Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:27]4[O:26][C:25]([CH3:29])([CH3:28])[CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[N:32]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:27]4[O:26][C:25]([CH3:28])([CH3:29])[CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:30][C:31]2[CH:35]=[CH:34][N:33]([CH2:36][C:37]([OH:39])([CH3:38])[CH3:40])[N:32]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)Cc2cccc(Oc3cnn(C(CC4CCCC4)C(=O)O)c(=O)c3)c2O1
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc4c3OC(C)(C)C4)cc2=O)n1
Yield: 84 %

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 67) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (1.13 g, 84%); ES+-HRMS m/e calcd for C29H37N5O5 [M+H+] 536.2868 found 536.2866. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (br. s., 3H), 1.06 (br. s., 3H), 1.06-1.16 (m, 1H), 1.24-1.74 (m, 8H), 1.40 (s, 6H), 1.91 (br. s., 1H), 2.20-2.35 (m, 1H), 3.09 (s, 2H), 3.89 (s, 2H), 4.68 (s, 1H), 5.46 (dd, J=11.0, 4.1 Hz, 1H), 5.69 (d, J=2.7 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 6.90 t, 7.5 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 7.19 (d, J=7.5 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 8.11 (d, J=2.7 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:5](F)=[CH:6][C:7]2[O:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:23]=1>>[Cl:3][C:4]1[C:5]([NH:2][CH3:1])=[CH:6][C:7]2[O:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:23]=1
Reactant: O=C1c2cc(Cl)c(F)cc2OCN1c1ccc([N+](=O)[O-])cc1
Reactant: CN
Product: CNc1cc2c(cc1Cl)C(=O)N(c1ccc([N+](=O)[O-])cc1)CO2
Yield: 81 %

Procedure:
Analogous to Ex. 3, methyl amine displacement was performed using 6-chloro-7-fluoro-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.21 g, 0.16 mmol) and methyl amine (0.3 ml, 2M solution in tetrahydrofuran) to give 0.134 mg (81%) of 6-chloro-7-(methylamino)-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one. RP-HPLC: 2.38 min; ES-MS (M+H)+=334; 1H-NMR (DMSO-d6) δ (ppm): 3.1 (s, 3), 5.73 (s, 2), 6.2 (d, 1), 7.38 (d, 1), 7.61 (d, 2), 8.2 (d, 2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[C:24]([O:28][C:29](=[O:38])[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:38])[NH:30][CH:31]1[CH2:32][CH2:33][CH:34]([NH:37][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=3[O:18][CH3:19])=[CH:6][N:5]=2)[CH2:35][CH2:36]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)c(C)cc2OC)c(N)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCC(NC(=O)OC(C)(C)C)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 341) and (trans-4-amino-cyclohexyl)-carbamic acid tert-butyl ester (Astatech) to give [4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-carbamic acid tert-butyl ester as a white solid. MS (M+H)+, 474
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[C:4]([CH3:10])[N:3]=1.C([Mg]Cl)(C)C.CN(C)[CH:18]=[O:19].O>O1CCCC1>[Br:1][C:2]1[N:3]=[C:4]([CH3:10])[C:5]([CH:18]=[O:19])=[CH:6][C:7]=1[CH3:8]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)c(C)nc1Br
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C=O)c(C)nc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
To a solution of 2,5-dibromo-3,6-dimethylpyridine (989 mg, 3.75 mmol) in tetrahydrofuran (6 mL) was added isopropylmagnesium chloride (2 mol/L in tetrahydrofuran; 2.0 mL, 4.0 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature for 1.5 h. Dimethylformamide (0.58 mL, 7.5 mmol) was added, and the mixture was stirred for additional 10 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (7:1 hexane/ethyl acetate) to afford 6-bromo-2,5-dimethyl-3-pyridinecarboxaldehyde (381 mg, 47%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)=[N:9][NH:10][CH:11]=2)=[CH:3][CH:2]=1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>ClCCl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:8]([C:12]3[CH:13]=[C:14]([NH:18][C:28](=[O:29])[CH2:27][C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:31])([F:19])[F:32])=[CH:26][CH:25]=4)[CH:15]=[CH:16][CH:17]=3)=[N:9][NH:10][CH:11]=2)=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (80 mg, 0.339 mmol) (prepared as described in Example 6) in dichloromethane (8 mL), were added in the following order: (4-trifluoromethyl-phenyl)-acetic acid (138 mg, 0.678 mmol), DIPEA (131 mg, 174 uL, 1.017 mol) and TBTU (326 mg, 1.017 mol). The reaction mixture was stirred at room temperature for 4 hours. Then it was poured into a solution of saturated NaHCO3, the phases separated, and the organic phase was washed twice with saturated NaHCO3, and twice with water. The organic solvent was evaporated, and the residue taken up with methanol (5 mL). TEA (2 mL) was added, and the solution was stirred at room temperature overnight. After evaporation to dryness the compound was purified by flash chromatography, over silica gel, using dichloromethane-methanol (97:3) as the eluant system. N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamide was obtained as a colorless solid (125 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH2:9]Cl)=[CH:5][CH:4]=1.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:9][CH:8]=[CH:7][C:6]3[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: COc1ccc(C=CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1
Yield: 10 %

Procedure:
Prepared from 4-methoxy-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in the presence of 1 equivalent of potassium carbonate in chloroform. Yield: 10% of theory, Melting point: 155-160° C. (ether).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:43])[CH3:44])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]
Reactant: Cc1ccc(NC(=O)c2ccc(Oc3ccc(NC(=O)OC(C)(C)C)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2ccc(Oc3ccc(N)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 86E (305 mg, 0.504 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL). The solution was stirred at room temperature for 1 hour at which time the solvent was removed on the under vacuum. The resultant residue was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (35 mg, 14%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H), 2.28 (s, 3 H), 3.28 (qt, J=13.70, 6.94 Hz, 1 H), 6.82-6.88 (m, 2 H), 6.91-6.99 (m, 3 H), 7.16 (d, J=8.46 Hz, 2 H), 7.63 (d, J=8.46 Hz, 2 H), 7.86 (d, J=8.46 Hz, 1 H), 7.98 (dd, J=8.46, 2.21 Hz, 1 H), 8.13 (d, J=2.21 Hz, 1 H), 8.87 (s, 1 H), 8.98 (d, J=8.46 Hz, 1 H), 10.17 (s, 1 H); MS (ESI+) m/z 505 (M+H-TFA)+; (ESI−) m/z 503 (M−H-TFA)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([F:34])=[CH:27][C:26]=4[O:35][CH3:36])=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)[C@H:13]2[CH3:41])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:42][CH:43]1[CH2:46][NH:45][CH2:44]1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([F:34])=[CH:27][C:26]=4[O:35][CH3:36])=[CH:23][N:22]=[C:21]([N:45]4[CH2:46][CH:43]([F:42])[CH2:44]4)[N:20]=3)[C@H:13]2[CH3:41])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(Br)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: FC1CNC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(Br)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 100 °C
Yield: 92.1 %

Procedure:
To (4S,5R)-5-[3-bromo-5-(trifluoromethyl)phenyl]-3-({5-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-2-(methylsulfonyl)pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (175 mg, 0.265 mmol) in THF (1 mL) was added TEA (0.369 mL, 2.65 mmol) and 3-fluoroazetidine (236 mg, 2.120 mmol). The reaction was capped and heated at 100° C. for 10 min by microwave irradiation. The reaction was diluted with EtOAc, washed with sat. aqueous NaHCO3, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated before purification by column chromatography to afford (4S,5R)-5-[3-bromo-5-(trifluoromethyl)phenyl]-3-({2-(3-fluoroazetidin-1-yl)-5-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (160 mg, 0.244 mmol). LCMS calc.=655.2/657.2. found=655.4/657.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9]2)=[N:6][CH:7]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:21][CH:18]3[CH2:20][CH2:19]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: NC1CC1
Reactant: CS(=O)(=O)O[C@H]1CCN(c2ccc(Br)cn2)C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc(N2CC[C@@H](NC3CC3)C2)nc1
Reaction time: 6 h
Yield: 61.2 %

Procedure:
Dissolve methanesulfonic acid (S)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl ester (3.07 g, 9.48 mmol) and cyclopropylamine (1.7 mL, 23.68 mmol) in THF (20 mL). Microwave the mixture at 130° C. for 6 h. Dilute the mixture with EtOAc (100 mL) and wash with saturated NaHCO3 (25 mL). Dry the organic portion over Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with a gradient of 75-100% EtOAc/hexane to give 1.638 g (61%) of the title compound. LC-MS/ES m/z (79Br) 283.0 [M+H]+.
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]2[C:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[S:18][C:12]=2[N:11]([CH3:34])[C:10]1=[O:35])=O.O[Li].O>C1COCC1.O.C(Cl)Cl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:16]2[C:13]3[C:14](=[O:15])[N:9]([CH2:8][CH2:7][CH2:6][OH:5])[C:10](=[O:35])[N:11]([CH3:34])[C:12]=3[S:18][C:17]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[CH:32][CH:31]=1
Reactant: Cn1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)sc21
Agent: [Li]O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)sc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propyl 2,2,2-trifluoroacetate (40 mg, 0.070 mmol) in THF (4 mL) and water (4 mL) was added LiOH.H2O (5.88 mg, 0.14 mmol). The reaction was stirred at RT for 15 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-3-(3-hydroxypropyl)-1-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (16 mg, 48.1% yield) as a white solid. 1H-NMR (DMSO-d6) δ: 7.49 (d, J=5.1 Hz, 2H), 7.40 (s, 1H), 7.36-7.32 (m, 1H), 7.29 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 4.45 (t, J=5.2 Hz, 1H), 4.30 (s, 2H), 3.97-3.82 (m, 2H), 3.52 (d, J=14.8 Hz, 3H), 3.42 (dd, J=11.7, 6.3 Hz, 2H), 1.67 (dd, J=14.2, 6.9 Hz, 2H). LCMS: MH+ 475 and TR=3.252 min.
Reaction SMILES: [OH:1][C:2]1([C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[CH3:23][O:1][C:2]1([C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: Cn1ccnc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2nccn2C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-hydroxy-4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (300 mg) in DMF (3 ml) was added NaH (60% dispersion in mineral oil; 77 mg) and MeI (120 μl) under ice bath cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with EtOAc and was washed with water and brine, and was dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by silica gel column (n-hexane:EtOAc=50:50 to EtOAc only) to give tert-butyl 4-methoxy-4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (182 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:19][C:20]([OH:22])=O)[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)(O)O.[NH2:39][C:40]([NH2:42])=[NH:41].C(N(CC)CC)C>CN(C=O)C>[NH2:41][C:40](=[NH:39])[NH:42][C:20](=[O:22])[CH2:19][N:9]1[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=[C:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: O=C(O)Cn1c(Cc2ccccc2)ccc1-c1ccccc1
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N=C(N)NC(=O)Cn1c(Cc2ccccc2)ccc1-c1ccccc1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a stirred solution of (2-benzyl-5-phenyl-1H-pyrrol-1-yl)acetic acid (155 mg, 0.53 mmol) in DMF (1.0 ml) was added 1,1′-carbonyldiimidazole (172 mg, 1.06 mmol) at room temperature. After 1 h stirring, the reaction mixture was treated with a solution of guanidine carbonate (286 mg, 1.59 mmol) in DMF (2.0 ml) and triethylamine (0.22 ml, 1.59 mmol). After stirring for 18 h, the reaction mixture was quenched with H2O (10 ml). The aqueous was extracted with EtOAc (3×30 ml). The combined organic extracts were washed with H2O (2×30 ml), brine (30 ml), dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica gel; EtOAc/2M NH3 in MeOH: 97/3) to give the titled compound (130 mg, 74%) as a solid: mp 155-158° C.; MS (+) ES, 333 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]([O:6][CH2:7][C@@H:8]([CH3:15])[CH2:9]OS(C)(=O)=O)=[CH:4][C:3]=1[CH3:19].[CH3:20][S:21]([O-:23])=[O:22].[Na+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:19])=[CH:4][C:5]([O:6][CH2:7][C@@H:8]([CH3:15])[CH2:9][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:16][C:17]=1[CH3:18]
Reactant: CS(=O)[O-]
Reactant: Cc1cc(OC[C@@H](C)COS(C)(=O)=O)cc(C)c1Br
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OC[C@@H](C)CS(C)(=O)=O)cc(C)c1Br
Temperature: 25 °C

Procedure:
Methanesulfonic acid (R)-3-(4-bromo-3,5-dimethyl-phenoxy)-2-methyl-propyl ester (148 mg) and sodium methanesulfinate (215 mg) are stirred in 3 mL of N,N-dimethylformamide at 80° C. for 4 h. The reaction mixture is cooled to room temperature, water is added and the reaction mixture is extracted with diethyl ether. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give the title compound. Yield: 118 mg.
Reaction SMILES: [C:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].O.S(=O)(=O)(O)O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([CH:4]([CH2:14][CH2:15][CH2:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCC(=O)CCCC(CCCCCCC(=O)O)C(C)=O
Reaction time: 0.5 h

Procedure:
A solution of 8-acetyl-12-hydroxyheptadecanoic acid (9.85 g., 0.03 mole) in acetone (29 ml) is cooled to 5°-10° and treated, dropwise, over 2-1/4 hours with a solution prepared from a mixture of chromium trioxide (2.57 g., 0.0257 mole) water (7.5 ml.) and concentrated sulfuric acid (2.1 ml.). Stirring is continued for an additional 30 minutes.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[N:9]=2)[NH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:15][CH:16]=3)[N:9]=2)[N:4]([S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:40])=[O:39])[CH:3]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(I)c3n2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of 7-iodo-2-(4-isopropylsulfonylphenyl)-5H-pyrrolo[2,3-b]pyrazine (5.0 g, 11.70 mmol) and DIPEA (3.024 g, 4.075 mL, 23.40 mmol) in DMF (25.00 mL) was added p-toluenesulfonyl chloride (2.454 g, 12.87 mmol). The resulting solution was stirred at room temperature for 2 hours. Water was added and the resultant precipitate collected, dried in vacuo at 40° C. to give the sub-title compound as an off-white solid (6.61 g, 97.16%). 1H NMR (400.0 MHz, DMSO) δ 9.18 (s, 1H), 8.64 (s, 1H), 8.42 (d, 2H), 8.05 (q, 4H), 7.48 (d, 2H), 3.50-3.45 (m, 1H), 2.36 (s, 3H) and 1.22-1.19 (m, 6H) ppm; MS (ES+) 581.9.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([Cl:12])[CH:6]=2.[F:13][C:14]1[CH:20]=[C:19]([CH3:21])[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][C:15]=1[NH2:16].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:18]3[C:19]([CH3:21])=[CH:20][C:14]([F:13])=[C:15]([CH:17]=3)[NH2:16])[CH:3]=[N:4]2)=[CH:9][N:8]=1
Reactant: Cc1cc(F)c(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1cc2ncc(Br)cc2cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(F)c(N)cc1-c1cnc2cc(Cl)ncc2c1
Temperature: 75 °C
Yield: 79.6 %

Procedure:
Sparge a solution of 3-bromo-7-chloro-1,6-naphthyridine (0.5 g, 2.053 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.516 g, 2.053 mmol) in dioxane (15 mL) with Ar, add a solution of K2CO3 (0.568 g, 4.11 mmol) in H2O (3 mL), followed by Pd(PPh3)4 (0.237 g, 0.205 mmol), heat at 75° C. for 8 h, then cool to RT. Add H2O, extract with EtOAc (2×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (470 mg, 80%) as an off-white solid. MS(ESI) m/z: 288.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH:10]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=O)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Li+].[OH-].O.Cl.[Li+].[Cl-].[C:36]1([NH2:43])[C:37]([NH2:42])=[CH:38][CH:39]=[CH:40][CH:41]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CO.CN(C=O)C.C(Cl)Cl>[NH2:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[NH:43][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH:10]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:29])=[CH:21][CH:20]=1
Reactant: Nc1ccccc1N
Reactant: COC(=O)c1ccc(CC(C(=O)Nc2ccc(Cl)cc2)N2CCN(C)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CN1CCN(C(Cc2ccc(C(=O)Nc3ccccc3N)cc2)C(=O)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound from Step A above (68.9 mg, 0.166 mmol) was dissolved in THF (1 mL) and methanol (0.2 mL). To this solution, was added LiOH solution in water (22.3 mg, 0.931 mmol/0.4 mL H2O). The resulting solution was stirred at room temperature for 8 hours to give 100% conversion, then neutralized with HCl (conc., 77 μL). The solvent was evaporated to afford white solid, which included the acid and small amount of LiCl. The white solid (66.5 mg), benzene-1,2-diamine (26.9 mg, 0.249 mmol), EDCI (47.7 mg, 0.249 mmol) and HOBt (33.6 mg, 0.249 mmol) were dissolved in 0.6 mL DMF. The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was diluted with 20 mL of CH2Cl2. The organic solution was washed with 10 mL of NaHCO3 (sat'd), 10 mL of H2O, and 10 mL of brine successively, dried over MgSO4. The filtrate was concentrated to give crude product which was purified by reversed phase HPLC to give the desired product. 1H NMR (600 MHz, (CD3)2CO) δ 9.37 (d, J=11.1 Hz, 1H), 8.93 (br s, 1H), 7.81 (dm, 2H, J=8.0 Hz, 2H), 7.50-7.56 (m, 2H), 7.28-7.36 (m, 2H), 7.12-7.20 (m, 3H), 6.86 (tm, J=7.3 Hz, 1H), 6.73 (dd, J=1.1 and 8.0 Hz, 1H), 6.54 (tm, J=7.3 Hz, 1H), 3.46-3.54 (m, 1H), 3.12-3.20 (m, 1H), 2.92 (dd, J=5.7 and 13.6 Hz, 1H), 2.62-2.84 (m, 4H), 2.14-2.36 (m, 4H), 1.92 (s, 3H). MS cal'd 492.2 (MH+), exp 492.2 (MH+).