Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:9])([O:11][CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[CH3:10])=[N:6][CH:7]=1
Reactant: CC(C)(O)c1ccc(Br)cn1
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(OCOCC[Si](C)(C)C)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from Step 1 (14 mmol) in methylene chloride (50 mL) at 0° C. was added N,N-diisopropylethylamine (37.3 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (15.3 mmol). The resulting mixture was stirred at room temperature for 18 hours, then refluxed for 24 hours. After cooling to room temperature the mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between methylene chloride and water. The crude product from the organic phase was chromatographed on silica gel eluting with 6% ethyl acetate in hexane to afford the 5-bromo-2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)pyridine compound.
Reaction SMILES: [ClH:1].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH2:11].Cl.[N:13]1([C:18](=N)[NH2:19])C=CC=N1.C(N(C(C)C)CC)(C)C>C(#N)C>[ClH:1].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH:11][C:18]([NH2:19])=[NH:13]
Reactant: N=C(N)n1cccn1
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NC1Cc2ccccc2C1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
Stir a solution of 2,3-dihydro-1H-inden-2-amine hydrochloride (197 g; 1.08 equiv; 1.16 moles), 1H-pyrazole-1-carboximidamide hydrochloride (158 g; 1.00 equiv; 1.08 moles) and diisopropylethylamine (400 g; 2.87 equiv; 3.09 moles; 539.74 mL) in acetonitrile (2 L) at 62° C. for 2 hours, during which time a white solid precipitates. Cool the mixture to 25° C., then filter and wash with 300 mL acetonitrile and 300 mL methyltert-butyl ether. Dry the product in air at 25° C. for 1 h to afford the title compound (200 g, 87%) as a white solid: MS (m/z): 176 (M+1).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[CH:12]=O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCCCCC.C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:12]=[CH:1][CH3:2])[CH:14]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: [Li]CCCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC=Cc1cc(Br)ccc1F
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 16.5 g (0.044 mol) of ethyltriphenylphosphonium bromide and 387 ml of anhydrous THF is cooled to -50° C. under a nitrogen atmosphere. 27.8 ml (0.044 mol) of a 1.6M solution of n-butyllithium in hexane are added dropwise. The mixture is allowed to return to 0° and is stirred for 1 h at 0° C. The mixture is cooled to -30° C. and a solution of 8.8 g (0.0433 mol) of 5-bromo-2-fluorobenzaldehyde in 43 ml of anhydrous THF is added dropwise. The mixture is stirred overnight at room temperature and then for 2 h at 40° C. Filtration is carried out and the filtrate is evaporated under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:29](=[O:31])[CH3:30])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27]Br)=[CH:11][CH:12]=2)[CH:7]=1.[OH:33][C:34]1[C:39]([CH2:40][CH2:41][CH3:42])=[C:38]([OH:43])[CH:37]=[CH:36][C:35]=1[C:44](=[O:46])[CH3:45].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:29](=[O:31])[CH3:30])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:43][C:38]3[CH:37]=[CH:36][C:35]([C:44](=[O:46])[CH3:45])=[C:34]([OH:33])[C:39]=3[CH2:40][CH2:41][CH3:42])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2ccc(OCCOCCOCCOCCBr)c(C(C)=O)c2c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOCCOCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 81.9 %

Procedure:
A mixture of 3 g of [[8-acetyl-7-[2-[2-[2-[2-bromoethoxy]ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 1.36 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 1.2 g of anhydrous potassium carbonate in 60 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 18 hours. The mixture was filtered and filtrate was concentrated in vacuo to an oil which was purified by high pressure liquid chromatography (35% ethyl acetate-toluene) to yield 3 g (82%) of [[8-acetyl-7-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][N:12]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[O:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:44]>C(Cl)Cl>[Br:44][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][N:12]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[O:6][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)n1ccc2c(-c3nc(CO)co3)cccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ccc2c(-c3nc(CBr)co3)cccc21
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-[4-(hydroxymethyl)-1,3-oxazol-2-yl]-1H-indole-1-carboxylate (330 mg) and PPh3 (330 mg) in DCM (6.6 mL) was added portionwise carbon tetrabromide (418 mg) at ambient temperature and the mixture was stirred at the same temperature for 4 hours. The resulting mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography(n-hexane:EtOAc=5:1) to afford tert-butyl 4-[4-(bromomethyl)-1,3-oxazol-2-yl]-1H-indole-1-carboxylate (396 mg) as a white solid.
Reaction SMILES: [Li+].[OH-].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=[O:15])[N:12]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([O:41]CC)=[O:40])[CH2:26][C:27]4[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=4)=[O:23])[CH2:18][CH2:17]3)[CH2:11][CH2:10][C:9]=2[CH:44]=1.Cl>O.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=[O:15])[N:12]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([OH:41])=[O:40])[CH2:26][C:27]4[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=4)=[O:23])[CH2:18][CH2:17]3)[CH2:11][CH2:10][C:9]=2[CH:44]=1
Reactant: CCOC(=O)[C@@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)OC(=O)N1CCC(N2CCc3cc(OC)ccc3NC2=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)C(=O)O)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.11 g (4.50 mmol) LiOH in 50 mL water was added to a solution of 1.80 g (2.94 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-ethoxycarbonyl-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 50 mL THF and the reaction mixture was stirred for 3 h at RT. The THF was eliminated i. vac., diluted with 100 mL water and acidified with 1 M HCl. The substance precipitated was suction filtered, washed with 50 mL water and dried in the vacuum drying cupboard at 65° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.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>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:22])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
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: CCc1nccc(-c2ccc(C(=O)N3CCOCC3)c(F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 120 mg (0.33 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid (A-38) using 43 mg (0.50 mmoL) morpholine, 139 mg (0.37 mmol) HATU and 96 μL DIEA in 1.2 mL DMF. After completion of the reaction, DMF is removed under reduced pressure and the product is purified by chromatography on silica gel using a DCM/MeOH-gradient. Yield: 66 mg (46%).
Reaction SMILES: BrCCCCC(C)(C1C=CC(C)=CC=1)CO.[Br:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22](OCC)=[O:23].[Li+].[BH4-].CO>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][OH:23]
Reactant: CCOC(=O)C(C)(CCCBr)c1ccccc1
Agent: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(CO)(CCCBr)c1ccccc1
Yield: 98.2 %

Procedure:
According to the procedure given for the synthesis of 206e, 205b (23.70 g, 79.21 mmol) was reduced with LiBH4 (3.45 g, 158.4 mmol) and methanol (5.24 g, 163.5 mmol) in anhydrous CH2Cl2 (150 mL) to give 206b (20.0 g, 98%) as an oil. 1H NMR (CDCl3): δ 7.34-7.14 (m, 5H), 3.60 (m, 1H), 3.48 (m, 1H), 3.29 (t, 2H, J=6.0), 1.96-1.44 (m, 5H), 1.32 (s, 3H). 13C NMR (CDCl3): δ 144.25, 128.59, 126.71, 126.41, 72.44, 43.15, 37.06, 34.64, 27.58, 21.61. HRMS (LSIMS, nba): Calcd for C12H16Br (MH+—H2O): 239.0435. found: 239.0444.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].[CH:16](Br)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCNC(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
5.0 g (26.6 mmol) N-(tert-butoxycarbonyl)-1,4-diaminobutane 5.5 g (39.8 mmol) potassium carbonate and 0.9 g (5.3 mmol) potassium iodide are placed in 50 ml DMF and 6.6 g (26.6 mmol) benzhydryl bromide are added dropwise at RT. The mixture is stirred for 12 hours at 70° C. and the suspension is filtered after cooling and the filtrate is concentrated under vacuum. The residue is taken up in 200 ml chloroform and washed with 100 ml water. The organic phase is dried over sodium sulfate and, subsequently, the solvent is removed under vacuum. The accumulated crude product is further processed without further purification: Yield 10.8 g.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=O)O[C:8](=O)[C:4]=2[CH:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14].[ClH:17].O1CCOCC1>C1(C)C=CC=CC=1>[ClH:17].[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[CH2:6][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:8]2
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: CC(C)N
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)N1Cc2ccc(Br)cc2C1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
5-bromo-2-benzofuran-1,3-dione (1 wt) was suspended in toluene (5 vol) with stirring under nitrogen. Isopropylamine (1.1 eq, 0.416 vol) was then added dropwise over 10-30 mins at such a rate as to maintain the temperature between 15-25° C. (exothermic addition). The batch was stirred for a further 30 mins at 15-25° C. once the addition was complete, before heating to reflux under Dean-Stark conditions. The batch was held at reflux for 5-8 hrs until residual 5-bromo-2-benzofuran-1,3-dione by HPLC is <1% a/a uncorrected, then the batch was concentrated atmospherically to ca 2.5 vols2. Added toluene (3 vols) and reconcentrated atmospherically to ca 2.5 vols. Batch then cooled to 55-60° C., diluted with THF (1.5 vols), and then further cooled to 15-25° C. This was added to a solution of borane-THF complex (1.0M, 4 eq, 14.1 vol) and the resultant solution was stirred at 20-30° C. for ca 30 mins. The batch was then heated to 48-52° C., and held thus for 16-24 hrs until complete by HPLC, before cooling back to 15-25° C. The reaction was quenched inversely into aqueous hydrochloric acid (2N, 9 vol) over at least 30 mins maintaining an internal temp of 15-30° C. (initially effervescent, evolves hydrogen). Once the addition was complete, the batch was heated to 60-63° C., and held thus for 1-1.5 hrs before cooling to 15-25° C. Ethyl acetate (6 vols) was added and the resultant biphase was shaken, settled and separated1. Organics back-extracted with 2N HCl (3 vols) before being discarded. The combined aqueous liquors were then neutralized to pH>12 with 40% w/v aq NaOH (approx 3.9 vols). Overlain with ethyl acetate (6 vols) then the resultant biphase was shaken, settled and separated. Aqueous back extracted with ethyl acetate (3 vols) before being discarded. The organics were combined and washed with saturated brine (2×2 vols) before being concentrated in vacuo to ca 4 vols. Ethyl acetate (8 vols) was added and the batch was reconcentrated in vacuo to ca 4 vols. Ethyl acetate (9 vols) was added and the batch was adjusted to 0±3° C. 4M HCl in dioxane (0.89 eq, 0.98 vol) was then added slowly maintaining the batch temp within the range 0±3° C. The batch was then aged within this range for 30 min before product was collected by vacuum filtration. Washed with chilled ethyl acetate (<5° C., 2×2 vols) and dried o/n in vacuo at 30° C. to constant weight.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]=[C:8]1[C:13]1[O:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.B(Br)(Br)Br.O>C(Cl)Cl>[C:18]1([C:16]2[N:17]=[C:13]([C:8]3[CH:7]([CH2:6][C:5]4[C:4]([CH3:33])=[C:3]([OH:2])[CH:32]=[CH:31][CH:30]=4)[CH2:12][CH2:11][CH2:10][CH:9]=3)[O:14][C:15]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1c(O)cccc1CC1CCCC=C1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 5 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 2-[1-(3-methoxy-2-methylbenzyl)-2-cyclohexen-2-yl]-4,5-diphenyloxazole (1.16 g) in CH2Cl2 (25 ml) was added boron tribromide (1M solution in CH2Cl2, 5.32 ml) at −60° C. and the mixture was warmed to 5° C. After stirring for 1 hour at the same temperature, the reaction mixture was stirred for further 1 hour at room temperature. To the mixture was added water under ice-cooling, extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogen carbonate, water, and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 5:1) to give 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-2-methylphenol (903.8 mg) as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4]>C1COCC1.C(O)C.[Pt](=O)=O>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:1])[CH2:3][OH:4])=[CH:11][CH:10]=1
Reactant: CC(C)(CO)c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(CO)c1ccc(N)cc1
Temperature: 25 °C
Yield: 134.2 %

Procedure:
The product from Example 194B (0.321 g, 1.644 mmole) was dissolved in a mixture of THF (10 mL) and ethanol (2 mL). To this was added platinum(IV)oxide (0.030 g, 0.131 mmole). The flask was capped with a septum and the contents vacuum degassed three times. Hydrogen was introduced via a balloon and the mixture stirred at room temperature. An additional 38.2 mg (0.167 mmole) of catalyst was added in two aliquots before chromatographic analysis indicated that the starting material was consumed. After stirring overnight under hydrogen the mixture was filtered through a sand/celite plug followed by an ethyl acetate rinse. The filtrate was concentrated to dryness and the residue purified by chromatography on amine modified silica gel eluting with ethyl acetate-hexane beginning at 8% and advancing to 66% ethyl acetate to provide the title compound (0.3645 g, 68% yield) as a clear oil. MS (DCI+) m/z@183.1 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].C1(=O)O[CH2:18][CH2:17][O:16]1.[I-].[K+].CN(C)C=O>C(OCC)(=O)C>[OH:16][CH2:17][CH2:18][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14]
Reactant: Oc1ccccc1-c1ccccc1O
Reactant: O=C1OCCO1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCOc1ccccc1-c1ccccc1O
Temperature: 150 °C
Reaction time: 4 h

Procedure:
To a 2000 ml 3 neck round bottom equipped with an overhead stirrer, temperature probe, heating mantel was added 2,2′-dihydroxy-biphenyl (500 g, 2.68 mole, 1.0 eq), ethylene carbonate (520.2 g, 5.9 mole, 2.2 eq.), potassium iodide (5 g, 0.03 mole, 0.01 eq.), N,N-dimethyl formamide (DMF) (47 g, 50 ml) and heated to 150° C. The reaction was monitored by GC and after 4 hours the reaction was complete. The reaction was cooled to 40° C., added 1000 ml ethyl acetate and washed 3 times with 500 ml sodium chloride brine. The ethyl acetate was dried over MgSO4, filtered and concentrated in vacuo to recover a dark brown product (736 g, 99%).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.O[Li].O>O1CCCC1>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCCCC2)nc(O)c1OCc1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(CC2(c3ccccc3)CCCCC2)nc(O)c1OCc1ccccc1

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (255) (2.5 g, 5.27 mmol) in tetrahydrofuran (60.0 mL) was added a aqueous solution (30.0 mL) of LiOH.H2O (2.21 g, 52.67 mmol) and the reaction mixture was refluxed for 16 h. After completion of the reaction, the organic solvent was removed on a rotary evaporator and water (10.0 mL) was added. The aqueous solution was acidified with concentrated HCl to pH=5.0 at 0° C. to give a white solid which was filtered off. The solid residue was triturated in diethyl ether and filtered. After drying, 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid (256) was obtained (1.6 g, 72.58%) as a white solid.
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:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl.[CH3:30][O:31][NH:32][CH3:33]>S(Cl)(Cl)=O>[CH3:30][O:31][N:32]([CH3:33])[C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:21][CH:20]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-(Quinolin-2-ylmethoxy)-benzoic acid (25.98 g, 93 mmole) was added 250 ml of thionyl chloride under N2. The reaction mixture stirred 3 h and the excess thionyl chloride was removed under vacuum. The acid chloride was dissolved in tetrahydrofuran (450 ml) and triethylamine (50 ml, 4 eq.) was slowly added. O,N-dimethyl hydroxylamine hydrochloride (27 g, 3 eq.) was added and the reaction stirred 18 h. The reaction mixture was placed on a rotovap to remove the solvent, partitioned between 1N NaOH and methylene chloride, separated, dried magnesium sulfate, filtered and concentrated. The crude product was filtered through silica gel eluting with 30-70% ethyl acetate/hexane to proved the title compound as a brown oil (26.26 g, 87%); 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=8.7 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.67 (m, 3H), 7.63 (d, J=8.3 Hz, 1H), 7.52 (m, 1H), 7.01 (M, 2H), 5.39 (s, 2H), 3.52 (s, 3H) 3.31 (s, 2H); MS: (M+H m/z=323.2).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:25]=[CH:24][C:8]2[N:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=4)[N:12]=[C:10]3[S:11][C:7]=2[CH:6]=1.[H][H]>CO.C1COCC1.[Pd]>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:25]=[CH:24][C:8]2[N:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[N:12]=[C:10]3[S:11][C:7]=2[CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(OCCCl)ccc23)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(-c2cn3c(n2)sc2cc(OCCCl)ccc23)cc1
Temperature: 25 °C

Procedure:
A mixture of 7-(2-chloro-ethoxy)-2-(4-nitro-phenyl)-benzo[d]imidazo[2,1-b]thiazole (1 equivalent) and 10% Pd/C (0.05-0.1 equivalents) in a mixture of MeOH and THF under 1 atmosphere of hydrogen gas is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is filtered through Celite and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 7-(2-chloro-ethoxy)-2-(4-amino-phenyl)-benzo[d]imidazo[2,1-b]thiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH:12]=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26]>>[CH:12]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[C:17]([C:25]([F:28])([F:26])[F:27])[CH:18]=3)=[CH:3][CH:4]=2)[CH2:9]1)=[O:13]
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: Nc1ccc2c(c1)CN(C=O)CC2
Product: COc1ccc(C(=O)Nc2ccc3c(c2)CN(C=O)CC3)cc1C(F)(F)F

Procedure:
7-Amino-2-formyl-1,2,3,4-tetrahydroisoquinoline (0.176 g) was converted into the title compound by reaction with 4-methoxy-3-trifluoromethylbenzoyl chloride, following the procedure of Example 3. The product was isolated as a white solid (0.035 g).
Reaction SMILES: [CH:1]1CCCC=1.C1C=CC=CC=1.S([O-])([O-])(=O)=O.[Ba+2].[C:18]([CH:22]1[C:26](=[O:27])[CH2:25][CH:24]([O:28][C:29](=[O:31])[CH3:30])[CH:23]1[CH2:32][C:33]([OH:35])=[O:34])([O:20][CH3:21])=[O:19]>C(Cl)(Cl)Cl>[CH3:1][O:34][C:33](=[O:35])[CH2:32][CH:23]1[CH:24]([O:28][C:29](=[O:31])[CH3:30])[CH2:25][C:26](=[O:27])[CH:22]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: C1=CCCC1
Reactant: COC(=O)C1C(=O)CC(OC(C)=O)C1CC(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)CC1C(OC(C)=O)CC(=O)C1C(=O)OC

Procedure:
The cyclopentene acid, V, (9.5 g.) is dissolved in 180 ml. of benzene and the solution is hydrogenated at room temperature and atmospheric pressure in the presence of 0.5 g. of palladiated barium sulfate. When the theoretical amount of hydrogen is absorbed, catalyst is filtered off and the solution is evaporated to dryness under vacuum, yielding 9 g. (95%) of the methy ester of 2-carbomethoxy-3-oxo-5-acetoxycyclopentaneacetic acid with the required stereochemical configuration. The compound is a rather unstable solid, melting at 54° C; [α]d25 :- 17.8 (C=1.017% in CHCl3).