Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][O:33][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:27]=3)[C:15](=[O:25])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][OH:33])[CH:27]=3)[C:15](=[O:25])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1N(c2ccccc2Br)Cc2cnc(Nc3ccccc3)nc2N1c1cccc(CO)c1
Yield: 54.7 %

Procedure:
A solution of 1.5 g (2 mmol) of 7-anilino-3-(2-bromophenyl)-1-[3-((tert-butyldiphenylsilyloxy)methyl)phenyl]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one in 30 ml of tetrahydrofuran was treated with 2.5 ml (2.5 mmol) of tetrabutylammonium fluoride (1M in tetrahydrofuran). The mixture was heated at reflux for 5 hours, cooled and evaporated. The residue was partitioned between 50 ml of ethyl acetate and 50 ml of 2M aqueous hydrochloric acid. The organic phase was washed with 40 ml of water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol 100:1 as eluent. Product-containing fractions were evaporated to give 550 mg (55%) of 7-anilino-3-(2-bromophenyl)-3,4-dihydro-1-[3-(hydroxymethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 136° C. [Mass spectrum (ESI) MH+ =486].
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH3:45])[CH:40]=2)[CH2:35]1)[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10](=[O:33])[C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[C:13]([O:25]CC2C=CC=CC=2)[CH:12]=1)[CH3:3].O>[Pd].C(O)C>[ClH:1].[CH2:2]([N:4]([CH:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH3:45])[CH:40]=2)[CH2:35]1)[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10](=[O:33])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:25])[CH:12]=1)[CH3:3]
Reactant: CCN(CCCCOC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C1CCc2cc(OC)ccc2C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCN(CCCCOC(=O)c1ccc(O)c(O)c1)C1CCc2cc(OC)ccc2C1
Yield: 84 %

Procedure:
2.5 g of N-ethyl-N-{4-[3,4-bis(benzyloxy)benzoyloxy]-butyl}-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride, 70 ml of water, 70 ml of ethanol and 0.5 g of a 5% palladium on carbon were mixed and reduced catalytically at a usual temperature under usual pressure. After absorption of the theoretical amount of hydrogen, the palladium on carbon catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to obtain 1.5 g of N-ethyl-N-[4-(3,4-dihydroxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride as a colorless resinous material.
Reaction SMILES: CN(C)/[CH:3]=[C:4](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:5](=O)[CH3:6].[NH:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][N:24]=1)[C:20]#[N:21])[NH2:16]>>[CH3:6][C:5]1[N:15]([C:17]2[CH:18]=[C:19]([C:20]#[N:21])[CH:22]=[CH:23][N:24]=2)[N:16]=[CH:3][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)/C(=C/N(C)C)c1ccccc1
Reactant: N#Cc1ccnc(NN)c1
Product: Cc1c(-c2ccccc2)cnn1-c1cc(C#N)ccn1
Yield: 34 %

Procedure:
The title compound was prepared in 34% yield from (3E)-4-(dimethylamino)-3-phenylbut-3-en-2-one and 2-hydrazinylisonicotinonitrile (PREPARATION 2) according to the procedure for the preparation of Example 28, part D. [M+H] Calc'd for C16H12N4, 261; Found, 261.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[CH3:23][C:24]1([CH3:32])[CH:29]([NH:30][CH3:31])[CH2:28][CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>CS(C)=O.C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][CH2:28][CH:29]([NH:30][CH3:31])[C:24]([CH3:32])([CH3:23])[CH2:25]2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: CNC1CCNCC1(C)C
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CC#N
Product: CNC1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)CC1(C)C
Temperature: 70 °C

Procedure:
A suspension of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylic acid (0.17 g, 0.55 mmol), 3,3-dimethyl-4-methylamino piperidine (0.15 g, 1.06 mmol) and triethylamine (1 g, 10 mmol) in a mixture of dimethylsulfoxide (10 ml) and acetonitrile (10 ml) was heated at 70° C. for 18 hr. Acetonitrile was distilled off, filtered to remove suspended impurities, diluted with water (5 ml). The precipitate thus separated was filtered, washed with water, dried and purified by silicagel column chromatography. Elute from a mixture of ethyl acetate and methanol furnished the required product. Yield 0.12 g (50%), m.p. 250° C. (decomp.), C22H29FN4O4, m/z 433 (M+1), PMR (DMSO-d6): 0.9 (m, 2H), 1.0 (m, 2H), 1.0 (s, 3H), 1.1 (s, 3H), 1.8-2.0 (m, 2H), 2.6 (s, 3H), 2.8-3.2 (m, 4H), 3.5 (s, 3H), 3.6 (s, 3H), 3.65 (m, 1H), 4.0 (m, 1H), 7.2 (bs, 2H, D2O exchangeable), 8.6 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][N:49]([CH3:53])[C:50](Cl)=[O:51]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:50]([N:49]([CH3:53])[CH3:48])=[O:51])[CH2:42][CH2:41]1
Reactant: CN(C)C(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 48 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and N,N-dimethylcarbamoyl chloride as starting materials in 48% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.57 (s, 1H), 9.43 (s, 1H), 9.32 (s, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.72 (s, 1H), 7.21 (d, 1H), 7.10 (m, 1H), 7.01 (d, 1H), 6.88 (d, 1H), 6.80 (d, 1H), 3.57 (d, 2H), 2.91 (m, 2H), 2.83 (m, 2H), 2.71 (m, 8H), 2.32 (d, 2H), 1.93 (m, 1H), 1.70 (m, 2H), 1.20 (m, 2H). LCMS for C28H33ClN7O2 (M+H)+: m/z=534.2.
Reaction SMILES: Br[C:2]1[C:3]([NH2:20])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:7]=1.[C:21]([C:23]1[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=1)#[CH:22].C1CCN2C(=NCCC2)CC1>C(#N)C.[Pd]>[NH2:29][C:27]1[N:28]=[C:23]([C:21]#[C:22][C:2]2[C:3]([NH2:20])=[N:4][CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=3)[N:7]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: C#Cc1cccc(N)n1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Agent: [Pd]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3cccc(N)n3)n2)cc1
Temperature: 100 °C
Yield: 25.4 %

Procedure:
3-bromo-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-amine (75 mg, 0.2105 mmol), 6-ethynylpyridin-2-amine (29.84 mg, 0.2526 mmol), Pd EnCat 30 (33.68 mg, 0.01347 mmol) and DBU (70.50 mg, 69.25 μL, 0.4631 mmol) were combined in acetonitrile (1.500 mL). The reaction mixture was heated at 100° C. under microwave conditions for 1.5 hours. After this time the solid residue was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 0 to 100% EtOAc/Petroleum Ether to 10% MeOH/DCM) to give the titled product as a beige solid (21 mg, 26% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.18 (d, 6H), 3.45 (sept, 1H), 6.20 (s, 2H), 6.52 (d, 1H), 7.06 (d, 1H), 7.07 (br s, 2H), 7.45 (dd, 1H), 7.90 (d, 2H), 8.25 (d, 2H) and 8.78 (s, 1H) ppm; MS (ES+) 394.1.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C1COCC1>[CH3:24][S:25]([O:1][N:2]=[C:3]1[CH:4]=[CH:5][C:6](=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:10]#[N:11])[CH:7]=[CH:8]1)(=[O:27])=[O:26]
Reactant: N#CC(=C1C=CC(=NO)C=C1)c1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON=C1C=CC(=C(C#N)c2cccs2)C=C1
Temperature: 0 °C
Yield: 29.4 %

Procedure:
4.5 g (20 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-thiophen-2-yl-acetonitrile are dissolved in 50 ml of THF and cooled in an ice bath. After adding 4.2 ml (30 mmol) of triethylamine to the solution, 1.7 ml (22 mmol) of methanesulfonyl chloride are added dropwise, keeping the temperature below 5° C. The reaction mixture is stirred in the ice bath for 30 min. The reaction mixture is poured into 200 ml of water, and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by recrystallization from toluene. 1.8 g (30%) of (4-Methylsulfonyloxyimino-cyclohexa-2,5-dienylidene)-thiophen-2-yl-acetonitrile are obtained in the form of orange crystals having a melting point of 123-125° C. (dec.).
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]([CH2:13][C:14](C)(C)[CH3:15])[C:10](O)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:38])([F:37])[O:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:32][C@@H:31]3[C@@H:33]([NH2:36])[CH2:34][CH2:35][C@@H:30]3[CH2:29]2)[CH:25]=[CH:26][CH:27]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:6][NH:8][C@H:9]([C:10]([NH:36][C@@H:33]1[C@@H:31]2[C@@H:30]([CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:19])([F:37])[F:38])[CH:23]=3)[CH2:32]2)[CH2:35][CH2:34]1)=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(OC(F)(F)F)c3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CCC[C@H](NC)C(=O)N[C@H]1CC[C@@H]2CN(c3cccc(OC(F)(F)F)c3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-norvaline for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(3-(trifluoromethoxy)phenyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 715 Step 1 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (400 MHz, pyridine-d5, temperature 90° C.) δ ppm 7.63-7.68 (bs, 1H), 7.18 (t, J=8.4 Hz, 1H), 6.60-6.64 (m, 1H), 6.51-6.54 (m, 2H), 4.27 (dt, J=13.2, 6.6 Hz, 1H), 3.47 (dd, J=9.9, 3.8 Hz, 1H), 3.35 (dd, J=9.9, 7.9 Hz, 1H), 3.22 (dd, J=9.6, 8.0 Hz, 1H), 3.10 (dd, J=6.9, 5.8 Hz, 1H), 3.01 (dd, J=9.6, 4.1 Hz, 1H), 2.63-2.80 (m, 2H), 2.39 (s, 3H), 2.05-2.13 (m, 1H), 1.92-2.01 (m, 1H), 1.74-1.83 (m, 1H), 1.58-1.69 (m, 2H), 1.37-1.54 (m, 3H), 0.88 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 400 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[C:1]([NH:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCI
Reactant: CC(C)(C)NC(=O)NCc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCNCc1ccc(CNC(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
A mixture of 0.97 g 4-(3-t-butylureidomethyl)-1-aminomethylbenzene obtained in Example 8, 0.57 g anhydrous potassium carbonate and 20 ml dimethylformamide was stirred at room temperature for 30 minutes, 0.93 g 1-iodoheptane was added, and stirring was continued at room temperature for an additional three hours. After distilling off the solvent under reduced pressure, the residue was extracted with chloroform, and the extract was washed with water. The chloroform was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography, giving 0.65 g of 4-(3-t-butylureidomethyl)-1-(N-heptylaminomethyl)benzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[S:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6](Br)[CH:5]=1.[CH2:13]([O:15]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:14].O.Cl>O1CCOCC1.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>[CH3:1][O:2][C:3](=[S:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:13](=[O:15])[CH3:14])[CH:5]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=S)c1ccc(C)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=S)c1ccc(C)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Bromo-4-methylthiobenzoic acid methyl ester (0.86 g), 1-ethoxyvinyl tributyl tin (1.39 ml) and tetrakis triphenylphosphinepalladium (IV) (0.15 g) were combined in dioxan (50 ml) and boiled for 24 h. The mixture was cooled, water (10 ml) and conc. hydrochloric acid (1 ml) added and the mixture stirred at room temperature overnight. Solvent was removed at reduced pressure, the residue dissolved in ethyl acetate and filtered through celite. The filtrate was evaporated to dryness and the residue triturated with hexane to give 3-acetyl-4-methylthiobenzoic acid methyl ester (0.45 g) as a yellow solid. m/z (API+): 225 (MH+).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@@H:10]([C@@H:12]([NH:17]C(=O)OC(C)(C)C)[CH2:13][CH2:14][CH2:15][CH3:16])[OH:11])[CH:5]=[CH:4][CH:3]=1.FC1N=C(NC[C@H]([C@@H](NC(=O)OC(C)(C)C)CCCC)O)C=CC=1.Cl.C(N(CC)C(C)C)(C)C.[C:59](=[O:92])(OC1C=CC([N+]([O-])=O)=CC=1)[O:60][C@H:61]([CH2:66][N:67]1[CH:71]=[CH:70][C:69]([C:72]2[CH:77]=[CH:76][C:75]([C:78]([F:81])([F:80])[F:79])=[CH:74][CH:73]=2)=[N:68]1)[C:62]([CH3:65])([CH3:64])[CH3:63]>O1CCOCC1.CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@@H:10]([C@@H:12]([NH:17][C:59](=[O:92])[O:60][C@H:61]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([C:72]3[CH:73]=[CH:74][C:75]([C:78]([F:80])([F:79])[F:81])=[CH:76][CH:77]=3)=[N:68]2)[C:62]([CH3:63])([CH3:65])[CH3:64])[CH2:13][CH2:14][CH2:15][CH3:16])[OH:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[C@@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNc1cccc(F)n1
Agent: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)CNc1cccc(F)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@@H](O)CNc1cccc(F)n1
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of 40 mg (0.12 mmol) of tert-butyl (1S)-1-{(1S)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate & tert-butyl (1S)-1-{(1R)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate in 1 mL dioxane was added 5 mL of 4M hydrochloric acid in dioxane. The reaction mixture was stirred for 2 h before being concentrated under reduced pressure. The residue was dissolved in 1 mL of N,N-dimethylformamide before 0.081 mL (0.47 mmol) of N,N-diisopropylethylamine and 56 mg (0.12 mmol) of (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl 4-nitrophenyl carbonate were added. The reaction mixture was stirred at room temperature for 18 h, diluted with ethyl acetate, washed with 1M sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexanes (2:3) to afford 40 mg (59%) of (1S)-2,2-dimethyl-1-({3-[4(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1S)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate & (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1R)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate. ES-LCMS m/z 602 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:40][C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (146 mg, 0.428 mmol), EDC (115 mg, 0.599 mmol), and HOBT (81 mg, 0.599 mmol) in DMF (8 mL) was added p-toluidine (46 mg, 0.43 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (94 mg) as a yellow solid. LC-MS (ES) m/z=431 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.Cl.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[N:27]2)=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Product: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1
Yield: 95.2 %

Procedure:
Using 4,4,4-trifluoro-1-phenyl-1,3-butanedione and 4-nitrophenylhydrazine hydrochloride as the raw materials, the same operation as the Example 538(1) gave the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(=O)C.[Na+]>CN(C=O)C>[C:9]([S:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[NH2:2])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
L-Cysteine hydrochloride (100 g, 0.634 mol) and trityl chloride (270 g, 0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature. A 10% sodium acetate solution (3.5 L) was then added dropwise and the white precipitate which formed was filtered and washed with distilled water. Afterward, the residue was stirred in acetone at 50° C. for 30 min after which it was cooled to 0° C. and filtered. The precipitate was washed with a little acetone and diethyl ether and dried in vacuo. S-Trityl-L-cysteine 1b (205 g, 89%) was obtained as a white powder. 1b: m.p. 192° C. (decomp). 1H NMR (DMSO-d6) δ 2.45 (dd, 1H, J=9 Hz, 12 Hz), 2.58 (dd, 1H, J=4.4 Hz, 12 Hz), 2.91 (m, 1H), 7.22-7.36 (m, 15H); 13C NMR (75.5 MHz, DMSO-d6): δ 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4, 129.5, 144.5, 168.4. This material was directly used in the next step without further purification.
Reaction SMILES: C([O:4][CH2:5][C:6](Cl)=[O:7])(=O)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:26][C@H:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:28]([NH2:30])[CH3:29])=[C:22]([CH3:25])[CH:23]=3)[CH:18]=[N:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:26][C@H:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C@@H:28]([NH:30][C:5](=[O:4])[CH2:6][OH:7])[CH3:29])=[C:22]([CH3:25])[CH:23]=3)[CH:18]=[N:17]2)=[CH:14][CH:15]=1
Reactant: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O[C@H](c1ccccc1)[C@H](C)N
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O[C@H](c1ccccc1)[C@H](C)NC(=O)CO
Reaction time: 8 h
Yield: 77.4 %

Procedure:
Acetoxyacetyl chloride (0.071 mL, 0.66 mmol) was added to a solution of (1R,2S)-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yloxy)-1-phenylpropan-2-amine (62 mg, 0.17 mmol) and triethylamine (0.18 mL, 1.3 mmol) in THF (2.5 mL) at r.t. The mixture was stirred overnight and concentrated. The residue was dissolved in methanol (2 mL) and 28% ammonia (2 mL) and stirred at r.t. overnight. The title compound (57 mg, 80%) was obtained after purification by semi-preparative HPLC.
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].O(C)S([C:24](F)(F)F)(=O)=O.C(O)(=O)C>ClCCCl.[Pt](=O)=O>[C:1]([C:3]1([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[CH3:24])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)(c2ccccn2)C1
Reactant: COS(=O)(=O)C(F)(F)F
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCCCC1C1(C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-butyl 3-cyano-3-pyridin-2-ylazetidine-1-carboxylate (14.2 g, 55 mmol) in 1,2-dichloroethane (120 ml) was cooled in an ice-bath and treated with methyl triflate. The reaction was stirred at room temperature for 1 hour then at reflux overnight (no starting material in the solution). The resulting orange/brown precipitate was filtered off and washed with more 1,2-dichloroethane. The solid was then dissolved in ethanol (150 ml) and acetic acid (1.5 eq, 5.5 ml) was added. Platinum dioxide (1.5 g) was added and the reaction hydrogenated on a parr at 40 psi overnight. Tlc and mass spec showed complete conversion. The reaction was filtered under nitrogen and the filtrate was evaporated to dryness to give tert-Butyl 3-cyano-3-(1-methylpiperidin-2-yl)azetidine-1-carboxylate as an oil which was used without further purification. m/z (M++H) 280.