Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[CH:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C[O:42][C:43]([C@@H:45]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C@@H:46]1[NH:52][CH2:53][C:54]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=1)=O.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:60][C:57]1[CH:58]=[CH:59][C:54]([CH2:53][N:52]2[C:17](=[O:18])[C:16]([C:11]3[NH:10][C:9]4[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=4[S:13](=[O:15])(=[O:14])[CH:12]=3)=[C:43]([OH:42])[C@@H:45]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]23)=[CH:55][CH:56]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(C1=C(O)[C@@H]3CCCCC[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (prepared as described in Example 25 h, 0.365 g, 1.10 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.223 g, 1.16 mmol) and N-methylmorpholine (0.256 mL, 2.33 mmol) were added sequentially to a solution of cis-2-(4-fluoro-benzylamino)-cycloheptanecarboxylic acid methyl ester (prepared as described in Example 2b, 0.310 g, 1.10 mmol) in N,N-dimethylformamide (6 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol (30 mL) at 25° C. A 21% w/w solution of sodium ethoxide in ethanol (1.44 mL, 4.44 mmol) was added and the reaction mixture was heated to 60° C. for 1 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep Column; 30-100% ethyl acetate in hexanes) to afford cis-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (0.340 g, 0.610 mmol, 55%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: (1:1 mixture of tautomers) 0.86-0.90 (m), 1.15-1.19 (m), 1.27-1.36 (m), 1.46-1.66 (m), 2.01-2.05 (m), 3.06 (s), 3.31 (s), 3.50-3.54 (m), 3.98-4.41 (1H, m), 4.26-4.33 (m), 4.95-5.05 (m), 5.52 (d, J=16.1 Hz), 5.61 (d, J=15.9 Hz), 5.69 (d, J=15.4 Hz), 5.89 (d, J=16.4 Hz), 7.15-7.26 (m), 7.40-7.41 (m), 7.48-7.51 (m), 7.57-7.61 (m), 10.14 (s), 10.18 (s). LC-MS (ESI) calcd for C26H28FN3O6S2 561.14, found 562.4 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=2)=O)=[N:5][N:4]=[N:3]1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][N:21]=[C:7]([C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: NO
Reactant: Cn1nnnc1C(=O)c1cccc(OC(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cn1nnnc1C(=NO)c1cccc(OC(F)(F)F)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a stirred solution of (1-methyl-1H-tetrazol-5-yl)[3-(trifluoromethoxy)phenyl]methanone (5.12 g, 16.2 mmol) in dry pyridine (25 mL) was added hydroxylamine hydrochloride (2.81 g, 40.4 mmol). The mixture was stirred at 70° C. for 3 h, then left to stand overnight. After concentration of the reaction mixture in vacuo, the residue was diluted with ethyl acetate (100 mL) and washed with water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL), the combined organic layers dried (MgSO4), concentrated in vacuo and dissolved in toluene. A crystalline precipitate appeared, which was filtered off to afford N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-[3-(trifluoromethoxy)phenyl]methanimine as a white solid [4.33 g, yield 92%; HPLC/MS:m/z=288 (M+H); log P(HCOOH)=2.37].
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:19][CH2:20][CH3:21])[C@H:14]([OH:18])[C:15](O)=[O:16])=[O:11])([CH3:8])([CH3:7])[CH3:6].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.C([O-])(O)=O.[Na+]>O.C1COCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:15](=[O:16])[C@@H:14]([OH:18])[C@@H:13]([NH:12][C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[CH2:19][CH2:20][CH3:21])[CH2:3][CH2:2]1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)O
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Temperature: 40 °C
Reaction time: 14 h

Procedure:
Cyclopropylamine (2.77 g, 48.53 mmol) was dropwise added to an ethyl acetate (108 g) solution of (2S,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid (10.0 g, 40.44 mmol). The mixture was cooled by ice. A mixed solution of HOBt monohydrate (1.86 g, 12.13 mmol)/THF (9.3 g)/water (1.9 g)=1/5/1 and a mixed solution of EDC hydrochloride (8.53 g, 44.48 mmol)/water (8.5 g)=1/1 were dropwise added in that order, and the mixture was stirred for 14 hours with cooling by ice. Next, 5% NaHCO3 aqueous solution (50 g) was added, and the mixture was heated up to 40° C. Then, the aqueous layer was removed. The organic layer was washed once with 5% NaHCO3 aqueous solution (50 g) at 40° C., and finally washed with water (50 g), to obtain a solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (reaction yield: 97 mol %, extraction yield: 98 mol %, chemical purity: 96.0 area %).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[F:42][C:39]([F:40])([F:41])[CH2:38][NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:25])([F:1])[F:26])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCC(F)(F)F)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCC(F)(F)F)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2,2,2-trifluoroethyl)-benzenesulfonamide (example B.1) according to general procedure II. Yellow solid. MS (ISP) 610.0 [(M−H)−]; mp 259° C.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: NCc1ccncc1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCc2ccncc2)cc1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
4-geranyloxybenzoic acid(2.47 g) was dissolved in chloroform(50 ml) and triethylamine(2.49 ml), and then diphenylphosphinic chloride(1.72 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(aminomethyl)pyridine(0.97 g) added thereto, was stirred for 4 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 3.10 g of the aimed compound.
Reaction SMILES: [CH2:1](I)[CH3:2].CN(C=O)C.[Br:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>O>[Br:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[O:22][CH2:1][CH3:2]
Reactant: COC(=O)c1cc(O)c(Br)c(OC)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 1.0-liter egg plant-type flaks, ethyl iodide (6.91 mL, 86 mmol) was added to a DMF (150 mL) solution of the previously-obtained methyl 4-bromo-3-hydroxy-5-methoxybenzoate and potassium carbonate (11.9 g, 86 mmol), and stirred overnight at room temperature. Water was added to the reaction solution, the formed precipitate was taken out through filtration and dried under reduced pressure to obtain the title compound as a colorless solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.Cl.[CH3:19]O>>[CH3:19][O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([NH2:2])=[CH:17][CH:16]=1
Reactant: Nc1ccc(OCCCCCC(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCCOc1ccc(N)cc1

Procedure:
To a mixture of 6-(4-Amino-phenoxy)-hexanoic acid hydrochloride 20 (150 grams, 578 mmol) in methanol (3 liters) was passed dry HCl gas at 10° C. for 1 hour and refluxed for 48 hours. Methanol (1.5 liter) was distilled off, ice water (1 liter) was added and the pH was adjusted to 7.5 with K2CO3. Crude 21 was extracted into chloroform, washed with 5% NaHCO3 solution in water, dried over Na2SO4 and distilled to give 21 (60 g, 43.8) as a thick brown syrup. The structure was confirmed with NMR.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)=O>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:23]([NH:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[CH2:14][NH:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:32]
Reactant: Cc1cccc(NC(=O)OCc2ccccn2)c1CCl
Reactant: Cc1nc2c(N)cccn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)OCc2ccccn2)c1CNc1cccn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 8-amino-2,3-dimethylimidazo[1,2-a]-pyridine (0.58 g), 2-pyridinylmethyl (2-chloromethyl-3-methylphenyl)carbamate (1.04 g), sodium carbonate (0.95 g) and sodium iodide (0.2 g) in acetone (25 ml) is stirred at RT for 16 h. The precipitate is filtered off and washed with acetone, and the filtrate is concentrated on a rotary evaporator. The residue is taken up in sodium hydrogencarbonate solution (40 ml) and extracted with dichloromethane (3×40 ml). The combined organic extracts are washed with water (70 ml), dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: ethyl acetate). After concentration of the main fraction and crystallization from acetone, 0.4 g (27%) of the title compound of m.p. 163-165° C. is obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1.Cl.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[C:12]1([N:8]2[CH2:7][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[O:10][C:9]2=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OC(CCCCCl)CN1c1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: O=C1OC(CCCCN2CCN(c3ccccc3)CC2)CN1c1ccccc1
Yield: 91.1 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(4-chlorobutyl)-3-phenyl-2-oxazolidinone (3.0 g, 0.01186 mol), 1-phenylpiperazine hydrochloride (2.35 g, 0.01186 mol), potassium carbonate (6.54 g, 0.0473 mol), and potassium iodide (1.0 g) in 1-butanol gave a liquid (4.1 g, 91% yield) which crystallized upon standing. Recrystallization from isopropanol/isopropyl/-ether and drying under high vacuum gave 1.44 g, mp 83°-85° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][O:27]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:31](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:31][N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:12][CH:11]=3)[N:15]=[C:16]([NH:24][CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][O:27]3)[C:17]=2[CH2:23]1
Reactant: CC(=O)O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@@H]4CCCO4)n2)CNCC3)cc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@@H]4CCCO4)n2)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
(5)-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (55 mg, 0.14 mmol) was dissolved in methanol (3 mL). Acetic acid (7.76 μL, 0.14 mmol) was added followed by formaldehyde (10.10 μL, 0.14 mmol) and sodium cyanoborohydride (8.52 mg, 0.14 mmol). The reaction mixture was stirred for 1 h at room temperature and the solvent was evaporated under reduced pressure. The crude was purified by preparative HPLC yielding (S)-6-methyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (19.30 mg, 33.9%). MS (ES+) m/z 417.8 (M−H)−
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([CH2:40][OH:41])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:42])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([CH2:40][OH:41])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:42])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1cc(CO)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(CO)c2ccc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C

Procedure:
To 10 mL of an ethyl acetate solution containing 220 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-hydroxymethyl-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 5 mL of 4 mol/L hydrogen chloride/ethyl acetate was added and stirred at room temperature. The resulting solid was filtered, 5 mL of 4 mol/L hydrochloric acid was added and stirred at room temperature. To the reaction mixture, methanol was added, and the solvent was removed under reduced pressure to give 118 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-hydroxymethyl-7-methoxyquinolin-2(1H)-one hydrochloride as a pale yellow solid.
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[CH:8]=[C:9]([CH2:23][CH2:24][C:25]#[N:26])[CH:10]=[C:11]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[C:12]=1[Cl:13].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCOCC>[Cl:6][C:7]1[CH:8]=[C:9]([CH2:23][CH2:24][C:25]#[N:26])[CH:10]=[C:11]([CH2:14][OH:15])[C:12]=1[Cl:13]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CCC#N)cc(Cl)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCCc1cc(Cl)c(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a THF (0.1 M) solution of 3-[3,4-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]propanenitrile (1 eq.) from the previous step was added TBAF (1.0 M THF solution, 1.2 eq.). The resulting solution was stirred at RT for 3 h. The reaction was then diluted with ether and quenched with water. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2([C:13](=[O:14])[NH:12][CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[O:5].[F:19][C:20]([F:31])([F:30])[CH:21]([C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)[OH:22]>>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2([C:13](=[O:14])[N:12]([C:26]3[CH:27]=[CH:28][C:23]([CH:21]([OH:22])[C:20]([F:30])([F:31])[F:19])=[CH:24][CH:25]=3)[CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)(C)CC(=O)N1CCC2(CCNC2=O)CC1
Reactant: OC(c1ccc(I)cc1)C(F)(F)F
Product: CC(C)(C)CC(=O)N1CCC2(CC1)CCN(c1ccc(C(O)C(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(3,3-dimethyl-butyryl)-2,8-diaza-spiro[4.5]decan-1-one and 2,2,2-trifluoro-1-(4-iodo-phenyl)-ethanol. Light yellow crystalline solid. MS (ESI): 427.3 MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:12]([CH3:21])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>C1(O)CCCCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22]([O:24][CH:25]2[CH2:4][CH2:3][CH2:2][CH2:7][CH2:26]2)=[O:23])[N:12]([CH3:21])[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: OC1CCCCC1
Product: Cn1c(C(=O)OC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxylate (28 mg, 0.07 mmol) from Example 36, Step A (Method B) in cyclohexanol (2 mL) and methylene chloride (1 mL) was added a catalytic amount of sodium hydride (60% in mineral oil, <5 mg). The mixture was stirred at rt for 2 hr and then poured into aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (3×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound. HPLC/MS: 463 (M+1), 465 (M+3); Rt=4.50 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11](O)=[O:12])=O.[CH3:15][NH:16][NH2:17]>C(O)C.C(OCC)(=O)C>[CH3:15][N:16]1[C:11](=[O:12])[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[C:4]([CH2:3][CH:2]([CH3:14])[CH3:1])=[N:17]1
Reactant: CNN
Reactant: CC(C)CC(=O)c1sccc1C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)Cc1nn(C)c(=O)c2ccsc12

Procedure:
2-(3-Methyl-1-oxobutyl)thiophene-3-carboxylic acid (5.3 g) prepared in a) above was dissolved in ethanol (30 ml) and methylhydrazine (1.5 ml) added. The resultant mixture was heated to reflux for 10 hours. The reaction mixture was evaporated and the residue obtained was dissolved in ethyl acetate. The organic phase was washed twice with dilute hydrochloric acid, twice with saturated sodium hydrogen carbonate solution and once with brine, then dried and evaporated. Purification by chromatography eluting with iso-hexane/ethyl acetate (2:1 to 1:1) gave the sub-title compound as an oil (3.05 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:3]=1[C:4]([OH:6])=[O:5].COC(C1C2N=C(N)[NH:23][C:22]=2C=CC=1)=O.BrC#N>CO>[NH2:23][C:22]1[NH:11][C:10]2[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[C:3]([C:4]([OH:6])=[O:5])[C:2]=2[N:1]=1
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: COc1ccc(N)c(N)c1C(=O)O
Agent: N#CBr
Solvent: CO
Product: COc1ccc2[nH]c(N)nc2c1C(=O)O

Procedure:
0.8 g (4.4 mmol) of 2,3-diamino-6-methoxy-benzoic acid was subjected to a similar cyclization condition as illustrated in intermediate A by using 0.7 g (6.6 mmol) of BrCN in methanol to produce 2-amino-5-methoxy-1H-benzoimidazole-4-carboxylic acid. LCMS: 208 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](O)=[O:7].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([Cl:17])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Yield: 100 %

Procedure:
3-methoxy-4-nitrobenzoic acid (Aldrich; 9 g, 45.65 mmol) was suspended in toluene (90 mL) and thionyl chloride (9.99 mL, 136.95 mmol) added and the mixture heated to reflux for 1 hour. The reaction was evaporated to yield the title compound as a brown solid (9.84 g, 100%).
Reaction SMILES: [C:1]([O:7]C)(=O)[CH2:2][C:3]([CH3:5])=O.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[C:18]1[CH:22]=[N:21][NH:20][C:19]=1[NH2:23].C(O)C>C(O)(=O)C>[CH3:5][C:3]1[NH:23][C:19]2[N:20]([N:21]=[CH:22][C:18]=2[C:11]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[CH3:9])[C:1](=[O:7])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1cc(C)c(-c2cn[nH]c2N)c(C)c1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)c(-c2cnn3c(=O)cc(C)[nH]c23)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
Methyl acetoacetate (0.7 ml) was added to a solution of 4-(2,4,6-Trimethyl-phenyl)-2H-pyrazol-3-ylamine (1.120 g, 5.57 mmol) in 5 ml of acetic acid and the resulting mixture was heated at reflux for two days. Reaction mixture cooled and a white solid formed. Ethanol (6 ml) was added and stirred at room temperature overnight, filtered to give white solid which was recrystallized from ethanol to give 673 mg(45.2%) of the title compound as white crystals. 1H NMR (DMSO-d6) ä 11.9(s, 1H), 7.7(s, 1H), 6.95(s, 2H), 5.55(s, 1H), 2.25(s, 3H), 2.20(s, 3H), 2.0(s, 6H)ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(F)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(F)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.5 %

Procedure:
To a solution of 4-(5-fluoro-2-methoxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (2.0 g, 6.5 mmol) produced in Example (106a) in methanol (30 mL) was added 10% palladium on carbon (0.99 g, wet), the mixture was stirred for 17 hours at atmospheric pressure and room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure to give 2.0 g of the title compound as a light yellow oil.