])[S:18][N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2OCc2ccccc2)ns1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1nc(-c2ccc(Cl)cc2OCc2ccccc2)ns1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of ethyl 3-(2-(benzyloxy)-4-chlorophenyl)-1,2,4-thiadiazole-5-carboxylate (0.45 g, 1.20 mmol) in EtOH (25 ml) was added sodium borohydride (0.113 g, 3.0 mmol) portion wise. The resulting reaction mixture was stirred at room temperature for 2 h. After the completion of the reaction (TLC monitoring), the reaction mass was cooled to 0° C., quenched it with 2 ml of water and concentrated under vacuum. Added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum to get the desired product (0.35 g, 88%) that was carried forward to the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[Na+].CN(C)CCN.O>CS(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1Br
Reactant: O=S([O-])c1ccc(Br)cc1
Agent: CN(C)CCN
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccccc1S(=O)(=O)c1ccc(Br)cc1
Temperature: 110 °C
Yield: 54.9 %

Procedure:
2-Bromobenzaldehyde (1.55 g, 8.4 mmol), sodium 4-bromophenylsulfinate (2.79 g, 10 mmol) and copper(I) trifluoromethanesulfonate benzene complex (500 mg, 1 mmol) were combined in dimethylsulfoxide (10 mL) under nitrogen and degassed. The suspension was heated to 110° C. and N,N-dimethylethylenediamine (176 mg, 2 mmol) was added. The reaction was heated until the colour became clear and pale yellow, then cooled and poured into water. The products were extracted into ethyl acetate. The organic layer was washed with water: brine (1:1, ×5), dried over MgSO4 and evaporated in vacuo. The residue was triturated with isohexane to give 2-[(4-bromophenyl)sulfonyl]benzaldehyde (1.5 g, 55%). δH (400 z, CDCl3): 10.76 (1H, s), 8.14–8.12 (1H; m), 7.98–7.96 (1H, m), 7.76–7.68 (4H, m), 7.64–7.62 (2H, m).