Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][N:12]=[C:11]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[N:10]=1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[C:14]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][N:12]=[C:11]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[N:10]=1
Reactant: O=C(O)Cc1cnc(-n2cccn2)nc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cnc(-n2cccn2)nc1O

Procedure:
To a solution of 2-(4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidin-5-yl)acetic acid, 12-c, (1.239 g, 4 mmol) in THF (40 ml) was added Pd(OH)2/C (0.14 g). The resulting mixture was hydrogenated at room temperature at 1 atm overnight. The mixture was filtered and the filtrate was concentrate under vacuum to give compound 12-d (800 mg, 91%). 1H NMR (DMSO-d6, 300 MHz): δ 12.59 (s, 2H), 8.53 (s, 1H), 7.89 (s, 2H), 6.61 (s, 1H), 3.37 (s, 2H). (M+H)+=221.1.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1.[F:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1.O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:2]3[C:7](=[O:8])[NH:6][C:5]4[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=4[S:3]3)[CH2:22][CH2:21]2)=[O:19])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C1Nc2ccccc2SC1Cl
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(C2Sc3ccccc3NC2=O)CC1
Yield: 15 %

Procedure:
7 g (=0.035 m) of 2-chloro-2H-1,4-benzothiazine-3(4H)-one, 7.25 g (=0.035 m) of 4-(4-fluorobenzoyl)-piperidine and 7.1 g of triethylamine in 200 ml of toluene were heated at reflux for 4 hours with stirring. The reaction mixture was worked up by cooling it and then adding 200 ml of toluene and 200 ml of water. The pH of the mixture was adjusted to pH 7 by adding 0.1N hydrochloric acid solution. The organic phase was separated, washed with 200 ml of water, and the solvent was distilled off. The title compound was recovered from the remaining oily residue by fractional column chromatography, crystallized from ethyl acetate, and recrystallized in an ethanol/diethyl ether mixture. 1.95 g of 2-[4-(4-fluorobenzoyl)-piperidin-1-yl]-2H-1,4-benzothiazine-3(4H)-one were obtained as a colorless crystalline powder having a melting point of 218° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]3)[S:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5].[OH-].[Na+].Cl>C(O)C.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]3)[S:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(NC(=O)COC)c3)cs2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCC(=O)Nc1cccc(-c2csc(Cn3cc(C(=O)O)cn3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution (4 mL) of the compound (339 mg, 0.85 mmol) obtained in Example 26b in ethanol was added 2N aqueous sodium hydroxide solution (1.7 mL, 3.4 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, saturated brine was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (221 mg, 70%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([CH:22]=1)[C:20]#[N:21].O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:11][CH2:10][CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[C:19]([CH:22]=1)[C:20]#[N:21]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: Cc1cccc(CCCO)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(CCCOc2ccc(Br)cc2C#N)c1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Compound 15-1 (1.30 g) was dissolved in N,N-dimethylformamide (30 ml) and sodium hydride (60%, 1.04 g) was added at room temperature. After stirring for 30 min, 5-bromo-2-fluorobenzonitrile (1.00 g) was added, and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (1.04 g) as a yellow oil.
Reaction SMILES: C[Li].[OH:3][C@H:4]1[CH2:30][C@@:29]2([CH3:31])[C@@H:15]([CH2:16][CH2:17][C@:18]2([OH:32])[C:19](=[O:28])[CH2:20][O:21]C(=O)CC(C)C)[C@H:14]2[C@H:5]1[C@:6]1([CH3:35])[C:11]([C@@H:12]([CH3:33])[CH2:13]2)=[CH:10][C:9](=[O:34])[CH:8]=[CH:7]1.[Cl-].[NH4+]>CCOCC.O1CCCC1.[Cu]I>[OH:3][C@H:4]1[CH2:30][C@@:29]2([CH3:31])[C@@H:15]([CH2:16][CH2:17][C@:18]2([O:32][C:4](=[O:3])[CH2:5][CH:6]([CH3:11])[CH3:7])[C:19](=[O:28])[CH2:20][OH:21])[C@H:14]2[C@H:5]1[C@:6]1([CH3:35])[C:11]([C@@H:12]([CH3:33])[CH2:13]2)=[CH:10][C:9](=[O:34])[CH:8]=[CH:7]1
Reactant: CC(C)CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 125.5 %

Procedure:
Under argon at 0° C., 200 ml of a 5% solution of methyllithium in ether is added dropwise to a suspension of 36.5 g of copper(I) iodide in 730 ml of anhydrous tetrahydrofuran. The yellow solution is cooled to -30° C., and a solution of 29.0 g of 11β,17-dihydroxy-21-isovaleryloxy-6α-methyl-1,4-pregnadiene-3,20-dione in 730 ml of anhydrous tetrahydrofuran is added thereto. The mixture is stirred further for 10 minutes at -25° C. and poured onto an aqueous ammonium chloride solution. After extraction with methylene chloride, the organic solution is washed, dried over sodium sulfate, and evaporated under vacuum. The crude product is purified on 750 g of silica gel with a methylene chloride-acetone gradient (0-20% acetone), yielding 18.2 g of 11β,21-dihydroxy-17-isovaleryloxy-6α-methyl-1,4-pregnadiene-3,20-dione, mp 164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([OH:22])=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[S:23]1[CH2:27][CH2:26][NH:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([N:25]3[CH2:26][CH2:27][S:23][CH2:24]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C1CSCN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1
Product: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCSC1

Procedure:
150 mg (0.43 mmol) of the compound of Example 22A is reacted analogously to the synthesis of the compound of Example 3 with 41 mg (0.46 mmol) of thiazolidine. After the crude product is purified by means of preparative HPLC (mobile solvent: acetonitrile/water gradient), 122 mg (74% of theory) of the title compound is obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]([OH:16])[CH2:13][CH:14]=[CH2:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:17](Br)[CH:18]=[CH2:19]>C1COCC1>[CH2:19]([O:16][CH:12]([CH2:13][CH:14]=[CH2:15])[CH2:11][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: C=CCC(O)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(CC=C)COCc1ccccc1
Temperature: 25 °C

Procedure:
NaH (4.8 g, 120 mmol) was added portion wise to a stirred solution of 1-(benzyloxy)pent-4-en-2-ol (11) (15.3 g, 79.6 mmol) in THF (100 mL) at 0° C. After addition, the mixture was warmed to room temperature and stirred for another hour before it was cooled to 0° C. Allyl bromide (9 mL, 103.5 mmol) was added to the reaction and the resulting mixture was warmed to room temperature and then heated to 50° C. overnight. After cooling to room temperature, the mixture was quenched with saturated NH4Cl and worked up under standard conditions. The residue was purified over silica using Et2O and hexane to give ((2-(allyloxy)pent-4-enyloxy)methyl)benzene (12).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=O.O.[NH2:16][NH2:17]>CO>[CH3:14][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([NH:16][NH2:17])=[O:2])[CH:13]=2)[CH:9]=[CH:10]1
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1ccc2ccc(C(=O)NN)cc21

Procedure:
A mixture of 1-methyl-1H-indole-6-carboxylic acid methyl ester (3.2 g, 16.1 mmol), hydrazine monohydrate (8.5 g, 169 mmol) and methanol (50 ml) was stirred reflux for 15 h. The mixture was evaporated, water was added and the product was isolated by extraction with chloroform, followed by evaporation.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH3:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[ClH:24].[NH2:25]O.O>C(O)C>[ClH:24].[NH2:25][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])=[CH:9][CH:10]=1)[CH2:15][CH3:16]
Reactant: NO
Reactant: CCC(=O)c1ccc(CC(=O)OC(C)(C)C)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(N)c1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
To tert-butyl(4-propionylphenyl)acetate (1 g) in ethanol (20 ml) solution, sodium acetate (0.7 g) and hydroxylamine hydrochloride (0.44 g) were added and the mixture was stirred at 90° C. for 3 hours. Distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over with anhydrous sodium sulfate, then concentrated. Ethanol (22 ml) and 10% palladium carbon (0.6 g) were added to the residue, and the mixture was stirred under hydrogen atmosphere at 5 atm for 40 hours. The insoluble compound was filtered out, then a 4N hydrochloric acid/ethyl acetate solution was added to the filtrate and the mixture concentrated. Hexane/ethyl acetate was added to the residue, and the precipitated solid was collected by filtration to obtain the title compound (0.74 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:39]([NH2:41])[CH3:40].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:37])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:41][CH2:39][CH3:40])=[O:34])=[CH:35][CH:36]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:8])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(C(=O)O)cc2)nc1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(CN(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)c2ncc(CC)cn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.8 %

Procedure:
4-{[(2-{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethyl)(5-ethylpyrimidin-2-yl)amino]methyl}benzoic acid (261 mg) synthesized in Example 437-2 and ethylamine hydrochloride (47 mg) were dissolved in N,N-dimethylformamide (2.5 mL), triethylamine (80 μL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (110 mg) and 1-hydroxybenztriazole (HOBt) monohydrate (86 mg) were successively added thereto, and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (268 mg) as a white solid.
Reaction SMILES: [C@@H]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])NC2=O)O[C@H](CO)[C@@H](O)C1.C1N(CCO)CCN(CCS(O)(=O)=O)C1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(C=C)=O.CCN(C(SSC(N(CC)CC)=S)=S)CC.C(=O)CC.[CH:149](=O)[C:150]1[CH:155]=[CH:154][CH:153]=[CH:152][CH:151]=1>>[CH2:155]([C:150]1[CH:149]=[CH:16][C:15]([CH:13]=[O:14])=[C:17]([NH2:9])[C:151]=1[CH2:152][CH3:153])[CH3:154]
Reactant: O=Cc1ccccc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: C=CC=O
Agent: CCN(CC)C(=S)SSC(=S)N(CC)CC
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Solvent: CCC=O
Product: CCc1ccc(C=O)c(N)c1CC

Procedure:
Materials: SDA was prepared by acid hydrolysis of the corresponding bioacetal supplied by the Department of Pharmaceutical Development at our Institute. [3H]-Thymidine was purchased from New England Nuclear, Boston, Mass. Concanavalin A, horse serum, RPMI-1640 and HEPES were from Gibco, Grand Island, N.Y. NAD and NADP were purchased from Boehringer, Mannheim. Acrolein and disulfiram were obtained from Aldrich Chemical Co., Milwaukee, Wis. Propionaldehyde and benzaldehyde were from Eastman Kodak Chemical Co., Rochester, N.Y. Diethyl aminobenzaldehyde (DEAB) was kindly provided by Dr. John Hilton, Johns Hopkins School of Medicine, Baltimore, Md.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([C:9]3[CH2:13][C:12]4([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[O:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1([CH3:32])[O:26]B(O)[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]1=2.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:11]1[C:12]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:13][C:9]([C:7]2[NH:6][C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[C:22]([OH:26])([CH3:32])[CH3:21])=[CH:3][C:4]=3[N:8]=2)=[N:10]1
Reactant: CC1(C)OB(O)c2ccccc21
Reactant: Brc1ccc2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CC(C)(O)c1ccccc1-c1ccc2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1
Yield: 9 %

Procedure:
Using the procedure for step D in Example 1, the title compound was prepared from 3-(5-bromo-1H-benzimidazol-2-yl)-1-oxa-2-aza-spiro[4.5]dec-2-ene (150 mg, 0.449 mmol, as prepared in the previous step) and 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (2.0 eq., 145 mg, 0.898 mmol, prepared as described in US2007/259936) and (dppf)PdCl2.DCM (0.10 eq., 36.6 mg, 0.045 mmol) in 9% yield (16.4 mg). 1H-NMR (400 MHz, d4-MeOH) δ: 7.82 (dd, J=8.1, 1.3 Hz, 1H), 7.53-7.68 (m, 1H), 7.47 (br. s., 1H), 7.35 (td, J=7.6, 1.6 Hz, 1H), 7.19-7.24 (m, 2H), 7.05 (dd, J=7.6, 1.3 Hz, 1H), 3.28 (s, 2H), 1.69-1.90 (m, 6H), 1.46-1.65 (m, 4H), 1.33 (s, 6H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C24H27N3O2: 390.2 (M+H). found: 390.4.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[N:8]=[C:7]([S:9]([CH:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH3:13])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:29][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>O1CCCC1>[CH3:13][C:12]([CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]1)([S:9]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:27])[F:28])[N:8]=1)(=[O:10])=[O:11])[CH3:29]
Reactant: CC(C1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1cccc(C(F)(F)F)n1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)OC(=O)N1CCC(C(C)(C)S(=O)(=O)c2cccc(C(F)(F)F)n2)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
To a 50 ml round bottom flask was added tert-butyl 4-(1-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}ethyl)piperidine-1-carboxylate (0.78 g, 1.85 mmol) and tetrahydrofuran (10 ml). The resulting solution was cooled with dry ice acetone bath. Sodium bis(trimethylsilyl)amide (NaHMDS) tetrahydrofuran solution (1M, 2.58 ml, 2.58 mmol) was added via a syringe. The resulting reaction solution was stirred at −78° C. for 10 minutes. MeI (0.173 ml, 2.77 mmol) was added. The reaction mixture was allowed to warm up to room temperature and quenched by addition of 50 ml saturated NH4Cl solution. It was diluted with 30 ml ether. The layers were separated, and the organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:4 to 1:2 ethyl acetate/hexane to give 0.806 g desired product (contains solvent).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:15]([CH3:41])([CH3:40])[CH2:14]2)[N:5]=[C:4]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]2[CH2:52][C:51]([CH3:54])([CH3:53])[N:50]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[C:49]([CH3:75])([CH3:74])[CH2:48]2)[N:3]=1.[CH2:76]([CH2:78][NH2:79])[OH:77]>>[OH:77][CH2:76][CH2:78][NH:79][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:19])([CH3:20])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:15]([CH3:40])([CH3:41])[CH2:14]2)[N:5]=[C:4]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]2[CH2:48][C:49]([CH3:74])([CH3:75])[N:50]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[C:51]([CH3:53])([CH3:54])[CH2:52]2)[N:3]=1
Reactant: NCCO
Reactant: CCCCCCCCCCCCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCCCCCCCCCCCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Product: CCCCCCCCCCCCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCC3CC(C)(C)N(OCCCCCCCCCCCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-octadecyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and ethanolamine according to the procedure of Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>CN(C)C(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(C#N)cc2)CC1
Yield: 88.3 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (9.19 g, 30.8 mmol) and 4-cyanobenzeneboronic acid (5.18 g, 35.2 mmol) in N,N-dimethylacetamide (90 mL) and water (35 mL), purge with nitrogen for 0.5 hr. and then add tetrakis(triphenylphosphine)palladium(0) (0.170 g, 0.15 mmol). Heat for 3 hr. at 110° C., allow to cool about 1.5 hr. to room temperature, filter and then dry the solid in an oven overnight to give 3′-(4-cyanophenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester as a white solid (9.94 g, 88%). MS (ES): m/z=366 [M+H]+. Add 4 M HCl in 1,4-dioxane (10 mL) to 3′-(4-cyanophenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (3.29 g, 9.0 mmol). Add more 4 M HCl in 1,4-dioxane (10 mL) to the reaction mixture and heat at 40° C. for 3 hr. Filter off the solid and wash with a mixture of 1,4-dioxane/isohexane to give the dihydrochloride salt as a yellow solid (4.2 g). MS (ES): m/z=266 [M+H]+. Dissolve the dihydrochloride in water (20 mL), add 2 N sodium hydroxide (10 mL), extract with DCM and concentrate the DCM extract to give the title preparation as a yellow solid (1.8 g). MS (ES): m/z=266 [M+H]+.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]3[CH2:25][CH2:24][N:23]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[C:22]3=[O:32])=[C:16]([Cl:33])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:33][C:16]1[CH:15]=[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=2)[CH:19]=[CH:18][C:17]=1[CH2:20][CH:21]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:22]1=[O:32]
Reactant: CC(C)(C)OC(=O)c1cccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)c1
Yield: 94.4 %

Procedure:
Dissolve 3′-chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-3-carboxylic acid tert-butyl ester (Preparation 82) (506 mg, 1.08 mmol) in methylene chloride (5 mL). Add trifluoroacetic acid (5 mL) and stir at room temperature for 1 hour. Concentrate and redissolve in methylene chloride. Pour into 1N NaOH. Extract with ether. Acidify aqueous phase to pH 1. Extract with ether. Dry over sodium sulfate, filter and concentrate to yield 420 mg (94%) of the title compound as a white solid. Mass spectrum (apci) m/z=410.3
Reaction SMILES: [H-].[Na+].[Na+].[I-].[Br:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)=[O:14])=[CH:8][C:7]=1[CH3:20].Cl[CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26]>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:5][C:6]1[C:7]([CH3:20])=[CH:8][C:9]([C:13]([N:15]2[CH2:16][CH:17]([O:19][CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:18]2)=[O:14])=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1cc(C(=O)N2CC(O)C2)cc(C)c1Br
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)N2CC(OCCCN(C)C)C2)cc(C)c1Br
Temperature: 110 °C
Reaction time: 15 h
Yield: 27.2 %

Procedure:
NaH (110 mg, 2.75 mmol, 60% oily suspension) and NaI (274 mg, 1.83 mmol) were added to a solution of (4-bromo-3,5-dimethyl-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone (130 mg, 0.458 mmol) and (3-chloro-propyl)-dimethyl-amine (289 mg, 1.83 mmol) in toluene (1.8 ml). The mixture was stirred at 110° C. for 15 hours. The reaction mixture was diluted with AcOEt, and the organic layer was then sequentially washed with a saturated aqueous NaHCO3 solution, water and a saturated aqueous NaCl solution. Further, the organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/AcOEt) to give (4-bromo-3,5-dimethyl-phenyl)-[3-(3-dimethylamino-propoxy)-azetidin-1-yl]-methanone (46 mg, 27%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:10][S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18])(=[O:13])=[O:12]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:17]([C:16]2[CH:15]=[C:14]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2cccc(S(=O)(=O)Cl)c2)cc1

Procedure:
The entitled compound was produced according to the method of Reference Example 1 but using 4-methoxyaniline and 3-(chlorosulfonyl)benzoyl chloride as the starting materials.