Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH:25]([OH:27])[CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13](B1OC(C)(C)C(C)(C)O1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:36]2[NH:44][C:43]3[CH2:42][CH2:41][NH:40][C:39](=[O:45])[C:38]=3[CH:37]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([NH:5][C:6]1[C:7]([CH:25]([OH:27])[CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:36]1[NH:44][C:43]3[CH2:42][CH2:41][NH:40][C:39](=[O:45])[C:38]=3[CH:37]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(O)c1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1NC(C)(C)C
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(O)c1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 105 °C
Yield: 26 %

Procedure:
A mixture of 1-(3-(tert-butylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-yl)ethanol (310b; 960 mg, 1.732 mmol), 2-bromo-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (608) (596 mg, 2.77 mmol), K2PO4 (1177 mg, 5.54 mmol), X-Phos (Strem Chemicals, Inc., 83 mg, 0.173 mmol), and Pd2dba3 (Aldrich) (79 mg, 0.087 mmol) in a mixture of 1,4-dioxane (15 mL) and water (3.00 mL) was heated under argon at 105° C. for 1.5 h. The reaction mixture was then cooled to RT, diluted with water (100 mL), and extracted with 5% MeOH/DCM (3×100 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) followed by trituration of the collected solid with Et2O (10 mL) furnished 2-(3-(tert-butylamino)-2-(1-hydroxyethyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (310) (172 mg, 0.45 mmol, 26% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (1H, br. s.), 7.85 (1H, dd, J=7.5, 1.3 Hz), 7.58 (1H, dd, J=8.0, 1.2 Hz), 7.47 (1H, s), 7.34 (1H, t, J=7.8 Hz), 7.04 (1H, d, J=2.2 Hz), 6.93 (1H, s), 6.43 (1H, br. s.), 4.96 (1H, q, J=6.8 Hz), 3.43 (2H, td, J=6.8, 2.5 Hz), 2.86 (2H, t, J=6.8 Hz), 1.54 (9H, s), 1.50 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 380.1 (M+H)+. Separation of this material (310c) by supercritical-fluid chromatography (Chiralpak IC (150×30 mm, 10 μm), 70% liquid CO2/30% MeOH (+20 mM NH4OH), 70 mL/min) separately afforded: first-eluting peak, (S)-2-(3-(tert-butylamino)-2-(1-hydroxyethyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, (310; 35.0 mg, 0.092 mmol, m/z (ESI, +ve) 380.1 (M+H)+); and second-eluting peak, (R)-2-(3-(tert-butylamino)-2-(1-hydroxyethyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (311; 39.0 mg, 0.103 mmol, m/z (ESI, +ve) 380.1 (M+H)+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.Br[C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][N:29]=3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Brc1ccc(Br)nc1
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: Cc1ccccc1
Solvent: CCO
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Br)cn3)cc2)CC1
Temperature: 60 °C

Procedure:
To a solution of {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (4.0 g, 11.2 mmol, 1.0 equiv) and 2,5-dibromopyridine (3.2 g, 13.4 mmol, 1.2 equiv) in 50 Ml toluene/ethanol (1:1) was added 2 M Na2CO3 (16.8 Ml, 3 equiv) followed by Pd(PPh3)4 (0.38 g, 0.34 mmol, 0.03 equiv). The biphasic mixture was sparged with nitrogen for 10 min, then heated to 60° C. for 3 days. The reaction was cooled to room temperature and then partitioned between ethyl acetate and saturated ammonium chloride solution. The organic extracts were washed with brine, then dried over sodium sulphate and concentrated in vacuo. Purification by silica gel chromatography (7-40% EtOAc in hexanes) afforded the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 1.11 (dd, J=13.01, 2.15 Hz, 2H) 1.41-1.54 (m, 2H) 1.76-1.90 (m, 5H) 2.20 (d, J=6.57 Hz, 2H) 2.46 (tt, J=12.09, 3.19 Hz, 1H) 3.62 (s, 3H) 7.23 (d, J=8.08 Hz, 2H) 7.53 (dd, J=8.59, 0.76 Hz, 1H) 7.77 (dd, J=8.46, 2.40 Hz, 1H) 7.81 (q, J=3.87 Hz, 1H) 7.81 (d, J=8.34 Hz, 1H) 8.64 (d, J=1.77 Hz, 1H); (M+H)+390.0.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:1]([CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:17]3[N:16]=[N:15][C:14]([Cl:13])=[CH:19][CH:18]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCC1CCC2CNCCN2C1
Reactant: Oc1ccccc1
Reactant: Clc1ccc(Cl)nn1
Product: Clc1ccc(N2CCN3CC(COc4ccccc4)CCC3C2)nn1

Procedure:
A mixture of (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (U.S. Pat. No. 5,326,874) and 3,6-dichloropyridazine were combined according to Preparation 3. The product from this reaction was coupled with phenol according to Example 1 to give the title compound. mp (—HCl) >265° C. (dec). HRMS calcd for C19H23ClN4O: 358.1555, found: 358.1550.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([NH:17][CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[S:15][CH:16]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].CI.[CH:31](OC(C)C)(C)C>CN(C)C=O.O>[CH3:31][N:17]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)[C:14]1[S:15][CH:16]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=2)[N:13]=1
Reactant: CC(C)OC(C)C
Reactant: COC(=O)c1ccc(CNc2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C)c2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
Under an argon atmosphere, to a suspension of sodium hydride (content 60%, 26.4 g, 0.661 mol) in N,N-dimethylformamide (530 ml, 2.5 v/w) were successively added dropwise a solution of methyl 4-((4-(4-nitrophenyl)-2-thiazolyl)aminomethyl)benzoate (212.4 g, 0.575 mol) obtained in Example 1(2) in N,N-dimethylformamide (743 ml, 3.5 v/w) and methyl iodide (41.2 ml, 0.661 mol) at 10° C. or below, and the mixture was stirred at room temperature for 2 hr. Sodium hydride (content 60%, 2.3 g, 0.057 mol) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added dropwise to water (2120 ml, 10.0 v/w) at 10° C. or below, and, after stirring at room temperature for 30 min., diisopropyl ether (848 ml, 4.0 v/w) was added and the mixture was stirred for 2 hr. The precipitated crystals were collected by filtration, washed successively with diisopropyl ether (424 ml) and water (424 ml) and dried in vacuo to give the title compound (201.9 g, yield 91.4%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:6])[CH2:2][CH3:3].C([N:27](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[O:17]1[CH:18]=[CH:19][N:20]=[C:16]1[C:14]1[CH:15]=[C:7]([C:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=[C:9]([CH:13]=1)[C:10]([NH2:27])=[O:11]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 148.5 %

Procedure:
A solution of 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoic acid 38 (120 mg, 0.38 mmol) in methylene chloride (3.8 mL) containing N,N-diisopropylethylamine (132 μL, 0.76 mmol) and HBTU (151 mg, 0.40 mmol) was stirred at room temperature for 0.5 h. To the above solution was added a solution of the orange oil from step 7 (207 mg, 0.57 mmol) in methylene chloride (3.8 mL) containing N,N-diisopropylethylamine (132 μL, 0.76 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with additional methylene chloride and washed with saturated sodium bicarbonate and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield an oily residue. Purification by flash column chromatography (silica, 90:10 methylene chloride/methanol) gave N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[({2-(dimethylamino) methyl]pyridin-4-yl}methyl)amino]-2-hydroxypropyl}-5-(1,3-oxazol-2-yl)-N3,N3-dipropylisophthalamide (178 mg): mp 63–66° C.; ESI MS m/z 663 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=4[Cl:28])[C:22](O)=[O:23])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][CH2:62][OH:63]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([C:22](=[O:23])[NH:60][CH2:61][CH2:62][OH:63])[CH:25]=[CH:26][C:27]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)NCCO)ccc1Cl
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a mixture of 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (3 g, 6.09 mmol) in THF (50 mL) was added EDCI (2.34 g, 12.18 mmol), HOBt (1.23 g, 9.13 mmol), DIPEA (5 mL) and 2-aminoethanol (0.56 g, 9.13 mmol) by sequence under nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight, diluted with water. The resulting precipitate was washed with water and EtOAc to give 8-bromo-N-(2-chloro-5-(2-hydroxyethylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (2.52 g, yield 77%). LC-MS: (ESI, m/z)=535 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[O:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:32][N:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[C:15](=[N:16][N:17]([CH2:28][C:29]4[O:30][C:31]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[N:32][N:33]=4)[N:18]=3)[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Reactant: ClCc1nnc(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3nn(Cc4nnc(-c5ccccc5)o4)nc23)c1
Reaction time: 16 h

Procedure:
3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (100 mg, 0.328 mmol), cesium carbonate (107 mg, 0.328 mmol) and 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole (64 mg, 0.328 mmol) were combined and suspended in DMF (2 mL). After 16 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride (1 mL) and extracted with EtOAc (2×25 mL). The combined organic fractions were evaporated under reduced pressure. The resulting residue was purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. The product fractions were concentrated to yield the title compound. 1H NMR (DMSO-d6) δ 8.01 (d, J=9.1 Hz, 1H) 7.92 (d, J=8.6 Hz, 2H), 7.72 (m, 1H), 7.68 (m, 1H), 7.60 (m, 5H), 6.50 (s, 1H). HRMS (M+1)=463.0464.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:16]#[N:17])[NH:12][CH:11]=[CH:10]2.O.[OH-].[Na+].CN([CH:24]=[O:25])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:16]#[N:17])[NH:12][CH:11]=[C:10]2[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: N#Cc1cc2[nH]ccc2cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2[nH]cc(C=O)c2cc1Br
Temperature: 80 °C
Yield: 92 %

Procedure:
Phosphorus oxychloride (1.39 mL, 14.9 mmol) was added dropwise over 5 minutes to DMF (10 mL) with stirring. The clear mixture was stirred at room temperature for 10 minutes. A solution of 5-bromo-1H-indole-6-carbonitrile (1.10 g, 4.97 mmol) in DMF (1.5 with 0.5 mL wash) was added to the clear red solution, and the reaction mixture was stirred at room temperature for 5 min. The resulting grey suspension was heated to 80° C. under nitrogen for 25 min, and then allowed to cool to room temperature. The reaction mixture was treated slowly with water (30 mL) and aqueous 1 N NaOH (30 mL) at room temperature. The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring. The reaction mixture was allowed to cool to room temperature over 5 minutes, and the solids were collected by filtration. The solids were dried in vacuo for 16 hours at 55° C. to afford the title compound (1.15 g, 92%) as a cream-colored solid. MS (ES−) 247.1 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.76 (br. s., 1H), 9.99 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H).
Reaction SMILES: COC1C=C([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH2:20][CH3:21])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)=[O:11])C=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:32]1([OH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[CH:39]1C=CC=CC=1>>[OH:18][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[CH:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:20][CH2:21][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([O:38][CH3:39])[CH:33]=2)=[CH:17][CH:16]=1
Reactant: Oc1ccccc1
Reactant: c1ccccc1
Reactant: CCC(C(=O)c1ccc(OC)cc1)(c1ccccc1)c1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1cccc(CCC(C(=O)c2ccc(O)cc2)c2ccccc2)c1

Procedure:
A mixture of 11.65 g. of 4-(m-methoxyphenyl-1-(p-methoxyphenyl)-2-phenyl-1-butanone and 13.6 g. of aluminum chloride in 270 ml. of benzene was heated at reflux for 31/2 hours. The solution was allowed to cool and washed in turn with 2.5 N hydroxhloric acid, water and a saturated solution of sodium chloride. The organic layer was then extracted with 5 portions of 110 ml. each of N sodium hydroxide. Acidification of this last extract gave 11.04 g. of the crude phenol. A single recrystallization from aqueous methanol afforded 8.42 g. of 1(p-hydroxyphenyl)-4-(m-methoxyphenyl)-2-phenyl-1-butanone, m.p. 125°-129° C. (yield, 75%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[F:22][C:23]([F:29])([F:28])[S:24](O)(=[O:26])=[O:25]>C1(C)C=CC=CC=1>[F:22][C:23]([F:29])([F:28])[S:24]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:26])=[O:25]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Into a 5 liter four-necked flask equipped with a thermometer, a Dimroth condenser, a calcium chloride tube and a stirrer, 190.0 g (0.904 moles) of dimethyl 5-hydroxyisophthalate, 3 liters of dehydrated toluene and 214.7 g (2.718 moles) of dehydrated pyridine were placed and the resultant mixture was cooled at −30° C. under stirring. To the cooled mixture, 510.2 g (1.808 moles) of anhydrous trifluoromethanesulfonic acid was slowly added dropwise with sufficient care so that the temperature did not exceed −25° C. It took 1 hour to complete the addition. After the addition was completed, the temperature of the reaction was elevated at 0° C. and the reaction was allowed to proceed for 1 hour. Then, the temperature was elevated to the room temperature and the reaction was allowed to proceed for 5 hours. The obtained reaction mixture was poured into 4 liters of ice water and separated into an aqueous layer and an organic layer. The aqueous layer was treated twice by extraction with 500 ml of toluene and the extract was combined with the organic layer. The obtained organic layer was washed twice with 3 liters of water and dried with 100 g of anhydrous magnesium sulfate. From the resultant mixture, anhydrous magnesium sulfate was removed by filtration and toluene was removed by distillation using a rotary evaporator. After drying under a reduced pressure, 294.0 g of dimethyl 5-trifluoromethanesulfonyloxyisophthalate was obtained as a light yellow solid substance (the yield: 95%). The crude product obtained above was recrystallized from hexane and white needle crystals were obtained. The obtained crystals were used for the next reaction.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[CH3:30][S:31](Cl)(=[O:33])=[O:32].CN1CCOCC1>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:12])[CH2:5][CH2:6][N:7]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:8][CH2:9]1)#[N:3]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CC1

Procedure:
The title compound is prepared by treatment of morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride with methanesulfonyl chloride and a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:19][OH:20].[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>CN(C=O)C>[C:10]([O:9][C:8]([NH:7][CH:4]1[CH2:3][CH2:2][N:1]([C:25]([O:20][CH2:19][C:18]2[CH:17]=[C:16]([Cl:15])[CH:23]=[C:22]([Cl:24])[CH:21]=2)=[O:26])[CH2:6][CH2:5]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1cc(Cl)cc(Cl)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reaction time: 72 h

Procedure:
A mixture comprising tert-butyl piperidin-4-ylcarbamate (5 g, 24.97 mmol), 3,5-dichlorobenzyl alcohol (4.42 g, 24.97 mmol) and carbonyldiimidazole (4.05 g, 24.97 mmol) in DMF (83 ml) was heated at 50° C. with stirring for 3 days. The resulting mixture was concentrated under reduced pressure. The crude material was redissolved in EtOAc and washed with 1M HCl, a saturated solution of sodium bicarbonate and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The mixture was purified by chromatography on silica eluting with 50-100% EtOAc in iso-hexane and then 1-10% MeOH in EtOAc to afford the title product;
Reaction SMILES: Cl.[C:2]([CH2:8][NH2:9])(=[O:7])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)(O)[O-].[Na+].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:9][CH2:8][C:2](=[O:7])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:21])=[CH:18][CH:17]=1
Reactant: CC(C)CC(=O)CN
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)CC(=O)CNC(=O)c1ccc(Cl)cc1
Yield: 97.5 %

Procedure:
3.8 g of isovalerylmethylamine hydrochloride, 5.04 g of sodium bicarbonate and 4.9 g of 4-chlorobenzoyl chloride are treated in the same manner as described in Preparation 1-(4). 6.2 g of N-(4-chlorobenzoyl)isovalerylmethylamine are thereby obtained. Yield: 98.0.
Reaction SMILES: CN1CCOCC1.[F:8][C:9]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])=[C:25]([CH2:36][O:37][CH3:38])[CH:24]=3)[O:20][N:19]=2)[CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].Cl.[CH3:40][O:41][C:42](=[O:46])[CH2:43][NH:44][CH3:45].[N-]=C=O>C1COCC1.CN(C=O)C>[F:8][C:9]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])=[C:25]([CH2:36][O:37][CH3:38])[CH:24]=3)[O:20][N:19]=2)[CH:15]=[CH:14][C:10]=1[C:11]([N:44]([CH3:45])[CH2:43][C:42]([O:41][CH3:40])=[O:46])=[O:12]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)Cl)c(F)c3)no2)ccc1-c1ccccc1C
Reactant: CNCC(=O)OC
Agent: Cl
Agent: [N-]=C=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCc1cc(-c2nc(-c3ccc(C(=O)N(C)CC(=O)OC)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of example 35 (2 170 mg; 5.2 mmol) in dry DCM (40 mL), oxalyl chloride (1 316 μl; 15.6 mmol) was added followed by dry DMF (40 μl). The reaction mixture was stirred at RT for 2 h and concentrated to afford 2-fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride as a white powder (2300 mg, 100%). In dry THF (1 mL) with a catalytic amount of DMF was swelled morpholinomethyl polystyrene high loading resin (NovaBiochem; 35.77 mg; 0.14 mmol), 3.9 mmol/g). 2-Fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride (25 mg; 0.06 mmol) was added followed by sarcosine methyl ester hydrochloride (15.98 mg; 0.11 mmol). The mixture was stirred overnight at rt. Isocyanate resin Si—NCO (Argonaut, 97 mg; 1.5 eq; 1.7 mmol/g) was added and the mixture stirred for 2 h. It was filtered through a SAX column (2 g) to obtain the title compound as a colorless oil. LC/MS (Method B): 504.2 (M+H)+ HPLC (Method A) Rt: 5.39 min (purity: 97%).
Reaction SMILES: [Na].Cl([O-])(=O)=[O:3].[Na+].[C:7]([OH:19])(=O)[CH2:8][C:9]([CH2:14][C:15]([OH:17])=[O:16])(C(O)=O)[OH:10].C([O-])(=O)C[C:22](CC([O-])=O)(C([O-])=O)[OH:23].[Li+].[Li+].[Li+]>CO.O>[O:17]=[C:15]1[O:16][C@H:8]([C@H:7]([CH2:22][OH:23])[OH:19])[C:9]([OH:10])=[C:14]1[OH:3]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: [O-][Cl+2]([O-])[O-]
Agent: [Li+]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
7 grams of the sodium salt of 2,18-phosphomolybdic acid, 4 grams of sodium chlorate, 40 grams of citric acid, and 13.5 grams of trilithium citrate are dissolved in a mixture of 600 ml of methanol and 380 ml of water. A filter paper, for example Type 2668, made by the Schleicher & Schull Company, is impregnated with this solution, which has a pH-value of 3.6, and is dried for 1 hour at 60° C. Pieces measuring 6×6 mm are cut from the test paper prepared in this way, and sealed between a plastic handle and a thin nylon net, according to German Pat. No. 2 118 455. In urines with ascorbic acid in the important decision range of 0-40 mg of ascorbic acid/dl of urine, these test strips give very graduated reaction colors from bright greenish-blue to dark bluish-violet.