Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10](=O)[CH3:11])[C:7](F)=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[Cl:23].C(O)(=O)C.[CH:29]([NH2:31])=[NH:30]>CC(N(C)C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[Cl:23])[N:31]=[CH:29][N:30]=[C:10]2[CH3:11])=[O:24]
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccc(Br)cc1Cl
Reactant: N=CN
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(C)ncnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 95 °C
Yield: 47.9 %

Procedure:
A mixture of 5-acetyl-2-(4-bromo-2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (288 mg, 0.688 mmol) and formamidine acetate (77 mg, 0.74 mmol) in DMA (7 mL) was heated for 4 hours at 95° C. Additional 10 mg (0.096 mmol) of formamidine acetate was added and the reaction mixture was heated for additional 4 hours at 95° C. The reaction mixture was diluted with EtOAc, and washed with water (3×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (100% CH2Cl2 to 1% MeOH in CH2Cl2) to afford the desired product (140 mg, 48%).
Reaction SMILES: [CH:1]([N:4]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH3:21]>N1C(C)=CC(C)=CC=1C>[CH:14]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([O:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH2:20][CH3:21])=[CH:24][CH:25]=3)=[CH:8][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Reactant: CCOc1ccc(O)cc1
Solvent: Cc1cc(C)nc(C)c1
Product: CCOc1ccc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc1

Procedure:
The reaction and workup are carried out in the same manner as described for Example 1 using p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (1.75g, 5.40 mmol), 4-ethoxy phenol (796 mg, 5.76 mmol) and cuprous oxide (390 mg, 2.73 mmol) in collidine (15 ml). The crude product is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:14]([C:26]([NH2:28])=[O:27])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:40][CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[CH:35]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CN1C(=O)CCC1>[C:37]([NH:36][C:34]1[CH:35]=[C:30]([NH:29][C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:14]([C:26]([NH2:28])=[O:27])=[CH:13][N:12]=2)[CH:31]=[CH:32][C:33]=1[O:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][CH2:46][CH2:47]1)(=[O:39])[CH3:38]
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1NCc1cccc(F)c1
Reactant: CC(=O)Nc1cc(N)ccc1OCCN1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cc(Nc2ncc(C(N)=O)c(NCc3cccc(F)c3)n2)ccc1OCCN1CCCC1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide (57 mg, 0.15 mmol) in NMP (0.6 mL) was added N-(5-amino-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)acetamide (47 mg, 0.18 mmol) and pTsOH.H2O (28 mg, 0.15 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, and purified by preparative HPLC to give 2-(3-acetamido-4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide (46 mg). MS found for C26H30FN7O3 as (M+H)+ 508.5. λ 248.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:14](=[O:26])[N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]([CH3:19])[C:17]=1[CH3:18])=[O:12].CC([O-])(C)C.[K+].[Cl:33][C:34]1[C:35](C(N)=O)=[N:36][CH:37]=[CH:38][C:39]=1Cl.C[N:45](C=O)C>>[NH2:45][C:35]1[C:34]([Cl:33])=[C:39]([O:8][C:6]2[C:5]([F:9])=[CH:4][C:3]([NH:10][C:11]([C:13]3[C:14](=[O:26])[N:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:16]([CH3:19])[C:17]=3[CH3:18])=[O:12])=[C:2]([F:1])[CH:7]=2)[CH:38]=[CH:37][N:36]=1
Reactant: CN(C)C=O
Reactant: NC(=O)c1nccc(Cl)c1Cl
Reactant: Cc1c(C(=O)Nc2cc(F)c(O)cc2F)c(=O)n(-c2ccccc2)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(N)c3Cl)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of N-(2,5-difluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (395 mg, 1.1 mmol) in DMF (5.0 mL) was added t-BuOK (202 mg, 1.8 mmol) and the mixture was stirred at rt for 30 minutes. Then 3,4-dichloropicolinamide (190 mg, 1.0 mmol) was added and the mixture was microwaved at 120° C. for 2 hours, then cooled to rt, quenched with water (30 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (MeOH/DCM (v/v)=1/30) to give the title compound as a pale yellow solid (310 mg, 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:10]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[CH2:27][NH:28][CH2:29][CH2:30][CH3:31])([O-])=O.S1C=CC=C1.O=[Si]=O>CO.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:10]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[CH2:27][NH:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCNCc1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=[Si]=O
Solvent: CO
Solvent: c1ccsc1
Product: CCCNCc1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1N

Procedure:
A mixture of N-[3-(4-nitro-3-propylaminomethyl-phenoxy)-phenyl]-benzenesulfonamide (0.0045 mol) in methanol (100 mL) was hydrogenated with 10% Pd/C (0.5 g) as a catalyst in the presence of thiophene solution (1 mL). After uptake of H2 gas (3 equiv.), the reaction mixture was filtered over Dicalite and the filtrate was evaporated to yield the title compound as a residue.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]([C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15]3[N:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:14]=3[CH2:13][N:12]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:11]=2[CH:38]=1)([CH3:6])[CH3:5].[Li+].[OH-]>O.C1COCC1.C(#N)C>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([S:25]([N:12]2[C:11]3[CH:38]=[C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:39])=[O:2])[CH:8]=[CH:9][C:10]=3[NH:16][C:15]3[N:17]=[C:18]([C:21]([F:23])([F:22])[F:24])[CH:19]=[CH:20][C:14]=3[CH2:13]2)(=[O:26])=[O:27])=[CH:33][CH:32]=1)([CH3:35])([CH3:36])[CH3:37]
Reactant: COC(=O)C(C)(C)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(C)(C)C(=O)O)cc32)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To the methyl ester (92 mg, 0.16 mmol) of Example 373 in 3 mL of H2O/THF/acetonitrile (1:1:1) was added LiOH (16 mg, 0.65 mmol). After stirring at rt for 48 hrs, the reaction was quenched with aqueous NH4Cl (25 mL) and the product was extracted with EtOAc (60 mL). The extracts were washed with water (30 mL) and brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified on silica gel column eluting with 20-50% EtOAc in hexanes to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.61 (1H, d), 7.46 (1H, s), 7.24 (1H, d), 7.17 (2H, d), 7.03 (1H, d), 6.93 (1H, d), 6.91 (2H, d), 1.58 (6H, s), 1.22 (9H, s). LCMS: m/e 548.2 (M+H)+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(=O)(O)O.N[NH:12][C:13]([NH2:15])=[NH:14].C(=O)(O)O.[NH2:20][C:21]([NH2:23])=[NH:22]>O>[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[NH2:14][C:13]([NH2:15])=[NH2+:12].[NH2:22][C:21]([NH2:23])=[NH2+:20]
Reactant: N=C(N)N
Reactant: O=C(O)C(=O)O
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: O
Product: NC(N)=[NH2+]
Product: O=C([O-])C(=O)[O-]
Temperature: 90 °C

Procedure:
Oxalic acid (200.0 g, 2.22 mol) was weighed into a 2-liter beaker with a magnetic stir bar and dissolved in 1500 ml of distilled water. Aminoguanidine bicarbonate (362.8 g, 2.67 mol) and guanidine carbonate (160.1 g, 0.89 mol) were added in portions with stirring as to avoid bubbling over the sides of the beaker due to the evolution of carbon dioxide during the reaction. The reaction was stirred at room temperature overnight (approximately 24 hours). The water was removed from the reaction mixture in vacuo with heating to approximately 90° C. for 4 hours. The product was recovered as a crystalline white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26](C2C=CN=CC=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[C@@H](N1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=C1)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.COC1C(C2C=CC(CCC)=CC=2)CC(OC)O1.Cl[Si](C)(C)C>ClCCCl>[CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:67]2[CH:68]=[CH:69][C:64]([CH2:61][CH2:62][CH3:63])=[CH:65][CH:66]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:17])[CH3:18])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccncc2)c1)C(C)(C)C
Agent: CCCc1ccc(C2CC(OC)OC2OC)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Product: CCCc1ccc(-c2ccn([C@H](CC(=O)OCc3ccccc3)C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2)cc1
Yield: 7 %

Procedure:
As described in Example 1(d) for the preparation of N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)-3(R)-(3-pyridin-4-yl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-amino-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester trifluoroacetate salt (prepared as described in Example 1(b); 522 mg, 1.16 mmol) was condensed with crude 2,5-dimethoxy-3-(4-propylphenyl)-tetrahydrofuran (1.29 mmol) in 1,2-dichloroethane with chlorotrimethylsilane at 90° C. over 3 days. The crude dark oil was purified via flash column chromatography with 1% HOAc/10% MeOH/CH2Cl2 as eluant to provide 40 mg (7%) of N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-[3-(4-propylphenyl)-1H-pyrrol-1-yl]succinamic acid benzyl ester as a solid, mp 63-5° C.: 1H NMR (CDCl3): ∂ 7.40 (d, 2H, J=8.1 Hz), 7.34-7.20 (m, 5H), 7.14 (d, 2H, J=8.1 Hz), 7.00 (t, 1H, J=1.9 Hz), 6.78 (t, 1H, J=2.5 Hz), 6.56 (t, 1H, J=1.9 Hz), 6.24 (d, 1H, J=8.7 Hz), 5.70 (d, 1H, J=4.7 Hz), 5.16-4.96 (m, 3H), 4.00 (d, 1H, J=9.0 Hz), 3.38 (dd, 1H, J=5.6, 16.8 Hz), 3.10 (dd, 1H, J=8.7, 16.8 Hz), 2.76 (d, 3H, J=5.0 Hz), 2.59 (d, 1H, J=7.2 Hz), 2.56 (d, 1H, J=7.8 Hz), 1.65 (q, 2H, J=7.5 Hz), 0.96 (t, 3H, J=7.5 Hz), 0.86 (s, 9H). IR (KBr): 3314, 2959, 1736, 1648, 1560, 1165, 697 cm-1. HRFABMS: Calculated for C31H39N3O4Cs (M+Cs+): 650.1995. Found: 650.1977. Anal: Calculated for C31H39N3O4.0.3 C6H14 : C, 72.33; H, 7.62; N, 7.71. Found: C, 72.36; H, 7.77; N, 7.38.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19]CC4C=CC(OC)=CC=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nccc(-c3c[nH]nc3-c3ccc(F)cc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1

Procedure:
A solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyrimidinamine prepared in accordance with Example A-305 (0.35 g, 0.00093 mol) in 15 mL of trifluoroacetic acid was heated at reflux for 16 hours. Solvent was removed and the residue was partitioned between ethyl acetate and 1 N ammonia hydroxide. Organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate) to give 0.14 g of product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine, as a pale yellow solid (59% yield), mp: 273-274° C.; Anal. Calc'd for C13H10FN50.25H2O: C, 60.11; H, 4.07; N, 26.96. Found: C, 60.15; H, 3.82; N, 26.38.
Reaction SMILES: O=C(C1(C(F)(F)F)CC1)CC#[N:5].[C:13](=[N:26][NH:27][C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)([C:20]1[CH:25]=CC=[CH:22][CH:21]=1)[C:14]1[CH:19]=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:25][C:20]1([C:13]2[CH:14]=[C:19]([NH2:5])[N:27]([C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[N:26]=2)[CH2:21][CH2:22]1
Reactant: N#CCC(=O)C1(C(F)(F)F)CC1
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2N)cn1
Yield: 66.9 %

Procedure:
Heat a mixture of 3-Oxo-3-(1-trifluoromethyl-cyclopropyl)-propionitrile (2.66 g, 15.0 mmol), N-benzhydrylidene-N′-(6-methyl-pyridin-3-yl)-hydrazine (TL, 2002, 43, 2171-2173) (4.31 g, 15.0 mmol), and p-tolylsulfonic acid (14.29 g, 75.0 mmol) in ethanol (85 mL) at 90° C. in a sealed tube for 18 hours. After removal of the solvent, subject residue to silica gel chromatography eluting with 0-5% methanol in dichloromethane to give a brown solid (2.29 g, 54% yield). MS(ES+): m/z=283.2 [M+H].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].CN(C=O)C.[N-:16]=[N+:17]=[N-:18].[Na+]>C(Cl)Cl>[N:16]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[N+:17]=[N-:18]
Reactant: O=C(O)CCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NCCCCCCC(=O)O
Temperature: 60 °C

Procedure:
7-azidoheptanoic acid (64) was synthesized from 7-bromoheptanoic acid 63 as shown above. To 914 mg of 7-bromoheptanoic acid (63) (commercially available from Matrix Scientific, Columbia, S.C.) (4.4 mmol) was added 15 mL anhydrous DMF. To the stirring solution was added 914 mg NaN3 (14 mmol, 3.2 eq) at room temperature. The clear solution was warmed to 60° C. for a period of 6 h. The solution was then cooled to room temperature and diluted with 50 mL CH2Cl2. The organic layer was washed with cold 1N HCl (7×50 mL) and brine (2×50 mL), then dried over anhydrous Na2SO4. Filtration and removal of solvent afforded 709 mg crude 7-azidoheptanoic acid 64 in 94% yield which was of suitable purity for continued progression enroute to materials 65 and 66. An NMR analysis was performed where: 1H NMR (400 MHz, CDCl3) δ 11.55 (bs, 1H), 3.14 (t, J=6.8 Hz, 2H), 2.22 (t, J=7.2 Hz, 2H), 1.56-1.45 (m, 4H), 1.30-1.24 (m, 4H); 13C NMR (400 MHz, CDCl3) δ 178.3, 51.1, 33.7, 28.5, 28.4, 26.2, 24.4. HRMS (ESI) calculated. for C7H13N3O2 (M−H): 170.0930, measured: 170.0930.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN(C(C)C)C(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([N:19]([O:20][CH3:21])[CH3:18])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Yield: 76.1 %

Procedure:
3-Bromo-5-(pentafluorosulfanyl)benzoic acid (1.35 g) was dissolved in thionyl chloride (10 ml) while stirring, and kept under reflux with exclusion of moisture for 5 h. Then the thionyl chloride was drawn off, the residue was taken up in DCM (40 ml) and the solution was admixed with N,O-dimethylhydroxylamine hydrochloride (381 mg). Subsequently Hünig's base (0.7 ml) was added and then the mixture was stirred for 2 h. Thereafter, the mixture was dried, the residue was taken up with EA and the solution was washed five times with water. The EA phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (60 g cartridge, 4:1 n-heptane/EA). 1.1 g of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11]C)=[O:9])=[C:5](C)[N:6]=1.NC1SC(C(OC)=O)=CN=1.Cl[CH2:24][CH2:25][N:26]=[C:27]=[O:28]>>[O:28]=[C:27]1[NH:26][CH2:25][CH2:24][N:1]1[C:2]1[S:3][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:6]=1
Reactant: O=C=NCCCl
Reactant: CCOC(=O)c1sc(N)nc1C
Agent: COC(=O)c1cnc(N)s1
Product: COC(=O)c1cnc(N2CCNC2=O)s1
Yield: 44 %

Procedure:
Following the procedure as described in Example 3, making variations as required to replace ethyl 2-amino-4-methylthiazole-5-carboxylate with methyl 2-aminothiazole-5-carboxylate to react with 2-chloroethyl isocyanate, the title compound was obtained as a colorless solid in 44% yield: mp 205-208° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 5.55 (s, 1H), 4.25-4.19 (m, 2H), 3.84 (s, 3H), 3.72-3.67 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.8, 162.5, 157.0, 145.1, 122.2, 52.1, 44.4, 38.1; MS (ES+) m/z 228.2 (M+1).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[C:1]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]([Cl:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cccc(C(=O)c2ccccc2)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1cccc(C(=O)c2ccccc2)c1

Procedure:
20 g of m-benzoyl-phenyl acetic acid (prepared by process of French Pat. No. 1,546,478) and 100 ml of thionyl chloride were refluxed for 3 hours and then evaporated to dryness. Excess thionyl chloride was removed by entrainment with benzene to obtain 21.47 g of m-benzoyl-phenyl-acetic acid chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)[C@H:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Br[C:31]1[CH:32]=[C:33](I)[C:34](=[O:37])[NH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:33]3[C:34](=[O:37])[NH:35][CH:36]=[CH:31][CH:32]=3)=[CH:10][CH:9]=2)[C@H:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)OC(=O)N(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@H]1c1ccccc1
Reactant: O=c1[nH]cc(Br)cc1I
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(-c3ccc[nH]c3=O)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A resealable tube was charged with (S)-5,5-dimethyl-4-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-2-one (Intermediate J)(0.100 g, 0.254 mmol), 5-bromo-3-iodopyridin-2(1H)-one (commercially available from Adesis, Inc., New Castle, Del.)(0.153 g, 0.509 mmol), sodium carbonate (0.108 g, 1.017 mmol), dioxane (2.0 mL), and water (0.40 mL). Tetrakis(triphenylphosphine)palladium(0) (0.147 g, 0.127 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture was then stirred at 100° C. for 16 hours. The reaction mixture was filtered through Celite® brand filter aid. The filtrate was then concentrated to afford a black oil. The oil thus obtained was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-100% EtOAc-hexane) to afford (S)-5,5-dimethyl-3-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)-4-phenyloxazolidin-2-one (0.021 g, 0.058 mmol, 23% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (s, 3H), 1.64 (s, 3H), 5.46 (s, 1H), 6.24 (t, J=6.70 Hz, 1H), 7.20-7.43 (m, 6H), 7.48 (d, J=8.90 Hz, 2H), 7.58 (dd, J=6.94, 2.05 Hz, 1H), 7.65 (d, J=8.80 Hz, 2H), 11.72 (br. s., 1H). m/z (ESI) 361 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH3:8])(C)(C)C.Cl[C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:24][C:21]1[CH:20]=[CH:19][C:18]([CH:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)=[CH:15][CH:16]=2)[CH2:9][NH:7][CH3:8])=[CH:23][CH:22]=1
Reactant: CN(CC(c1ccc(O)cc1)c1ccc(Br)cc1)C(=O)OC(C)(C)C
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNCC(c1ccc(Br)cc1)c1ccc(Oc2cnccn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.8 %

Procedure:
A solution of [2-(4-Bromo-phenyl)-2-(4-hydroxy-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (125 mg, 0.31 mmol), 2-chloropyrazine (35.2 mg, 0.31 mmol) and K2CO3 (213 mg, 1.54 mmol) in dimethylformamide (8 ml) was heated to 100° C. for 17 hours. Upon cooling, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was then treated with saturated HCl in diethyl ether (15 ml) and stirred at room temperature for 72 hours. The solvent was then removed under reduced pressure and the crude product was purified by Phenomenex_Strata_SCX column chromatography eluting with methanol followed by 2N ammonia in methanol to afford the desired product (82 mg). LC/MS: (PS-B3) Rt 3.17 [M+H]+ 384.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=O)[NH:8]2)=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[F:19][C:20]([F:34])([F:33])[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)[NH2:22].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:13])[NH:22][CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)[C:20]([F:34])([F:33])[F:19])[NH:8]2)=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)[nH]c2cc1Cl
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 26.6 %

Procedure:
A solution of the crude product of 6-chloro-5-(ethoxycarbonyl)-1H-indole-2-carboxylic acid (1.9 g) from Synthesis Example 1, Stage 2 and 2,2,2-trifluoro-1-[3-trifluoromethylphenyl]ethanamine (1.12 g, 4.60 mmol) (lit. DE 2723464) in N,N-dimethylformamide (15 ml) was admixed with 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (953 mg, 4.60 mmol), and the mixture was stirred at room temperature for 4 days. The reaction solution was admixed with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with sat. sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 25% ethyl acetate) gave 603 mg (26% of theory over 2 stages) of ethyl 6-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate.