Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:21][C:22]([C:24]1[CH:35]=[CH:34][C:27]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)=[O:23]>C(#N)C>[N:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:21][C:22]([C:24]3[CH:35]=[CH:34][C:27]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)=[O:23])[CH2:3][CH2:2]2)=[N:8][CH:9]=1
Reactant: COC(=O)COc1ccc(C(=O)CBr)cc1
Reactant: c1cc(N2CCNCC2)ncn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncn3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 26.1 %

Procedure:
To a mixture of 4-(1-piperazinyl)pyrimidine (preparation described in DE 2316920) (1.57 g) and triethylamine (3.87 g) in acetonitrile (40 ml) at room temperature was added dropwise over about 0.5 hour a solution of methyl 4-bromoacetylphenoxyacetate (2.73 g) in acetonitrile (25 ml). On completion of the addition the reaction mixture was stirred at room temperature for 2 days. The precipitated solid was filtered off, washed with acetonitrile and the combined filtrate and washings evaporated to dryness. The resultant red oil was purified by flash chromatography, first on silica by elution with 1-5% v/v methanol/dichloromethane, then on neutral alumina by elution with 3% v/v methanol/dichloromethane, to yield the title compound (0.92 g) as an off-white solid: NMR (CDCl3) δ2.69 (4H, m), 3.72 (4H, m), 3.80 (2H, s), 3.82 (3H, s), 4.71 (2H, s), 6.49 (1H, m), 6.94 (2H, d), 8.01 (2H, d), 8.20 (1H, d), 8.60 (1H, s); m/Z 371 (M+H)+ ; calculated for C19H22N4O4. 0.4 H2O: C 60.4%; H, 6.09%; N, 14.8%; found: C, 60.7%; H, 6.2%; N, 14.7%.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[Cl:24][C:25]1[CH:26]=[C:27]([NH:28][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:8][CH2:9]3)=[O:3])[CH:29]=[CH:30][CH:31]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1cccc(Cl)c1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3cccc(Cl)c3)(CC1)CC2

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 3-chloroaniline (36.0 μL) were used to obtain (2S,4S)-1-[[N-[4-[N-(3-chlorophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (23.3 mg).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:10]1[CH:22]=[C:21]([CH3:23])[C:13]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[C:12]([CH3:24])[CH:11]=1)([O:8][CH3:9])[C:4]([F:7])([F:6])[F:5].[OH-].[Na+]>CO>[F:1][C:2]([F:25])([F:26])[C:3]([C:10]1[CH:22]=[C:21]([CH3:23])[C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[C:12]([CH3:24])[CH:11]=1)([O:8][CH3:9])[C:4]([F:5])([F:7])[F:6]
Reactant: CCOC(=O)COc1c(C)cc(C(OC)(C(F)(F)F)C(F)(F)F)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(c1cc(C)c(OCC(=O)O)c(C)c1)(C(F)(F)F)C(F)(F)F

Procedure:
Add ethyl 2-[4-(hexafluoro-2-methoxy-2-propyl)-2,6-dimethylphenoxy]acetate (2.6 g=6.7 mmol) to 30 ml 1.0 N NaOH. Add 20 ml methanol and reflux 3 hours. Acidify with 1.0 N HCl and extract with ether. Dry, concentrate and recrystallize the combined extracts from hexane to obtain, as a white solid, 2-[4-(hexafluoro-2-methoxy-2-propyl)-2,6-dimethylphenoxy]acetic acid, m.p. 105°-108° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:5])[CH3:2].C1(C)C=CC=CC=1.C(Cl)(=O)C([Cl:24])=O>CN(C)C=O>[CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:24])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)COCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)COCCCC(=O)Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
36 g (0.19 mol) of 4-ethoxycarbonyhnethoxybutyric acid are charged to 180 ml of toluene and 0.1 ml of dimethyl formamide is added. Then 24.4 ml (0.28 mol) of oxalyl chloride are added dropwise over 30 minutes. When the addition is complete, the reaction mixture is heated to 50° C., stirred for 1 hour and concentrated by evaporation. Distillation of the residue gives 4-ethoxycarbonylmethoxybutyric acid chloride as a clear colourless liquid of b.p. 87°-89° C./2.10-2 torr.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[OH:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12](N(OC)C)=[O:13])[CH2:8][CH2:7]1.CCOC(C)=O>C1COCC1>[OH:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:13])[CH2:2][CH3:1])[CH2:8][CH2:7]1
Reactant: CON(C)C(=O)C1CCC(O)CC1
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)C1CCC(O)CC1
Reaction time: 8 h
Yield: 72 %

Procedure:
EtMgBr (1 M, 3.0 eq, 20 mL) was added to a solution of 4-hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (1.0 g, 1.0 eq) in dry THF at 0° C. Once addition was complete, the mixture was stirred overnight. The reaction mixture was washed with saturated NH4Cl (aq), and extracted by EtOAc. The extract was dried, concentrated, and purified by column chromatography with petroleum ether:EtOAc=1:1 to give the desired product (0.6 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ 3.50-3.64 (m, 1H), 2.47 (q, J=7.2 Hz, 2H), 2.28-2.37 (m, 1H), 2.00-2.10 (m, 2H), 1.88-1.94 (m, 2H), 1.70-1.80 (m, 1H), 1.21-1.49 (m, 4H), 1.05 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:22]#[C:21][C:20]([CH3:24])([CH3:23])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)C)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at the boiling temperature for 24 hours with 1.46 ml (12 mmol) of 3,3-dimethyl-1-butyne, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. After evaporation of the reaction mixture the residue was taken up in methylene chloride and washed twice with water. The organic phase was dried over magnesium sulphate, evaporated and the residue was chromatographed on silica gel while eluting with cyclohexane/ether/isopropanol (3:3:1). After crystallization from ethyl acetate and hexane there was obtained 7-chloro-3-(3,3-dimethyl-1-butynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 126°-128°.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)=[O:4].[NH2:14][C@H:15]([CH3:31])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=2)=[N:18]1>>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@H:15]([NH:14][C:11]([C:9]3[N:10]=[C:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[S:7][CH:8]=3)=[O:13])[CH3:31])[N:18]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: COC(=O)Nc1nc(C(=O)O)cs1
Product: COC(=O)Nc1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 27.2 %

Procedure:
(R)-methyl 4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazol-2-ylcarbamate was prepared using the method of Example 34(d) starting from 2-(methoxycarbonylamino)thiazole-4-carboxylic acid (0.36 g, 1.460 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.334 g, 1.217 mmol). The product was triturated using diethyl ether and DCM, respectively. Yield 27.2%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 3.77 (s, 3H), 4.33 (d, 1H), 4.34 (d, 1H), 4.37-4.45 (m, 1H), 6.96 (d, 1H), 7.72 (s, 1H), 7.83 (d, 1H), 7.87 (d, 1H), 7.93-7.94 (m, 2H), 8.04 (t, 1H), 11.85 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:30])[C:4]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:5]2[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:8][CH2:7][N:6]2[CH:21]=1.N1C=CC=CC=1.[C:37](Cl)(=[O:41])[CH:38]([CH3:40])[CH3:39].S([O-])(O)(=O)=O.[K+]>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:4]1[C:3](=[O:30])[C:2]([NH:1][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])=[CH:21][N:6]2[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[C:10](=[O:11])[C:5]=12)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: CC(C)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 7-amino-9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (29 mg) in chloroform (0.6 ml) were added pyridine (0.0082 ml) and isobutyryl chloride (0.01 ml) at 0° C., and the mixture was stirred at room temperature for 1.5 hr. 5% Aqueous potassium hydrogen sulfate solution was added and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was dried, concentrated and purified by silica gel thin layer chromatography (chloroform:methanol=10:1) to give N-[9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide (29 mg).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:16][N:17]([CH3:21])[C:18]([N:7]1[C:8]([S:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:19]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)c1n[nH]c(SCS(C)(=O)=O)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCS(C)(=O)=O
Yield: 54.5 %

Procedure:
2 g (8.0 mmle) of 3-t-butyl-5-(methylsulfonylmethylthio)-1H-1,2,4-triazole, 0.8 ml (8.8 mmole) of dimethyl carbamoyl chloride, 1.25 ml (9.0 mmole) of triethylamine and 0.1 g (0.8 mmole) of 4-dirmthylaminopyridine were dissolved in 20 ml of tetrahydrofuran and refluxed for 4 hours. After removal of the solvent the mixture was partitioned between ether and water, dried over magnesium sulfate and concentrated under vaccum. After chromatography on silica gel, trituration with ether afforded 1.4 g of 1-dimethylcarbamoYl-3-t-butyl-5-(methyl-sulfonylmethylthio)-1H-1,2,4-triazole. m.p. 109°-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:6]([CH2:12]Cl)=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[Si]([O:36][C:37]1[CH:38]=[C:39]([C:43]2[C:51]3[C:46](=[N:47][CH:48]=[N:49][C:50]=3[NH2:52])[NH:45][N:44]=2)[CH:40]=[CH:41][CH:42]=1)(C(C)(C)C)(C)C>CN(C=O)C>[NH2:52][C:50]1[N:49]=[CH:48][N:47]=[C:46]2[N:45]([CH2:12][C:6]3[N:5]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:4](=[O:22])[C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[Br:1])[N:7]=3)[N:44]=[C:43]([C:39]3[CH:40]=[CH:41][CH:42]=[C:37]([OH:36])[CH:38]=3)[C:51]=12
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(-c2n[nH]c3ncnc(N)c23)c1
Reactant: O=c1c2c(Br)cccc2nc(CCl)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1cccc(O)c1)nn2Cc1nc2cccc(Br)c2c(=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 5-bromo-3-(2-chlorobenzyl)-2-(chloromethyl)quinazolin-4(3H)-one (2) (100 mg, 0.25 mmol) and potassium carbonate (42 mg, 0.30 mmol) in DMF (2.5 mL) was added a solution of 3-(3-(tert-Butyldimethylsilyloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6) (94 mg, 0.28 mmol) in DMF (2.5mL) and the reaction mixture was stirred at RT for 18 hr. Potassium carbonate (3×35 mg, 0.75 mmol) was added in three portions over 30 hr. after which the solvent was removed in vacuo and the crude material was purified by flash column chromatography, eluting with 4.5% methanol in DCM, to afford the title compound, Intermediate A, (94 mg, 64%) as a off-white solid: Rt 2.01 min; m/z 588/590 (M+H)+, (ES+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH2:24]([O:26][C:27]1[C:28]([C:38](Cl)=[O:39])=[N:29][N:30]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:31]=1)[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([C:28]2[C:27]([O:26][CH2:24][CH3:25])=[CH:31][N:30]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[N:29]=2)=[O:39])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CCOc1cn(-c2cccnc2)nc1C(=O)Cl
Product: CCOc1cn(-c2cccnc2)nc1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(F)c1

Procedure:
Following the general procedure reported in Preparative Example 16 Step 5 X19 was prepared from A2 and 4-ethoxy-1-(pyridin-3-yl)-1H-pyrazole-3-carbonyl chloride, which was prepared similar to Preparative Example 16 step 1-4. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.39 (t, J=7.0 Hz, 3H), 3.96 (s, 6H), 4.10 (q, J=7.0 Hz, 2H), 6.56 (d, J=5.5 Hz, 1H), 7.43 (s, 1H), 7.49 (t, J=9.0 Hz, 1H), 7.57 (s, 1H), 7.60 (dd, J=4.7 Hz, J=8.4 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 8.04 (dd, J=2.4 Hz, J=13.2 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.57 (dd, J=1.4 Hz, J=4.7 Hz, 1H), 8.59 (s, 1H), 9.24 (s, 1H), 10.25 (s, 1H). MS (ES) C28H24FN6O6 requires: 529. Found: 530 (M+H)+.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[C@H:11]([CH2:13][CH3:14])[CH3:12])=[O:8]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[C@H:11]([CH2:13][CH3:14])[CH3:12])=[O:8]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(N)=O
Yield: 89.5 %

Procedure:
4.72 g (10 mmoles) of Z-Glp-Ile-Pro-NH2 are dissolved in 100 ml of methanol, 1 g of a 10% palladium-on-carbon catalyst is added, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the residue is triturated with ether. The resulting 3.22 g of amorphous crude product are dissolved in water, the solution is decolourized, filtered, and the clear filtrate is freeze-dried. 3.03 g (89%) of Glp-Ile-Pro-NH2 are obtained; Rf4 =0.45, [α]D25 =-100.7° (c=1%, in acetic acid). Amino acid analysis: Glu: 0.95 (1.0), Ile: 1.00 (1.0), Pro: 1.02 (1.0).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc([N+](=O)[O-])ccc1C
Solvent: CO
Product: COc1cc(N)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of 1-methyl-2-(methyloxy)-4-nitrobenzene (2.5 g, 14.96 mmol) in methanol (50 mL) Ni-Raney (˜2 g) was added and the reaction mixture was stirred overnight at room temperature under H2 atmosphere (1 atm). The catalyst was filtered off and the residue was purified by SCX cartridge (50 g) to afford the title compound (1.86 g) as a colourless oil.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Ca+2:5].[C:6]1([P:12](=[O:15])([OH:14])[OH:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:1](=[O:2])([O-:4])[O-:3].[Ca+2:5].[C:6]1([P:12](=[O:13])([O-:15])[O-:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Ca+2:5]
Reactant: O=P(O)(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=P([O-])([O-])c1ccccc1

Procedure:
An aqueous slurry of calcium carbonate was prepared by charging a 300 mL reaction flask equipped with a stirrer with 10.0 g (100 mmol) of calcium carbonate (Escalon #2300 (average particle size, 1.7 μm), available from Sankyo Seifun KK) and 90.0 g of water. An aqueous solution of 15.8 g (100 mmol) of phenylphosphonic acid (Nissan Chemical Industries, Ltd.) dissolved in 89.5 g of water was gradually added dropwise at room temperature (about 25° C.) to this slurry with stirring, thereby effecting a reaction for one hour. The slurry was then filtered and the wet cake was thoroughly rinsed with water. The wet cake was subsequently dried at 200° C. for at least 12 hours, yielding a white powder of calcium phenylphosphonate. FIG. 4 shows a micrograph taken with a field-emission scanning electron microscope (SEM: JSM-7400F, manufactured by JEOL Ltd.) of the white powder of calcium phenylphosphonate thus obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: CCCn1c(N)cc(=O)n(C)c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCn1c(N)c(N=O)c(=O)n(C)c1=O
Yield: 81.7 %

Procedure:
6-Amino-3-methyl-1-n-propyluracil (10.46 g, 57.8 mmol) was dissolved in 10 ml of acetic acid at 90° C. Then, with stirring, a solution of sodium nitrite (4.19 g, 60.8 mmol) in 100 ml of water was added in 10 ml portions over 5 minutes. A purple color formed immediately followed by a purple precipitate. The mixture was cooled in the freezer for 20 minutes and then the precipitate was collected by vacuum filtration, washed with water (2×30 ml) and acetone (2×10 ml), and air-dried to give 6-amino-3-methyl-5-nitroso-1-n-propyluracil as purple needles (10.02 g, 83%). 1H NMR (DMSO-d6 +D2O) δ0.89 (t, J=8 Hz, 3 H), 1.55 (sextet, J=8 Hz, 2 H), 3.27 (s, 3 H), 3.80 (t, J=8 Hz, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH2:16])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl[CH2:18][C:19]([NH2:21])=[O:20].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH:16][CH2:18][C:19]([NH2:21])=[O:20])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NC(=O)CCl
Reactant: Cc1ccc(-c2ccccc2CN)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccccc2CNCC(N)=O)cc1C

Procedure:
A reaction vessel was charged with 11.5 g (54.5 mmole) of [(3,4-dimethylphenyl)phenyl]methylamine dissolved in 200 ml of absolute ethanol. A mixture of 5.05 g (54 mmole) of chloracetamide and 4.62 g (55 mmole) of sodium bicarbonate was added to the reaction vessel and the solution was brought to refulux and held at reflux for 42 hours. Solvent was evaporated under reduced pressure and the residue was diluted with water. The aqueous phase was extracted with dichloromethane and the organic solution dried over potassium carbonate. After evaporation of solvent under reduced pressure, the solid residue was crystallized in ethyl acetate.
Reaction SMILES: [Br:1][CH:2]1[CH2:23][CH2:22][C:5]2=[CH:6][C:7]3[C:8]4[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[C:3]1=[O:24].[C:25]([O:29][C:30]([N:32]1[C@@H:36]([CH3:37])[CH2:35][CH2:34][C@H:33]1[C:38]([OH:40])=[O:39])=[O:31])([CH3:28])([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH3:37][C@@H:36]1[N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[C@H:33]([C:38]([O:40][CH2:19][C:18]([C:15]2[CH:16]=[CH:17][C:8]3[C:7]4[CH:6]=[C:5]5[CH2:22][CH2:23][CH:2]([Br:1])[C:3](=[O:24])[C:4]5=[CH:13][C:12]=4[O:11][CH2:10][C:9]=3[CH:14]=2)=[O:21])=[O:39])[CH2:34][CH2:35]1
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 84.9 %

Procedure:
9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (1.43 g, 3.17 mmol) was treated with a solution of (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (800 mg, 3.49 mmol) in dichloromethane (14 mL) and K2CO3 (658 mg, 1.18 mmol). The stirred reaction mixture was stirred at RT and diluted with CH2Cl2 and extracted 3×. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure to afford ((2S,5S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (1.61 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)=[O:18])=[CH:15][CH:14]=1
Reactant: Nc1cccc2cnccc12
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cccc2cnccc12)c1ccc(Br)cc1
Yield: 81.7 %

Procedure:
A solution of 5-aminoisoquinoline (800 mg, 5.54 mmol), 4-bromobenzoic acid (1.68 g, 8.3 mmol), (3-dimethylaminopropyl)-ethyl-carbodiimide hydrochloride (1.64 g, 8.3 mmol) and 4-dimethylaminopyridine (70 mg, 0.6 mmol) was stirred at room temperature overnight. The mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate solution and water, then dried over MgSO4 and concentrated in vacuo to give the crude product. Purification by flash column chromatography eluting with an EtOAc/40-60° C. pet. ether gradient gave the title compound as a white solid (1.48 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.29 (br, 2H), 8.57 (d, 1H), 8.11 (d, 1H), 7.97, (d, 2H), 7.90 (d, 2H), 7.66 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1.CS(O[C@H:18]([C@@H:20]1[CH2:24][C:23](=[O:25])[N:22]([C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH3:27])[CH2:21]1)[CH3:19])(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C@@H:18]([C@H:20]2[CH2:21][N:22]([C@@H:26]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[CH3:27])[C:23](=[O:25])[CH2:24]2)[CH3:19])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1
Reactant: Cc1cnn2cc(Cl)cc(O)c12
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)OS(C)(=O)=O)CC2=O)cc1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4ncc(C)c34)CC2=O)cc1

Procedure:
This reaction was conducted in an analogous fashion to step 1 in General Procedure 6A, beginning with 6-chloro-3-methylpyrazolo[1,5-a]pyridin-4-ol and mesylate 1.30 to afford (R)-4-((R)-1-((6-chloro-3-methylpyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.31. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H26ClN3O3: 428.2; found 428.2.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].O1CCCC1.[CH3:11][C:12]1[NH:24][C:15]2=[N:16][C:17]3[C:22]([N:23]=[C:14]2[N:13]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3>N1C=CC=CC=1>[CH3:5][O:4][C:2]([N:13]1[C:14]2=[N:23][C:22]3[C:17]([N:16]=[C:15]2[N:24]=[C:12]1[CH3:11])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:3]
Reactant: COC(=O)Cl
Reactant: Cc1nc2nc3ccccc3nc2[nH]1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)n1c(C)nc2nc3ccccc3nc21
Reaction time: 17 h

Procedure:
A solution of 6 parts of methyl chloroformate in 50 parts of tetrahydrofuran was added over 30 minutes to a suspension of 4 parts of 2-methyl-1H-imidazo[4,5-b]quinoxaline in 200 parts of tetrahydrofuran and 6 parts of pyridine. The heterogeneous reaction mixture was stirred at 25° for 17 hours. Concentration in vacuo, addition of 200 parts of CH2Cl2, washing with 500 parts of 5% HCl, drying over sodium sulfate, and concentrating in vacuo left a pale yellow solid. Recrystallization from chloroform-hexane gave almost colorless 1-methoxycarbonyl-2-methyl-1H-imidazo[4,5-b]quinoxaline, m.p. 184° (dec.).