Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccccc2C)ccn1
Reactant: NO
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 22 h
Yield: 55 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (37 mg, 0.09 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:8) to furnish III as a yellow oil (20 mg, 55%).
Reaction SMILES: [CH3:1][S:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=O.[CH2:14]([Cl:16])Cl>C(N(CC)CC)C>[C:7]([CH:6]1[CH:9]([C:10]2[CH:11]=[CH:12][CH:5]=[CH:4][C:14]=2[Cl:16])[N:3]([S:2][CH3:1])[C:7]1=[O:8])(=[O:8])[CH:6]=[CH2:5]
Reactant: CSN1C(=O)c2ccccc2C1=O
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)C1C(=O)N(SC)C1c1ccccc1Cl
Yield: 88 %

Procedure:
To a solution of 25 (4.00 g, 11.2 mmol) in 40 ml of CH3CN in an ice-water bath was added ceric ammonium nitrate (18.39 g, 33.54 mmol) in 40 ml of water. The resultant mixture was stirred for 5 min, and 20 ml of water was added. The solution was extracted (3×5 ml) with EtOAc. The combined organic layers were washed with 5% NaHSO3, 5% NaHCO3, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to yield 2.14 g (76%) of 26 as a crude brown oil. Without further purification, compound 26 (2.00 g, 8.0 mmol) was dissolved in 30 ml of dry CH2Cl2 and N-(methylthio)phthalimide (2.30 g, 11.9 mmol) and 3-5 drops of triethylamine were added. The resultant mixture was refluxed for overnight. The solvent was removed under reduced pressure to yield a brown solid. The brown solid was redissolved in CH2Cl2, and washed with 1% NaOH. The organic layer was dried over anhydrous MgSO4. The solvent was removed under reduced pressure to yield a brown semi-solid, which was purified by column chromatography on silica gel with gradient elution (1:9 then 1:4 EtOAc:hexanes) to yield 2.00 g (88%) of 27 as a white solid. 1H NMR (250 MHz) δ 7.35-7.26 (m, 4H), 6.20 (d, J=5.1 Hz, 1H), 6.06 (dd, J=16.7, 1.9 Hz, 1H), 5.78 (dd, J=16.7, 10.4 Hz, 1H), 5.68 (dd, J=10.4, 1.9 Hz, 1H), 5.54 (d, J=10.4 Hz, 1H), 2.51 (s, 3H). 13C NMR (63 MHz) δ 168.3, 163.4, 156.6, 134.3, 132.6, 129.8, 128.6, 126.6, 126.3, 62.1, 21.9.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[N:11]=[CH:12][C:13]3[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:14]=3[N:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:21]([CH2:28][CH2:29][CH2:30]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[O:21]([CH2:28][CH2:29][CH2:30][N:16]1[C:14]2[N:15]=[C:10]([NH:9][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:11]=[CH:12][C:13]=2[CH:19]=[CH:18][C:17]1=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCCCOc1ccccc1
Reactant: O=c1ccc2cnc(Nc3ccccc3)nc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc2cnc(Nc3ccccc3)nc2n1CCCOc1ccccc1
Temperature: 50 °C

Procedure:
To a suspension of NaH (51 mg of a 60% suspension of NaH in mineral oil) in 6 mL of dimethylformamide was added 2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one (200 mg, 0.84 mmol). The reaction mixture was heated to 50° C. resulting in a yellow solution. The solution was cooled slightly, and 3-phenoxypropyl bromide (230 μL, 1.47 mmol) was added. The reaction mixture was heated at 50° C. for 10 minutes, then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Methanol and ethyl acetate were added to the residue, and 60 mg (19%) of 8-(3-phenoxypropyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one was collected by filtration, mp 175-176° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:33][CH:34]=1
Reactant: COC(=O)CCc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of methyl 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (0.54 g), lithium hydroxide monohydrate (0.0743 g), tetrahydrofuran (6 mL), water (4 mL) and methanol (4 mL) was stirred at room temperature for 1.5 hrs. 1N Hydrochloric acid (1.8 mL) was added to acidify the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals (0.49 g, 94%). melting point: 98-99° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)=[C:10]([C:36](O)=[O:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:41]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([C:36](=[O:37])[NH2:41])=[C:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:32])[CH3:33])[N:28]=[CH:29][N:30]=2)[N:19]=4)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(=O)O)CN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(N)=O)CN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.4 %

Procedure:
4-[2-(2-isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester (0.921 g, 1.77 mmol) was stirred in DMF (7 mL). EDCI (0.407 g, 2.12 mmol), HOBt (0.286 g, 2.12 mmol) and DIPEA (1.55 mL, 8.85 mmol) were added and the reaction stirred at RT for 5 min. Ammonium chloride (0.284 g, 5.31 mmol) was added and the reaction mixture stirred at RT for 18 h. Ethyl acetate and water were added, the organic layer separated and washed with water, dried (MgSO4), filtered and concentrated in vacuo to give 5-Carbamoyl-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.917 g, 1.76 mmol). LCMS RT=3.13 min, [M+H]+=520
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([C:50]([F:53])([F:52])[F:51])[CH:39]=2)/[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([C:50]([F:52])([F:51])[F:53])[CH:39]=2)/[C:35]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
A solution of triphenylphosphine (204 mg, 0.78 mmol) in methylene chloride (8 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (138 mg, 0.78 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylic acid (143 mg, 0.39 mmol) in methylene chloride (5 mL). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (117 mg, 1.17 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (20 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/2 hexanes/ethyl acetate) afforded the (E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-acrylamide (27 mg, 15.5%) as an amorphous white solid: EI-HRMS m/e calcd for C20H19F3N6OS (M+) 448.1293, found 448.1285.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[CH:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[N:13][N:7]3[C:6]=2[CH:26]=1.F[C:28]1[CH:29]=CC2OC[C@@H]3[C@H](C4C=CC=CC=4)C(C(N(OC)C)=O)=NN3C=2[CH:52]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(Br)C=C>C1COCC1.C1(C)C=CC=CC=1>[CH2:29]([C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:8]2[CH2:9][O:10][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:26][C:6]=3[N:7]2[N:13]=[C:12]1[C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])[CH:28]=[CH2:52]
Reactant: CON(C)C(=O)C1=NN2c3cc(F)ccc3OC[C@@H]2[C@@H]1c1ccccc1
Reactant: CON(C)C(=O)C1=NN2c3cc(F)ccc3OCC2C1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(c2ccccc2)C(C(=O)N(C)OC)=NN2c3cc(F)ccc3OCC21
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
Either cis (1-7) or trans-8-Fluoro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-5, 4.8 g, 13.5 mmol) was dissolved in anhydrous THF (50 mL) and cooled to −78° C. in an acetone/dry ice bath under an N2 atmosphere. The resulting solution was treated with LHMDS (16.2 mL of a 1M toluene solution, 16.2 mmol) and stirred 2 minutes to produce a deep red color. Allyl bromide (2.3 mL, 26.9 mmol) was added neat and the solution was allowed to stir 10 minutes at −78° C. and then removed from the ice bath. Upon reaching ambient temperature, the reaction was judged complete by TLC and quenched by at addition of sat. aqueous NH4Cl (100 mL). The mixture was extracted with Et2O (3×100 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified using flash column chromatography (ISCO Redisep 120 g SiO2 column, 0-40% EtOAc/hexanes gradient) to provide pure 3-allyl-8-fluoro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-6; a racemic mixture): 1H NMR (300 MHz, CDCl3) δ 7.40-7.22 (m, 3H), 7.20-7.12 (m, 3H), 6.77 (dd, J=8.9, 5.2 Hz, 1H), 6.53 (dt, J=8.6, 3.1 Hz, 1H), 5.57 (m, 1H), 5.27 (d, J=16.8 Hz, 1H), 5.22 (d, J=7.6 Hz, 1H), 4.12 (dd, J=10.5, 3.5 Hz, 1H), 3.90 (s, 3H), 3.63 (dd, J=11.0, 3.6 Hz, 1H), 3.37 (dd, J=13.7, 6.0 Hz, 1H), 3.32 (s, 3H), 2.96 (m, 2H); MS (M+H+, C22H22FN3O3) 396.3 found 396.4 required.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:15][C:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccccc1

Procedure:
To a mixture of phenol (0.01 mol) and ethyl 2-bromo-2-methylpropanoate (0.01 mol) in acetonitrile was added Cs2CO3 (0.015 mol), and the reaction mixture was refluxed overnight. After removal of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 1 N aqueous NaOH solution, water, and brine, and then dried sodium sulfate. Concentration gave the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.21˜7.25 (m, 2H), 6.98 (t, J=7.2 Hz 1H), 6.83˜6.86 (m, 2H), 4.23 (q, J=7.2 Hz 4H), 1.60 (s, 6H), 1.24 (t, J=7.2 Hz 3H); LCMS (ESI+) m/z 209 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:13][C:14]([CH3:20])([CH2:17][C:18]#[CH:19])[CH2:15][OH:16]>N1CCCCC1.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.[Cu]I>[CH3:13][C:14]([CH3:20])([CH2:17][C:18]#[C:19][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1)[CH2:15][OH:16]
Reactant: C#CCC(C)(C)CO
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(C)(CO)CC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a degassed (argon) solution of 3.56 g (12.00 mmol) 1-iodo-4-trifluoromethoxy-benzene in 40 ml piperidine was added 0.58 g (0.50 mmol) Pd(PPh3)4 and 0.095 g. (0.50 mmol) CuI. The reaction mixture was stirred at 50° C. for 10 min, then 1.25 g (10.00 mmol) of above synthesized 2,2-dimethyl-pent-4-yn-1-ol in 20 ml of piperidine was added dropwise within 1 h. During the addition the oil bath was slowly heated to 80° C. starting after 30 min. The reaction mixture was stirred at this temperature for 2 h and then extracted with chilled aqueous 10% KHSO4/ether (three times). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (n-heptane/EtOAc 2:1 to 1:1) yielded 1.91 g of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:18][CH2:19][CH2:20][N:21]=[N+]=[N-])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]>CCO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([O:3][C:4]([C:6]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCCN=[N+]=[N-])CCCCC1c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CCOC(=O)C1(CCCN)CCCCC1c1ccccc1
Yield: 83 %

Procedure:
A solution of 3.52 g (10 mmol) of the bromo ester and 1.95 g (30 mmol) NaN3 in 30 ml DMF was stirred overnight at 50°. Upon cooling, the contents were poured into 100 ml H2O and extracted with 2×50 ml Et2O. The organic extracts were washed with brine and dried over MgSO4. Filtration and concentration of the organic material provided 3.09 g crude 1-(3-azidopropyl)-2-phenylcyclohexane carboxylic acid ethyl ester. The crude azide from above (3.09 g) was dissolved in 50 ml EtOH (absolute). Lindlar catalyst (0.5 g) was added and the mixture was subjected to hydrogenation. The solution was filtered through Celite and concentrated in vacuo. The residue was dissolved in Et2O. Dilute hydrochloric acid was added and the organic layer was removed. The aqueous layer was basified and extracted with Et2O (2×50 ml). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford 2.43 g crude material. Distillation (140°-143°/0.3 mm) provides 2.40 g (83%) of 1-(3-aminopropyl)-2-phenylcyclohexanecarboxylic acid ethyl ester as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1)CCCC3
Yield: 69.4 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.254 g; 0.66 mmol), LHMDS 1N in THF (0.727 mL; 0.727 mmol), 1-iodopropane (0.097 mL; 0.99 mmol) in DMF (2.6 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.196 g (69%) of the title compound as a yellow oil.
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]1[C:11]([C:12](=[O:14])[CH3:13])=[C:10]([F:15])[C:9]([F:16])=[C:8]([F:17])[C:7]=1[F:18].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>C(O)C.CCOCC>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:13][C:12]([C:11]2[C:6]([F:5])=[C:7]([F:18])[C:8]([F:17])=[C:9]([F:16])[C:10]=2[F:15])=[O:14])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)c1c(F)c(F)c(F)c(F)c1F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.6 %

Procedure:
A solution of sodium ethoxide (21% in EtOH, 0.32 gm, 4.76 mmol) was added to a mixture of 1-(pentafluorophenyl)-1-ethanone (5.91 gm, 47.6 mmol, Aldrich) and 4-fluorobenzaldehyde (10.00 gm, 47.6 mmol) stirring in ethanol (100 ml) under argon. The solution was allowed to stir at room temperature for 18 hours, then EtOH was evaporated to afford a yellowish, oily solid. The solid was redissolved in ether, washed with water and brine, then dried over MgSO4, filtered and concentrated to give a yellow residue. The residue was purified by flash chromatography on Merck silica gel in 5% EtOAc/hexane. Fractions containing the product were combined and concentrated to a yellow solid. The solid was recrystallized from hexane to afford the title compound as large yellow crystals (8.220 gm, 52%).
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.C(O)C.CCCCCCC>C(O)C.[Pd]>[OH:15][C:14]1[C:9](=[O:8])[NH:10][N:11]=[C:12]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][N:26]=2)[CH:13]=1
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCCC
Product: O=c1[nH]nc(CCc2ccc(C(F)(F)F)cn2)cc1O
Yield: 48.1 %

Procedure:
3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6; 460 mg, 0.997 mmol) was dissolved in ethanol and palladium on carbon was added before the mixture was purged and subjected to hydrogen gas. On completion of the reaction the solvent was removed in vacuo to yield a residue which was purified by reverse phase chromatography using 5-90% acetonitrile in acidic water (0.05% trifluoroacetic acid) to give, after recrystallisation from an ethanol-heptane mixture, 4-hydroxy-6-(2-(5-(trifluoromethyl)pyridin-2-yl)ethyl)pyridazin-3(2H)-one (136 mg, 0.48 mmol, 48% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23](I)[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([C:32]#[CH:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>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.[Cu]Br.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([C:33]#[C:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc(I)cc1OCc1ccccc1
Reactant: C#Cc1ccccc1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)c1ccc(C#Cc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
Benzyl 2-benzyloxy-4-iodobenzoate (7.6 g) is added to triethylamine (120 mL) followed by phenylacetylene (2.94 g) then tetrakis(triphenylphosphine)palladium(0) (0.664 g) and copper (I) bromide (0.248 g). The resulting mixture is stirred at room temperature for 3 hours. The triethylamine is distilled off and the residue partitioned between ether (600 mL) and saturated aqueous ammonium chloride solution. The organic phase is dried over magnesium sulphate and evaporated. The residue is purified by flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (5:1 v/v). Fractions homogeneous in the required product are combined and evaporated to give benzyl 2-benzyloxy-4-phenylethynyl-benzoate (2 g) as a cream solid, m.p. 98-100° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.C([SiH2][O:34][C:35](C)(C)[C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([CH3:43])[CH:37]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C.O.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)[CH2:17][C:18](=[O:20])[NH:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][OH:34])=[CH:37][C:38]=1[CH3:43])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(F)c(F)c1
Reactant: Cc1cc(C(C)(C)O[SiH2]C(C)(C)C)ccc1N
Agent: CC(C)COC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CO)ccc1NC(=O)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.6 %

Procedure:
To a solution of [tert-butoxycarbonyl-(3,4-difluorophenyl)-amino]-acetic acid (5.74 g) in tetrahydrofuran (40 ml) at 0° C. was added triethylamine (3.2 ml) followed by isobutylchloroformate (2.9 ml) dropwise. After stirring for lhr, triethylamine (3.2 ml) was added followed by 4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-phenylamine (5.0 g) in tetrahydrofuran (3 ml), and the reaction warmed to room temperature and then heated at 58° C. overnight. After cooling to 0° C., tetrabutylammonium fluoride (7.6 ml of a 1M solution in tetrahydrofuran) was added dropwise and the reaction warmed to room temperature. After 3 hrs, the solution was poured into ethyl acetate/water and the organic layer separated, washed with KHSO4 (10% solution in water), water and brine, dried (Na2SO4) and concentrated. Purification of the residue by silica gel chromatography (eluting with 3% methanol in dichloromethane) gave an orange solid. Recrystallisation from 2-propanol/isohexane gave the sub-title compound as white crystals (2.8 g).