Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][O:5][CH2:4]1.Cl.[NH2:16][OH:17].C(N(CC)CC)C>C(O)C>[OH:17][N:16]=[C:11]([C:10]1[CH:9]=[CH:8][C:7]([C:3]2([O:2][CH3:1])[CH2:6][O:5][CH2:4]2)=[CH:14][CH:13]=1)[NH2:12]
Reactant: COC1(c2ccc(C#N)cc2)COC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC1(c2ccc(C(N)=NO)cc2)COC1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A solution of 4-(3-methoxyoxetan-3-yl)benzonitrile (Step 1, 500 mg, 2.64 mmol), hydroxylamine hydrochloride (403 mg, 5.81 mmol) and triethylamine (810 μL, 5.81 mmol) in ethanol (12.5 mL) was stirred and heated at reflux for 2 h. After being cooled to rt, the reaction mixture was evaporated to dryness. The resulting material was treated with a mixture of water (5 mL) and diethyl ether (0.5 mL). The solid was isolated by filtration, washed with a small amount of cold water and dried in a vacuum oven to afford the title compound as a colorless solid (520 mg, 86%): 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.73 (d, 2H), 7.43 (d, 2H), 5.84 (broad s, 2H), 4.79-4.75 (m, 4H), 3.01 (s, 3H); DCI(NH3)-MS m/z 223 (MH)+; HPLC RT (Method I) 2.54 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH:10]([OH:21])[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+]>O1CCCC1>[CH2:23]([O:21][CH:10]([CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH3:22])[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:13])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(CC(O)CN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CC(CN(C)C(=O)OC(C)(C)C)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To an ice-cold solution of N,N′-bis(t-butoxy-carbonyl)-2-hydroxy-N,N′-dimethyl-1,3-propanediamine (87.0 mg, 0.27 mmol) in tetrahydrofuran (4.0 mL) were added benzyl bromide (230.0 mg, 1.35 mmol) and a 50% dispersion of sodium hydride in mineral oil (35.0 mg, 0.81 mmol). The reaction mixture was stirred at room temperature for 15 hours and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield 2-benzyloxy-N,N′-bis(t-butoxycarbonyl)-N,N′-dimethyl-1,3-propanediamine, obtained as a colorless oil (54.0 mg, yield: 49%).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[C:18]3[N:19]=[C:20]([CH2:35][CH2:36][CH2:37][CH3:38])[N:21]=[C:22]([NH:23]CC4C=CC(OC)=CC=4OC)[C:17]=3[NH:16][N:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[N:1]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[C:18]3[N:19]=[C:20]([CH2:35][CH2:36][CH2:37][CH3:38])[N:21]=[C:22]([NH2:23])[C:17]=3[NH:16][N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(CCCCCCN3CCCCCC3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc(N)c2[nH]nc(CCCCCCN3CCCCCC3)c2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 220.6 %

Procedure:
3-(6-(Azepan-1-yl)hexyl)-5-butyl-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (0.100 g, 0.191 mmol) was dissolved in trifluoroacetic acid (2 mL, 26.0 mmol) at ambient temperature. The reaction mixture was stirred at 60° C. for 4 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in 3:1 chloroform:IPA (15 mL) and washed with aqueous sodium hydroxide (0.1 M, 5 mL). The organic phase was separated using a hydrophobic frit and evaporated in vacuo to give a brown oil (0.157 g). The oil was dissolved in MeOH:DMSO (1:1) (2 mL) and purified by MDAP (Method B). Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as an off-white solid (38 mg).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].ClCCl.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]1[CH:42]=[C:41]([O:43][CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[N:40]=[CH:39][N:38]=1)[CH2:32][CH2:31]2)(=[O:27])=[O:26]>O>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]1[N:38]=[CH:39][N:40]=[C:41]([O:43][CH:44]3[CH2:49][CH2:48][N:47]([C:11]([O:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:12])[CH2:46][CH2:45]3)[CH:42]=1)[CH2:32][CH2:31]2)(=[O:27])=[O:26]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
Diisopropylethylamine (93 μL, 0.53 mmol) and benzyl chloroformate (57 μL, 0.40 mmol) were added at 0° C. to a dichloromethane (5 mL) solution of the 5-(methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]indoline (100 mg, 0.267 mmol) produced in Reference Example 28, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, water was added, followed by extraction with dichloromethane three times. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1-1:1, V/V). The obtained crude product was washed with diisopropyl ether to obtain the title compound as white powder (67.3 mg, yield: 50%).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1>CO.[Pd]>[OH:1][NH:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: O=C(CCCCC/C=C/c1ccc2ccccc2c1)NO
Agent: [Pd]
Solvent: CO
Product: O=C(CCCCCCCc1ccc2ccccc2c1)NO
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
To a solution of compound 179 (30 mg, 0.106 mmol) in methanol (2 mL) was added a catalytic amount of 10% palladium on charcoal. The mixture was degassed and applied under hydrogen atmosphere and stirred for 15 minutes. Hydrogen was evacuated by vacuum and the mixture was filtered through Celite and rinsed with methanol. The filtrate was concentrated in vacuo, affording the title compound 180 (29.1 mg) in 97% yield. 1H NMR: (300 MHz, CD3OD) δ: 7.80-7.74 (m, 3H), 7.60 (s, 1H), 7.44-7.37 (m, 2H), 7.33 (dd, J=8.2, 1.6 Hz, 1H), 2.77 (t, J=7.4 Hz, 2H), 2.07 (t, J=7.1 Hz, 2H), 1.71-1.64 (m, 2H), 1.62-1.57 (m, 2H), 1.37-1.28 (m, 6H). HRMS (calc.): 285.1729, (found): 285.1727.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:16])O[C:10](C)(C)[O:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[N:18][C:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C(C)=CC=CC=1>[CH3:13][C:12]1[O:11][CH2:10][N:18]([C:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:8](=[O:16])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Reactant: C=NC(C)(C)C(C)(C)C
Solvent: Cc1ccccc1C
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(C)(C)C)CO1
Yield: 46.7 %

Procedure:
A mixture of 5-phenyl-2,2,6-trimethyl-2h,4h-1,3-dioxin-4-one (0.65 g), N-methylene-1,1,2,2-tetramethylpropylamine (0.54 g) and xylene (2 ml) was heated at reflux for 30 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.40 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:17][C:13]1[N:14]([CH3:16])[O:15][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]#[N:25])[CH:3]=3)[O:8][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[CH2:10]2)[N:12]=1
Reactant: CN1OC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(C3CCCOC3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 12.4 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (40 mg, 0.1 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.4 mL) and 3-cyanophenylboronic acid (31 mg, 0.2 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-(3′-amino-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (5 mg, 10%). 1H-NMR (MeOD): 1.69 (m, 2.5H), 2.01 (m, 3H), 2.51 (m, 1H), 2.72 (m, 1H), 3.42 (d, 2H), 3.52 (m, 3H), 3.90 (m, 2H), 4.15 (m, 1.5H), 7.02 (d, 1H), 7.59 (t, 1H), 7.68 (m, 2H), 7.94 (m, 3H).
Reaction SMILES: CN([CH2:4][CH2:5]N(C)C)C.C([Li])(CC)C.[F:14][S:15]([F:28])([F:27])([F:26])([F:25])[C:16]1[CH:24]=C[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.CI.Cl>C1COCC1.C1CCCCC1.O>[F:14][S:15]([F:25])([F:26])([F:27])([F:28])[C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[C:4]([CH3:5])[CH:24]=1
Reactant: CN(C)CCN(C)C
Reactant: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCCCC1
Product: Cc1cc(S(F)(F)(F)(F)F)ccc1C(=O)O
Temperature: -90 °C
Reaction time: 1 h

Procedure:
3.09 g of TMEDA were dissolved in 30 ml of THF (anhydrous) and added dropwise at −90° C. to 20.5 ml of a 1.3M solution of sec-butyllithium in cyclohexane. A solution of 3.0 g of 4-pentafluorosulfanylbenzoic acid in 20 ml of THF (anhydrous) was then added dropwise at −90° C. After stirring at −90° C. for one hour, a solution of 5.15 g of methyl iodide in 20 ml of THF (anhydrous) was added dropwise. The temperature was kept at −80° C. during this. After stirring at −78° C. for 20 minutes, 100 ml of water were injected, a dilute aqueous HCl solution was used to adjust to pH=1, and the mixture was extracted 3 times with 100 ml of MTB each time. After drying over MgSO4, the solvent was removed in vacuo. The residue was initially chromatographed on silica gel with DIP/2% HOAc, and 1.60 g of a mixture of 4-pentafluorosulfanylbenzoic acid and 4-pentafluorosulfanyl-2-methylbenzoic acid were obtained. This mixture was rechromatographed under the following conditions:
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][C:18]([O:20]CC)=[O:19])[N:16]=1)=[CH:8]2.[OH-].[Na+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][C:18]([OH:20])=[O:19])[N:16]=1)=[CH:8]2
Reactant: CCOC(=O)Cc1csc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(-c3nc(CC(=O)O)cs3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A mixture of ethyl (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-4-yl)acetate (0.31 g), 1N aqueous sodium hydroxide solution (2.0 mL), tetrahydrofuran (6 mL) and methanol (6 mL) was stirred at 50° C. for 2 hr. To the reaction mixture was added 10% citric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.18 g, yield 63%) was obtained as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 214-215° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:20][C:21]1([C:24]([O:26][CH3:27])=[O:25])[CH2:23][CH2:22]1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12][NH:20][C:21]1([C:24]([O:26][CH3:27])=[O:25])[CH2:23][CH2:22]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Reactant: COC(=O)C1(N)CC1
Agent: Cl
Product: COC(=O)C1(NCc2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)CC1
Yield: 79 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)-4-methoxybenzaldehyde (Example 12-2c) and methyl 1-aminocyclopropanecarboxylate hydrochloride. Yield 79%. MS 366 (MH+).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][NH:12][C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1.O1CCCC1.C(N(CC)CC)C>O>[CH2:1]([NH:8][C:9](=[O:10])[N:12]([C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)CCc1ccc(-c2cccc(NC)c2)nc1
Reactant: CCCCCCCN=C=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OCC)cn2)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 65.2 %

Procedure:
572 μL (3.5 mmol, 2 eq) of heptyl isocyanate are added to a solution of 500 mg (1.76 mmol, 1 eq) of ethyl 3-[6-(3-methylaminophenyl)pyrid-3-yl]propanoate in 10 mL of a 4/1 tetrahydrofuran/triethylamine mixture. The reaction mixture is stirred for 24 hours at 40° C. The reaction is stopped by adding 30 ml of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 488 mg of ethyl 3-{6-[3-(3-heptyl-1-methylureido)phenyl]pyrid-3-yl}propanoate are obtained. Yield=65%.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:5]=2[O:4]1.[CH3:15][O:16][CH2:17]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:15][O:16][CH2:17][O:1][CH2:2][CH:3]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:5]=2[O:4]1
Reactant: COc1cccc2c1OC(CO)C2=O
Reactant: COCOC
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: ClCCl
Product: COCOCC1Oc2c(OC)cccc2C1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58 %

Procedure:
2,3-dihydro-2-hydroxymethyl-3-oxo-7-methoxybenzofuran (1.79 g) and dimethoxymethane (10 ml) were dissolved in dichloromethane (25 ml) and phosphorus pentoxide (3.47 g) was added to the obtained solution, followed by stirring the resulting solution at room temperature for 3.5 hours. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layers were combined and washed with water and with saturated brine, followed by drying over magnesium sulfate. Magnesium sulfate was removed by filtration and the solvent was evaporated off. The residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=1/1) to obtain the desired compound (912 mg, yield: 58%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1>>[Br:1][C:2]1[C:3]([N:25]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 171.1 using 5-bromo-6-chloro-N-(4-(2-chloro-1,1,2,2-tetrafluoroethyl)phenyl)nicotinamide (Stage 278.2) and (R)-pyrrolidin-3-ol to afford a white powder. HPLC (Condition 4) tR=6.05 min, UPLC-MS (Condition 3) tR=1.18 min, m/z=498 [M+H]+.
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH:29](=O)[CH2:30][CH2:31]C>>[CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[C:21]=4[CH2:29][CH2:30][CH3:31])[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Reactant: CCCC=O
Product: CCCc1c2c(nc3cc(F)ccc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 2 is treated with butyraldehyde according to a procedure similar to Stage 13e in order to produce the expected solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:12]([F:17])([F:16])([F:15])([F:14])[F:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([S:12]([F:14])([F:15])([F:16])([F:17])[F:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([N:20]([O:21][CH3:22])[CH3:19])=[O:9]
Reactant: CNOC
Reactant: Cc1cc(S(F)(F)(F)(F)F)c(N)cc1C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(N)c(S(F)(F)(F)(F)F)cc1C
Reaction time: 4 h

Procedure:
5-Amino-2-methyl-4-(pentafluorosulfanyl)benzoic acid (500 mg, WO 2005/47239) was dissolved in methylene chloride (30 ml) and admixed while stirring with N,O-dimethylhydroxylamine hydrochloride (176 mg), 1-propanephosphonic anhydride (1.1 ml) and triethylamine (0.25 ml). After stirring for 4 h and leaving to stand overnight, the reaction mixture was concentrated, the residue was taken up with ethyl acetate and the solution was washed twice with potassium hydrogen sulfate solution and twice with sodium hydrogencarbonate solution. After drying over magnesium sulfate, the organic phase was filtered and concentrated. The resulting crude product (500 mg) was converted further directly.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([C:13]2[CH:14]=[N:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[NH2:29][CH:8]([C:6]1[C:5]([O:11][CH3:12])=[C:4]([C:13]2[CH:14]=[N:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=2)[C:3]([CH3:22])=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: [BH3-]C#N
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cnc(N(C)C)nc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1cnc(N(C)C)nc1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-methoxy-4-methylphenyl}ethanone (60 mg, 0.2 mmol), ammonium acetate (150 mg, 1.9 mmol) and sodium cyanoborohydride (24 mg, 0.38 mmol) in methanol (0.7 mL) and acetonitrile (0.7 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (60 mg, 100%). LCMS calculated for C16H22ClN4O (M+H)+: m/z=321.1. found: 321.1.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:7](=[O:8])[C@@H:6]([CH3:9])[S:5][C@H:4]1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>C(O)C>[ClH:1].[CH3:2][N:3]1[C:7](=[O:8])[CH:6]([CH3:9])[S:5][CH:4]1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[C@H]1S[C@@H](c2cccnc2)N(C)C1=O
Agent: Cl
Solvent: CCO
Product: CC1SC(c2cccnc2)N(C)C1=O
Temperature: 0 °C
Yield: 86.2 %

Procedure:
Conc. aqueous HCl (4.75 g, 45.6 mmol) was added dropwise to a solution of cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one (10 g, 48 mmol) from Example 2 in ethanol (50 ml) at room temperature. Then the mixture was cooled to 0° C., and the precipitated crystals were filtered and the title compound (9.621 g, 86.28 yield) was obtained. m.p. 190°-193° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:34])[C:12]([CH3:33])([CH3:32])[CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH2:7][CH2:6]1.S.[OH-].[Li+].Cl.[N:40]1C=CC=CC=1>CO.C(N(CC)CC)C>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:15]([NH:14][CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[C:12]([CH3:32])([CH3:33])[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:2])=[O:35])[CH2:6][CH2:7]2)=[O:34])=[O:24])=[CH:21][CH:20]=1)(=[NH:40])[NH2:23]
Reactant: c1ccncc1
Reactant: COC(=O)CC1CCN(C(=O)C(C)(C)C(NC(=O)c2ccc(C#N)cc2)c2cccc(Cl)c2)CC1
Agent: Cl
Agent: S
Agent: [Li+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C(=O)N1CCC(CC(=O)O)CC1)C(NC(=O)c1ccc(C(=N)N)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
N-4-Cyanobenzoyl-β-m-chlorophenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid methyl ester (80 mg, 0.16 mmol) was dissolved in pyridine (10 ml). To the resulting solution was added triethylamine (1 ml) and the mixture was saturated with hydrogen sulfide gas. The reaction vessel was sealed and the reaction mixture was stirred at room temperature overnight. The pyridine was distilled off and the volatile products were removed by two cycles of toluene azeotropy. The residue was dissolved in acetone (15 ml) and methyl iodide (1 ml) was added thereto, followed by refluxing for 30 minutes. The solvent was distilled off and the residue was dissolved in methanol (10 ml). To the obtained solution was added ammonium acetate (100 mg) and the mixture was refluxed for 2 hours. After the solvent was distilled off, the residue was dissolved in chloroform, washed with a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate. The obtained crude N-4-amidinobenzoyl-β-m-chlorophenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid methyl ester (18 mg) was dissolved in an 50% aqueous methanol solution (10 ml). To the resulting solution was added a 2N aqueous solution of lithium hydroxide (3 ml) at room temperature and the mixture was stirred for 15 minutes. After the reaction solution was neutralized with 3N HCl to pH 7, the solvents were distilled off and the residue was dissolved in a 1N aqueous solution of acetic acid. The resulting solution was purified with a HPLC to yield N-(N-4-amidinobenzoyl-β-m-chlorophenyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid (3.5 mg, 20.0%).