Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[N:5]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.C(O)(C(F)(F)F)=O>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:5]([C:4]2[CH:27]=[CH:28][CH:29]=[C:2]([F:1])[CH:3]=2)[CH:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2ccc(F)cc2)c2cccc(F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(CN(c2cccc(F)c2)C2CCNCC2)cc1
Temperature: 0 °C
Yield: 96 %

Procedure:
Tert-butyl 4-[3-fluoro(4-fluorobenzyl)anilino]-1-piperidinecarboxylate 8 (25.5 g) was dissolved in dichloromethane and the solution was cooled to 0° C. TFA (30 ml) was added to the solution and the reaction mixture was stirred at room temperature. After 1 h 30, TFA (20 ml) was added and the reaction mixture was stirred for a further 30 minutes. The solvent was removed under vacuum and the residue was taken up in dichloromethane and water. The aqueous phase was alkalized by addition of NaOH and washed with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated. The crude was purified by chromatography (eluant: CH2Cl2/MeOH/NH4OH 95/5/0.5) to give N-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine (18.4 g) as a free base.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.O=S(Cl)Cl.[CH2:41]1COCC1>C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH2:11][O:12][CH3:41])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C1CCOC1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1COC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a solution of Example 23 (N-{4-[4-amino-7-(hydroxymethyl)-6-(methoxy-methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)-phenyl]urea (22 mg, 0.04 mmol)) in anhydrous THF (1 mL) and CH2Cl2 (1 mL) was added SOCl2 (0.006 ml, 0.08 mmol). After 20 min, analytical HPLC showed half of the starting material remained. Additional SOCl2 (0.01 ml) was added and the reaction was stirred at rt for 2.5 h until completion. The mixture was evaporated to dryness and CH2Cl2 (3 ml) was added. The solvent was evaporated to dryness and the crude concentrate was re-suspended in CH2Cl2 and evaporated to remove the excess SOCl2 completely. To the resulting solid was added anhydrous MeOH (1 ml) and Hunig's base (0.008 ml), the reaction was stirred at 70° C. overnight. After 16 h, the reaction was cooled to rt and solvent was evaporated. The crude material was taken up in ethyl acetate, washed with aq. saturated sodium bicarbonate three times and dried over Na2SO4. After concentration, the resulting crude was purified via column chromatography (5:95 v/v MeOH—CH2Cl2) to afford 12 mg of the title compound (yield 53%). 1H-NMR (DMSO-d6) 9.32 (s, 1H), 8.96 (d, J=3 Hz, 1H), 8.63 (dd, J=7, 3 Hz, 1H), 7.92 (s, 1H), 7.59 (t, J=3 Hz, 2H), 7.57 to 7.32 (m, 4H), 4.73 (s, 2H), 4.28 (s, 2H), 3.26 (s, 3H), 3.24 (s, 3H) ppm; MS [M+H]+=519.1; LCMS RT=2.84 rain
Reaction SMILES: FC1C=CC(CN[C:10](=[O:18])[C@@H:11]2[CH2:15][CH2:14][C:13](=[O:16])[N:12]2[CH3:17])=C(C(F)(F)F)C=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][NH2:32].FC1C=CC(CN)=C(C(F)(F)F)C=1>>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][NH:32][C:10](=[O:18])[C@@H:11]1[CH2:15][CH2:14][C:13](=[O:16])[N:12]1[CH3:17]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CN1C(=O)CC[C@H]1C(=O)NCc1ccc(F)cc1C(F)(F)F
Agent: NCc1ccc(F)cc1C(F)(F)F
Product: CN1C(=O)CC[C@H]1C(=O)NCc1ccc(Cl)cc1Cl

Procedure:
N-[(2,4-dichlorophenyl)methyl]-1-methyl-5-oxoprolinamide was prepared in a manner analogous to that described above for the synthesis of N-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-1-methyl-5-oxoprolinamide (Example 83) but [(2,4-dichlorophenyl)methyl]amine was substituted for {[4-fluoro-2-(trifluoromethyl)phenyl]methyl}amine.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH:6]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:17]=[C:10]3[C:9]2=[O:23])[CH2:5][C:4]([CH3:25])([CH3:24])[NH:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C)C1C=CN=CC=1>[C:27]([N:3]1[C:4]([CH3:25])([CH3:24])[CH2:5][CH:6]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:17]=[C:10]3[C:9]2=[O:23])[CH2:7][C:2]1([CH3:1])[CH3:26])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)N(C1CC(C)(C)NC(C)(C)C1)C2=O
Agent: CN(C)c1ccncc1
Product: CCOC(=O)c1ccc2c(c1)C(=O)N(C1CC(C)(C)N(C(C)=O)C(C)(C)C1)C2=O
Temperature: 0 °C

Procedure:
Into a 125 ml reaction flask equipped with a magnetic stirrer, thermometer, condenser and nitrogen atmosphere were placed the HALS of Example 4 (0.9 g, 0.0025 mol), 4-dimethylaminopyridine (0.03 g) and 25 ml of acetic anhydride. The reaction was refluxed for 2 hours, then poured into a beaker containing 200 ml ice water. A brown oil separated immediately and the mixture was stirred until the oil solidified into a tan solid. This solid was isolated by filtration and washed on the filter funnel with several portions of water. The wet solid was dissolved in 50 ml methylene chloride and dried with anhydrous magnesium sulfate. The solvent was stripped to give 0.9 g of light tan crystals melting at 119°-121° C. The infrared spectrum (in chloroform) showed a broad carbonyl absorption at 1710 cm-1 (imide and ester) and an amide carbonyl at 1615 cm-1.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH:31]1([CH2:34][NH2:35])[CH2:33]C1.[CH2:36](O)C>>[CH:34]1([N:35]([CH3:36])[C:2]2[N:6]=[C:5]([CH:7]3[CH2:12][CH:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[CH2:10][N:9]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH2:8]3)[O:4][N:3]=2)[CH2:31][CH2:33]1
Reactant: CCO
Reactant: NCC1CC1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Product: CN(c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1)C1CC1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a solution of 109 mg (0.245 mmol) of the oxadiazole from Example 23A in 2.0 ml of ethanol were added 523 mg (7.35 mmol) of cyclopropylmethylamine, and then the reaction mixture was stirred in the microwave at 90° C. for 12 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 42.0 mg (36% of theory)
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]([C:16]2[C:17](=[O:32])[NH:18][C:19](=[O:31])[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[CH:6]1)#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[C:1]([CH2:3][CH2:4][N:5]1[C:6]2[C:22]3[N:23]([CH3:30])[C:24]4[C:29]([C:21]=3[C:20]3[C:19](=[O:31])[NH:18][C:17](=[O:32])[C:16]=3[C:7]=2[C:8]2[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]1=2)=[CH:28][CH:27]=[CH:26][CH:25]=4)#[N:2]
Reactant: COc1ccc2c(c1)c(C1=C(c3cn(C)c4ccccc34)C(=O)NC1=O)cn2CCC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)c1c3c(c4c5ccccc5n(C)c4c1n2CCC#N)C(=O)NC3=O
Yield: 54.2 %

Procedure:
500 mg (1.18 mmol) 3-[1-(2-cyanoethyl)-5-methoxy-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione in 50 ml toluene are heated under reflux for 30 minutes with 225 mg (1.18 mmol) p-toluenesulphonic acid hydrate and 315 mg (1.39 mmol) 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). After cooling, the reaction mixture is evaporated in a vacuum and the residue is stirred with 100 ml 0.1N sodium hydroxide solution. The aqueous suspension is saturated with sodium chloride and extracted twice with, in each case, 100 ml tetrahydrofuran. The tetrahydrofuran solutions are washed twice with, in each case, 100 ml saturated sodium chloride solution. The residue is chromatographed on silica gel with toluene/acetone (4:1 v/v). The fraction with the Rf 0.3 is isolated, stirred up with diisopropyl ether and the crystals formed are filtered off. There are obtained 270 mg (54% of theory) 13-(2-cyanoethyl)-6,7,12,13-tetrahydro-3-methoxy-12-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole in the form of yellow crystals which decompose from about 260° C. with the evolution of gas.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[C:4]([C:18]([OH:20])=[O:19])=[CH:5][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[C:7]=1[CH3:8].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[C:7]([CH3:8])=[C:2]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[CH:29]=3)[C:3](=[O:21])[C:4]([C:18]([OH:20])=[O:19])=[CH:5]2)=[CH:11][CH:12]=1)#[N:17]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1c, 2.55 g, 7.34 mmol), 3-(trifluoromethyl)phenylboronic acid (1.65 g, 8.69 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (340 mg, 0.47 mmol) and Cs2CO3 (4.20 g, 12.9 mmol) in dioxane (20.0 mL) is heated for 72 h at 80° C. The reaction mixture is filtered over silica, the filtrate is concentrated under reduced pressure and purified by preparative reversed-phase HPLC (first purification: Sunfire, gradient of methanol in water, 0.1% TFA; second purification: Xbridge, gradient of methanol in water, 0.1% NH4OH, 60° C.). Yield: 514 mg (17% of theory); ESI mass spectrum: [M+H]+=413; Retention time HPLC: 1.37 min (Z002—005).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][N:26]1[C:30](=[O:31])[CH2:29][NH:28][C:27]1=[O:32]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:29][C:30](=[O:31])[N:26]([CH3:25])[C:27]4=[O:32])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1C(=O)CNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(=O)N(C)C4=O)cc3F)CC2)c(C)c1
Yield: 23.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and 3-methylimidazolidine-2,4-dione (46 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (40 mg) was obtained.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>O>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:17][CH:18]([C:19]3[N:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[S:22][CH:23]=3)[O:28][CH:30]2[C:29]([O:33][CH3:34])=[O:32])[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C=O
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OC2C(=O)OC)cc1

Procedure:
0.52 g (0.0012 mol) of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine and 0.211 g (0.0024 mol) of methyl glyoxylate and 25 ml toluene are heated at 120° C. for 10 minutes and then boiled under a water trap for 1 hour. The solution is cooled, 50 ml of ethyl acetate are added, and the mixture is shaken with 30 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated. The residue is purified on a laboratory size B prepacked column (supplied by Merck) using toluene/ethyl acetate =20:1.5 as eluant. Fraction A (diastereomer pairs A and B),
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][CH:3]=1.CO.[OH-].[Na+].[I:16]I>O>[I:16][C:11]#[C:10][CH2:9][O:8][C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: II
Reactant: C#CCOc1ccc(C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(OCC#CI)cn1
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A solution of 160 g (1.10 moles) 6-methyl-3-(2-propynyloxy)pyridine and 2000 ml methanol was cooled to 0° C. and 750 g 25% sodium hydroxide solution was slowly added. Iodine (362 g, 1.4 moles) was added portionwise and the resulting suspension stirred at 0°-10° C. for an additional 30 min. The reaction mixture was then poured into 4000 ml water and the solids filtered to give 250 g 3-(3-iodo-2-propynyloxy)-6-methylpyridine. Yield=90% Recrystallization from methanol gave analytically pure material, mp 155°-157° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26](=[O:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[CH3:29][Mg]Cl.C1COCC1>C(OCC)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:26]([OH:28])([CH3:29])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanone (0.732 g, 1.88 mmol) in diethyl ether (15.7 mL) and toluene (14.7 mL) at 0° C. under argon was added methylmagnesium chloride, 3.0 M solution in THF (1.38 mL, 4.14 mmol). After stirring at 0° C. for 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for another 1 hour. The reaction mixture was quenched with saturated NH4Cl solution and diluted with CH2Cl2; the aqueous layer was back-extracted with CH2Cl2. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification with 10% to 30% EtOAc/Hexanes afforded 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propan-2-ol as a colorless foam. MS (ESI) m/z: Calculated: 404.1; Observed: 405.1 (M++1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:13]1[NH:14][N:15]=[N:16][C:17]=1[CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1.ClC1C=CC(CN2N=NC(C3CCNCC3)=N2)=CC=1>>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:14]2[N:15]=[N:16][C:17]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:13]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nn[nH]n2)CC1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: Clc1ccc(Cn2nnc(C3CCNCC3)n2)cc1
Product: CS(=O)(=O)c1ccc(Cn2nnc(C3CCNCC3)n2)cc1

Procedure:
This was prepared from 4-methanesulphonylbenzyl bromide and tert-butyl 4-(2H-tetrazol-5-yl)piperidine-1-carboxylate using a similar method to that used to prepare 4-[2-(4-chloro-benzyl)-2H-tetrazol-5-yl]-piperidine (Method G, Steps 4 and 5); NMR (CDCl3): 1.8 (m, 2H), 2.05 (m, 2H), 2.8 (m, 2H), 3.05 (s, 3H), 3.1 (m, 1H), 3.2 (m, 2H), 5.89 (s, 2H), 7.55 (d, 2H), 7.95 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@H:13]3[OH:14])[C:6]=2[N:7]=1.[OH-:22].[Na+].Cl>>[NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c2nc(N)nc(Cl)c12
Agent: Cl
Agent: [Na+]
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c2nc(N)[nH]c(=O)c12
Reaction time: 1 h

Procedure:
To the compound from Step B (157 mg, 0.50 mmol) was added NaOH (2M, aqueous) (2 mL). The resulting solution was stirred at relux for 1 h, cooled and neutralized by addition of HCl (2M, aqueous). The mixture was evaporated in vacuo and the crude product purified on silica using methanol/dichloromehane (2:8) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (53 mg) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](C)(C)O[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])(=O)=O.Cl>CN(C)C=O.O.CO>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:11]=1[C:10]([O:9][CH3:8])=[O:12]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COC(=O)c1c(O)cccc1OCC(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A mixture of 5-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one (123 g, 633 mmol, Synth. Commun. 1994, 24, 1025), potassium carbonate (262 g, 1.9 mol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (95.8 mL, 665 mmol) in N,N-dimethylformamide (600 mL) was stirred at 50° C. for 30 min. Then methanol (300 mL) was added to the mixture, and stirring was continued for 5 h at that temperature. After cooling to room temperature, the mixture was diluted with water (500 mL) and neutralized with 2N hydrochloric acid. Product was extracted with a mixture of ethyl acetate-hexane (5:1, 500 mL×3). Combined organic layers were washed with water (500 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residual solid was recrystallized from methanol-water to afford 125 g (79%) of the desired product as colorless crystals.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][CH:33]1[CH2:37][N:36]([C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])[C@H:35]([C:44]([OH:46])=O)[CH2:34]1)=[O:6])[CH:2]=[CH2:3].ClC(OCC(C)C)=O.[CH2:55]([N:57](CC)[CH2:58]C)C>>[CH3:5][NH:7][CH3:8].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][C@H:8]1[CH2:32][CH:33]1[CH2:37][N:36]([C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])[C@H:35]([C:44](=[O:46])[N:57]([CH3:58])[CH3:55])[CH2:34]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1C[C@@H](C(=O)O)N(C(=O)OCC=C)C1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1C[C@@H](C(=O)N(C)C)N(C(=O)OCC=C)C1
Product: CNC
Yield: 184.8 %
Yield: 50 %

Procedure:
The same procedure as in Reference Example 25-8 was carried out by using (2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-carboxypyrrolidin-4-ylmethyl]-4-tritylthiopyrrolidine (300 mg, 0.47 mmol), isobutyl chloroformate (74 μl, 0.56 mmol), triethylamine (78 μl, 0.56 mmol) and a 50% dimethylamine aqueous solution (0.27 ml) to obtain (2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-(dimethylcarbamoyl)pyrrolidin-4-ylmethyl]-4-tritylthiopyrrolidine (290 mg, yield: 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[C:13]=1[CH:14]=O.[Si](C#N)(C)(C)C.[N:29]1([C:34](N2C=CN=C2)=[O:35])C=CN=[CH:30]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:14]([C:13]4[C:12]([F:11])=[CH:19][C:18]([O:20][CH3:21])=[CH:17][C:16]=4[F:22])[CH2:30][NH:29][C:34]3=[O:35])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: COc1cc(F)c(C=O)c(F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: C[Si](C)(C)C#N
Product: COc1cc(F)c(C2CNC(=O)N2c2ccc3[nH]cnc3c2)c(F)c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 2,6-difluoro-4-methoxybenzaldehyde (0.688 mL, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (1.2 mL, 8.6 mmol), di-(imidazol-1-yl)methanone (0.761 g, 4.69 mmol) as described in method 2. The product was purified by means of FPLC.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7](/[C:10](/[CH3:16])=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H][H].CCCCCC.C(OCC)(=O)C>CO.[Pt]=O>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7]([CH:10]([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1ncc(/C(C)=C/C(=O)OC)n1Cc1ccccc1Cl
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CCCCc1ncc(C(C)CC(=O)OC)n1Cc1ccccc1Cl

Procedure:
A mixture of methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-3-methyl-2-propenoate (165 rag, 0.476 mmol) in methanol (10 mL) and platinum oxide (20 mg) was shaken under one atmosphere of hydrogen for 3 hours. TLC on silica gel with 6:4 hexane/ethyl acetate showed a homogenous spot with an Rf 0.54. The catalyst was filtered, and the filtrate was concentrated to 154 mg (93%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](B(O)O)=[CH:24][CH:23]=1.[CH3:35][PH:36](=[O:38])[CH3:37]>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([P:36]([CH3:37])([CH3:35])=[O:38])=[CH:24][CH:23]=2)[CH:3]=1)[CH3:11]
Reactant: OB(O)c1ccc(Br)c2ccccc12
Reactant: C[PH](C)=O
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: CC(Oc1cc(-c2ccc(P(C)(C)=O)c3ccccc23)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 1-bromo-4-(dihydroxyboryl)naphthalene, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3. ESMS: m/z 503 (M+H)+.