Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[C:25]([NH:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.O.[OH-].[Li+].O.Cl>C1COCC1>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([NH:26][C:25]2[C:16]([NH:15][S:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:7][CH:8]=3)(=[O:14])=[O:13])=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Nc2cc(OC)cc(OC)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CCC(=O)O)cc2)cc(OC)c1
Yield: 74.9 %

Procedure:
Methyl-3-{4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}propanoate (50 mg, 0.10 mmol, 1 eq.) and lithium hydroxide monohydrate (20.1 mg, 0.48 mmol, 5 eq.) are dissolved in THF (1 ml) and water (1 ml) and the yellow solution is heated up to 50° C. for 1 h. Aqueous HCl 1N is added until reaching acidic pH and the precipitate formed is filtered off then washed with water until neutral. The solid is dried under vacuum at 40° C. overnight, affording 38.1 mg (78%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 12.30-11.95 (m, 2H), 8.91 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.95-7.82 (br s, 1H), 7.60-7.50 (m, 1H), 7.48-7.23 (m, 6H), 6.23 (s, 1H), 3.75 (s, 6H), 2.88 (t, J=7.2 Hz, 2H), 2.56 (t, J=7.5 Hz, 2H). HPLC (max plot) 100%; Rt 4.10 min. LC/MS: (ES+): 509.4; (ES−): 507.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([C:7]#[N:8])=[C:5](O)[CH:4]=1.N[C@@H:15]([C:18]([OH:20])=[O:19])[CH2:16][SH:17].C(=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([C@H:7]2[NH:8][C:15]([C:18]([OH:20])=[O:19])=[CH:16][S:17]2)=[CH:5][CH:4]=1
Reactant: COc1cc(O)c(C#N)cc1OC
Reactant: N[C@H](CS)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc([C@H]2NC(C(=O)O)=CS2)cc1OC

Procedure:
(S)-2-(4′,5′-dimethoxyphenyl)-4-thiazoline-4-carboxylic acid (1) and (S)-2-(4′,5′-dimethoxyphenyl)-4-methylthiazoline-4-carboxylic acid (2) (also referred to as (S)-4′,5′-dimethoxydesazadesmethyldesferrithiocin and (S)-4′,5′-dimethoxydesazadesferrithiocin, respectively) were prepared starting with 2-benzyloxy-4,5-dimethoxybenzaldehyde (6), which was converted to the corresponding oxime by reacting 6 with hydroxylamine hydrochloride and triethylamine in acetonitrile at about 50° C. for about 18 hours. The corresponding nitrile (7) was prepared from the oxime by refluxing the intermediate product with phthalic anhydride for 1 day to give nitrile 7 in 87% yield. Nitrile 7 was reacted with hydrogen on a Pd—C catalyst in an ethanol/ethyl acetate mixture for about 50 minutes to remove the O-benzyl group and form 4,5-dimethoxy-2-hydroxybenzonitrile (8) in 84% yield. The deprotected nitrile 8 was subsequently reacted with D-cysteine or D-alpha-methylcysteine in a pH 6 buffer containing sodium bicarbonate and methanol to form products 1 and 2, respectively.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.O>[CH:1]1([CH2:7][O:8][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: OCC1CCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc(OCC2CCCCC2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
Cyclohexyl methanol (2.0 g, 17.5 mmol), ethyl 3-hydroxybenzoate (2.6 g, 15.8 mmol), tri-n-butyl phosphin (5.3 g, 26 mmol), and ADDP (6.6 g, 26 mmol) were dissolved in dry THF (100 ml) and stirred overnight at 20° C. under N2. Water (100 ml) is added, and the resulting solution is extracted with DCM (3×100 ml). The combined organic layers were washed with water (100 ml), dried (MgSO4) and evaporated. The crude mixture was purified by preparative HPLC to give 1.8 g of the title compound. LC-MS (m/z): 264 (M+2).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:17]CC3C=CC=CC=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.C(OCC)(=O)C.[Pd]>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(OCc3ccccc3)cccc2n1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc2c(O)cccc2n1Cc1ccccc1

Procedure:
To a solution of 1-Benzyl-4-benzyloxy-2-methyl-1H-indole (2) (35 g, 0.107 mole) in methanol (1 L) and ethyl acetate (500 mL), Pd/C (10%, 17 g) was added. Hydrogen was bubbled through the mixture at room pressure and temperature for 6 h. The reaction mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography (6:1 Hex:EtOAc) to afford intermediate (3) as an orange solid. Yield: 22 g (60%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:18])=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(-c3ccccc3)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCCCC3)c(-c3ccccc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.9 %

Procedure:
4-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenylbenzoic acid (18 mg, 0.0459 mmol) and piperidine (5.9 mg, 0.0692 mmol) were dissolved in methylene chloride (3 ml), then WSC-HCl (22 mg, 0.1147 mmol) was added thereto and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (12 mg, 0.0261 mmol, 57%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].Cl>CCO.O>[O:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCCCBr
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCCCOc1ccccc1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
Phenol (1.88 g, 20 mmol) was mixed with NaOH (0.80 g, 20 mmol) in EtOH (50 mL). 8-Bromooctanoic acid (2.23 g, 10 mmol) was then added to the mixture and refluxed for 12 h. After cooling to room temperature, water (100 mL) was added and the mixture was acidified with 2N HCl (pH=2). The solid was filtered and washed with water (2×50 mL), and recrystallized from hexane-ethyl acetate (5:1) to give the product as white brick-like crystals (1.79 g, 76%), mp 67-68° C.; 1H-NMR: 1.42 (m, 6H), 1.65 (m, 2H), 1.80 (m, 2H), 2.37 (t, 2H), 3.97 (t, 2H), 6.93 (m, 3H), 7.30 (t, 2H), 10.05 (bs, 1H). Anal. Calcd. for C14H20O3 : C, 71.16, H, 8.53%; Found: C, 71.09, H, 8.54%.
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:9])(=[O:8])[CH2:7][CH2:6][CH2:5][NH:4]1.[CH3:10][C:11]1([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH2:13][O:12]1>CN(C=O)C>[OH:12][C:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)([CH3:10])[CH2:13][N:4]1[CH2:5][CH2:6][CH2:7][S:3]1(=[O:9])=[O:8]
Reactant: COc1cc2ncnc(N3CCC(C4(C)CO4)CC3)c2cc1OC
Reactant: O=S1(=O)CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCC(C(C)(O)CN4CCCS4(=O)=O)CC3)c2cc1OC
Reaction time: 4 h

Procedure:
Sodium hydride (1.25 g of a 50% dispersion in oil) was added at room temperature to a stirred solution of isothiazolidine-1,1-dioxide (2.42 g) in DMF (15 cm3). After stirring for 0.5 hours 2-methyl-2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]oxirane (5.0 g) was added and the mixture was stirred for 4 hours at 100°. Volatile material was removed in vacuo, the residue was partitioned between chloroform (100 cm3) and water (50 cm3) and the chloroform layer was dried (MgSO4) and evaporated. The residue was chromatographed on silica ("Merck" 60.9385) eluting with methanol:ethyl acetate, 1:4, to give a solid which was recrystallised from ethyl acetate-methanol to give 2-{2-hydroxy-2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]prop-1-yl}isothiazolidine-1,1-dioxide, m.p. 173°-174° (4.15 g).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C(=O)O)c1Br
Solvent: ClCCl
Product: Cc1cccc(C(=O)Cl)c1Br
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of 2-bromo-3-methylbenzoic acid (2.07 g, 9.63 mmol) in DCM (48.1 mL) was cooled to 0° C. Oxalyl chloride (0.9 mL, 10.14 mmol) was added dropwise via syringe. After addition, the cooling bath was removed and the reaction mixture stirred overnight. The mixture was concentrated in vacuo to remove solvent and excess reagent, affording 2-bromo-3-methylbenzoyl chloride as a cloudy white oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].N1C=CC=CC=1>O>[C:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Reaction time: 24 h

Procedure:
10 Grams of p-hydroxybenzoic acid and 15 g of decanoic acid chloride were stirred at room temperature, and 7.2 g of pyridine was dropwise added. After the mixture was stirred for 1 day, a reaction product was poured into water, and an organic layer was extracted with dichloromethane. The organic layer was washed with 1N hydrochloric acid and dried over anhydrous sodium sulfate, the solvent was distilled off, and then residue was washed with n-hexane and then dried to give a crude end product.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1.[NH:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][OH:32]>>[OH:32][CH2:31][CH2:30][N:29]([CH2:14][CH2:13][CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:6]=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=2)[CH:8]=1)[CH2:33][CH2:34][OH:35]
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: OCCNCCO
Product: COc1ccc(-c2cc(CCCN(CCO)CCO)c(=O)n(CC3CC3)n2)cc1F
Yield: 13.1 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and diethanolamine were reacted to yield the title compound as a yellow oil (yield: 13.1%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]1[CH2:20][CH:21]=[N:22][OH:23]>CN(C=O)C.C(OCC)(=O)C>[O:19]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:9])[N:11]1[CH2:20][C:21]([Cl:1])=[N:22][OH:23]
Reactant: O=C1c2ccccc2C(=O)N1CC=NO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CC(Cl)=NO
Temperature: 50 °C
Yield: 98.7 %

Procedure:
N-Chlorosuccinimide (8.50 g, 63.7 mmol) was added to a solution of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanal oxime (13.0 g, 63.7 mmol) in DMF (100 mL), and the solution was heated at 50° C. gently for two hours and allowed to cool to room temperature. The solution was diluted with ethyl acetate and washed three times with water and once with brine, dried over magnesium sulfate, filtered, and concentrated to provide 15.0 g of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxyethanimidoyl chloride as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:2]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=[CH:27][C:5]([CH2:6][CH:7]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(Cc1ccc(Br)cc1)C(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC(Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 95 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
A solution of benzyl 2-(4-bromobenzyl)-3-(tert-butoxycarbonylamino)propanoate (44 mg, 0.098 mmol), phenylboronic acid (17.95 mg, 0.147 mmol), Pd(PPh3)4 (11.34 mg, 9.81 μmol) and 2M aqueous Na2CO3 (0.098 ml, 0.196 mmol) in toluene (1 ml) was allowed to stir under nitrogen at 95° C. for 18 hours. The reaction mixture was cooled to room temperature, and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 0:100) to give benzyl 3-(biphenyl-4-yl)-2-((tert-butoxycarbonylamino)methyl)propanoate (27.3 mg); Retention time=1.78 minutes (condition B); MS (m+1)=446.1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1)[CH2:12][C:13]#[CH:14]>>[N:16]1[N:15]([CH2:11][CH2:12][C:13]#[C:14][C:2]2[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=2)[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: C#CCCn1nc2ccccc2n1
Reactant: CC(=O)c1cccc(Br)n1
Product: CC(=O)c1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 51.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 1-(6-bromo-pyridin-2-yl)-ethanone (500 mg, 2.66 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (455 mg, 2.66 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 380 mg (1.36 mmol, 51%) of 1-[6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-yl]-ethanone as a white solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[CH3:39][CH:40]([O:42][CH2:43][CH2:44][NH2:45])[CH3:41].NN>CCO.O>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:45][CH2:44][CH2:43][O:42][CH:40]([CH3:41])[CH3:39])=[O:34])[C:15]1=[O:38]
Reactant: CC(C)OCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)OCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.143 g, 0.28 mmol) in EtOH (3 mL) under nitrogen was treated with 2-[(1-methylethyl)oxy]ethanamine (0.102 mL, 0.83 mmol) for 50 min. (130° C. in a microwave vessel. The reaction was transferred to a test tube, diluted with EtOH (35 mL), and treated with hydrazine (0.174 mL, 5.55 mmol) for 4 h@50° C. After the reaction was cooled to ambient temperature the resulting suspension was diluted with water (150 mL) and refrigerated overnight. The resulting suspension was filtered, washed with 3:1 water:EtOH and thoroughly dried under high vacuum to provide the title compound as an off-white solid: 1H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (d, J=6.2 Hz, 6 H), 2.8 (bs, 2 H), 3.3 (s, 2 H), 3.5 (m, 4 H), 3.6 (m, 1 H), 4.2 (s, 2 H), 7.1 (t, J=9.3 Hz, 2 H), 7.4 (dd, J=8.5, 5.4 Hz, 2 H), 8.1 (s, 1 H), 8.5 (s, 1 H), 10.4 (s, 1 H); ES+ MS: 443 (M+H+).
Reaction SMILES: N1CCOC[CH2:2]1.C[Mg]Br.C[O:11][C:12]([C:14]1([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[C:18]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:16][CH2:15]1)=O>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[C:32]([Si:29]([CH3:31])([CH3:30])[O:28][C:25]1[CH:24]=[CH:23][C:22]([C:19]2[C:18]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[C:17]([C:14]3([C:12](=[O:11])[CH3:2])[CH2:16][CH2:15]3)[O:21][N:20]=2)=[CH:27][CH:26]=1)([CH3:33])([CH3:34])[CH3:35]
Reactant: COC(=O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Reactant: C1COCCN1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution consisting of morpholine (7.5 mL) in THF (100 mL) is cooled to 0° C. (ice/salt bath) and a solution of methylmagnesium bromide (55 mL of a 1.4 M solution in toluene/THF 3:1 v/v) is added by addition funnel while the temperature is maintained between 0 and 5° C. (over 15 minutes.) The orange reaction mixture is stirred at 0° C. for 30 minutes and subsequently a mixture consisting of 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropanecarboxylic acid methyl ester (12.8 g) in THF (50 mL) is added by addition funnel over 5 minutes. The flask is removed from the ice bath. The reaction mixture is cooled to 0° C. and a solution consisting of methylmagnesium bromide (55 mL of a 1.4 M solution in toluene/THF 3:1 v/v) is added over 10 minutes. After 20 min further methylmagnesium bromide (55 mL of a 1.4 M solution in toluene/THF 3:1 v/v) is added over 10 minutes. The ice bath is removed and the reaction mixture is allowed to warm to room temperature overnight. The reaction mixture is poured into an ice/ammonium chloride solution. The mixture is twice extracted with ethyl acetate and the combined extracts are dried and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with a gradient (1% to 5% ethyl acetate in hexanes) afforded 1-(1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropyl)-ethanone (4.8 g); MS (APCI+) m/z 434 (MH+.)
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27].[NH2:31][OH:32]>CS(C)=O>[OH:32][N:31]=[C:26]([C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([CH2:14][O:13][C:12]4[CH:15]=[C:16]5[C:20](=[CH:21][C:11]3=4)[CH2:19][CH2:18][O:17]5)[C:2]2=[O:1])[CH:24]=1)[NH2:27]
Reactant: N#Cc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Reactant: NO
Solvent: CS(C)=O
Product: NC(=NO)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
To a solution of 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile (1.15 g, 2.92 mmol) in dimethyl sulfoxide (20 mL) was added hydroxylamine (50% wt in H2O, 2 mL, 32.67 mmol). The reaction was stirred at 80° C. for 3 h, cooled to ambient temperature. The precipitate was collected by filtration and washed with water and diethyl ether and dried in vacuo to afford N′-hydroxy-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H) yl)methyl]benzenecarboximidamide (0.85 g, 68%): 1H NMR (300 MHz, CDCl3) δ7.61 (m, 1H), 7.96 (m, 1H), 7.51 (m, 1H), 7.38 (m, 2H), 7.16 (m, 2H), 7.01 (m, 1H), 6.75 (m, 1H), 6.48 (s, 1H), 6.40 (s, 1H), 5.09 (d, 1H, J=15.7 Hz), 4.98 (d, 1H, J=9.0 Hz), 4.83 (m, 3H), 4.70 (d, 1H, J=9.0 Hz), 4.49 (t, 2H, J=8.6 Hz), 2.96 (m, 2H); MS (ES+) m/z 427.8 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br.CCN(C(C)C)C(C)C>C1COCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]([N:15]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[CH:13][CH:14]=2)[O:5]1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: BrCCOCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C

Procedure:
A solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (164 mg, 0.75 mmol), 1-bromo-2-(2-bromoethoxy)ethane (418 mg, 1.8 mmol), and DIPEA (0.64 mL, 3.6 mmol) in THF (2 mL) was stirred at reflux overnight. The mixture was concentrated, diluted with water, and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography to give the title compound. MS (m/z): 290 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH:17][CH:18]1[CH:26]2[CH:21]([CH:22]3[CH2:27][CH:25]2[CH:24]=[CH:23]3)[C:20](=O)[O:19]1>C1C=CC=CC=1>[O:17]=[C:18]1[C@H:26]2[C@H:21]([C@@H:22]3[CH2:27][C@H:25]2[CH:24]=[CH:23]3)[C@@H:20]([NH:1][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[O:19]1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C1OC(O)C2C3C=CC(C3)C12
Solvent: c1ccccc1
Product: CC(C)C[C@H](N[C@H]1OC(=O)[C@H]2[C@@H]1[C@H]1C=C[C@@H]2C1)C(=O)OCc1ccccc1

Procedure:
A mixture of 5.2 g of benzyl L-leucinate, 4 g of (3RS, 3aRS,4RS,7RS,7aRS) 3-hydroxy-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran1-one and 40 ml of anhydrous benzene was refluxed for 90 minutes while azeotropically distilling off the water of reaction formed and was then evaporated to dryness under reduced pressure. The residue was added to isopropyl ether and the mixture was vacuum filtered to obtain 2.3 g of benzyl (αS,3S,3aS,4R,7S,7aR) α-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-3-yl)-amino]-isohexanoate melting at 95° C.