Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C([Mg]Cl)(C)C.[C:21](=[O:23])=[O:22].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:21]([OH:23])=[O:22]
Reactant: Fc1cc(Br)ccc1C(F)(F)C(F)(F)F
Reactant: O=C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)C(F)(F)F)c(F)c1
Temperature: -10 °C
Reaction time: 2.5 h

Procedure:
A solution of 16.0 g (99% by weight; 54.1 mmol) of 3-fluoro-4-(pentafluoroethyl)-bromobenzene in 110 ml of THF was cooled to −10° C. Added dropwise over the course of 30 minutes were 36.8 ml of a 2M (73.6 mmol) solution of isopropyl-magnesium chloride. The mixture was stirred at −10° C. for 2.5 hours and then cautiously poured onto an excess of dry ice. For working up, 130 ml of water were added, and the mixture was subsequently extracted once with 10 ml of diethyl ether. The aqueous phase was acidified with half-concentrated hydrochloric acid and then extracted with four times 150 ml of diethyl ether. The combined organic phases were dried and the filtrate was freed from the solvent. The residue was recrystallized from CHCl3, giving 10.7 g of product with a purity of 98% by weight.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)cc2)cc1
Yield: 86.9 %

Procedure:
In a manner similar to the procedure described in Example 7, 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) and para-tolyl isocyanate (0.0096 mL, 0.076 mmol) were reacted to give the title compound as a pale tan solid (25.5 mg, 87%). 1H NMR (DMSO-d6) δ: 10.68 (s, 1H), 8.59 (s, 1H), 8.53 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.40-7.45 (m, 3H), 7.33 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.05-7.09 (m, 3H), 7.01 (d, J=8.2 Hz, 1H), 4.22 (dt, J=12.6, 3.5 Hz, 1H), 3.72 (dt, J=16.0, 3.4 Hz, 1H), 3.51-3.59 (m, 2H), 2.92-2.99 (m, 1H), 2.24 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:16]1(CBr)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[CH3:28]CO>>[CH:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:23]=1[CH2:28][S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: CCO
Reactant: BrCc1cccc2ccccc12
Product: c1ccc2cc(CSc3nnc(-c4ccc5[nH]cnc5c4)o3)ccc2c1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and naphtylmethylbromide (0.332 g, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.Cl[CH2:34][C:35](Cl)=[O:36].C(=O)([O-])O.[Na+].C(N(CC)CC)C.[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>CN(C)C(=O)C>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:11]([CH3:32])[C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][N:54]4[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]4)[S:3][C:4]=3[N:5]=2)[CH:13]=1)=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: CN1CCNCC1
Reactant: O=C(Cl)CCl
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CN1CCN(CC(=O)Nc2nc3cnc(N(C)c4cccc(NC(=O)c5cccc(C(C)(C)C#N)c5)c4)nc3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (152 mg, 343 μmol) produced in Example D5(i) in N,N-dimethylacetamide (4 mL) was added chloroacetyl chloride (68 μL, 858 μmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (20 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (4 mL), triethylamine (143 μL, 1.03 mmol) and 1-methylpiperazine (115 μL, 1.03 mmol) were added, and the mixture was stirred at 60° C. for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→96/4), and the fractions containing the object product were concentrated under reduced pressure. To the obtained residue were added diisopropyl ether and ethyl acetate and the precipitate was collected by filtration to give the title compound (101 mg, 50%) as a colorless amorphous solid.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=C(CCC[O:29]CCN2C3C4C(=CC=CC=4)N4N=NN=C4C=3N=C2)C=1.Cl.O>ClC1C=CC=CC=1Cl>[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:14]1([P:7](=[O:29])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1cncc(CCCOCCn2cnc3c2c2ccccc2n2nnnc32)c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Triphenylphosphine (27.0 g, 115 mmol) was added to a solution of 6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline (28.7 g, 76.9 mmol) in 1,2-dichlorobenzene (1 L). The reaction was heated at reflux temperature overnight. The dark red solution was cooled to room temperature and treated with 1N HCl (225 ml). A tan precipitate formed. The resulting mixture was concentrated in vacuo to yield a dark red/brown solid. This material was treated with 500 ml water and vigorously stirred. Excess triphenylphosphine and triphenylphosphine oxide formed as precipitates and were removed by vacuum filtration. The solid was washed with several portions of water followed by a final wash with dilute HCl (1:5, 1N HCl:water). The red/brown filtrate was collected, washed with ether (3×150 ml), and treated with 10% NaOH solution until the pH reached 12. The crude product formed as a tan precipitate and was collected by filtration. Purification of the crude material was accomplished by treatment (2×) with activated charcoal (Darco-G60) in refluxing methanol. The charcoal was removed by filtration. The desired product formed as a precipitate during concentration of the filtrate.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)C>ClCCl>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: C1CCNCC1
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(-c2nc(CN3CCCCC3)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.6 %

Procedure:
A mixture of 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (2.0 g), piperidine (2.27 g) and ethanol (40 ml)-dichloromethane (10 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and dichloromethane (50 ml) was added to the residue. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (1/1, v/v) gave 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-piperidinomethylquinazoline (1.46 g, 65%) which was then recrystallized from ethyl acetate-hexane. Colorless needles. mp. 130°-132° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[C:5]([CH3:25])=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:25][C:5]1[C:6]([NH:8][CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)=[N:7][C:2]([NH:32][C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1NC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Reactant: Cn1cc(N)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Temperature: 150 °C
Reaction time: 16 h
Yield: 110.8 %

Procedure:
To a solution of tert-butyl 4-((2-chloro-5-methylpyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (0.35 g, 0.95 mmol) and 1-methyl-1H-pyrazol-4-amine (0.14 g, 1.43 mmol) in n-BuOH (5 mL) was added DIPEA (0.25 g, 1.9 mmol). The reaction mixture was stirred at 150° C. for 16 h then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as black oil (0.45 g, 86%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](Cl)([Cl:14])=[O:13]>C1C=CC=CC=1>[Cl:14][C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(Cl)Cl
Reactant: OCCOCc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)OCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
22.7 G. (150 mmoles) of 2-benzyloxyethanol is added dropwise with stirring to 188 ml. (300 mmoles) of a 17.2% phosgene solution in benzene cooled in an ice bath with protection from moisture. The addition is complete in 40 minutes and the solution is stirred in the ice bath for an additional hour. The reaction mixture is allowed to warm to room temperature and stirred overnight. A stream of nitrogen is passed through the solution to remove the excess phosgene and HCl. The reaction mixture is evaporated to dryness in vacuo affording 32.2 g. of a light orange residual oil. Infrared analysis reveals a strong carbonyl absorption and minimal hydroxy absorption. The material is used as is in the next step.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].Cl.C(C1C=C[C:10]([O:11]CCCCCOC2C=CC(C([Cl:24])=O)=CC=2OC)=CC=1)#N.[C:31]([C:33]1[CH:62]=[CH:61][C:36]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:44]2[CH:58]=[CH:57][C:47]([C:48]([N:50]([CH:54]([CH3:56])[CH3:55])[CH:51]([CH3:53])[CH3:52])=[O:49])=[CH:46][C:45]=2OC)=[CH:35][CH:34]=1)#[N:32]>C(OCC)(=O)C.CCCCCC>[ClH:24].[CH3:10][O:11][C:46]1[CH:45]=[C:44]([CH:58]=[CH:57][C:47]=1[C:48]([N:50]([CH:54]([CH3:56])[CH3:55])[CH:51]([CH3:52])[CH3:53])=[O:49])[O:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][O:37][C:36]1[CH:61]=[CH:62][C:33]([C:31](=[NH:32])[O:3][CH2:1][CH3:2])=[CH:34][CH:35]=1
Reactant: CCO
Reactant: COc1cc(C(=O)Cl)ccc1OCCCCCOc1ccc(C#N)cc1
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(C#N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=N)c1ccc(OCCCCCOc2ccc(C(=O)N(C(C)C)C(C)C)c(OC)c2)cc1
Temperature: 10 °C
Reaction time: 6 h

Procedure:
Ethanol (2B,6.0 L) is cooled in an ice bath to 0° C. and saturated with anhydrous hydrogen chloride over a period of 7 1/2hours. The solution is left in the ice bath overnight and the hydrogen chloride addition is continued an additional hour at 0° C. 4-[5-(4-Cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)- benzamide (4200 g, 9.57 mole) is added rapidly over 30 minutes and an exotherm raises the reaction mixture temperature to 10° C. Hydrogen chloride addition is continued for 6 hours and the purple solution stirred overnight at 20° C. The reaction mixture is followed by TLC (ethyl acetate/hexane, 2:1) using silica plates. A total of 4-5 days is required for completion of this reaction with periodic resaturation with hydrogen chloride. The thick purple solution is transferred into a 20 gallon reactor and triturated with anhydrous diethyl ether (2×30 L), removing the ether solution after each wash. The reactor is put under vacuum (3 mm Hg) for 0.5 hour to dispel most of the hydrogen chloride leaving ethyl 4-[5-[3-methoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate monohydrochloride as a thick purple oil.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[C:17]2[C:4]=1[C@H:5]1[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.[CH3:29]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>C1COCC1.CN(C=O)C>[OH:2][C:3]1[CH:20]=[C:19]([C:21]([N:60]2[CH2:65][CH2:64][O:63][CH2:62][CH2:61]2)=[O:23])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:29])[C@H:14]([CH2:15][S:16]2(=[O:24])=[O:25])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1
Reactant: C1COCCN1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)cc2c1[C@@H]1CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(C(=O)N5CCOCC5)cc(O)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.6 %

Procedure:
A mixture of (1R,10S,11S,16S)-3-methoxy-11,15,15-trimethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (61) (0.08 g, 0.2 mmol), HATU (0.15 g, 0.40 mmol), N-methylmorpholine (0.04 mL, 0.6 mmol) and morpholine (0.086 mL, 1.0 mmol) in THF (4.0 mL) and DMF (1.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (Hexanes/EtOAc, 3:1) to give (1R,10R,11S,16S)-3-hydroxy-1,11,15,15-tetramethyl-5-[(morpholin-4-yl)-carbonyl]-8λ6-thiatetracyclo[8.8.0.02,7.011,16]-octadeca-2,4,6-triene-8,8-dione (87) (0.05 g, 54%) as a white solid. 1H NMR (DMSO-d6): δ 7.18 (d, 1H), 7.00 (d, 1H), 3.70-3.24 (m, 10H), 1.90 (d, 1H), 1.83 (d, 1H), 1.70-1.32 (m, 8H), 1.28-1.08 (m, 3H), 0.97 (d, 1H), 0.92 (s, 3H), 0.85 (m, 4H), 0.81 (s, 3H). MS m/z 476 (C26H37NO5S+H+).
Reaction SMILES: P(Cl)(=O)[O-].[C:5]1([CH2:11][O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]([OH:38])[C:21]([N:23]2[CH2:37][CH2:36][CH2:35][C@H:24]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:22])=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:55]([O:63][CH:64]([P:69](OC)([O:71][CH:72](NC(OCC1C=CC=CC=1)=O)CCCCC([C@]1(C(OCC2C=CC=CC=2)=O)CCCN1)=O)=[O:70])[CH2:65][CH2:66][CH2:67][CH3:68])(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C(Cl)Cl>[C:55]([O:63][CH:64]([P:69]([O:71][CH3:72])([O:38][C@@H:20]([CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:13]([O:12][CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:14])[C:21]([N:23]1[CH2:37][CH2:36][CH2:35][C@H:24]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22])=[O:70])[CH2:65][CH2:66][CH2:67][CH3:68])(=[O:62])[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: CCCCC(OC(=O)c1ccccc1)P(=O)(OC)OC(CCCCC(=O)[C@]1(C(=O)OCc2ccccc2)CCCN1)NC(=O)OCc1ccccc1
Reactant: O=C(NCCCC[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccccn1
Agent: O=[PH]([O-])Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(OC(=O)c1ccccc1)P(=O)(OC)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
The resulting crude phosphonochloridate is taken up in dry methylene chloride (2 ml.) and added dropwise to a methylene chloride (8 ml.) solution of 1-[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-hydroxy-1-oxohexyl]-L-proline, phenylmethyl ester (1.97 g., 4.2 mmole), triethylamine (0.66 g., 6.5 mmole) and dimethylaminopyridine (0.1 g.) at 0° under argon and stirred at 0°-15° for 2 hours. The mixture is partitioned between methylene chloride and 5% potassium bisulfate. The organic phase is washed with brine, dried over magnesium sulfate, and evaporated to dryness. The resulting crude oil is purified by chromatography (LPS-1 silica gel) eluting with (7:3) hexane:acetone. The product containing fractions are combined and concentrated in vacuo to yield 1.55 g. of 1-[(S)-2-[[[1-(benzoyloxy)pentyl]methoxyphosphinyl]oxy-1-oxo-6-[[(phenylmethoxy)carbonyl]amino]hexyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[C:31](=[O:32])[N:23]3[CH:24]([C:29]#[N:30])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:33]=[N+:34]=[N-:35].[Na+].CN1CCCCC1.Cl.CN1CCCCC1>C(O)C.O>[C:1]1([C:7]([NH:20][CH:21]2[C:31](=[O:32])[N:23]3[CH:24]([C:29]4[NH:35][N:34]=[N:33][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCCC1
Solvent: CCO
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Temperature: 25 °C

Procedure:
A mixture of 6-triphenylmethylamino-2,2-dimethyl-3-cyanopenam (4.39 g. 0.01 mole), anhydrous ethanol-free chloroform (20 ml.), powdered sodium azide (650 mg., 0.01 mole) and dry N-methylpiperidine (2.98 g., 0.03 mole) is heated to 58°-60° C. (internal temperature). To the mixture is added with stirring 5 ml. of a solution of dry N-methylpiperidine hydrochloride (1.5 g., 0.011 mole) in ethanol-free chloroform (20 ml.) every 15 minutes over a period of one hour. The mixture is stirred and heated for 1.5 hours at 58°-60° C. following the additions of N-methylpiperidine and is then charged with finely powdered sodium azide (650 mg.) and N-methylpiperidine hydrochloride (1.5 g., 0.011 mole) in ethanol-free chloroform (20 ml.). The reaction mixture is heated for an additional hour and is then cooled to room temperature and diluted with water (150 ml.) and ethanol-free chloroform (250 ml.). The mixture is thoroughly shaken and the chloroform phase then separated and washed with successively with 1N HCl (1 × 250 ml.) and water (1 × 150 ml.).
Reaction SMILES: [C:1](OC(=O)C(C)C)(=O)[CH:2](C)[CH3:3].[F:12][C:13]1[C:14]([C:19]2[N:20]([CH2:24][C:25]3[N:30]=[CH:29][N:28]=[C:27]([NH:31][NH2:32])[C:26]=3[CH2:33][CH2:34][CH3:35])[CH:21]=[CH:22][N:23]=2)=[N:15][CH:16]=[CH:17][CH:18]=1.[CH2:36](Cl)Cl>O=P(Cl)(Cl)Cl>[F:12][C:13]1[C:14]([C:19]2[N:20]([CH2:24][C:25]3[N:30]=[CH:36][N:31]4[N:32]=[C:29]([CH:2]([CH3:3])[CH3:1])[N:28]=[C:27]4[C:26]=3[CH2:33][CH2:34][CH3:35])[CH:21]=[CH:22][N:23]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClCCl
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1NN
Reactant: CC(C)C(=O)OC(=O)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(C(C)C)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isobutyric anhydride (0.5 mL) is added to a mixture of 131 (45 mg) in methylene chloride (10 mL). The mixture is stirred at room temperature for 1 hour. The solvent is removed to get residue, LC-MS (M+1) 398.17. The residue is dissolved in POCl3 (1 mL), and the mixture is heated at 85° C. for 1 hour. Excess POCl3 is removed. The residue is dissolved in methylene chloride, and washed with sat. NaHCO3, dried, and purified by TLC with 5% MeOH in methylene chloride to give the title product (156). 1H NMR δ (CDCl3) 1.02 (t, 3H, J=5.4 Hz), 1.43 (d, 6H, J=6.0 Hz), 1.71 (p, 2H, J=5.4 Hz), 2.93 (m, 2H), 3.29 (sep, 1H, J=6.0 Hz), 5.57 (s, 2H), 7.22–7.36 (m, 2H), 7.70–7.82 (m, 2H), 8.82 (d, 1H, J=3.3 Hz), 9.04 (s, 1H). LC-MS (M+1) 380.17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(O)C.Cl[CH:13]([CH:19]=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][N:5]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:8]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Nc1cc(F)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(F)ccn12
Temperature: 60 °C

Procedure:
4-Fluoropyridin-2-amine (10.0 g, 48.0 mmol) was mixed with ethanol (40 mL) in a reaction flask, under an atmosphere of dry nitrogen. A solution of ethyl 2-chloro-3-oxopropanoate (5% in benzene, 178 mL (commercial solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60° C. under nitrogen for 4 hours. After allowing the mixture to cool the solvent was removed under vacuum to give a brown solid. The solid was mixed with ethyl acetate (300 mL) and sodium bicarbonate solution (75 mL) and stirred to dissolve. The phases were separated and the bicarbonate solution was extracted further with ethyl acetate (75 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated under vacuum to give a solid. The crude material was dissolved in ethyl acetate and passed through a short column of silica, eluting with ethyl acetate. Factions containing the desired product were concentrated to give ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate as a white solid (13 g).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([CH3:19])[CH:4]=1)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:21]=1.[BH4-].[Na+]>CO>[CH3:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: Cc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: NCCc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CNCCc2cccnc2)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Place 5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (Example 404, part D) (0.600 g, 2.33 mmol), 2-pyridin-3-ylethylamine (0.285 g, 2.33 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (11.7 mL), cap and stir overnight. Add NaBH4 (0.088 g, 2.33 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 25% (2.0 M NH3 in methanol) in ethyl acetate. Concentrate the fraction containing the product, then take it up in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4 and concentrate it to give the title compound (0.315 g, 37.2%): TOF MS ES+ 364.2 (M+H)+, HRMS calcd for C20H22N5O2 364.1773 (M+H)+, found 367.1774, time 0.39 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=6.1 min, 100% purity.