Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: C1COCCN1
Reactant: Cc1nc(NC(=O)CCBr)sc1-c1ccnc(Nc2ccc(F)cc2)n1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)CCN2CCOCC2)sc1-c1ccnc(Nc2ccc(F)cc2)n1

Procedure:
A solution of 3-bromo-N-{5-[2-(4-fluoro-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide (20 mg, 0.046 mmol) and morpholine (8 μL, 0.092 mmol,) in DMF (2 mL) was stirred at room temperature for 2 h. The reaction mixture was purified by preparative RP-HPLC (0-60% MeCN in 0.1% aq CF3COOH over 40 min, 9 mL/min) to afford the title compound as a pale solid. Anal. RP-HPLC: tR=13.3 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity >93%). 1H-NMR (CD3OD) δ: 2.66 (s, 3H, CH3), 3.23 (m, 2H, CH2), 3.33 (m, 2H, CH2), 3.41 (m, 4H, CH2), 3.87 (m, 2H, CH2), 4.13 (m, 2H, CH2), 7.04-7.09 (m, 3H, pyrimidinyl-H & Ph-H), 7.68 (m, 2H, Ph-H), 8.39 (d, 1H, J=5.5 Hz, pyrimidinyl-H). MS (ESI+) m/z 443.3 (C21H23FN6O2S requires 442.5).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([N:20]([CH3:22])[CH3:21])=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=1.CN(C)[CH:29]=[O:30]>>[C:23]([C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([Cl:19])[C:16]=1[N:20]([CH3:22])[CH3:21])[CH:29]=[O:30])([CH3:26])([CH3:25])[CH3:24]
Reactant: CN(C)c1c(Cl)cc(Br)cc1C(C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN(C)c1c(Cl)cc(C=O)cc1C(C)(C)C
Yield: 98.7 %

Procedure:
In a manner analogous to example 1 d, the process is carried out by a reaction of 2.25 ml (5.6 mmol) of 2.5M n-butyllithium/hexane with 1.5 g (5.2 mmol) of (4-bromo-2-tert-butyl-6-chlorophenyl)dimethylamine and 450 μl (5.8 mmol) of dimethylformamide. 1.23 g of 3-tert-butyl-5-chloro-4-dimethylaminobenzaldehyde are obtained in the form of a yellow oil (yield=99%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]1[C:14](=[O:38])[N:15]([CH2:24][C:25]([NH:27][CH:28]([CH:35]([CH3:37])[CH3:36])[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[O:26])[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:10]2=1)=[O:4].C1(C)C=CC=CC=1.ClC(Cl)C(O)=O.C(OCC)(=O)C>CS(C)=O>[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]1[C:14](=[O:38])[N:15]([CH2:24][C:25]([NH:27][CH:28]([CH:35]([CH3:36])[CH3:37])[C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])=[O:26])[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:17][C:10]2=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cccc2c1[nH]c1c(=O)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c(-c3ccccc3)cc12
Agent: O=C(O)C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)cc2c([nH]c3c(C(=O)O)cccc32)c1=O)C(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
2-(8-Methoxycarbonyl-1-oxo-3-phenyl-1,2-dihydropyrido[3,4-b]-indol-2-yl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide. To a solution of the product from Example 3.a. (0.1 g) in dimethyl sulfoxide (1 mL) and toluene (1 mL) was added 1-(3-dimethyl- aminopropyl)-3-ethylcarbodiimide hydrochloride (0.34 g) and dichloroacetic acid (0.06 mL), and the resulting solution was allowed to stir for 2 hours. The mixture was poured into ethyl acetate, washed (1N hydrochloric acid, H2O), dried and evaporated. The resulting material was chromatographed, with ether as the eluent, give the ketone (0.90 g) as a white solid; TLC: Rf =0.65, methanol:dichloromethane (2:98); MS: m/z=528(M+1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[C:15]1(O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1.O1CCCC1>[C:23]1([O:1][CH2:2][CH:3]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]2)[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: Oc1cccc2ccccc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc3ccccc23)C1
Reaction time: 24 h
Yield: 49.9 %

Procedure:
A solution of 1.0 g (4.9 mmol) of 1,1-dimethylethyl 3-(hydroxymethyl)-1-pyrrolidinecarboxylate (described in WO 0066557), 0.95 g (6.4 mmol) of 1-naphthalenol and 1.4 g (6.9 mmol) of tri-n-butylphosphine in 40 ml of toluene and 20 ml of tetrahydrofuran, cooled under nitrogen by means of an ice bath, is admixed dropwise with a solution of 1.74 g (6.9 mmol) of ADDP. The reaction mixture is allowed to return to ambient temperature and stirring is continued for 24 hours. The mixture is filtered and the precipitate is rinsed with toluene. It is evaporated to dryness. The residue is taken up in dichloromethane and washed with a 1M aqueous sodium hydroxide solution. It is dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on a silica gel column, eluting with dichloromethane and then with a 98/2 mixture of dichloromethane and methanol, to give 0.80 g of product in colorless oil form.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1.OCC1NC(=O)CC1>>[CH:2]([CH:3]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1)=[O:1]
Reactant: O=C1CCCC(CO)N1
Agent: O=C1CCC(CO)N1
Product: O=CC1CCCC(=O)N1

Procedure:
When in the procedure of Example 6 (A) an appropriate amount of 6-hydroxymethyl-2-piperidone is substituted for 5-hydroxymethyl-2-pyrrolidone, 6-formyl-2-piperidone is obtained. When an appropriate amount of 6-formyl-2-piperidone is substituted for 5-formyl-2-pyrrolidone in the procedure of Example 6 (B), 6-difluoromethyl-2-piperidone is obtained which, when substituted for 5-difluoromethyl-2-pyrrolidone in an appropriate amount in the procedure of Example 5, yields 5-amino-5-difluoromethylpentanoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].Cl[CH2:11][CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][CH2:11][CH:12]=[O:13]
Reactant: O=CCCl
Reactant: Cc1ccc(Cl)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(Cl)cc1NCC=O
Temperature: 150 °C

Procedure:
2-Methyl-5-chloroaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at about 150°C for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-chloroanilino)acetaldehyde.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:23]1(B(O)O)[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>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].O.C1(C)C=CC=CC=1>[CH:23]1([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:25][CH2:24]1
Reactant: COC(=O)c1cc(Br)c(-c2ccc(F)cc2)nc1OC(C)C
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2)nc1OC(C)C
Temperature: 25 °C
Yield: 97.4 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (635 mg) was added to a mixture of methyl 5-bromo-6-(4-fluorophenyl)-2-isopropoxynicotinate (3.65 g), cyclopropylboronic acid (2.55 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (610 mg), a 2 M aqueous sodium carbonate solution (14.9 mL), and toluene (25 mL), and the resultant mixture was stirred at 100° C. for 2 hours in an argon atmosphere. The reaction mixture was allowed to cool to room temperature and poured to water, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.18 g).
Reaction SMILES: [CH3:1][C:2]([NH:12][C:13](=O)[CH:14]=[CH2:15])([CH3:11])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:17]([CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)#[N:18]>>[NH2:18][CH2:17][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:15][CH2:14][CH2:13][NH:12][C:2]([CH3:11])([CH3:1])[CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:24]=1
Reactant: C=CC(=O)NC(C)(C)COc1ccccc1
Reactant: N#CCc1c[nH]cn1
Product: CC(C)(COc1ccccc1)NCCCn1cnc(CCN)c1

Procedure:
The title compound was prepared in a similar manner to the Example immediately above from N-(1,1-dimethyl-2-phenoxyethyl)acrylamide and 4-cyanomethyl-imidazole.
Reaction SMILES: I.[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH2:14].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>>[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH:14][C:20]([C:16]1[S:15][CH:19]=[CH:18][CH:17]=1)=[O:21]
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Agent: I
Product: O=C(Nc1nc2c(s1)Cc1ccccc1-2)c1cccs1
Yield: 17.8 %

Procedure:
Acylation 8H-Indeno[1,2-d]thiazol-2-ylamine hydroiodide 1a (Prepared in Example 1, Step 1, 100 mg; 0.32 mmol) with 2-thiophenecarbonyl chloride (0.106 mL; 0.96 mmol) in a manner similar to that described in Example 1, Step 3 provided 17 mg of Thiophene-2-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)-amide 6. EI-HRMS m/e calcd for C15H10N2OS2 (M+) 298.0235, found 298.0233.
Reaction SMILES: C[Si](N[Si](C)(C)C)(C)C.[Li]CCCC.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=O)=[CH:18][CH:17]=1.[CH2:30]([O:32][C:33](=[O:39])[CH2:34][Si](C)(C)C)[CH3:31]>C1COCC1>[OH:15][C:16]1[CH:21]=[CH:20][C:19](/[C:22](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:34]\[C:33]([O:32][CH2:30][CH3:31])=[O:39])=[CH:18][CH:17]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CCOC(=O)C[Si](C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(/c1ccccc1)c1ccc(O)cc1
Reaction time: 0.75 h
Yield: 55.9 %

Procedure:
To a solution of HMDS (21.17 g, 131.1 mmol) in THF (200 mL) was cooled to −40° C. Then it was added with n-BuLi (56.7 mL, 136.22 mmol) and stirred at same temperature for 45 min. After that (4-hydroxyphenyl)(phenyl)methanone (2 g, 10 mmol) in THF was added slowly over a period of 10 min and stirred at −40° C. to −30° C. for one hour. Then Ethyl(trimethylsilyl)acetate (2.42 g, 15.1 mmol) was added drop wise and stirred at 0° C. to 15° C. for completion of starting material (4 h). After reaction completed reaction was quenched with ammonium chloride and then THF was evaporated under vacuum and the resulted solution was partitioned between water and Ethyl acetate. The combined organic layer was dried and evaporated to get crude. The crude was purified through chromatography and triturated with n-Hexane to afford red color oil as product (1.5 g, Yield: 55.9%); 1H NMR (300 MHz, CDCl3): δ 7.31-7.33 (m, 4H), 7.01-7.74 (d, 1H), 6.7-7.16 (m, 4H), 6.25 (s, 1H), 3.94-3.99 (q, 2H), 1.07-1.10 (t, 3H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:28][CH3:29].CCOC(C)=O>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH2:28][CH3:29])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (490 mg, 1.4 mmol) in Acetone (5 mL) was added Cesium Carbonate (706 mg, 2.17 mmol); after 15 min, Iodoethane (122 uL, 1.53 mmol) was added and the mixture stirred at room temperature 5d. Conc. in vacuo onto Celite and chromatography (0-20% EtOAc:Hex, ISCO silica gel) afforded N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-ethyl-methanesulfonamide as a clear oil (400 mg, 75%). 1H-NMR (CDCl3): 8.01 (s, 1H), 6.32 (d, 1H, J=6.8 Hz), 4.03 (m, 1H), 3.76 (m, 1H), 3.33 (m, 1H), 3.20 (m, 1H), 2.91 (s, 3H), 2.41 (m, 1H), 1.92 (m, 2H), 1.72 (m, 2H), 1.40 (m, 2H), 1.21 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26]C)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]([CH3:31])[CH2:19][C:20]([F:21])([F:23])[F:22])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NCC(F)(F)F)nc2c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CC(F)(F)F)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Reaction time: 0.67 h
Yield: 20.2 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[(2,2,2-trifluoroethyl)amino]quinoxaline-6-carboxylate (400 mg, 1.05 mmol) in tetrahydrofuran (30 ml) was added sodium hydride (101 mg, 4.21 mmol) at 0° C. with stirring for 40 minutes and then iodomethane (899 mg, 6.33 mmol) was added to the reaction mixture, and the resulting mixture was allowed to react with stirring overnight at room temperature. The reaction mixture was adjusted pH to 4 with HCl to give the solid, which was collected by filtration to afford 2-(4-fluorophenyl)-3-[methyl(2,2,2-trifluoroethyl)amino]quinoxaline-6-carboxylic acid as a yellow solid (80.6 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[N:21]1([C:27]([CH3:32])([CH3:31])[C:28]([NH2:30])=[O:29])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:24]3[CH2:23][CH2:22][N:21]([C:27]([CH3:32])([CH3:31])[C:28]([NH2:30])=[O:29])[CH2:26][CH2:25]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: CC(C)(C(N)=O)N1CCNCC1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: Cn1c(CCN2CCN(C(C)(C)C(N)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (110 mg, 0.37 mmol) in DCE (10 mL) was added 2-piperazin-1-ylisobutyramide (90 mg, 0.53 mmol), trimethyl orthoformate (0.20 mL, 1.86 mmol) and acetic acid (0.02 mL, 0.37 mmol). The reaction mixture was stirred at room temperature for 3 h, sodium triacetoxyborohydride (118 mg, 0.56 mmol) was added and the resulting mixture stirred for a further 2 days. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-20% MeOH in EtOAc) to give the title compound as a pale yellow solid (71 mg, 42%). LCMS (Method H): RT=2.40 min, [M+H]+ 451.5
Reaction SMILES: CN(C=O)C.[C:6]([OH:16])(=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)([Cl:19])=O>>[C:6]([Cl:19])(=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCCC(=O)Cl

Procedure:
100.5 g (1.38 mol) of N,N,-dimethylformamide were added to 2.75 mol of pelargonic acid in a stirred apparatus. The reaction solution was brought to a temperature of from 20 to 30° C. with stirring, and a total of 2.78 mol of gaseous phosgene were introduced under atmospheric pressure. After the addition of phosgene was complete, the two phases were separated from one another. The catalyst phase comprised a molar proportion of the catalyst adduct, based on the molar amount of N,N-dimethylformamide plus catalyst adduct, of <0.05. The carbonyl chloride phase comprised 97.1 area % of pelargonoyl. chloride and 1.9 area % of pelargonic anhydride. The color number was 16 APHA.
Reaction SMILES: O([CH2:3][C:4]([OH:6])=[O:5])N.[CH3:7][C:8](=[N:10][OH:11])[CH3:9].ClCC(O)=O.[OH-].[Na+]>>[CH3:7][C:8](=[N:10][OH:11])[CH3:9].[C:4]([OH:6])(=[O:5])[CH3:3]
Reactant: NOCC(=O)O
Agent: CC(C)=NO
Agent: O=C(O)CCl
Agent: [Na+]
Product: CC(=O)O

Procedure:
Zhang, Feng and Shi, "The Preparation of Aminoxyacetic Acid", Chem. World, Vol. 9, No. 30, pp. 397-399, 1989 discloses condensing acetone oxime and chloroacetic acid in the presence of a solid acid or halide of a quaternary ammonium salt catalyst, organic solvent and sodium hydroxide at room temperature to form acetone oxime-acetic acid. Chloroacetic acid is added in excess relative to the acetone oxime. Benzene is used as the organic solvent. An approximately 6% aqueous solution of sodium hydroxide is used in an amount equimolar to the combined amount of acetone oxime and chloroacetic acid. After completion of the reaction, the aqueous solution is saturated with sodium chloride prior to exhaustive extractions with ethyl ether. Acetone oxime-acetic acid is obtained as a crude yellow oil which requires purification by vacuum distillation prior to hydrolysis to aminooxyacetic acid hemihydrochloride.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]=[CH:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:18]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1ccc(N=Cc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(C=Nc2ccc(OC)cc2)cc1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
(a) 2.38 g of 50% sodium hydride is suspended in 75 ml of anhydrous dimethylformamide, and 7.5 g of 4-[N-(4-methoxyphenyl)formimidoyl]phenol is added in four portions to the suspension at room temperature with stirring. Subsequently, 9.65 g of ethyl 2-bromo-2-methylpropionate is added dropwise to the resulting mixture at 20° to 25° C. over a period of about 40 minutes. The mixture is stirred at room temperature for 1 hour and then at 50° to 55° C. for 2 hours. The reaction mixture is poured into cold water, extracted with ether, and the extract is washed with 5% aqueous solution of sodium hydroxide until disappearance of the color of the aqueous layer, then washed with water and dried. After drying, the ether is distilled off to give 7.5 g of ethyl 2-[4-{N-(4-methoxyphenyl)formimidoyl}phenoxy]-2-methylpropionate in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1Cl.[CH:31]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CS(C)=O>Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[NH:36][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NC1CCCC1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1nc(NC2CCCC2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 130 °C
Yield: 54.2 %

Procedure:
A microwave vessel was charged 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (50 mg, 0.107 mmol), cyclopentanamine (456 μl, 5.35 mmol), hunig's base (93 μl, 0.535 mmol) and DMSO (1070 μl). The vial was sealed and heated to 130° C. for 2 hrs in a Biotage Initiator microwave reactor. The reaction mixture was brought to ambient temperature and then diluted with 1N HCl and Ethyl Acetate. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by chromatography on silica gel (100-g SNAP Ultra column, 10-100% EtOAc/Heptanes) to give 1-(5-chloro-6-(cyclopentylamino)-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (30 mg, 0.058 mmol, 54.3% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (br. s, 1 H) 8.72 (d, J=1.71 Hz, 1 H) 8.32-8.35 (m, 1 H) 8.18 (d, J=9.59 Hz, 1 H) 7.86 (dd, J=8.97, 2.23 Hz, 1 H) 7.66 (s, 1 H) 7.00 (d, J=9.02 Hz, 1 H) 6.77 (d, J=9.64 Hz, 1 H) 6.46 (d, J=6.79 Hz, 1 H) 5.57 (br. s., 1 H) 4.30-4.37 (m, 1 H) 3.72 (s, 3 H) 1.99-2.03 (m, 2H) 1.47-1.85 (m, 6 H). m/z (ESI) 516.0 (M+H)+.
Reaction SMILES: COS([O-])(=O)=O.[N+:7]([C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[CH3:20])([O-])=O.[H][H]>C(O)C.[Pt]>[NH2:7][C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH3:20]
Reactant: [H][H]
Reactant: C[n+]1ccccc1C=Cc1ccccc1[N+](=O)[O-]
Agent: [Pt]
Agent: COS(=O)(=O)[O-]
Solvent: CCO
Product: CN1CCCCC1CCc1ccccc1N
Yield: 93.6 %

Procedure:
2-(2-Nitrostyrenyl)-1-methylpyridinium methyl sulfate (III; 25 g, 0.07 moles) and 10 g of 5% Pt on carbon (50% water wet) in 300 mL of 95% ethanol was put in a 2L Parr hydrogenation flask and hydrogenated at approximately 2 psi of hydrogen for 16 hours. The hydrogenation mixture rapidly turned orange and then slowly became colorless as the organic solid dissolved. Catalyst was removed by filtration and held for subsequent runs. The filtrate was concentrated in vacuo to an oil which was dissolved in 50 mL water and made basic (pH~11) with 50% sodium hydroxide solution. The basic aqueous phase was extracted with 50 and 25 mL portions of methylene chloride, the extracts were combined and dried (anhyd. K2CO3) , filtered and the solid removed in vacuo to yield 14.3 g (92%) of product II as an amber oil. This intermediate diamine oil (cf: U.S. 3,931,195; Example 1) was used directly in the next step of the process.