Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:29]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1[Br:36])=[O:30].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.CCCCCCC>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:29]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1[Br:36])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1sccc1Br
Reactant: COc1ccc2ncn(COCc3ccccc3)c2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2nc(C(=O)c3sccc3Br)n(COCc3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 32.1 %

Procedure:
To a stirred solution of 1-benzyloxymethyl-6-methoxy-1H-benzoimidazole (1.00 g, 3.72 mmol, Example 2A) in anhydrous tetrahydrofuran (15 mL) at −78° C. under nitrogen is added n-butyllithium (1.80 mL of a 2.5 M solution in hexanes, 4.5 mmol) over 8 minutes and the resulting yellow solution is stirred a −78° C. After 25 minutes, a solution of 3-bromo-thiophene-2-carboxylic acid methoxy-methyl-amide (1.03 g, 4.12 mmol) in tetrahydrofuran (10 mL) is added over 20 minutes, to the reaction at −78° C. The reaction is allowed to gradually warm to ambient temperature overnight. The reaction is poured into 10% aqueous ammonium chloride (75 mL) and the mixture extracted twice with ethyl acetate (50 mL). The organic layer is washed with water and brine successively, dried over magnesium sulfate, and concentrated under reduced pressure to a yellow oil. The crude material is chromatographed on silica, eluting with 30% ethyl acetate/heptane followed by 40% ethyl acetate/heptane, to give a waxy solid. Trituration with 25% ethyl acetate/heptane afforded 546 mg (32%) of (1-benzyloxymethyl-6-methoxy-1H-benzoimidazol-2-yl)-(3-bromo-thiophen-2-yl)-methanone, as a powder: TLC Rf 0.43 (silica, 40% ethyl acetate/heptane); LC/MS: (M+H 457, RT=3.85 minutes); 1H NMR [(CD3)2SO), 300 MHz]: δ 8.14 (d, 5.2 Hz, 1H), 7.76 (d, 9.0 Hz, 1H), 7.36 (d, 5.0 Hz, 1H), 7.29-7.20 (m, 6H), 7.04 (dd, 2.5, 9.0 Hz, 1H), 6.13 (s, 2H), 4.59 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:18])[CH:6]([NH2:17])[CH2:7][S:8][S:9][CH2:10][CH:11]([NH2:16])[C:12]([O:14][CH3:15])=[O:13].C(N([CH:25]([CH3:27])[CH3:26])C(C)C)C.[C:28](Cl)(=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O1CCCC1>[CH3:3][O:4][C:5](=[O:18])[C@@H:6]([NH:17][C:5](=[O:4])[CH2:6][CH2:7][CH2:27][CH2:25][CH3:26])[CH2:7][S:8][S:9][CH2:10][C@H:11]([NH:16][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(N)CSSCC(N)C(=O)OC
Reactant: CCCCCC(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCC(=O)N[C@@H](CSSC[C@H](NC(=O)CCCCC)C(=O)OC)C(=O)OC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A suspension of 1 equiv. 3,3'-dithiobis(2-aminopropionic acid) dimethylester dihydrochloride in tetrahydrofuran (white slurry) was stirred and cooled to 0° C. To the reaction mixture was added 4 equiv. of N-ethyldiiso-propylamine and 2.2 equiv. of hexanoylchloride. The mixture was stirred for 4 hrs on an ice bath and the white precipitate of N-ethyldiisopropylammonium chloride was filtered off. The solvent was removed by evaporation under reduced pressure and the crude product was redissolved in dichlormethane. After washing with water, the organic phase was dried over sodium sulphate. Filtration and evaporation of the solvent gave crude (R,R)-N,N'-dihexanoyl-3,3'-dithiobis(2-aminopropionic acid) dimethylester, which was recrystallized from methanol/water and triturated with diethylether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:13](=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][O:20][P:21]([CH:25](C)[C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)(=[O:24])[O:22][CH3:23]>CN(C=O)C.C(OCC)(=O)C>[CH3:23][O:22][P:21]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:13][N:10]2[N:11]=[N:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)=[N:9]2)=[CH:30][CH:31]=1)(=[O:24])[O:20][CH3:19]
Reactant: O=C([O-])[O-]
Reactant: COP(=O)(OC)C(C)c1ccc(Br)cc1
Reactant: Brc1cccc(-c2nn[nH]n2)c1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COP(=O)(Cc1ccc(Cn2nnc(-c3cccc(Br)c3)n2)cc1)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(3-bromophenyl)-2H-tetrazole (0.5 g, 2.22 mmol) in DMF (15 mL) was added cesium carbonate (0.94 g, 2.89) and the mixture stirred at room temperature for 15 minutes. To this was added (4-bromo-methylbenzyl) phosphonic acid dimethyl ester (0.85 g, 3.05 mmol) and the reaction mixture stirred over night at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, filtered, and the evaporated to dryness.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=4)[NH:12][N:11]=3)[CH:8]=[CH:9][C:2]1=2.[OH:21]O.[OH-].[Na+].Cl>O.C(O)C>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH2:20])=[O:21])[CH:17]=4)[NH:12][N:11]=3)[CH:8]=[CH:9][C:2]1=2
Reactant: N#Cc1ccc2[nH]nc(-c3ccc4c(c3)CCO4)c2c1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc2[nH]nc(-c3ccc4c(c3)CCO4)c2c1
Temperature: 45 °C
Yield: 53 %

Procedure:
A mixture of 3-(2,3-dihydrobenzo[b]furan-5-yl)-1H-indazole-5-carbonitrile (0.50 g, 1.9 mmol), 95% ethanol (6 mL), aqueous 30% hydrogen peroxide (3 mL), and 6.0 N aqueous sodium hydroxide (1 mL) was heated at 45° C. for 3 h. The reaction mixture was diluted with water (40 mL) and acidified to pH 6 with 3 N hydrochloric acid. The solid was filtered and dried in a vacuum oven to give product (0.080 g, 53% yield): 1H NMR (DMSO-d6) δ 13.22 (s, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 7.90 (d, 2H), 7.76 (d, 1H), 7.55 (d, 1H), 7.32 (s, 1H), 6.91 (d, 1H), 4.59 (t, 2H), 3.28 (t, 2H); ES-MS (m/z) 280 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][CH:13]1[CH2:15][O:14]1)[CH:7]=[CH:6][C:5]=2[CH3:16].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]1[CH2:34][C@H:33]2[NH:35][CH2:36][C@@H:28]1[CH2:29][CH:30]=[CH:31][CH2:32]2.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][CH:13]([OH:14])[CH2:15][N:35]1[CH2:36][CH:28]3[N:27]([C:18]4[CH:19]=[CH:20][C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:17]=4)[CH2:34][CH:33]1[CH2:32][CH:31]=[CH:30][CH2:29]3)[CH:7]=[CH:6][C:5]=2[CH3:16]
Reactant: Cc1cc2c(OCC3CO3)ccc(C)c2[nH]1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc2c(OCC(O)CN3CC4CC=CCC3CN4c3ccc4ccccc4c3)ccc(C)c2[nH]1

Procedure:
2,7-Dimethyl-4-oxiranylmethoxy-1H-indole (30 mg, 0.138 mmol), Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (40 mg, 0.15 mmol), DIPEA (0.1 mL, 0.55 mmol), ethanol (2 mL) were heated for 900 sec. at 120° C. in a μW reaction tube to yield crude product. The solvent was evaporated under reduced pressure to yield a solid that was purified with flash chromatography gradient [0% Ethyl acetate/heptane to 100% Ethyl acetate] to yield the title compound as a residue.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:17]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][C:27]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:22][N:21]=1)([CH3:19])[CH3:18].C(OCC)(=O)C>CN(C=O)C.O>[CH:17]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][C:27]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:22]([C:4]2[C:3]([CH3:10])=[CH:2][CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[N:21]=1)([CH3:19])[CH3:18]
Reactant: Cc1cc(C#N)ccc1F
Reactant: CC(C)c1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(C#N)c1-n1nc(C(C)C)c2c(-c3cnc4ccccc4c3)ccnc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
4-Fluoro-3-methylbenzonitrile (0.077 g) and cesium carbonate (0.203 g) were added to a solution of compound (6c) (0.150 g) in DMF (1.73 mL), followed by stirring at 80° C. for 18 hr. The reaction solution was distributed between ethyl acetate and water. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain 4-{(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-methylbenzonitrile (0.154 g, 73%). This 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-methylbenzonitrile was dissolved in DMSO (5.0 mL) and ethanol (5.0 mL). A 4 N aqueous sodium hydroxide solution (0.195 mL) and a 30% hydrogen peroxide solution (0.088 mL) were added to the resulting solution, followed by stirring at room temperature for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain compound (80) (0.135 g, 83%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH2:19])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1.C(Cl)Cl.CO>CN(C=O)C>[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[O:27])[N:19]([CH2:18][CH2:17][N:14]3[CH2:13][CH2:12][CH:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[CH2:16][CH2:15]3)[C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: O=C1c2ccc(F)cc2C(=O)N1CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 37.8 %

Procedure:
To a solution consisting of 2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethylamine (6.1 g, 23.2 mmol) in DMF (2 30 ml) was added 4-fluorophthalic anhydride (4.2 g, 25.5 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to 80 C for 2.5 hours at which time it was allowed to cool to room temperature. The DMF was removed under reduced pressure (<0.5 mmHg, 55 C) to give a brown oil which was dissolved into DCM/MeOH. Purification via flash column chromatography (silica gel, 2% MeOH/DCM) afforded 3.6 g of 4-fluoro-N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimide. To a solution of the latter compound (3.6 g 8.8 mmol) in anhydrous THF (100 ml) was added LAH (18.4 ml of a 1.0M solution in THF, 18.4 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux for 4 hours. Upon cooling to room temperature, the reaction was quenched with water (1.5 ml, dropwise). The precipitated salts were removed via filtration and washed with DCM. The combined filtrates were concentrated to give a solid which was purified via flash column chromatography (silica gel, 0-8% MeOH/DCM). The product containing fractions were concentrated to give 2.4 g product as an off-white solid. The dimaleate salt was prepared in methanol using 2.4 eq. of maleic acid. The white precipitate was collected via filtration and washed with methanol, m.p. 186°-188° C.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH3:22][C:23]1([CH3:31])[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][C:24]1=[O:30].CC(C)(O)C#N>C(Cl)(=O)C(Cl)=O.CN(C)C=O.C(#N)C>[OH:30][C:24]1[C:23]([CH3:31])([CH3:22])[CH2:28][CH2:27][C:26](=[O:29])[C:25]=1[C:4]([C:3]1[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=1)=[O:6]
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)O
Reactant: CC1(C)CCC(=O)CC1=O
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)C(C)(C)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
The 2-methyl-6-trifluoromethyl-nicotinic acid (1.026 g, 0.005 mol) obtained is dissolved in 20 ml of oxalyl chloride. Three drops of dimethylformamide are added and the mixture is refluxed for 1 hour. The mixture is then concentrated by evaporation using a rotary evaporator and the residue (2-methyl-6-trifluoromethyl-nicotinoyl chloride) is taken up in 100 ml of methylene-chloride. At a temperature of 0° C., 1.6 ml (0.0115 mol) of triethylamine and 0.7 g (0.005 mol) 4,4-dimethyl-cyclohexane-1,3-dione are added. After 2 hours at a temperature of 22° C., the solvent is removed using a vacuum rotary evaporator, the residue that remains is dissolved in 55 ml of acetonitrile and, for rearrangement of the intermediate, 0.15 ml (0.0016 mol) of acetone cyanohydrin and 0.79 ml (0.0057 mol) of triethylamine are added. After stirring for four hours at room temperature, the reaction solution is concentrated by evaporation. The syrup that remains is chromatographed on silica gel. The light-yellow, viscous oil obtained by eluting with a mixture of toluene, ethyl alcohol, dioxane, triethylamine and water (100:40:20:20:5 parts by volume) (Rf=0.39 based on the said mixture as mobile phase) is dissolved in dichloromethane and washed with 75 ml of hydrochloric acid 5% and 75 ml of water in succession. After drying the organic solution with Na2SO4, concentration by evaporation yields 1.05 g (63%) of pure title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:9]([Br:28])[CH:8]=1)[C:3]([OH:5])=[O:4].[C:29]1([N:35]([CH2:39][CH2:40]O)[CH2:36][CH2:37]O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Br:28][C:9]1[CH:8]=[C:7]([CH2:6][C@H:2]([N:1]2[CH2:37][CH2:36][N:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:39][CH2:40]2)[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1Br
Reactant: OCCN(CCO)c1ccccc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@@H](C(=O)O)N2CCN(c3ccccc3)CC2)cc1Br
Yield: 30 %

Procedure:
Following the procedures described in Example 1, Intermediate 3B was used in place of Intermediate 3A, and 2,2′-(phenylazanediyl)diethanol was used in place of 2,2′-(m-tolylazanediyl)diethanol to give (2S)-3-{3-bromo-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-phenylpiperazin-1-yl)-propanoic acid as a white solid with the yield of 30% and mp of 220-222° C.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][O:6][C:5](=[O:9])[CH2:4]1)=[CH2:2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>C(N(CC)CC)C.C(#N)C.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH:2]=[CH:1][CH:3]2[CH2:8][CH2:7][O:6][C:5](=[O:9])[CH2:4]2)[CH:34]=1
Reactant: Brc1cccnc1
Reactant: C=CC1CCOC(=O)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC(C=Cc2cccnc2)CCO1

Procedure:
To a solution of 0.879 g (7 mmol) of 4-ethenyltetrahydro-2H-pyran-2-one in 5 ml triethylamine and 5 ml acetonitrile is added 0.081 g (0.36 mmol) Palladium-(II)-acetate followed by 0.659 g (2.5 mmol) tri-o-tolylphosphine and 0.76 ml (7.9 mmol) 3-bromopyridine and the mixture is heated at 125° for 20 h in a sealed tube. It is then cooled, diluted with methylene chloride and washed with water. The organic phase is dried (MgSO4), filtered and evaporated to give a reddish oil which is flash chromatographed using ethyl acetate as eluent to obtain 4-[2-(3-pyridyl)ethenyl]-tetrahydro-2H-pyran-2-one as an oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([OH:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1.O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([O:28][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Cl)c2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Di-tert-butylazodicarboxylate (9.22 g) in methylene chloride (20 ml) was added slowly to a stirred suspension of 4-chloro-6-hydroxy-7-methoxyquinazoline (5.63 g), 4-hydroxy-1-tert-butoxycarbonylpiperidine (8.06 g) and triphenylphosphine (10.5 g) in methylene chloride (100 ml) at 5° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature for 16 hours. The reaction mixture was then evaporated under vacuum and adsorbed onto silica and the product was eluted with isohexane/ethyl acetate/triethylamine (75/24/1 followed by 70/29/1). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1-carboxylate as a white solid (10.3 g); 1H NMR Spectrum: (DMSO d6) 1.40 (s, 9H), 1.56–1.69 (m, 2H), 1.93–2.04 (m, 2H), 3.20–3.31 (m, 2H), 3.60–3.70 (m, 2H), 4.00 (s, 3H), 4.89 (m, 1H), 7.45 (s, 1H), 7.50 (s, 1H), 8.86 (s, 1H); Mass Spectrum: (M+H)30 394.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH:13][C:14]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)=[O:15])[CH:7]=1.CO.[OH-].[Na+]>C1COCC1>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:27])=[O:2])=[CH:7][C:8]=1[NH:13][C:14]([C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:15]
Reactant: COC(=O)C=Cc1ccc(F)c(NC(=O)c2ccc(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(F)c(NC(=O)c2ccc(-c3ccccc3)o2)c1
Reaction time: 1 h

Procedure:
The ester (44) (18 mg, 0.049 mmol) was hydrolysed using Method C, except that MeOH (1 mL), THF (1 mL) and 1M NaOH (2 mL) were used, and the reaction was stirred for 1 hour. Yield: 3 mg, 17%; LC-MS tr 1.44 min; HPLC Purity: 91%; MS (ES+) m/z 352 (M+H); 1H NMR (400 MHz; MeOH): δ 6.50 (d, 1H), 7.05 (d, 1H), 7.25-7.60 (m, 6H), 7.70 (d, 1H), 7.95 (d, 2H), 8.15 (d, 1H)
Reaction SMILES: [CH:1]#[C:2][CH:3](O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.NC1C=CC=CC=1>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru].C(OCC)C>[CH3:1][C:2]1[NH:10][C:11]2[C:16]([C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: Nc1ccccc1
Reactant: C#CC(O)CCCCC
Agent: [Ru]
Agent: Cl
Agent: [C-]#[O+]
Solvent: CCOCC
Product: CCCCCc1c(C)[nH]c2ccccc12
Temperature: 140 °C
Reaction time: 9 h
Yield: 105 %

Procedure:
1-Octyne-3-ol (1.136 g, 9 mmol), aniline (0.559 g, 6 mmol), Ru3(CO)12 (16.0 mg, 0.025 mmol) and aniline hydrochloride (0.130 g, 1.0 mmol) were placed in a 10 ml round-bottomed flask, and the mixture was stirred at 140° C. for 9 hours. After cooling, diethyl ether (3 mL) was added, and the organic layer was washed twice with 1 M hydrochloric acid (2 mL) and once with water (2 mL). The organic layer was dried over sodium sulfate, and the solvent was distilled away, whereby an 11:1 mixture of 3-methyl-2-pentyl indole and 2-methyl-3-pentyl indole (1.262 g; 6.3 mmol; yield, 95%; purity, about 95% or more) was obtained.
Reaction SMILES: [Si]([N:8]1[C@H:11]([CH2:12][C:13](=[O:28])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@@H:10]([C@H:29]([O:31][Si](C(C)(C)C)(C)C)[CH3:30])[C:9]1=[O:39])(C(C)(C)C)(C)C.Cl>CO.O.C(OCC)(=O)C>[OH:31][C@@H:29]([C@@H:10]1[C@@H:11]([CH2:12][C:13](=[O:28])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[NH:8][C:9]1=[O:39])[CH3:30]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(3S,4R)-1-(t-butyldimethylsilyl)3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one (7.9 mmol) is dissolved in 160 ml of 9:1 (v/v) methanol-water and cooled to 0° C. Concentrated hydrochloric acid (2.75 ml) is added and the resulting solution is stirred at 0° C. for 15 min., then allowed to warm to room temperature. The solution is stirred at room temperature for 2.5 hrs, then diluted with ethyl acetate (200 ml) and washed with water, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to yield (3S,4R)-3-[(R)1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]-azetidin-2-one.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[CH3:34][NH:35][CH2:36][CH:37]([C:39]1[O:40][C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:42][CH:43]=1)[OH:38].O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:35]([CH2:36][CH:37]([OH:38])[C:39]4[O:40][C:41]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[CH:42][CH:43]=4)[CH3:34])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: CNCC(O)c1ccc(-c2ccccc2)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1ccc(-c2ccccc2)o1
Temperature: 90 °C
Yield: 80.4 %

Procedure:
N,N-Diisopropylethylamine (0.17 mL) was added to a solution of N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.183 g) and rac-2-(methylamino)-1-(5-phenyl-2-furyl)ethanol (Preparation 55, 0.217 g) in DMF (15 mL). The reaction mixture was heated to 90° C. for 2 h. The mixture was allowed to cool to room temperature, poured into water (50 mL), and was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (CH2Cl2/methanol, 100/1; 50/1; 25/1) and crystallized from ethyl acetate/CH2Cl2/diethyl ether to afford 0.22 g of the title compound as a white solid. Physical characteristics. M.p. 115-119°C.; 1H NMR (400 MHz, DMSO-d6) δ 10.63, 8.40, 7.56, 7.42-7.30, 7.17, 6.89, 6.84, 6.37, 5.34, 4.74, 4.54, 3.80, 3.74, 3.67, 2.88, 2.68, 2.33; MS (ESI+) m/z 546 (M+H)+.