Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:20][CH2:21][OH:22])(=[N:10][S:11]([CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=1.Cl.[Br:24][C:25]1[C:26]([NH:32][C@H:33]([CH3:38])[C:34]([CH3:37])([OH:36])[CH3:35])=[N:27][C:28](Cl)=[N:29][CH:30]=1>C(#N)C.O.O1CCOCC1>[Br:24][C:25]1[C:26]([NH:32][C@H:33]([CH3:38])[C:34]([OH:36])([CH3:35])[CH3:37])=[N:27][C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:20][CH2:21][OH:22])(=[N:10][S:11]([CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])(=[O:12])=[O:13])=[O:9])=[CH:4][CH:3]=2)=[N:29][CH:30]=1
Reactant: C[Si](C)(C)CCS(=O)(=O)N=S(=O)(CCO)c1ccc(N)cc1
Reactant: C[C@@H](Nc1nc(Cl)ncc1Br)C(C)(C)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: C[C@@H](Nc1nc(Nc2ccc(S(=O)(CCO)=NS(=O)(=O)CC[Si](C)(C)C)cc2)ncc1Br)C(C)(C)O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A solution of 200 mg (0.55 mmol) of (RS)-S-(4-aminophenyl)-S-(2-hydroxyethyl)-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide in 2 ml of acetonitrile and 0.5 ml of water is mixed with 0.17 ml of a 4N solution of HCl in dioxane. 198 mg (0.67 mmol) of (R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol in 1.5 ml of acetonitrile is added, and the batch is stirred for 20 hours at 80° C. The solvent is removed, and the remaining residue is purified by chromatography (DCM/EtOH 9: 1). 148 mg (0.24 mmol, corresponding to 44% of theory) of the product is obtained.
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:22])=[N-]>ClCCl>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19][CH3:22])=[O:18])[C:12]2=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(c1ccccc1)c1ccc2n1CCC2C(=O)O
Solvent: ClCCl
Product: COC(=O)C1CCn2c(C(=O)c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
A solution of 200 mg. of 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml. of dichloromethane is treated with an excess of ethereal diazomethane, and the reaction mixture is maintained at room temperature for 30 minutes. The solvents and excess reagent are eliminated under reduced pressure and the residue crystallized from ethyl acetate-methanol, to yield methyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5]1[N:6]=[N:7][NH:8][N:9]=1.[Cl:12][C:13]1[C:14]([N:19]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]([CH:28]3[CH2:30][O:29]3)=[N:20]2)=[N:15][CH:16]=[CH:17][CH:18]=1.O>O1CCCC1.C(O)(=O)C>[Cl:12][C:13]1[C:14]([N:19]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]([CH:28]([OH:29])[CH2:30][N:7]3[N:8]=[N:9][C:5]([C:4]([F:11])([F:10])[F:3])=[N:6]3)=[N:20]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1nn[nH]n1
Reactant: COC(=O)c1cc(C2CO2)nn1-c1ncccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(O)Cn2nnc(C(F)(F)F)n2)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
51.5 mg (2.14 mmol) of sodium hydride were initially charged in 15 ml of tetrahydrofuran, and a solution of 1380 mg (2.32 mmol) of a 25% strength solution of 5-(trifluoromethyl)-2H-tetrazole in tetrahydrofuran was added at 0° C. After 20 minutes of stirring at 0° C., 500 mg (1.78 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-(oxiran-2-yl)-1H-pyrazole-5-carboxylate were added, and the mixture was stirred at reflux temperature for 20 hours. The reaction mixture was poured into water, acidified with glacial acetic acid and then extracted repeatedly with ethyl acetate. The combined organic phases were washed with water and then dried over magnesium sulphate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel, which gave 286 mg (80% of theory) of methyl 1-(3-chloropyridin-2-yl)-3-{1-hydroxy-2-[5-(trifluoromethyl)-2H-tetrazol-2-yl]ethyl}-1H-pyrazole-5-carboxylate and methyl 1-(3-chloropyridin-2-yl)-3-{1-hydroxy-2-[5-(trifluoromethyl)-1H-tetrazol-1-yl]ethyl}-1H-pyrazole-5-carboxylate in a ratio of 66:34. (logP: 2.64/2.68; MH+: 418.0; 1H-NMR (400 MHz, CD3CN, δ, ppm): 3.73 (s, 3H), 4.31 (m, 2H), 4.48 (m, 1H), 7.10 (m, 1H), 7.54 (m, 1H), 8.05 (m, 1H), 8.50 (m, 1H).)
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:21])[CH2:7][CH2:8][N:9]2[C:14]=1[CH2:13][CH2:12][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10]2)([O:3][CH3:4])=[O:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.C(Cl)(Cl)Cl>CCOCC>[C:1]([CH:5]1[CH:14]2[N:9]([CH2:10][CH:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)[CH2:8][CH2:7][C:6]1=[O:21])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1=C2CCC(c3ccccc3)CN2CCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1C(=O)CCN2CC(c3ccccc3)CCC12
Reaction time: 1 h
Yield: 44.9 %

Procedure:
Compound I (15.1 g.) was suspended in ether and LiAlH4 (1.5 g.; 0.75 equiv.) was added portionwise at room temperature. The mixture was stirred for 1 hr. at room temperature. The mixture was treated with wet THF and the mixture filtered. The filtrate was treated with CHCl3 /H2O, the CHCl3 separated, dried and the solvent removed in vacuo. Yield, 9 g. The filter-cake was stirred repeatedly with CHCl3 and an additional 4.1 g. of material was obtained. The 13.1 g. was chromatographed on a silica gel column. Compound II was eluted with CHCl3. Yield, 6.82 g. (44.9% yield).
Reaction SMILES: Cl[C:2]1N=C2C(N=CN2C2CC(N3C=C(CC)N=N3)C(O)C2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:47]1([CH:53]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH2:54][NH:55][C:56]2[N:64]=[C:63](NCCN3CCCCC3)[N:62]=[C:61]3[C:57]=2[N:58]=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3C=[C:82]([CH2:84]O)[CH:81]=[N:80]3)[C@@H:76]([OH:86])[C@H:75]2[OH:87])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[N:94]1([C@@H:99]2[CH2:103][CH2:102][NH:101][CH2:100]2)[CH2:98][CH2:97][CH2:96][CH2:95]1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[N:94]1([C@@H:99]2[CH2:103][CH2:102][N:101]([C:63]3[N:62]=[C:61]4[C:57]([N:58]=[CH:59][N:60]4[C@@H:74]4[CH2:78][C@H:77]([N:79]5[N:80]=[C:81]([CH2:82][CH3:84])[CH:2]=[N:3]5)[C@@H:76]([OH:86])[C@H:75]4[OH:87])=[C:56]([NH:55][CH2:54][CH:53]([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:88]4[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=4)[N:64]=3)[CH2:100]2)[CH2:98][CH2:97][CH2:96][CH2:95]1
Reactant: CCc1cn(C2CC(n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C(O)C2O)nn1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: C1CCN([C@@H]2CCNC2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N6CCCC6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from 3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA9) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 461 by replacing 1-(2-amino-ethyl)piperidine with (R)-[1,3′]bipyrrolidinyl (intermediate EB). MS (ES+) m/e 649.46 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[C:21]1([O:27][CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>B(F)(F)F.CCOCC.C(Cl)Cl>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([C:24]1[CH:25]=[CH:26][C:21]([O:27][CH3:28])=[CH:22][CH:23]=1)[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: COc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(OC)cc1

Procedure:
A solution of 290 mg. (1 mmol.) of N-t-butyoxycarbonyl-2-acetoxyglycine n-butyl ester, 0.5 ml. of anisole and 3 drops of boron trifluoride etherate in 5 ml. of methylene chloride was stirred at 25° for 4 hours. The solvent was removed and the residue was chromatographed on silica gel and eluted with 1:1 chloroform-hexane to give the title compound.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][O:27]5)[CH:20]=4)[C:15]3=[O:31])=[CH:10][C:9]=2[O:32][CH3:33])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:35][CH2:36][CH2:37][F:38].[C:39](=O)([O-:41])[O-:40].[Cs+].[Cs+]>CN(C=O)C>[F:38][CH2:37][CH2:36][CH2:35][O:41][C:39]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][O:27]5)[CH:20]=4)[C:15]3=[O:31])=[CH:10][C:9]=2[O:32][CH3:33])[CH2:2][CH2:3]1)=[O:40]
Reactant: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCNCC1
Reactant: FCCCBr
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCN(C(=O)OCCCF)CC1
Reaction time: 8 h

Procedure:
To a solution of 2-(4-[1,4]Diazepan-1-yl-3-methoxy-phenyl)-6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-2H-isoquinolin-1-one (50 mg) and 1-Bromo-3-fluoro-propane (18 mg) in DMF (1 mL) was added cesium carbonate (54 mg) and the mixture was stirred overnight. The crude mixture was purified by preparative HPLC. The product with the molecular weight of 553.64 (C30H36FN3O6) was obtained in this way; MS (ESI): 554 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:6][C:5]=1[CH2:32][CH3:33])[CH3:2].[OH-].[Na+].Cl>O1CCCC1.O>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:6][C:5]=1[CH2:32][CH3:33])[CH3:35]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO)c(-c3ccc(N(CC)CC)c(CC)c3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2OCCCO)ccc1N(CC)CC
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
Into a 25 mL three-necked flask under a nitrogen atmosphere, equipped with a magnetic stirrer, are placed 270 mg (0.57 mmol) of ethyl 4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate (Example 10d) and 22 mg (5.7 mmol) of solid sodium hydroxide in 5.4 mL of tetrahydrofuran. The reaction medium is heated at the reflux temperature of the tetrahydrofuran for 5 hours. The reaction medium is concentrated under vacuum. The crude reaction product obtained is taken up in water and the pH of the medium thus obtained is adjusted to pH=4 by addition of hydrochloric acid solution in a proportion of 1 mol/L. The precipitate obtained, after stirring for 30 minutes, is purified by chromatography on silica (eluent: 40/60 heptane/ethyl acetate) to give, after evaporation of the fractions, 80 mg (yield=31%) of 4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid in the form of a cream-colored powder (m.p.=204° C.).
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:14]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[C:28]5[C:33](=[CH:34][CH:35]=4)[N:32]=[C:31]([C:36]4[N:37]=[C:38]([C@@H:41]6[CH2:46][C@@H:45]7[C@@H:43]([CH2:44]7)[N:42]6C(OC(C)(C)C)=O)[NH:39][CH:40]=4)[CH:30]=[CH:29]5)=[CH:22][CH:21]=3)[N:19]=2)[CH2:13][C@@H:12]2[C@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1.CO.C(Cl)Cl>[ClH:1].[C@@H:43]12[CH2:44][C@@H:45]1[CH2:46][C@@H:41]([C:38]1[NH:39][CH:40]=[C:36]([C:31]3[CH:30]=[CH:29][C:28]4[C:33](=[CH:34][CH:35]=[C:26]([C:23]5[CH:24]=[CH:25][C:20]([C:18]6[N:19]=[C:15]([C@@H:14]7[CH2:13][C@@H:12]8[C@@H:10]([CH2:11]8)[NH:9]7)[NH:16][CH:17]=6)=[CH:21][CH:22]=5)[CH:27]=4)[N:32]=3)[N:37]=1)[NH:42]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(-c2ccc(-c3ccc4nc(-c5c[nH]c([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)n5)ccc4c3)cc2)c[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: c1cc(-c2c[nH]c([C@@H]3C[C@H]4C[C@H]4N3)n2)ccc1-c1ccc2nc(-c3c[nH]c([C@@H]4C[C@H]5C[C@H]5N4)n3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 150.7 %

Procedure:
A solution of 4M HCl (1 mL, 4.00 mmol) in dioxane was added to a suspension of tert-butyl (1R,3S,5R)-3-(4-(6-(4-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)-2-quinolinyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (130 mg, 0.186 mmol) in dioxane (3 mL), MeOH (0.5 mL) and DCM (3 mL) and the mixture was stirred at rt for 2 h. The reaction was concentrated to yield an HCl salt of 2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-6-(4-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)quinoline (140 mg) as yellow solid. LC-MS retention time 2.063 min; m/z 500.37 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 9.09 (d, J=9.0 Hz, 1H), 8.66 (s, 1H), 8.56-8.62 (m, 2H), 8.47-8.53 (m, 2H), 8.07 (s, 1H), 8.02-8.06 (m, 4H), 4.97 (dd, J=10.8, 8.0 Hz, 1H), 3.65-3.71 (m, 1H), 3.55-3.65 (m, 2H), 2.73-2.86 (m, 3H), 2.61-2.72 (m, 1H), 2.07-2.20 (m, 2H), 1.25-1.35 (m, 2H), 1.07 (t, 2H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:26]([C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=4)(=[O:28])=[O:27])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(N2CCC3(CC2)OCCO3)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC4(CC3)OCCO4)cc2)cc1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine (which was obtained in Example 214) and 4-methoxybenzenesulfonyl chloride according to the procedure of Example 215 as a crystalline solid; 1H NMR (300 MHz, DMSO-d6) δ 1.65 (t, J=5.6 Hz, 4H), 3.15 (t, J=5.6 Hz, 4H), 3.79 (s, 3H), 3.88 (s, 4H), 6.79 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0Hz, 2H), 7.60 (d, J=9.0Hz, 2H), 9.63 (s, 1H); MS (ES) m/z: 405.3 (MH+); HRMS Calcd. for C20H24N2O5S(M+): 404.1406. Found: 404.1402. Anal. Calcd. for C20H24N2O5S: C, 59.39; H, 5.98; N, 6.93. Found: C, 59.48; H, 6.03; N, 6.85.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]=O>>[Br:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(F)ccc1Br
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(F)ccc3Br)CC2)nc[nH]1

Procedure:
6-[4-(2-Bromo-5-fluoro-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-bromo-5-fluorobenzaldehyde. Mass spectrum (ES) MH+=367.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([NH2:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]([O:18][C:19](=[O:24])[NH:20][CH2:21][CH:22]=O)([CH3:17])([CH3:16])[CH3:15].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C@H:4]([NH:12][CH2:22][CH2:21][NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H](Cc1ccccc1)NCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
(2R)-2-Amino-3-phenylpropionic acid methyl ester (3.2 g; 15.0 mmol) and (2-oxoethyl)carbamic acid tert-butyl ester (3.2 g; 20.0 mmol) (prepared as in Dueholm et al, Org. Prep. Proced. Int. 25(4), 457-61 (1993)) were dissolved in a mixture of methanol (100 ml) and acetic acid (5 ml). Molecular sieves (3 Å; 100 g) were added and the reaction mixture was cooled to 0° C. Sodium cyanoborohydride (1.38 g; 22.0 mmol) was added portionwise and the reaction mixture was left without stirring for 12 h. The reaction mixture was filtered and water (100 ml), aqueous sodium hydrogencarbonate/sodium carbonate (10%; 100 ml; pH 9) and methylene chloride (50 ml) were added to the filtrate. The aqueous phase was extracted with methylene chloride (2×50 ml) and the combined organic phases were dried over magnesium sulfate. The organic phase was evaporated in vacuo and the residue was chromatographed on silica (4×40 cm) using ethyl acetate/heptane (3:2) as eluent to afford 2.07 g of (2R)-2-(2-(tert-butoxycarbonylamino)ethylamino)-3-phenylpropionic acid methyl ester.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[F:19][C:20]([F:29])([F:28])[C:21]([O:23]C(C)(C)C)=O.[CH3:30][N:31]([CH3:38])[C:32]1[O:36][N:35]=[C:34]([CH3:37])[N:33]=1.Cl>O1CCCC1>[CH3:30][N:31]([CH3:38])[C:32]([NH:33][C:34]1[CH:37]=[C:21]([C:20]([F:19])([F:28])[F:29])[O:23][N:35]=1)=[O:36]
Reactant: Cc1noc(N(C)C)n1
Reactant: CC(C)(C)OC(=O)C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)C(=O)Nc1cc(C(F)(F)F)on1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Dry tetrahydrofuran (84.6 ml) was added to diisopropylamine (dried with potassium hydroxide, 9.85 g, 0.0973 mole) nder a nitrogen atmosphere. The solution was cooled to -60° C. and thereto was added a 15% solution of n-butyllithium in n-hexane (58.5 ml, 0.0901 mole). After being stirred at 0° C. for 30 minutes, it was cooled to -75° C. A mixture of t-butyl trifluoroacetate (10.80 g, 0.0635 mole), 5-dimethylamino-3-methyl-1,2,4-oxadiazole (5.72 g, 0.0423 mole) and dry tetrahydrofuran (423 ml) was added dropwise to it at -73--75° C. over 1.5 hours. After being stirred at -75° C. for 1 hour, it was allowed to warm to room temperature over 1 hour. It was further heated to 50° C. and stirred for 30 minutes. 1N hydrochloric acid (190 ml) was then added thereto with ice cooling and tetrahydrofuran and n-hexane were distilled off under reudced pressure in a water bath at 40° C. After being extracted with methylene chloride, the extract was concentrated and purified column chromatrography on silica gel to give the crude title compound (8.91 g, crude yield 94.4%). Repeated recrystallizations from benzene gave colorless fine needles, m.p. 126.0°-126.5° C. The structure of this compound was confirmed by IR, NMR and elemental analysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:27]([F:30])([F:29])[F:28])=[C:18]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCN(C2N=NC(C(F)(F)F)=C([C:50]3[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=3)C=2)CC1)=O)(C)(C)C.FC1C=CC(B(O)O)=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:27]([F:30])([F:29])[F:28])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:50]4[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=4)=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(Br)cc3)c(C(F)(F)F)nn2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(F)cc3)c(C(F)(F)F)nn2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)c1ccc(F)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(-c4ccc(F)cc4)cc3)c(C(F)(F)F)nn2)CC1
Yield: 56 %

Procedure:
A mixture of 4-[5-(4-bromophenyl)-6-trifluoromethyl-pyridazin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.2 g, 0.41 mmol) (prepared by procedures similar to those described for D8), 4-fluorobenzeneboronic acid (0.069 g, 0.49 mmol), trans-Pd(OAc)2(Cy2NH)2 (0.015 g, 0.026 mmol), prepared by following the procedure described in Tao, B.; Boykin, D. W. Tetrahedron Lett. 2003, 44, 7993-7996, and potassium phosphate (0.261 g, 1.23 mmol) in dioxane (3 ml) was stirred at 80° C. overnight. The reaction mixture was then diluted with dichloromethane and extracted with a saturated solution of sodium carbonate. The organic layers were separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was then purified by column chromatography (silica gel; dichloromethane/heptane 3:7 to 10:0). The desired fractions were collected and evaporated in vacuo to yield D12 (0.115 g, 56%). C26H26F4N4O2 requires 502; Found 503 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cc(F)cc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cc(F)cc(Cl)c1

Procedure:
The title compound was synthesized from methyl 4-(3-chloro-5-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.045 g, 0.15 mmol) and lithium hydroxide (0.063 g, 1.5 mmol in 2 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane followed by reverse phase chromatography from MeOH and water (0.1% formic acid) to afford the title compound: 3.7 mg, 8.4% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.03-2.16 (m, 1H) 2.46-2.60 (m, 1H) 2.60-2.73 (m, 2H) 2.79 (dd, J=7.35, 2.03 Hz, 2H) 3.26 (m, 1H) 6.32 (s, 1H) 6.91 (dd, J=9.57, 1.51 Hz, 1H) 7.02 (dt, J=8.63, 2.13 Hz, 1H) 7.06 (s, 1H); 19F NMR δ ppm −114.32 (t, J=0.8 Hz); LCMS-MS (ESI−) 292.0 (M−H); HPLC (UV=100%), (ELSD=100%).