Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C@H:11]([S:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[F:44])=[N:6][CH:7]=1.[C:45]([Si:47]([CH3:50])([CH3:49])[CH3:48])#[CH:46].CCN(CC)CC>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:44][C:37]1[CH:38]=[C:39]([F:43])[C:40]([F:42])=[CH:41][C:36]=1[CH2:35][O:34][CH2:33][C@@H:9]1[CH2:10][C@@H:11]([S:13][C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][N:8]1[C:5]1[N:6]=[CH:7][C:2]([C:46]#[C:45][Si:47]([CH3:50])([CH3:49])[CH3:48])=[CH:3][N:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ncc(Br)cn2)cc1F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COCc2cc(F)c(F)cc2F)nc1
Yield: 9.1 %

Procedure:
A solution of 0.68 g (1 mmol) (2S,4R)-5-Bromo-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine, 15 mg (0.022 mmol) of bis(triphenylphosphine)palladium(II)dichloride and 9.5 mg copper(I)iodide in 0.4 ml DMF was treated at 80° C. for 1 h with a solution of 0.35 ml (2.5 mmol) ethinyltrimethylsilane and 1.87 ml Et3N in 1.5 ml DMF. The same solution was added again during 1 h and after 4 h extracted with pentane (3×)/H2O (2×). The organic phase was dried (Na2SO4), evaporated and purified by flash-chromatography on silica gel (toluene) to give 0.063 g (9%) (2S,4R)-2-[2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-5-trimethylsilanylethynyl-pyrimidine, MS: 694 (MH+). TFA/triisopropylsilane deprotection (see General method for S-deprotection, Method D) gave (3R,5S)-5-(2,4,5-Trifluoro-benzyloxymethyl)-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidine-3-thiol, MS: 452 (MH+).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1.[OH-].[Na+]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:2][C:3](=[O:5])[CH3:4])=[CH:9][CH:8]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99084.2 %

Procedure:
Chloroacetone (32.3 g, 0.347 mol) was added to a mixture of 4-chlorothiophenol (50 g, 0.347 mmol) and sodium hydroxide (14 g, 0.347 mol) in water (400 ml) and the mixture was stirred at 25° C.. for 1 hour. The mixture was extracted with ethyl ether and the organic phase was washed with water, dried with magnesium sulfate and concentrated to give 69 g (99%) of 1-[(4-chlorophenyl)thio]-2-propanone.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](OC)=[O:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[OH-].[NH4+:30]>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:25])[NH2:30])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(C#N)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Yield: 49 %

Procedure:
A solution of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (114 mg, 0.32 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 7 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 40 mg (49%) of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.7 (d, 1H, J=8 Hz), 7.6 (s, 1H), 7.5-7.4 (m, 3H), 7.3 (t, 1H, J=8 Hz), 7.25 (d, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 5.75 (s, 2H). IR (KBr, cm−1) 3430, 3347, 2231, 1628, and 1601. MS (ES) m/e 340, 342.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)C=O.OO.[OH:14]S([O-])=O.[Na+]>[OH-].[Na+].O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[C:4]([OH:14])[C:3]=1[OH:11]
Reactant: O=S([O-])O
Reactant: O=Cc1c(F)ccc(Br)c1O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1c(F)ccc(Br)c1O
Reaction time: 2 h

Procedure:
3-Bromo-6-fluoro-2-hydroxybenzaldehyde (9.0 g, 41 mmol, prepared according to Castro, Alfred C.; Depew, Kristopher M.; Grogan, Michael J.; Holson, Edward B.; Hopkins, Brian T.; Johannes, Charles W.; Keaney, Gregg F.; Koney, Nii O.; Liu, Tao; Mann, David A.; Nevalainen, Marta; Peluso, Stephane; Perez, Lawrence Blas; Snyder, Daniel A.; Tibbitts, Thomas T., WO 2008024337 A2) was stirred in 1.0 M NaOH (47 mL) and treated with hydrogen peroxide (6%; 49 g, 86 mmol). External cooling was applied to keep the temperature controlled below 50° C. After 2 h total stirring, the mixture was stirred with a solution of NaHSO3 in 50 mL water and extracted with ethyl acetate (2×75 mL). The combined extracts were washed with saturated NaCl (20 mL), dried (Na2SO4) and evaporated. The catechol derivative, as a dark orange liquid, was carried to the next step without further purification (8.9 g, qt): EIMS m/z 206.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][CH2:2][C:3]1[O:15][C:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[N:6][N:5]=1
Reactant: Cc1ccc(C(=O)NNC(=O)CCl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1ccc(-c2nnc(CCl)o2)cc1
Yield: 72.4 %

Procedure:
To a mixture of 4-methylbenzohydrazide 14 (10 g, 66.59 mmol) and K2CO3 (16.57 g, 119.86 mmol) in acetonitrile (100 mL) was added 2-chloroacetyl chloride (9.02 g, 79.9 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was collected, washed with H2O and ether, and dried to afford N′-(2-chloroacetyl)-4-methylbenzohydrazide 15 (13 g, 82%) which was used for the next step without further purification. A mixture of N′-(2-chloroacetyl)-4-methylbenzohydrazide 15 (6.0 g, 26.47 mmol) and phosphorous oxychloride (5.0 g, 32.84 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated. The residue was subjected to flush column chromatography eluting with 10-25% acetone/hexanes to give compound 16 (4 g). Yield: 72%.
Reaction SMILES: [H-].[Na+].[CH2:3]([P:14](=[O:23])([O:19][CH:20]([CH3:22])[CH3:21])[O:15][CH:16]([CH3:18])[CH3:17])[P:4](=[O:13])([O:9][CH:10]([CH3:12])[CH3:11])[O:5][CH:6]([CH3:8])[CH3:7].[CH2:24](Br)/[CH:25]=[C:26](/[CH2:28][CH2:29]/[CH:30]=[C:31](/[CH2:33][CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])\[CH3:32])\[CH3:27].O>C(COC)OC>[CH2:24]([CH:3]([P:4](=[O:13])([O:9][CH:10]([CH3:11])[CH3:12])[O:5][CH:6]([CH3:8])[CH3:7])[P:14](=[O:23])([O:15][CH:16]([CH3:18])[CH3:17])[O:19][CH:20]([CH3:22])[CH3:21])/[CH:25]=[C:26](/[CH2:28][CH2:29]/[CH:30]=[C:31](/[CH2:33][CH2:34][CH:35]=[C:36]([CH3:37])[CH3:38])\[CH3:32])\[CH3:27]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
Oily sodium hydride (60%, 0.24 g) was added to a solution of tetraisopropyl methylenebisphosphonate (3.44 g) in dimethoxyethane (25 ml). The mixture was stirred at room temperature for 1 hour. Then, a solution of (E,E)-farnesyl bromide (1.43 g) in dimethoxyethane (5 ml) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 hour, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), and then the solvent was distilled off under reduced pressure. The oily residue was subjected to column chromatography on silica gel. Tetraisopropyl (E,E)-farnesylmethylenebisphosphonate (1.67 g, 60.9%) was obtained as an oil from the fractions obtained by elution with ethyl acetate-chloroform (1:1, v/v).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:40].[CH2:42](I)[CH3:43]>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH2:42][CH3:43])[C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:40]
Reactant: CCI
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4Cl)c(Cl)c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OCc1ccccc1Cl)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 2-chlorobenzyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (65 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (84 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:7](=O)[NH:8][CH:9]=[CH:10][C:11]=2[CH:12]=1.P(Cl)(Cl)([Cl:16])=O>C(#N)C>[Cl:16][C:7]1[N:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnc2c(=O)[nH]ccc2c1
Solvent: CC#N
Product: COc1cnc2c(Cl)nccc2c1
Temperature: 85 °C
Yield: 60.4 %

Procedure:
To a mixture of 3-methoxy-1,7-naphthyridin-8(7H)-one (4.50 g, 25.5 mmol) in acetonitrile (102 ml) was added phosphorus oxychloride (11.69 ml, 128 mmol). The reaction mixture was heated to 85° C. for 5 h. The solution was cooled to rt and concentrated in vacuo. The resulting brown residue was partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, the filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (5%-30% of 9:1 DCM:MeOH in DCM) to afford 8-chloro-3-methoxy-1,7-naphthyridine (3.00 g, 15.41 mmol, 60.3% yield) as an off-white solid. MS m/z=195 (M+H)+.
Reaction SMILES: [Na].[CH3:2][C:3]1[N+:8]([O-:9])=[C:7]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:6]2=[C:5]([N+]([O-])=O)[C:4]=1[C:18]([O:20][CH2:21]C)=[O:19].[CH3:23][OH:24]>>[CH3:23][O:24][C:5]1[C:4]([C:18]([O:20][CH3:21])=[O:19])=[C:3]([CH3:2])[N+:8]([O-:9])=[C:7]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:6]=12
Reactant: CO
Reactant: CCOC(=O)c1c([N+](=O)[O-])c2c([n+]([O-])c1C)CCCCC2
Agent: [Na]
Product: COC(=O)c1c(OC)c2c([n+]([O-])c1C)CCCCC2
Temperature: 25 °C
Reaction time: 29 h
Yield: 86.3 %

Procedure:
In an atmosphere of argon and at room temperature, metallic sodium (86.0 mg, 0.005 g atom) was dissolved in anhydrous methanol (8.0 ml) to which was subsequently added dropwise methanol solution (20.0 ml) of ethyl 2-methyl-4-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate N-oxide (1.00 g, 3.40 mmol), and the resulting mixture was stirred at room temperature for 29 hours. After evaporation of the solvent under reduced pressure, the resulting residue was mixed with water and extracted with chloroform, and the thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was purified by a silica gel column chromatography (ethyl acetate:hexane=5:1—ethyl acetate:methanol=15:1) to obtain the title compound (777.9 mg, 86.3%) as pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17]([OH:19])=O)=[O:12].[NH2:24][C:25]1[CH:26]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1C(=O)CCC1>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]([C:17](=[O:19])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)[CH:20]=[CH:21][C:22]=1[CH3:23])=[O:12]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1sc2nccnc2c1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1sc2nccnc2c1N
Yield: 9.7 %

Procedure:
A solution of 109 (0.305 mmol, 100 mg), 3-aminobenzotrifluoride (0.305 mmol, 0.038 mL), TBTU (0.457 mmol, 147 mg) and DIPEA (0.914 mmol, 0.150 mL) in NMP (5 ml) stirred overnight at 80° C. The light brown solution was poured into citric acid solution and extracted with ethyl acetate. The combined organic layers were washed with brine and evaporated. The crude compound was purified by HPLC and chromatography (0-5% methanol in CH2Cl2) gave 7-amino-N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 110 (14 mg, 10%). NMR (400 MHz, DMSO-d6) 2.33 (s, 3H), 7.10 (s, 2H), 7.47 (m, 2H), 7.61 (m, 1H), 7.85 (dd, J=7.8 Hz and 1.6 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 8.25 (s, 1H), 8.79 (d, J=2.3 Hz, 1H), 8.80 (d, J=2.3 Hz, 1H), 9.62 (s, 1H), 10.52 (s, 1H). (m/z)=472 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([S:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].NC1C=C(Cl)C(O)=C(Cl)C=1.ClC1N=C(SC2C=C(C)C=C(C)C=2)C=CN=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:72][CH2:73][N:74]1[CH2:78][CH2:77][CH2:76][CH2:75]1>O1CCCC1>[Cl:9][C:6]1[CH:5]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([S:17][C:18]3[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH:14]=[CH:13][N:12]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][CH2:72][CH2:73][N:74]1[CH2:78][CH2:77][CH2:76][CH2:75]1
Reactant: Cc1cc(C)cc(Sc2ccnc(Nc3cc(Cl)c(O)c(Cl)c3)n2)c1
Reactant: OCCN1CCCC1
Agent: Cc1cc(C)cc(Sc2ccnc(Cl)n2)c1
Agent: Nc1cc(Cl)c(O)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(Sc2ccnc(Nc3cc(Cl)c(OCCN4CCCC4)c(Cl)c3)n2)c1

Procedure:
To a solution of N-(3,5-dichloro-4-hydroxyphenyl)-4-(3,5-dimethylphenylsulphanyl)-2-pyrimidineamine (1.0 g, 2.55 mmol--prepared from 4-amino-2,6-dichlorophenol and 2-chloro-4-(3,5-dimethylphenylsulphanyl)-pyrimidine according to the method of Example 4) in dry tetrahydrofuran were added triphenylphosphine (802 mg, 3.06 mmol) and N-(2-hydroxyethyl)pyrrolidine (0.3 ml, 2.55 mmol), followed by diethyl azadicarboxylate (0.49 ml, 3.1 mmol). The resulting solution was heated at reflux for 18 h and on cooling the reaction was partitioned between ethyl acetate (200 ml) and saturated aqueous NaHCO3 (200 ml). The organic phase was dried (MgSO4), evaporated and the residue columned (silica;ethyl acetate) to give the title compound (400 mg) as a white foam. δH 8.08 (1H, d, J 5.8 Hz), 7.56 92H, s), 7.17 (2H, s), 7.09 (1H, s), 7.05 (1H, s), 6.28 (1H, d, J 5.8 Hz), 4.18 (2H, t, J 8.6 Hz), 2.59 (2H, t, J 8.6 Hz), 2.59 (2H, t, J 8.6 Hz), 2.69 (4H, m), 2.31 (6H, s) and 1.80 (4H, m). MS m/z 489.2/490.9 (MH+).
Reaction SMILES: Br[C:2]1[N:3]([CH2:12][C:13]#[C:14][CH3:15])[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].O>CN(C)C=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:3]([CH2:12][C:13]#[C:14][CH3:15])[C:4]3[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=3[N:11]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC#CCn1c(Br)nc2cn[nH]c(=O)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cn[nH]c(=O)c21
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 2.11 g of 2-bromo-3-(2-butyn-1-yl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one, 1.64 g potassium carbonate and 1.91 g 1-tert.-butyloxycarbonyl-piperazine in 20 ml N,N-dimethylformamide is stirred for six hours at 80° C. After cooling to ambient temperature the reaction mixture is combined with water and the precipitate formed is suction filtered. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol (95:5 to 90:10).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:26])[CH:21](OCC)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1([CH2:31][CH2:32][N:33]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[C:36]([CH3:44])([CH3:43])[O:35][C:34]2=[O:45])[CH2:30][CH2:29]1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:26])[CH2:21][NH:27][C:28]2([CH2:31][CH2:32][N:33]3[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[C:36]([CH3:43])([CH3:44])[O:35][C:34]3=[O:45])[CH2:30][CH2:29]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)N(CCC2(N)CC2)c2ccccc21
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c2c1OCC(=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)OC(=O)N(CCC2(NCC(O)c3ccc(OCc4ccccc4)c4c3OCC(=O)N4)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
900 mg (2.5 mmol) of 5-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 700 mg (2.7 mmol) of 1-[2-(1-aminocyclopropyl)ethyl]-4,4-dimethyl-1,4-dihydrobenzo [d][1,3]oxazin-2-one is dissolved in 20 mL of ethanol and stirred in each case for 30 minutes at 80° C. and 50° C. The reaction mixture is cooled, combined with 200 mg (5.3 mmol) sodium borohydride, and stirred for 2 hours at ambient temperature. Glacial acetic acid is added, the mixture is stirred for 10 minutes, and evaporated down. The residue is taken up in dichloromethane and washed successively with potassium hydrogen sulfate solution, 15% potassium carbonate solution, and sodium hydrogen carbonate solution. Then the organic phase is dried with sodium sulfate and freed from solvent. The residue is purified by column chromatography (silica gel; ethyl acetate/methanol/ammonia gradient). Recrystallization from diisopropylether. White solid. Yield: 690 mg (49%); mass spectroscopy: [M+H]+=558.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([C:39]6[NH:40][C:41]([CH:44]7[CH:49]8[CH2:50][CH:46]([CH2:47][CH2:48]8)[N:45]7C(=O)C(C7CC7)NC(OC)=O)=[N:42][CH:43]=6)[CH:35]=5)[CH:30]=4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:63][O:64][C:65]([CH3:76])([CH3:75])[CH:66]([NH:70][C:71]([O:73][CH3:74])=[O:72])[C:67]([OH:69])=O>>[CH3:74][O:73][C:71](=[O:72])[NH:70][CH:66]([C:67]([N:45]1[CH:44]([C:41]2[NH:40][C:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([C:26]5[CH:27]=[CH:28][C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:14][CH2:15]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:62])[CH:6]([CH3:7])[CH3:8])=[N:22][CH:21]=6)=[CH:24][CH:25]=5)[CH:30]=4)[CH:35]=3)=[CH:43][N:42]=2)[CH:49]2[CH2:50][CH:46]1[CH2:47][CH2:48]2)=[O:69])[C:65]([O:64][CH3:63])([CH3:76])[CH3:75]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C6CC6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)C(C)(C)OC
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)(C)OC)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Yield: 35 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example from JJC) using 3-Methoxy-2-methoxycarbonylamino-3-methyl-butyric acid (0.020 g, 0.096 mmol) to provide [2-Methoxy-1-(3-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.019 g, 35%) as a white solid.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][NH:32][CH2:33][CH3:34]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:32]([CH2:33][CH3:34])[CH3:31])=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: CCNC
Agent: Cl
Product: CCN(C)C(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 13.9 mg (0.23 mmol) of methylethylamine are reacted together by general method E. 19.8 mg (29.4% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(N)c1cccc(OC)c1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cccc(OC)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(3-methoxyphenyl)acetate hydrochloride (prepared by the Bucherer Modification of the Strecker procedure as described in J. P. Greenstein et al., “The Chemistry of Amino Acids”, Vol. 1, p. 698, Wiley, New York (1961)), the title compound was prepared as a solid (mp=163-170° C.). The reaction was monitored by tlc (Rf=0.45 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.