Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]([NH:33][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:19])=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)[N:3]=1
Reactant: NC1CCCC1
Reactant: CN1CCN(c2cc(N3CCc4ccc(C(=O)O)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(C(=O)NC5CCCC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid and cyclopentylamine (Aldrich Cat. No. C115002). LCMS (M+H)+: m/z=436.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[N:6]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([NH:11]C(=O)C)=[CH:9][CH:8]=2)[CH2:4][CH:3]1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[K+]>C(O)C>[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH2:4][CH:3]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:2]([CH3:23])([CH3:1])[N:6]=2)=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1ccc(C2=NC(C)(C)C(c3ccncc3)C2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)N=C(c2ccc(N)cc2)CC1c1ccncc1

Procedure:
5.8 G. of 4'-[5,5-dimethyl-4-(4-pyridyl)-1-pyrrolin-2-yl]-acetanilide are treated with a solution of 5.8 g. of potassium hydroxide in 58 ml. of ethanol and heated under reflux for 5 hours. Then the reaction mixture is evaporated under reduced pressure and the residue is treated with water. The resulting crystals are filtered and washed well with water. The mineral is dried and recrystallized from methanol/ether to yield 4-[2-(p-aminophenyl)-5,5-dimethyl-1-pyrrolin-4-yl]-pyridine of melting point 175°-178° C. The hydrochloride, recrystallized from methanol/ether, has a melting point of 290°-300° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[N:8]([CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2[nH]c1=O
Reactant: Fc1ccc(CBr)cc1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2n(Cc2ccc(F)cc2)c1=O

Procedure:
This compound was prepared from 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridin-3-carboxylic acid ethyl ester (121) and 4-fluorobenzyl bromide according to General Procedure B. Yield 210 mg (55%), MP 132° C.; 1H-NMR (DMSO-d6): δ 1.30 (t, J=7.2 Hz, 3H), 3.21 (m, 4H), 3.91 (m, 4H), 4.31 (q, J=7.2 Hz, 2H), 5.41 (s, 2H), 7.13-7.29 (m, 5H), 7.41 (d, J=6.0 Hz, 1H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (dd, J=4.8, 1.2 Hz, 1H), 8.57 (d, J=6.0 Hz, 1H), 9.09 (s, 1H); EIMS: 521 (M+1). Anal. (C27H25FN4O4S) C, H, N.
Reaction SMILES: [C:1]([C:6]1[CH:16]=[C:15]([C:17]([CH2:20][CH3:21])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10](O)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:24])=O>>[C:1]([C:6]1[CH:16]=[C:15]([C:17]([CH2:20][CH3:21])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([Cl:24])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1ccc(OCC(=O)O)c(C(C)(C)CC)c1
Reactant: O=S(Cl)Cl
Product: CCC(C)(C)c1ccc(OCC(=O)Cl)c(C(C)(C)CC)c1

Procedure:
2-(2,4-Di-t-pentylphenoxy)ethanoic acid (12.0 g, 0.041 mol) (CAS Registry Number 13402-96-5) and thionyl chloride (60 ml) were heated under reflux on a steam-bath for 1.5 h. The resulting yellow solution was allowed to cool before being distilled under reduced pressure to remove volatiles. The residue was dissolved in 60-80 petroleum-ether (200 ml) and the solution was distilled under reduced pressure to remove any remaining traces of volatiles, leaving 2-(2,4-di-t-pentyl-phenoxy)ethanoyl chloride as a red oil which was used without further purification.
Reaction SMILES: [C:1]1([B:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(O)O.[N+:13](C1C=C(B(O)O)C=CC=1)([O-:15])=[O:14]>>[N+:13]([C:4]1[CH:5]=[CH:6][C:1]([B:7]([OH:9])[OH:8])=[CH:2][CH:3]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: OB(O)c1ccccc1
Agent: OBO
Product: O=[N+]([O-])c1ccc(B(O)O)cc1
Yield: 60 %

Procedure:
The literature on this subject describes attempts to introduce the amino group into phenylboronic acid by nitrating the boronic acid and reducing the nitro group introduced. This provides an isomer mixture which, depending on the reaction conditions, consists mainly of ortho- or of meta-nitrophenylboronic acid (in each case 60–70% yield); para-nitrophenylboronic acid could only be obtained as a by-product in very small amounts, but could not be fully characterized. Ortho- and meta-aminophenylboronic acids were prepared in moderate yields by reducing the nitro compounds, either with iron(II) salts or hydrogen over platinum, and isolated as the carboxanilides (Seaman and Johnson, J. Am. Chem. Soc. 1931, 53, 713). In the nitration, a certain fraction of nitrobenzene and boric acid was always obtained, even though operation was effected at low temperatures (down to −30° C., see below). In the subsequent publication (Bean and Johnson, J. Am. Chem. Soc. 1932, 54, 4415), this loss of the boron group was even described as an exclusive reaction in the nitration of 4-methoxyphenylboronic acid. Here too, later functionalization of phenylboronic acids in the para-position failed completely. The sensitivity of the boron-carbon bond in aromatics toward electrophiles was demonstrated by Kuivila and Hendrickson (J. Am. Chem. Soc. 1952, 74, 5068) by brominolysis of phenylboronic acids. It was found that electron-deficient phenylboronic acids were more stable than electron-rich phenylboronic acids, which was later utilized to synthesize some boronic acids having electron-withdrawing substituents (Torssell, Meyer, Zacharias, Ark. Kemi 1957, 10, 35, 497). The same publication also describes the preparation of a 4-amino-3-nitrophenylboronic acid in a multistage sequence starting from tolylboronic acid. In this synthesis, tolylboronic acid was nitrated at low temperature (−40° C.), the methyl group was oxidized to the acid, an azide was introduced via the acid chloride, the former was decomposed by Curtius reaction to give the acetylamino group and this was hydrolyzed (14% overall yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[OH-].[Li+]>C1COCC1.O>[OH:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.6 %

Procedure:
To a stirred solution of methyl 2-hydroxy-2′-methyl-1,1′-biphenyl-4-carboxylate (12 g, 0.05 mol) in a mixture of THF/water (150 mL:15 mL) was added lithium hydroxide (6.23 g, 0.1485 mol) in portions. After being stirred at RT for 24 h, the reaction mass was evaporated to dryness and the residue diluted with little amount of water. The aqueous phase was acidified with conc.hydrochloric acid and extracted with EtOAc. Organic layer was washed with brine solution and was dried over Na2SO4. Evaporation of the solvents afforded the title compound as a white solid (10 g, 89%). 1H NMR (DMSO-d6, 400 MHz) δ 12.72 (1H, bs), 9.78 (1H, bs), 7.50 (1H, s), 7.41-7.43 (1H, m), 7.08-7.24 (5H, m), 2.09 (3H, s). LC/MS (Method A): 227 (M−H)−. HPLC (Method B), Rt 4.09 min (purity: 99.69%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=1.C([O:12][C:13](=[O:35])[C@@:14]([CH2:32][O:33][CH3:34])([CH3:31])[CH2:15][C@H:16]([NH2:30])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)C>>[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:19][C:18]([CH2:17][C@@H:16]([NH:30][C:7]([C:5]2[O:4][N:3]=[C:2]([OH:1])[CH:6]=2)=[O:9])[CH2:15][C@:14]([CH2:32][O:33][CH3:34])([CH3:31])[C:13]([OH:35])=[O:12])=[CH:23][CH:22]=1
Reactant: CCOC(=O)[C@](C)(COC)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(O)no1
Product: COC[C@](C)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(O)no1)C(=O)O

Procedure:
3-Hydroxy-isoxazole-5-carboxylic acid and (2S,4R)-4-amino-5-biphenyl-4-yl-2-methoxymethyl-2-methylpentanoic acid ethyl ester were reacted as described herein to yield the title compound (2.4 mg). MS m/z [M+H]+ calc'd for C24H26N2O6, 439.18. found 439.2.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.N#N.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC>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>[CH:14]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[CH2:15]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: Cc1ccccc1
Product: C=Cc1ccc2ccccc2n1
Temperature: 125 °C
Yield: 73.9 %

Procedure:
2-chloroquinoline (1-1) (1.00 g, 6.1 mmol) in toluene (25 mL) was sparged with N2 gas for 5 min, and tributyl(vinyl)stannane (2.52 g, 2.33 mL, 8.0 mmol) and tetrakis(triphenylphosphine)palladium (0.353 g, 0.31 mmol) were added. The mixture was heated at 125° C. for 1 h, then cooled and concentrated in vacuo. The residue was suspended in CH2Cl2 (20 mL) and purified by silica gel flash column chromatography (80 g cartridge), eluting with 0-30% EtOAc/hexanes over 20 min. The fractions containing the desired product (1-2) were pooled, and after solvent removal in vacuo, 700 mg (74%) of a clear oil were obtained. LC/MS: m/z (M+H)=156.0.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>O>[C:9]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)[CH:10]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: Cc1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccnc(-c2cccc(-c3ccccc3)c2)c1

Procedure:
9.0 g (0.05 mol) of 2-bromo-4-methylpyridine, 12.0 g (0.06 mol) of 3-biphenylboronic acid, 1.7 g (0.0015 mol) of Pd(Ph3)4, 19.0 g (0.135 mol) of K2CO3, 50 mL of DME and 50 mL of water. The reaction mixture was refluxed for 20 hours and separated on silica gel column. MS confirmed the desired product.
Reaction SMILES: [Br:1]Br.[OH:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH3:17])[CH:8]=1>C(O)(=O)C>[Br:1][C:8]1[C:9]([CH3:17])=[N:10][C:11]2[C:16]([C:7]=1[NH:6][CH2:5][CH2:4][OH:3])=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: BrBr
Reactant: Cc1cc(NCCO)c2ccccc2n1
Solvent: CC(=O)O
Product: Cc1nc2ccccc2c(NCCO)c1Br

Procedure:
Bromine (15.6 g) was added dropwise to a solution of N-(2-hydroxyetyl)-2-methyl-4-quinolinamine (26 g) in 400 ml of acetic acid. A solid separated which after one hour of stirring was filtered and dissolved in 400 ml of water. The free base was precipitated by adding 20% KOH solution until pH became 10. The solid was filtered and recrystallized from isopropanol. The yield was 14.5 g, mp 154°-155° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)=[C:6]([N+:22]([O-])=O)[CH:5]=[N:4]1)[CH3:2].[C:25]([O:29][C:30]([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])=[N:35][C:34]=1[C:45](O)=[O:46])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:36]1[S:37][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:34]([C:45](=[O:46])[NH:22][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[N:8]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)[N:35]=1
Reactant: CCn1ncc([N+](=O)[O-])c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Product: CCn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 72 %

Procedure:
Following the procedure for Example 506 starting with (R)-N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid gave (R)-tert-butyl 2-(2-fluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (330 mg, 72%). 1H-NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 8.66 (s, 1H), 8.15-8.05 (m, 1H), 7.45-7.35 (m, 1H), 7.30-7.15 (m, 3H), 6.31 (d, J=8 Hz, 1H), 4.25-4.15 (m, 1H), 4.07 (q, J=7 Hz, 2H), 3.43-3.31 (m, 2H), 3.25-3.15 (m, 2H), 2.25-2.10 (m, 2H), 2.10-1.70 (m, 4H), 1.57 (s, 9H) 1.47 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>CN(C)C=O>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH:5]=1)[C:10]([Cl:16])=[O:12]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Chloro-O-anisic acid (187 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2 hours. The excess oxalyl chloride was removed in vacuo to afford 5-chloro-2-methoxybenzoyl chloride.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[C:26]([CH3:34])[CH:25]=1.[NH4+].[Cl-]>C(Cl)Cl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:32])=[O:31])=[C:26]([CH3:34])[CH:25]=1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Br)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (1.86 g, 9.99 mmol, supplier Aldrich) and DIPEA (2.62 ml, 14.98 mmol) in dry DCM (20 ml) at 0° C. under argon was added 4-bromo-2-methylbenzenesulfonyl chloride (2.96 g, 10.99 mmol) and the resulting yellow solution allowed to warm to rt, then stirred at rt for 18 h. Semi-saturated NH4Cl (40 ml) was added, then the aq extracted with DCM (30 ml). The combined organics were passed through a hydrophobic frit, then concentrated in vacuo to give the title compound as a yellow gum that became a solid on standing (4.72 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:17]3)=[CH:12][CH:11]=2)O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:17]3)=[CH:12][CH:11]=2)[N:30]2[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]2=[O:31])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: OC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: 0 °C

Procedure:
To a suspension of (3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methanol (1.215 g, 3.49 mmol), phthalimide (566 mg, 3.85 mmol), and PS-PPh3 (loading 2.12 mmol/g; 3.29 g, 6.97 mmol) in dry THF (40 mL), cooled by ice/water, is added DIAD (830 μL, 852 mg, 4.22 mmol). The cooling bath is removed and the flask is vortexed at it for ld. More phthalimide (50 mg, 0.34 mmol), PS-PPh3 (300 mg, 0.636 mmol), and DIAD (80 μL, 82 mg, 0.41 mmol) are added, and vortexing is continued for 2d. The resin is filtered off on a glass frit (porosity M) and washed with CH2Cl2. The combined filtrates and washings are concentrated in vacuo and chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (1-22)→2% EtOAc in CH2Cl2 (23-38)→5% (39-61)], mixed fractions are combined and chromatographed again [50 g/150 mL cartridge, eluting with CH2Cl2 (1-22)→2% EtOAc in CH2Cl2 (23-33)→3% (34-55)→5% (56-68)] to obtain the title compound as white foam. 1H NMR (CDCl3, 400 MHz) δ 7.14 (s, 1H), 7.43-7.55 (m, 3H), 7.72-7.79 (m, 3H), 7.82-7.90 (m, 4H), 8.09 (s, 1H), 8.09-8.14 (m, 2H), 8.22 (d, J=8.8 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H). MS (ES+): m/z 476.9/478.9 (100/38) [MH+]. HPLC: tR=3.5 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: [CH3:1][C:2]([S:7][CH3:8])([CH3:6])[CH:3]=[N:4][OH:5].[CH3:9][N:10]=[C:11]=[O:12]>>[CH3:9][NH:10][C:11]([O:5][N:4]=[CH:3][C:2]([CH3:6])([S:7][CH3:8])[CH3:1])=[O:12]
Reactant: CN=C=O
Reactant: CSC(C)(C)C=NO
Product: CNC(=O)ON=CC(C)(C)SC

Procedure:
A process for preparing 2-methyl-2-(methylsulfonyl) propionaldehyde 0-(methylcarbamoyl) oxime which comprises (i) reacting 2-methyl-2-(methylthio) propionaldehyde oxime with methyl isocyanate in the presence of an aqueous medium for a period sufficient to form 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime and (ii) reacting 2-methyl-2-(methylthio) propionaldehyde 0-(methylcarbamoyl) oxime with a mixture of hydrogen peroxide and a carboxylic acid in the presence of a substantially aqueous medium and a catalytically effective amount of a mineral or organic sulfonic acid for a period sufficient to form 2-methyl-2-(methylsulfonyl) propionaldehyde 0-(methylcarbamoyl) oxime.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH3:7].[NH2:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[CH2:4]([C:3]1[N:9]=[C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][N:19]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:20][CH2:21]3)=[N:14][N:15]2[CH:2]=1)[CH2:5][CH2:6][CH3:7]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCCCC(=O)CBr
Product: CCCCc1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 42 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 1-bromohexan-2-one in place of 1-bromobutan-2-one to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid in 42% yield. 1H NMR (300 MHz, CDCl3) δ 7.72-7.48 (m, 4H), 7.43 (s, 1H), 7.35-7.32 (m, 1H), 6.71 (d, J=9.9 Hz, 1H), 4.02-3.83 (m, 2H), 3.53 (m, 2H), 3.37-3.3 (m, 4H), 2.74-2.69 (m, 2H), 1.76-1.61 (m, 2H), 1.48-1.3 (m, 2H), 0.91 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.4, 154.3, 146.8, 135.7, 134.4, 132.3, 129.4, 127.0, 126.8, 126.76, 126.7, 126.6, 126.2, 125.4, 125.3, 121.8, 113.6, 109.3, 46.5, 46.3, 46.2, 41.1, 31.5, 28.8, 22.4, 13.9. MS (ES+) m/z 432.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:23])[C:11]([C:13]1[CH:20]=[C:19]([CH3:21])[C:16]([C:17]#[N:18])=[C:15]([CH3:22])[CH:14]=1)=[O:12].[F:24][C:25]([Si](C)(C)C)([F:27])[F:26].[F-].C[N+](C)(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:23])[C:11]([C:13]1[CH:14]=[C:15]([CH3:22])[C:16]([C:17]#[N:18])=[C:19]([CH3:21])[CH:20]=1)([OH:12])[C:25]([F:27])([F:26])[F:24]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(C(C)C(=O)c2cc(C)c(C#N)c(C)c2)c(Cl)c1
Agent: C[N+](C)(C)C
Agent: [F-]
Product: COc1ccc(C(C)C(O)(c2cc(C)c(C#N)c(C)c2)C(F)(F)F)c(Cl)c1

Procedure:
In analogy to Example 1, step 3, 4-[2-(2-chloro-4-methoxy-phenyl)-propionyl]-2,6-dimethyl-benzonitrile was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=395.9 [M−H+].
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:4][CH:3]1[CH2:5][NH2:6].[CH2:13]([O:15][C:16](Cl)=[O:17])[CH3:14].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][C:2]1([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:4][CH:3]1[CH2:5][NH:6][C:16](=[O:17])[O:15][CH2:13][CH3:14]
Reactant: CCOC(=O)Cl
Reactant: CC(C)=CCCC1(C)CC1CN
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)NCC1CC1(C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
1-[2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropyl]methanamine (20.0 g, 0.12 mol) in 150 mL of ethyl acetate and ethylchloroformate (17.9 g, 0.165 mol) were charged to a reaction flask. The reaction mixture was then cooled to 0° C. Triethylamine (23.8 g, 0.165 mol) was slowly added while maintaining the reaction temperature at 0° C. Once the feed was complete the reaction mixture was aged for 2 hours than quenched with saturated sodium chloride solution. Kugelrohr distillation afforded 19.2 g of the product, 67% yield. 1H NMR (500 MHz, CDCl3) S: 0.07-0.12 (m, 1H), 0.44-0.49 (m, 1H), 0.75-0.79 (m, 1H), 1.04-1.06 (2s, 3H), 1.24 (t, J=6.89 Hz, 3H), 1.24-1.42 (m, 1H), 1.29-1.42 (m, 1H), 1.61 (s, 3H), 1.69 (s, 3H), 2.04-2.08 (m, 2H), 2.99-3.35 (m, 2H), 4.11 (q, J=6.82 Hz, 2H), 4.62 (br. s, 1H), 5.07-5.13 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.[H][H].C(N(CC)CC)C>O1CCCC1.[Pd]>[O:12]=[S:9]1(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]2[CH:14]=[CH:2][CH:3]=[C:4]([S:15]([NH2:18])(=[O:16])=[O:17])[C:5]=2[O:10]1
Reactant: CC1=Cc2cc(Br)cc(S(N)(=O)=O)c2OS1(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Temperature: 0 °C
Yield: 75.1 %

Procedure:
120 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide are dissolved in 2.4 liters of tetrahydrofuran and the solution is hydrogenated with hydrogen for 40 minutes, in the presence of 41.3 g of triethylamine and 12.0 g of 5% palladium on carbon catalyst, under normal pressure and in the temperature range from 20° to 25° C. The mixture is filtered, the filtrate is concentrated, and the residue is taken up in 1300 ml of hot 90% aqueous ethanol. The insoluble constituents are separated and the solution is cooled to 0° C. The precipitate is separated and dried, affording 70 g of 2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide of m.p. 204°-205° C.