Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C@H:4]1[C@H:7]([C:8]#[CH:9])[NH:6][C:5]1=[O:10])[CH3:3].[H][H]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[OH:1][CH:2]([C@H:4]1[C@H:7]([CH:8]=[CH2:9])[NH:6][C:5]1=[O:10])[CH3:3]
Reactant: C#C[C@@H]1NC(=O)[C@H]1C(C)O
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: C=C[C@@H]1NC(=O)[C@H]1C(C)O
Yield: 98.6 %

Procedure:
A solution of trans-3-(1-hydroxyethyl)-4-ethynyl-2-azetidinone (0.10 g) in ethanol (5 ml) is subjected to catalytic reduction with hydrogen gas in the presence of Lindlar catalyst (0.01 g). The reduction is continued until 14 ml of hydrogen gas has been absorbed. The catalyst is then filtered off and the filtrate is concentrated under reduced pressure to give 0.1 g of trans-3-(1-hydroxyethyl)-4-vinyl-2-azetidinone.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:8])([CH3:7])[C:5]([CH3:10])([CH3:9])[NH:4][C:3]1=[O:11].C([Li])CCC.CCCCCC.[Br:23][CH:24]([CH3:28])[C:25](Br)=[O:26].P([O-])([O-])([O-])=O>O1CCCC1>[Br:23][CH:24]([CH3:28])[C:25]([N:4]1[C:5]([CH3:9])([CH3:10])[C:6]([CH3:8])([CH3:7])[N:2]([CH3:1])[C:3]1=[O:11])=[O:26]
Reactant: CN1C(=O)NC(C)(C)C1(C)C
Reactant: CC(Br)C(=O)Br
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(Br)C(=O)N1C(=O)N(C)C(C)(C)C1(C)C
Reaction time: 0.08 h

Procedure:
To a solution of 1,4,4,5,5-pentamethylimidazolidin-2-one (14 mg; 0.091 mmol) in dry tetrahydrofuran (0.2 ml), a 1.57 N solution of n-butyl lithium in hexane (0.06 ml; 0.1 mmol) was added at 0° C. After 5 minutes, a solution of 2-bromopropionyl bromide (24 mg; 0.11 mmol) in dry tetrahydrofuran (0.1 ml) was added thereto at the same temperature and followed by stirring for 10 minutes. A phosphate buffer (pH 7.0) was added to decompose the excess reaction agent. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were successively washed with a 5% aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was purified by preparative thin layer chromatography (benzene:ethyl acetate=5:1) to give 3-(2'-bromopropionyl)-1,4,4,5,5-pentamethylimidazolidin-2-one.
Reaction SMILES: [CH2:1]([NH:7][C@@H:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].C([Li])CCC.[C:21]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[CH3:26]>>[CH2:1]([N:7]([C@@H:8]([CH3:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C@@H:23]([CH:24]=[CH:25][CH3:26])[CH2:22][C:21]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6]
Reactant: C/C=C/C=C/CN[C@@H](C)c1ccccc1
Reactant: C/C=C/C=C/C(=O)OC(C)(C)C
Agent: [Li]CCCC
Product: CC=CC=CCN([C@@H](C=CC)CC(=O)OC(C)(C)C)[C@@H](C)c1ccccc1
Yield: 128.9 %

Procedure:
(S)-(E,E)-N-Hexa-2,4-dienyl-α-methylbenzylamine (3) (0.500 g, 2.49 mmol), 1.6M butyllithium (1.35 ml, 2.16 mmol) and t-butyl sorbate (11) (0.279 g, 1.66 mmol) were reacted according the procedure of Example 1. Flash chromatography of the product on silica gel [ethyl acetate/petroleum ether (1:19)] afforded the title compound as a colourless oil (0.791 g, 72%). δH (200 MHz; CDCl3) 7.39-7.18 (5H, m, Ph), 6.12-5.93 (2H, m, CH=CH--CH=CH), 5.69-5.41 (4H, m, CH3CH=CH and CH=CH--CH=CH), 4.0 (1H, q, J=6.8, PhCHCH3), 3.87-3.75 (1H, m, CH3CH=CHCH), 3.21-3.09 (2H, m, NCH2), 2.40 (1H, dd, J=14.1 and 6.4, CH2CO2), 2.25 (1H, dd, J=14.1 and 8.5, CH2CO2), 1.76-1.71 (6H, m, CH3CH=CHCH and CH=CHCH3), 1.41 (9H, s, (CH3)3C), 1.37 (3H, d, J=6.7, PhCHCH3).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][NH:8]C(OC(C)(C)C)=O)[CH2:2]1.C(OCC)(=O)C.[ClH:22]>ClCCl>[ClH:22].[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][NH2:8])[CH2:2]1
Reactant: CC(C)(C)OC(=O)NNC1CCCOC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NNC1CCCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 2-(tetrahydro-2H-pyran-3-yl)hydrazinecarboxylate (216 mg, 1.00 mmol) was dissolved in dichloromethane (10 mL) and ethyl acetate (10 mL) and cooled to 0° C. The mixture was saturated with gaseous hydrogen chloride, warmed to ambient temperature and stirred for 1 hour. The mixture was concentrated in vacuo and the residue was concentrated with toluene (2×20 mL) to afford the titled compound.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[C:35]([O:37][CH:38]2[CH2:43][CH2:42][CH2:41][O:40][CH2:39]2)[CH:34]=[C:33]([F:44])[C:32]=1[C:45]1[N:50]=[C:49]([C:51](O)=[O:52])[CH:48]=[CH:47][C:46]=1[F:54].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:51]([C:49]3[CH:48]=[CH:47][C:46]([F:54])=[C:45]([C:32]4[C:31]([F:30])=[CH:36][C:35]([O:37][CH:38]5[CH2:43][CH2:42][CH2:41][O:40][CH2:39]5)=[CH:34][C:33]=4[F:44])[N:50]=3)=[O:52])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(OC3CCCOC3)cc2F)n1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(OC4CCCOC4)cc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (30 mg, 0.074 mmol), 6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxylic acid (26 mg, 0.074 mmol) and HATU (56 mg, 0.15 mmol) in DMF (0.3 mL) and DIPEA (39 μL, 0.22 mmol) was stirred at room temperature for 2 h. The reaction mixture was quenched with water and the resulting mixture was extracted with EtOAc (2 times). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to afford an amide intermediate, 4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13].CCN(C(C)C)C(C)C.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Reactant: BrCC1CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)Cc1cn(CC2CC2)c2ccc(Br)cc12
Temperature: 50 °C
Yield: 85.9 %

Procedure:
To 5-bromoindole-3-acetic acid (890 mg, 3.5 mmol) in 1-methyl-2-pyrrolidinone (12 mL) at 0° C. were added iPr2NEt (21 mmol) and bromomethylcyclopropane (10.5 mmol). The reaction mixture was heated at 50° C. for 19 h before partitioning between diethyl ether and ice water. After adjusting the pH to 3, the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with NaH2PO4, dried over MgSO4 and evaporated to dryness. Purification on silica gel column (30% EtOAc in hexane) yielded 927 mg (86% yield) of the product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl.CCOC(C)=O>[C:20]([Si:17]([CH3:19])([CH3:18])[O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C1CCc2c(O)cccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1CCC2=O
Reaction time: 0.08 h
Yield: 114.8 %

Procedure:
To a solution of 4-hydroxy-indan-1-one (1.0 g, 6.75 mmol) in CH2Cl2 (20 mL) was added imidazole (690 mg, 10.12 mmol). The mixture was stirred for 5 minutes, to which was added portionwise tert-butyldimethylsilyl chloride (1.05 g, 5.31 mmol). The mixture was stirred for 3 hours at room temperature and was diluted with EtOAc. The organic layer was washed with 1N HCl, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 4-(tert-butyl-dimethyl-silanyloxy)-indan-1-one (1600 mg, 90%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]([CH:35]3[CH2:38][CH2:37][CH2:36]3)[N:28]3[C:33]=2C(=O)NC=N3)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]([CH:35]3[CH2:36][CH2:37][CH2:38]3)[N:28]3[C:33]=2[C:5]([NH2:1])=[N:4][CH:3]=[N:2]3)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1nc[nH]n1
Reactant: O=c1[nH]cnn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3)c12
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ncnn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2,4-triazole (167 mg, 2.417 mmol) in anhydrous pyridine (1.5 mL) was added phosphorous oxychloride (POCl3) (75 μL, 0.806 mmol) and stirred at rt for 15 min. To this mixture was added dropwise a solution of 5-(3-benzyloxy-phenyl)-7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (100 mg, 0.269 mmol) in anhydrous pyridine (2.5 mL) over a 3.5 min period and stirred at rt for an additional 3 h. The reaction was cooled to 0° C. and quenched with 2M NH3 in i-PrOH (10 mL ) and stirred for an additional 30 min at rt. The mixture was filtered through a fritted funnel and the filtrate was concentrated in vacuo, partitioned between CHCl3 and H2O and separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined CHCl3 fractions were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo and the crude material was chromatographed on silica gel [eluting with 2% MEOH in CHCl3] resulting in a dark brown oil which was crystallized from EtOAc/hexanes to obtain the title compound as a light tan solid. 1H NMR (CDCl3, 400 MHz) δ 1.95-2.08 (m, 1H), 2.09-2.22 (m, 1H), 2.39-2.50 (m, 2H), 2.59-2.72 (m, 2H), 4.14 (quint, J=8.4 Hz, 1H), 5.16 (s, 2H), 5.57 (brs, 2H), 7.02-7.09 (m, 1H), 7.22-7.28 (m, 3H), 7.31-7.50 (m, 5H), 7.85 (s, 1H); MS (ES+): m/z 372.1 (100) [MH+]; HPLC: tR=3.05 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: [N:1]#[N:2].C(O[C:11]([N:13](C)[C@@H:14]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17])[CH3:15])=O)C1C=CC=CC=1>C(O)C.[Pd]>[N:1]#[N:2].[CH3:11][NH:13][C@@H:14]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17])[CH3:15]
Reactant: C[C@H](C(=O)NCCCc1ccccc1)N(C)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CN[C@H](C)C(=O)NCCCc1ccccc1

Procedure:
A solution of N2 -benzyloxycarbonyl-N2 -methyl-N-(3-phenylpropyl)-D-alaninamide (7.54 g.) in ethanol (200 ml.) containing palladium on carbon (10%, 200 mg.) was hydrogenated under pressure (40 p.s.i.g.), filtered and stripped of volatiles, affording N2 -methyl-N-(3-phenylpropyl)-D-alaninamide.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:56]([OH:58])=O)[CH2:19][S:20][CH2:21][C@H:22]([O:40][C:41](=[O:55])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:23][O:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])C3C(=CC=CC=3)C=2C=CC=1.[NH2:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][P:72](=[O:79])([O:76]CC)[O:73]CC>>[NH2:17][C@@H:18]([CH2:19][S:20][CH2:21][C@H:22]([O:40][C:41](=[O:55])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:23][O:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:56](=[O:58])[NH:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][P:72](=[O:73])([OH:79])[OH:76]
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Reactant: CCCCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCCCC
Product: CCCCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(O)O)OC(=O)CCCCCCCCCCCCC

Procedure:
The title product was prepared from (5R,9R)-1-(9H-fluoren-9-yl)-3,12-dioxo-9-(tetradecanoyloxy)-2,11-dioxa-7-thia-4-azapentacosane-5-carboxylic acid (1 eq) and diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.3 eq, from example 18, step 4) by following the procedure described for example 20, step 6-8. 1H NMR (CDCl3): δ 7.30 (br s, 1H), 5.13-5.23 (m, 2H), 4.30-4.43 (m, 2H), 4.07-4.20 (m, 2H), 3.44-3.87 (m, 11H), 2.92-3.13 (m, 3H), 2.68-2.92 (m, 4H), 2.22-2.38 (m, 4H), 1.69-2.17 (m, 8H), 1.52-1.67 (m, 4H), 1.10-1.36 (m, 32H), 0.88 (t, 6H). LRMS [M+H]=855.6.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=1)[CH3:15].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:39]2[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=2)=[CH:36][CH2:37]O)=[CH:31][CH:30]=1>C1COCC1>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:37][CH:36]=[C:35]([C:32]2[CH:31]=[CH:30][C:29]([Br:28])=[CH:34][CH:33]=2)[C:39]2[CH:40]=[CH:41][C:42]([Br:45])=[CH:43][CH:44]=2)=[C:21]([Cl:26])[CH:20]=1)[CH3:15]
Reactant: OCC=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: CCOC(=O)Cc1ccc(O)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)c(Cl)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A solution of tributylphosphine (955 μl, 3.0 mmol), 3-chloro-4-hydroxyphenylacetic acid ethyl ester (472 mg, 2.2 mmol) and 3,3-bis-(4-bromophenyl)prop-2-en-1-ol (736 mg, 2.0 mmol) in dry THF (15 ml) was stirred at 0-5° C. for 30 min, under a atmosphere of nitrogen. Azodicarboxylic dipiperidide (756 mg, 3.0 mmol) was added the mixture stirred at 0-5° C. for 2 h, and at room temperature over night. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude product was then purified by column chromatography on silica (eluent graduated from heptane to toluene) to give 1.0 g (89%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7][O:8][C:9]2[C:10]([F:18])=[C:11]([C:14]([F:17])=[CH:15][CH:16]=2)[C:12]#[N:13])[S:5][CH:6]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>CCO>[Br:1][C:2]1[N:3]=[C:4]([CH2:7][O:8][C:9]2[C:10]([F:18])=[C:11]([C:14]([F:17])=[CH:15][CH:16]=2)[C:12](=[N:20][OH:21])[NH2:13])[S:5][CH:6]=1
Reactant: NO
Reactant: N#Cc1c(F)ccc(OCc2nc(Br)cs2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=NO)c1c(F)ccc(OCc2nc(Br)cs2)c1F

Procedure:
To a solution of 3-((4-bromothiazol-2-yl)methoxy)-2,6-difluorobenzonitrile (0.10 g, 0.30 mmol) in EtOH (5 ml) was added hydroxylamine hydrochloride (0.103 g, 1.50 mmol) and NaOH (0.060 g, 1.50 mmol). The resulting reaction mixture was refluxed for 3 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated in vaccuo and used as such for the next step (crude yield 0.07 g, 63%). MS: 363.93 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]2[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[N:19]=[CH:20][CH:21]=[CH:22][C:5]=3[C:4]=2[C:3]=1[F:23].[CH3:24][N:25](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:3]1[C:4]2[C:5]3[CH:22]=[CH:21][CH:20]=[N:19][C:6]=3[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:8]=2[CH:9]=[N:10][C:2]=1[C:24]#[N:25]
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1c2cnc(Cl)c(F)c2c2cccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)c(F)c2c2cccnc21
Temperature: 130 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
A solution of 6-chloro-5-fluoro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′3′-d]pyrrole (12.2 g, 34.7 mmol) in DMF (120 mL) was treated with zinc cyanide (4.88 g, 41.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (6 g, 5.2 mmol). The mixture was degassed and stirred under a nitrogen atmosphere at 130° C. for 3 hours. After cooling to ambient temperature the mixture was filtered through Celite© and the filter cake washed with DMF (10 mL). The filtrate was partitioned between ethyl acetate and water and the aqueous phase further extracted with ethyl acetate. The combined organic layer was washed with water (×2) and brine, dried (Na2SO4), filtered and evaporated. The resultant residue was dissolved in dichloromethane, stirred with flash silica gel, filtered to remove the solid and the solid washed well with dichloromethane. The filtrate was evaporated and the resultant residue triturated with pentane:diethyl ether (ca. 4:1) to afford the title compound as a white solid (8.15 g, 68%). The trituration liquors were evaporated and the resultant residue purified by flash chromatography to afford a second crop of title compound (0.92 g, 8%). Total yield=9.07 g, 76%. 1H NMR (400 MHz, CDCl3): 8.99 (d, J=2.1 Hz, 1H), 8.75 (dd, J=4.8, 1.7 Hz, 1H), 8.57 (dd, J=7.9, 1.7 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 6.02 (s, 2H), 3.63-3.56 (m, 2H), 0.93 (t, J=8.2 Hz, 2H), −0.08 (d, J=0.6 Hz, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: Nc1ccncc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccncc1
Temperature: 0 °C

Procedure:
A suspension of 4-aminopyridine (0.96 g) in dry dichloromethane (10 mL) under nitrogen was cooled to 0° C. in an ice bath. Triethylamine (1.56 mL) was added, followed by the slow addition of chloroacetyl chloride (0.89 mL). The ice bath was removed and the reaction mixture allowed to reach room temperature. The reaction mixture was diluted with water (20 mL) and dichloromethane (25 mL). The solid was filtered off, washed with pentane and dried to give the title compound as a brown solid (0.87 g). The layers of the filtrate were separated and the organic layer was washed with water, dried and the solvent was evaporated to give a dark brown glass. Trituration with pentane gave another batch of the title compound (0.91 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4ccc(Cl)cc4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-chlorophenylboronic acid (134 mg, 0.85 mmol) the subtitle compound was obtained (148 mg, 68%). 1H NMR (CDCl3) δ 8.74(s, 1H), 8.45(dd, 1H), 7.90(d, 1H), 7.64(d, 1H), 7.55(d, 3H), 7.44(d, 2H), 7.26(d, 1H), 4.07(s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH2:8][CH:7]2[NH:9][CH:4]([CH2:5][CH2:6]2)[C:3]=1[C:10]1[C:11]([Cl:15])=[N:12][S:13][N:14]=1.C=O.[CH:18](O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:18][N:9]1[CH:7]2[CH2:6][CH2:5][CH:4]1[C:3]([C:10]1[C:11]([Cl:15])=[N:12][S:13][N:14]=1)=[C:2]([Cl:1])[CH2:8]2
Reactant: O=CO
Reactant: ClC1=C(c2nsnc2Cl)C2CCC(C1)N2
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1C2CCC1C(c1nsnc1Cl)=C(Cl)C2

Procedure:
A mixture of 3-chloro-2-(3-chloro-1,2,5-thiadiazol-4-yl)-8-azabicyclo[3.2.1]oct-2-ene (1.0 g, 3.8 mmol), formaldehyde (37% water solution, 10 ml) and formic acid (6.0 ml) was heated at reflux for 2 h. After cooling water was added (100 ml) and the water solution was made basic with potassium carbonate. The water solution was extracted with diethylether (3×50 ml). The organic extracts were dried over magnesium sulfate and evaporated. The residue was crystallized as the oxalate salt from acetone in 1.2 g yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:47])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([O:33][CH2:34][CH2:35]Br)=[C:19]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[OH:54][C:55]1[CH:64]=[C:63]([OH:65])[CH:62]=[CH:61][C:56]=1[C:57]([O:59][CH3:60])=[O:58]>CC(C)=O>[CH3:60][O:59][C:57](=[O:58])[C:56]1[CH:61]=[CH:62][C:63]([O:65][CH2:35][CH2:34][O:33][C:20]2[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[CH:22][C:17]([C:16](=[O:47])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:18][C:19]=2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=2)=[CH:64][C:55]=1[OH:54]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCBr)c(-c2cccc(C(F)(F)F)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCOc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Yield: 59.2 %

Procedure:
To a solution of N-(8-phenyl octyl)-4-(2-bromo-ethoxy)-3,5-bis(m-trifluoromethylphenyl) benzamide (1.48 g, 2.05 mmol, 1 eq) in acetone (21 mL) was added K2CO3 (1.42 g, 10.25 mmol, 5eq) and methyl 2,4-dihydroxybenzoate (0.340 g, 2.05 mmol, 1.0 eq). The reaction was heated at reflux for overnight, cooled to rt and concentrated in vacuo. The residue was partitioned between EtOAc and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane) to afford 2-hydroxy-4-{2-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl-[1,1′:3′,1″]terphenyl-2′-yloxy]-ethoxy}-benzoic acid methyl ester (0.98 g, 60%) as a colorless oil. 1H NMR (CDCl3) δ 10.90 (s, 1H); 7.92-7.78 (m, 7H); 7.66-7.50 (m, 4H); 7.27-7.12 (m, 5H); 6.18-6.10 (m, 3H); 3.92 (s, 3H); 3.66-3.40 (m, 6H); 2.58 (t, 2H); 1.60 (m, 4H); 1.28 (m, 8H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH:13]1([N:17]2[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1>O1CCCC1.N(C(OCC)=O)=NC(OCC)=O>[CH:13]1([N:17]2[CH2:22][CH2:21][CH:20]([O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]4)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1
Reactant: OC1CCN(C2CCC2)CC1
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: O=C1CCc2cc(OC3CCN(C4CCC4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 40 h
Yield: 25 %

Procedure:
Under a nitrogen atmosphere, to a solution of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (5.00 g) and N-cyclobutyl-4-hydroxypiperidine (which can be synthesized as described in WO2005/108384) (7.10 g) in tetrahydrofuran (50 mL), diethyl azodicarboxylate (40% in toluene, 16.7 mL) was added dropwise under ice cooling. After completion of the dropwise addition, the reaction mixture was warmed to room temperature and stirred for 40 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform/methanol=95/5) to give the titled compound (2.30 g, 25%) as a colorless powder.