Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH:8]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])[C:9]([Cl:12])([Cl:11])[Cl:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]=[C:25]=[O:26].O>CC(C)=O.C(N(CC)CC)C>[O:1]([CH:8]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:25](=[O:26])[NH:24][CH3:23])[C:9]([Cl:10])([Cl:11])[Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: O=C(NC(Oc1ccccc1)C(Cl)(Cl)Cl)c1ccccc1O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CNC(=O)Oc1ccccc1C(=O)NC(Oc1ccccc1)C(Cl)(Cl)Cl
Reaction time: 8 h
Yield: 36.3 %

Procedure:
10 g of N-(1'-phenoxy-2',2',2'-trichloroethyl)-2-hydroxybenzamide and 1.8 g of methyl isocyanate were dissolved in 150 mml of acetone. Two or three drops of triethylamine were added to the solution under stirring. After allowing to stand overnight, the reaction mixture was poured into water and the crystals which thus resulted were recrystallized from methanol to obtain 4.2 g of N-(1'-phenoxy-2',2',2'-trichloroethyl)-2-methylcarbamoyloxybenzamide as white crystals. Melting point: 138°-141° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([CH3:16])[CH:6]=1)=O.[CH3:17][N:18]([CH3:23])[C:19](=[S:22])[NH:20][NH2:21]>C(O)C>[BrH:1].[C:11]([C:9]1[C:8]([OH:15])=[C:7]([CH3:16])[CH:6]=[C:5]([C:3]2[CH2:2][S:22][C:19]([N:18]([CH3:23])[CH3:17])=[N:20][N:21]=2)[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: CN(C)C(=S)NN
Solvent: CCO
Product: Br
Product: Cc1cc(C2=NN=C(N(C)C)SC2)cc(C(C)(C)C)c1O

Procedure:
A solution of 11.7 g (0.041 mol) of 2-bromo-1-(5-tert.butyl)-3-methyl-4-hydroxyphenyl)-ethanone from step (a) and 4.4 g (0.037 mol) of 4,4-dimethylthiosemicarbazide in 130 ml of ethanol was refluxed briefly. After cooling, the reaction mixture was worked up corresponding to Example 1(b).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21]C(=O)OC(C)(C)C)[CH:9]([OH:20])[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[NH2:21][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)[OH:20]
Reactant: CC(C)(C)OC(=O)NC(c1ccc(F)cc1)C(O)c1cccc2cccnc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(c1ccc(F)cc1)C(O)c1cccc2cccnc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 134 %

Procedure:
2.78 g (7.27 mmol) of tert-butyl [1-(4-fluorophenyl)-2-hydroxy-2-quinolin-8-ylethyl]carbamate were dissolved in 75 ml of methylene chloride and cooled to 0° C. 18 ml of an HCl solution (4N) in dioxane were added, and the mixture was stirred at 0° C. for 20 minutes and allowed to reach room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was treated with diisopropyl ether. Filtration was followed by washing with diisopropyl ether and pentane and drying in vacuo. 2.75 g of 2-amino-2-(4-fluorophenyl)-1-quinolin-8-ylethanol were obtained as hydrochloride (diastereoisomer mixture: 85/15) as a pale yellow very hygroscopic powder (yield: quantitative). The substance was used without further purification for the next stage.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:18])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)n1ccc2cc(C(=O)O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(ccn2C(C)C)c1

Procedure:
A mixture of 2.20 g (8.97 mmol) of isopropyl 1-isopropyl-5-indolecarboxylate, 100 ml of 2N sodium hydroxide solution and 100 ml of ethanol was refluxed for an hour. The solvent was then distilled off under reduced pressure. Thereafter water was added to the residue and the resulting mixture was acidified with conc. hydrochloric acid. The precipitated solid was filtered and dried under reduced pressure to give 2.00 g of crude 1-isopropyl-5-indole-carboxylic acid. The reaction was carried out in a manner similar to Reference Example 4 using 2.00 g of the crude 1-isopropyl-5-indolecarboxylic acid, 0.44 g (11.1 mmol) of 60% sodium hydride, 2.87 g (20.2 mmol) of methyl iodide and 50 ml of dimethyl-formamide. Thus, 1.64 g (84.2%; yield based on isopropyl 1-isopropyl-5-indolecarboxylic acid) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:22])[N:14]([CH3:21])[N:15]=[C:16]([CH3:20])[C:17]=1[S:18]C)[CH3:2].CN1CCCC1=[O:29].C[O-].[Na+]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:22])[N:14]([CH3:21])[N:15]=[C:16]([CH3:20])[C:17]=1[OH:29])[CH3:2].[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:22])[N:14]([CH3:21])[N:15]=[C:16]([CH3:20])[C:17]=1[SH:18])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(SC)c(C)nn(C)c1=O
Reactant: CN1CCCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Product: CCc1cc(C)cc(CC)c1-c1c(S)c(C)nn(C)c1=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a test-tube (outside diameter: 21 mm φ×overall length: 160 mm), 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfanyl-2,3-dihydro-3-pyridazinone ((2-4)-(1)-39) (300 mg), N-methyl-2-pyrrolidone (875 mg), and sodium methoxide (410 mg) were added, and stirred at 90° C. for 16 hours. After the mixture was cooled to room temperature, water was added and washed with toluene. To the aqueous layer, 10 w/w % of hydrochloric acid was added to adjust pH to 1, and extracted with toluene 3 times. The organic layers were combined and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane:ethyl acetate=3:1) to give 185 mg of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39) and 33 mg of 4-(2,6-diethyl-4-methylphenyl)-5-mercapto-2,6-dimethyl-2,3-dihydro-3-pyridazinone (30-a).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:9]([C:10](O)=[O:11])[CH:8]=1)=[O:2].[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>O1CCCC1.CN(C)C=O>[CH:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:9]([C:10]([NH:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[O:11])[CH:8]=1)=[O:2]
Reactant: Nc1nnn[nH]1
Reactant: O=COCCOc1cc(C(=O)O)nc2ccccc12
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=COCCOc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12

Procedure:
N,N'-Carbonyldiimidazole (1.55 g) was added to 4(2-formyloxyethoxy)quinaldic acid (2.5 g) in hot tetrahydrofuran (200 ml) and the solution was heated under reflux for 1.5 hours. 5-Aminotetrazole (0.85 g) in dimethylformamide (4 ml) was added and the mixture was heated under reflux for 2.5 hours. 4(2-Formyloxyethoxy)-N(1H-tetrazol- 5-yl)quinaldamide was filtered off and dried, m.p. 263° .
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]I)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH:18](=[C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH:18](=[C:22]1[CH2:27][CH2:26][N:25]([CH2:13][C@@H:12]([CH3:15])[CH2:11][N:6]2[C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=3[O:9][CH2:8][C:7]2=[O:10])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Reactant: CCCC=C1CCNCC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)COc3cc(F)ccc32)CC1
Yield: 73 %

Procedure:
The compound (S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20)_(0.515 g, 1.47 mmol) and 4-butylidenepiperidine (0.205 g, 1.47 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF29) (0.393 g, 73%). 1H NMR (CDCl3) δ 7.17-7.12 (m, 1H), 6.74-6.69 (m, 2H), 5.15-5.11 (t, J=7.2 Hz, 1H), 4.61 (q, J=15.2 Hz, 2H), 4.04-3.92 (m, 2H), 2.48-2.40 (m, 2H), 2.32-2.13 (m, 9H), 1.96 (q, J=7.2 Hz, 2H), 1.38-1.30 (m, 2H), 0.91-0.86 (m, 6H); 13C NMR (CDCl3) δ 164.1, 158.9 (d, J=243.4 Hz), 146.5 (d, J=11.9 Hz), 136.1, 125.2 (d, J=3.0 Hz), 128.9, 116.2 (d, J=22.7 Hz), 109.0 (d, J=22.7 Hz), 105.2 (d, J=26.2 Hz), 67.8, 63.7, 56.5, 55.7, 54.6, 36.3, 29.3, 28.5, 23.3, 17.1, 13.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Br:12]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1C
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a solution of 2-methyl-benzoic acid methyl ester (4.58 g, 30.5 mmol) in CCl4 (75 mL) was added N-bromosuccinimide (5.79 g, 32.5 mmol) followed by 1,1′-azobis(cyclohexanecarbonitrile) (1.42 g, 5.80 mmol). The resultant mixture was refluxed for 6 hours then cooled to room temperature, filtered through filter paper, and concentrated. Purification of the crude material by column chromatography on silica gel (20:1 :hexanes-EtOAc) provided 5.44 g (78%) of 2-bromomethyl-benzoic acid methyl ester as a colorles oil. 1H NMR (CDCl3) δ 3.95 (s, 3H), 4.96 (s, 2H), 7.36-7.50 (m, 3H), 7.97 (d, 1H, J=7.8 Hz).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](O)(=[O:11])C.C(N)=O>O>[C:1]1([NH:7][NH:8][CH:9]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)O
Solvent: NC=O
Solvent: O
Product: O=CNNc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Phenylhydrazine (75 g) was added dropwise at <20° C. to stirred acetic acid (198 ml). When the addition was complete, formamide (27.9 ml) was added in one portion, and the mixture was stirred at ambient temperature for 4 hours. Water (225 ml) was added, and the resulting solid was collected by filtration, washed well with water, and dried in vacuo to give N'-phenylformohydrazide (68.8 g) as a cream solid, m.p. 138-143° C.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1.N1C=CC=NC=1>CC(C)=O>[CH:1]1([N:6]([C:22]2[C:23]([N+:27]([O-:29])=[O:28])=[CH:24][N:25]=[C:20]([Cl:19])[N:21]=2)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)CCNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1cncnc1
Solvent: CC(C)=O
Product: COC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
Methyl 3-(cyclopentylamino)propanoate (838 mg, 0.005 mol) and K2CO3 (676 mg, 0.005 mol) were added to acetone (5 ml) and the resulting mixture cooled to 0° C. using an ice-bath before the addition of 2,4-dichloro-5-nitropyrimidine (1.044 g, 1.1 eq). The reaction mixture (RM) was then warmed to rt and stirring continued for an additional 16h before the addition of a further 0.12 eq of the pyrimidine. Stirring was then continued for a further 3h. The RM was then evaporated under reduced pressure and the product extracted using EtOAc/H2O. The organic extracts were combined, washed with sat NaCl, dried using MgSO4, filtered and the filtrate evaporated under reduced pressure and further dried in vacuo to give the product as a brown oily residue (1.04 g, 65%); Rt=16 min (Vydac 1); ME+ve: 329.1.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][O:5][CH2:6][CH2:7]O)[CH3:2].S(Cl)([Cl:15])=O>>[CH2:1]([CH:3]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][O:5][CH2:6][CH2:7][Cl:15])[CH3:2]
Reactant: CCCCC(CC)COCCO
Reactant: O=S(Cl)Cl
Product: CCCCC(CC)COCCCl
Yield: 94.2 %

Procedure:
500 g (2.81 mol) of 2-(2-ethylhexyloxy)ethanol and 500 g of thionyl chloride were placed in a 2-liter four-neck flask and refluxed with heat for 2 hours. Subsequently, a distillation under reduced pressure was conducted to obtain 510 g of 2-(2-ethylhexyloxy)ethylchloride as a colorless oil.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([C:12]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=1[C:14](O)=[O:15])(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH3:22][O:21][C:18]1[CH:17]=[C:13]2[C:12]([C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:2][NH:3][C:14]2=[O:15])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)c2ccccc2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc2c(-c3ccccc3)n[nH]c(=O)c2c1
Yield: 13.9 %

Procedure:
10.55 g (210 mmol) of hydrazine hydrate are added to a solution of 5.4 g of 2-benzoyl-5-methoxy-benzoic acid in 50 mL of ethanol, and the mixture is refluxed for 2 hours 30 minutes. The reaction medium is cooled and then filtered. The precipitate obtained is washed with ethanol and then dried under reduced pressure at 40° C. 740 mg of product are obtained in the form of a white solid.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C@H:9]2OC(=O)N[C@@H:10]2C2C=CC=C(C#CC3C=CC=CC=3)C=2)[CH:6]=[CH:7][CH:8]=1.Br[C:30]1[CH:31]=[C:32]([C@@H:36]2[C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[O:39][C:38](=[O:48])[NH:37]2)[CH:33]=[N:34][CH:35]=1.C1(C#C)C=CC=CC=1>>[F:47][C:43]1[CH:42]=[C:41]([C@H:40]2[O:39][C:38](=[O:48])[NH:37][C@@H:36]2[C:32]2[CH:33]=[N:34][CH:35]=[C:30]([C:10]#[C:9][C:5]3[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=3)[CH:31]=2)[CH:46]=[CH:45][CH:44]=1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cccc(F)c2)O1
Solvent: C#Cc1ccccc1
Product: O=C1N[C@H](c2cncc(C#Cc3ccccc3)c2)[C@@H](c2cccc(F)c2)O1

Procedure:
Prepared according to the same procedure as (+)-(4R,5R)-5-(3-methoxyphenyl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one, starting with (4R,5R)-4-(5-bromopyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one and phenylacetylene. 1H-NMR (CDCl3, 500 MHz) δ 8.78 (bs, 1H), 8.42 (bs, 1H), 7.90 (m, 1H), 7.57 (m, 2H), 7.35-7.45 (m, 4H), 7.02-7.17 (m, 3H), 6.83 (bs, 1H), 5.30 (d, J=7.3, 1H), 4.83 (d, J=7.3, 1H). 13C-NMR (CDCl3, 126 MHz) δ 164.2, 162.2, 158.6, 152.9, 146.9, 139.1 (d, J=7.7), 136.4, 133.7 (br), 131.9, 131.1 (d, J=8.6), 129.3, 128.7, 122.1, 121.6 (d, J=2.9), 116.6 (d, J=21), 113.0 (d, J=23), 94.2, 85.2, 84.9, 62.5. Mass spec.: 359.3 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][OH:13])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[CH3:18][N-:19][CH3:20].[CH3:21][N-:22][CH3:23].C[N-]C.C[N-]C.[Ti+4:30]>C1(C)C=CC=CC=1>[CH3:18][N-:19][CH3:20].[CH3:21][N-:22][CH3:23].[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][O:13][Ti+2:30])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CC1=C(C)C(c2ccccc2CO)C(C)=C1C
Reactant: [Ti+4]
Agent: C[N-]C
Solvent: Cc1ccccc1
Product: CC1=C(C)C(c2ccccc2CO[Ti+2])C(C)=C1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzylalcohol (0.3 g, 1.3 mmol) in toluene (5.2 mL) was added dropwise a solution of tetrakis(dimethylamido)titanium (0.29 g, 1.3 mmol) in toluene (1.7 mL) at −30° C. The mixture was stirred for 30 min at room temperature and then at 110° C. for 5 hrs. The solvent was distilled off to give 2-(2,3,4,5-tetramethylcyclopentadienyl)benzyloxytitanium bis(dimethylamide) (0.30 g, yield 83.3%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:10][C:11]=2[NH2:17].[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26].C(N(CC)CC)C.Cl[S:37]([C:40]1[CH:41]=[C:42]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]=[CH:44][CH:45]=1)(=[O:39])=[O:38]>C(#N)C>[NH2:17][C:11]1[N:10]=[C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:23]([CH2:24][C:25]([OH:27])([CH3:28])[CH3:26])[S:37]([C:40]1[CH:41]=[C:42]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]=[CH:44][CH:45]=1)(=[O:39])=[O:38]
Reactant: CC(C)(O)CN
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCBr)c2n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CC(C)(C)O)S(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1

Procedure:
The compound obtained in Example 2-13 step (i) (371 mg) and 1-amino-2-methylpropane-2-ol (400 mg) were dissolved in acetonitrile (5 ml) and the same manner to Example 2-19 using triethylamine (0.055 ml) and methyl [3-(chlorosulfonyl)phenyl]acetate (93 mg) was conducted to give the titled compound as a white solid. Yield: 140 mg (24%); mp 192-193° C., MS APCI+ve 579 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:18][S:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)=[O:20])([OH:17])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].O1CCCC1.C[Si](C)(C)[O-].[K+].[Cl:42]CCl>>[ClH:42].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][C:14]([CH2:18][S:19]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)=[O:20])([OH:17])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: ClCCl
Reactant: COC(=O)c1ccc(S(=O)CC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cl
Product: N#Cc1ccc(CCN2CCC(O)(CS(=O)c3ccc(C(=O)O)cc3)CC2)cc1
Reaction time: 4 h

Procedure:
To a solution of the compound (150 mg) obtained in Example 44 in a mixture of anhydrous tetrahydrofuran (8 mL) and anhydrous dichloromethane (8 mL) was added 90% potassium trimethylsilanolate (125 mg) at room temperature, followed by stirring at the same temperature under nitrogen atmosphere for four hours. Insoluble matter was collected by filtration, was washed with dichloromethane and was dried. The insoluble matter was dissolved in water (1 mL) and was then treated with 1 N hydrochloric acid to adjust the pH of the mixture to 5 to 5.6. The precipitate was collected by filtration, washed with water and dried. The precipitate was suspended in methanol, and mixed with 10% solution of hydrogen chloride in methanol, then the mixture was stirred at room temperature, and the solvent was removed under reduced pressure. The residue was suspended in acetonitrile, washed at 40 to 50° C. with stirring for one hour, was collected by filtration, and dried under reduced pressure to yield the titled compound (58 mg) as crystals.
Reaction SMILES: C[O:2][C:3]1C=C(NS(C)(=O)=O)C=[CH:7][C:8]=1NC1C2C=CC=CC=2N=C2C=CC=CC=12.[C:29]([O:34][C:35](=[O:39])[CH:36]([CH3:38])[OH:37])(=[O:33])[CH:30]([CH3:32])[OH:31].CC(C)=[O:42]>>[C:3]([C:36]([CH3:38])([OH:37])[C:35]([OH:34])=[O:39])(=[O:2])[CH:8]([CH3:7])[OH:42].[C:29]([OH:34])(=[O:33])[CH:30]([CH3:32])[OH:31]
Reactant: CC(C)=O
Reactant: CC(O)C(=O)OC(=O)C(C)O
Reactant: COc1cc(NS(C)(=O)=O)ccc1Nc1c2ccccc2nc2ccccc12
Product: CC(O)C(=O)C(C)(O)C(=O)O
Product: CC(O)C(=O)O
Yield: 20 %

Procedure:
NMR spectrum of the product was consistent for a monolactate salt of m-AMSA containing 0.6 mole of acetone per mole of salt. The product contained as an impurity approximately 0.1 mole % of lactyl lactate salt which is formed due to the presence of up to 20% of lactyl lactic acid in ACS purity DL-lactic acid.*
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].[CH2:6]=[CH2:7].[C:8](OOC(=O)[C:19]1[CH:24]=CC=CC=1)(=O)[C:9]1C=CC=CC=1.O.O.O.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Al+3:39].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O>[CH2:8]([P:2]([CH2:6][CH3:7])(=[O:4])[O-:3])[CH3:9].[Al+3:39].[CH2:6]([P:2]([CH2:24][CH3:19])(=[O:4])[O-:3])[CH3:7].[CH2:8]([P:2]([CH2:6][CH3:7])(=[O:4])[O-:3])[CH3:9]
Reactant: O=[PH2][O-]
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: C=C
Agent: O=[N+]([O-])[O-]
Agent: [Al+3]
Agent: [Na+]
Solvent: O
Product: CCP(=O)([O-])CC
Temperature: 100 °C

Procedure:
1500 g (14 mol) of sodium hypophosphite monohydrate were dissolved in 7.5 kg of water and used as initial charge in a 16 l jacketed pressure reactor composed of enameled steel. Once the reaction mixture had been heated to 100° C., ethylene was introduced by way of a reducing valve set to 6 bar until saturation had been reached in the reactor. A solution of 49 g (1 mol %) of dibenzoyl peroxide (70% by weight in water) in 300 g of water was uniformly metered in over a period of 6 h with constant stirring, at an ethylene pressure of 6 bar and a temperature of from 100 to 110° C. After a continued reaction time of 1 h, depressurization of the reactor, and cooling to about 90° C., 1725 g (4.67 mol of aluminum) of aluminum nitrate nonahydrate dissolved in 1275 g of water were added over a period of 60 min. The resultant solid was then filtered off, washed with 2 l of hot water and vacuum-dried at 130° C. Yield: 1697 g (92.2% of theory).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([C:18]1[C:19]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[CH:36]=[N:35][CH:34]=[CH:33]3)=[N:20][O:21][C:22]=1[NH:23][C:24](=O)OCC=C)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH:40]1C2C(=CC(C3C=C(NC(=O)OCC=C)ON=3)=CC=2)C=C[N:41]=1>C(#N)C>[NH2:10][C@@H:9]([CH2:8][C:7]1[C:1]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:41][CH:40]=1)[CH2:24][NH:23][C:22]1[O:21][N:20]=[C:19]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[CH:36]=[N:35][CH:34]=[CH:33]3)[C:18]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CCOC(=O)Nc1onc(-c2ccc3cnccc3c2)c1Cc1ccccc1
Reactant: N#CCCc1ccccc1
Reactant: C=CCOC(=O)Nc1cc(-c2ccc3cnccc3c2)no1
Solvent: CC#N
Product: N[C@H](CNc1onc(-c2ccc3cnccc3c2)c1Cc1ccccc1)Cc1c[nH]c2ccccc12

Procedure:
This compound was synthesized in an analogous manner to Example 32 but using 3-phenylpropionitrile (commercially available from Acros Organics Order Number 17399) instead of acetonitrile in the preparation of allyl 4-benzyl-3-(isoquinolin-6-yl)isoxazol-5-ylcarbamate according to Scheme 6 instead of allyl 3-(isoquinolin-6-yl)isoxazol-5-ylcarbamate. MS m/z: 474 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 9.24 (s, 1H), 8.44 (d, J=5.87 Hz, 1H), 8.11 (d, J=8.61 Hz, 1H), 7.93 (s, 1H), 7.75 (dd, J=8.61, 1.37 Hz, 1H), 7.70 (d, J=5.87 Hz, 1H), 7.55 (d, J=7.82 Hz, 1H), 7.39 (d, J=8.02 Hz, 1H), 7.04-7.24 (m, 8H), 3.82 (m, 3H), 3.60-3.73 (m, 2H), 3.21-3.25 (m, 1H), 3.13 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[CH2:6][CH2:7][C:8](=[O:11])[C:9]=2[CH:10]=1.O.ON1C2C=CC=CC=2N=N1.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[C:4]([C:12]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:14])[CH:3]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1cc(Br)cc2c1CCC2=O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)c1cc(Br)cc2c1CCC2=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of Example 6 (250 mg, 0.98 mmol) in N,N-dimethylformamide (5 mL) was added N-cyclohexylcarbodiimide-N′-methyl polystyrene (761 mg, 1.5 mmol) and 1-hydroxybenzotriazole hydrate (255 mg, 1.7 mmol). The mixture was agitated at room temperature for about 5 minutes, treated with t-butyl glycinate (150 mg, 1.2 mmol), shaken for about 15 hours, and filtered. The filtrate was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (1:1) as the moblie phase to provide the desired product. MS (APCI): m/z 311, 313 (M+H-tBu)+.