Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22](Cl)=[C:23]([Br:25])[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[H-].[Na+].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.C(O)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22]([O:37][C:34]4[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=4)=[C:23]([Br:25])[CH:24]=3)(=[O:17])=[O:18])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cnc(Oc2ccc(Cl)cc2)c(Br)c1
Temperature: 100 °C
Yield: 52.6 %

Procedure:
The mixture of [4-(5-Bromo-6-chloro-pyridine-3-sulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (50 mg, 0.10 mmol), sodium hydride (60% dispersed in mineral oil, 20 mg, 0.50 mmol) and 4-chlorophenol (0.4 mL, 3.79 mmol) in N,N-dimethylformamide (1.5 mL) was heated in a microwave oven at 100° C. for 15 minutes, then acidified with acetic acid to pH 5, filtered through a glass funnel and purified by preparative HPLC to afford {4-[5-bromo-6-(4-chloro-phenoxy)-pyridine-3-sulfonylamino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (30 mg, 52.6%) as a white powder. MS calcd for C22H22BrClN4O5S 548, obsd (ESI+) [(M+H)+]: 569.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:19]([O-])([OH:21])=[O:20]>CC(O)=O.CC(OC(C)=O)=O>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:11]2([C:17]#[N:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[C:6]([N+:19]([O-:21])=[O:20])[CH:7]=1
Reactant: COc1ccc(C2(C#N)CCCCC2)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(C2(C#N)CCCCC2)cc1OC
Temperature: 0 °C
Yield: 28.8 %

Procedure:
1-(3,4-Dimethoxyphenyl)cyclohexanecarbonitrile (0.736 g, 3 mmol), prepared in Step 1, was dissolved in HOAc/Ac2O 1/1 (6 mL) was cooled to 0° C. and treated slowly with nitric acid (0.582 g, 6 mmol, 65%). The reaction was left stirring in the ice bath for 10 min, poured into ice and extracted with EtOAc. Organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 5-25% EtOAc/hexane) afforded (251 mg, 29%) of 1-(4,5-dimethoxy-2-nitrophenyl)cyclohexanecarbonitrile. MS (ESI) m/z 291 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][CH2:12][N:7]2[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N[C@@H]1C(=[O:39])N2[C@H](C(OC(C)(C)C)=O)CCCN2CCC1>>[O:39]=[C:6]1[CH2:5][CH2:4][C@H:3]([NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:2](=[O:1])[N:8]2[C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][CH2:12][N:7]12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2CCC[C@H](NC(=O)CCc3ccccc3)C(=O)N12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2CCC[C@H](N)C(=O)N12
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)CCc3ccccc3)C(=O)N12

Procedure:
(1S,9S) t-Butyl octahydro-10-oxo-9-(3-phenylpropionylamino)-6H-pyridazino-[1,2-a] [1,2]diazepine-1-carboxylate (44b), was prepared from (1S,9S) t-butyl 9-amino-octahydro-10-oxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (Attwood et al., J. Chem. Soc. Perkin 1, pp. 1011-19 (1986)) as for 44a, to afford 810 mg (81%) of a colorless oil: [α]D23 −33.5° (C 0.545, CH2Cl2); IR (film) 3334, 2935, 1737, 1728, 1659, 1642; 1H NMR (CDCl3) δ 7.24 (5H, m), 6.75 (1H, d, J=6.7), 5.27 (1H, m), 4.92 (1H, m), 3.39 (1H, m), 3.03 (4H, m), 2.55 (3H, m), 2.33 (1H, m), 2.17 (1H, m), 1.80 (5H, m), 1.47 (9H, s), 1.39 (1H, m). MS(FAB, m/z): 416 (M++1), 360, 211, 143, 97.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:28]1([CH2:34][C:35]([N:37]=[C:38]=[S:39])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:38]([NH:37][C:35](=[O:36])[CH2:34][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[S:39])=[CH:20][C:19]=4[F:25])=[C:11]3[CH:10]=[N:9]2)=[CH:26][CH:27]=1
Reactant: COc1ccc(Cn2ncc3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: COc1ccc(Cn2ncc3c(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a stirred solution of 4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.504 g, 1.38 mmol; obtained from Example 1, Step D in THF (5 mL) was added 2-phenylethanoyl isothiocyanate (0.294 g, 1.66 mmol; prepared according to J. Org. Chem. 1964, 29, 1115-1119). The reaction was stirred at room temperature for 30 minutes. The reaction mixture was loaded directly onto a preparative TLC plate, eluting with 5% MeOH/DCM. The product was obtained as a waxy solid (630 mg, 71%). LRMS (APCI+): 93% purity, 220 nm, m/z 542 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 12.49 (br s, 1H), 8.50 (br s, 1H), 8.38 (d, J=5.5 Hz, 1H), 7.94 (m, 1H), 7.82 (s, 1H), 7.42 (m, 4H), 7.32 (m, 4H), 7.26 (m, 1H, overlaps CHCl3), 6.83 (d, J=8.6 Hz, 2H), 6.42 (d, J=5.5 Hz, 1H), 5.63 (s, 2H), 3.76 (s, 3H), 3.75 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −126.3 (m).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C@@H:14]([OH:20])[CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:24][C:23]([O:20][C@@H:14]1[C@@H:13]2[O:12][C:11]3=[C:10]([O:21][CH3:22])[CH:9]=[CH:8][C:7]4=[C:6]3[C@:5]32[CH2:4][CH2:3][N:2]([CH3:1])[C@H:18]([CH2:19]4)[C@@H:17]3[CH:16]=[CH:15]1)=[O:25]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc2c3c1O[C@H]1[C@@H](OC(C)=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reaction time: 12 h
Yield: 99.4 %

Procedure:
A solution of codeine (30 g, 100.2 mmol), acetic anhydride (18.4 g, 180.2 mmol), triethylamine (18.25 g, 180.2 mmol) and 4-dimethylaminopyridine (0.5 g) in dry ethyl acetate (620 ml) was stirred at rt. under nitrogen for 12 hr, added saturated aqueous sodium bicarbonate solution until no acetic anhydride detected. The organic portion was separated, in washed with water (3×120 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to give 6-acetylcodeine as white solids (34.0 g, 99% yield). IR (KBr)(v, cm-1): 1725 (st, sharp, 3-AcO); NMR (δH)(CDCl3): 6.66 (1, d, J, 8.2, 2-H), 6.53 (1, d, J, 8.2, 1-H), 5.63 (1, ddd, J, 10.0, 2.4 & 1.0, 7-H), 5.42 (1, dt, J, 9.9 & 2.3, 8-H), 5.22-5.51 (1, m, 6-H), 5.06 (dd, J, 6.7 & 1.0, 5-H), 3.85 (3, s, 3-OCH3), 3.39 (1, dd, J, 6.0 & 3.3, 9-H), 3.03 (1, d, Jjem, 18.6, 10-Hβ), 2.78 (1, dd, J, 5.2 & 2.6, 14-H), 2.63 (1, dd, J, 11.9 & 4.6, 16-Ha), 2.45 (3, s, N--CH3), 2.40 (1, td, J, 12.0 & 3.8, 16-He), 2.33 (1, dd, J, 18.5 & 6.0, 10-Hα), 2.15 (3, s, 6-OAc), 2.06 (1, td, J, 12.0 & 5.0, 15-Ha) and 1.85 (1, dm, J, 12.0, 15-He).
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.CCCCCCC.S(=O)(=O)(O)O.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>C(O)C>[C:5]12([C:32]3[CH:33]=[C:28]([Br:27])[CH:29]=[CH:30][C:31]=3[OH:34])[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][CH:7]([CH2:13]3)[CH2:6]1)[CH2:14]2
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Reactant: Oc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: CCO
Product: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 20 °C

Procedure:
In a 100 ml three-necked flask, and under a nitrogen environment, is placed 1 g of 1-acetoxyadamantane and 10 ml of n-heptane. After total dissolution, 0.25 g of concentrated sulfuric acid is added drop by drop while keeping the temperature at 20° C., then 0.886 g of 4bromophenol is poured in slowly. After leaving 24 hours in vigorous agitation, 20 ml of denatured ethanol are added while maintaining the temperature at 20° C. Next, the solvent is evaporated to dryness under reduced pressure and a whitish raw product is obtained. The product is redissolved in water at approximately 60° C., it is washed to pH 6 and dried in a vacuum oven for 24 hours at 25° C. One collected 1.24 g of expected raw product (Melting point: 140°-141° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C)C=O>[CH3:39][S:40]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1)(=[O:42])=[O:41]
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCN(S(C)(=O)=O)CC4)CC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
2-Isopropyl-1H-benzoimidazole-4-carboxylic acid (1-piperidin-4-ylmethylpiperidin-4-ylmethyl)amide (40 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (1.0 mL) at room temperature. To this solution was added N,N-diisopropylethylamine (0.175 mL, 1 mmol) followed by methanesulfonyl chloride (11.5 mg, 0.1 mmol). The mixture was stirred at room temperature for 16 h, then concentrated in vacuo and the residue purified by preparative reverse-phase HPLC to afford the bis trifluoroacetate salt of the title compound as a white solid (27.2 mg, 0.04 mmol, 40%). (m/z): [M+H]+ calcd for C24H37N5O3S 476.27; found 476.2. Retention time (anal. HPLC: 2-65% MeCN/H2O over 4 min)=1.66 min.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCOc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5-bromosalicylaldehyde (5.00 g) and potassium carbonate (10.3 g) in N,N-dimethylformamide (50 ml) was added heptyl bromide (4.10 ml), and the mixture was stirred at room temperature for 1.5 hr, and further at 50° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (7.61 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:7]=2[S:8][C:9]=1[OH:10])=[O:4].C(Cl)Cl.[O:19](S(C(F)(F)F)(=O)=O)[S:20]([C:23]([F:26])([F:25])[F:24])(=O)=[O:21]>CCN(CC)CC>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:7]=2[S:8][C:9]=1[O:10][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:21])=[O:19])=[O:4]
Reactant: COC(=O)c1c(O)sc2cc(Cl)ccc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)sc2cc(Cl)ccc12
Reaction time: 1 h
Yield: 69 %

Procedure:
6-chloro-2-hydroxy-benzo[b]thiophene-3-carboxylic acid methyl ester (2.46 g, 10.1 mmol) was cooled to 0° C. in a solution of DCM (25 ml) and Et3N (25 ml). Tf2O (2.56 ml, 15.2 mmol, 1.5 equiv) was added dropwise, then stirred for 1 hr. The resulting solution was washed twice with water, saturated NaHCO3, then water, followed by drying over MgSO4. This was filtered and the solvent removed in vacuo. The crude material was purified by column chromatography leaving 2.61 g (68%) of 6-chloro-2-trifluoromethanesulfonyloxy-benzo[b]thiophene-3-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1([S:18]([N:21]2[CH2:24][C:23](=O)[CH2:22]2)(=[O:20])=[O:19])[CH2:17][CH2:16]1.[Na+].[Cl-]>O1CCCC1.O>[CH3:14][C:15]1([S:18]([N:21]2[CH2:24][C:23](=[CH:5][C:3]#[N:4])[CH2:22]2)(=[O:19])=[O:20])[CH2:17][CH2:16]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC1(S(=O)(=O)N2CC(=O)C2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(S(=O)(=O)N2CC(=CC#N)C2)CC1
Reaction time: 0.75 h
Yield: 100 %

Procedure:
To a mixture of sodium hydride (60% dispersion in mineral oil, 17 mg, 0.42 mmol) in tetrahydrofuran (2 mL) at 0° C. was added diethyl cyanomethylphosphonate (70 μL, 0.43 mmol) dropwise. The mixture was then allowed to reach room temperature and stir for a further 45 minutes. A solution of 1-[(1-methylcyclopropyl)sulfonyl]azetidin-3-one (prepared in Step 5) in tetrahydrofuran (1.0 mL) was added and the mixture was allowed to stir at ambient temperature for 16 hours. Into the reaction was added water and solid NaCl, and the product was extracted with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted and concentrated to afford product (71 mg, 100%), used without further purification in Step 7.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7](OC)(=O)[CH:8](C)[OH:9]>>[C:8]([O:3][CH:2]([CH3:4])[C:1]([OH:6])=[O:5])(=[O:9])[CH3:7]
Reactant: COC(=O)C(C)O
Reactant: CC(O)C(=O)O
Product: CC(=O)OC(C)C(=O)O
Yield: 90 %

Procedure:
In an independent experiment, a molar equivalent of lactic acid was utilized as a starting reagent in place of methyl lactate. The lactic acid reagent utilized was an aqueous solution containing approximately 85% lactic acid, by weight. The reaction conditions were otherwise as indicated above. NMR analysis of the resulting product material indicated a 2-acetoxy propionic acid product yield of greater than about 90% with some dimer or polymer byproduct formation apparent.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([F:22])[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([C:2]2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=2)[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2cc(F)cc(F)c2)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B25 from 2-Iodo-5-methanesulfonyl-benzoic acid (example B19(b)) and 3,5-difluoro-benzeneboronic acid. Light brown solid. MS (m/e): 311.1 ([M−H], 100%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][N:20]([CH3:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([N:20]([CH3:35])[CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(N(C)C)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[CH2:19][NH2:20]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=2)[CH3:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(CC(C)=O)c(OC)c1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)c(OC)c1

Procedure:
The title compound was prepared as in Example 1b from 1-(4-carbomethoxy-2-methoxyphenyl)propan-2-one (3.0 g) and 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (2.77 g). The compound crystallised from hexane m.p. 88°-100° as a 70:30 mixture of diastereoisomers. τ(CDCl3) 8.8 (3H,d,J=6 Hz), 6.7-7.7 (5H,m,+2H replaceable by D2O), 6.1 (3H,s), 6.0 (3H,s), 5.2 (1H, m), 2.8 (2H,d,J=8 Hz), 2.2-2.6 (6H,m).
Reaction SMILES: CO[C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][O:6][Si](C(C)(C)C)(C)C.[C:17](#[N:19])[CH3:18].[H-].[Na+]>C1(C)C=CC=CC=1.Cl>[OH:6][CH2:5][C:4]([CH3:14])([CH3:15])[C:3](=[O:16])[CH2:18][C:17]#[N:19]
Reactant: CC#N
Reactant: COC(=O)C(C)(C)CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(CO)C(=O)CC#N
Temperature: 110 °C
Yield: 90.7 %

Procedure:
A solution of 9.22 g of 3-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-propionic acid methyl ester and acetonitrile (2.34 mL, 44.88 mmol) in toluene (25 mL) is added dropwise over 1 h at reflux to a suspension of 1.80 g (44.88 mmol) NaH (60% dispersion in mineral oil) in anhydrous toluene (50 mL). The reaction mixture is heated to 110° C. for 18 h. The reaction mixture is diluted with 1M aqueous HCl solution to pH 7 and extracted with ethyl acetate (3×200 mL). The organic layers are combined, washed with water and brine, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to afford 4.79 g of 5-hydroxy-4,4-dimethyl-3-oxo-pentanenitrile as a dark biphasic oil which is used crude in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17 (s, 6H), 3.55 (s, 2H), 3.61 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[N:5]=[C:4]([N:23]([CH3:25])[CH3:24])[N:3]=1.[OH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:22][O:21][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([N:23]([CH3:25])[CH3:24])[N:3]=[C:2]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:34])([F:35])[F:36])[N:7]=2)[CH:14]=[CH:13][C:12]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1
Reactant: COc1cc(Nc2nc(Cl)nc(N(C)C)n2)ccc1-n1cnc(C)c1
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(Nc2nc(Oc3ccccc3C(F)(F)F)nc(N(C)C)n2)ccc1-n1cnc(C)c1
Yield: 15.4 %

Procedure:
6-Chloro-N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′,N′-dimethyl-[1,3,5]triazine-2,4-diamine (200 mg, 0.56 mmol) in 7 ml acetonitrile was treated with 2-hydroxy-benzotrifluoride (95 mg, 0.59 mmol) and potassium carbonate (85 mg, 0.62 mmol). The resulting mixture was stirred under reflux for 5 days. The mixture was then diluted with 25 ml of water and extracted with ethyl acetate. Chromatography on silica gel using ethyl acetate as a solvent and subsequent crystallization from methanol gave the title compound as colorless solid (42 mg, 16%).
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].[CH3:16][NH:17][CH2:18][C@@H:19]([C@H:21]([C@@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])[OH:22])[OH:20].O>C1(C)C=CC=CC=1>[CH3:16][NH:17][CH2:18][C@@H:19]([C@H:21]([C@@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])[OH:22])[OH:20].[OH:3][C:2]([C@H:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
Racemic ibuprofen (18.03 g, 87.4 mmol), N-methyl-D-glucamine (8.2 g, 42 mmol), water (0.5 mL), and toluene (150 mL) were heated to 50° C., forming a clear solution. The solution was cooled to 20° C., then in an ice bath, and allowed to stand for 48 hours. The resulting crystalline precipitate was recovered by filtration at 20° C., washed with toluene (30 mL), and dried to give (S)-ibuprofen N-methyl-D-glucamine salt (11.9 g, 68% yield, 92% ee).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:16]3[C:15]4[CH2:17][NH:18][CH2:19][CH2:20][C:14]=4[NH:13][C:12]=3[N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>ClCCCl>[C:1]1([NH:7][C:8]2[C:16]3[C:15]4[CH2:17][N:18]([C:21](=[O:23])[CH3:22])[CH2:19][CH2:20][C:14]=4[NH:13][C:12]=3[N:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccccc4)c3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
Phenyl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (40 mg, 0.15 mmol), acetic anhydride (18 mg, 0.18 mmol), and triethylamine (0.06 mL, 0.45 mmol) were dissolved in 1,2-dichloroethane (2.0 mL), and stirred overnight at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with CH2Cl2/MeOH (9/1, v/v) to provide 8 (5 mg, 11% yield) as a tan solid. LC-MS (M+H=307, obsd.=307).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:20])[C:11](=[C:15]3[S:19][CH:18]=[CH:17][S:16]3)[C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:20])[C:11](=[C:15]3[S:19][CH:18]=[CH:17][S:16]3)[C:12]([NH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)CN
Reactant: O=C(O)C(C(=O)c1ccc2c(c1)OCO2)=C1SC=CS1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)C(C(=O)c1ccc2c(c1)OCO2)=C1SC=CS1
Reaction time: 3 h
Yield: 20.9 %

Procedure:
Dissolved in 15.0 ml of N,N-dimethylformamide were 959 mg of 3-(1,3-benzodioxol-5-yl)-2-(1,3-dithiol-2-ylidene)-3-oxopropionic acid and 997 μl of triethylamine, followed by the addition of 469 mg of methyl glycinate hydrochloride. The reaction mixture was ice-cooled, to which 737 μl of diphenylphosphoryl azide were added. The resulting mixture was stirred for 3 hours and, while allowing its temperature to rise to room temperature, was stirred overnight. The reaction mixture was extracted with ethyl acetate. The resulting organic layer was washed with water, shaken together with a saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The solvent was distilled off, whereby crude oil was obtained. The oil was purified by column chromatography (silica gel: "Fuji Davidson BW-300", column: 35 mm across×190 mm long, N2 pressure: 0.3 kg/cm2, developer: ethyl acetate:n-hexane=3:2) and then recrystallized from a mixed solvent of ethyl acetate and n-hexane, whereby 247 mg of methyl N-[3-(1,3-benzodioxol-5-yl)-2-(1,3-dithiol-2-ylidene)-3-oxopropionyl]glycinate were obtained as yellow crystals (yield: 21.6%).