Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[N:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[OH:8]
Reactant: Clc1cccc(Cl)c1N=C1NCCN1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: ON1CCNC1=Nc1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
1.0 g. of 1-benzyloxy-2-[(2,6-dichlorophenyl)-imino]imidazolidine is dissolved in 10 ml. of methylene chloride, and 1 ml. of boron tribromide is added carefully at room temperature. After 1 hour, the solution is evaporated in vacuo. The residue is dissolved in water and the solution is adjusted to pH 10 with caustic soda solution and extracted, first with methylene chloride and then with ethyl acetate. The organic extracts are dried over sodium sulfate and evaporated in vacuo. The residue is recrystallized from acetonitrile, whereupon 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine, m.p. 211° (decomp.), is obtained.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].[Li]CCCC.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[C:3][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C#CCOC1CCCCO1
Reactant: CCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC#CCOC1CCCCO1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of tetrahydro-2-(2-propynyloxy)-2H-pyran (47) (2.8 g, 20 mmol) in THF (30 mL) was cooled to -78° C. and n-BuLi (2.5 M, 8 mL) was added over 15 minutes. The mixture was stirred for 30 minutes at which time octyl bromide (4.24 g, 2.2 mmol, 1.1 equiv) in THF (10 mL) was added. The reaction mixture was then stirred at -78° C. for 1 hour, allowed to warm to 0° C. and stirred for an additional 30 minutes. The reaction mixture was quenched with NH4Cl (10 mL) and poured into ether (150 mL) and water (150 mL). The organic layer was separated, dried (MgSO4) and concentrated by rotary evaporation to yield a yellow oil used in the next step without purification. ##STR21##
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[CH3:22][O:23][N:24]([CH3:31])[C:25](N(OC)C)=[O:26].[Cl-].[NH4+]>C1COCC1>[CH:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:25]([N:24]([O:23][CH3:22])[CH3:31])=[O:26])=[CH:14][CH:15]=2)[CH2:21][CH2:20]1
Reactant: CON(C)C(=O)N(C)OC
Reactant: Brc1ccc(C2CC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C2CC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 6.0 mL, 9.59 mmol) was added dropwise to an solution of 1-bromo-4-cyclopropylbenzene (1.8 g, 9.13 mmol) in anhydrous THF (30 mL) at −78° C. over 15 minutes. This solution was stirred at −78° C. for 10 minutes, and a solution of N,N′-dimethoxy-N,N′-dimethylurea (1.42 g, 9.59 mmol) in THF (15 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated ammonium chloride aqueous solution and the mixture was extracted with ether, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=n-hexane:ethyl acetate (4:1)] to obtain the title compound (875 mg, 95%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].Cl.[CH3:17]O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:17])=[O:14]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCCCCCCCCO
Temperature: 22 °C
Reaction time: 3.5 h
Yield: 90 %

Procedure:
12-Hydroxydodecanoic acid (10.82 g, 50 mmol) was added to 3% HCl in CH3OH (210 ml). The reaction was stirred at 22° C. for 3.5 hours and concentrated on a rotary evaporator. The residue was taken up in ethyl acetate (200 ml) and washed with 1M K2CO3 (2×150 ml), and once with saturated aqueous NaCl (150 ml), dried over Na2SO4, concentrated and vacuum distilled to yield 10.3 g of methyl 12-hydroxydodecanoate in 90% yield; mp 33.5-35.0° C., 1H NMR (CDCl3) delta 3.66 (s, 3H), 3.62 (t, 2H), 2.88 (t, 2H), 1.28 (br s, 18H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: C1COCCN1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
In a 5 mL volume glass vessel equipped with a stirrer and a thermometer were placed 0.5 g (1.9 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 0.5 g (5.7 mmol) of morpholine, and 1.0 mL (4.0 mmol) of aqueous sodium hydroxide solution (4.0 mol/L). The resulting mixture was stirred at 50° C. for 2 hours. After the reaction was complete, the reaction mixture was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 0.57 g (reaction yield: 94%) of 6-methoxy-7-(3-morpholinopropoxy)-quinazolin-4-one.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9]C(C)(C)C)=[O:8])[N:4]([C:14](=[O:37])[C@@H:15]([NH:17][C@H:18]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:16])[C:3]1=[O:38].Cl.O1CCOCC1>>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[N:4]([C:14](=[O:37])[C@@H:15]([NH:17][C@H:18]([C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:16])[C:3]1=[O:38]
Reactant: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1)C(=O)N1C(=O)N(C)C[C@H]1C(=O)O
Yield: 84 %

Procedure:
1.2 g of tert.-butyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate and 20 ml of a 13% hydrogen chloride-dioxane solution are treated in the same manner as described in Example 10-(3), whereby 0.9 g of (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless viscous oil. This oil (0.9 g) and 50 mg of palladium black are treated in the same manner as described in Example 10-(5), whereby 0.7 g of (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-carboxy-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless crystals. Yield: 80.9% The physico-chemical properties of this product are identical with those of the sample obtained in Example 4-(2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([C:41]#[N:42])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([C:41]#[N:42])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C#N)nc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C#N)nc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(6-cyano-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K26) (242 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (305 mg, 78%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].BrC1C=CC(S([O:17][C@@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)(=O)=O)=CC=1.[CH2:34]([CH:37]1[CH:46](O)[C:45]23[N:48]=[CH:49][CH:50]=[C:44]2[CH:43]=[CH:42][CH:41]=[C:40]3[N:39]([CH3:51])[CH2:38]1)[CH:35]=[CH2:36]>CN1C(=O)CCC1.CCOC(C)=O.Cl>[CH2:34]([CH:37]1[CH:46]([O:17][C@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)[C:45]23[N:48]=[CH:49][CH:50]=[C:44]2[CH:43]=[CH:42][CH:41]=[C:40]3[N:39]([CH3:51])[CH2:38]1)[CH:35]=[CH2:36]
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: C=CCC1CN(C)C2=CC=CC3=CC=NC32C1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=CCC1CN(C)C2=CC=CC3=CC=NC32C1O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Yield: 44 %

Procedure:
Cs2CO3 (8.20 g, 25.20 mmol) and 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (3.80 g, 8.18 mmol) were added in sequence to a solution of 3-allyl-1-methyl-3H-pyrrolo[2,3-e]quinolin-4-ol (1.50 g, 6.29 mmol) in NMP (42 mL). The mixture was heated at 60° C. for 12 h, then cooled and diluted with EtOAc and aqueous HCl (1 N). The organic layer was separated, washed with brine and dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was purified on silica gel (gradient elution, 20-100% EtOAc/petrol ether) to afford the title compound (1.30 g, 44%) as a solid. LCMS (ES+) m/z 466 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]=3[O:13][CH:14]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[N+:23]([O-:28])([N+]([O-])=O)=[O:24]>C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]=3[O:13][C:14]=2[N+:23]([O-:28])=[O:24])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)c1ccc(-c2coc3c2ccc2ccccc23)cc1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccc(-c2c([N+](=O)[O-])oc3c2ccc2ccccc23)cc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a mixture of 4.0 g. of the product of step A in 250 ml. of chloroform is added 4.0 g. of dinitrogen tetraoxide. The mixture is stirred at about 20° C. for 20 hours. The mixture is filtered, and the solid obtained is recrystallized from a mixture of N,N-dimethylformamide and water to provide yellow crystals of 3-(4-carboxyphenyl)-2-nitronaphtho-[1,2-b]furan, m.p. greater than 300° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1.[CH:13]1[C:18]2[CH2:19][NH:20][CH2:21][CH2:22][S:23](=[O:24])[C:17]=2[CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:24]=[S:23]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:18]=2[CH2:19][N:20]([C:2]2[NH:3][C:4](=[O:12])[C:5]3[S:10][C:9]([CH3:11])=[CH:8][C:6]=3[N:7]=2)[CH2:21][CH2:22]1
Reactant: Cc1cc2nc(Cl)[nH]c(=O)c2s1
Reactant: O=S1CCNCc2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2s1
Yield: 81.1 %

Procedure:
2-Chloro-6-methylthieno[3,2-d]pyrimidin-4(3H)-one (3.01 g, 15 mmol) was dissolved in toluene (50 mL), followed by addition of 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene-5-oxide (3.39 g, 18.7 mmol), triethylamine (6 mL, 43 mmol). Then the solution was heated to reflux overnight. The suspension was filtrated and the solid was washed by methanol to afford 4.2 g of 2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthieno[3,2-d]pyrimidin-4(3H)-one (yield was 81.1%) as a slight brown solid. MS obsd. (ESI+) [(M+H)+] 346.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([NH:31][CH2:32][CH2:33][NH:34][C:35](=[O:55])[C@H:36]([CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:37][C:38]([O:40][CH3:41])=[O:39])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH3-][C:57]#N.[Na+]>CC#N.CC(O)=O.C=O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[C@H:10]([N:31]([CH3:57])[CH2:32][CH2:33][NH:34][C:35](=[O:55])[C@H:36]([CH:42]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:37][C:38]([O:40][CH3:41])=[O:39])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: COC(=O)N[C@H](C(=O)NCCN[C@@H]1CN(Cc2ccccc2)C[C@H]1N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)N[C@H](C(=O)NCCN(C)[C@@H]1CN(Cc2ccccc2)C[C@H]1N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-(2-{[(3R,4R)-1-benzyl-4-{(3-methylbutyl)[(4-nitrophenyl)sulfonyl]amino}pyrrolidin-3-yl]amino}ethyl)-Nα-(methoxycarbonyl)-β-phenyl-L-phenylalaninamide (see Example 1, Step 12) (200 mg, 0.259 mmol) was dissolved in 20:1 MeCN—AcOH (3.5 mL) and 37% aqueous formaldehyde was added (0.68 mL) following by addition of NaBH3CN (49 mg, 0.78 mmol). The mixture was stirred at ambient temperature for 3 hours and quenched with water (50 mL). The mixture was extracted with CHCl3, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was passed through silica gel layer eluting with 1% MeOH in CHCl3. The solvent was evaporated giving the desired compound. LC-MS APCI: m/z 785.3 [M+H]+.
Reaction SMILES: N#N.C(OC(=O)[N:9]([C:22]([C:24]1[N:25]=[C:26]([CH3:36])[O:27][C:28]=1[C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1)=[O:23])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:21]=[C:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[O:13][CH:14]=[C:10]([NH:9][C:22]([C:24]2[N:25]=[C:26]([CH3:36])[O:27][C:28]=2[C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[O:23])[N:11]=1
Reactant: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2nc(C)oc2-c2cccc(C)c2)co1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)CCCCc1nc(NC(=O)c2nc(C)oc2-c2cccc(C)c2)co1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-methyl-5-m-tolyl-oxazole-4-carbonyl)-[2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.10 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with trifluoroacetic acid (0.08 mL, 1.07 mmol). After stirring at rt for 16 h, the reaction mixture was quenched with sat. aq. NaHCO3, extracted with CH2Cl2 (3×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave the title compound as a colorless oil. TLC: rf (6:4 hept-EA)=0.26. LC-MS-conditions 02: tR=1.08 min, [M+H]+=382.50.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].[CH3:10][CH2:11][CH2:12][C:13](=O)[CH2:14][C:15](=O)[CH2:16][CH2:17][CH3:18]>C(O)(=O)C>[CH3:7][C:4]1[C:3]([C:8]#[N:9])=[C:2]2[N:1]=[C:13]([CH2:12][CH2:11][CH3:10])[CH:14]=[C:15]([CH2:16][CH2:17][CH3:18])[N:6]2[N:5]=1
Reactant: Cc1n[nH]c(N)c1C#N
Reactant: CCCC(=O)CC(=O)CCC
Solvent: CC(=O)O
Product: CCCc1cc(CCC)n2nc(C)c(C#N)c2n1

Procedure:
A stirred mixture of 4.88 g of 5-amino-3-methylpyrazole-4-carbonitrile and 6.25 g of 4,6-nonanedione in 50 ml of glacial acetic acid was heated at reflux for 10 hours. The reaction mixture after reflux was worked up as described in Example 50 to give 7.80 of 2-methyl-5,7-dipropylpyrazolo[1,5-a]pyrimidine-3-carbonitrile, mp 73°-74° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:13][C:14]1[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:14]([CH3:13])[N:19]=1)=[O:8])=[O:5]
Reactant: Cc1nc(N)ccc1-c1ccccc1
Reactant: O=C=NC(=O)c1ccccc1Br
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)NC(=O)c2ccccc2Br)ccc1-c1ccccc1

Procedure:
2-Bromobenzoyl isocyanate (650 mg) is reacted with 6-methyl-5-phenyl-2-pyridylamine (500 mg) in 25 ml of ethyl acetate. A precipitate forms which upon filtering constitutes the desired product.
Reaction SMILES: C[O:2][C:3](=[O:54])[C@H:4]([CH2:6][C:7]([C:10](=[O:53])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][C:19]2[N:20]=[CH:21][N:22]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=2)[C:12]=1[C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45][CH:44]=1)([CH3:9])[CH3:8])[NH2:5].[Li+].[OH-]>C1COCC1.O>[C:24]([N:22]1[CH:23]=[C:19]([CH2:18][NH:17][C:13]2[C:12]([C:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:46]=[CH:45][CH:44]=3)=[C:11]([CH:16]=[CH:15][CH:14]=2)[C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C@@H:4]([C:3]([OH:54])=[O:2])[NH2:5])=[O:53])[N:20]=[CH:21]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@@H](N)CC(C)(C)C(=O)c1cccc(NCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1-c1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C[C@H](N)C(=O)O)C(=O)c1cccc(NCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 388A (0.24 g, 0.34 mmoles) was dissolved in 10 mL of THF/H2O (2:1) and LiOH (0.029 g, 0.68 mmoles) was added. The reaction was stirred at room temperature for 2 h. The THF was evaporated and the residue dissolved in 15 mL water, and 1N HCl added to lower the pH to 2. The compound is then extracted with ethyl acetate (3×25 mL), dried and the solvents evaporated to afford the free carboxylic acid as a white solid. (0.20 g, 84%).
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[CH2:3][C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5].C(NC1C=CC(S([N:40]=[N+:41]=[N-])(=O)=O)=CC=1)(=O)C.C(#N)C>C(N(CC)CC)C>[N+:40](=[C:3]([C:2](=[O:1])[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5])=[N-:41]
Reactant: COc1cccc(OC(=O)CC(=O)c2cc(OC)c(OC)c(OC)c2)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc(OC(=O)C(=[N+]=[N-])C(=O)c2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
The procedure of Baumm et al, Synthetic Communication 1987, 17(14), 1709-1716, was used. To a stirred solution of 0.0561 g (0.156 mmol) of the product of Step 2 and 0.041 g (0.171 mmol) of 4-acetamidobenzenesulfonyl azide in 2 ml of anhydrous acetonitrile 0.065 ml (0.47 mmol) of triethylamine was added at 0° C. After stirring for 3 hours at room temperature the solvent was evaporated to dryness under reduced pressure and the residue was purified by flash column chromatography (silica gel, methylene chloride) to give 0.059 g (98% yield) of 3-methoxyphenyl 2-diazo-3-oxo-3-(3,4,5-trimethoxyphenyl)propanoate. This was dissolved in 2 ml of anhydrous methylene chloride and 3.5 mg (7.9 μmol) of rhodium (III) acetate was added at room temperature under nitrogen atmosphere. The resulting mixture turned deep green after 1 h of stirring at room temperature. After filtration through Celite and washing with fresh methylene chloride, the filtrate was evaporated to dryness under reduced pressure to give the title compound as an deep yellow crystals (0.049 g, 91%); 1H NMR (CDCl3) δ 3.8 (s, 3H, OMe); 3.9 (s, 6H, OMe); 3.94 (s, 3H, OMe); 6.58 (dd, 1H, CH aromatic, J=2.4 Hz; 8.6 Hz); 6.76 (d, 1H CH aromatic; J=2.4 Hz); 7.04 (s, 2H, CH aromatic); 7.25 (d, 1H, CH aromatic, J=8.6 Hz).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28](O)=[O:29])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:32]=[C:33]([C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1)[NH2:34]>>[N:36]1[CH:37]=[CH:38][N:39]=[CH:40][C:35]=1[C:33]1[N:34]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:29][N:32]=1
Reactant: NC(=NO)c1cnccn1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(OC(F)(F)F)cc3)CC(c3nc(-c4cnccn4)no3)C2)CC1

Procedure:
100 mg (0.24 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 108A) and 49 mg (0.35 mmol) of N′-hydroxypyrazine-2-carboximidamide were reacted according to the General Method 2. Yield: 69 mg (56% of theory).
Reaction SMILES: C(N(CC)CC)C.[I-].[CH2:9]([O:11][C:12]([C@@:14]1([NH:19][C:20](N2C=C[N+](C)=C2)=[O:21])[CH2:16][C@H:15]1[CH:17]=[CH2:18])=[O:13])[CH3:10].[CH2:28]([N:34]([CH3:43])[C:35]([C@@H:37]1[CH2:41][C@@H:40]([OH:42])[CH2:39][NH:38]1)=[O:36])[CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33]>C(Cl)Cl>[CH2:9]([O:11][C:12]([C@@:14]1([NH:19][C:20]([N:38]2[CH2:39][C@H:40]([OH:42])[CH2:41][C@H:37]2[C:35](=[O:36])[N:34]([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[CH3:43])=[O:21])[CH2:16][C@@H:15]1[CH:17]=[CH2:18])=[O:13])[CH3:10]
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)n1cc[n+](C)c1)C(=O)OCC
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Triethylamine (1.3 mL, 3 eq.) was added at room temperature under nitrogen to a mixture of 1-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropyl-carbamoyl)-3-methyl-1H-imidazol-3-ium iodide 34 (0.7 g, 1 eq.) and compound 49 (1.2 g, 1 eq.) in DCM (15 mL). The reaction mixture was stirred overnight at room temperature and then quenched with 1M aqueous hydrochloric acid. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to yield compound 50 as a white solid in 70% yield. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.10-1.14 (td, J=7.07 and 2.01 Hz, 3H), 1.15-1.17 (m, 1H), 1.22-1.30 (m, 1H), 1.33-1.41 (m, 2H), 1.42-1.50 (m, 1H), 1.54-1.57 (m, 1H), 1.71-1.79 (m, 1H), 1.97-2.07 (m, 4H), 2.74 (s, 1H), 2.97 (s, 2H), 3.11 (d, J=10.24 Hz, 1H), 3.15-3.21 (m, 1H), 3.43-3.48 (m, 1H), 3.91-4.07 (m, 2H), 4.29-4.30 (m, 1H), 4.65-4.69 (d, J=6.50 Hz, 1H), 4.90-4.96 (m, 3H), 5.00-5.06 (m, 2H), 5.19-5.25 (dd, J=17.04 and 6.50 Hz, 1H), 5.51-5.61 (m, 1H), 5.71-5.83 (m, 1H), 7.08 (s, 1H); MS (ESI−): m/z=406 (MH−).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:9][CH2:10][CH:12]1[CH2:13][O:14]1
Reactant: Cc1ccc(O)cc1C
Reactant: ClCC1CO1
Product: Cc1ccc(OCC2CO2)cc1C

Procedure:
The title compound was prepared from 3,4-dimethyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.