Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10](=O)[C:11](=[O:13])[NH:12][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl.O>CCOC(C)=O>[O:13]=[C:11]1[NH:12][C:7]2[CH:6]=[CH:5][C:4]3[NH:3][N:2]=[CH:1][C:9]=3[C:8]=2[C:10]1=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccc3[nH]ncc3c2C1=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4[nH]ncc4c32)cc1
Yield: 8 %

Procedure:
The title compound was prepared from 3,6-dihydro-pyrrolo[3,2-e]indazole-7,8-dione (Cuny, et al., Chemie Berichte 1981, 114, 1624-35) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 8% yield: 1H NMR (DMSO-d6): δ 7.02 (d, J=8.7 Hz, 1H), 7.28 Z (s, 2H), 7.51 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.7 Hz, 2H), 8.34 (s, 1H), 10.98 (s, 1H), 12.90 (s, 1H), 13.20 (s, 1H); APCI−MS m/z 356 (M)−. Anal. Calcd for C15H12N6O3S.1.46 H2O.0.2 EtOAc: C, 47.41, H, 4.16; N, 20.99; S, 8.01. Found C, 47.40, H, 3.70; N, 21.00; S, 7.85.
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1>C(#N)C>[CH3:11][C@H:1]1[CH2:2][C@@H:3]([OH:10])[C@H:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6]1
Reactant: CC1CCC(C(C)C)C(O)C1
Solvent: CC#N
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Temperature: 30 °C
Yield: 72.4 %

Procedure:
50 ml of acetonitrile was added to 16.3 g of crude menthol (chemical purity of (L)-menthol: 95%; optical purity: 97.3% e.e.), and the mixture was warmed to 30° C. to dissolve. This solution was cooled to 5° C., and crystals precipitated were collected by filtration and distilled to obtain 11.8 g (yield: 72%) of purified (L)-menthol. Chemical purity: >99%; optical purity: 99.6% e.e.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:8][CH:9]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(OC(F)(F)F)cc1

Procedure:
4-(trifluoromethoxy)phenol (1.36 ml, 10.6 mmol), 2-fluoro-1-nitrobenzene (0.74 ml, 7 mmol), potassium carbonate (1.46 g, 10.5 mmol) were mixed together in DMF (4 ml) and heated at reflux for 5 h. Allowed to cool and evaporated in-vacuo. Residue partitioned between diethyl ether and sodium hydroxide (1 M). Organic layers combined and dried over anhydrous magnesium sulphate and evaporated in-vacuo, 2.34 g, >100%. Rf: 0.72 (DCM), 1HNMR (CDCl3, 270 MHz) δ 7.03 (3H, m, Ar HD, Ar HF), 7.20 (2H, dd, J=0.9, 10.1 Hz, Ar HE), 7.23 (1H, m, Ar HB), 7.53 (1H, m, Ar HC), 7.97 (1H, dd, J=1.5, 8.2 Hz, Ar HA).
Reaction SMILES: S(=O)(=O)(O)O.[K].[CH2:7]([O:9][C:10](=[O:15])[CH:11](Cl)[CH:12]=O)[CH3:8].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1>C(O)C.C(=O)(O)[O-].[Na+]>[CH2:7]([O:9][C:10]([C:11]1[N:18]2[CH:19]=[C:20]([Br:23])[CH:21]=[CH:22][C:17]2=[N:16][CH:12]=1)=[O:15])[CH3:8]
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(Br)cn12
Yield: 54.6 %

Procedure:
Add concentrated sulfuric acid (0.56 g, 5.78 mmol) to a suspension of 2-chloro-3-oxo-propionic acid ethyl ester potassium salt (Tetrahedron 2000, 58(40), 7915-7921; 3.27 g, 17.3 mmol) and 2-amino-5-bromopyridine (1.0 g, 5.78 mmol) in ethanol (100 mL). Reflux for 2 h, cool, and carefully dilute with saturated aqueous sodium bicarbonate. Extract in ethyl acetate, combine organic extracts, and concentrate. Flash chromatography using appropriate ethyl acetate/methanol mixtures gives 0.85 g (55%) of the subtitled compound as a white solid. MS ES+m/e 269.0, 271.0 (M+1) bromine isotope. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (m, 1H), 8.28 (s, 1H), 7.79 (d, J=10 Hz, 1H), 7.70 (dd, J=10, 2 Hz, 1H), 4.36 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:12]Br.CCOCC>O>[Br:12][C:5]1[N:4]=[C:3]([C:8]([O:10][CH3:11])=[O:9])[C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: BrBr
Reactant: COC(=O)c1ncccc1O
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1nc(Br)ccc1O
Yield: 70.7 %

Procedure:
To a mechanically stirred solution of methyl 3-hydroxypicolinate (30.6 g) in water (800 mL) was slowly added bromine (32 g) over a 30 minute period. After the addition was complete, stirring was continued for an additional hour. Ether (300 mL) was added and stirring continued until all the solids had dissolved. The organic layer was separated and the aqueous phase extracted with ether (200 mL). The organic phases were combined, dried (MgSO4) and the solvent evaporated to give 32.8 g of methyl 6-bromo-3-hydroxypicolinate as an off-white solid. Recrystallization from methanol/water gave an analytical sample, m.p. 115-117° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:35][C:19]3=[N:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=4[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=[C:18]3[CH:17]=2)=[CH:12][CH:11]=1>[Al].ClC(Cl)C.CCOC(C)=O>[Br:8][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=2)[O:35][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reaction time: 8 h

Procedure:
The reaction flask was wrapped in aluminum foil. NBS (175 mg, 0.983 mmol) was added to a stirring solution of methyl 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (289 mg, 0.800 mmol) in dichloroethane (8 mL) at room temperature. It was allowed to stir overnight. The mixture was diluted with EtOAc and quenched with 10% sodium metabisulfate and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) the expected product consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (1H, d, J=2.01 Hz), 8.16-8.26 (2H, m), 8.06 (1H, d, J=2.26 Hz), 7.95 (1H, dd, J=8.03, 1.76 Hz), 7.87 (1H, d), 7.45-7.57 (3 H, m), 3.86 (3H, s), 2.34 (3H, s). LC-MS retention time: 2.85 min; m/z (MH+): 440, 442. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:5]1(=[O:7])=[O:6].[CH3:16][O:17][C:18](=[O:21])[CH2:19]Cl.Cl>CS(C)=O>[OH:15][C:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:5](=[O:7])(=[O:6])[N:4]([CH3:3])[C:19]=1[C:18]([O:17][CH3:16])=[O:21]
Reactant: COC(=O)CCl
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reaction time: 2 h

Procedure:
In a manner similar to Example 6, 864 mg. (0.036 mole) of 99% sodium hydride was added over a two hour period to a solution of 2.9 g. (0.015 mole) of N-methylsaccharin and 9.8 g. (0.09 mole) of methylchloroacetate in 10 ml. of dimethylsulfoxide at 40° C. Stirring was continued at 40°-45° C. for an additional two hours, and the reaction mixture was poured into 150 ml. of 5% hydrochloric acid solution. The precipitate was filtered and dried to give 3.07 (76%) of the desired product.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[Br:13][O-].[Na+].BrBr.Cl>O>[Br:13][C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([OH:1])=[N:10][CH:9]=1
Reactant: [O-]Br
Reactant: O=C(O)c1cccnc1O
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)cnc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.5 %

Procedure:
To a solution of 10 g (0.07 mole) of 2-hydroxy-nicotinic acid in 16.8 g of 50% sodium hydroxide (0.21 mole) diluted with 25 ml of water was added 200 ml of sodium hypobromite solution prepared by adding 13.6 g (0.17 mole) of bromine to a solution of 20.16 g of 50% sodium hydroxide (0.25 mole) in 125 ml of water at 0° C. diluted to 400 ml. After 24 hrs of stirring at room temperature, another 100 ml portion of the above sodium hypobromite solution was added and the reaction solution was stirred for another 24 hr. The reaction solution was cooled in an ice bath and acidified carefully with 12N hydrochloric acid. Crystallization from isopropyl alcohol gave 9.7 g (63.5%) of product. A sample was further recrystallized from 95% ethanol, m.p. 245° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CN(C)[C:15](=[O:17])[CH3:16]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)N(C)C
Reactant: Cc1ccccn1
Agent: [Li]CCCC
Product: CC(=O)Cc1ccccn1

Procedure:
This was prepared from 2-methylpyridine, butyllithium and N,N-dimethylacetamide according to the procedure of R. Cassity, L. T. Taylor and J. F. Wolfe, J. Org. Chem., 43(11), 2286, (1986).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:36](O)[C@@H:35]([CH2:47][O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[C@@H]1[C@@H](OCC2C=CC=CC=2)[C@@H](OC(F)(F)F)[C@@H](C(=S(=O)=O)OCC2C=CC=CC=2)O[C@@H]1OC)C1C=CC=CC=1>C(Cl)Cl>[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@@H:36]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[C@@H:35]([CH2:47][O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CO[C@H]1O[C@H](C(OCc2ccccc2)=S(=O)=O)[C@H](OC(F)(F)F)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OS(=O)(=O)C(F)(F)F)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of dry pyridine (0.46 ml) in methylene chloride (17.5 ml) cooled to -15° C. is added trifluoromethane sulfonic anhydride (0.87 ml). The mixture is stirred during 15 min at -10° C., then methyl 2,3,6-tri-O-benzyl-α-D-galacto-pyranoside (1.2 g, 2.58 mmol) in methylene chloride (5 ml) is added (N. Morishima, S. Koto, M. Oshima, A. Sugimoto and S. Zen, Bull. Chem. Soc. Jpn., 56, 2849 (1983)). The mixture is washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure so as to afford an oil which is the expected trillate methyl 2,3,6-tri-O-benzyl-4-O-trifluoromethyl-sulfonyl-α-D-galactopyranoside.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][OH:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].[CH2:19](Br)[C:20]#[CH:21]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl>[CH2:21]([O:16][CH2:15][CH2:14][N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1)[C:20]#[CH:19]
Reactant: OCCn1cnc2cnc3ccccc3c21
Reactant: C#CCBr
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOCCn1cnc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
2-(1H-Imidazo[4,5-c]quinolin-1-yl)-1-ethanol (28.5 g, 0.133 mol) was added in portions over a period of 1 hour to a mixture of sodium hydroxide (240 mL of 50%), dichloromethane (240 mL), propargyl bromide (39.6 g of 80%, 0.266 mol) and benzyltrimethylammonium chloride (2.46 g, 0.013 mmol). The resulting reaction mixture was allowed to stir at ambient temperature for 16 hours. The layers were separated. The aqueous fraction was extracted with additional dichloromethane. The organic fractions were combined, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was combined with diethyl ether and the mixture was allowed to stir. An orange solid was isolated by filtration. This material was recrystallized from ethyl acetate to provide 19.8 g of 2-(1H-imidazo[4,5-c]quinolin-1-yl)ethyl (2-propynyl) ether as a yellow crystalline solid, m.p. 124-126° C.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Br:12]Br.O>C(O)(=O)C>[Br:12][C:10]1[C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=[C:3]([CH:11]=1)[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C=O)cc(Br)c1O
Reaction time: 8 h

Procedure:
In a 250 mL round bottom flask vanillin (Aldrich, 33.3 g, 0.22 moles) was dissolved in glacial acetic acid (100 mL) with stirring. A solution of bromine (Baker, 35.0 g, 0.43 mol, 11.2 mL) in glacial acetic acid (100 mL) was added to the solution of vanillin. After 5 min a precipitate formed but the reaction was allowed to stir for an additional 15 min. The solid was collected by filtration giving 18.2 g, 35%. The filtrate was then slowly added to water (300 mL) and allowed to stand overnight. The resulting solid was filtered and dried under vacuum giving additional product (18.4 g, 35%, total yield 36.6 g, 70%), mp 159°-163° C. (lit, 163°-164° C.), 1H NMR (CDCl3) δ3.99 (s, 3H), 6.61 (bs, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.64 (d, J=1.3 Hz, 1H), 9.79 (s, 1H).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Br:12]Br.O>CO>[Br:12][C:10]1[C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=[C:3]([CH:11]=1)[CH:2]=[O:1]
Reactant: BrBr
Reactant: COc1cc(C=O)ccc1O
Solvent: O
Solvent: CO
Product: COc1cc(C=O)cc(Br)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a solution of vanillin (7.6 g, 50 mmol) in MeOH (60 mL) was added dropwise Br2 (2.8 mL, 50 mmol) over a 2 h period at 0° C. The mixture was warm to room temperature for another 1 h. Then cooling to 0° C., water (25 mL) was poured over a 20 min period and resulted in the precipitation of white solid. The mixture was stirred for further 15 min. The precipitate was filtered, washed with ice water and dried to give 10.7 g of white solid. Spectrum analysis verified the compound is 5-Br-vanillin.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[F:11].ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N>>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Agent: CC1(C)OB(c2cccc(N)c2Cl)OC1(C)C
Product: Nc1cccc(Br)c1F

Procedure:
This material was prepared from 1-bromo-2-fluoro-3-nitrobenzene, following the procedure used for SM-9, step 2 (94%): LCMS (m/z) 189.9, tR=0.74 minute; 1H NMR (300 MHz, CDCl3) δ 3.81 (br s, 2H) 6.64-6.75 (m, 1H) 6.80 (t, J=8.2 Hz, 1H) 6.84-6.95 (m, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH3:31])[CH2:27][NH:26][CH:25]([C:28]([NH2:30])=[O:29])[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C:23]([CH3:31])([CH3:22])[CH2:24][CH:25]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(C)CNC(C(N)=O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(C(N)=O)N(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 4,4-dimethyl-pyrrolidine-2-carboxylic acid amide hydrochloride (Example 90 d)) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=380.6 [MH+].
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH:9]1[C:25](=[O:37])[NH:26][C:27]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:29][CH:28]1[CH:30]=[CH2:31])=O)(C)(C)C>FC(F)(F)S(O)(=O)=O.ClCCl>[CH2:35]([O:34][C:32]([C:27]1([NH:26][C:25]([CH:9]2[NH:8][CH2:12][CH:11]([O:13][C:14](=[O:24])[C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)[CH2:10]2)=[O:37])[CH2:29][CH:28]1[CH:30]=[CH2:31])=[O:33])[CH3:36]
Reactant: C=CC1CC1(NC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1)C(=O)OCC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
Compound 133 (6.2 g, 12 mmol) was dissolved in an ice-cold mixture of trifluoro-methanesulfonic acid 33% in dichloromethane. The ice-bath was then removed and the mixture was left at room temperature for ˜1.5 h. The solvent was evaporated and 0.25 M sodium carbonate added and the mixture was extracted with dichloromethane. Evaporation gave the title compound (4.8 g, 95%) as a yellowish powder.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1.C(N(CC)CC)C.C(Cl)Cl>CN(C=O)C>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:21][C:22]3[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: Nc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(CO)cc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
A solution of 6-(cyclohexyl-cyclopropylmethyl-amino)-pyrimidine-4-carboxylic acid (Intermediate 13, 1.00 g; 3.63 mmol) in dry DMF (100 ml) was treated with polymer-supported Mukaiyama reagent, prepared as described in “S. Crosignani et al. Org. Lett. 2004, 6(24), 4579-4582” (2987 mg; 6.54 mmol), 4-aminobenzyl alcohol (Fluka, 492 mg; 3.99 mmol) and triethylamine (1.52 ml; 10.9 mmol). The reaction mixture was then stirred at room temperature for 18 hours. DCM was added and the product was filtered through an SPE column (Isolute NH2, 10g) and the column washed with DCM. The mixture was concentrated then rediluted in EtOAc. The organic phase was washed 5 times with brine, dried over MgSO4 and the solvent removed under vacuum to give the title compound (990 mg, 72%).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1>CC(N(C)C)=O>[CH:15]1([CH2:18][N:6]2[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]23)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1oc(=O)n(CC2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 20 g. isatoic anhydride in 200 ml. dimethylacetamide is added under nitrogen with stirring sodium hydride obtained from 6 g. of a 57% dispersion in mineral oil, while maintaining the temperature below 25°C. The resulting mixture is stirred at 25°C. for 1 hour and to it is added 17 g. cyclopropylmethylbromide. The mixture is then stirred at room temperature for about 20 hours. It is then poured on water. The mixture is stirred for 15 minutes, the solids collected by filtration, washed with several portions of water and then three times with 0.7 kg. of diethylether. The washed solids are dried to obtain N-(cyclopropylmethyl)isatoic anhydride, m.p. 118°-121°C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=O)=[CH:4][C:3]=2[O:2]1.S(Cl)([Cl:16])=O>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([Cl:16])=[O:13])=[CH:4][C:3]=2[O:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Product: O=C(Cl)Cc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
3,4-methylenedioxyphenyl acetic acid, 50.4 grams, 0.28 mole, was reacted with an excess amount of thionyl chloride, 58 grams, 0.49 moles, in a 250 milliliter round bottom flask at 60° C. for 3 hours. The product mixture resulting was cooled to room temperature, about 25° C., and any excess thionyl chloride was removed with a water aspirator. Pure, about 99.5 percent purity, 3,4-methylenedioxyphenylacetylchloride was isolated as a light reddish oil by vacuum distillation yielding 48.2 grams, an 80 percent yield of product. The boiling point of the aforementioned product was 116° C. at 1.4 millimeters of mercury. IR (neat): 1,795 cm-1 (C=O).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[CH:17][C:16]=1[N+:28]([O-:30])=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:15]2[C:16]([N+:28]([O-:30])=[O:29])=[CH:17][C:18]([C:24]([F:27])([F:25])[F:26])=[CH:19][C:20]=2[N+:21]([O-:23])=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2c([N+](=O)[O-])cc(C(F)(F)F)cc2[N+](=O)[O-])C1

Procedure:
deprotonating (R)-3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, and reacting the resultant compound with 2-chloro-1,3-dinitro-5-trifluoromethylbenzene to form (R)-3-(2,6-dinitro-4-trifluoromethylphenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester;
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][F:27])[CH:20]=2)[CH2:14]1)=O.B.C1COCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][F:27])[CH:20]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2cccc(OCF)c2)C1
Agent: B
Solvent: C1CCOC1
Product: FCOc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1

Procedure:
(R)-2,3-Dihydro-benzo[1,4]dioxin-2-yl-[(R*)-3-(3-fluoromethoxy-phenyl)-piperidin-1-yl]-methanone (0.13 mmol, 50 mg) was treated with BH3THF according to the above general procedure. Flash chromatography gave the title compound.