Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[OH:14])([O-:3])=[O:2].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-:23].[K+].[K+].[Cl-].[Li+]>CN(C)C=O>[CH2:20]([O:19][C:17]([CH2:16][O:14][C:5]1([OH:23])[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=[CH:11][CH:6]1[C:7]([O:9][CH3:10])=[O:8])=[O:18])[CH3:21]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)COC1(O)C([N+](=O)[O-])=CC=CC1C(=O)OC
Temperature: 90 °C

Procedure:
In a flask are placed 4.14 g (0.021 mole) of methyl 3-nitrosalicylate, 3.70 g (0.022 mole) of ethyl bromoacetate, 3.2 g (0.023 mole) of potassium carbonate, and 80 mL of N,N-dimethylformamide. The resulting mixture is heated at 90° C. for approximately 16 hours. At the conclusion of this period, the reaction mixture is cooled to room temperature, and 400 mL of a 10% aqueous solution of lithium chloride is added to the reaction mixture. The resulting mixture is extracted three times with ethyl acetate. The combined extracts are washed with 200 mL of the 10% aqueous solution of lithium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate is concentrated under reduced pressure, leaving a residue which is then passed through a column of silica gel, eluting with ethyl acetate. The product-containing fractions are combined, and the solvent is evaporated under reduced pressure, leaving methyl 2-ethoxycarbonylmethoxy-3-nitrosalicylate as a residue.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[S].[NH2:19][CH2:20][CH2:21][CH2:22][NH2:23].Cl>C1(C)C=CC=CC=1>[ClH:1].[NH:19]1[CH:20]=[CH:21][CH2:22][NH:23][CH:2]1[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: ClCc1ccc(-c2nsc3ccccc23)cc1
Reactant: NCCCN
Agent: Cl
Agent: [S]
Solvent: Cc1ccccc1
Product: C1=CNC(c2ccc(-c3nsc4ccccc34)cc2)NC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
26 g of 3-(4-chloromethylphenyl)-1,2-benzisothiazole, 6.4 g of sulfur and 300 ml of toluene are heated to 50° C. 15 g of 1,3-diaminopropane are added slowly at the same temperature. The reaction mixture is then stirred for 20 hours under reflux. 20 g of hydrogen chloride gas are then passed in over one hour, the mixture is cooled to room temperature and the resulting solid is filtered off. After recrystallization from water in the presence of active charcoal, 18 g of 3-[4-tetrahydropyrimidin-2-yl)-phenyl]-1,2-benzisothiazole hydrochloride, melting, with decomposition, at 314° C., are obtained. The yield corresponds to 54.6% of theory.
Reaction SMILES: [NH3:1].[C:2]1([CH2:8][O:9][C:10](=[O:29])[NH:11][CH:12](SC(C)C)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=O)[CH3:23])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Hg](Cl)Cl>[CH3:23][C:22]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:13](=[O:14])[CH:12]([NH:11][C:10](=[O:29])[O:9][CH2:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:1]=1
Reactant: N
Reactant: CC(=O)c1ccccc1NC(=O)C(NC(=O)OCc1ccccc1)SC(C)C
Agent: Cl[Hg]Cl
Solvent: C1CCOC1
Product: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Reaction time: 6 h

Procedure:
Ammonia gas was passed through a solution of phenylmethyl[2-[(2-acetylphenyl)amino]-1-[(1-methylethyl)thio]-2-oxoethyl]carbamate (14.74 g) in dry THF (250 ml) at 0° for 0.5 h. Mercury (II) chloride (10.00 g) was added and the mixture was rapidly stirred for 6 h whilst continuing to pass ammonia gas through the mixture. The mixture was filtered through hyflo and the solvent removed from the filtrate by evaporation in vacuo. The residue was treated with acetic acid (290 ml) and sodium acetate (13.35 g) and the resulting mixture stirred at 23° for 18 h. The solvent was evaporated in vacuo and the residue was purified by chromatography. Elution with EA gave the title compound (5.70 g).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)OCC)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2,-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with ethyl bromoacetate according to the method of Example 1. The product was purified by chromatography on a 60-100 mesh Florisil and graded ethanol-chloroform mixtures.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9](N)C(NC)=C[CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:16]([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)(N1C=CN=C1)=O.[O:28]1CCCC1>>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:27]3[N:23]([CH3:16])[C:24]([OH:28])=[N:25][C:26]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CNc1ccc(Cn2ccnc2)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Product: Cn1c(O)nc2cc(Cn3ccnc3)ccc21
Temperature: 25 °C
Reaction time: 100 h
Yield: 77 %

Procedure:
A mixture of 4.04 parts of 4-(1H-imidazol-1-ylmethyl)-N1 -methyl-1,2-benzenediamine, 3.6 parts of 1,1'-carbonylbis[1H-imidazole] and 80 parts of tetrahydrofuran was stirred for about 100 hours at room temperature. The formed precipitate was filtered off, washed with tetrahydrofuran, dried and purified twice by column chromatography over silica gel using each time a mixture of trichloromethane, methanol and methanol, saturated with ammonia (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The solid residue was crystallized from 2-propanol. The product was filtered off, washed with 2-propanol and 2,2'-oxybispropane, and dried, yielding 3.5 parts (77%) of 5-(1H-imidazol-1-ylmethyl)-1-methyl-1H-benzimidazol-2-ol; mp. 207.2° C. (compound 222).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:24](O)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1C(=O)O
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1CO
Temperature: 25 °C
Yield: 102.3 %

Procedure:
To a stirred solution of (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylic acid (1.12 g, 3.13 mmol) in THF (30 ml) was added BH3.DMS (0.63 ml, 6.3 mmol) at 0° C. The mixture was raised to room temperature immediately and then heated at 50° C. for 1.5 h. After cooling to room temperature, the mixture was quenched by the addition of water at 0° C. and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel [50 g, CHCl3/MeOH (50/1)], to give (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylmethanol (1.10 g, 100%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.48 (s, 9H), 2.45 (m, 1H), 3.58-4.80 (m, 4H), 5.01 (br, 1H), 7.04-7.99 (m, 7H).
Reaction SMILES: O=S(Cl)[Cl:3].O=[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][NH:7]1.CN(C=O)C.[ClH:28]>CC#N>[ClH:3].[Cl:28][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=Cc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=Cc1ccc(-c2ccc3ncnc(Cl)c3c2)o1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Over a 1.5 hour period under an atmosphere of N2, SOCl2 (86.2 g) in MeCN (145 mL) was added dropwise into a mixture, that had been preheated at reflux for 0.5 h, of the compound of formula (IX) (29 g, 0.121 mol), MeCN (435 mL) and DMF (0.88 g) at reflux. The reaction was terminated when less than 2% (HPLC) of the compound of formula (IX) was remaining. If the reaction did not achieve complete reaction, extra SOCl2 was added. The mixture was cooled to about 25±5° C. (internal temperature), and was then filtered and washed with MeCN (58 mL) to give ca. 55 g of (Xa).HCl (moist with MeCN) with 82A % purity by HPLC. (Xa).HCl: 1H NMR (300 MHz, d6-DMSO): δ 9.68 (s, 1H), 9.17 (s, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.46 (dd, J=8.6, 2.1 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.74 (d, J=3.8 Hz, 1H), 7.60 (d, J=3.8 Hz, 1H). See FIG. 5 for the 1H NMR spectrum of (Xa).HCl; 13C NMR (75 MHz, d6-DMSO) δ 179.0, 159.6, 156.4, 152.9, 149.5, 141.0, 132.6, 129.2, 125.9, 123.2, 122.9, 122.7, 111.5.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.F[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:14]([C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)#[N:15]
Reactant: N#Cc1ccccc1F
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccccc1Oc1ccc(C(=O)O)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 48.5 %

Procedure:
To a solution of 4-hydroxybenzoic acid (7 g, 50 mmol) and 2-fluorobenzonitrile (7.36 g, 60 mmol) in dimethylsulfoxide (40 mL) was added potassium carbonate (20 g, 150 mmol). The reaction mixture was stirred at 120° C. for 4 hours. After the reaction, the temperature was allowed to cool to room temperature, then the mixture was poured into ice water (100 mL). The mixture was neutralized to pH=3 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1) to give 4-(2-cyanophenoxy)benzoic acid as a white solid (5.80 g, 48.5%). LRMS (M+H)− m/z: calcd 239.06. found 239. 1H NMR (300 MHz, d6-DMSO): δ 12.94 (s, 1H), 7.99-7.91 (m, 3H), 7.71 (t, J=8.4 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.17-7.14 (m, 3H).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[CH:7][CH:6]=1)=[O:4].C(O)(=O)C>CO>[OH:4][CH2:3][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(CSCCN2C(=O)c3ccccc3C2=O)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CCSCc1ccc(CO)o1
Reaction time: 0.75 h

Procedure:
Sodium borohydride (165 mg) was added in portions over a period of 10 mins to a solution of 2-[2-[(5-formyl-2-furanylmethyl)thio]ethyl]-1H-isoindole-1,3(2H)-dione (5.0 g) in methanol (100 ml) at 0° C. After stirring for 45 mins, acetic acid (1 ml) was added and the mixture evaporated. Water (100 ml) was added and the solid that precipitated extracted into ethyl acetate (2×150 ml). The ethyl acetate extracts were dried (magnesium sulphate) and evaporated yielding an oil which solidified on trituration in light petroleum (b.p. 60°-80° C.). Crystallisation from methyl acetate-light petroleum (b.p. 60°-80° C.) afforded the title compound as a light, white solid (4.05 g) m.p. 82.5°-84° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH2:19][CH2:20][CH2:21][CH3:22])[C:4](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:5].[OH:23]O.O.[OH-].[Li+]>C1COCC1.O.O>[OH:1][CH2:2][C@@H:3]([CH2:19][CH2:20][CH2:21][CH3:22])[C:4]([OH:5])=[O:23]
Reactant: CCCC[C@H](CO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@H](CO)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To a 2000 mL roundbottom flask was added (4S)-3-[(2R)-2-(hydroxymethyl)hexanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (4) (82 g, 0.268 mol) in THF/water (4:1, 750 mL). The solution was cooled to 0° C. and H2O2 (130 mL, 1.07 mol) was added dropwise, followed by lithium hydroxide monohydrate (22.58 g, 0.537 mol) in water (130 mL). The reaction mixture was warmed up to rt and stirred overnight. THF was removed under vacuum, and the aqueous solution was washed with ethyl acetate. The aqueous solution was then acidified to pH ˜3.0 and extracted with ethyl acetate. The extracts were dried (Na2SO4), filtered and concentrated to provide the title compound (42 g, 107%). LCMS: (2M+H)+: 313.2.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:17](=[O:23])[CH2:18][CH2:19][C:20](O)=[O:21])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:24])[O:5][N:4]=1)[CH3:2].O[N:26]1[C:30](=O)CC[C:27]1=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:17](=[O:23])[CH2:18][CH2:19][C:20]([N:26]([CH3:30])[CH3:27])=[O:21])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:24])[O:5][N:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1O
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(=O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(=O)CCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 978 mg (0.003 mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-γ-oxo-indole-3-butanoic acid in 15 ml of methylene chloride is treated with 345 mg (0.003 mole) of N-hydroxy-succinimide followed by the dropwise addition of 618 mg (0.003 mole) of dicyclohexylcarbodiimide in 10 ml CH2Cl2. The resulting mixture is stirred 5 hours at room temperature. The mixture is then filtered, and the filter cake is washed with CH2Cl2. The combined CH2Cl2 layers are added dropwise to 20 ml of 40% aqueous dimethylamine and 20 ml of CH2Cl. The mixture is stirred overnight; following which water is added and the layers separated. The CH2Cl2 layer is washed with water, brine, dried over MgSO4, filtered and evaporated. The residue is crystallized to give the title compound, m.p. 144.5°-148° C.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)O.[S-:12][C:13]#[N:14].[Na+].[CH3:16][O:17][C:18](=[O:29])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH2:20]>C(O)C>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:13]([NH:20][C@@H:19]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[C:18]([O:17][CH3:16])=[O:29])[S:12][CH:2]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: N#C[S-]
Reactant: Cc1ccc(C(O)CBr)cc1
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1nc(-c2ccc(C)cc2)cs1
Reaction time: 12 h

Procedure:
21.2 g (0.1 mol) of 2-bromo-1-(4-methylphenyl)ethanol and 8.66 g (0.107 mol) of dry sodium thiocyanate in ethanol (200 ml) were stirred for 3 h at 50° C. The solution of 19.51 g (0.1 mol) of (S)-tyrosine methyl ester in ethanol (100 ml) was then added in one portion and the reaction mixture was stirred for 12 h. After removing ethanol by distillation, water and ethyl acetate were added. Aqueous phase was extracted twice with ethyl acetate, combined organic phases were dried over sodium sulfate and the solvent was evaporated. The product was purified by chromatography (SiO2, ethyl acetate/hexane). The yield was 17.67 g (48%). MS (ES) 368 (M+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[CH2:10][CH:11]([CH2:18][CH2:19][OH:20])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[CH2:10][CH:11]([CH2:18][CH2:19][O:20][S:31]([CH3:30])(=[O:33])=[O:32])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)CC(CCO)c1ccccc1)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccccc1)c1ccc(Cl)cc1
Yield: 92.5 %

Procedure:
N-(4-Chlorophenyl)-beta-(2-hydroxyethyl)-N-methyl-benzenepropanamide (1.25 g) in CH2Cl2 (25 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (0.497 g), and methanesulfonyl chloride (0.563 g). After two hours the reaction mixture was washed with water (3×25 mL), sat. NaHCO3 (20 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (1.44 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]([OH:11])=O.[Cl:12][C:13]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:14]=1[O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20].ClCCl.CO.N>>[ClH:12].[Cl:12][C:13]1[CH:26]=[C:25]([NH:27][C:9](=[O:11])[C:8]#[C:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:24]=[CH:23][C:14]=1[O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20]
Reactant: O=C(O)C#Cc1ccccn1
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccccn2)cc1Cl
Product: Cl

Procedure:
Prepared analogously to Example 2.3.f. from pyridin-2-ylpropynoic acid and [2-(2-chloro-4-aminophenoxy)ethyl]diethylamine. Yield: 0.37 g (53.3% of theory); C20H22ClN3O2*HCl (M=408.33); calc.: molecular ion peak (M+H)+: 372/374; found: molecular ion peak (M+H)+: 372/374; Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:19])[N:13]([CH2:17][CH3:18])[N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:20]([OH:22])=[O:21])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33](O)[CH:32]=1.CCN=C=NCCCN(C)C>O1CCCC1>[F:23][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:19])[N:13]([CH2:17][CH3:18])[N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:20]([O:22][C:33]2[CH:32]=[CH:31][C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=2)=[O:21])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCn1ncc2c(oc3c(OC(F)F)ccc(C(=O)O)c32)c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1ncc2c(oc3c(OC(F)F)ccc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c32)c1=O
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
A mixture of 6-difluoromethoxy-3-ethyl-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine-9-carboxylic acid (form step II) (90 mg, 0.276 mmol), triethyl amine (41 mg, 0.415 mmol), p-nitro phenol (43 mg, 0.304 mmol) and EDCI (79 mg, 0.415 mmol) in tetrahydrofuran (3 ml) was stirred at room temp for 16-17 hrs. Progress of reaction was monitored by TLC. At the end, reaction mixture was concentrated under vacuum. Then water (50 ml) was added to reaction mixture and acidified with dilute HCl. The precipitate obtained was filtered and dried in oven. 87 mg buff colored solid was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:13]([Cl:23])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:24]1(=O)[CH2:27][CH2:26][CH2:25]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:19][CH2:18]3)[C:13]([Cl:23])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cc(OC3CCNCC3)c(Cl)cc2c1C
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1oc2cc(OC3CCN(C4CCC4)CC3)c(Cl)cc2c1C
Reaction time: 5 h

Procedure:
The above prepared 5-chloro-3-methyl-6-(piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester (1.35 g, 3.32 mmol) was dissolved in 45 mL of CH2Cl2 and treated successively with cyclobutanone (0.506 g, 2 eq.), acetic acid (0.413 mL, 2 eq.) and sodium triacetoxyborohydride (1.529 g, 2 eq.), and the mixture then kept at ambient temperature for 5 h. Pouring onto crashed ice/NaHCO3, five fold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by followed by flash chromatography (SiO2, NEt3/AcOEt=2/98) generated 1.190 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(C(C)=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:18]=3)[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2cc3ccc(Cl)cc3cn2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1ccc(Oc2cc3ccc(Cl)cc3cn2)cc1
Yield: 86.3 %

Procedure:
4-[(7-chloroisoquinolin-3-yl)oxy]phenol (2.82 g) and ethyl 2-bromopropionate (2.07 g) in the presence of anhydrous potassium carbonate (1.58 g) were refluxed in methyl ethyl ketone (50 ml) for 4 hrs. The mixture was cooled, poured into dichloromethane, washed with water, dried (MgSO4) and evaporated. Purification by column chromatography over silica gel (eluant dichloromethane) gave ethyl 2-{4-[(7-chloroisoquinolin-3-yl)oxy]phenoxy}propionate (3.33 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[C:21]1([CH2:27][C:28]2[O:32][N:31]=[C:30]([CH2:33][CH2:34][CH2:35]O)[N:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:35][CH2:34][CH2:33][C:30]3[N:29]=[C:28]([CH2:27][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:32][N:31]=3)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: OCCCc1noc(Cc2ccccc2)n1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n(CCCc2noc(Cc3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 18 h
Yield: 16.7 %

Procedure:
To a stirred solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.20, 0.67 mmol) in THF (5 ml) was added 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (0.162 g, 0.74 mmol), DBAD (0.186 g, 0.81 mmol) and triphenylphosphine (0.212 g, 0.81 mmol) and the solution stirred for 18 h. To the solution was added Pd(PPh3)4 (75 mg, 0.067 mmol) and morpholine (604 μl, 6.7 mmol) were added and stirred for at rt under nitrogen for a further 3 h. 75 mg of Pd(PPh3)4 was added and the mixture left to stir for another 3 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude material was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities, then with 2-4% AcOH/MeOH to elute the compound. The product fractions were combined and concentrated then further purified by MDAP. The product fractions were combined and concentrated give the title compound as a white solid (51 mg, 20%).