Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].N1C=CN=C1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].C(OCC)C>CN(C)C=O>[Si:17]([O:7][CH2:1][CH2:2][CH2:3][CH:4]([CH3:5])[OH:6])([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(O)CCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(O)CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In N,N-dimethylformamide (200 ml) were dissolved 1,4-pentanediol (10.0 g, 96.0 mmol) and imidazole (6.6 g, 96.9 mmol). Under ice cooling, t-butyl chlorodiphenylsilane (25.2 ml, 96.4 mmol) was added dropwise. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 2 days. To the reaction mixture was added diethyl ether, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=5:1), whereby the title compound (32.0 g, 97%) was obtained as a colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.CC(C)([O-])C.[K+].C[N:25]1CCCC1=O.[NH2:31][O:32][S:33]([OH:36])(=[O:35])=[O:34].CN1CCCC1=O>CN1CCCC1=O>[NH2:31][O:32][S:33]([OH:36])(=[O:35])=[O:34].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([NH2:25])[CH:13]=[CH:12]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CN1CCCC1=O
Agent: CC(C)(C)[O-]
Agent: NOS(=O)(=O)O
Agent: [K+]
Product: COc1ccc2c(ccn2N)c1
Reaction time: 1.43 h
Yield: 87 %

Procedure:
A solution of 10.0 g (9.7 g corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 33.7 g of N-methylpyrrolidinone (NMP) is prepared and chilled to 0–5° C. A second solution is prepared from 20.1 g (19.1 g corrected for 95% purity) of potassium tert-butoxide and 34.4 g of NMP. An amination vessel is charged with 5.9 g of 5-methoxyindole, 17.8 g of NMP and an initial charge of 0.7 g of the potassium tert-butoxide/NMP solution. The HOSA/NMP solution and the remaining potassium tert-butoxide/NMP solution are then simultaneously and proportionally metered into the amination vessel over a period of 86 minutes while maintaining a reaction temperature of 15–22° C. to yield a solution containing 5.6 g (87% yield) of 5-methoxy-1H-indol-1-amine as determined by internal standard HPLC assay.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([OH:17])[C:15]#[CH:16])[CH:5]=[C:4]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:3]1=2.I[C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1.[Cl-].[NH4+]>CN(C=O)C.C(N(CC)CC)C.[Cu](I)I>[OH:17][CH:14]([C:6]1[CH:5]=[C:4]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:3]2[C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)[C:15]#[C:16][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1
Reactant: C#CC(O)c1cc(OCCOCC)c2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C(O)c1ccc(I)cc1
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCCOc1cc(C(O)C#Cc2ccc(C(=O)O)cc2)cc2c1C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
5.4 g (15 mmol) of 1-[5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphth-2-yl]prop-2-yn-1-ol and 2.6 g (11 mmol) of 4-iodobenzoic acid are dissolved in 125 mL of DMF and 50 mL of triethylamine. 110 mg of copper iodide and 210 mg of dichloropalladiumbis(triphenylphosphine) are added, and the reaction medium is stirred at 50° C. for 2 hours 30 minutes. The reaction medium is poured into ammonium chloride solution and extracted with ethyl acetate. The residue is purified on a column of silica (eluent: 6/4 heptane/EtOAc). The desired product is obtained in the form of yellowish crystals (m=2.5 g; yield=50%; m.p.=158° C.) 1H NMR (DMSO D6): 1.12 (t, J=7.0 Hz, 3H); 1.23 (s, 6H); 1.35 (s, 6H); 1.56-1.60 (m, 4H); 3.50 (q, J=7.0 Hz, 2H); 3.75 (m, 2H); 4.06 (m, 2H); 5.52 (d, J=5.0 Hz, 1H); 6.09 (d, J=4.9 Hz, 1H); 6.90 (s, 1H); 7.11 (s, 1H); 7.54 (d, J=8.3 Hz, 2H); 7.93 (d, J=8.3 Hz, 2H), 13.1 (bs, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][C:27]=4[Cl:29])=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4ccc(Cl)cc4Cl)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 2,4-dichlorophenylboronic acid (164 mg, 0.86 mmol) the subtitle compound was obtained, (148 mg, 62%). 1H NMR (DMSO) δ 8.69(s, 1H), 8.51(d, 1H), 7.93(d, 1H), 7.84(s, 1H), 7.60(m, 3H), 4.12(s, 3H). MS 415 m/z (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@@H:12]3[CH2:14][C@H:13]3[CH2:15][NH2:16])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@@H:12]3[CH2:14][C@H:13]3[CH2:15][NH:16][C:25](=[O:27])[CH3:26])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@@H]1C[C@H]1c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
To a suspension of 1-[(1R,2R)-2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine dihydrochloride (750 mg, 2.74 mmol) and triethylamine (1.52 mL, 10.9 mmol) in tetrahydrofuran (27 mL) was added acetic anhydride (388 μL, 4.10 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (600 mg, yield 90%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([F:18])([F:17])[C:14](O)=[O:15].C(OCC)(=O)C>C1COCC1.O>[F:18][C:13]([F:17])([CH2:14][OH:15])[CH2:12][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11]
Reactant: O=C1c2ccccc2C(=O)N1CC(F)(F)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)CO
Reaction time: 8 h

Procedure:
Under argon atmosphere 3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2,2-difluoro-propionic acid, A2 (13.74 g, 53.85 mmol), dissolved in THF (200 mL) was treated with borane-methylsulfide complex (6.3 mL, 5.04 g, 66.6 mmol). After stirring overnight an additional portion of borane-methylsulfide complex (6.0 mL, 4.80 g, 63.43 mmol) was added. When the reaction was complete it was cautiously diluted with water and extracted with ethyl acetate (2×). An ethyl acetate solution prepared from the residue obtained by evaporation of the initial ethyl acetate extractions at 30° C. in vacuo was washed with water, brine (2×), dried (Na2SO4), filtered, and evaporated in vacuo at 30° C. Crude A3 was sonicated in ethyl acetate, and filtered to give pure 2-(2,2-Difluoro-3-hydroxy-propyl)-isoindole-1,3-dione, A3 (7.45 g). Flash chromatography of the liquor residue (Yamazen, 5 L silica gel cartridge, ethyl acetate/hexane gradient) afforded additional pure 2-(2,2-Difluoro-3-hydroxy-propyl)-isoindole-1,3-dione, A3 (1.39 g).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:2]2[O:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccccc1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1oc(Sc2ccc(O)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A mixture of methyl 3-(2-chloro-4-phenyl-5-oxazolyl)propionate (500 mg), 4-hydroxythiophenol (475 mg), potassium carbonate (520 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 3-[2-(4-hydroxyphenylthio)-4-phenyl-5-oxazolyl]propionate as colorless crystals (637 mg, yield 95%). The crystals were recrystallized from toluene-hexane. melting point: 157–158° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[OH-:30].[Na+].OO>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:30])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(CCO)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a stirred solution of the obtained methyl 2-benzyloxy-5-vinylbenzoate (1.52 g) in tetrahydrofuran (15 ml) was added dropwise a solution of 9-borabicyclo[3.3.1]nonane (726 mg) in tetrahydrofuran (15 ml) at −20° C., and the mixture was stirred for 17.5 hours at room temperature. After the reaction mixture was cooled to 0° C., 2N aqueous sodium hydroxide solution (8.5 ml) and 30% aqueous hydrogen peroxide solution (6.8 ml) were added to the mixture, and the resulting mixture was stirred for 3 hours at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2) gave methyl 2-benzyloxy-5-(2-hydroxyethyl)benzoate (1.30 g).
Reaction SMILES: N1C(F)=NC(F)=NC=1[F:3].[C:10]([OH:29])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].N1C=CC=CC=1>C(#N)C>[C:10]([F:3])(=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCC/C=C\CCCCCCCC(=O)F
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 85 %

Procedure:
To a solution of cyanuric fluoride (16 g, 0.12 mole in acetonitrile (125 ml) was added within 10 mins. a solution of oleic acid (80 g., 0.30 mole) and pyridine (24 g., 0.3 mole) in 125 ml. acetonitrile. The reaction mixture was stirred for 50 min and poured into ice-water, extracted with ether, and the organics dried over sodium sulfate. Removal of solvent and distillation in vacuo afforded oleoyl fluoride (85%, bp 184-186/12 torr).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([C:33]2[C:34](F)=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:32])[CH:25]=1)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=O)(C)(C)C.Cl.Cl.[NH:42]1[C:46]2=[N:47][CH:48]=[CH:49][C:50]([CH2:51][NH2:52])=[C:45]2[CH:44]=[CH:43]1>>[NH:42]1[C:46]2=[N:47][CH:48]=[CH:49][C:50]([CH2:51][NH:52][C:34]3[N:35]=[CH:36][CH:37]=[CH:38][C:33]=3[C:31]([NH:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([C:15]([O:14][CH2:13][C@@H:9]4[CH2:10][CH2:11][CH2:12][NH:8]4)([C:16]([F:18])([F:19])[F:17])[C:20]([F:22])([F:23])[F:21])[CH:25]=3)=[O:32])=[C:45]2[CH:44]=[CH:43]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COC(c1cccc(NC(=O)c2cccnc2F)c1)(C(F)(F)F)C(F)(F)F
Reactant: NCc1ccnc2[nH]ccc12
Agent: Cl
Product: O=C(Nc1cccc(C(OC[C@@H]2CCCN2)(C(F)(F)F)C(F)(F)F)c1)c1cccnc1NCc1ccnc2[nH]ccc12

Procedure:
The titled compound was prepared from (S)-2-(2,2,2-trifluoro-1-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-phenyl}-1-trifluoromethyl-ethoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Example 1. MS (ES+): 593 (M+H). Calc'd. for C28H26F6N6O2—592.54.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:21]1[CH:33]=[CH:32][C:24]2[C:25]([C:29]([OH:31])=[O:30])=[C:26]([CH3:28])[O:27][C:23]=2[CH:22]=1.[C:34]([O-:37])([O-])=O.[Cs+].[Cs+].O>CS(C)=O.CC(O)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:34]([O:37][C:32]3[C:24]4[C:25]([C:29]([OH:31])=[O:30])=[C:26]([CH3:28])[O:27][C:23]=4[CH:22]=[CH:21][CH:33]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1oc2cc(O)ccc2c1C(=O)O
Agent: Clc1ccnc2cc(OCc3ccccc3)ccc12
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1oc2cccc(Oc3ccnc4cc(OCc5ccccc5)ccc34)c2c1C(=O)O
Temperature: 130 °C
Yield: 189.9 %

Procedure:
7-(benzyloxy)-4-chloroquinoline 90-B was prepared (see general synthesis Scheme I) from the commercially available compound 90-A (from Aldrich). A mixture of 90-B (2.8 g, 10.4 mmol), 6-hydroxy-2-methyl-1-benzofuran-3-carboxylic acid 90-C (2 g, 10.4 mmol) and Cs2CO3 (10.1 g, 31.4 mmol) in DMSO (70 ml) was heated to 130° C. for 2 hours. The solution was poured into water, neutralized with AcOH and extracted with EtOAc. The concentrated residue was purified by silica gel chromatography using 2-5% MeOH in CH2Cl2 to give 6-{([7-(benzyloxy)quinolin-4-yl]oxy}-2-methyl-1-benzofuran-3-carboxylic acid 90-D (4.2 g, 94% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7](=[C:9]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=3)=[O:11])[NH:8][C:4]=2[CH:3]=1.O[CH2:31]C1C2N=NNC=2C=CC=1>C(O)C>[F:18][C:16]1[CH:17]=[C:12]([C:10](=[O:11])[C:9](=[C:7]2[NH:6][C:5]3[CH:28]=[CH:29][C:2]([NH:1][CH3:31])=[CH:3][C:4]=3[NH:8]2)[C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH:13]=[C:14]([F:19])[CH:15]=1
Reactant: Nc1ccc2c(c1)NC(=C(C(=O)c1ccccc1)C(=O)c1cc(F)cc(F)c1)N2
Reactant: OCc1cccc2[nH]nnc12
Solvent: CCO
Product: CNc1ccc2c(c1)NC(=C(C(=O)c1ccccc1)C(=O)c1cc(F)cc(F)c1)N2
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.3 %

Procedure:
To a solution of 2-(5-amino-1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3,5-difluorophenyl)-3-phenylpropane-1,3-dione (400 mg) and ethanol (10 ml) was added hydroxymethylbenzotriazole (168 mg) at room temperature, and the reaction solution was stirred at room temperature for 20 hours. The reaction solution was filtered and the resulting solid matter was dissolved in THF (10 ml). Thereto was added sodium borohydride (78 mg) at room temperature and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (10 ml) and the organic layer was washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (100:1 (v/v)) to obtain 1-(3,5-difluorophenyl)-2-[5-methylamino-1,3-dihydro-2H-benzimidazol-2-ylidene]-3-phenylpropane-1,3-dione (163 mg, 48%).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[O:4].[C:24]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])([CH3:27])([CH3:26])[CH3:25].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:32][CH2:31][CH2:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:33])=[O:13])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: O=C(O)CNC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCNC(=O)CNC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
1.3 g (4.0 mmol) of Z-Gly-Gly-Gly-OH, 0.583 g (4.0 mmol) of tert-butyl-3-aminopropionate 0.651 g (4.25 mmol) of hydroxybenzotriazole and 0.81 g (4.23 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were weighed into a 50 mL flask then dissolved in 20 mL of dimethylformamide with magnetic stirring under a nitrogen atmosphere. After 3 hours the reaction mixture was purified in 5 mL portions by reverse phase HPLC using a 5.0 cm×25 cm C18 column. The column was run at 100 mL/min with deionized water containing 0.3% formic acid 5% acetonitrile for 10 min followed by a 15 min linear gradient from 5% acetonitrile to 90% acetonitrile. Product fractions (retention time of 19 min) were combined and solvent was removed by rotary evaporation under vacuum to give 1.35 g (75%) of the title compound. 1H NMR (d6-DMSO) 8.16 (t, J=5.2 Hz, 1H), 8.10 (t, J=5.2 Hz, 1H), 7.82 (t, J=5.2 Hz, 1H), 7.25-7.4 (m, 5H), 5.04 (s, 2H), 3.74 (d, J=5.6 Hz, 2H), 3.67 (t, J=6.4 Hz, 4H), 3.25 (q, J=6.1 Hz, 2H), 2.35 (t, J=6.8 Hz, 2H), 1.39 (s, 9H). 13C NMR (d6-DMSO) 170.45, 169.61, 169.00, 168.63, 156.49, 136.94, 128.30, 127.76, 127.69, 79.89, 65.51, 43.56, 42.10, 41.90, 34.89, 34.78, 27.70. HRMS (M+Na+) Calc. 473.2012 found 473.1995.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[S:15])[N:6]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[C:7]=1[NH2:8].[CH:17](O)=O>>[O:11]1[CH2:12][CH2:13][CH2:14][CH:10]1[CH2:9][N:6]1[C:7]2[N:8]=[CH:17][NH:1][C:2]=2[C:3](=[O:16])[NH:4][C:5]1=[S:15]
Reactant: O=CO
Reactant: Nc1c(N)n(CC2CCCO2)c(=S)[nH]c1=O
Product: O=c1[nH]c(=S)n(CC2CCCO2)c2nc[nH]c12
Temperature: 70 °C
Yield: 87 %

Procedure:
5,6-Diamino-1-(2-tetrahydrofuryl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.25 g, 1.0 mmol) was dissolved in formic acid (1 mL) and heated at 70° C. for 0.5 h. After a few minutes a pink solid formed in the solution. The excess of formic acid was evaporated off and the resulting solid dissolved in 10% sodium hydroxide solution (4 mL). This solution was heated at 70° C. for 40 minutes, then neutralized with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried, giving pure product (0.23 g, 87%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].O.NN>C(O)C.[Pd]>[CH3:3][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)c1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)c1cccc(Oc2ccc(N)cn2)c1
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
2-{[3-(1-methylethyl)phenyl]oxy}-5-nitropyridine (Intermediate 23, 1.39 g) was dissolved in ethanol (25 mL). Hydrazine monohydrate (0.524 mL, 1076 mmol) and palladium on carbon (401 mg, 0.377 mmol) were added. The reaction mixture was heated at reflux under argon for 1 hour. The reaction was cooled down and then filtered on celite. The organic phase was evaporated under vacuum. The residue was purified by flash chromatography on silica (Companion instrument, 120 g silica cartridge, gradient cyclohexane/ethylacetate from 100/0 to 30/70 in 15 min then 30/70 during 30 min). Evaporation afforded the title compound as a yellow oil (821 mg).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[CH:23]([N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([C:9]4[CH:26]=[C:5]([CH:3]5[CH2:2][N:1]([C:27](=[O:29])[CH3:28])[CH2:4]5)[CH:6]=[CH:7][C:8]=4[O:17][CH2:16][CH2:15]3)[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CC(c2ccc3c(c2)-n2nc(-c4ncnn4C(C)C)cc2CCO3)C1

Procedure:
Following the procedure for 148, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with acetic anhydride to give 149 as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.93 (s, 1H); 7.85 (d, J=2.17 Hz, 1H); 7.27-7.20 (m, 1H); 7.19 (d, J=8.32 Hz, 1H); 6.85 (s, 1H); 5.68-5.59 (m, 1H); 4.59-4.50 (m, 3H); 4.44 (t, J=9.38 Hz, 1H); 4.18-4.11 (m, 1H); 4.13-4.05 (m, 1H); 3.89-3.80 (m, 1H); 3.16 (t, J=5.93 Hz, 2H); 1.91 (s, 3H); 1.57 (d, J=6.62 Hz, 6H). LCMS: RT=9.50 min, M+H+=393
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C([Li])CCC.[Br:16]C(Cl)(Cl)C(Br)(Cl)Cl.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.O>[Br:16][C:9]1[N:4]2[N:3]=[C:2]([CH3:1])[CH:10]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc2ccccn2n1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution of 2-methylpyrazolo[1,5-a]pyridine (Reference; Chem. Pharm. Bull., 1983, 31, 4568-5572) (1.0 g) dissolved in tetrahydrofuran (20 mL) was added n-butyllithium (2.66 M hexane solution; 3.7 mL) dropwise at −78° C. under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. To the reaction mixture was added a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (2.7 g) in tetrahydrofuran (5 mL) dropwise, and stirring was continued for 30 minutes. After adding saturated aqueous ammonium chloride to the obtained reaction mixture, the temperature was raised to room temperature, water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic extract was separated, then washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (1.34 g) was obtained as a yellow oil from the n-hexane:ethyl acetate (10:1) fraction.