Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CS(C)=O>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:33][CH2:32][C:29]4[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[CH:31][CH:30]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCc1ccc(OCCN2CCOCC2)cc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccc(OCCN4CCOCC4)cc3)c3ccccc3nc21
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (0.7 g, 3 mmol), 4-[2-(4-morpholinyl)ethoxy]phenylmethylamine (0.75 g, 3.2 mmol) and DMSO (3 mL) was heated on a steam bath for 8 hours. Additional 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (0.7 g, 3 mmol) was then added and the reaction mixture was heated on a steam bath for another 4 hours. The reaction mixture was cooled to room temperature and then was poured into water. The mixture was extracted with CH2Cl2 (3×100 mL) and then CH2Cl2 layers were combined, dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /methanol (95/5), followed by recrystallization from ethyl acetate, to afford 1.0 g of 1-ethyl-N-[4-[2-(4-morpholinyl) ethoxy]phenylmethyl]-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid, m.p. 170-172° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:18]=3[N:19]=2)[CH2:12][CH2:13]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOc1cc(CN2CCC(Nc3nc4cc([N+](=O)[O-])ccc4o3)CC2)ccc1OC
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc(CN2CCC(Nc3nc4cc(N)ccc4o3)CC2)ccc1OC
Temperature: 60 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To a solution of [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(5-nitro-benzooxazol-2-yl)-amine (1.0 g, 2.35 mmol, 1.0 equiv; example 225) in ethanol (10 mL) was added palladium on activated charcoal 10% (0.1 g, 0.10 mmol, 0.04 equiv), the reaction vessel filled with hydrogen (3.5 bar) and stirred at 60° C. for 18 h. The catalyst was removed by filtration over celite and the solvent removed under reduced pressure yielding 0.79 g (85%) of the title compound which was used directly without further purification. MS (ESI): 397.4 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH3:11][O:12]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:1]1([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: COC(Cl)Cl
Reactant: c1ccc(CC2CC2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc(CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of (cyclopropylmethyl)benzene (1.32 g) and dichloromethyl methyl ether (1.25 ml) in dichloromethane (20 ml) was added 1.0M solution of titanium(IV) chloride in dichloromethane (15 ml) at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for 10 minutes, then poured into ice water. The organic layer was separated and washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (9:1) to give 4-(cyclopropylmethyl)benzaldehyde (580 mg) as an oil.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:8]=[C:9](I)[CH:10]=[C:11]([CH3:13])[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCCCCCCCCCCC>[Cu]I.C1(C)C=CC=CC=1>[CH2:1]([O:5][C:9]1[CH:10]=[C:11]([CH3:13])[CH:12]=[C:7]([CH3:6])[CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCOc1cc(C)cc(C)c1
Temperature: 105 °C

Procedure:
A screw cap test tube was charged with n-butanol (573 μL, 6.26 mmol), 3,5-dimethyliodobenzene (144 μL, 1.00 mmol), CuI (19.0 mg, 0.100 mmol), Cs2CO3 (977 mg, 3.00 mmol), the ligand (0.500 mmol) and toluene (1 mL). The test tube was sealed with a screw cap. The reaction mixture was stirred magnetically and heated at 105° C. for 36 hours. The reaction mixture was allowed to reach room temperature. Dodecane (227 μL, 1.00 mmol; internal standard) was added and a GC sample was filtered through Celite and eluted with CH2Cl2. The yield of the desired product was determined using GC analysis; the results are tabulated below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][C:14]=1[CH3:31])[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33].C[O-].[Na+:37]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[CH:15][C:14]=1[CH3:31])[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O-:34])=[O:33].[Na+:37]
Reactant: Cc1cc(C(=O)NCCc2ccc(Cl)cc2)ccc1Oc1cc2c(cc1Cl)C(C(=O)O)CCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=O)NCCc2ccc(Cl)cc2)ccc1Oc1cc2c(cc1Cl)C(C(=O)[O-])CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a solution of 6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylic acid (0.011 g, 0.0220 mmol) in methanol (2 ml) was added 0.5 M sodium methanolate in methanol (0.0462 ml, 0.0231 mmol), and the reaction was stirred at ambient temperature for 3 hours. The reaction was concentrated, and the residue was diluted with dichloromethane and hexanes, and concentrated again to yield 11 mg of the title compound (95.8% yield). MS (apci) m/z=500.0 (M-Na+2H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13]C)=O)[N:5]=[C:4]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[N:19]=2)[N:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.N1C=NC=N1.C1CCN2C(=NCCC2)CC1>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([C:11]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[O:13])[CH:15]=[CH:16][CH:17]=2)[N:5]=[C:4]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:32])([F:31])[F:33])=[CH:27][CH:28]=3)[N:19]=2)[N:3]=1
Reactant: COC(=O)c1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Reactant: CN1CCNCC1
Agent: c1nc[nH]n1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(C(=O)N2CCN(C)CC2)c1
Temperature: 100 °C
Yield: 37.9 %

Procedure:
A mixture of methyl 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)benzoate (46 mg, 0.1 mmol) and 1-methylpiperazine (10 mg, 0.1 mmol) was treated with 1,2,4-triazole (1.4 mg, 0.02 mmol) and DBU (3 mg, 0.02 mmol)), and heated to 100° C. overnight. The crude product was purified by a silica gel column (MeOH/EtOAc 1% to 10% MeOH) to give (3-((5-Methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenyl)(4-methylpiperazin-1-yl)methanone as a yellow solid (20 mg, 38%). MS (ES+) C25H24F3N7O3 requires: 527. found: 528 [M+H]+. 1H NMR (600 MHz, CDCl3) δ8.28 (d, J=8.8 Hz, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.32 (s, 1H), 7.29 (d, J=7.7 Hz, 1H), 5.48 (s, 2H), 3.82-3.74 (m, 2H), 3.42-3.36 (m, 2H), 2.57 (s, 3H), 2.51-2.44 (m, 2H), 2.35-2.30 (m, 2H), 2.29 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[CH:64]=[CH:63][N:62]=[C:61]([CH3:65])[N:60]=1.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:58][C:59]2[CH:64]=[CH:63][N:62]=[C:61]([CH3:65])[N:60]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nccc(N)n1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nccc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)c([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 14, 250 mg, 0.732 mmol), triethylamine (0.306 mL, 2.19 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (487 mg, 1.10 mmol), and 4-amino-2-methylpyrimidine (120 mg, 1.10 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 24 h. The reaction mixture was then diluted with water (25 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/3 hexanes/ethyl acetate) afforded impure 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide. Re-purification by flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 then 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide (59 mg, 18%) as a white foam: mp 96–99° C. (foam to gel); EI-HRMS m/e calcd for C20H24N4O5S (M+) 432.1467, found 432.1470.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH:47]([C:52]1[N:53]=[N:54][C:55]([Cl:58])=[CH:56][CH:57]=1)C(OC)=O.CO.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:58][C:55]1[N:54]=[N:53][C:52]([CH2:47][C:3]2[CH:4]=[C:5]([C@H:8]3[C@H:13]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C@@H:12]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:11]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[O:9]3)[CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:57][CH:56]=1
Reactant: COC(=O)C(c1ccc(Cl)nn1)c1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution of Methyl 2-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenyl)-2-(6-chloropyridazin-3-yl)acetate (compound 23, 9.9 g, 12 mmol) from Step 1 in terahydrofuran (40 mL) was added methanol (56 mL) and lithium hydroxide solution (0.1 M in water, 180 mL, 180 mmol). The reaction mixture was allowed to stir at room temperature overnight. After cooling to 0° C., hydrochloric acid (1.0 M) was added to neutralize the reaction mixture. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was slurried in methanol (100 mL) and the slurry was stirred at ambient temperature for 2 h. The resulting solid was isolated by filtration and dried in vacuo to yield the title compound (7.8 g, 10 mmol, 86%) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:4][CH2:3]1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH:21]([O:20][C:11]1[CH:12]=[CH:13][C:14]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:15][C:10]=1[C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:30]2[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:23])[CH3:22]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
To a solution of 0.15 mmol (4-hydroxy-piperidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 3(a)) in 3 ml tetrahydrofuran were added successively 0.18 mmol 4-nitrophenol, 0.18 mmol triphenylphosphine and 0.18 mmol di-tert-butyl azodicarboxylate. The reaction mixture was stirred at 50° C. for 16 h and was then cooled to room temperature and concentrated in vacuo. The crude material was purified by reversed phase HPLC (acetonitrile/water) to afford the title compound as a white crystalline solid (yield 27%). MS (m/e): 463.4 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.C(O)C>C(OC(OCC)N(C)C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9](=[CH:10][N:11]([CH3:12])[CH3:5])[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: CN1C(=O)CN=C(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: CCOC(OCC)N(C)C
Solvent: CCO
Product: CN(C)C=C1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(C)C1=O
Temperature: 130 °C

Procedure:
A suspension of 55 gm of 7-chloro-5-(2'-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one in 85 ml of N,N-dimethyl-formamide diethylacetal was heated to 130°C in a vessel equipped with a descending condenser, whereby a clear solution was formed after a short time. The temperature of the reaction solution was maintained at 130°C for 41 hours, during which time the ethanol formed by the reaction slowly distilled over. Thereafter, the reaction solution was cooled to about 80°C and then admixed with 50 ml of isopropanol. Upon further cooling of the mixture, a reddish-orange crystalline substance separated out which was collected by vacuum filtration, washed with petroleum ether and recrystallized from isopropanol, whereupon it had a melting point of 202°-203°C. It was identified to be the compound of the formula ##SPC5##
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].C(OC(Cl)=O)C.[NH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1>C(Cl)Cl>[OH:26][CH:23]1[CH2:24][CH2:25][N:20]([C:8]([C:7]2[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=2)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[CH2:21][CH2:22]1
Reactant: OC1CCNCC1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N2CCC(O)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.9 %

Procedure:
To 3-[(methyloxy)carbonyl]benzoic acid (0.901 g, 5 mmol) in DCM (25 mL) was added TEA (0.697 mL, 5.00 mmol), EtOCOCl (0.480 mL, 5.0 mmol). This mixture was stirred at 0° C. for 10 mins and then 4-piperidinol (0.506 g, 5.00 mmol) was added. Stirring was continued at room temperature for 16 h. The reaction mixture was diluted with DCM (35 mL), washed with HOAc (20 mL, 10%), NaHCO3 (20 mL, 10%), water (20 mL), dried over Na2SO4, filtered and concentrated and purified by CombiFlash chomatograph to afford the title compound (0.696 g, 53%). LC-MS m/z 264 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[CH2:12][NH:13][CH2:14][CH3:15])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:24]1([C:27]([OH:29])=O)[CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:11]=2[CH2:12][N:13]([CH2:14][CH3:15])[C:27]([CH:24]2[CH2:26][CH2:25]2)=[O:29])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(Br)cnc1OC
Reactant: O=C(O)C1CC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Br)cnc1OC)C(=O)C1CC1

Procedure:
[2-(5-Bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-ethyl-amine and cyclopropanecarboxylic acid were reacted as described in Example 8, Step 6 to provide cyclopropanecarboxylic acid [2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-ethyl-amide.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([NH2:6])(=[O:5])=[O:4].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CC(C)=O>[F:1][C:2]([F:8])([F:7])[S:3]([NH2:6])(=[O:5])=[O:4].[NH2+:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Agent: NS(=O)(=O)C(F)(F)F
Solvent: CC(C)=O
Product: C1COCC[NH2+]1

Procedure:
Trifluoromethanesulfonamide (14.9g, 0.10 mole), morpholine (8.7g, 0.10 mole) and acetone (100 ml) were stirred together for one hour. The solvent was evaporated in vacuo to give morpholinium trifluoromethanesulfonamide, m.p. 84°-87° C. Analysis: Calculated for C5H11F3N2O3S: %C 25.4; %H, 4.7; %N, 11.8; found: %C, 25.3;D %H, 4.7; %N, 11.7.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C([Li])CCC.[C:14](=[O:16])=[O:15]>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([C:14]([OH:16])=[O:15])=[C:2]1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccs1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccsc1C(=O)O
Temperature: -78 °C
Yield: 82 %

Procedure:
A dry, 2 L, 3-necked, round-bottomed flask was equipped with a mechanical stirrer and addition funnel. To the flask was added 2-thiophenecarboxylic acid (25 g, 195 mmol) in anhydrous THF (500 mL) under argon. The mixture was cooled to −78° C. with a dry ice-isopropanol bath and allowed to stir for 30 min. n-Butyllithium in Hexanes (2.5 M, 172 mL) was added dropwise over 30 min. The reaction was kept at −78° C. for an additional hour with stirring then placed under an atmosphere of dry carbon dioxide. With addition of the carbon dioxide the reaction became thick. The reaction remained at −78° C. for an additional hour before warming to −10° C. The reaction was quenched with 2 N HCl (213 mL) and allowed to reach rt. The layers were separated and the aqueous layer was extracted with EtOAc (3×200 mL). The organic layers were combined, dried (Na2SO4) and concentrated by rotary evaporation. The brown solid was crystallized from hot isopropanol and dried overnight under vacuum. Desired thiophene-2,3-dicarboxylic acid was obtained (27.3 g, 159 mmol; 82% yield); 1H NMR (DMSO-d6) 7.69 (d, J=1.5, 1), 7.38 (d, J=4.8, 1); ES MS (M+H)+=173; TLC (Chloroform-MeOH-water, 6:4:1); Rf=0.74.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][C:16]([CH3:21])([CH3:20])[CH2:15]2)[C:3]=1[CH3:22].[CH3:23][C:24]1([CH3:39])[C:28]2=[N:29][CH:30]=[C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:32]=[C:27]2[NH:26][CH2:25]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH3:20][C:16]1([CH3:21])[O:17][CH2:18][CH2:19][N:14]([C:4]2[C:3]([CH3:22])=[C:2]([N:26]3[C:27]4[C:28](=[N:29][CH:30]=[C:31]([N:33]5[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)[CH:32]=4)[C:24]([CH3:39])([CH3:23])[CH2:25]3)[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=2)[CH2:15]1
Reactant: Cc1c(N2CCOC(C)(C)C2)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCOC(C)(C)C2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Preparing according to procedure Y by using 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-2,2-dimethylmorpholine (70.0 mg, 0.21 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (50 mg, 0.21 mmol), sodium tert-butoxide (20.60 mg, 0.21 mmol) and XPhos precatalyst (16 mg, 0.02 mmol) in toluene (4 mL) at reflux for 2 h. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 2-(2,2-dimethyl-4-morpholinyl)-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methylquinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 7.56 (1H, d, J=2.3 Hz), 7.34-7.40 (1H, m), 6.69-6.82 (1H, m), 5.67 (1H, d, J=2.3 Hz), 3.90-4.02 (2H, m), 3.77-3.81 (1H, m), 3.71-3.76 (4H, m), 3.66 (1H, d, J=9.0 Hz), 3.27-3.37 (2H, m), 3.10-3.23 (2H, m), 2.92-3.01 (4H, m), 2.28 (3H, s), 1.53 (3H, d, J=0.8 Hz), 1.49 (3H, s), 1.40 (3H, s), 1.35 (3H, s). Mass Spectrum (ESI) m/e=524.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
196MBT36 (100 mg, 0.455 mmol) was dissolved in methanol (2 mL). Sodium borohydride (17 mg, 0.455 mmol) was added and the mixture was stirred for 30 minutes at room temperature. Saturated aqueous ammonium chloride (1 mL) was added and extracted with dichloromethane (2×10 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated to give 2,3-dichloro-6-nitrobenzyl alcohol (196MBT46-A, 92 mg, 91%) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4]([OH:6])=[O:5].[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]Cl)([O-:14])=[O:13].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][NH:2][CH:3]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4]([OH:6])=[O:5])([O-:14])=[O:13]
Reactant: COC(=O)CC(N)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1SCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC(NSc1ccccc1[N+](=O)[O-])C(=O)O

Procedure:
9.2 g (50 millimoles) of DL-2-amino-3-methoxycarbonyl-propionic acid hydrochloride (i.e., DL-aspartic acid O62 -methyl ester HCl), 10.5 g of o-nitrophenylsulfenyl chloride, 50 ml of water, 70 ml of tetrahydrofuran and 24.3 g of potassium carbonate are treated in the same manner as described in Example 1-(1). 9.8 g of DL-2-(o-nitrophenylsulfenylamino)-3-methoxycarbonyl-propionic acid are obtained. M.p. 108°- 109° C.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[NH:20][CH2:21][C:22]([O:24]CC)=[O:23])=[C:10]([Cl:29])[CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[C:13]([O:12][C:11]2[CH:27]=[CH:28][C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:9][C:10]=2[Cl:29])[CH:18]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(N)cc1Cl
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2cc(Cl)ccc2NCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethanesulphonyl chloride (0.1 ml) was added to a mixture of the product from step (iii) (0.11 g) and pyridine (0.5 ml) in DCM (4 ml). After stirring at room temperature for 4 h the mixture was partitioned between diethylether/2 M HCl. The organics separated, dried and evaporated under reduced pressure. The residue was dissolved in methanol (5 ml) then 2M NaOH added and stirred at room temperature for 20 h. The solvent was removed under reduced pressure and the residue partitioned between ethylacetate/1M HCl. The organics were separated, washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 80% ethylacetate/isohexane, yield 0.025 g.