Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1O[CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].CC(C)=O.[CH3:14][NH2:15]>O>[CH3:14][N:15]1[CH:7]=[CH:6][C:4](=[O:5])[C:3]([OH:9])=[C:2]1[CH3:1]
Reactant: CN
Reactant: Cc1occc(=O)c1O
Solvent: CC(C)=O
Solvent: O
Product: Cc1c(O)c(=O)ccn1C
Reaction time: 6.5 h
Yield: 53 %

Procedure:
Maltol (i.e. 2-methyl-3-hydroxypyran-4-one) 250 g) was dissolved in 25% aqueous methylamine (750 ml) and water (125 ml). The solution was pumped through the CMR (18 ml/min; 160°-2° C.; 900 kPa) and the hot reaction mixture passed directly into acetone (2.5 liters), cooled in an ice water bath. The crystalline product (146 g; 53% yield) was collected by filtration, and washed with acetone (2×250 ml). The corresponding literature method17 involved 6.5 hours at reflux, followed by laborious work up.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12](=[O:34])[NH:13][C:14]1[CH:15]=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:33])=O)=[CH:27][CH:26]=2)[C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][S:36]([N:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=2)[CH2:41][CH2:40]1)(=[O:38])=[O:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12](=[O:34])[NH:13][C:14]1[CH:15]=[C:16]([C:25]2[CH:26]=[CH:27][C:28]([C:31](=[O:33])[NH:52][C:49]3[CH:50]=[CH:51][C:46]([CH2:45][N:42]4[CH2:41][CH2:40][N:39]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:44][CH2:43]4)=[CH:47][CH:48]=3)=[CH:29][CH:30]=2)[C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)O)cc2)c1
Reactant: CS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2-(4′-Carboxy-6-trifluoromethoxy-biphenyl-3-ylcarbamoyl)-azetidine-1-carboxylic acid tert-butyl ester (50 mg), 4-(4-methanesulfonyl-piperazin-1-ylmethyl)-phenylamine (29 mg), HBTU (61 mg) and N-methyl morpholine (0.033 ml) in dry DMF (3 ml) was stirred at room temp for 18 h. Water (10 ml) was then added and the cream solid collected by filtration and used without purification or characterisation.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:11]>>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1)=[O:11]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(F)F
Product: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Yield: 101.4 %

Procedure:
Prepared from commercially available ethyl difluoroacetate (14.49 g, 117 mmol) and commercially available 4-(trifluoromethyl)acetophenone (15.36 g, 80 mmol) as described in example C.1 step 1 to give 4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (21.60 g, 101%) as a light brown oil. MS (ISN) 265.0 [(M−H)−].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]([O:17]C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]([NH2:22])=[O:21].C[O-].[Na+].O>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]2[NH:19][C:20](=[O:21])[NH:22][C:15](=[O:17])[CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: NC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1NC(=O)C2CN(Cc3ccccc3)CCC2N1
Temperature: 0 °C
Yield: 64.2 %

Procedure:
Methyl 1-benzyl-4-oxo-3-piperidinecarboxylate (20.194 g, 71.168 mmol) and urea (9.031 g, 150.4 mmol) were dissolved in methanol (150 mL). 4.63 M of sodium methoxide in methanol (46 mL) was added dropwise. Then the reaction was heated to reflux under nitrogen for 96 h. The reaction was cooled to 0° C. and filtered to give a white solid. This was stirred vigorously for 30 minutes with 50 ml water, then cooled to 0° C. and filtered to give 6-benzylhexahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (ao) as a white solid (11.77 g, 45.7 mmol) which was dried under high vacuum overnight and then used without further purification: 1H NMR (D6-DMSO, 400 MHz) δ 7.47-7.07 (m, 5H), 3.56 (s, 2H), 2.96 (s, 2H), 2.51 (t, 4H), 2.27 (t, J=5.6, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:4][C:5]3[CH:6]=[C:7]4[C:11](=[C:12]([CH:26]=3)[CH2:13][CH2:14][C:15]3[CH:25]=[C:19]([NH:20][C:21]([N:24]=2)=[N:22][CH:23]=1)[CH:18]=[CH:17][CH:16]=3)[O:10][C:9](=[O:27])[N:8]4COCC[Si](C)(C)C.N.O.C(OCC)(=O)C>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:3]2[NH:4][C:5]3[CH:6]=[C:7]4[C:11](=[C:12]([CH:26]=3)[CH2:13][CH2:14][C:15]3[CH:25]=[C:19]([NH:20][C:21]([N:24]=2)=[N:22][CH:23]=1)[CH:18]=[CH:17][CH:16]=3)[O:10][C:9](=[O:27])[NH:8]4
Reactant: C[Si](C)(C)CCOCn1c(=O)oc2c3cc(cc21)Nc1nc(ncc1Cl)Nc1cccc(c1)CC3
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cc3cc(c2o1)CCc1cccc(c1)Nc1ncc(Cl)c(n1)N3
Temperature: 20 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
A solution of 4-chloro-20-{[2-(trimethylsilyl)ethoxy]methyl}-18-oxa-2,6,8,20,25-pentaazapentacyclo[14.6.1.1(3,7).1(9,13).0(17,21)]pentacosa-1(23),3(25),4,6,9(24),10,12,16,21-nonaen-19-one (25 mg, 49 μmol) in TFA (1.5 mL) was stirred at 20° C. for 30 min. The reaction mixture was concentrated and reconcentrated from dichloromethane to a residue. This residue was dissolved in THF (1.5 mL) and treated with 20 M of ammonia in water (1 mL, 20 mmol) dropwise and stirred at 20° C. for 1 h. The reaction mixture was poured into water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product (19 mg, quantitative) as a white solid. LCMS for C19H15ClN5O2 (M+H)+: m/z=380.0.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[F:9][C:10]([F:23])([F:22])[C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[NH2:14]>N1C=CC=CC=1>[F:9][C:10]([F:22])([F:23])[C:11]1[CH:12]=[C:13]([NH:14][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=S(=O)(CCCCl)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 69 %

Procedure:
A solution of 3-chloropropanesulfonyl chloride (5.0 g) and 3,5-bis(trifluoromethyl)aniline (6.47 g) in pyridine (50 ml) was stirred at room temperature for 16 hr. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 95:5-60:40) to give the title compound (7.20 g, yield 69%) as a pale-brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])C=CC(O)=O)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=1.[OH:32][C:33]1C2N=NNC=2C=[CH:35][CH:34]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:20][C:17]([C:14]1[CH:13]=[C:7]([C:34](=[CH2:35])[C:33]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=2)=[O:32])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:15]=1[OH:16])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Reactant: Oc1cccc2[nH]nnc12
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: C=C(C(=O)Nc1ccc(O)c([N+](=O)[O-])c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.9 %

Procedure:
1.78 g (6.4 mmoles) of 3,5-di-tert-butyl-4-hydroxycinnamic acid, 0.99 g (6.4 mmoles) of 4-amino-2-nitrophenol, previously diluted in 10 ml of DNMF, 0.86 g (6.4 mmoles) of hydroxybenzotriazol and 1.32 g (6.4 mmoles) of dicyclohexylcarbodiimide are introduced into a 50 ml flask containing 10 ml of THF. The reaction medium is agitated for 15 hours at ambient temperature, the precipitate which appears is filtered and rinsed with ethyl acetate. After concentration of the solution under reduced pressure, the residue is diluted in 20 ml of ethyl acetate and the insoluble part is filtered again. The filtrate is washed with 20 ml of a saturated solution of sodium carbonate followed by 20 ml of water and 20 ml of a saturated solution of sodium chloride. After drying over sodium sulphate, the organic solution is filtered and concentrated to dryness under reduced pressure. The residue is purified on a silica column (eluant: heptane/ethyl acetate: 8/2). The pure fractions are collected and concentrated under vacuum to produce 1.95 g (47%) of the expected compound in the form of a yellow-orange powder. Melting point: 231-232° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][NH:20]3)[C:7]1=[O:26].C([OH:32])(C)(C)C>[Zn]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]3[C:17]=2[CH2:18][C:19](=[O:32])[NH:20]3)[C:7]1=[O:26]
Reactant: COC(=O)CCn1c(=O)n(Cc2cc(Cl)cc3[nH]ccc23)c2ccccc21
Reactant: CC(C)(C)O
Agent: [Zn]
Product: COC(=O)CCn1c(=O)n(Cc2cc(Cl)cc3c2CC(=O)N3)c2ccccc21
Yield: 36 %

Procedure:
3-[3-(6-Chloro-1H-indol-4-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-propionic acid methyl ester (248 mg, 0.64 mmol) is dissolved it tert-butanol (20 mL) at 40° C. The reaction is stirred and pyridiniumtrbromide is added portion wise over 5 minutes. The reaction is stirred for 10 minutes and concentrated in vacuo. The crude material is dissolved in acetic acid (10 mL) and zinc powder (211 mg, 3.2 mmol)is added to the reaction. The reaction is stirred at room temperature for one hour, then the solvent evaporated in vacuo. The residue is taken up in dimethyl sulfoxide and filtered. The crude material is purified by preparative reverse phase LC to give the title compound (34 mg 0.09 mmol, 36%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH2:28])[C:19]2=[O:29])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.CO>C(O)C>[CH:30]1([C:33]([NH:28][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:25]=2[C:26](=[O:27])[N:18]([C@@H:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:19]3=[O:29])=[O:34])[CH2:32][CH2:31]1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Reactant: O=C(Cl)C1CC1
Solvent: CO
Solvent: CCO
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A stirred mixture of 2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-aminoisoindoline-1,3-dione (1.3 g, 3.1 mmol) and cyclopropane carbonyl chloride (3 mL) was heated to reflux for 45 min. To the cooled mixture was added methanol (10 mL) at 0° C. and the mixture stirred for 30 min. The solvent was removed in vacuo to give an oil. The oil was stirred in ethanol (10 mL) for 2 h to give a suspension. The suspension was filtered and the solid washed with ethanol to give cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}carboxamide as a white solid (1.3 g, 86% yield); mp, 140-141° C.; 1H NMR (CDCl3) δ 0.92-0.99 (m, 2H, 2CHH), 1.11-1.17 (m, 2H, 2CHH), 1.48 (t, J=6.9 Hz, 3H, CH3), 1.61-1.71 (m, 1H, CH), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.12 (q, J=7.1 Hz, 2H, CH2), 4.57 (dd, J=10.4, 14.3 Hz, 1H, CHH), 5.89 (dd, J=4.4, 10.3 Hz, 1H, NCH), 6.84-6.88 (m, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.48 (d, J=7.2 Hz, 1H, Ar), 7.65 (t, J=7.4 Hz, 1H, Ar), 8.76 (d, J=8.5 Hz, 1H, Ar), 9.69 (s, 1H, NH); 13C NMR (CDCl3) δ 8.71, 14.62, 16.16, 41.58, 48.59, 54.60, 55.89, 64.50, 111.49, 112.44, 114.83, 117.91, 120.26, 124.99, 129.27, 130.99, 136.02, 137.77, 148.63, 149.76, 167.49, 169.52, 172.79; Anal Calcd for C24H26N2O7S: C, 59.25; H, 5.39; N, 5.76. Found: C, 58.92; H, 5.21; N, 5.56.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:31])[CH2:29][OH:30])=[CH:24][C:23]=1[O:32][CH3:33].C([O-])(O)=O.[Na+].CN1CCCC1=O>O>[F:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:31])[CH2:29][OH:30])=[CH:24][C:23]=4[O:32][CH3:33])[CH2:6][CH2:5]3)=[N:8][O:9][C:10]=2[CH:15]=1
Reactant: COc1cc(C(=O)CO)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)CO)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 3-(4-piperidinyl)-6-fluoro-1,2-benzisoxazole (1.3 g, 5.8 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2-hydroxyethanone (1.5 g, 5.8 mmol), NaHCO3 (1.5 g) and 1-methyl-2-pyrrolidinone (50 ml) was stirred under N2 at 100° C. for 6 hours. The reaction was poured into H2O, and the aqueous suspension was extracted with EtOAc. The extract was washed (H2O), dried (MgSO4) and concentrated to afford the product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:36])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31][CH2:32][C:33]([O-:35])=[O:34])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[Na+].[NH2:38][OH:39].Cl>O>[OH:36][C:6]1[CH:5]=[CH:4][C:3]([C:1](=[NH:2])[NH:38][OH:39])=[CH:8][C:7]=1[S:9]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=1[O:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:10])=[O:11]
Reactant: NO
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)[O-])c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C(=N)NO)ccc2O)c(OCC(=O)O)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
Method 2) To a stirred solution of 117 g of sodium [4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate in 1.17 L of water was added 56 g of 50% aqueous hydroxylamine solution at room temperature, and the mixture was stirred at 70° C. for 4 hours. To the reaction mixture was added dropwise 1 mol/L hydrochloric acid at room temperature, and the mixture was stirred at the same temperature over night. The obtained solid was collected by filtration to give 110 g of [4-[2-[2-hydroxy-5-(N-hydroxy-carbamimidoyl)benzenesulfonylamino]ethyl]-2′-methane-sulfonylbiphenyl-3-yloxy]acetic acid.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:14](Cl)=[N:15][OH:16].[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([Cl:31])[CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]2([C:27]([F:30])([F:28])[F:29])[O:16][N:15]=[C:14]([C:3]3[CH:4]=[CH:5][C:6]4[B:7]([OH:13])[O:8][C:9]([CH3:12])([CH3:11])[C:10]=4[C:2]=3[F:1])[CH2:26]2)[CH:22]=[C:21]([Cl:31])[CH:20]=1
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)c(F)c21
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c(F)c21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of the crude compound 4-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (180 mg. 0.70 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (203 mg, 0.84 mmol) in DMF (5 mL) at rt was added TEA (117 μL, 0.84 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol [80 mg; yield 24.8% over the last 3 steps] as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.479 (s, 1H), 7.810 (t, J=1.5 Hz, 1H), 7.753 (t, J=7.5 Hz, 1H), 7.671 (d, J=1.5 Hz, 2H), 7.582 (d, J=7.5 Hz, 1H), 4.376 (d, J=18.0 Hz, 1H), 4.270 (d, J=18.0 Hz, 1H), 1.55 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=462.0 (M+1, ESI+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[CH3:24])=[CH:4][CH:3]=1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].N(C)(C1CCCCC1)C1CCCCC1>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccccc2c1CCN1CCCC1c1ccc(Br)cc1
Reactant: C=CC(=O)OC
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCc2c(C)[nH]c3ccccc23)cc1
Yield: 63.2 %

Procedure:
A solution of 3-{2-[2-(4-bromo-phenyl)-pyrrolidin-1-yl]-ethyl}-2-methyl-1H-indole (630 mg, 1.63 mmol), methyl acrylate (286 mg, 3.26 mmol), Pd2(dba)3 (14.9 mg, 0.0162 mmol), P(t-Bu)3HBF4 (18.9 mg, 0.0652 mmol) and Cy2NMe (414 μL, 1.95 mmol) in dioxane (10 mL) was heated at 100° C. by microwave for 60 minutes. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to provide a crude product, which was purified on silica gel column chromatography to give (E)-3-(4-{1-[2-(2-Methyl-1H-indol-3-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester (400 mg, 63%). LCMS (m/z): 388.97 (M+1).
Reaction SMILES: [CH2:1]([P:3]([OH:9])([CH2:5][C:6]([OH:8])=[O:7])=[O:4])[CH3:2].[OH-].[Na+:11]>>[Na+:11].[CH2:1]([P:3]([OH:9])([CH2:5][C:6]([O-:8])=[O:7])=[O:4])[CH3:2]
Reactant: CCP(=O)(O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCP(=O)(O)CC(=O)[O-]
Yield: 98 %

Procedure:
An aqueous solution of 304 g (2 mol) of 2-(ethylhydroxyphosphinyl)acetic acid (produced according to Example 10) is reacted with about 160 g of a 50% strength aqueous solution of sodium hydroxide and the water is distilled off in vacuo to obtain 384 g (98% of theory) of 2-(ethylhydroxyphosphinyl)acetic acid sodium salt as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]=2[C:28]([O:30]CC)=[O:29])=[CH:5][CH:4]=1.[OH-].[Na+].O>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]=2[C:28]([OH:30])=[O:29])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c2cccnc2n1Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c(C(=O)O)n(Cc3ccc4c(c3)OCO4)c3ncccc23)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl 3-(4-methoxyphenyl)-1-(3,4-methylenedioxybenzyl)-pyrrolo[2,3-b]pyridine-2-carboxylate in EtOH with aqueous 1 N NaOH is stirred under an argon atmosphere first at room temperature then at reflux temperature. The reaction mixture is cooled to room temperature then poured into H2O and the solvent volume reduced in vacuo. The aqueous solution is extracted with Et2O and the Et2O extract discarded. The aqueous layer is acidified with 6 N HCl and the product extracted into EtOAc. The organic extract is washed with H2O then saturated aqueous NaCl, dried (Na2SO4) and the solvent removed in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[O:23][CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[S:44]1[CH:48]=[CH:47][N:46]=[C:45]1[CH:49]([NH2:51])[CH3:50]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:51][CH:49]([C:45]2[S:44][CH:48]=[CH:47][N:46]=2)[CH3:50])=[O:42])=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3OC)c2cc1OC
Reactant: CC(N)c1nccs1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4nccs4)cc3OC)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (28 mg, yield 62%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2].Cl[CH2:19][C:20]([CH3:22])=[CH2:21].C(O)(=O)C>ClCCl.[Cl-].[Zn+2].[Cl-]>[C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]2[O:14][C:20]([CH3:22])([CH3:21])[CH2:19][C:7]=2[C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)C)cc(O)cc1C(C)C
Reactant: C=C(C)CCl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)Oc1c(C(C)C)cc2c(c1C(C)C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.5 %

Procedure:
Under argon atmosphere, 294 mg of 4-acetoxy-3,5-diisopropylphenol was dissolved in 10 ml of anhydrous dichloromethane, 2.25 g of 3-chloro-2-methyl-1-propene, 202 mg of anhydrous zinc chloride and 0.5 ml of acetic acid were added, and the mixture was stirred at room temperature for 3 days. After the reaction was quenched with water, the reaction solution was extracted with hexane. The organic layers were washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1% ethyl acetate) to give 316 mg of 5-acetoxy-2,2-dimethyl-4,6-diisopropyl-2,3-dihydrobenzofuran as a yellow oil (yield 88%).