Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=O)[CH2:6][C:7](=O)[CH3:8])[CH3:2].Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1>C(O)C.O>[CH2:1]([O:3][C:4]([C:5]1[N:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:22]=[C:7]([CH3:8])[CH:6]=1)=[O:11])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(C)nn1-c1ccc(OC)cc1
Temperature: 80 °C

Procedure:
Ethyl-2,4-dioxovalerate (0.555 g, 3.5 mmol) and 4-methoxyphenylhydrazine hydrochloride (0.67 g, 3.8 mmol) were mixed in ethanol and heated to 80° C. overnight. The reaction was cooled, diluted with water and extracted with EtOAc. Organic layers were combined and washed with water, 10% HCl, sat. NaHCO3, dried over MgSO4 and concentrated under reduced pressure. The residue was purified on silica gel (20% EtOAc in hexanes to 30% EtOAc in hexanes). Two regioisomers were isolated, the title regioisomer being the more polar (yield 492 mg). LC-MS (C14H16N2O3 calculated 260) m/z 261 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].CO>[Pd].ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(N)ccc1OC
Reaction time: 17 h

Procedure:
Combine methyl 2-methoxy-5-nitrobenzoate (13.3 g, 63 mrnol) and methanol. Add 5% palladium-on-carbon (0.66 g). Hydrogenate on a pressure apparatus at 50 psi. After 17 hours, filter through celite to remove the catalyst and evaporate the filtrate in vacuo to give a residue. Combine the residue and dichloromethane and extract with water. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give methyl 2-methoxy-5-aminobenzoate. Rf =0.18 (silica gel, ethyl acetate/methanol 1/1). Elemental Analysis calculated for C9H11NO3 : C, 59.66; H, 6.12; N, 7.73. Found: C, 59.44; H, 6.04; N, 7.62.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:31])[C@@H:12]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][O:14]CC1C=CC=CC=1)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.C(O)C.[Pd]>[CH3:9][C:2]([NH:10][C:11](=[O:31])[C@@H:12]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][OH:14])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CC(C)(NC(=O)[C@H](COCc1ccccc1)NC(=O)c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(NC(=O)[C@H](CO)NC(=O)c1ccccc1)c1ccccc1
Yield: 89.3 %

Procedure:
2.0 g of (2S)-N-(α,α-dimethylbenzyl)-2-benzoylamino-3-benzyloxypropionamide (prepared as described in Example 5) was catalytically reduced with hydrogen gas in the presence of 0.4 g of 10% w/w palladium-on-carbon in a mixture of 4 ml of acetic acid and 60 ml of ethanol. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off. Recrystallization of the resulting residue from acetic acid and hexane gave 1.4 g of the title compound, melting at 152°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([CH3:23])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:10](=[O:12])[CH:11]=1.[Cl:29]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>C(#N)C>[Cl:29][C:11]1[C:10](=[O:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:8]([CH3:23])=[N:7][C:6]=1[O:5][CH2:4][C:3]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=1[F:1]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)cc1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CC#N
Product: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 70 °C

Procedure:
To a suspension of 3-[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (1.0 g, 2.6 mmol) in anhydrous acetonitrile (15 mL) was added N-chlorosuccinimide (0.38 g, 2.9 mmol) and dichloroacetic acid (0.2 mL, 2.6 mmol). The reaction was heated in oil bath (70° C.) overnight under nitrogen. The reaction mixture was concentrated under reduced pressure to remove acetonitrile. The resulting residue was washed with water for 30 min, filtered, and rinsed with water. The white solid (830 mg, 82%) was dried in vacuo. 1H-NMR (CD3OD, 400 MHz) δ 8.09 (dd, 1H, J=1.6 Hz), 7.88 (d, 1H, J=2 Hz), 7.56 (m, 2H), 7.01 (m, 2H), 5.57 (s, 2H), 2.16 (s, 3H), 2.13(s, 3H); ES-HRMS m/z 421.0753 (M+H C20H16ClF2N2O4 requires 421.0761).
Reaction SMILES: [Na+].O[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1)S([O-])(=O)=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH:22]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:3][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:9][CH:10]=2)=[O:15])[CH2:17][CH2:18]1)([CH3:24])[CH3:23]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C(O)S(=O)(=O)[O-])cc2)CC1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc(CN3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of hydroxyl-[4-(4-isopropyl-piperazine-1-carbonyl)-phenyl]-methanesulfonic acid sodium salt (54.6 g, 0.150 mol), piperidine (28.0 g, 0.330 mol), and Montmorillonite-K10 (10.9 g, 20% by wt. relative to starting material) in dichloroethane (820 mL) was stirred at room temperature for 16 h. NaBH(OAc)3 (44.5 g, 210.0 mmol) was added in portions over 1 h, and the resulting suspension was stirred at room temperature for 5 h. Diatomaceous earth (5.4 g) was added and the suspension was stirred for an additional 30 min. The reaction mixture was filtered through a pad of diatomaceous earth, rinsing with dichloroethane (2×100 mL). The filtrate was washed with 1 N NaOH (2×200 mL). The aqueous layers were combined and back-extracted with dichloroethane (2×100 mL). The organic layers were combined, dried (Na2SO4), and concentrated to yield the title compound as its corresponding free base, as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][N:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=2)=[N:10]1
Reactant: FC(F)(F)c1ccc(-c2n[nH]cc2-c2ccncc2)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2ccncc2)cc1
Reaction time: 24 h
Yield: 33.1 %

Procedure:
To a solution of 4-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (0.5 g, 1.73 mmol) and epichlorohydrin (1.35 mL, 17.3 mmol) in DMF (2 mL) was added cesium carbonate (0.676 g, 2.07 mmol). The reaction mixture was allowed to stir for 24 h, diluted with EtOAc and washed successively with saturated NaHCO3, water, and brine. The organic layer was dried over Na2SO4, concentrated and partially purified by running through a plug of silica gel (5% acetone/CH2Cl2) to afford 4-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (0.198 g, 33%) as an unstable oil. TLC (silica, 20% acetone/CH2Cl2): Rf=0.39. MS (electrospray): exact mass calculated for C18H14F3N3O, 346.1 [M+H]+. m/z found, 346.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.C[O:26][C:27](=[O:78])[C@@H:28]([NH:45][C:46]([C@@H:48]1[CH2:57][C:56]2[CH:55]=[C:54]3[O:58][CH2:59][C@H:60]([C:62]4[CH:67]=[CH:66][C:65]([O:68][CH2:69][C:70]5[CH:75]=[CH:74][C:73]([Cl:76])=[C:72]([Cl:77])[CH:71]=5)=[CH:64][CH:63]=4)[O:61][C:53]3=[CH:52][C:51]=2[CH2:50][NH:49]1)=[O:47])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[C:38]=2[CH3:44])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:77][C:72]1[CH:71]=[C:70]([CH:75]=[CH:74][C:73]=1[Cl:76])[CH2:69][O:68][C:65]1[CH:66]=[CH:67][C:62]([C@H:60]2[CH2:59][O:58][C:54]3=[CH:55][C:56]4[CH2:57][C@@H:48]([C:46]([NH:45][C@@H:28]([CH2:29][C:30]5[CH:35]=[CH:34][C:33]([O:36][C:37]6[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[C:38]=6[CH3:44])=[CH:32][CH:31]=5)[C:27]([OH:78])=[O:26])=[O:47])[N:49]([C:6](=[O:8])[C:5]5[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH2:50][C:51]=4[CH:52]=[C:53]3[O:61]2)=[CH:63][CH:64]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(Oc3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)cc1OC
Reaction time: 16 h

Procedure:
3,4-Dimethoxybenzoic acid (1 eq.) was stirred in dry DCM with 0.5 eq EDCI at RT for 1 h. (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester in dry DCM (10 eq benzoic acid relative to amine) was added and the resulting mixture stirred 16 h, then directly purified by flash chromatography. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (5 mg). LCMS (m/z) 919.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:34])(=[O:33])[NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[CH:27]1([NH:26][S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:34])=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)NC3CCCCC3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)NC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
Lithium hydroxide monohydrate (0.018 g, 0.42 mmol) was added to a solution of [4-(4-cyclohexylsulfamoyl-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.05 g, 0.10 mmol) in a 3:1 mixture of THF—H2O mixture (6 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave [4-(4-cyclohexylsulfamoyl-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid (0.042 g, 87%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.46 (br. s, 1 H), 7.95-8.06 (m, 3 H), 7.90 (s, 1 H), 7.72 (d, J=7.80 Hz, 1 H), 7.46 (d, J=8.31 Hz, 2 H), 7.38 (td, J=8.40, 2.40 Hz, 1 H), 6.63 (dd, J=11.20, 2.40 Hz, 1 H), 3.85 (s, 2 H), 3.00-3.09 (m, 1 H), 2.08 (s, 3 H), 1.52-1.67 (m, 4 H), 1.41-1.51 (m, 1H), 1.03-1.25 (m, 5H). MS calcd. for C25H25FNO4S [(M−H)−] 454, obsd. 454.4.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[N:14]O)[CH2:12][CH3:13].C([O-])(=O)C.[NH4+].N.[OH-].[Na+]>C(OCC)C.[Zn].CN(C)C=O.C(O)C>[CH2:12]([CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[NH2:14])[CH3:13]
Reactant: CCC(=NO)c1ccc2ccccc2c1
Agent: CC(=O)[O-]
Agent: N
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOCC
Product: CCC(N)c1ccc2ccccc2c1
Temperature: 85 °C
Yield: 97.2 %

Procedure:
A mixture of2 g (10 mmol) of 1-(2-naphthyl)-1-propanone oxime, 3.6 g (55.1 mmol) of zinc, 0.4 g (6 mmol) of ammonium acetate, 50 ml of aqueous ammonia, 12 ml of ethanol and 5 ml of dimethylformamide was stirred and heated at 85° C. for 1 hour. The mixture was cooled to room temperature, diluted with diethyl ether and basified with 35% aqueous sodium hydroxide solution. The ethereal layer was separated, dried over magnesium sulphate, filtered and evaporated to dryness to give 1.8 g of α(RS)-ethyl-2-naphthalenemethylamine as a colorless oil, 1H NMR (400 MHz, CDCL3) δ: 0.9 (t,3H), 1.7-1.8 (br,s,2H), 3.9-4.0 (t,1H), 4.1-4.2 (q,2H), 7.4-7.5 (m,3H), 7.75 (s,1H), 7.8-7.9 (m,3H).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][CH2:20][N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.O1CCCCC1[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>>[N:21]1([CH2:20][CH2:19][N:15]2[C:14]([C:8]3[S:9][C:10]4[CH2:11][CH2:12][O:13][C:4]5[CH:3]=[C:2]([C:41]6[CH:40]=[N:39][N:38]([CH2:37][CH2:36][OH:35])[CH:42]=6)[CH:28]=[CH:27][C:5]=5[C:6]=4[N:7]=3)=[N:18][CH:17]=[N:16]2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3CCN3CCOCC3)nc1-2
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Product: OCCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CCN4CCOCC4)nc2-3)cn1

Procedure:
Following the procedure for 258, 8-bromo-2-[2-(2-morpholin-4-yl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give 467. MS(ESI+) 494.1. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.3, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.38 (dd, J=8.3, 1.7, 1H), 7.30 (d, J=1.7, 1H), 4.95 (t, J=6.5, 2H), 4.91 (t, J=5.3, 1H), 4.39 (t, J=5.0, 2H), 4.16 (t, J=5.7, 2H), 3.77 (q, J=5.6, 2H), 3.51-3.38 (m, 6H), 2.82 (t, J=6.5, 2H), 2.46-2.36 (m, 4H)
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([OH:22])=O)[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[N:26]1[NH:27][CH:28]=[C:29]2[C:34]=1[CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]2.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([NH:35][CH:31]2[CH2:32][CH2:33][C:34]3[C:29](=[CH:28][NH:27][N:26]=3)[CH2:30]2)=[O:22])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCc2n[nH]cc2C1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NC1CCc2n[nH]cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a solution of 2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetic acid (94.1 mg, 0.28 mmol) and 4,5,6,7-tetrahydro-2H-indazol-5-ylamine dihydrochloride (58.8 mg, 0.28 mmol) in 1 mL of DMF was added HOBt (42.8 mg, 0.28 mmol). The pH of the solution was adjusted to 8 with N-methylmorpholine and EDC (53.7 mg, 0.28 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and ethylacetate and saturated NaHCO3 solution were added to the residue. The water phase was extracted with ethyl acetate three times, and the combined organic phases were washed with saturated NaCl solution, dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The product was purified by column chromatography (silicagel, eluant CH2Cl2/MeOH=9/1) to give 48 mg (38%) of a white solid compound.
Reaction SMILES: C([S:4][C@@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.Cl.C[O:49][C:50](=[O:71])[C:51]1[CH:56]=[CH:55][C:54]([CH2:57][N:58]2[C:62]([CH2:63][NH2:64])=[CH:61][N:60]=[C:59]2[CH2:65][CH2:66][CH2:67][CH3:68])=[C:53]([F:69])[C:52]=1[F:70]>CN(C=O)C>[CH2:65]([C:59]1[N:58]([CH2:57][C:54]2[CH:55]=[CH:56][C:51]([C:50]([OH:71])=[O:49])=[C:52]([F:70])[C:53]=2[F:69])[C:62]([CH2:63][NH:64][C:6](=[O:8])[C@@H:5]([SH:4])[CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:61][N:60]=1)[CH2:66][CH2:67][CH3:68]
Reactant: CCCCc1ncc(CN)n1Cc1ccc(C(=O)OC)c(F)c1F
Reactant: CC(=O)S[C@@H](CC(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1ncc(CNC(=O)[C@@H](S)CC(C)C)n1Cc1ccc(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
(S)-2-Acetylsulfanyl-4-methylpentanoic acid (205 mg, 1.1 mmol) was dissolved in DMF (8.1 mL, 104 mmol). HATU (409 mg, 1.1 mmol) and DIPEA (170 μL, 1.0 mmol) were added and the mixture was stirred at room temperature for 30 minutes. 4-(5-Aminomethyl-2-butyl-imidazol-1-ylmethyl)-2,3-difluorobenzoic acid methyl ester dihydrochloride salt (401 mg, 1.0 mmol) was dissolved in DMF (1 ml) with DIPEA (170 pt, 1.0 mmol) and added. to the mixture. The mixture was stirred at room temperature for 2 hours. The reaction was then quenched with water, and the mixture extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude residue was then redissolved in 1:1 MeOH:NaOH (4 mL) and stirred at room temperature under nitrogen for 1 hour. The reaction was quenched with acetic acid and the mixture was concentrated. The product was purified by preparative HPLC (2-90%) to yield 108 mg of the title compound as a white solid. MS m/z: [M+H] calcd for C22H29F2N3O3S, 454.19; found 454.2. 1H-NMR (DMSO): 8.44 (1H, t), 7.59 (1H, t), 7.25 (1H, s), 6.62 (1H, t), 5.56 (2H, s), 4.24 (2H, m), 3.14 (2H, q), 2.79 (2H, t), 2.72 (1H, d), 1.2-1.6 (7H, m), 0.78 (6H, d), 0.71 (3H, d).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.CCN(C(C)C)C(C)C.[P:27]([O-:44])([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C.CN(C1C=CN=CC=1)C>[CH2:29]([O:28][P:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:44])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)Cc1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
To a solution of methyl 2-(4-hydroxyphenyl)acetate (1.89 g, 11.4 mmol) in acetonitrile (90 mL) at −10° C. was added CCl4 (5.5 mL, 57 mmol), DIPEA (4.16 mL, 23.9 mmol) and DMAP (139 mg, 1.14 mmol). After stirring for 10 mins, the mixture was added dibenzyl phosphite (3.7 mL, 16.5 mmol) slowly to keep the temperature below −10° C. The reaction was stirred at −10° C. for 1 h. The reaction was quenched with aqueous K2HPO4 (0.5 M) in acetonitrile (60 mL) and allowed to stirred at rt. The mixture was extracted by ethyl acetate (150 mL×3). The combined organic layers was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to ISCO (30-50% AcOEt/hexanes) to give the title compound (4.3 g, 88.5% yield) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([OH:16])=O)=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Cl.[CH3:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[NH2:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:21]([NH:22][C:14](=[O:16])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:11])([F:12])[F:13])[N:6]=1)([CH3:24])[C:20]([O:19][CH3:18])=[O:25]
Reactant: COC(=O)C(C)(C)N
Reactant: Cc1ccc(C(=O)O)nc1OCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ccc(C)c(OCC(F)(F)F)n1
Yield: 123.9 %

Procedure:
A solution of 5-methyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (30 mg, 128 μmol), 2-methyl-alanine methyl ester hydrochloride (23.5 mg, 153 μmol), HATU (CAN 148893-10-1, 97.0 mg, 255 μmol) and DIEA (82.4 mg, 109 μl, 638 μmol) in DMF was stirred at ambient temperature for 72 h. The crude reaction mixture was concentrated in vacuo to give 53 mg of a yellow solid. This solid was purified by preparative TLC (silica gel, 2.0 mm, 1:1 heptane/i-PrOAc) and eluted from the silica gel with i-PrOAc. Filtration over speedex and evaporation under reduced pressure provided the title compound (10 mg, 23%) as colorless liquid, MS (EI): m/e=335.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[C:4]([CH3:9])=[N:3]1.[NH2:10][C:11]1[CH:16]=[N:15][C:14]([Br:17])=[CH:13][N:12]=1.[B-][N+](C)(C)C.C(O)(=O)C>C(OCC)(=O)C>[Br:17][C:14]1[N:15]=[CH:16][C:11]([NH:10][CH2:7][C:5]2[C:4]([CH3:9])=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:12][CH:13]=1
Reactant: Cc1nn(C)cc1C=O
Reactant: Nc1cnc(Br)cn1
Agent: [B-][N+](C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nn(C)cc1CNc1cnc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (142 mg, 1.145 mmol), 2-amino-5-bromopyrazine (200 mg, 1.149 mmol), borane trimethylamine complex (126 mg, 1.73 mmol) and glacial acetic acid (137 mg, 2.29 mmol) in anhydrous methonol (3 ml) was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over MgSO4 and filtered. The filtrate was concentrated to give 300 mg of (5-bromo-pyrazin-2-yl)-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)amine as crude product, which was used for next step reaction without further purification. Crude yield: 93%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][Cl:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[CH2:9][CH2:10][Cl:11])=[CH:6][CH:7]=1
Reactant: O=C(CCCl)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OC(CCCl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-one (1 g, 4.04 mmol) in tetrahydrofuran (9 ml) and water (0.58 ml) was added sodium borohydride (0.16 g, 4.28 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with careful addition of water and extracted with ethyl acetate. The organic layers were separated, dried (MgSO4), filtered and concentrated to afford the title compound, which was used in the next step without further purification. LC/MS: (PS-A2) Rt 3.07 [M+H]+ No ionization.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[CH3:18][NH:19][CH:20]1[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>CS(C)=O>[CH:20]1([N:19]([CH3:18])[C:2]2[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:22][CH2:21]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CNC1CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)C3CC3)nc2c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.26 mmol) in DMSO (2 mL), was added N-methylcyclopropanamine hydrochloride (175 mg, 1.63 mmol) and DIEA (325 mg, 2.52 mmol) with stirring for 2 h at 75° C. in an oil bath. Then the reaction was quenched by the addition of water (10 mL) to give the precipitate, which was collected by filtration to afford methyl 3-[cyclopropyl(methyl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as an off-white solid (297 mg, 86%).