Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([CH2:23][CH:24]1[CH2:27][CH2:26][CH2:25]1)[C:20]([NH2:22])=[O:21]>>[C:20]([CH:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:23][CH:24]1[CH2:27][CH2:26][CH2:25]1)(=[O:21])[NH2:22]
Reactant: NC(=O)C(N)CC1CCC1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: NC(=O)C(CC1CCC1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 2-amino-3-cyclobutyl-propionamide (52.5 mg, 0.26 mmol) as starting materials and isolated (30 mg, 39.4%) as white solid; LC-MS (UV peak area, ESI) 99.04%%, 357.4 (M−H)'.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:16]3[C:17]([C:21]([O:23]C)=[O:22])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[CH:13]1)[CH2:2]2.O.[OH-].[Li+:27].O>O1CCCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:16]3[C:17]([C:21]([O-:23])=[O:22])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[CH:13]1)[CH2:2]2.[Li+:27]
Reactant: COC(=O)c1cccc2ncn(CCN[C@@H]3CN4CCC3CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cccc2ncn(CCN[C@@H]3CN4CCC3CC4)c12
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A mixture of (S)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-benzo[d]imidazole-7-carboxylate (0.2 g, 0.7 mmol) from Step F above, lithium hydroxide monohydrate (0.1 g, 2.1 mmol), water (5 mL), and tetrahydrofuran (5 mL) was heated at reflux for 5 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give lithium (S)-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-benzo[d]imidazole-7-carboxylate (0.2 g): MS (ESI+) m/z 315 (M+H).
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([O:14]CC)(=O)[CH2:7][C:8]([O:10]CC)=O.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[NH:21]>C(O)C>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]1[N:22]=[C:6]([OH:14])[CH:7]=[C:8]([OH:10])[N:21]=1
Reactant: N=C(N)c1ccccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Oc1cc(O)nc(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A solution of sodium ethoxide (19.83 g, 291 mmol) in ethanol [previously prepared by dissolving sodium (6.7 g, 291 mmol) in ethanol (200 mL)] was treated with diethyl malonate (14.73 mL, 97 mmol) with stirring at ambient temperature. A solution of 2-chlorobenzamidine (15 g, 97 mmol) in ethanol (100 mL) was then added dropwise with stirring at room temperature. On completion of addition the reaction mixture was then heated at reflux for 5 h and allowed to stand overnight. The reaction mixture was concentrated in vacuo, water added and the pH adjusted to pH 3-4 using 2N HCl. The resulting solid formed was filtered and washed with water and diethyl ether to give the title compound as a solid (17.12 g, 79%). MS (ES+) m/e=223. 1H NMR: (DMSO) 5.33 (1H, s), 7.43-7.70 (4H, m), 12.00 (2H, brs).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]1COCC1.[F:16][C:17]1[CH:18]=[C:19]([C@@H:24]2[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[N:25]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:20]=[C:21]([F:23])[CH:22]=1.IC>COCCOC>[F:16][C:17]1[CH:18]=[C:19]([C@H:24]2[N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:26](=[O:30])[C@H:27]([CH3:11])[CH2:28][CH2:29]2)[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC[C@H]1c1cc(F)cc(F)c1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: COCCOC
Product: C[C@@H]1CC[C@@H](c2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a 1 M solution of sodium bis(trimethylsilyl)amide in THF (0.642 mL, 0.642 mmol) at −78° C. was added dropwise a solution of tert-butyl (2S)-2-(3,5-difluorophenyl)-6-oxopiperidine-1-carboxylate (200 mg, 0.642 mmol, described in Intermediate 26) in DME (10 mL) at −78° C. The resulting mixture was stirred at −78° C. for 10 min then iodomethane (0.040 mL, 0.642 mmol) was added. After stirring at −78° C. for 30 min and at −30° C. for 30 min, the reaction mixture was cooled to −78° C. and quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 90:10. MS: m/z=270 (M−C4H7).
Reaction SMILES: O[C:2]1[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.P(Cl)(Cl)([Cl:15])=O.CN(C)C1C=CC=CC=1>C(#N)C>[Cl:15][C:2]1[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(O)c2sccc2n1
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CSc1nc(Cl)c2sccc2n1
Yield: 90.5 %

Procedure:
4-Hydroxy-2-methylthiothiopheno[3,2-d ]pyrimidine (15.4 g, 78 mmol) was combined with 50 mL of dry acetonitrile and 29 mL (312 mmol) of phosphoryl chloride and 10 mL (78 mmol) of N,N-dimethylaniline were added with stirring. The mixture was heated to reflux with stirring for 2 hours. It was then allowed to cool and most of the acetonitrile was removed by evaporation under reduced pressure. The residue was poured slowly into 200 mL of cold water with cooling and agitation. The resulting mixture was extracted with 4×500 mL of ether and the combined ethereal extracts were dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The 15.3 g of tan solid title compound obtained melted at 115°-118° C. and had a proton NMR spectrum consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16][C:17]#[N:18])[C:6]1=[O:19])=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].Cl>O.CN(C=O)C>[CH3:32][C:31]([O:30][C:28](=[O:29])[CH2:27][C:5]1([C:3]([O:2][CH3:1])=[O:4])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16][C:17]#[N:18])[C:6]1=[O:19])([CH3:34])[CH3:33]
Reactant: COC(=O)C1C(=O)N(CC#N)C(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(CC(=O)OC(C)(C)C)C(=O)N(CC#N)C(=O)c2ccccc21
Temperature: 85 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a suspension of 2-(cyanomethyl)-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinoline carboxylic acid methyl ester (6.5 g, 25.19 mmol), K2CO3 (6.95 g, 50.38 mmol) and anhydrous DMF (100 mL) was added tert-butyl bromoacetate (6.1 mL, 37.79 mmol). After stirring at 85° C. for 3 hours, the mixture was poured into H2O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/EtOAc 4/1) gave a white solid (8.5 g, 90.7%).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([OH:22])[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[C:12]#[N:13])(C(C)(C)C)(C)C.CO[C:25](OC)([CH3:27])[CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:15]=[C:14]([CH:11]([CH:10]2[CH2:9][O:8][C:25]([CH3:27])([CH3:26])[O:22]2)[C:12]#[N:13])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C(C#N)c1ccc(Cl)c(Cl)c1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)OCC(C(C#N)c2ccc(Cl)c(Cl)c2)O1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of (2RS,3RS)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(3,4-dichlorophenyl)-3-hydroxybutanenitrile (152 g) in toluene (1000 ml) were added 2,2-dimethoxypropane (131.8 g) and p-toluenesulfonic acid (8.02 g), and the mixture was stirred under nitrogen purging at 80° C. for 2 hr. Under ice-cooling, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was crystallized from diisopropyl ether to give the title compound (99 g) as colorless crystals.
Reaction SMILES: B(Br)(Br)[Br:2].C(Cl)Cl.[CH2:8]([N:11]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([O:25]C)[CH:18]=1)[CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10]>C(Cl)Cl>[BrH:2].[OH:25][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[OH:23])[CH2:16][CH2:15][N:11]([CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13][CH3:14]
Reactant: BrB(Br)Br
Reactant: CCCN(CCC)CCc1ccc(OC)c(OC)c1
Solvent: ClCCl
Product: Br
Product: CCCN(CCC)CCc1ccc(O)c(O)c1
Temperature: 25 °C

Procedure:
A solution (150 ml.) of boron tribromide/methylene chloride (1 g./5 ml., 0.12 mole) was added to a solution of 5.0 g. (0.019 mole) of N,N-di-(n-propyl)-3,4-dimethoxyphenethylamine in 100 ml. of methylene chloride, cooled in an ice bath. The bath was removed and the reaction mixture was stirred at room temperature. Methanol (about 50 ml.) was added to the reaction mixture, with cooling, and the resulting solution was evaporated in vacuo. The residue crystallized to give 3,4-dihydroxy-N,N-di-(n-propyl)phenethylamine hydrobromide, m.p. 153.5°-154.5° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.O.O.[Sn](Cl)[Cl:23]>O.Cl>[ClH:23].[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:19]=[CH:18][C:16]([NH:17][NH2:1])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccc(Sc2ccc(F)cc2)cc1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Sc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A solution of sodium nitrite (5.90 g, 86 mmol) in water (110 mL) is added drop wise to a pre-cooled (−10° C.) slurry of 4-(4-fluorophenyl)sulfanylaniline (14.39 g, 66 mmol) in concentrated hydrochloric acid (250 mL). The resulting mixture is stirred at 0° C. for 15 min and then at room temperature for 30 min. The temperature is lowered to −5° C. and a solution of tin (II) chloride dihydrate (44.4 g, 197 mmol) in concentrated hydrochloric acid (170 mL) is added drop wise. The resulting suspension is stirred at −5° C. for 30 min and is then allowed to warm up to room temperature over 1 h. The off-white solids are isolated by filtration, washed with cold water and then with diethyl ether and finally dried to afford the desired product (18.04 g, 66 mmol, quantitative yield) (HPLC-MS Method 3: retention time: 2.129 min, m/z 235.1).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(O)(=O)C.[CH3:25][C:26]1[N:27]=[CH:28][S:29][C:30]=1[CH2:31][NH:32][CH2:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:32]([CH2:31][C:30]3[S:29][CH:28]=[N:27][C:26]=3[CH3:25])[CH2:33][CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: Cc1ncsc1CNCCc1cccnc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)Cc3scnc3C)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (0.423 g) and acetic acid (0.14 g) were added to a 1,2-dichloroethane solution (10 ml) of N-(4-methylthiazol-5-ylmethyl)-N-(2-pyridin-3-ylethyl)amine (0.36 g). The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.48 g) was added, and the mixture was stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→50:50). The purified product was condensed under reduced pressure. The residue was washed with diethyl ether, and dried to give the title compound (0.37 g) as a white powder.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[C:19]([CH3:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:21])[CH:11]=1.[C:22](Cl)(=[O:24])[CH3:23].C(=O)([O-])O.[Na+]>ClCCl>[C:22]([NH:9][C:10]1[C:19]([CH3:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:21])[CH:11]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc(C)c(N)cc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)c(NC(C)=O)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.4 %

Procedure:
Triethylamine (1.16 ml, 8.32 mmol) was added to a suspension of methyl 4-amino-2,5-dimethylbenzoate monohydrochloride (0.600 g, 2.78 mmol) in dichloromethane (8 ml), and the resulting mixture was cooled with ice water, followed by adding dropwise thereto a solution of acetyl chloride (0.263 g, 3.35 mmol) in dichloromethane (2 ml). The resulting mixture was heated to room temperature and stirred for 3 hours, and then acetyl chloride (0.262 g, 3.34 mmol) was further added thereto and stirred for 1.5 hours. The resulting mixture was added to a saturated aqueous sodium hydrogencarbonate solution and extracted three times with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain methyl 4-(acetylamino)-2,5-dimethylbenzoate (0.685 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)=[C:20]=[O:21].FC1C=CC(C)=CC=1N=C=O>>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[O:21])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Agent: Cc1ccc(F)c(N=C=O)c1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3cncc4c3c(N)nn4C)cc2)c1

Procedure:
The title compound was prepared using the procedure described in Example 1E using the product from Example 6A and 1-isocyanato-3-methyl-benzene instead of the product from Example 1D and 1-fluoro-2-isocyanato-4-methyl-benzene. MS (ESI(+)) m/e 373 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 4.02 (s, 3H) 6.81 (d, J=7.12 Hz, 1H) 7.17 (t, J=7.80 Hz, 1H) 7.26 (d, J=8.14 Hz, 1H) 7.32 (s, 1H) 7.52 (d, J=8.82 Hz, 2H) 7.68 (d, J=8.82 Hz, 2H) 8.10 (s, 1H) 8.71 (s, 1H) 8.95 (s, 1H) 9.20 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([OH:52])[CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]=1.[C:53](=[O:56])([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:62][CH2:63][CH2:64][N:65]1[C:69](=[O:70])[C:68]2=[CH:71][CH:72]=[CH:73][CH:74]=[C:67]2[C:66]1=[O:75]>CN(C)C=O>[C:53]1(=[O:56])[N:65]([CH2:64][CH2:63][CH2:62][O:52][C:48]2[CH:47]=[C:46]([C:14]3[C:12]4[NH:13][C:9]([C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:62][CH2:63][CH2:64][N:65]6[C:69](=[O:70])[C:68]7=[CH:71][CH:72]=[CH:73][CH:74]=[C:67]7[C:66]6=[O:75])[CH:3]=5)=[C:28]5[N:29]=[C:25]([C:24]([C:30]6[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:62][CH2:63][CH2:64][N:65]7[C:69](=[O:70])[C:68]8=[CH:71][CH:72]=[CH:73][CH:74]=[C:67]8[C:66]7=[O:75])[CH:31]=6)=[C:23]6[NH:37][C:20](=[C:19]([C:38]7[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH2:62][CH2:63][CH2:64][N:65]8[C:69](=[O:70])[C:68]9=[CH:71][CH:72]=[CH:73][CH:74]=[C:67]9[C:66]8=[O:75])[CH:39]=7)[C:18]7[CH:17]=[CH:16][C:15]=3[N:45]=7)[CH:21]=[CH:22]6)[CH:26]=[CH:27]5)=[CH:10][CH:11]=4)[CH:51]=[CH:50][CH:49]=2)[C:66](=[O:75])[C:67]2=[CH:68][CH:71]=[CH:72][CH:73]=[C:74]12
Reactant: Oc1cccc(-c2c3nc(c(-c4cccc(O)c4)c4ccc([nH]4)c(-c4cccc(O)c4)c4nc(c(-c5cccc(O)c5)c5ccc2[nH]5)C=C4)C=C3)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(-c2c3nc(c(-c4cccc(OCCCN5C(=O)c6ccccc6C5=O)c4)c4ccc([nH]4)c(-c4cccc(OCCCN5C(=O)c6ccccc6C5=O)c4)c4nc(c(-c5cccc(OCCCN6C(=O)c7ccccc7C6=O)c5)c5ccc2[nH]5)C=C4)C=C3)c1
Temperature: 21 °C

Procedure:
7.56 g (11.14 mmol) of 5,10,15,20-tetrakis-(3-hydroxyphenyl)-porphyrin [CARN 22112-79-4] is dissolved in 300 ml of anhydrous N,N-dimethylformamide and mixed with 30.79 g (222.8 mmol) of potassium carbonate and 7.40 g (44.55 mmol) of potassium iodide. 59.72 g (222.8 mmol) of N-(3-bromopropyl)-phthalimide is added to the suspension that is stirred under argon at 21° C. After 24 hours of stirring with exclusion of light, the suspension is filtered, the filtrate is largely concentrated by evaporation in a vacuum, mixed with dichloromethane and shaken out twice with water. The organic phase is dried on anhydrous magnesium sulfate, filtered and concentrated by evaporation, the residue is chromatographed on silica gel 60 (Merck) with dichloromethane/methanol. The product fractions are concentrated by evaporation, taken up in a little dichloromethane and the title compound is precipitated by the addition of diethyl ether.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17](O)=O)[CH:11]=[C:10]([CH3:20])[N:9]=2)[N:3]=1.[CH3:21][NH:22][C:23]1[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[N:22]([CH3:21])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:29]=3)[CH:11]=[C:10]([CH3:20])[N:9]=2)[N:3]=1
Reactant: Cc1cc([C@@H]2C[C@H]2C(=O)O)cc(-n2nc(C)nc2C)n1
Reactant: CNc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-2-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-4-yl)cyclopropanecarboxylic acid (25-3) (45 mg, 0.165 mmol), N1-methylbenzene-1,2-diamine (28 mg, 0.231 mmol), EDC.HCl (47 mg, 0.248 mmol), HOBt (38 mg, 0.248 mmol), diisopropylethylamine (85 mg, 0.660 mmol), and tetrahydrofuran (3 mL) was stirred at room temperature overnight and evaporated. Acetic acid (3 mL) was added and the mixture was heated at 95° C. for 1 hour, cooled to room temperature, and evaporated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The extract was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (5-10% methanol in DCM) and reverse phase (10-100% acetonitrile in water) to give trans-2-(2-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (25-4) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.74-7.65 (m, 1H), 7.38 (br s, 1H), 7.34-7.20 (m, 3H), 6.98 (br s, 1H), 3.81 (s, 3H), 2.83 (s, 3H), 2.78-2.67 (m, 1H), 2.54 (s, 3H), 2.46-2.36 (m, 1H), 2.41 (s, 3H), 2.12-2.02 (m, 1H), 1.80-1.69 (m, 1H). LRMS m/z (M+H) 359 found, 359 required. m.p. 157-159° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10](OC)=[C:9]([O:15][CH3:16])[CH:8]=1.[C:18](=O)([O-])[O-:19].[Na+].[Na+].[C:24](Cl)(Cl)=[O:25].C(N(CC)CC)C>C1(C)C=CC=CC=1.O>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[O:25][CH3:24])[CH2:6][N:5]1[CH:4]=[C:3]([O:2][CH3:1])[O:17][C:18]1=[O:19]
Reactant: COC(=O)CNCc1ccc(OC)c(OC)c1
Reactant: O=C(Cl)Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cn(Cc2ccc(OC)c(OC)c2)c(=O)o1
Temperature: 15 °C
Yield: 43.6 %

Procedure:
In 30 ml of toluene was dissolved 4.78 g (20 mmol) of N-(3,4-dimethoxybenzyl)-glycine-methyl ester, and to the solution was added an aqueous solution containing 1.17 g (11 mmol) of anhydrous sodium carbonate dissolved in water. The mixture was cooled to 15° C. and 2.18 g (22 mmol) of a phosgene gas was blown under stirring to carry out the reaction. After completion of the phosgene blowing, the mixture was further stirred at room temperature for 2 hours. After completion of the reaction, the aqueous layer was separated from the resulting reaction mixture (1). The toluene layer was dried over anhydrous magnesium sulfate followed by filtration, and 2.02 g (20 mmol) of triethylamine was added to the filtrate and the mixture was reacted at 120° C. for 17 hours. After completion of the reaction, the resulting reaction mixture (2) was cooled to room temperature, and the precipitated triethylamine hydrochloride was removed by filtration. The filtrate was washed with 100 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting concentrated residue was applied to silica gel column chromatography (eluent; hexane:ethyl acetate=4:1 (volume ratio)) to obtain 1.74 g (4.8 mmol) of 3-(3,4-dimethoxybenzyl)-5-methoxy-2(3H)oxazolone as white crystals. (Yield based on N-(3,4-dimethoxybenzyl)-glycine-methyl ester 32.8%)
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:13]2=[O:25])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:27]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:58][C@@H:59]([CH2:89]O)[CH2:60][N:61]1[CH:65]=[CH:64][C:63]([NH:66]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:62]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:13]2=[O:25])[C:9]([NH:66][C:63]2[CH:64]=[CH:65][N:61]([CH2:60][C:59]([OH:58])([CH3:89])[CH3:27])[N:62]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 8.3 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-(2-oxo-4-m-tolyloxy-2,5-dihydro-pyrrol-1-yl)-propionic acid (150 mg, 0.4 mmol) in dichloromethane (10 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (250 mg, 1.3 mmol) and N,N-diisopropylethylamine (0.280 g, 2.17 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (200 mg, 1.3 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 67 mg, 0.4 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(2-oxo-4-m-tolyloxy-2,5-dihydro-pyrrol-1-yl)-propionamide (16 mg, 8%) as an off-white sticky solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.84-1.06 (m, 2H), 1.15 (s, 6H), 1.17-1.30 (m, 3H), 1.58-1.93 (m, 8H), 2.35 (s, 3H), 3.00 (br. s., 1H), 3.94 (s, 2H), 4.07 (d, J=18.0 Hz, 1H), 4.30 (d, J=18.0 Hz, 1H), 4.83-4.94 (m, 1H), 4.97 (s, 1H), 6.67 (br. s., 1H), 6.91-6.99 (m, 2H), 7.06 (d, J=7.8 Hz, 1H), 7.26-7.32 (m, 2H), 8.96 (br. s., 1H).