Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[NH2:22][C:23]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[O:36]([C:34]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])=[C:23]([NH:22][C:19]([C:16]2[CH:17]=[N:18][C:13]([N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)=[CH:14][CH:15]=2)=[O:21])[CH:35]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: O=C(O)c1ccc(N2CCCCC2)nc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1ccc(N2CCCCC2)nc1
Reaction time: 1 h

Procedure:
1.3 mL of methylene chloride, 1.3 μL of N,N-dimethylformamide and 0.031 mL of oxalyl chloride were added sequentially to 69 mg of 6-(piperidin-1-yl)pyridine-3-carboxylic acid at room temperature, and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 57 mg of tert-butyl 2-amino-4-phenoxybenzoate, 3.7 mL of methylene chloride and 0.22 mL of triethylamine and stirred at room temperature for 2 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=8:1] to obtain tert-butyl 4-phenoxy-2-(6-(piperidin-1-yl)pyridine-3-carboxamido)benzoate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[Cl:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:17][C:15]=2[N:16]=1.C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([NH:6][S:21]([C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([Cl:11])[S:13][C:14]=2[CH:20]=1)(=[O:22])=[O:23])[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: O=S(=O)(Cl)c1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](NS(=O)(=O)c1ccc2nc(Cl)sc2c1)C(C)C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
(D)-valine methylester hydrochloride (0.33 g, 2.0 mmol) was dispersed in dichloromethane (5 mL) and cooled down to 0° C. 2-Chloro-6-benzthiazolsulfonyl chloride (0.5 g, 1.0 equi.) prepared in Example 13 was dissolved in dichloromethane (3 mL) to give a dichloromethane solution. Triethylamine (0.83 mL, 3 equi.) and the dichloromethane solution were added while maintaining the temperature of 0° C. When starting material was exhausted after 5 hours, the organic phase was washed with 1N HCl, dried over MgSO4 and distilled under reduced pressure. Then, the product was eluted and purified on silica gel chromatography using ethylacetate/n-hexane (1/3) solvent to prepare the titled compound, (2R)-3-methyl-2-[(2-chlorobenzthiazol-6-sulfonyl)amino] butanoic acid methylester (0.65 g, 90%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2[C@@H:11]3[C@H:16]([CH2:17][CH2:18][C:9]=2[CH:8]=[CH:7][CH:6]=1)[N:15]([C:19]([C:21]1[CH:29]=[CH:28][C:24]2[NH:25][CH:26]=[N:27][C:23]=2[CH:22]=1)=[O:20])[CH2:14][CH2:13][CH2:12]3)=O>C(Cl)Cl.CO>[NH:25]1[C:24]2[CH:28]=[CH:29][C:21]([C:19]([N:15]3[C@@H:16]4[C@@H:11]([C:10]5[C:5]([CH2:3][OH:2])=[CH:6][CH:7]=[CH:8][C:9]=5[CH2:18][CH2:17]4)[CH2:12][CH2:13][CH2:14]3)=[O:20])=[CH:22][C:23]=2[N:27]=[CH:26]1
Reactant: COC(=O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3c(CO)cccc3CC[C@@H]21
Yield: 46 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-10-carboxylic acid methyl ester following a procedure analogous to that described in Example 34. Yield: 46% of theory; TLC: rf=0.27 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:29][CH:30]=3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: Cc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.273 g, 2.4 mmol) and 6-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.279 g, 2.4 mmol) in the presence of 2.0 equivalents of K2CO3 (0.593, 4.3 mmol) in dimethylformamide at 90° C. Yield 0.167 g (50%) of a tan powder. mp C. FDMS m/e=405 (M+ of free base).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH3:11][O:12][CH2:13][CH2:14]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:12][CH2:13][CH2:14][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COCCCl
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccccc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
140 g (1010 mmol) 2-nitrophenol, 105 g (1110 mmol) chloroethyl methyl ether, 84.2 g (507 mmol) KI and 153 g (1110 mmol) K2CO3, were suspended in 500 ml DMF, in a 2 l Erlenmeyer flask heated at 110±5° C. for 6 h. The solvent was evaporated and the residue was dissolved in 500 ml CHCl3 and 500 ml water. The organic phase was washed with 2×500 ml 2.5% Na2CO3, 500 ml sat. NaCl and dried over Na2SO4. The solvent was evaporated to afford 201 g (100%) light yellow oil. H1NMR (CDCl3) δ (ppm) 3.45 (s,3H), 3.78(t,2H), 4.25(t,2H), 7.02(dd,1H), 7.10(dd,1H), 7.50(dd,1H), 7.82(dd,1H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[F:15].C([Li])CCC.[C:21](=[O:23])=[O:22].[F-].[Cs+]>C(#N)C>[F:15][C:3]1[C:4]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:5]([F:10])[C:6]([F:9])=[C:7]([CH3:8])[C:2]=1[C:21]([OH:23])=[O:22]
Reactant: O=C=O
Reactant: Cc1c(F)c(F)c([Si](C)(C)C)c(F)c1Br
Agent: [Cs+]
Agent: [F-]
Agent: [Li]CCCC
Solvent: CC#N
Product: Cc1c(F)c(F)c([Si](C)(C)C)c(F)c1C(=O)O
Yield: 62 %

Procedure:
This preparation route is very expensive. The first and the second synthesis step each involve reaction with butyllithium and diisopropylamine in tetrahydrofuran at −78° C., and the third synthesis step involves reaction with butyllithium in ether, likewise at −78° C. In the first step, 1-bromo-2,4,5-trifluorobenzene is reacted first with lithium diisopropylamide and then with trimethylsilyl chloride, the resulting 1-bromo-2,4,5-trifluoro-3-(trimethylsilyl)benzene (88% yield) is once more reacted with lithium diisopropylamide and subsequently with methyl trifluoromethanesulfonate, the resulting 1-bromo-2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)benzene (75% yield) is reacted with butyllithium and subsequently with CO2 in the form of dry ice, and the resulting 2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)- benzoic acid (62% yield) is reacted with cesium fluoride in acetonitrile to give 6-methyl-2,4,5-trifluorobenzoic acid (89% yield).
Reaction SMILES: C1([C:11](=[O:31])/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)C2C(=CC=CC=2)C=CC=1.C(C1C2C(=CC=CC=2)C=CC=1)(=[O:34])C.O(C[CH2:53][CH2:54][CH2:55][C:56]1[CH:63]=[CH:62][CH:61]=[CH:60][C:57]=1[CH:58]=[O:59])C1C=CC=CC=1>>[O:24]([CH2:23][CH2:22][CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C@@H:13]1[O:34][C@H:12]1[C:11]([O:59][C:58]1[C:57]2[C:56](=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:55]=[CH:54][CH:53]=1)=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)c1cccc2ccccc12
Reactant: O=C(/C=C/c1ccccc1CCCCOc1ccccc1)c1cccc2ccccc12
Reactant: O=Cc1ccccc1CCCCOc1ccccc1
Product: O=C(Oc1cccc2ccccc12)[C@@H]1O[C@H]1c1ccccc1CCCCOc1ccccc1

Procedure:
Preparation of (E)-1-(1-naphthalenyl)-3-[2-(4-phenoxybutyl)phenyl]-2-propen-1-one. Using the method of Example 5a, 1'-acetonaphthone is reacted with 2-(4-phenoxybutyl)benzaldehyde in alcohol solution to give the titled compound.
Reaction SMILES: Br[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17]3[C:22]([C:23](Br)=[C:24]4[C:29]=2[CH:28]=[CH:27][CH:26]=[CH:25]4)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:31]1([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].[N+:50]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([O-])=O>[Cu].C1(C)C=CC=CC=1>[C:38]1([N:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[C:17]4[C:22]([C:23]([N:50]([C:2]5[CH:15]=[CH:10][CH:9]=[CH:8][CH:3]=5)[C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)=[C:24]5[C:29]=3[CH:28]=[CH:27][CH:26]=[CH:25]5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]3)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Brc1c2ccccc2c(-c2c3ccccc3c(Br)c3ccccc23)c2ccccc12
Reactant: O=[N+]([O-])c1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccccc2)c2c3ccccc3c(-c3c4ccccc4c(N(c4ccccc4)c4ccccc4)c4ccccc34)c3ccccc23)cc1
Yield: 55 %

Procedure:
In a flask were placed 35 g of 9,9′-bianthryl and 300 mL of carbon tetrachloride, and to the vigorously stirred mixture was slowly added 40 g of bromine under cooling. After addition, the mixture was slowly warmed and then refluxed for 1 hour with stirring. Carbon tetrachloride was evaporated from the reaction mixture under a reduced pressure, the residual solid was extracted with carbon tetrachloride using a Soxhlet extractor. The extract was dried and concentrated to give 42 g(yield 81%) of 10,10′-dibromo-9,9′-bianthryl. Then, in a 100 mL three-necked flask were placed 25 g of 10,10′-dibromo-9,9′-bianthryl, 20 g of diphenylamine, 17 g of potassium carbonate, 0.4 g of copper powder and 80 mL of nitrobenzene, and the mixture was stirred at 200° C. for 30 hours. After completion of the reaction, toluene was added to the mixture. The mixture was filtered to remove inorganics. Toluene and nitrobenzene were evaporated under a reduced pressure. The residue was purified by column chromatography on silica gel eluting with a 1:2 mixture of toluene and ligroin, to give 19 g(yield: 55%) of 10,10′-bis(diphenylamino)-9,9′-bianthryl.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH:10]([C:13]1[CH:32]=[CH:31][CH:30]=[CH:29][C:14]=1[O:15][CH2:16][C:17]([NH:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1)=[O:18])([CH3:12])[CH3:11].O>ClCCCl.CCCCCC>[CH:10]([C:13]1[CH:32]=[C:31]([C:3](=[O:4])[CH2:2][Cl:1])[CH:30]=[CH:29][C:14]=1[O:15][CH2:16][C:17]([NH:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1)=[O:18])([CH3:12])[CH3:11]
Reactant: CC(C)c1ccccc1OCC(=O)Nc1nc2ccccc2s1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Solvent: CCCCCC
Product: CC(C)c1cc(C(=O)CCl)ccc1OCC(=O)Nc1nc2ccccc2s1
Reaction time: 0.33 h

Procedure:
To a solution of chloroacetyl chloride (10.0 ml) in anhydrous 1,2-dichloroethane (250 ml) is added aluminum chloride (12 g) at room temperature, and the mixture is stirred for 20 minutes. To the mixture is added at once 2-(2-isopropylphenoxymethylcarbonylamino)benzothiazole (20 g), and the mixture is stirred at room temperature for one hour. The reaction mixture is poured into water, and thereto is added n-hexane. The precipitates are collected by filtration, washed with water, and dried to give 2-[2-isopropyl-4-(2-chloroacetyl)phenoxymethylcarbonylamino]benzothiazole (25.9 g).
Reaction SMILES: [CH:1]([NH:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.Cl.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:22][NH2:23]>C(O)(=O)C>[CH2:5]([C:4]1[N:22]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=2[Cl:14])[N:23]=[CH:1][N:3]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CNC(=O)Cc1ccccc1
Reactant: NNc1cccc(Cl)c1Cl
Agent: Cl
Solvent: CC(=O)O
Product: Clc1cccc(-n2ncnc2Cc2ccccc2)c1Cl

Procedure:
N-Formylphenylacetamide (Finkbeiner J. Org. Chem. 1965, 30; 2861) (200 mg, 1.22 mmol) and 2,3-dichlorophenylhydrazine hydrochloride (314 mg, 1.47 mmol) were combined in glacial acetic acid (8 mL) and refluxed under a nitrogen atmosphere for 1 hour and then concentrated under reduced pressure at 60° C. The residue was purified by flash chromatography eluting with hexanes/ethyl acetate (6/1) to provide the title compound. MS (ESI+) m/z 305 (M+1H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 4.02 (s, 2H) 6.97-7.02 (m, 2H) 7.16-7.25 (m, 3H) 7.52-7.58 (m, 2H) 7.88 (dd, J=6.8, 3.1 Hz, 1H) 8.16 9s, 1 H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1>CN(C)C=O.C(OCC)(=O)C>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([N:22]2[CH2:21][CH2:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:1]2=[O:2])[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (8.73 g, 53.8 mmol) was added to a solution of tert-butyl 4-{[2-(2-aminophenyl)ethyl]amino}piperidine-1-carboxylate (17.2 g, 53.8 mmol) in dimethylformamide (200 mL), and stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate and extracted with water, then saturated brine. The crude product was purified by chromatography (silica gel, 0-30% ethyl acetate in methylene chloride gradient elution). The title compound was obtained as a dark solid (4.8 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24](O)=[O:25])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH2:39])[CH:34]=[CH:35][C:36]=1[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH:39][C:24](=[O:25])[CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:28][CH3:29])=[O:27])[CH:34]=[CH:35][C:36]=1[CH3:37]
Reactant: Cc1ccc(CN)cc1Br
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(C)c(Br)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (1.110 g, 2.75 mmol), 1-(3-bromo-4-methylphenyl)methanamine (0.600 g, 3.00 mmol), HATU (1.331 g, 3.5 mmol) and triethylamine (0.976 ml, 7.0 mmol) in dichloromethane (35 mL) was stirred at room temperature under N2. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated NaHCO3, followed by saturated NaCl. The organic layer was dried over Na2SO4, and then evaporated to dryness which gave, initially, a glassy gum, but then appeared to very slowly crystallize. The residue was taken up in a small amount of MeOH and sonicated whereupon a crystalline white solid formed and was collected and dried to give N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (1.16 g, 72%). LC-MS m/z 585.4 (M+H)+, 0.87 min (ret time).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])C.[NH4+:14].[OH-]>>[CH3:12][S:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([NH2:14])=[O:3])(=[O:11])=[O:10]
Reactant: [NH4+]
Reactant: CCOC(=O)CCCNS(C)(=O)=O
Agent: [OH-]
Product: CS(=O)(=O)NCCCC(N)=O

Procedure:
A solution of 4-methanesulfonylamino-butyric Acid ethyl ester (7.08 g, 33.8 mmol) in concentrated NH4OH (200 mL) was stirred at room temperature for 66 h. The reaction mixture was concentrated to afford the title compound as a white solid (6.16 g). The product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.30 (s, 3H), 3.05-3.09 (m, 2H), 2.91 (s, 3H), 2.24-2.30 (m, 2H), 1.80-1.85 (m, 2H); MS 181 (M++1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[NH2:15][CH:16]([CH3:18])[CH3:17].[BH4-].[Na+].O>CO.C(Cl)Cl>[CH:16]([NH:15][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: CC(C)N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)NC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.3 %

Procedure:
A solution of tert-butyl 3-oxopiperidine-1-carboxylate (2 g, 10.03 mmol) and 2-aminopropane (710 mg, 12.04 mmol) in MeOH (40 mL) was stirred at rt for 1 h. To the solution was added NaBH4 (758 mg, 20.06 mmol) at 0° C. and the reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with ice-cooled water and the solvent was reduced to afford a residue which was dissolved in CH2Cl2 and washed with water. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled compound (2 g, 82%). 1H NMR (400 MHz, CDCl3): δ 4.01-3.90 (m, 1H), 3.78 (dt, J=3.6, 9.2 Hz, 1H), 3.48 (s, 1H), 2.96 (heptate, 0.1=6.4 Hz, 1H), 2.92-2.79 (m, 1H), 2.69-2.55 (m, 1H), 1.90-1.87 (m, 1H), 1.68-1.61 (m, 1H), 1.46 (s, 9H), 1.29-1.18 (m, 2H), 1.05 (d, J=6.0 Hz, 6H). ES-MS: m/z [M+1]=243.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH2:14][OH:15])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:23]1([C:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:23]1([C:29]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:3]2[N:2]=[N:1][C:5]([C:6]3[CH:7]=[C:8]([CH:12]=[CH:13][CH2:14][OH:15])[CH:9]=[CH:10][CH:11]=3)=[N:4]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCC=Cc1cccc(-c2nnn[nH]2)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCC=Cc1cccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-[3-(1H-tetrazol-5-yl)phenyl]-2-propenol (2.02 g) in dry dichloromethane (50 ml) was added triethylamine (1.5 ml) followed by triphenylchloromethane (2.8 g) in dry dichloromethane. The solution was stirred at room temperature for 90 minutes, washed with water (50 ml), followed by sodium bicarbonate solution (5%; 50 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a pale brown viscous oil which crystallised on standing to a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23](O)=[O:24])=[CH:13][C:12]=2[N:11]=1.C(Cl)(=O)C(Cl)=O.[F:32][C:33]1([F:40])[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:39][CH:36]3[CH2:37][CH2:38][C:33]([F:40])([F:32])[CH2:34][CH2:35]3)=[O:24])=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Reactant: NC1CCC(F)(F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc2c(o1)c(C(=O)NC1CCC(F)(F)CC1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 11.5 %

Procedure:
The title compound was prepared following the procedure described for Example-177 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.100 g, 0.265 mmol), oxalyl chloride (0.2 mL), 4,4-difluorocyclohexanamine (0.069 g, 0.397 mmol), THF (5.0 mL), DIPEA (0.103 g, 0.795 mmol) and TEA (0.2 mL). The obtained crude product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.66-1.68 (m, 2H), 1.90-2.15 (m, 6H), 2.60 (s, 3H), 4.01 (s, 1H), 7.36 (m, 1H), 7.50 (s, 1H), 7.58 (d, J=7.2 Hz, 2H), 7.89 (s, 1H), 9.38 (s, 1H), 11.46 (s, 1H); MS [M+H]+: 494.41.
Reaction SMILES: [CH3:1][C:2]1[O:11][C:10](=[O:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([CH:14]([CH3:16])[CH3:15])[O:5][C:4]=2[CH:3]=1.[F-].[Cs+].CC(O)(C)C.Cl>C(OC)(C)(C)C>[OH:5][C:4]1[CH:3]=[C:2]([CH3:1])[O:11][C:10](=[O:12])[C:9]=1[C:8](=[O:13])[CH:7]=[CH:6][CH:14]([CH3:15])[CH3:16]
Reactant: Cc1cc2c(c(=O)o1)C(=O)CC(C(C)C)O2
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: COC(C)(C)C
Product: Cc1cc(O)c(C(=O)C=CC(C)C)c(=O)o1
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A mixture of 108 mg of 2,3-dihydro-7-methyl-2-(1-methylethyl)-4H, 5H-pyrano[4,3-b]pyran-4,5-dione, 200 mg of cesium fluoride and 5m1 of 2-methyl-2-propanol was stirred for 2 hours under reflux-heating. After that, methyl t-butyl ether and 3% hydrochloric acid were added to the reaction mixture. The separated organic layer was washed with saturated brine once, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 86 mg of 4-hydroxy-6-methyl-3-(4-methyl-2-pentenoyl)-2-pyrone.