Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[O:11]=[C:12]1[C:17]2[S:18][CH:19]=[C:20]([S:21](Cl)(=[O:23])=[O:22])[C:16]=2[CH2:15][CH2:14][CH2:13]1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[S:21]([C:20]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:11])[C:17]=2[S:18][CH:19]=1)(=[O:22])=[O:23]
Reactant: CNCCc1ccncc1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Product: CN(CCc1ccncc1)S(=O)(=O)c1csc2c1CCCC2=O

Procedure:
From methyl-(2-pyridine-4-yl-ethyl)-amine (the compound of Preparation Example 16) (82 mg) and 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (150 mg), the title compound (100 mg) was obtained as a colorless oily matter, in the same way as Preparation Example 41.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:20]([O-])=O)=[C:13]([C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])[CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:20][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][C:13]=1[C:15](=[O:19])[CH:16]([CH3:17])[CH3:18]
Reactant: C=C(C)C(=O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)c1cc(O)ccc1N
Reaction time: 4.5 h
Yield: 63.2 %

Procedure:
0.2 g of palladium/carbon (10%) is suspended in a solution of 1.34 g (4.51 mmol) of 1-[5-(benzyloxy)-2-nitrophenyl]-2-methyl-2-propen-1-one in 50 ml of ethanol. The mixture is shaken under a hydrogen atmosphere at 3 bar for 4.5 h, then the mixture is filtered off through kieselguhr, the filtrate is concentrated in vacuo and the residue is purified on silica gel (cyclohexane/ethyl acetate 5:2-1:1). 511 mg (63%) of 1-(2-amino-5-hydroxyphenyl)-2-methyl-1-propanone are obtained.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].O.[NH3:13]>C(#N)C>[NH2:13][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: N#Cc1c(F)ccc(F)c1F
Solvent: CC#N
Solvent: O
Product: N#Cc1c(F)ccc(F)c1N

Procedure:
2,3,6-Trifluorobenzonitrile (1.76 ml, 15.2 mmol) in aqueous ammonia (20 ml) and acetonitrile (10 ml) was stirred for 7 days. Water was added. The whole was extracted with ether, the ether was dried (sodium sulphate) and evaporated. Flash column chromatography on silica gel, eluting with dichloromethane, gave the product (1.2 g), MS (+EI) 154 (M+), 1H NMR (CDCl3) 7.07-7.16 (1H, m), 6.36-6.43 (1H, m), 4.62 (2H, s).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:20](=[O:36])[CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)(=O)=O)C=CC=CC=1>CO.[OH-].[Na+]>[NH2:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11]([C:20](=[O:36])[CH2:21][CH2:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:27][CH2:28]1)=[CH:12]2
Reactant: Nc1ccc2c(c1)cc(C(=O)CCC1CCN(Cc3ccccc3)CC1)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc2[nH]c(C(=O)CCC3CCN(Cc4ccccc4)CC3)cc2c1
Yield: 124.5 %

Procedure:
A solution of 1-(1-Phenylsulfonyl-5-amino-indol-2-yl)-3-(N-phenylmethylpiperidin-4-yl)-1-propanone (160 mg, 0.32 mmol) in 3 ml of methanol and 2 ml of 2N NaOH was heated at reflux for 2 hours. The mixture was concentrated to dryness and the residue was diluted with brine and extracted with chloroform. The organic layer was dried and concentrated to dryness to give 144 mg of brown solid which was purified through silica gel column chromatography to give 31 mg of the title compound as a brown solid.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][CH2:6][S:7][C:8]1[N:12]([CH3:13])[N:11]=[N:10][N:9]=1)C.Cl.O>C(O)(=O)C>[CH3:13][N:12]1[C:8]([S:7][CH2:6][CH2:5][C:4]([OH:14])=[O:3])=[N:9][N:10]=[N:11]1
Reactant: CCOC(=O)CCSc1nnnn1C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cn1nnnc1SCCC(=O)O

Procedure:
5.43 g of 3-(1-methyltetrazol-5-ylthio)-propionic acid ethyl ester are dissolved in 20 ml of acetic acid, 4 ml of conc. HCl and 8 ml of water and the whole is stirred for 3.5 hours at 100°. After concentration of the reaction mixture by evaporation, the residue is partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous phase is separated off, acidified with 4N HCl and extracted twice with ethyl acetate. After drying and concentration by evaporation the title compound is obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:10][O:9]1)([CH3:3])[CH3:2].[NH2:18][CH2:19][C@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=3)[CH:26]=2)[O:21]1.[OH-].[Na+]>C(O)(C)C>[CH:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:5]=1[O:6][CH2:7][C@@H:8]([OH:9])[CH2:10][NH:18][CH2:19][C@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]3[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)[CH:26]=2)[O:21]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CN)O3)cc1
Reactant: CC(C)c1cccc(C(C)C)c1OC[C@@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)c1cccc(C(C)C)c1OC[C@@H](O)CNC[C@H]1CCc2cc(-c3ccc(C(=O)O)cc3)ccc2O1
Temperature: 80 °C
Reaction time: 72 h
Yield: 41.8 %

Procedure:
Crude (2S)-2-[(2,6-diisopropylphenoxy)methyl]oxirane (Example 17, 0.55 mmol), was diluted in 2 mL of isopropanol (10% water), and treated with methyl 4-[(2R)-2-(aminomethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 39, 88 mg, 0.26 mmol). This mixture was stirred at 80° C. for 72 hours, then 1N sodium hydroxide (2 mL) was added to the solution at room temperature, and stirred for another 0.5 hour. The product was then purified by preparative HPLC (Gradient 0-70% Acetonitrile/0.1% aq. TFA) to obtain 56.3 mg of product (as a TFA salt) MH+518.3 (free base).
Reaction SMILES: Cl[C:2]1[C:3]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(OCCO)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[C:3]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2c1oc1ccccc12
Reactant: Nc1cccc(Br)c1
Solvent: CCOCCO
Product: Brc1cccc(Nc2ncnc3c2oc2ccccc23)c1
Yield: 8.1 %

Procedure:
A mixture of 4-chlorobenzofurano[3,2-d]pyrimidine (116mg, 0.57 mmol) and 3-bromoaniline (0.07 mL, 0.6 mmol) is heated at 135° C. under N2 in stirred 2-ethoxyethanol for 3 h. The mixture precipitates upon cooling, and the solid is collected and recrystallized from EtOH to give 4-(3-bromoanilino)benzofurano[3,2-d]pyrimidine (15.7 mg, 8%). 1H NMR (DMSO) δ10.35 (1H, s), 8.73 (1H, s), 8.34 (1H, t, J=1.9 Hz), 8.17 (1H, ddd, J=7.2, 1.2, 0.7 Hz), 7.93 (1H, ddd, J=8.2, 2.2, 1.0 Hz), 7.88 (1H, d, J=8.4 Hz), 7.77 (1H, dt, Jd =1.4 Hz, Jt =7.2 Hz), 7.56 (1H, dt, Jd =0.8 Hz, Jt =8.0 Hz), 7.34 (1H, t, J=8.0 Hz), 7.27 (1H, ddd, J=8.0, 2.0, 1.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[CH:44][C:45]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH3:57])[CH2:52][CH2:51]2)=[O:49])=[N:46][CH:47]=1.COC(=O)C1C=CC(Br)=CC=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[CH:44][C:45]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH2:56][CH3:57])[CH2:54][CH2:55]6)=[O:49])=[N:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CCN1CCN(C(=O)c2ccc(Br)cn2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: COC(=O)c1ccc(Br)cc1
Product: CCN1CCN(C(=O)c2ccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)cn2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (5-bromo-pyridin-2-yl)-(4-ethyl-piperazin-1-yl)-methanone (61 mg) obtained in the same manner as Step A in Example 1-D-79 instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, to obtain a crude product of [5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-(4-ethyl-piperazin-1-yl)-methanone, and then the PMB groups were removed according to the above Deprotection method 1, to obtain the desired compound (D-95) as a milky white powder (52 mg, 54%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>>[CH2:15]([N:17]([CH2:18][CH3:19])[C:12]([C:8]1[CH:9]=[N:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:14])[CH3:16]
Reactant: O=C(O)c1cnoc1-c1ccccc1
Reactant: CCNCC
Product: CCN(CC)C(=O)c1cnoc1-c1ccccc1

Procedure:
The title compound was prepared from 5-(phenyl)isoxazole-4-carboxylic acid (9.5 mg, 0.050 mmol) and diethylamine (4.4 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (4.6 mg). MS (pos) m/z 245.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C@@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]3[C@@H:11]([CH2:19][OH:20])[CH2:10]2)[C:5]([C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[C:4]([O:30][CH3:31])[N:3]=1.Br[C:33]1[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([CH3:40])[CH:34]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]C1C=CC=CC=1.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[C:5]1[C:6]([NH:8][C@H:9]2[C@@H:13]3[O:14][C:15]([CH3:17])([CH3:18])[O:16][C@@H:12]3[C@@H:11]([CH2:19][OH:20])[CH2:10]2)=[N:7][C:2]([NH:1][C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([CH3:40])[CH:34]=2)=[N:3][C:4]=1[O:30][CH3:31]
Reactant: COc1nc(N)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1-c1nc2ccccc2s1
Reactant: Cc1cc(Br)cc(C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1nc(Nc2cc(C)nc(C)c2)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1-c1nc2ccccc2s1
Temperature: 25 °C

Procedure:
A mixture of Compound 10 (0.10 g, 0.225 mmol), 4-bromo-2,6-dimethylpyridine (0.108 g, 0.676 mmol), Xantphos (0.078 g, 0.135 mmol), sodium phenoxide (0.044 g, 0.383 mmol) and Pd2(dba)3 (0.041 g, 0.045 mmol) in dioxane (3.0 ml) were degassed and heated under nitrogen to reflux for 18 h. The reaction was cooled to room temperature and concentrated. The residue was then purified by column chromatrography on silica gel (MeOH/DCM) to give the title compound. LCMS 1.86 min, 549 (M+H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:12]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of ethyl piperidine-3-carboxylate (67.74 g, 266 mmol) in dry CH2Cl2 (300 mL) was added TEA (40.34 g, 399 mmol) at 0° C. Benzoyl chloride (41.13 g, 293 mmol) was added slowly to control any rise in reaction temperature. After addition was complete, the mixture was stirred at rt overnight. The mixture was washed with 1N aq HCl and brine. The organic layer was dried with anhydrous Na2SO4 and concentrated to leave a residue, which was purified by silica gel column chromatography (petroleum/ethyl acetate 5:1 to 3:1) to afford ethyl 1-benzoylpiperidine-3-carboxylate (62.63 g, 90%). 1H NMR (CD3OD, 400 MHz): δ=1.41 (t, 3H), 1.52 (m, 2H), 1.85 (m, 2H), 2.36 (s, 1H), 3.29 (m, 2H), 3.81 (m, 4H), 7.22 (m, 3H), 7.42 (m, 2H).
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][S:22][CH3:23])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][S:22][CH3:23])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCCCSC)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSCCCOc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)c2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{3-methyl-5-[3-(methylsulfanyl)propoxy]-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (0.37 g) synthesized in the above-mentioned (3) was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (2.0 mL) was added to the solution at room temperature, and the mixture was stirred at 50° C. for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (2.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (0.28 g, 79%) as a colorless solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].[Br:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18]Br>C(#N)C>[Br:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18][NH:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: Fc1ccc(Br)c(CBr)c1
Reactant: NCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: OCCCNCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Hunig's base (1.3 eq) and 3-aminopropan-1-ol (1.3 eq) were added to a solution of 2-bromo-5-fluoro-benzyl bromide (1 eq) in acetonitrile (0.6 M) and the resulting mixture stirred at RT under nitrogen for 12 h. Concentrated in vacuo to give 3-(((2-bromo-5-fluorophenyl)methyl)amino)propan-1-ol as a clear oil. EI-MS m/z 262, 264 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:35])[CH:34]=1)[C:29](Cl)=[O:30]>C(Cl)Cl.C(OCC)C>[CH3:17][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:29]([C:28]2[CH:27]=[C:26]([F:25])[CH:34]=[C:33]([F:35])[CH:32]=2)=[O:30])=[CH:7][CH:6]=1)[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12]
Reactant: CC(C)S(=O)(=O)NC[C@H](C)c1ccc(N)cc1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC[C@H](C)c1ccc(NC(=O)c2cc(F)cc(F)c2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a 0° C. solution of [(2R)-2-(4-aminophenyl)propyl][(methylethyl)sulfonyl]amine (21.5 g, 0.0838 mol) and triethylamine (9.75 g, 13.4 mL, 0.0964 mol) in CH2Cl2 (86 mL) was added 3,5-difluorobenzoyl chloride (16.3 g, 0.0922 mol) dropwise over 30 min. After the addition was complete, the reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was washed with deionized water (2×100 mL) and 0.1 N HCl (2×100 mL). The organic phase was diluted with acetone (50 mL) to ensure complete dissolution of the product and the organic phase was washed with saturated K2CO3 (100 mL), 0.1 N HCl (100 mL), dried (MgSO4, 3 g), filtered and co-evaporated with EtOAc to afford an oil. This oil was diluted with diethyl ether (125 mL), which induced crystallization. The solids were collected by filtration, washed with diethyl ether (2×20 mL), and dried under reduced pressure at room temperature overnight to afford N-[4-((1R)-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (31.8 g, 95.7%) as a white crystalline powder.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:28])[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:18][CH2:17]1.C(C(CC)C(O)=O)C.Cl>C1COCC1>[CH2:26]([CH:23]([CH2:24][CH3:25])[C:22]([N:19]1[CH2:18][CH2:17][CH:16]([NH:15][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)=[O:12])[CH2:21][CH2:20]1)=[O:28])[CH3:27]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CCC(CC)C(=O)N1CCC(N)CC1
Agent: CCC(CC)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: CCC(CC)C(=O)N1CCC(NC(=O)Nc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To an ice cold solution of 4-(trifluoromethoxy)phenyl isocyanate (60.9 mg, 0.3 mmol) in THF (1.5 ml) was added 1-(4-aminopiperidin-1-yl)-2-ethylbutan-1-one (59.4 mg, 0.3 mmol), prepared via Example 14 and Example 15 using 2-ethylbutanoic acid. The reaction mixture was allowed to warm to rt and stirred overnight. 1 M HCl aqueous solution was added followed by extraction with EtOAc. Flash chromatography eluted with 50:1 DCM:MeOH followed by recrystallization from acetone afforded desired compound (65 mg, 54%) as a white solid. Mp 167.0-167.4° C. 1H NMR (600 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 6.28 (d, J=7.8 Hz, 1H), 4.27 (brd, J=13.2 Hz, 1H), 3.95 (brd, J=15.6 Hz, 1H), 3.75-3.69 (m, 1H), 3.18 (t, J=11.1 Hz, 1H), 2.81 (t, J=10.8 Hz, 1H), 2.68-2.60 (m, 1H), 1.88 (d, J=10.8 Hz, 1H), 1.82 (d, J=10.8 Hz, 1H), 1.51-1.45 (m, 2H), 1.45-1.30 (m, 2H), 1.30-1.10 (m, 2H), 0.83-0.75 (m, 6H). F NMR (300 MHz, DMSO-d6) −57.545 (s).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:12][C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][C:8]2=[O:11]
Reactant: [H][H]
Reactant: O=C1OCc2c1cc(F)cc2[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(F)cc2c1COC2=O
Yield: 92.1 %

Procedure:
A suspension of 6-fluoro-4-nitroisobenzofuran-1(3H)-one (9.6 g, 48.7 mmol) and Pd/C (10%, 1 g) in EtOAc (300 mL) was stirred at 25° C. under 1 atmosphere of hydrogen for 12 hr. TLC (petroleum ether/EtOAc=2:1) showed the reaction was complete. The mixture was filtered, and the cake was washed with EtOAc (100 mL×3). The filtrate was concentrated to give 4-amino-6-fluoroisobenzofuran-1(3H)-one (7.5 g, yield 92%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.85 (br s, 2H), 5.14-5.15 (d, 2H), 6.62-6.65 (dd, 1H), 6.98-7.00 (dd, 1H); LC-MS (ESI) m/z: 168 (M+1)+.
Reaction SMILES: O[C@@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:39]([OH:42])(=[S:41])[CH3:40]>O1CCCC1>[C:39]([S:41][C@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1)(=[O:42])[CH3:40]
Reactant: O=C1C[C@H](O)CN1
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1CNC(=O)C1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
380 mg of (4S)-4-hydroxy-2-oxopyrrolidine were suspended in 21 ml of anhydrous tetrahydrofuran, and 1.18 g of triphenylphosphine were added to the suspension at room temperature. 783 mg of diethyl azodicarboxylate were then added dropwise to the solution, whilst maintaining a temperature of -30° C. The mixture was then gradually heated to 4° C., after which the mixture was stirred at the same temperature for 30 minutes to produce a homogeneous mixture. At the end of this time, the reaction mixture was cooled to -20° C., and then 320 μl of thioacetic acid were added dropwise to the cooled mixture. The resulting mixture was gradually heated to a temperature equivalent to ice-cooling; and the mixture was stirred for 1.5 hours at that temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and then subjected to column chromatography (Merck 9385, 60 ml) through silica gel using a gradient elution method, with mixtures of benzene and acetonitrile ranging from 2:1 and 1:1 by volume as the eluent. The desired fraction was concentrated by evaporation under reduced pressure to give 69 mg of a crystalline residue. This residue was recrystallized from a mixture of ethyl acetate and cyclohexane to give 54 mg of the title compound as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][C:34]([CH3:37])(C)[CH3:35])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrCC(C1C([F:52])=CC=C2C=1N=C(NC(C)C)C(C)=N2)=O.C(OC(NC1(C(=O)CC(OCC)=O)CC1)=O)(C)(C)C>CCO.CC(O)=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[C:31]([F:52])=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][CH:34]([CH3:37])[CH3:35])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC(C)C
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2c(F)ccc3nc(C)c(NC(C)C)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Yield: 85 %

Procedure:
This compound (1.07 g, 85% yield) as a yellow amorphous solid was prepared according to the procedures described for Intermediate 324b, using 2-bromo-1-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)ethanone (619) (840 mg, 2.47 mmol), ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate (604) (804 mg, 2.96 mmol) as the starting materials, followed by the subsequent treatment of the resulting 330a (m/z (ESI, +ve) 531.2 (M+H)+) with NH4OAc (952 mg, 12.35 mmol) in 3 mL of EtOH and 1.5 mL of HOAc at 50° C. for 4 h. m/z (ESI, +ve) 512.2 (M+H)+.