Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1
Reactant: C1CNCCN1
Reactant: COc1ccc(Cl)cc1C(C)Nc1cc(F)ccc1S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(Cl)cc1C(C)Nc1cc(N2CCNCC2)ccc1S(C)(=O)=O
Yield: 25.3 %

Procedure:
N-(1-(5-Chloro-2-methoxyphenyl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (50.0 mg, 0.14 mmol), piperazine (36.0 mg, 0.42 mmol), N,N-diisopropylethylamine (36.0 mg, 0.28 mmol) were stirred at 80° C. in dry acetonitrile (5 mL) for 48 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 15% methanol in dichloromethane to afford the title compound (15.0 mg, 25% yield). 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 1H), 7.16 (d, 1H), 6.81 (d, 1H), 6.58 (d, 1H), 6.22 (d, 1H), 5.83 (s, 1H), 5.30 (s, 1H), 4.85 (m, 1H), 3.87 (s, 3H), 3.11 (m, 4H), 2.91 (m, 4H), 1.51 (d, 3H); MS (ESI) m/z: Calculated for C20H27ClN3O3S: 424.15; Observed: 424.4 (M+).
Reaction SMILES: [Br:1][C:2]([Br:13])([Br:12])[CH2:3][C:4]1(Cl)[C:7]([CH3:9])([CH3:8])[CH2:6][C:5]1=[O:10].[ClH:14]>C(O)C>[Br:1][C:2]([Br:13])([Br:12])[CH2:3][CH:4]1[C:7]([CH3:9])([CH3:8])[CH:6]([Cl:14])[C:5]1=[O:10]
Reactant: Cl
Reactant: CC1(C)CC(=O)C1(Cl)CC(Br)(Br)Br
Solvent: CCO
Product: CC1(C)C(Cl)C(=O)C1CC(Br)(Br)Br
Temperature: 80 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
22,8 g (0,054 mole) of 2-(2',2',2'-tribromoethyl)-2-chloro-3,3-dimethylcyclobutan-1-on is dissolved in 220 ml of absolute ethanol saturated with hydrogen chloride and the solution is stirred for 5 hours at 80° C. Then solvent is evaporated until the volume of the reaction mixture is reduced to one third of the starting volume and, after addition of water, the mixture is extracted with ether. The etheral extract is washed at first with saturated sodium chloride solution and subsequently with sodium bicarbonate solution and thereafter dried over sodium sulphate. The residue obtained after evaporation of the ether is purified by chromatography on silica gel using toluene as eluent. After combination of the pure fractions and evaporation of the solvent there is obtained 17,1 g (75% of theory) of 2-(2',2',2'-tribromoethyl)-3,3-dimethyl-4-chloro-cyclobutane-1-one, melting point 87°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]1[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: OC1CCNCC1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCC(O)CC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 4-hydroxypiperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.09 minutes; C21H20Cl2N4O3 (447.32); mass spectrum: (M+H)+=447.2.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=O)[CH2:13]Cl)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:16][C:17]([NH2:19])=[S:18].O.O.O.C([O-])(=O)C.[Na+].O>C(O)C>[NH2:19][C:17]1[S:18][CH:13]=[C:12]([C:6](=[N:5][O:4][CH2:3][CH2:2][Br:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:16]=1
Reactant: CCOC(=O)C(=NOCCBr)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCCBr)c1csc(N)n1
Temperature: 40 °C
Yield: 27.8 %

Procedure:
A mixture of ethyl 2-(2-bromoethoxyimino)-4-chloro-3-oxobutyrate (syn isomer, 156 g.), thiourea (39.4 g.) sodium acetate trihydrate (70.5 g.), water (300 ml.) and ethanol (500 ml.) was stirred at 40° C. for an hour. The resultant solution was concentrated in vacuo and the residue was extracted twice with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. After adding diethyl ether (1 l.) to the oily residue, the soluble substance was separated by decantation and the solution was concentrated in vacuo. The residue was crystallized with diisopropyl ether and the precipitates were collected by filtration to give ethyl 2-(2-aminothiazol-4-yl)-2-(2-bromoethoxyimino)acetate (syn isomer, 46.4 g.), mp. 111° to 114° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[OH:1][C:2]1[C:11]([N+:21]([O-:23])=[O:22])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:13])([F:14])[F:15])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(O)cc1C(F)(F)F
Temperature: 65 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
Methyl 4-hydroxy-2-(trifluoromethyl)benzoate (32.0 g) was dissolved in acetic acid (180 ml), and thereto was added conc. sulfuric acid (0.45 ml), and the mixture was heated to 65° C. Then, thereto was slowly added a 70% solution of conc. nitric acid (12.4 g) in acetic acid (60 ml) dropwise, and the mixture was stirred at 65° C. for one hour. The reaction mixture was cooled to room temperature, and poured into ice-water (500 ml), and the mixture was extracted twice with toluene (800 ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (15.0 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:19]([Zn]CC)[CH3:20].CCCCCC>O1CCCC1.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>[CH2:19]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:20]
Reactant: Cc1csc(Nc2nccc3ccc(Cl)nc23)n1
Reactant: CC[Zn]CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccc2ccnc(Nc3nc(C)cs3)c2n1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a solution of (2-chloro-[1,7]naphthyridin-8-yl)-(4-methyl-thiazol-2-yl)-amine (0.055 g, 0.20 mmol) in 2 ml dry tetrahydrofuran (purged with argon) were subsequently added tetrakis(triphenylphosphine)palladium (0.011 g, 0.0095 mmol) and a 1.0 M solution of diethylzinc in n-hexane (0.4 ml, 0.4 mmol). The reaction mixture was heated at reflux for 1 h. Cooling to room temperature was followed by quenching with saturated aqueous ammonium chloride solution at 0-5° C. The aquous layer was basified to pH 12 with 1 M aqueous sodium hydroxide solution and extracted with three portions of methyl-tert.-butyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. Flash-chromatography gave the title compound (0.015 g, 28%) as light yellow solid, MS m/e (%): 271 (M+H+, 100).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[Cl-].[NH4+]>CS(C)=O>[O:9]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of trimethylsulfoxonium iodide (2.62 g, 0.012 mol) and sodium hydride (0.44 g, 0.011 mol) in anhydrous dimethylsulfoxide (30 mL) was stirred at room temperature under an atmosphere of nitrogen for thirty minutes. The reaction mixture was cooled to 10° C. and tert-butyl 4-oxo-1-piperidinecarboxylate (2.0 g, 0.010 mol) in anhydrous dimethylsulfoxide (10 mL) was added. The reaction mixture was warmed to room temperature and stirred for one and a half hours. The mixture was poured into an aqueous saturated ammonium chloride solution (60 mL). The water phase was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (1×60 mL) and brine (1×50 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2.12 g, 0.0099 mol).
Reaction SMILES: C([O:4][CH:5]([C:14](=[O:16])[NH2:15])[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])(=O)C.C(OC[C@@H](C1C=CC=CC=1)CC(=O)N)(=O)C>>[C:14]([CH:5]([OH:4])[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])(=[O:16])[NH2:15]
Reactant: CC(=O)OC(C(N)=O)C(C)c1ccccc1
Agent: CC(=O)OC[C@H](CC(N)=O)c1ccccc1
Product: CC(c1ccccc1)C(O)C(N)=O

Procedure:
Except for using (R)-3-N-morphoryl carbamoyl-2-phenyl propanol acetate, instead of (R)-3-carbamoyl-2-phenyl propanol acetate, as the starting material, the same procedure with that of Example 67 was repeated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][C:7]2([CH3:13])[CH3:12].I[CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:18][CH2:19][CH3:20])[CH2:9][CH2:8][C:7]2([CH3:12])[CH3:13]
Reactant: CC(C)c1cc(Br)c2c(c1)C(C)(C)CCN2
Reactant: CCCI
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(Br)c21

Procedure:
Following General Procedure A, 8-bromo-6-isopropyl-4,4-dimethyl-1-alkyl-1,2,3,4-tetrahydro-quinoline (Intermediate 4, 3.0 g, 9.1 mmol) and 1-iodopropane (5.2 g, 46 mmol) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]([O:13][CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:15])[CH:9]=2)[N:4]=1.[Br:16]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:15][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([O:2][CH3:1])[N:12]=[C:11]2[O:13][CH3:14]
Reactant: COc1nc(OC)c2cc(C)ccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc(OC)c2cc(CBr)ccc2n1
Yield: 102.9 %

Procedure:
A mixture of 2,4-dimethoxy-6-methylquinazoline (8.2 g), N-bromosuccinimide (7.9 g), benzoyl peroxide (0.19 g) and carbon tetrachloride (200 ml) was heated to reflux for 2 hours. The warm solution was filtered and the filtrate was evaporated to give 6-bromomethyl-2,4-dimethoxyquinazoline (11.7 g), m.p. 138°-143° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29](O)=[O:30])[CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.O.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([C:29]([C:25]3[CH:24]=[C:23]([CH3:22])[CH:28]=[CH:27][N:26]=3)=[O:30])[CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: Cc1ccnc(C(=O)O)c1
Reactant: Fc1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccnc(C(=O)N2CCC(OC(c3ccccc3)c3ccc(F)cc3)CC2)c1
Reaction time: 1.8 h
Yield: 58 %

Procedure:
A mixture of 2.431 g of a known compound (±)-4-[(4-fluorophenyl)phenylmethoxy]piperidine, 974 mg of 4-methylpyridine-2-carboxylic acid, 2.922 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1.956 g of 1-hydroxybenzotriazole monohydrate, 29 mL of pyridine, and 208 mg of 4-dimethylaminopyridine was stirred for 1.8 hours. The mixture was poured into salt water and extracted with ethyl acetate twice. The extract was washed with a saturated saline solution and dried over magnesium sulfate. The solvent was distilled off, and then the residue was purified by silica gel column chromatography (chloroform/methanol (volume ratio)=20:1 to 15:1) to give the title compound (1.661 g (58%)).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C(Cl)Cl.CN(C=O)C>[CH2:20]([N:22]([CH2:23][CH3:24])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[C:2]([F:1])([F:13])[F:12])[CH3:21]
Reactant: CCNCC
Reactant: O=C(O)c1ccccc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a solution of 2-trifluoromethylbenzoic acid (20.0 g, 105 mmol) in 500 mL of methylene chloride was added oxalyl chloride (18.4 mL, 210 mmol) followed by ˜8 drops of DMF. The reaction was allowed to stir at ambient temperature for 4 h and then was concentrated in vacuo to a solid. The solid was taken up in 500 mL of methylene chloride and then there was added diethylamine (24 mL, 231 mmol) dropwise as a solution in 50 mL of methylene chloride. The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was concentrated in vacuo. The residue was diluted with EtOAc, washed sequentially with 1N HCl, sat'd. aq. NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to afford 22 g (85%) of the title compound as an oil. 1H NMR (CDCl3): δ 7.68 (d, 1H, J=7.7 Hz), 7.57 (t, 1H, J=7.4 Hz), 7.49 (t, 1H, J=7.7 Hz), 7.32 (d, 1H, J=7.1 Hz), 3.90-3.82 (m, 2H), 3.29-3.22 (m, 2H), 1.23 (t, 3H, J=7.2 Hz), 1.03 (t, 3H, J=7.2 Hz). LRMS (ESI): 246.12 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[CH:22]1([C:25]2[O:26][CH:27]=[C:28]([CH2:30][NH2:31])[N:29]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[O:26][CH:27]=[C:28]([CH2:30][NH:31][C:14]([C:12]3[CH:11]=[CH:10][C:9]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:13]=3)=[O:16])[N:29]=2)[CH2:24][CH2:23]1
Reactant: O=C(O)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Reactant: NCc1coc(C2CC2)n1
Product: O=C(NCc1coc(C2CC2)n1)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 41, using 6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (example AW) and 2-cyclopropyl-4-oxazolmethanamine (example BH) as starting materials, LC-MS (UV peak area/ESI) 97.6%, 424.0 (M+H)+.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])=[CH:8][CH:7]=1.[NH2:18][NH2:19].N>CO.C(OCC)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:16][CH2:15][OH:14])[C:13]([NH:18][NH2:19])=[O:17])=[CH:8][CH:7]=1
Reactant: O=C1OCCC1c1ccc(F)cc1
Reactant: NN
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NNC(=O)C(CCO)c1ccc(F)cc1
Temperature: 25 °C
Yield: 31.8 %

Procedure:
Acetic acid (1 mL) was added to a solution of 3-(4-fluorophenyl)dihydrofuran-2-one (393 mg) and hydrazine (699 mg) in methanol (10 mL), and the reaction solution was heated to reflux for two hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and concentrated aqueous ammonia were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Chloroforum was added to the residue, and the precipitated solid was collected by filtration to obtain 147 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:18])[C:9]1[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:11]([OH:13])=O.OS(O)(=O)=O>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:8](=[O:18])[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]1=[O:13]
Reactant: O=C(O)c1ccccc1C(=O)NCc1cccs1
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1Cc1cccs1
Yield: 69.9 %

Procedure:
A solution of 2-aminomethyl-thiophene (2.1 ml, 20.5 mmol) in CHCl3 (25 ml) is treated with phthalic anhydride (3.0 g, 20.5 mmol) at r.t. for 5 min, then at reflux for 20 min, whereupon a white powder precipitated out. This powder is collected by filtration and dried in vacuo to give N-thiophen-2-ylmethyl-phthalamic acid (4.42 g, 83%) as white crystals. An aliquot of this phthalamic acid (2.13 g, 8.12 mmol) is dissolved in MeOH (12 ml), treated with H2SO4 (440 μl, 8.25 mmol) and heated to reflux for 1.5 h, whereupon a white powder precipitated out. This powder is collected by filtration and dried in vacuo to give 1.38 g (70%) of the title phthalimide as white crystals: 1H NMR (DMSO-d6) δ7.92-7.82 (m., 4H), 7.42 (dd, J=5.1, 1.2 Hz, 1H), 7.08 (dd, J=4.0, 0.8 Hz, 1H), 6.95 (dd, J=5.1, 3.5 Hz, 1H), 4.92 (s, 2H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][CH:9]([CH2:11][CH2:12][CH2:13][C@H:14]([C@@H:16]1[C@:34]2([CH3:35])[C@H:19]([C@H:20]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:23]([CH2:24][C@H:25]([CH2:27][CH2:28]2)[OH:26])=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])[CH3:10]>>[CH3:15][C@@H:14]([C@@H:16]1[C@@:34]2([CH3:35])[CH2:33][CH2:32][C@@H:31]3[C@@:29]4([CH3:30])[CH2:28][CH2:27][C@H:25]([O:26][C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])[CH2:24][C:23]4=[CH:22][CH2:21][C@H:20]3[C@@H:19]2[CH2:18][CH2:17]1)[CH2:13][CH2:12][CH2:11][CH:9]([CH3:8])[CH3:10]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)CCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
As shown in FIG. 1, butterfat 102 at a fluid temperature greater than 40° C. is continuously introduced at a predetermined rate (e.g., 10 lb/min) into a continuous reactor system 104, which is maintained at a reaction temperature of 170° C. Molten succinic anhydride 106 is metered from storage tank 106 into reactor 104 together with a recycle succinic anhydride stream 108, which will be described in more detail hereinafter. The combined succinic anhydride streams 106, 108 are metered into the continuous reactor system 104 at a temperature of 170° C. at a predetermined rate (e.g., 0.78 pounds per minute) which provides a substantial molar excess with respect to the cholesterol, moisture and mono and diglycerides content of the butterfat 102. The reactor 104 maintains the butterfat and the succinic anhydride at reaction temperature under conditions of mixing, and may be a multitubular reactor, a continuous staged horizontal reactor, a vertical reactor, or one or more serially connected continuously stirred tank reactors, or other suitable reactors. The reaction conditions are maintained in the reactor for a time period of less than about one hour, which is sufficient to react substantially all of the free cholesterol of the butterfat 102 with the succinic anhydride 106 to form cholesteryl hemisuccinate. The resulting reaction mixture, containing butterfat, cholesteryl hemisuccinate and excess succinic anhydride, is conducted to liquid/liquid centrifuge 110 (e.g., at a rate of 10.78 pounds per minute) where the more dense, excess succinic anhydride phase 108 (e.g.,at a rate of about 0.77 pounds per minute) is separated and returned to the reactor 104, as succinic anhydride stream 108.
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]#[N:19])[C:15]([OH:20])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:32][NH2:33])=O)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][C:30]2[NH:19][C:18]([C:16]3[C:15]([OH:20])=[C:14]4[C:9]([CH:10]=[CH:11][CH:12]=[N:13]4)=[C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][S:2]4(=[O:1])=[O:21])[N:17]=3)=[N:33][N:32]=2)=[CH:27][CH:28]=1
Reactant: N#Cc1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Reactant: NNC(=O)Cc1ccc(Cl)cc1
Product: O=S1(=O)CCCCN1c1nc(-c2nnc(Cc3ccc(Cl)cc3)[nH]2)c(O)c2ncccc12

Procedure:
The title compound was prepared in a similar manner to that described in example 3 from 5-(1,1-dioxido-1,2-thiazinan-2-yl)-8-hydroxy-1,6-naphthyridine-7-carbonitrile (75 mg, 0.24 mmol) and 2-(4-chlorophenyl)acetic hydrazide (137 mg, 0.74 mmol) to give a white solid (49 mg, 43%). 1H NMR (CDCl3/CD3OD): δ 9.06 (d, J=3.6 Hz, 1 H), 8.62 (d, J=8.4 Hz, 1 H), 7.66 (dd, J=8.4, 4.0 Hz, 1 H), 7.28-7.21 (m, 4 H), 4.15 (s, 2 H), 3.89 (m, 1 H), 3.82 (m, 1 H), 3.63 (m, 1 H), 3.31 (m, 1 H), 2.41 (m, 3 H), 1.79 (m, 1 H); MS m/z 471 (M+1).
Reaction SMILES: [CH:1]1([CH:7]([O:35][CH3:36])[C:8]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:9]=2[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:43](Cl)(=[O:45])[CH3:44]>ClCCl>[F:24][C:23]([F:26])([F:25])[C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=1)[CH2:12][N:11]([CH2:10][C:9]1[CH:27]=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:29]=[CH:30][C:8]=1[CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:35][CH3:36])[C:43](=[O:45])[CH3:44]
Reactant: COC(c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)=O)C1CCCCC1
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution (3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-amine (Example 41, STEP E, 20 mg, 0.038 mmol) in dichloromethane (1 ml) was added pyridine (9.0 mg, 0.114 mmol) followed by acetyl chloride (2.98 mg, 0.038 mmol) at room temperature and stirred for overnight. Reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulphate and concentrated in vacuo. The product was purified on Biotage column (12+S), eluting with 2% ethyl acetate in heptane (1 CV), 2-20% (10CV), 20% (2CV) to yield the title compound (8 mg, 37%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.9 (m, 6H) 1.2 (m, 3H) 1.7 (m, 1H) 1.9 (m, 1H) 2.2 (s, 3H) 3.1 (s, 3H) 3.9 (m, 1H) 4.6 (m, 4H) 7.4 (m, 1H) 7.5 (m, 2H) 7.6 (m, 2H) 7.8 (s, 1H). MS (ES+) Calc: 569.2, Found: 614.2 (M+45).
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH:19]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]3)[C:14]([C:31](=[O:33])[NH2:32])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:34][C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)[NH:38][C:39](=[O:41])[CH3:40].CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:39]([NH:38][C:37]1[CH:36]=[C:35]([NH:34][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH:19]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20]3)[C:14]([C:31](=[O:33])[NH2:32])=[CH:13][N:12]=2)[CH:44]=[CH:43][CH:42]=1)(=[O:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc(On3nnc4ccccc43)ncc2C(N)=O)C1
Reactant: CC(=O)Nc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCN(C(=O)OC(C)(C)C)C3)n2)c1
Reaction time: 18 h
Yield: 56.5 %

Procedure:
A mixture of tert-butyl 3-((2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5-carbamoylpyrimidin-4-ylamino)methyl)pyrrolidine-1-carboxylate (118 mg, 0.260 mmol), 3′-amino-acetanilide (47 mg, 0.31 mmol) and pTsOH (57 mg, 0.30 mmol) in dioxane (2 mL) was stirred at 100 C for 18 h, during which time white solids precipitated out, which were collected and purified by HPLC to give the titled compound (69 mg). MS 470.6 (M+H); UV 202.2, 248.6 nm.