Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:12]([C:10]1[CH:9]=[CH:8][C:7]([N+:15]([O-:17])=[O:16])=[C:6]([NH2:5])[CH:11]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1ccc([N+](=O)[O-])c(NC(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2,2-Trifluoro-N-(5-isopropyl-2-nitro-phenyl)-acetamide (prepared in Example OO-1; 9.4 g, 34 mmol) was dissolved in MeOH (30 mL) and treated with 7% aqueous potassium carbonate solution. The reaction mixture was stirred overnight at room temperature. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×50 mL). The organic layer was washed with saturated NaHCO3 solution and brine, dried (MgSO4), and concentrated. The crude product was used further without any purification. MS(APCI): 181 (M+H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:32])([F:31])[CH:28]1[O:30][CH2:29]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.O.C(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:29][CH:28]([OH:30])[C:27]([F:32])([F:31])[F:26])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)C1CO1
Reactant: COC(=O)c1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Temperature: 50 °C
Yield: 94.5 %

Procedure:
EX-612B) To a mixture of methyl 3-[[(3-phenoxyphenyl)amino]methyl]benzoate (6.2 g, 0.019 mol) from EX-612A and 1,1,1-trifluoro-2,3-epoxypropane (8.58 g, 0.077 mol) in 12 mL of acetonitrile was added ytterbium (III) trifluoromethanesulfonate (1.2 g, 0.0019 mol). The resulting mixture was heated at 50° C. in a sealed glass tube for 18 h. The reaction mixture was cooled to room temperature, then diluted with water and methylene chloride. The aqueous layer was extracted with methylene chloride. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:9 ethyl acetate in hexane to afford 8.0 g (96%) of the desired methyl 3-[[(3-phenoxy-phenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate product as a yellow oil. Anal. calcd. for C24H22F3NO4.1.4 H2O: C, 61.25; H, 5.31; N, 2.98. found: C, 61.52; H, 5.06; N, 2.89. HRMS calcd.: 446.1579 [M+H]+, found: 446.1596. 1H NMR (CDCl3) δ7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H). 6.35 (t, 1H), 5.84 (t, 1H), 4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d, 1H), 3.48 (m, 1H), 2.51 (s, 1H). 19F NMR (CDCl3) δ−79.0 (d, 3F).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][O:19][CH2:20][C:21](Cl)=[O:22]>>[CH3:18][O:19][CH2:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 84.1 %

Procedure:
Beginning with 13 mg (0.056 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 6.5 mg (0.059 mMol) methoxyacetyl chloride, 14.2 mg (84%) of the title compound were recovered.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:16]=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:16]=[N:15]2)[N:3]=1
Reactant: C#CCCn1cc(-c2ccc(F)cc2)cn1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2cc(-c3ccc(F)cc3)cn2)n1
Yield: 38.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (49 mg, 0.26 mmol) and 1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-pyrazole (50 mg, 0.23 mmol, Example 140(A)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 29 mg (88 μmol, 38%) of 2-(fluoromethyl)-6-(4-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellow solid.
Reaction SMILES: C[CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]([C:17]([O:19][CH3:20])=[S:18])[S:14][C:15]=2[CH3:16])[CH:7]=[CH:8][CH:9]=1)C.N[C:22]1C=C(C(OC)=S)S[C:26]=1C.C(C1C=C(B(O)O)C=CC=1)(C)C>>[CH3:2][C:4]1[C:5]([CH2:22][CH3:26])=[C:6]([NH:10][C:11]2[CH:12]=[C:13]([C:17]([O:19][CH3:20])=[S:18])[S:14][C:15]=2[CH3:16])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=S)c1cc(Nc2cccc(C(C)C)c2)c(C)s1
Reactant: COC(=S)c1cc(N)c(C)s1
Agent: CC(C)c1cccc(B(O)O)c1
Product: CCc1c(C)cccc1Nc1cc(C(=S)OC)sc1C
Yield: 19.5 %

Procedure:
Methyl 4-{[3-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxylate: Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 118 mg (2 equiv, 0.72 mmol) of 3-isopropylphenyl boronic acid to give 22.6 mg (19.5%) of methyl 4-[(3-methylethylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ 1.27 (d, 6H, J=6.9 Hz), 2.40 (s, 3H), 2.89 (m, 1H), 3.88 (s, 3H), 6.15 (s, 1H), 6.86-6.89 (m, 3H), 7.24 (m, 1H), 7.77 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[H-].[Na+].I[CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:22])[CH2:14]3)=[O:12])[S:10][C:3]=12
Reactant: CI
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
A solution of 7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4a (1.86 g, 6.6 mmole) in THF (150 ml) was cooled to −10° prior to addition of NaH (920 mg, 23 mmole as a 60% by wt. mineral oil dispersion). The resultant mixture was stirred at 0° for 40 minutes. Iodomethane (4 ml, 9.12 g, 64 mmole) was then added to the reaction which was stirred for another 3 hours, gradually warming to room temperature. The crude reaction mixture was quenched with saturated NaHCO3 (150 ml), then extracted with EtOAc (2×100 ml). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 2.4 g of an amber paste, which was purified by silica gel chromatography. Elution with CH2Cl2: CH3OH (98:2) and evaporation of the appropriate fractions gave 1.64 g (84%) of a yellow solid. 1H NMR (DMSO-d6): δ 8.73 (1H, d, J=5.1 Hz), 8.15 (1H, s), 7.69 (1H, d, J=5.1 Hz), 4.11–3.83 (3H, m), 3.69–3.47 (2H, m), 3.27, 3.24 (3H, s), 2.18–1.93 (2H, m). Anal. Calcd. for C13H23N2O2SCl: C, 52.61; H, 4.42; N, 9.44; S, 10.80; Cl, 11.95. Found: C, 52.76; H, 4.47; N, 9.38; S, 10.84; Cl, 12.01.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25](O)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.CCOCC>C(Cl)Cl>[ClH:13].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([NH:18][C:17]3[CH:32]=[CH:33][C:14]([Cl:13])=[CH:15][C:16]=3[F:34])=[N:20][CH:21]=[N:22]2)=[CH:27][C:26]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCOCc1ccccc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCOCc1ccccc1
Product: Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A solution of 3-benzyloxy-1-propanol (150 μl, 0.9 mmol) was added to tributyephosphine (376 mg, 1.9 mmol) and 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.63 mmol), (prepared as described for the starting material in Example 4), in methylene chloride (20 ml) at 5° C. To the resulting mixture 1,1′-azodicarbonyldipiperidine (480 mg, 1.9 mmol) was added, the mixture stirred at 5° C. for 1 hour, allowed to warm to ambient temperature and stirred overnight. Ether (10 ml) was added, the mixture stirred for 15 minutes and the precipitated solids removed by filtration. The volatiles were removed from the filtrate by evaporation, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was dissolved in acetone, and hydrogen chloride in ether (0.6 ml of a 1M solution, 0.6 mmol) added. The resulting precipitated product was collected by filtration and dried to give 7-(3-benzyloxypropoxy)4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (90 mg, 31%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29]Cl)[N:21]=2)=[CH:4][CH:3]=1.[C:31]([O:35][P:36]([O-:43])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([CH3:34])([CH3:33])[CH3:32]>CC#N>[C:39]([O:38][P:36](=[O:37])([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])[O:43][CH2:29][N:22]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:28]2[C:20]([CH2:19][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][C:9]3[CH:10]=[C:11]([C:12]#[N:13])[CH:14]=[C:15]([Cl:17])[CH:16]=3)[C:6]=2[F:18])=[N:21]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Cc3nn(CCl)c4ncccc34)c2F)c1
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Solvent: CC#N
Product: CC(C)(C)OP(=O)(OCn1nc(Cc2ccc(Br)c(Oc3cc(Cl)cc(C#N)c3)c2F)c2cccnc21)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
step 2—To a mixture of 16 (1.28 g, 2.54 mmol), di-tert-butylphosphate (1.06 g, 5.08 mmol), in MeCN (70 mL) was added Ag2O (0.59 g, 2.54 mmol) and the resulting mixture was stirred for 1 d at RT. The resulting mixture was filtered through CELITE®, the filtrate was evaporated and the crude product purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0 to 1% MeOH) to afford 1.1 g of phosphoric acid 3-[4-bromo-3-(3-chloro-5-cyano-phenoxy)-2-fluoro-benzyl]-pyrazolo[3,4-b]pyridin-1-ylmethyl ester di-tert-butyl ester (18)
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][CH:6]([CH2:8][CH2:9][CH2:10][C@H:11]([CH2:13][CH2:14][CH2:15][C@H:16]([CH2:18][CH2:19][CH2:20]/[C:21](=[CH:23]/[CH2:24][OH:25])/[CH3:22])[CH3:17])[CH3:12])[CH3:7]>C(Cl)Cl>[CH3:1][NH:2][C:3](=[O:4])[O:25][CH2:24]/[CH:23]=[C:21](/[CH2:20][CH2:19][CH2:18][C@@H:16]([CH2:15][CH2:14][CH2:13][C@@H:11]([CH2:10][CH2:9][CH2:8][CH:6]([CH3:5])[CH3:7])[CH3:12])[CH3:17])\[CH3:22]
Reactant: CN=C=O
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Solvent: ClCCl
Product: CNC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Yield: 92.3 %

Procedure:
2.0 g of methyl isocyanate was added to a solution of 5.0 g of phytol dissolved in 15 ml of methylene chloride. The resulting mixture was refluxed for 6 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by a column chromatography (eluant: benzene) to obtain 5.5 g (yield: 99.2%) of oily phytyl N-methylcarbamate.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].IC.[CH3:40]COC(C)=O>CN(C=O)C>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:28]=3[N:27]([CH3:40])[CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)c[nH]c34)no2)cc1C#N
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)cn(C)c34)no2)cc1C#N
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 9.14 mg) was added to a solution of 1,1-dimethylethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D9) (120 mg) in dry DMF (5 mL) at RT. After stirring for 5 min, iodomethane (0.032 mL) was added. The resulting solution was stirred at RT for 15 min, then 1 hour more. EtOAc (50 mL) was added and the resulting solution was washed with saturated aqueous sodium bicarbonate solution (50 mL), followed by water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was purified by Biotage (25% EtOAc in hexane) to afford 1,1-dimethylethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoate (D10) (60 mg) as a pale yellow oil. MS (ES): C28H30N4O4 requires 486; found 487.0 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[OH:18][C@@:19]([CH3:31])([C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[OH:18][C@@:19]([CH3:31])([C:23]([NH:25][CH2:26][C:27]([F:28])([F:29])[F:30])=[O:24])[C:20]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:21]
Reactant: C[C@@](O)(C(=O)O)C(=O)NCC(F)(F)F
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@](O)(C(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 16 h
Yield: 79.6 %

Procedure:
A solution of 70.0 mg (0.31 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 73.9 mg (0.34 mmol) (S)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid in 6 ml tetrahydrofuran were cooled to 0° C. and 46.4 mg (0.34 mmol) 1-hydroxy-benzotriazole hydrate, 117 μl (0.69 mmol) diisopropylethylamine and 65.8 mg (0.34 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued for 16 hours. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 100/0 to 25/75) yielded 104 mg (79%) (S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,2-trifluoro-ethyl)-malonamide, MS (m/e): 422.0 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][OH:5].Br[CH2:7][C:8]12[CH2:25][N:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:23][C:9]1([CH2:36]Br)[CH2:10][N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:12]2>CS(C)=O>[CH3:1][O:2][CH2:7][C:8]12[CH2:25][N:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:23][C:9]1([CH2:36][O:5][CH3:4])[CH2:10][N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:12]2
Reactant: Cc1ccc(S(=O)(=O)N2CC3(CBr)CN(S(=O)(=O)c4ccc(C)cc4)CC3(CBr)C2)cc1
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Solvent: CS(C)=O
Product: COCC12CN(S(=O)(=O)c3ccc(C)cc3)CC1(COC)CN(S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 120 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
25 wt. % Sodium methoxide in MeOH (3.8 mL, 16 mmol) was added to a suspension of 3a,6a-bis(bromomethyl)-2,5-bis((4-methylphenyl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole (Intermediate 1) (2 g, 3.30 mmol) in DMSO (10 mL) and the mixture was stirred at 120° C. under N2 for 16 h. The solvent was evaporated under vacuum and the residue was partitioned between CHCl3 and sat. NH4Cl (aq). The organic layer was washed with brine, dried (MgSO4) and concentrated to an orange solid, which was triturated with CH2Cl2 to yield the first crop of 3a,6a-bis(methoxymethyl)-2,5-bis((4-methylphenyl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole (720 mg, 1.4 mmol, 43%) as a white solid. The mother liquor was purified by flash silica chromatography (SiO2, eluted with EtOAc/Hexanes 1:2) to yield additional desired product (130 mg, 0.26 mmol, 8%) as awhite solid. LCMS: m/e=509 (M+H)+. LCMS retention time: 1.85 min. (Column: SunFire C18 5u 4.6×50 mm. Solvent A=90% Water/10% Acetonitrile/0.1% TFA. Solvent B=10% Water/90% Acetonitrile/0.1% TFA. Start % B=0. Final % B=100. Gradient Time=2 min. Flow Rate=4 mL/min.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](OC3C=CC(N)=CC=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](Cl)=[O:36])=[CH:31][CH:30]=1.C([N:40]([CH2:43][CH3:44])CC)C>O1CCOCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:7]3[CH:8]=[CH:3][C:4]([C:35]([C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)=[O:36])=[CH:44][C:43]=3[NH2:40])[N:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Nc2cncc(Oc3ccc(N)cc3)n2)cc(OC)c1OC
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1COCCO1
Product: COc1cc(Nc2cncc(-c3ccc(C(=O)c4ccc(F)cc4)cc3N)n2)cc(OC)c1OC
Yield: 50 %

Procedure:
Method LL. In a tube suitable for parallel synthesis, 2-(3,4,5-trimethoxyphenylamino)-6-(4-aminophenyloxy)-pyrazine (50 mg, 0.14 mmol) and 4-fluorophenylcarbonyl chloride (21 μL, 0.17 mmol) were stirred under nitrogen for 20 hours in dry dioxane (5 mL) in the presence of triethylamine (25 mL, 1.2 eq). The reaction mixture was evaporated to dryness, redissolved in 10 mL AcOEt, the solution washed (2×10 mL brine), dried, and purified by column chromatography (AcOEt) to give the title compound (33 mg). Yield: 50%. 1H NMR (250 MHz, DMSO-d6) δ 3.69 (s, 3H, [CH3O]4), 3.89 (s, 6H, [CH3O]3+5), 7.32 (s, 2H, Harom2′+6′), 7.44 (t, 2H, Harom 2″+6″, J=8.8 Hz), 7.98 (d, 2H, Harom 3+5, J=8.6 Hz), 8.10-8.21 (m, 4H, Harom 3″+5″ and Harom 2+6), 8.18 (s, 1H, HPz 5), 8.57 (s, 1H, HPz 3), 9.61 (s, 1H, NH), 10.50 (s, 1H, NHamide). m/z 475.2 [(M+H)+ calcd for C26H23FN4O4 474.2].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:57]([C:60]1[CH:65]=[CH:64][C:63]([N:66]2[CH2:70][CH2:69][CH:68]([C:71](O)=[O:72])[C:67]2=[O:74])=[CH:62][CH:61]=1)([CH3:59])[CH3:58]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:71]([CH:68]1[CH2:69][CH2:70][N:66]([C:63]2[CH:64]=[CH:65][C:60]([CH:57]([CH3:58])[CH3:59])=[CH:61][CH:62]=2)[C:67]1=[O:74])=[O:72]
Reactant: CC(C)c1ccc(N2CCC(C(=O)O)C2=O)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 32.3 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.036 g; 0.146 mmol), PyBOP (0.113 g; 0.219 mmol), N,N-diisopropylethylamine (0.075 mL; 0.437 mmol) and 1-(4-isopropylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.425 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.020 g (32%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])OC1C=CC=CC=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.O.Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:22][CH:19]1[CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(Nc1ccc(O)cc1Cl)Oc1ccccc1
Reactant: NC1CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)cc1Cl)NC1CC1
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL) was added cyclopropylamine (22.7 mL) while cooling in an ice bath, and the stirring was continued at room temperature overnight. Water (400 mL), ethyl acetate (300 mL), and 6N—HCl (55 mL) were added thereto, and the mixture was stirred. The organic layer was then separated, washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give prism crystals, which were collected by filtration and washed with heptane to give 22.8 g of the titled compound (yield from 4-amino-3-chlorophenol: 77%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([NH:28][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=1)=[O:4])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cc1ccccc1)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)c1c[nH]c(C(=O)NCc2ccccc2)c1
Reaction time: 24 h

Procedure:
To a solution of compound 1 (1 equivalent) in DMF, at ambient temperature, was added benzylamine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 2 was utilized without purification. HPLC using method B (as described below for Example 5) provided a retention time of 3.8 minutes. FIA/MS (M+1) 319.3, (M−1) 317.2.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][C@@H:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH3:14])=[O:11])=[CH:6][C:5]=1[Cl:25].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:25][C:5]1[CH:6]=[C:7]([C:10]([NH:12][C@@H:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH3:14])=[O:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:26])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a solution of (R)-2-chloro-4-[[1-(naphthalen-1-yl)ethylamino]carbonyl]benzoic acid methyl ester (Example 82; 3.00 g, ˜8.5 mmol) in tetrahydrofuran/methanol/water (3:1:1; 20 mL) was added lithium hydroxide monohydrate (1.43 g, 34 mmol). The mixture was allowed to stir at room temperature for 4 h and then concentrated in vacuo to remove tetrahydrofuran and methanol. The concentrate was diluted with water and extracted with three portions of ethyl acetate. The organic extracts were discarded and the aqueous layer was acidified with 1N hydrochloric acid solution. Ethyl acetate was added and the resulting colorless solid was recovered by filtration and washed with ethyl acetate. The layers in the filtrate were separated and the organic phase was dried (MgSO4), filtered and concentrated. The resulting residue was combined with the previously recovered solid to give (R)-2-chloro-4-[[1-(naphthalen-1-yl)ethylamino]carbonyl]benzoic acid (2.42 g, 84% yield).