Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[S:30][C:29]([NH2:31])=[N:28][N:27]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Br[CH2:33][C:34]([C:36]1[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=1)=O.C(OC(C)C)(C)C>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[S:30][C:29]5=[N:31][C:34]([C:36]6[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=6)=[CH:33][N:28]5[N:27]=4)=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: Nc1nnc(-c2ccc(C3CCN(C4CCCCC4)CC3)cc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1ccc(-c2cn3nc(-c4ccc(C5CCN(C6CCCCC6)CC5)cc4)sc3n2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 41.9 %

Procedure:
A mixture of 5-[4-(1-cyclohexyl-4-piperidyl)phenyl]-1,3,4-thiadiazol-2-amine trifluoroacetate (0.78 g) and ethyl 4-(bromoacetyl)benzoate (0.6 g) in ethanol (15 ml) was stirred for 5 hours at 80° C. After being cooled to room temperature, the reaction mixture was poured into isopropyl ether. The resulting precipitate was collected by filtration, washed with isopropyl ether and added to a solution of trifluoroacetic acid (1.5 ml) in xylene (15 ml). Then a mixture was stirred for 3 hours at 130° C. After being cooled to room temperature, the reaction mixture was poured into isopropyl ether. The resulting precipitate was collected by filtration and washed with isopropyl ether to give ethyl 4-[2-[4-(1-cyclohexyl-4-piperidyl)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoate trifluroacetate (0.45 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.O=S(Cl)[Cl:22]>C(Cl)Cl>[Cl:22][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:19])([F:18])[F:1])=[CH:5][CH:6]=2)=[N:15][CH:14]=1
Reactant: OCc1ccc(-c2ccc(OC(F)(F)F)cc2)nc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(-c2ccc(CCl)cn2)cc1

Procedure:
0.400 g (1.49 mmol) of the above prepared [6-(4-trifluoromethoxy-phenyl)-pyridin-3-yl]-methanol was dissolved in 7.2 ml of CH2Cl2 and treated dropwise at 0° C. with 0.22 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at RT for 30 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents produced 0.419 g of pure title compound as off-white solid of mp. 34–36° C.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH2:8]([C:11]1[C:12]([OH:22])=[N:13][C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH2:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:5][O:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([OH:22])[C:11]=1[CH2:8][CH:9]=[CH2:10]
Reactant: C=CCc1c(O)nc2ccccc2c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1c(O)nc2ccccc2c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl sulfate (0.237 ml) was added to a mixture of 3-(prop-2-en-1-yl)quinoline-2,4-diol (1.0 g) and potassium carbonate (1.37 g) in acetone (100 ml) and the mixture was stirred at room temperature for 3 hours then warmed to 40° C. for 30 minutes. The reaction mixture was cooled and the solids were removed by filtration. The filtrate was concentrated in vacuo. Purification by flash chromatography (ISCO, 4-10% acetone/DCM) gave the desired product (0.70 g). LRMS (ES+) M/Z (M+H)+ 216.0.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11]Br)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]12[NH:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2>COCCO>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11][N:25]2[CH:19]3[CH2:24][CH2:23][CH:22]2[CH2:21][CH2:20]3)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CC2CCC1N2
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Solvent: COCCO
Product: N#CC(CCN1C2CCC1CC2)(c1ccccc1)c1ccccc1

Procedure:
15 Parts of 2,2-diphenyl-4-bromobutyronitrile are condensed with 12.9 parts of 7-azabicyclo[2.2.1]heptane by reflux in 100 parts by volume of ethylene glycol monomethyl ether. The reaction mixture is cooled and extracted with dilute hydrochloric acid. The aqueous hydrochloric acid extract is made basic with sodium hydroxide solution and extracted with ether. The ether extracts are dried over anhydrous sodium sulfate. Filtration and removal of the ether by evaporation at reduced pressure provides 2,2-diphenyl-4-(7-azabicyclo[2.2.1]hept-7-yl)butyronitrile, melting at 79°-81°. 4.9 Parts of this butyronitrile, 1.5 parts of sodium azide, 1.2 parts of ammonium chloride, and 0.023 part of lithium chloride are placed in 50 parts by volume of dimethylformamide and heated at 125° for 12 hours. The mixture is cooled and the solid is filtered from the dimethylformamide. The solid is washed with dimethylformamide and water. The dried solid is 5-{[1,1-diphenyl-3-(7-azabicyclo[2.2.1]hept-7 -yl)]propyl}-1H-tetrazole, melting at 284°-286°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:28]([S:31][CH2:32][CH:33]([C:37]([F:40])([F:39])[F:38])[C:34](O)=[O:35])(=[O:30])[CH3:29]>ClCCl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:34](=[O:35])[CH:33]([C:37]([F:38])([F:39])[F:40])[CH2:32][S:31][C:28](=[O:30])[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCC(C(=O)O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(F)(F)F
Temperature: 0 °C

Procedure:
L-proline tert-butyl ester (5.1 g.) is dissolved in dichloromethane (40 ml.) and the solution is stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6.2 g.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-trifluoromethylpropanoic acid (6.5 g.) in dichloromethane (5 ml.). After fifteen minutes stirring in the ice bath and sixteen hours at room temperature, the precipitate formed is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to give N-(3-acetylthio-2-trifluoromethylpropanoyl)-L-proline tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:11]([N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)c1ccc[nH]1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCn1cccc1C(=O)OC
Temperature: 80 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
To a solution of methylpyrrole-2-carboxylate (1.01 g, 8.07 mmol) in N,N-dimethylformamide (12 ml) were added 1-bromohexane (1.36 ml, 9.69 mmol) and potassium carbonate (1.474 g, 10.7 mmol), and the mixture was stirred at 80° C. for 20 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 1-hexylpyrrole-2-carboxylate (0.980 g, 4.68 mmol, yield 58%). This was dissolved in methanol (8 ml), 1N-aqueous sodium hydroxide solution (8 ml) was added at room temperature, and the mixture was stirred at 60° C. for 20 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 1N-aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 1-hexylpyrrole-2-carboxylic acid (0.877 g, 4.49 mmol, yield 96%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[NH:11][C:10]([C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=3)=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)[NH2:27].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[ClH:2].[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:3]2[C:4]3[NH:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=4)=[CH:9][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: CCOC(=O)c1ccc(-c2cc3ncnc(Cl)c3[nH]2)cc1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1ccc(-c2cc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3[nH]2)cc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
A mixture of ethyl 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate hydrochloride (517 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (462 mg) and 1-methyl-2-pyrrolidinone (8 mL) was stirred at 140° C. for 5 hrs, poured into water (40 mL), and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The precipitated solid was collected by filtration, washed with water and suspended in methanol (15 mL). After stirring at room temperature for 30 min, the solid was collected by filtration and dried under reduced pressure at 60° C. The obtained solid was suspended in ethanol (10 mL) and 1N aqueous sodium hydroxide solution (1.5 mL) was added. After stirring at room temperature for 6.5 hrs, and at 60° C. for 3.5 hrs, the mixture was cooled to room temperature. 1N Hydrochloric acid (155 mL) was added, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure at 60° C. to give the title compound (498 mg).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[C:10]([CH3:11])=[N:9][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1.[OH-].[Na+]>CN(C=O)C>[CH3:11][C:10]1[C:6]([CH2:5][C:1]#[N:2])=[N:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=1
Reactant: [C-]#N
Reactant: Cc1nn(-c2ccccc2)nc1CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)nc1CC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
1.8 g of sodium cyanide was suspended in 30 ml of DMF, and 5.0 g of 4-chloromethyl-5-methyl-2-phenyl-1,2,3-triazol was added under cooling with ice. After stirring for 3 hours at room temperature, an aqueous solution of sodium hydroxide was added to the reaction solution to make it alkaline, and extracted with toluene. The organic phase was washed with water and a saturated salt solution, then dried over anhydrous sodium sulfate. After the solvent was distilled off, the deposited crystals were washed with hexane to obtain 4.3 g of the aimed compound.
Reaction SMILES: [O-:1][P:2]([O-:5])([O-:4])=[O:3].[O-][P:7]([O-:10])([O-:9])=[O:8].[O-][P:12]([O-:15])([O-])=[O:13].[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[P:22](=O)(O)(O)[OH:23].S(=O)(=O)(O)O.N>>[O:3]=[P:2]12[O:5][P:7]3([O:10][P:12]([O:15][P:22]([O:9]3)([O:4]1)=[O:23])(=[O:13])[O:1]2)=[O:8]
Reactant: O=P(O)(O)O
Reactant: O=P([O-])([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Product: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3

Procedure:
In 1970, Richmond et al ('641 supra) reacted phosphate rock with phosphoric acid and then with sulfuric acid. The resulting acidulate was subsequently neutralized with anhydrous ammonia to produce a 7-21-0 (N--P2O5 --K2O) grade slurrey fertilizer. In later investigations Pottgiesser et al ('162 supra) produced a 13.5-6-0 (N--P2O5K2O) grade slurry by reacting nitric acid with phosphate rock and subsequently feeding the resulting slurry into a body of preneutralized solution maintained at pH 7-10 by addition thereto of aqua ammonia.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])=[O:4]
Reactant: O=C1CCC(=O)N1O
Reactant: C[C@@H](CCCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@@H](CCCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture consisting of (S)-2-methyl-5-phenylpentanoic acid (20mb(i), 290 mg, 1.51 mmol) in dichloromethane (20 mL) was added N-hydroxysuccinimide (191 mg, 1.66 mmol), 4-dimethylaminopyridine (203 mg, 1.66 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (318 mg, 1.66 mmol). The resulting reaction mixture was stirred for two hours at room temperature. The reaction mixture comprising 18mb(i) was carried on directly to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH:22]=[C:23]([C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[C:24]([OH:26])=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(OC(=O)C(C1C=C(C)C=CC=1)=CC1C=C(C2C=CC(Cl)=C(Cl)C=2)N(C2C=CC(OC)=CC=2)N=1)C.[Li+].[OH-]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11](/[CH:22]=[C:23](\[C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)/[C:24]([OH:26])=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(-n2nc(C=C(C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: CCOC(=O)C(=Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Agent: [Li+]
Agent: [OH-]
Product: COc1ccc(-n2nc(/C=C(/C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 4 h
Yield: 72.3 %

Procedure:
3-[5-(3.4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-acrylic acid. To a stirred solution containing 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1-H-pyrazol-3-yl]-2-m-tolyl-acrylic acid ethyl ester (Step B, 50 mg, 0.10 mmol) was added 2 mL LiOH (2 M). After 4 h at 50° C., the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography with 5:95 MeOH/CH2Cl2 to afford 34 mg (72.3%) of the title compound. HPLC: Rt=10.65 (Method A). MS (ES+): mass calculated for C26H20Cl2N2O3, 478.09; m/z found 479.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.35 (t, J=8.0 Hz, 1H), 7.28-7.23 (m, 3H), 7.15-7.11 (m, 3H), 7.09 (d, J=2.0 Hz, 1H), 6.88-6.86 (m, 2H), 6.77 (dd, J=8.3, 2.0 Hz, 1H), 5.45 (s, 1H), 3.82 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O)(=[O:26])[CH3:25]>C(O)C>[C:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=[N:23][NH:22][C:9]1[CH:8]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:12]2[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:15]=[C:11]2[N:10]=1)(=[O:26])[CH3:25]
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccncc3)cc2n1
Reactant: CC(=O)c1cccc(C=O)c1
Solvent: CCO
Product: CC(=O)c1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccncc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
There was dissolved, in ethanol (2 mL), (7-morpholin-4-yl-2-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.6 mg, 0.0983 mM), then 3-acetyl-benzaldehyde (14.6 mg, 0.0983 mM) was added to the solution and the mixture was stirred at room temperature overnight. The reaction liquid was filtered and then the resulting solid was washed with diethyl ether to thus give the title compound (33.6 mg, yield: 77%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1.P(Br)(Br)[Br:18].O>ClCCl>[Br:18][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=1
Reactant: BrP(Br)Br
Reactant: COCCOCCOc1ccc(CO)cc1
Solvent: ClCCl
Solvent: O
Product: COCCOCCOc1ccc(CBr)cc1
Reaction time: 1 h

Procedure:
To a solution of {4-[2-(2-methoxyethoxy)ethoxy]phenyl}methanol (Step 2, 500 mg, 2.21 mmol) in 10 mL dichloromethane was added dropwise phosphorous tribromide (210 μL, 2.21 mmol) at 0° C. After the addition was completed, stirring of the reaction mixture was continued for 1 h at the same temperature. Then, water was added with caution, and it was extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo to yield a crude product which was purified by MPLC (silica, cyclohexane/ethyl acetate 10:1) affording the title compound in pure form (530 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 7.31 (d, 2H), 6.88 (d, 2H), 4.50 (s, 2H), 4.13 (t, 2H), 3.85 (t, 2H), 3.71 (t, 2H), 3.58 (t, 2H), 3.40 (s, 3H); DCI(NH3)-MS m/z 306/308 (M+NH4)+; HPLC RT (Method I) 3.20 min.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.O.[F:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd]Cl>[F:18][C:19]1[C:24]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: OB(O)c1cccnc1F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Temperature: 100 °C
Yield: 52.7 %

Procedure:
A solution of 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1) (6.00 g, 25.1 mmol) in dioxane (54 mL) was sequentially treated with water (7.2 mL), 2-fluoropyridin-3-ylboronic acid (Asymchem Laboratories, Inc., Morrisville, N.C.) (5.31 g, 37.7 mmol), sodium carbonate monohydrate (9.35 g, 75.4 mmol) and PdCl2 (dppf) (Strem Chemicals, Inc., Newburyport, Mass.) (0.616 g, 0.754 mmol). The stirred mixture was degassed (alternating vacuum/nitrogen) and heated under nitrogen at 100° C. for 10 h. The mixture was cooled and extracted into EtOAc (500 mL) from water (400 mL). The aqueous layer was extracted with EtOAc (200 mL) and the combined organic extracts were dried (MgSO4), filtered through Celite® (diatomaceous earth), and concentrated. The crude product was dissolved in a small volume of DCM and purified by flash chromatography (50% to 75% to 100% EtOAc/hexane) to give 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.96 g, 53% yield) as an off-white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.11 (s, 1H), 8.91 (s, 1H), 8.58 (m, 1H), 8.49 (s, 1H), 7.62 (m, 1H), 5.85 (d, 1H), 4.05 (m, 1H), 3.75 (m, 1H), 2.38 (m, 1H), 2.05 (m, 2H), 1.79 (m, 1H), 1.61 (m, 2H).
Reaction SMILES: C1(Br)CC1.[Mg].[Br-].[O:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[F:12][C:13]([F:24])([F:23])[O:14][C:15]1[CH:22]=[CH:21][C:18](C#N)=[CH:17][CH:16]=1.Cl>O1CCCC1>[CH:10]1([C:11]([C:18]2[CH:17]=[CH:16][C:15]([O:14][C:13]([F:12])([F:23])[F:24])=[CH:22][CH:21]=2)=[O:7])[CH2:8][CH2:9]1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(OC(F)(F)F)cc1
Agent: BrC1CC1
Agent: Cl
Agent: [Br-]
Product: O=C(c1ccc(OC(F)(F)F)cc1)C1CC1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, 10% of a solution of 119.0 grams (0.98 mole) of cyclopropyl bromide in 125 mL of tetrahydrofuran was added to a suspension of 25.5 grams (1.03 moles) of magnesium turnings in 300 mL of tetrahydrofuran. The reaction was initiated by warming the reaction mixture to 35° C. Upon initiation of the reaction the remainder of the bromide/tetrahydrofuran solution was added dropwise while maintaining the reaction mixture temperature at 40°-50° C. The complete addition required approximately 90 minutes, after which time the reaction mixture was stirred at 40°-50° C. for an additional 1 hour. The reaction mixture was cooled to 15°-20° C., and 140.0 grams (0.75 mole) of 4-trifluoromethoxybenzonitrile was added dropwise during a 90 minute period. The reaction mixture temperature was maintained at 25° C. or less throughout the addition. Upon completion of the addition the reaction mixture was allowed to return to ambient temperature where it stirred for 18 hours. After this time the reaction mixture was poured into 1000 mL of cold (10° C.) aqueous 2N hydrochloric acid. The mixture was stirred for 1 hour, and then it was extracted with one 1000 mL portion and two 50 mL portions of diethyl ether. The combined extracts were concentrated under reduced pressure to a residue. The residue was redissolved in 2000 mL of diethyl ether, and the solution was washed in turn with two 500 mL portions of aqueous 1N hydrochloric acid, one 500 mL portion of an aqueous solution saturated with sodium bicarbonate, two 500 mL portions of water, and one 300 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under high vacuum yielding 149.7 grams of 4-trifluoromethoxyphenyl cyclopropyl ketone; b.p. 53°-56° C./0.04 mm.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:28])[C:13]2[CH:12]=[CH:11][C:10]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:9][C:8]=2[C:7](=[O:27])[CH2:6][CH2:5]1>C1COCC1.C(O)C.O>[OH:27][CH:7]1[CH2:6][CH2:5][C:4]([CH3:3])([CH3:28])[C:13]2[CH:12]=[CH:11][C:10]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)=[CH:9][C:8]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(O)CCC3(C)C)cc1
Reaction time: 6 h

Procedure:
1 g (2.88 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 9) was converted into the title compound using 60 mg (1.6 mmol) of sodium borohydride. The procedure was as follows: To a cold solution (0° C.) of Compound 9 in 5 ml of THF and 10 ml of ethanol was added sodium borohydride. The mixture was stirred for 6 hours, diluted with water (10 ml) and extracted with Et2O (4×40 ml). The combined organic layers were washed with 10% HCl (5 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]2[C:9]3[S:10][C:11]([C:17](=[O:27])[N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH3:19])=[CH:12][C:13]=3[CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:18]([CH3:19])[C:17]([C:11]1[S:10][C:9]2[C:8]3[CH:28]=[CH:29][C:5]([CH2:3][OH:2])=[CH:6][C:7]=3[O:16][CH2:15][CH2:14][C:13]=2[CH:12]=1)=[O:27]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(CO)cc1OCC2)c1ccccc1Cl
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
To a solution of 2-[(2-chloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylic acid methyl ester (1 g, 2.3 mmol) in dry THF (30 mL) was added lithium aluminum hydride (174 mg, 4.6 mmol) by portion at 0° C. The resulting mixture was stirred under nitrogen atmosphere for 30 minutes. The reaction was monitored by LC-MS. When the starting material was disappeared, the reaction mixture was quenched by the slow addition of water and 10% NaOH aqueous solution. After filtered, the filtrate was concentrated to the crude product, which was recrystallized from MeOH to give 190 as a yellow solid (450 mg, yield 48.9%). MS (ESI) 399.8