Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1.[O:13]=[C:14]1[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15]1.Cl>CCOCC.C1COCC1>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:14]2([OH:13])[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15]2)=[CH:7][CH:6]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C1CC(C(=O)O)C1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)C1CC(O)(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
In a dry flask, under argon, magnesium (1.7 g, 70.11 mmol), a crystal of I2 and just enough Et2O to cover the magnesium was heated to reflux until the purple color dissipated (ca. 10 min.). Approximately 10% of a solution of 4-chlorobenzyl chloride (11.3 g, 70.11 mmol) in Et2O (20 mL) was added all at once and reflux was continued until the solution became brown. While maintaining a gentle reflux, the remainder of the 4-chlorobenzyl chloride solution was slowly added. After the addition was complete, heating was continued for 0.5 h. The solution was cooled to room temperature and added to a solution of 3-oxocyclobutanecarboxylic acid (2 g, 17.53 mmol) in THF (30 mL) pre-cooled to 0° C. Once the addition was complete, the resulting solution was allowed to warm to room temperature with continued stirring for 16 h. The reaction mixture was then poured into a solution of ether and 1 M HCl. The layers were separated and the aqueous phase was extracted with ether (3×). The combined extracts were concentrated, dissolved in 1 M NaOH and washed with ether. The aqueous phase was re-acidified with 2 M HCl and extracted with Et2O, dried over MgSO4 and concentrated to give the subject compound as a white solid (2.5 g, 59%) of white solid. 1H NMR (CDCl3, 500 MHz) δ 7.44 (d, J=8.24 Hz, 2H), 7.35 (d, J=8.24 Hz, 2H), 3.02 (s, 2H), 2.90-2.84 (m, 1H), 2.66-2.62 (m, 2H), 2.47-2.42 (m, 2H). ESI MS found for C12H13ClO3 m/z [239.1 (M−1)].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][CH3:17])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:24]=1[N:38]1[CH2:50][CH2:49][N:41]2[C:42]3[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=3[CH:48]=[C:40]2[C:39]1=[O:51])(=[O:20])[CH3:19]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[CH:25][CH:26]=[CH:27][C:28]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][CH3:17])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:20])[CH3:19]
Reactant: CCc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1cc(Nc2cc(-c3cccc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)n[nH]1
Temperature: 125 °C
Reaction time: 0.12 h
Yield: 23.1 %

Procedure:
In a 10-mL glass vessel equipped with a magnetic stirring bar were placed 125a (116 mg, 0.39 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (200 mg, 0.43 mmol), Pd(PPh3)4 (30 mg, 0.0.26 mmol) in 2 N Na2CO3 (2 mL) and 1,2-dimethoxyethane (5 mL). The vessel was sealed with a septum and placed into the microwave cavity. After the reaction mixture was stirred at 125° C. for 7 min., it was purified by flash chromatography (dichloromethane:methanol, 85:15) to give 23% (50 mg) of 125b as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:31])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][C:24]=1[CH3:30])[CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.CCOCC>[CH2:17]([O:19][C:20](=[O:31])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][C:26]([O:16][C:11]2[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:25][C:24]=1[CH3:30])[CH3:18]
Reactant: Cc1cc(O)cc(OCc2ccccc2)c1
Reactant: CCOC(=O)C=Cc1ccc(F)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)C=Cc1ccc(Oc2cc(C)cc(OCc3ccccc3)c2)cc1C
Temperature: 130 °C
Reaction time: 20 h
Yield: 58.6 %

Procedure:
A mixture of 3-benzyloxy-5-methyl-phenol (3.24 g, 15.1 mmol), 3-(4-fluoro-2-methyl-phenyl)-acrylic acid ethyl ester (3.15 g, 15.1 mmol) and 325 mesh potassium carbonate (2.51 g, 18.2 mmol) in dry DMSO (40 mL) is heated to 130° C. and stirred for 20 hours under N2. The reaction is cooled and acidified with 1 N HCl (30 mL). The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 3.56 g (58%) of the title compound. Rf=0.39 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C26H26O4 402, found 403 (M+1, 100%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+]>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(=O)CCCCOCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ccc(CCCCCOCc2ccccc2)cc1
Reaction time: 20 h

Procedure:
To a mixture of 16 g of formula (VIII) compound obtained in the preceding example and 21 g of triethylsilane were added 30.1 ml of trifluoroacetic acid and it was left under agitation for 20 hours at room temperature. Then, it was diluted with water, basified by means of concentrated NaOH, extracted with methylene chloride, washed with water, dried on sodium sulfate, the filtrate was evaporated and the residue chromatographed on a silica column [eluent: methylene chloride (99)-methanol (1) mixture]. Thus, 14 g of the expected compound were obtained in the form of an oil (Yield: 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20](N)[CH:21]=[CH:22][CH:23]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:34]([F:37])([F:36])[F:35])=[C:30]([CH:33]=1)[CH:31]=[O:32]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:32][CH2:31][C:30]2[CH:33]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH:19]=1
Reactant: O=Cc1cc(Cl)ccc1C(F)(F)F
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: FC(F)(F)c1ccc(Cl)cc1COc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 5-chloro-2-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 525.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].CCCCCC.C([Li])CCC.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[Cl-].[NH4+]>O1CCCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([OH:34])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccccc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
2-Bromoanisole (5.0 g, 27 mmol) was dissolved in anhydrous tetrahydrofuran (60 ml) to which, while stirring, was subsequently added dropwise n-butyl lithium hexane solution (17 ml, 27 mmol) spending 20 minutes at −78° C. in an atmosphere of argon. After additional 30 minutes of stirring, to this was added dropwise anhydrous tetrahydrofuran solution (40 ml) of 1-t-butoxycarbonyl-4-piperidone (5.3 g, 27 mmol) spending 40 minutes. After additional 3.5 hours of stirring, to this was added saturated ammonium chloride aqueous solution (200 ml). The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then 5.2 g of the aforementioned compound of interest (17 mmol, 63% in yield) was obtained by evaporating the solvent under a reduced pressure.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.[CH:21]1([C:24]2[C:25]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=2)[CH2:23][CH2:22]1>>[CH:21]1([C:24]2[C:25]([N:34]3[CH2:39][CH2:38][N:37]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:20])=[CH:8][C:9]=4[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:36][CH2:35]3)=[N:26][CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=2)[CH2:22][CH2:23]1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Product: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 79.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (319 mg) described in Preparation Example 22 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine (271 mg) described in Preparation Example 90 and by the reaction and treatment in the same manner as in Example 87, the title compound (455 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=2)[CH2:4][CH2:3]1>C(O)C.[Pd]>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:9][C:10]=1[NH2:16]
Reactant: COc1ccc(N2CCN(C)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N2CCN(C)CC2)cc1N
Yield: 85.9 %

Procedure:
A solution of 1-methyl-4-[4-(methyloxy)-3-nitrophenyl]piperazine (0.25 g, 1.0 mmol) in absolute ethanol (100 mL) was hydrogenated with 10% Pd/C at 50 psi overnight. The catalyst was removed by vacuum filtration through a celite pad, rinsed with methanol, filtrate was concentrated under reduced pressure, and the crude aniline was purified by chromatography on SiO2 (dichloromethane to 10% methanol/dichloromethane with 0.1% NH4OH) to afford 2-(methyloxy)-5-(4-methyl-1-piperazinyl)aniline (0.19 g, 85%) as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.35 (s, 3 H) 2.55-2.64 (m, 4 H) 3.06-3.13 (m, 4 H) 3.78 (s, 3 H) 6.29 (dd, J=8.61, 2.75 Hz, 1 H) 6.38 (d, J=2.75 Hz, 1 H) 6.69 (d, J=8.61 Hz, 1 H). ESIMS (M+H)+=222.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:13]2[C:14](=[O:19])[O:15][C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[CH:10][CH:9]=1.S(OC)(OC)(=O)=O>CS(C)=O>[CH3:1][N:17]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([Cl:7])[C:13]=2[C:14](=[O:19])[O:15][C:16]1=[O:18]
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CS(C)=O
Product: Cn1c(=O)oc(=O)c2c(Cl)cccc21
Reaction time: 0.2 h

Procedure:
Anhydrous potassium carbonate (16.8 g.) was added gradually to a suspension of the known compound 1,2-dihydro-5-chloro-2,4-dioxo-3,1-(4H)-benzoxazine (11.7 g.) in dry dimethyl sulphoxide (110 ml.) and the mixture stirred at room temperature for 20 minutes Dimethyl sulphate (7 ml.) was added dropwise with vigorous stirring at 30°-35° for 12 minutes and the mixture allowed to settle. The supernatant liquid was decanted into an ice/dilute hydrochloric acid mixture (600 ml.; 0.05 M.HCl). The resulting precipitate was collected, washed with water and dried in vacuo to give 1,2-dihydro-1-methyl-5-chloro-2,4-dioxo-3,1-(4H)-benzoxazine m.p. 199°-201° (dec.).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9]>N1C=CC=CC=1>[C:2]([C:1]([O:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1)=[O:6])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
161.1 mmol (19.48 g) of pivaloyl chloride are added, at 0° C., to a solution of 107.8 mmol (15 g) of 4-nitrophenol in 250 ml of pyridine. The reaction mixture is stirred for 72 hours at ambient temperature. The reaction mixture is evaporated in vacuo and the oily residue is diluted with ethyl acetate and then washed with aqueous hydrochloric acid solution (0.1N) and then with 10% aqueous sodium chloride solution. The expected product is obtained by drying the organic phase and then concentrating.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1.[N+:17]([O-])([OH:19])=[O:18].O>C(O)(=O)C>[F:8][C:4]1[CH:5]=[C:6]([N+:17]([O-:19])=[O:18])[CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[CH2:10][CH2:11][S:12](=[O:16])(=[O:15])[CH2:13][CH2:14]1
Reactant: O=[N+]([O-])O
Reactant: O=S1(=O)CCN(c2c(F)cccc2F)CC1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Reaction time: 18 h

Procedure:
To a suspension of 4-(2,6-difluorophenyl)thiomorpholine 1,1-dioxide (Step 1, 300 g, 1.21 mol) in 3 L of acetic acid, nitric acid (255 mL, ca. 6 mol, fuming, 90%) was added over 30 minutes at ambient temperature. A yellow precipitate forms within minutes and increases over time. The reaction was kept at room temperature for 18 hours and was then poured into 6 L of water. After stirring for 2 hours, the yellow suspension was filtered. The precipitate was washed with water (1.5 L×3) and ethanol (0.5 L×2) and dried at 50° C. overnight to give the title compound, 1H NMR (DMSO-d6) (δ): 8.05 (m, 2H), 3.69 (m, 4H), 3.26 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH3:17])[C:11](=[O:12])[NH:10][C@@H:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]2[O:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:20]I>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([CH3:17])[C:11](=[O:12])[N:10]([CH3:20])[C@@H:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]2[O:7]1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C1(C)O[C@@H]2CCCC[C@H]2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C)O[C@@H]2CCCC[C@H]2N(C)C1=O
Yield: 62.5 %

Procedure:
To a solution of trans-ethyl-2-methyl-3-oxo-octahydro-2H-1,4-benzoxazine-2-carboxylate (483 mg, 2 mmoles) in anhydrous toluene (10 ml), NaH (96 mg, 4 mmoles) and methyl iodide (710 mg, 5 mmoles) were added and the mixture was heated for 30 minutes at reflux temperature. After the completion of the reaction, the toluene solution was washed with 1N HCl (10 ml), 1N NaOH (10 ml) and a saturated NaCl solution (10 ml). The solution was dried over MgSO4 and the solvent was evaporated. Thus there were obtained 319 mg (62%) of a yellow product, which was purified by column chromatography (silica gel; chloroform/methanol=9:1). Thus there were obtained 246 mg (48%) of the title compound in the form of a viscous oil.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CC([O-])(C)C.[Na+].[C:17]([CH2:19][C:20](OC(C)(C)C)=O)#[N:18]>O1CCOCC1.ClCCl>[Cl:8][C:5]1[N:4]=[C:3]([O:9][CH3:10])[C:2]([CH:19]([CH3:20])[C:17]#[N:18])=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: COc1nc(Cl)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1nc(Cl)ccc1C(C)C#N
Temperature: 75 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a suspension of 3-bromo-6-chloro-2-methoxypyridine (99.9 g, 449 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (2.76 g, 3.38 mmol), and NaOtBu (105 g, 1090 mmol) in dioxane (805 mL) was added tert-butyl cyanoacetate (64.8 mL, 454 mmol) under nitrogen. The reaction mixture was heated for 235 min while maintaining the internal reaction temperature at 75° C. under nitrogen. After being cooled to 20° C., to the reaction mixture was added Mel (55.9 mL, 898 mmol) in one portion, and the resulting mixture was stirred overnight at r.t. Celite® (24 g) was added to the reaction mixture, and the resulting mixture was filtered through a 370 g silica plug. The plug was eluted with EtOAc/heptanes (1/3, 2.0 L), and the combined filtrate was concentrated. A solution of the crude residue (133.9 g) in DMSO (330 mL) and water (67 mL) was heated at 130° C. for 15.8 h. The reaction mixture was filtered through a plug of Celite®, and the filter cake was rinsed with MTBE and water. The filtrate was filtered again through a plug of Celite® and the filter cake was washed with MTBE and water. The filtrate was partitioned between MTBE (total volume=2.0 L), water (total volume=1.0 L) and brine (100 mL). The layers were separated and the organic layer was washed with water (1.0 L) and brine (750 mL), dried over Na2SO4, and concentrated to afford the crude 2-(6-Chloro-2-methoxypyridin-3-yl)propanenitrile (87.6 g, 99%) as a dark brown oil, which was used for the next step without any further purification. 1H NMR (600 MHz, CDCl3) δ 1.58 (d, 3H), 4.01 (s, 3H), 4.11 (q, 1H), 6.97 (d, 1H), 7.66 (d, 1H). MS (ES+)(M+H) 197.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[Br-].[Li+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN1CCCC1=O>[NH2:1][C@H:2]([C:4]([O:6][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:3]
Reactant: C[C@H](N)C(=O)O
Reactant: BrCc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: C[C@H](N)C(=O)OCc1ccccc1

Procedure:
In a similar operation, 0.45 gram (0.005 mole) of alanine, 0.87 gram (0.01 mole) of lithium bromide, 0.95 gram (0.0055 mole) of benzyl bromide and 4.8 grams of N-methylpyrrolidinone were stirred together for 5.5 hours at 55° C. to obtain the desired benzyl alaninate product. High pressure liquid chromatographic assay showed yield of the product to be 89 percent.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[O:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:13][CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 103.9 %

Procedure:
4-Methylbenzenesulfonyl chloride (22.7 g) was added portionwise to a stirred, cooled solution of tert-butyl (S)-2-hydroxyoxymethylpyrrolidine-1-carboxylate (20.0 g) in pyridine (70 mL) while maintaining the temperature at 0° C. The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and the residue was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give tert-butyl (S)-2-(4-methylbenzenesulfonyl-oxymethyl)pyrrolidine-1-carboxylate (34 g) as a yellow oil which was used without further characterisation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:18][CH2:17]1)[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.Cl.[CH3:41][NH:42][O:43][CH3:44]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([C:7]1[CH:8]=[CH:9][C:10]([C:11](=[O:12])[N:42]([O:43][CH3:44])[CH3:41])=[CH:14][CH:15]=1)[CH:16]1[CH2:17][CH2:18][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:20][CH2:21]1
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(=O)O)cc2)CC1
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)c1ccc(N(Cc2cccc(Cl)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Yield: 83.4 %

Procedure:
Using general procedure E, 4-((3-chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 86) (40 mg, 0.074) and N,O-dimethylhydroxylamine hydrochloride (11 mg, 0.11 mmol) afforded COMPOUND 88 as a white solid (36 mg, 84%). 1H NMR (CDCl3) δ 0.91-1.21 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.50-1.54 (m, 1H), 1.71-1.88 (m, 3H), 2.17 (t, 1H, J=11.4 Hz), 2.30 (s, 6H), 2.56 (t, 1H, J=11.4 Hz), 2.74-2.90 (m, 3H), 3.24-3.30 (m, 1H), 3.30 (s, 3H), 3.57 (s, 3H), 3.65-3.72 (m, 1H), 3.84 (s, 2H), 3.84-3.90 (m, 1H), 6.52 (d, 2H, J=8.7 Hz), 6.96 (d, 2H, J=7.5 Hz), 7.02-7.11 (m, 3H), 7.21-7.26 (m, 2H), 7.62 (d, 2H, J=8.4 Hz), 8.39 (br s, 1H). 13C NMR (CDCl3) δ 13.82, 19.54, 29.37, 30.69, 31.32, 34.49, 40.23, 43.97, 48.64, 52.50, 56.07, 60.93, 61.16, 111.89, 121.77, 124.65, 126.60, 127.34, 127.77, 128.88, 130.19, 131.09, 134.41, 134.85, 138.97, 142.35, 150.90, 169.94, 170.31. ES-MS m/z 591 (M+H). Anal. Calcd. for C34H43N4ClO3.0.3CH2Cl2: C, 66.84; H, 7.13; N, 9.09. Found. C, 66.87; H, 7.06; N, 8.94.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:11])[O:12][CH2:13][CH3:14]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccccc1Cl
Reaction time: 1 h
Yield: 98 %

Procedure:
2-Chloroaniline (1.4463 g) was dissolved in pyridine (10 ml), and to the solution was added dropwise ethyl chloroformate (1.30 ml) under ice-cooling. After the mixture was stirred for 1 hour, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (2.2203 g, 98%).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.Cl.[CH2:13]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[CH3:14].C(N(CC)CC)C>CN(C=O)C>[NH2:9][C:6]1[C:5]([CH2:10][NH:18][C@@H:17]([CH3:19])[C:16]([O:15][CH2:13][CH3:14])=[O:20])=[CH:4][C:3]([Br:2])=[CH:8][N:7]=1
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)[C@H](C)N
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NCc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of 5-bromo-3-(bromomethyl)pyridin-2-amine hydrobromide (2.5 g, 7.3 mmol) in DMF (10 mL) is added L-alanine ethyl ester hydrochloride (1.67 g, 10.9 mmol) and triethylamine (5 mL, 36 mmol) and the reaction was stirred at room temperature overnight. The reaction was quenched with water (20 mL) and the product extracted with ethyl acetate (4×20 mL), the combined organic layers are dried over sodium sulfate and concentrated. The crude reaction mixture is purified using preparative HPLC to give the final product as a white solid (530 mg, 25%): 1H NMR (300 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.47 (s, 1H), 6.20 (b, 1H), 4.15-4.07 (m, 2H), 3.49 (b, 2H), 3.27 (m, 1H), 3.34 (s, 2H), 1.17-1.24 (m, 6H).