Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:16]([C:18]([OH:20])=O)[CH:17]=1.Cl.Cl.[NH2:23][CH:24]1[CH2:31][CH:30]2[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:33][N:32]1[CH:26]2[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH:24]([NH:23][C:18]([C:16]1[CH:17]=[C:2]([Br:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:20])[CH2:25]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cc(Br)cc3o2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3c(C(=O)NC4CC5CCCC(C4)N5C)cc(Br)cc3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.6 %

Procedure:
A mixture of 6-bromo-2-p-tolylbenzoxazole-4-carboxylic acid (85 mg, 0.26 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (85 mg, 0.31 mmol), 1-hydroxybenzotriazole (69 mg, 0.51 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (98 mg, 0.51 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then triethylamine (0.12 mL, 1.02 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) followed by recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-p-tolylbenzoxazole-4-carboxamide (30 mg, 25%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.94 (d, J=7.3 Hz, 1H), 8.33 (d, J=1.8 Hz, 1H), 8.12 (d, J=8.2 Hz, 2H), 7.83 (d, J=1.9 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 4.63-4.50 (m, 1H), 3.12 (d, J=10.6 Hz, 2H), 2.70-2.55 (m, 2H), 2.54 (s, 3H), 2.48 (s, 3H), 2.20-1.95 (m, 2H), 1.65-1.45 (m, 4H), 1.20-1.10 (m, 2H); MS (ESI+) m/z 468 (M+H); HPLC 98.4% (AUC), tR=14.06 min.
Reaction SMILES: [OH-].[K+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=O)[CH:9]=[CH:10][C:11]([OH:13])=[O:12].[NH2:15][NH2:16]>CO>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH2:9][CH:10]([C:11]([OH:13])=[O:12])[NH:16][N:15]=1
Reactant: NN
Reactant: O=C(O)C=CC(=O)c1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC(c2ccco2)=NN1
Yield: 66.7 %

Procedure:
Potassium hydroxide (660 mg) is dissolved in 25 cc of methanol and 1.66 g of 4-(2-furanyl)-4-oxo-2-butenoic acid is added. Hydrazine (320 mg) is then added and the solution is refluxed for 2 hours. The methanol is removed and the viscous residue is dissolved in 50 cc of water. The solution is made strongly acid with 20% HCl and a precipitate forms. The solid is filtered quickly to yield 1.2 g of the title compound, melting point 185°-190° C., dec.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15]([NH2:18])(=[O:17])=[O:16].[Br:19][C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>N1C=CC=CC=1>[Br:19][C:20]1[CH:21]=[C:22]([S:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:4][C:3]=2[S:15]([NH2:18])(=[O:16])=[O:17])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc(Oc2ccccc2)ccc1NS(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a solution of 2-amino-5-phenoxybenzenesulfonamide (528 mg, 2 mmol) in pyridine (15 mL), 3-bromobenzenesulphonyl chloride (669.3 mg, 2.3 mmol) was added portionwise at 0° C. The reaction was stirred at RT overnight. The pyridine was removed in vacuo and the residue was dissolved in ethyl acetate. The organic phase was washed with aqueous 1N HCl, water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/hexane (1:3) as eluent to give the title compound (700 mg, 72%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].C(N(CC)CC)C.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:38]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:39])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)N1CCOCC1
Reaction time: 18 h
Yield: 29.8 %

Procedure:
A solution of the compound of Example 47, 1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (980 mg, 2.98 mmol) in 20 mL of CH2Cl2 was treated with triethylamine (1.04 mL, 7.45 mmol) and chilled in an ice water bath. With vigorous stirring, the solution was treated with 4-morpholinecarbonyl chloride (0.365 mL, 3.13 mmol). After 18 h, the reaction was treated with 25 mL CH2Cl2 and 25 mL water and the layers were separated. The organic portion was washed with 1% Na2CO3 solution, water and brine. The organic portion was then dried over Na2SO4, filtered and concentrated to yield a yellow foam. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave 393 mg of N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[C:20](Cl)[N:19]=[C:18]([NH2:23])[N:17]=3)=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2].N1C=CC=CC=1>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:23])[N:17]=3)=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc2cc(Oc3cc(Cl)nc(N)n3)ccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)c1csc2cc(Oc3ccnc(N)n3)ccc12

Procedure:
A solution of 3.70 g (10.6 mMol) 6-(2-amino-6-chloro-pyrimidin-4-yloxy)-benzo[b]thiophene-3-carboxylic acid ethyl ester in 300 ml THF and 8.68 ml (108 mMol) pyridine is hydrogenated in presence of 3.0 g Pd/C (10%; added in 3 portions during 23 h). The mixture is filtered and the solid washed extensively with MeOH. The filter cake still contains product and is therefore stirred in EtOAc and water. The separated EtOAc layer is washed twice with water, added to the filtrate and concentrated. The residue is re-dissolved in 300 ml EtOAc and 50 ml MeOH. Then water is added, the aq. layer separated off and extracted 4× with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated together with 21 g SiO2. The resulting powder is put on top of a SiO2-column and the title compound eluated with EtOAc/hexane 9:1: m.p.: 144-145° C.; TLC(EtOAc/hexane 9:1): Rf=0.27.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([C:18]3[CH:19]=[C:20]([NH:24][CH:25]=[O:26])[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[N:14][C:13]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:29](I)[CH3:30]>CN(C)C=O>[C:1]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([C:18]3[CH:19]=[C:20]([N:24]([CH2:29][CH3:30])[CH:25]=[O:26])[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[N:14][C:13]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=CNc1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C=O)c1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1
Reaction time: 8 h

Procedure:
As described for Example 59, 0.01 mole of N-[3-(3-benzoylpyrazolo[1,5-a]pyrimidin-7-yl]phenyl]formamide in 30 ml of dimethylformamide is reacted with 0.384 g of 60% sodium hydride in oil. To the mixture is added 0.85 ml of ethyl iodide and the mixture stirred overnight. Work up as for Example 59 gives the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[NH:15]1.[I-].[Na+]>>[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[N:15]1[CH:4]([CH2:3][CH3:2])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(CCCCl)c1ccccc1
Reactant: C[C@@H]1CCC[C@H](C)N1
Agent: [I-]
Agent: [Na+]
Product: CCC(C(=O)c1ccccc1)N1[C@H](C)CCC[C@@H]1C
Temperature: 25 °C

Procedure:
A mixture of 619 g. of γ-chlorobutyrophenone, ethylene ketal, 700 g. of cis-2,6-dimethylpiperidine and 16 g. of sodium iodide is stirred and heated at reflux for 48 hours. The mixture is cooled, diluted with 1 l. of anhydrous ether and filtered to remove cis-2,6-dimethylpiperidine hydrochloride. The filter cake is washed with 1 l. of ether and the filtrate and washings combined. The resulting ether solution is washed five times with 500 ml. portions of water, then extracted with a solution of 300 ml. of concentrated hydrochloric acid in 3 l. of water. The acid extract is washed with 500 ml. of ether, then heated to 70°-80° and allowed to cool to room temperature over a period of 16 hours. The resulting solution is basified with 50% aqueous sodium hydroxide and the organic layer is separated. The aqueous layer is extracted with 500 ml. of ether and the extract is combined with the organic layer. The combined extract is washed several times with water, dried and evaporated. The oily residue is distilled at reduced pressure to give cis-α-(2,6-dimethylpiperidino)butyrophenone; b.p. 138°-141° C./0.1 mm.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[C:12](Cl)(=[O:15])[CH:13]=[CH2:14]>C(OCC)(=O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][C:12](=[O:15])[CH:13]=[CH2:14])[CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: C=CC(=O)Cl
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1c(CC)cccc1CC
Reaction time: 4 h

Procedure:
To a cold solution of 2.6-diethylaniline (60.6 g, 0.07 mole) in ethyl acetate (600 ml) was added a solution of acryloyl chloride (45.2 g, 0.5 mole) in ethyl acetate (50 ml) over a 30 minute period. The ice bath was removed and the solution stirred for 4 hours. 10 Percher hydrochloric acid was added and the solution stirred gently for 15 minutes. The layers were separated and the organic layer washed with water, dried over sodium sulfate, filtered and the solvents removed on a rotary evaporator leaving an orange solid. The solid was recrystallized from ethyl acetate/hexane and the product filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-])=O)(=[O:13])=[O:12].Cl.C(O)(=O)C>O>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[Cl:1])[C:6]([OH:8])=[O:7])(=[O:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccccc1S(=O)(=O)c1cc(C(=O)O)ccc1Cl

Procedure:
A mixture of 4-chloro-3-(o-nitrophenylsulphonyl)benzoic acid (1.71g), stannous chloride (3.12g), concentrated hydrochloric acid (6.6 ml) and acetic acid (25 ml) was heated on the steamm bath for 30 min., cooled, and diluted with water. 3-(o-Aminophenylsulhonyl)-4-chlorobenzoic acid was filtered off, washed with water and dried, m.p. 235°-238° C, providing on recrystallisation from acetic acid, m.p. 246°-248° C.
Reaction SMILES: C(#N)C.[C:4]([C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH3:27])[N:20]=2)=[CH:15]\C(O)=O)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].[Br:28]N1C(=O)CCC1=O>C(N(CC)CC)C>[Br:28]/[CH:15]=[C:14](/[C:19]1[N:20]=[C:21]([O:26][CH3:27])[C:22]([Cl:25])=[CH:23][CH:24]=1)\[C:11]1[CH:12]=[CH:13][C:8]([C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc(/C(=C/C(=O)O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1nc(/C(=C/Br)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.4 %

Procedure:
A 97% acetonitrile solution (52 mL) containing triethylamine (26 μL) was added to (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-enoic acid (1.3 g). N-bromosuccinimide (806 mg) was added thereto and the mixture was stirred at room temperature for 15 minutes. The solvent was evaporated under reduced pressure from the reaction solution. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) to give the title compound as a colorless powder (363 mg, 25%).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:3]=1.[NH:19]1[CH:23]=[CH:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.[Cu](I)I>[N:9]1([C:7]([C:4]2[CH:3]=[C:2]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)[S:6][CH:5]=2)=[O:8])[CH:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1
Reactant: c1cn[nH]c1
Reactant: O=C(c1csc(Br)c1)N1CCC[C@@H]2CCCC[C@@H]21
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C(c1csc(-n2cccn2)c1)N1CCCC2CCCCC21
Temperature: 120 °C
Yield: 21.9 %

Procedure:
To a solution of cis-(5-bromo-thiophen-3-yl)-(octahydro-quinolin-1-yl)-methanone (0.095 g, 0.29 mmol) in DME (2 mL) was added N′N′-dimethylethylenediamine (0.005 g), pyrazole (0.039 g, 0.58 mmol), copper iodide (0.011 g) and potassium carbonate (0.040 g, 0.29 mmol). The reaction mixture was placed under nitrogen then sealed in a vial and heated at 120° C. for 79 hours. The solution was partitioned between DCM and water and the phases separated using a hydrophobic frit. The organic phase was evaporated and the compound was purified by chromatography on a silica cartridge eluting 0-10% methanol in DCM then re-purified on a larger cartridge using 0-3% methanol in DCM. The compound was further purified by HPLC on a C6 phenyl column, eluting with 50%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were evaporated to give the title compound as a colourless oil (0.02 g). LCMS m/z 316.19 [M+H]+ R.T.=10.74 min (Analytical Method 2).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17].[C:21]([NH:29][CH:30]1[C:42](=[O:43])[N:32]2[C:33]([C:39](O)=[O:40])=[C:34]([CH3:38])[CH2:35][S:36](=[O:37])[C@H:31]12)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:21]([NH:29][CH:30]1[C:42](=[O:43])[N:32]2[C:33]([C:39]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:40])=[C:34]([CH3:38])[CH2:35][S:36](=[O:37])[C@H:31]12)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48 %

Procedure:
A mixture of 103.2 g of dicyclohexylcarbodiimide, 43.5 g of t-butyl alcohol and 1.1 g of cuprous chloride was held at room temperature for 3 days and the mixture was then dissolved in 200 ml of methylene chloride. The resulting solution was added dropwise to a suspension of 35 g of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 500 ml of methylene chloride and after stirring for 24 hours at room temperature, the precipitated N,N'-dicyclohexyl urea was removed by filtration and the precipitate washed with methylene chloride. The combined filtrates were washed sequentially with 2 N hydrochloric acid, saturated sodium bicarbonate solution (three times) and with water (twice). Methylene chloride was removed by evaporation in vacuo and toluene was added to the residue. The crystalline solid was isolated by filtration and washed with toluene. Upon crystallization from a methylene chloride/toluene mixture, 19.6 g (48% yield) of t-butyl 7-benzamido-3-methyl-3-cephem-4-carboxylate 1-oxide were obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:40])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([CH2:26][OH:27])[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[H-].[Na+].[CH2:43](Br)[CH:44]=[CH2:45]>CN(C=O)C>[CH2:1]([O:4][C:5]1([CH3:40])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([CH2:26][O:27][CH2:45][CH:44]=[CH2:43])[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(CO)nn4)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCc1cn(Cc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N4CCC(C)(OCC=C)CC4)n3n2)nn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 57.2 %

Procedure:
To a stirred colorless solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate in DMF (2 mL) was added at once 60% NaH (10 mg, 0.250 mmol) at 0° C. After 5 min, allyl bromide (0.085 ml, 0.981 mmol) was added to the brown reaction mixture and stirred for 30 min at 0° C. and 1 h at rt. Then, quenched with EtOH and purified by prep-HPLC to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-((allyloxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0334 g, 0.056 mmol, 57.2% yield) as brown paste. 1H NMR (500 MHz, CDCl3) δ 7.67 (s, 1H), 6.45 (s, 1H), 5.98-6.08 (m, 1H), 5.83-5.97 (m, 2H), 5.73 (s, 2H), 5.40-5.53 (m, 1H), 5.30 (qd, J=1.6, 17.2 Hz, 1H), 5.17-5.24 (m, 2H), 4.64 (d, J=0.5 Hz, 2H), 4.13-4.28 (m, 2H), 4.06 (td, J=1.4, 5.7 Hz, 2H), 4.00-4.03 (m, 2H), 2.60 (s, 3H), 1.87-2.03 (m, 3H), 1.64-1.75 (m, 1H), 1.34 (s, 3H), 1.20-1.26 (m, 12H). LCMS (M+H)=596.6.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Mg].C(O[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C.Cl>O1CCCC1>[O:28]=[C:22]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCC(=O)C(=O)OCC

Procedure:
A slurry of 40 ml of hexadecyl bromide in 250 ml of tetrahydrofuran containing 3.64 g of magnesium chips is put in a sonic bath. This solution is added dropwise to a stirred solution of 35.3 ml of diethyloxalate in 70 ml of tetrahydrofuran at -15° C. over 1 hour. The reaction mixture is poured into 3N hydrochloric acid and extracted with methylene chloride. The extract is dried and evaporated. The concentrate is purified by chromatography on silica gel using 5% ethyl acetate:petroleum ether. Fractions containing product are combined and evaporated. The residue is crystallized from petroleum ether to give 21.9 g of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH:36]2[CH2:38][CH2:37]2)=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH:36]3[CH2:38][CH2:37]3)=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C
Temperature: 25 °C

Procedure:
To 0.102 g (0.428 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.134 g (0.429 mmol) of the above prepared 3-chloromethyl-2-cyclopropyl-6-(4-trifluoromethyl-phenyl)-pyridine, dissolved in 2.5 ml of abs. acetonitrile, was added 0.168 g of Cs2CO3 (0.516 mmol). The reaction was stirred over night at ambient temperature. Pouring onto crashed ice/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=88/12) yielded 0.221 g of pure title compound as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:39])[CH2:10][N:11](CC2C=CC=CC=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]#[C:21][C:22]2[N:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=2)=[CH:4][C:3]=1[Cl:40].Cl>C(O)C.[Pd]=O>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:39])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[N:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=2)=[CH:4][C:3]=1[Cl:40]
Reactant: CC(=O)Nc1ccc(C#CCOCCCCCCN(Cc2ccccc2)CC(O)c2cc(Cl)c(N)c(Cl)c2)nc1
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1ccc(CCCOCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)nc1
Yield: 29.3 %

Procedure:
A solution of N-[6-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl](phenylmethyl)amino]hexyl]oxy]-1-propynyl]-3-pyridinyl]acetamide (1 g) was hydrogenated over palladium oxide on carbon (50% aqueous paste, 1 g) in ethanol (50 ml) containing hydrochloric acid for 24 h. The catalyst was removed by filtration through hyflo, the solvent was evaporated and the residual oil was partitioned between 8% sodium bicarbonate solution (150 ml) and ethyl acetate (150 ml). The combined organic extracts were dried and concentrated to give an oil. Purification by FCC eluting with System A (95:5:1) gave an oil which was triturated under ether (50 ml) to give the title compound as a white solid (250 mg) m.p. 66°-67°.
Reaction SMILES: [F:1][C:2]1([F:17])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:4]=2[O:3]1.[Cl-].[NH4+].C(Cl)Cl>CCO.O.[Fe]>[F:17][C:2]1([F:1])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:4]=2[O:3]1
Reactant: CN1C(=O)C(F)(F)Oc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CN1C(=O)C(F)(F)Oc2cc(N)ccc21
Temperature: 80 °C
Yield: 92.2 %

Procedure:
To a stirred suspension of 2,2-difluoro-4-methyl-7-nitro-4H-1,4-benzoxazin-3-one (Step 1, 1.3 g, 5.32 mmol) in EtOH (20 mL) and water (10 mL) is added ammonium chloride (2.85 g, 53.32 mmol). To this mixture is added iron (892 mg, 15.09 mmol) in 3 equal portions. The resulting mixture is heated to 80° C. for 2 h at which time the reaction is cooled to room temperature followed by addition of CH2Cl2 (50 mL). The resulting mixture is filtered through celite and the filtrate is further diluted with water (50 mL). The organic layer is separated followed by further extraction of the aqueous phase with CH2Cl2 (50 mL×3). The combined organic phase is dried over Na2SO4 and concentrated under reduced pressure, and the residue is purified by passing it through a short silica gel column with EtOAc to give the title compound (1.05 g, Quant.), MS (m/z): 215.5 [M+H]+.