Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:11][CH2:10][N:9]([C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[OH:18])[CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH:19]1([CH2:25][CH2:26][CH2:27]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O>CN(C)C=O>[O:6]1[C:7]2([CH2:11][CH2:10][N:9]([C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[O:18][CH2:27][CH2:26][CH2:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:8]2)[O:3][CH2:4][CH2:5]1
Reactant: O[C@H]1CCCC[C@@H]1N1CCC2(C1)OCCO2
Reactant: BrCCCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C1CCC(CCCO[C@H]2CCCC[C@@H]2N2CCC3(C2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (200 mg, 8.33 mmol) in anhydrous dimethylformamide (20 mL) was added a solution of (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)cyclohexanol (1.5 g, 6.6 mmol) in anhydrous dimethylformamide (10 mL). The resulting mixture was stirred at room temperature for 30 min. and then a solution of 3-(cyclohexyl)propyl bromide (1.67 g, 8.15 mmols) in anhydrous dimethylformamide was quickly added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (200 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic extracts were back-washed with brine (50 mL) and the solvent was evaporated in vacuo. The residue was taken up with water (50 mL) and the pH was adjusted to pH 1.0 with 6M HCl aqueous solution. The acidic aqueous solution was extracted with diethyl ether (2×50 mL), then basified to pH 5.0-5.5 with 5M NaOH aqueous solution and extracted with diethyl ether (3×50 mL). The combined organic extracts at pH 5.0-5.5 were concentrated in vacuo to provide the crude title compound suitable for the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]2[NH:20][CH:19]([CH3:21])[O:18][C:17]([CH3:23])([CH3:22])[C:16]=2[CH:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH:19]([CH3:21])[O:18][C:17]([CH3:23])([CH3:22])[C:16]=3[CH:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Product: CC1Nc2ccc(-c3cccc(F)c3)cc2C(C)(C)O1

Procedure:
Prepared according to the coupling procedure for Example 17 from 3-fluorophenyl boronic acid and 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine. A yellow solid: mp 139-140° C.; 1H-NMR (CDCl3) δ 7.40-7.19 (m, 6H), 7.01-6.94 (m, 1H), 6.72 (d, 1H, J=8.24 Hz), 4.90 (q, 1H, J=5.48 Hz), 1.62 (s, 3H), 1.59 (s, 3H), 1.46 (d, 3H, J=5.5 Hz); MS (ES) m/z 272 ([M+H]+).
Reaction SMILES: C(OC([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:15]2)[CH:13]([CH3:29])[CH2:12]1)=O)C1C=CC=CC=1>CO.O1CCCC1.[C].[Pd]>[CH3:29][CH:13]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:15]2)[NH:11][CH2:12]1
Reactant: CC1CN(C(=O)OCc2ccccc2)C12CCCN(c1ncnc3[nH]ccc13)C2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CNC12CCCN(c1ncnc3[nH]ccc13)C2
Yield: 93.2 %

Procedure:
To a solution of an optically-active compound of 3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylic acid benzyl ester (2.84 g) in methanol/tetrahydrofuran (14 ml/14 ml) was added 10% palladium carbon (568 mg), and the mixture was hydrogenated under 4 atmospheres. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was slurry-washed with toluene/tetrahydrofuran (95/5, 9 ml) to give the titled compound (1.74 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][CH2:13][CH:14]=O)[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:14]=[CH:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1
Reactant: O=CCNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Agent: O=S(=O)(O)O
Product: Brc1ccc2c(c1)C(c1ccccn1)=NCc1nccn1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A solution of 15 g. (37 mmol) of [[7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2-yl]amino]acetaldehyde, dimethyl-acetal in 50 ml. of concentrated sulfuric acid, is allowed to stir at room temperature under nitrogen overnight, poured onto crushed ice and crystallized with an aqueous sodium hydroxide solution. After the product is extracted with chloroform the chloroform extract is washed with brine, dried over sodium sulfate and concentrated to an oil in vacuo. On trituration, with ethyl acetate 10.2 g. (81%) of yellow crystalline 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine of melting point 208°-210° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:17]=[CH:16][N:15]=1.C(N(CC)C(C)C)(C)C.Cl[C:43]([C:45]1[CH:46]=[C:47]([CH:56]=[CH:57][CH:58]=1)[CH2:48][S:49][CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:44]>ClCCl>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:43]([C:45]3[CH:46]=[C:47]([CH:56]=[CH:57][CH:58]=3)[CH2:48][S:49][CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:44])=[C:3]([C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=4)[CH:17]=[CH:16][N:15]=3)[CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccn1
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 0 °C
Yield: 109.2 %

Procedure:
Into a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(2-(2-amino-5-(piperidin-1-yl)phenyl)pyridin-4-yl)-3-(trifluoromethyl)benzamide (100.0 mg, 0.23 mmol, 1.00 equiv) and N,N-diisopropylethylamine (0.2 mL) in dichloromethane (20 mL). This was followed by dropwise addition of a solution of methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate 22d (74.0 mg, 0.27 mmol, 1.20 equiv) in dichloromethane (2.0 mL) with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was combined with the solution of the previous batch and then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (100˜100:1˜50:1). The product was obtained as 170 mg (70%) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[CH:29]=O)=[CH:17][CH:16]=1.N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2/[CH:29]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)=[CH:17][CH:16]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COC(=O)c1ccc(Oc2ccc(Br)cc2C=O)cc1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)c1ccc(Oc2ccc(Br)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)cc1
Yield: 73.7 %

Procedure:
In a manner similar to the method described in Example 1a, 6-chlorooxindole (1.6 g, 9.2 mmol) (Crescent) was reacted with 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester (2.8 g, 8.4 mmol) and pyrrolidine in methanol at 90° C. for 2 h to give E/Z-4-[4-bromo-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-benzoic acid methyl ester as a bright yellow solid (Yield 3 g, 81%).
Reaction SMILES: CC(C)([S@@]([NH:6][C@H:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH3:8])=O)C.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CO>[NH2:6][CH:7]([CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]1)[CH3:8]
Reactant: C[C@H](N[S@@](=O)C(C)(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(N)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 110.5 %

Procedure:
To a 1 L round bottomed flask charged with a magnetic stir bar was added crude tert-butyl 4-((S)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)piperidine-1-carboxylate (29 g) was taken up in MeOH (200 mL) before addition of a 4 N solution of HCl in 1,4-dioxane (24.06 ml, 96 mmol). The resulting solution was then stirred at room temperature for 1H at rt. The methanol was then removed in vacuo to afford viscous oil which was treated with sat'd aqueous NaHCO3 (˜500 mL) and extracted with ethyl acetate (2×500 mL). This organic phase was combined, dried with MgSO4, filtered, and solvent was then removed in vacuo affording the title compound (22 g) which was used without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[C:20]([OH:21])=[C:19]2[C:14]([CH:15]=[C:16]([C:23]([OH:25])=O)[C:17](=[O:22])[O:18]2)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12>CN(C=O)C>[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:23]([C:16]3[C:17](=[O:22])[O:18][C:19]4[C:14]([CH:15]=3)=[CH:13][CH:12]=[C:11]([OH:10])[C:20]=4[OH:21])=[O:25])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2ccc(O)c(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2ccc(O)c(O)c2oc1=O
Temperature: 25 °C

Procedure:
DIEA (43.1 μL, 0.25 mmol) was added to 7,8-dihydroxy-3-carboxy-coumarin (50 mg, 0.23 mmol) and HATU (94.1 mg, 0.25 mmol) in 2 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (47.1 mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo for final product: LCMS (ESI) m/z 414 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][NH2:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[OH:8].S1C2C=CC=CC=2N=C1S[C:24](=[O:40])[C:25]([CH3:39])([O:27][N:28]1C(=O)C2=CC=CC=C2C1=O)[CH3:26]>C(#N)C>[NH2:28][O:27][C:25]([CH3:39])([CH3:26])[C:24]([NH:13][NH:12][S:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)(=[O:10])=[O:11])=[O:40]
Reactant: CC(C)(ON1C(=O)c2ccccc2C1=O)C(=O)Sc1nc2ccccc2s1
Reactant: NNS(=O)(=O)c1ccc(O)c(O)c1
Solvent: CC#N
Product: CC(C)(ON)C(=O)NNS(=O)(=O)c1ccc(O)c(O)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 204 mg of 3,4-dihydroxybenzenesulphonic hydrazide and 379 mg of 2-methyl-2-(phthalimidooxy)thiopropionic acid S-(2-benzothiazolyl) ester was heated to 60° C. in 5 ml of acetonitrile for 3 hours. After cooling, any undissolved material was filtered off under suction. The filtrate was freed from solvent in a vacuum and the residue was taken up in 3 ml of ethanol. The suspension was treated with 100 mg of hydrazine hydrate and stirred at 20° C. for 1 hour. A clear solution first resulted, from which a white precipitate separated out. Undissolved material was filtered off and the filtrate was evaporated in a vacuum. The crystalline residue was triturated with 10 ml of 0.1N aqueous hydrochloric acid for 10 minutes and the insoluble material was separated by filtration. The filtrate was adjusted to pH 7 by the addition of 2N aqueous sodium hydroxide solution and chromatographed on MCI gel CHP2OP, with elution being carried out first with 2% aqueous acetic acid and then with water/methanol (9:1, v/v). By evaporation of the product fractions in a vacuum, there was obtained 2-[2-(aminooxy)-2-methylpropionyl]-1-[(3,4-di-hydroxyphenyl)sulphonyl]hydrazine as white crystals of melting point 220° C. (dec.).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:23])[C:12]3[C:17]([S:18](=[O:22])(=[O:21])[C:19]=2[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3>C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:23])[C:12]3[C:17]([S:18](=[O:22])(=[O:21])[C:19]=2[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CN1c2ccccc2S(=O)(=O)c2cc(CO)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN1c2ccccc2S(=O)(=O)c2cc(CCl)ccc21
Reaction time: 1 h
Yield: 100 %

Procedure:
Thionyl chloride (5 ml) was added to a mixture of 3-hydroxymethyl-10-methylphenothiazine-5,5-dioxide (1.23 g, 4.47 mmol) and chloroform (15 ml), and the mixture was stirred for 1 hour. The reaction mixture was concentrated under a reduced pressure, water was added to the residue, and the reaction product was extracted with chloroform. The extract was washed with water and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure to give the title compound (1.32 g, 100%) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]=[N+]=[N-])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+]>CO>[CH2:23]([NH:1][CH2:2][CH2:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(Oc2ccc(CCN)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
Take up the mixture of 4-[4-(2-aminoethyl)phenoxy]benzenesulfonyl azide (0.210 g, 0.661 mmol) in methanol (9.9 mL). Add benzaldehyde (0.20 mL, 1.98 mmol) and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH4 (0.075 g, 1.98 mmol) and stir for 1.5 hours. Filter the reaction mixture and purify by flash 40 chromatography, eluting with 3% (2.0 M NH3 in methanol), 30% hexanes and 67% ethyl acetate to give the title compound (0.0696 g, 25.8%): TOF MS ES+383.1 (M+H)+, HRMS calcd for C21H23N2O3S 383.1429 (M+H)+. found 383.1436, time 0.33 min; TLC [silica gel 60 F254, 10% (2.0 M NH3 in methanol) in dichloromethane] Rf=0.31.
Reaction SMILES: Cl.Cl.[F:3][C@H:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[C@H:6]([CH3:19])[CH2:5]1.C(OC([N:27]([CH2:40][CH:41]1[CH2:43][CH2:42]1)[CH2:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([C@@H:29]([CH2:28][NH:27][CH2:40][CH:41]2[CH2:43][CH2:42]2)[C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:12]3[C:7]4[C@H:6]([CH3:19])[CH2:5][C@@H:4]([F:3])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:18][CH2:17]2)=[O:31])=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1C[C@@H](F)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](F)c2ncnc(N3CCN(C(=O)[C@H](CNCC4CC4)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(5R,7R)-7-Fluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.535 g, 1.730 mmol) and (S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chloropheny)propanoic acid (0.6122 g, 1.730 mmol) were combined in methylene chloride (15 mL) and treated with diisopropylethylamine (0.9041 ml, 5.191 mmol). HBTU (0.6579 g, 1.730 mmol) was then added. The reaction was stirred at ambient temperature for 16 hours. ESI MS looked excellent for desired product. The reaction was quenched with 10% Na2CO3, diluted with methylene chloride and separated. The aqueous portion was washed with methylene chloride (2×), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The material was applied to a 40 mm samplet and air-dried. This was placed on top of a column (Biotage 40S) and eluted with 3:2 hexane/EtOAc. The major spot was collected to give tert-butyl(S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(cyclopropylmethyl)carbamate as a white solid (955 mg, 96%). LC/MS (APCI+) m/z 571.9 [M+H]+
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([Br:21])[N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@H]1CC[C@H](c2ncc3c(C)nccn32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1
Temperature: 25 °C

Procedure:
To (trans)-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (5.49 mmol, 1.5 g) in N,N-dimethylformamide (15 ml) was added N-bromosuccinimide (5.49 mmol, 0.977 g) and the mixture was stirred at room temperature. After one hour saturated aqueous sodium hydrogencarbonate solution was added and extracted with dichloromethane three times. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. The crude product was purified using column chromatography (silica gel; dichloromethane/methanol (gradient 0 to 5% methanol)) to give the title compound (1.8 g).
Reaction SMILES: Cl.[C:2]1([C:7]2([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.O>C(O)C.[OH-].[Na+]>[ClH:18].[C:2]1([C:7]2([CH2:13][CH2:14][N:15]([CH3:16])[CH3:17])[CH2:11][CH2:10]/[C:9](=[CH:23]\[C:22]3[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=3)/[C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: CN(C)CCC1(C2=CCCC2)CCCC1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)CCC1(C2=CCCC2)CC/C(=C\c2ccc(Cl)cc2)C1=O
Reaction time: 12 h

Procedure:
To a solution of 1.0 g (3.9 mmole) of 2-(1-cyclopenten-1-yl)-2-dimethylaminoethyl cyclopentanone hydrochloride and 8.1 mmole of 4-chloro-benzaldehyde in 40 ml of ethanol, 3.2 ml of 5N NaOH was added dropwise. The resulting mixture was stirred at about room temperature for about 12 hours and then mixed with 60 ml of water and extracted with ether. The ether extract was extracted with 6N HCl. The HCl extract was basified and extracted with ether, and then dried over anhydrous MgSO4. The ether solution was treated with ethanolic hydrogen chloride to give a precipitate, which was recrystallized from ethanol to give the 2-(1-Cyclopenten-1-yl)-2-dimethylaminoethyl-5-(E)-[(4-chloro) benzylidene] cyclopentanone hydrochloride. The melting point of the product was determined to be 234°-236° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:22])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:22][S:24]([CH3:23])(=[O:26])=[O:25])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1CC1(NS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of N-t-butoxycarbonyl-4-amino-4-(2-methylbenzyl)piperidine (305 mg, 1.0 mmol), methane-sulfonyl chloride (0.31 ml, 4.0 mmol), and pyridine (0.1 ml, 1.2 mmol) in CH2Cl2 (2 mL) is stirred at room temp. overnight. Then concentrate the reaction mixture in vacuo and purify the residue by column chromatography on silica to afford the product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21](OC)=[O:22])=[CH:15][CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[CH2:21][OH:22])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
Methyl 3-(4-(2-quinolinylmethyloxy)benzyl)benzoate (0.002 mol) in tetrahydrofuran (50 ml) is added dropwise to a tetrahydrofuran (50 ml) suspension of lithium aluminium hydride (0.004 mol). After consumption of the ester, the remaining lithium aluminum hydride is quenched by the addition of water and filtration to remove the resulting salts. Evaporation of the solvent gives 3-(4-(2-quinolinylmethyloxy)benzyl)benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:25][CH2:24][O:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:26])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:25][CH2:24][O:23][CH2:22]3)[C:17]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=3)=[O:18])[C:10](=[O:26])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC2CCOC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CC2CCOC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
900 mg (purity 94%, 2.1 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoic acid (mixture of racemic diastereomers) and 446 mg (2.3 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 682 mg (purity 97%, 54% of theory) and 113 mg (purity 92%, 9% of theory)
Reaction SMILES: CN([CH:4]=[N:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:10]=1)=[S:7])C.[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22](=[O:25])[CH2:23]Br.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([C:23]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:16])=[O:17])[CH:10]=2)=[N:5][CH:4]=1)=[O:25]
Reactant: CN(C)C=NC(=S)Nc1cccc(S(C)(=O)=O)c1
Reactant: O=C(CBr)c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(Nc2ncc(C(=O)c3ccccc3F)s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
To a solution of 37 mg (0.13 mmol) 1-Dimethylaminomethylene-3-(3-methanesulfonyl-phenyl)-thiourea in 0.33 ml DMF was added 28 mg (0.13 mmol) 2-Fluorophenacyl bromide and the mixture was allowed to stir at room temperature for 16 h. 17 mg (0.13 mmol) diisopropylethylamine was added and the mixture was subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient to yield 38.5 mg (79%) of the title compound after evaporation of the product fractions.