Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[O:5][C:6]=1[Br:7].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:44][CH:45]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:44][CH:45]([CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:10])[O:5][C:6]=1[Br:7]
Reactant: CC(C)(C)OC(=O)NCC(N)Cc1ccccc1
Reactant: O=C(O)c1cc(Br)c(Br)o1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(Cc1ccccc1)NC(=O)c1cc(Br)c(Br)o1
Reaction time: 16 h
Yield: 107 %

Procedure:
To a solution of 4,5-dibromo-2-furancarboxylic acid (2.81 g, 10.4 mmol), PyBrOP (5.6 g, 12.0 mmol) and diisopropylethyl amine (4.2 mL, 24.0 mmol) in DCM (70 mL) at 25° C. was added 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (2.0 g, 8.0 mmol). After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, hexanes/EtOAc, 2:1) affording the title compound (4.3 g, 82%) as a white solid: LC-MS (ES) m/z=503 (M+H)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1>>[N:14]1([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Product: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1

Procedure:
3-(chlorosulfonyl)benzoic acid (2.0 g, 9.1 mmol) was treated with was treated with indoline (2.7 g, 22.7 mmol) using method A to give 3-(indolin-1-ylsulfonyl)benzoic acid as a light purple solid. Yield: 1.6 g (58%). 1H-NMR: 8.23 (t, J=1.5 Hz, 1H), 8.19 (dt, J=8.0, 1.5, 1.5 Hz, 1H), 8.04 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 3.92 (t, J=8.5 Hz, 2H), 2.90 (t, J=8.5 Hz, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)[CH3:11]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCc1ccc(C=Nc2ccc(C#N)cc2)cc1
Temperature: 120 °C

Procedure:
A mixture of 5.9 g. of p-aminobenzonitrile and 6.7 g. of p-ethylbenzaldehyde in 100 ml. of benzene is treated with 150 mg. of p-toluenesulfonic acid, gassed with nitrogen and heated at reflux for 1 hour (bath temperature 120°C.). The water which forms is separated by means of a water separator. During an additional 1 hour of refluxing, the benzene which condenses in the reflux condenser is led back to the reaction vessel through a layer of 50 g. of aluminum oxide (activity I). After cooling, 2 g. of solid potassium carbonate are added. The mixture is filtered and the filtrate freed from the solvent under vacuum at 50°C. (bath temperature), whereby there remains 11.5 g. of a yellow oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol to a constant melting point and until by-products are no longer observed by gas chromatogram. The p-[(p-ethylbenzyliden)amino]benzonitrile which is obtained melts at 76.2°-77.0°C. and is liquid crystalline with cooling from 63.0°-59.7°C. UV (ethanol): ε277 = 25800 (shoulder at 316 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis date confirm the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]3([CH2:25][CH:24]3[CH3:26])[N:9]=2)=[CH:4][CH:3]=1.C(O)[C@H](O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH3:26])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(CC1C)c1nnc(C)n1-2
Agent: C[C@@H](O)CO
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C)c1nnc(C)n1-2

Procedure:
A procedure analogous to the scheme set forth for the synthesis of Compound 215 was followed, with the exception that (R)-propane-1,2-diol was used as starting material. LRMS (M+H)+: 383 m/z. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 4H), 3.80 (t, J=6.98 Hz, 1H), 2.55-2.63 (m, 3H), 2.39 (s, 3H), 1.95-2.03 (m, 1H), 1.58 (s, 3H), 1.39 (d, J=5.95 Hz, 1H), 1.05-1.12 (m, 1H), 0.79 (d, J=5.49 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([Cl:18])=[C:16]([C:19]#[N:20])[C:15]([S:21][C:22]([F:25])([F:24])[F:23])=[C:14]1[CH2:26][CH:27](Cl)[C:28]#[N:29].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([Cl:18])=[C:16]([C:19]#[N:20])[C:15]([S:21][C:22]([F:25])([F:24])[F:23])=[C:14]1[CH:26]=[CH:27][C:28]#[N:29]
Reactant: N#Cc1c(SC(F)(F)F)c(CC(Cl)C#N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Cl
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: N#CC=Cc1c(SC(F)(F)F)c(C#N)c(Cl)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 98 %

Procedure:
The 1-(2,6-dichloro-4-trifluoromethylphenyl)-2-(2-chloro-2-cyanoethyl)-3-trifluoromethylthio-4-cyano-5-chloropyrrole prepared above was dissolved in 125 mL of toluene and treated with 1.65 mL (1.68 g, 11.1 mmoles) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature for 1 hour. The reaction mixture was then diluted with ether, washed with water, dried over anhydrous MgSO4 and concentrated to give 4.84 g (98%) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2-(2-cyanoethenyl)-3-trifluoromethylthio-4-cyano-5-chloropyrrole as a yellow solid.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:17]2[S:16][C:15]=1[NH2:35])(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([CH2:13][C:14]2[CH:19]([C:20]([OH:22])=[O:21])[N:18]3[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:17]3[S:16][C:15]=2[NH2:35])=[CH:3][CH:2]=1
Reactant: CC(=O)OCC1=C(N)S[C@@H]2[C@H](C(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CSc1ccc(CC2=C(N)S[C@@H]3[C@H](C(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
A solution of 1.5 ml of thioanisol in 10 ml of trifluoroacetic acid is treated with 1.17 g of 3-acetyloxymethyl-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid and the mixture is left to stand for 30 minutes at room temperature. After diluting the mixture with an equal volume of toluene, the volatile fractions are evaporated under reduced pressure. The residue is partitioned between ethyl acetate and a 10% aqueous dipotassium hydrogen phosphate solution (pH = 7.5). The layers are separated; the aqueous phase is washed several times with ethyl acetate, adjusted to pH 2.5 with 20% aqueous phosphoric acid and extracted with ethyl acetate. The resulting organic extracts are washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure, to yield the 3-(4-methylthio-benzyl)-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid, which is further processed without purification.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]1[CH:20]2[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:22][CH:14]1[CH2:15]3)[CH2:19]2)(=O)=O)([O-])=O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C1(S)C=CC=CC=1>O.CO.C(#N)C>[CH:14]12[CH2:22][CH:18]3[CH2:17][CH:16]([CH2:21][CH:20]([CH2:19]3)[NH:13]1)[CH2:15]2
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1C2CC3CC(C2)CC1C3
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C1C2CC3CC1CC(C2)N3
Reaction time: 5 h
Yield: 88 %

Procedure:
To 100 mg (0.311 mmol) of N-(2-nitrophenylsulfonyl)-2-azaadamantane, 51.6 mg (0.373 mmol) of potassium carbonate and 0.54 g of toluene were added, and after adjusting the temperature to 50° C., 0.039 mL (0.380 mmol) of thiophenol was added. After stirring for 5 hours, acetonitrile, methanol and water were added to obtain a uniform solution of 2-azaadamantane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[H+].[B-](F)(F)(F)F.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[N:10]([CH3:9])[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: Cn1ccnc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Cn1cncc1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
1-Chloro-4-iodobenzene (10 g, 42 mmol) was combined with 1-methyl-1H-imidazole (13.3 mL, 168 mmol), Pd(OAc)2 (470 mg), PCy3.HBF4 (1.54 g), Cs2CO3 (13.7 g, 42 mmol) in DMF (200 mL). The reaction was heated to 120° C. for 15 hr. After cooling to ambient temperature, the reaction was filtered to remove solids and the eluent was partitioned between EtOAc and H2O. The organics were separated, washed with saturated aqueous NaHCO3, and dried with saturated aqueous NaCl. Solvents were removed in vacuo and the residue purified by column chromatography on silica to provide the desired product. MS (m/z) 193.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:24])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([Cl:23])[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[Cl:23][C:13]1[CH:12]=[C:11](/[C:4](=[CH:5]\[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)/[C:3]([OH:24])=[O:2])[CH:16]=[CH:15][C:14]=1[N:17]1[C:21]([CH3:22])=[N:20][N:19]=[N:18]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1Cl
Temperature: 47.5 °C
Yield: 101.3 %

Procedure:
A solution of (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylic acid methyl ester (160 mg, 0.46 mmol) in ethanol (5 mL) was treated with a 1N aqueous sodium hydroxide solution (1 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (10 mL) and extracted with diethyl ether (1×30 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×20 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylic acid (155 mg, 100%) as a white solid: mp 216-219° C.; EI-HRMS m/e calcd for C16H17ClN4O2 (M+) 332.1040, found 332.1048.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)C=CC=CC=1.[F:26][CH2:27][CH2:28][NH2:29]>>[F:26][CH2:27][CH2:28][NH:29][C:8]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([B:16]2[O:17][C:18]([CH3:23])([CH3:24])[C:19]([CH3:22])([CH3:21])[O:20]2)=[CH:12][CH:11]=1)=[O:7]
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2)OC1(C)C
Reactant: NCCF
Product: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2)OC1(C)C

Procedure:
Method as described for intermediate 13 using phenyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (intermediate 17) and 2-fluoroethylamine to afford a pink wax (3.8 g) used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:5]([CH3:15])=[CH:4][N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>C(Cl)Cl.CO>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH3:15])=[CH:4][N:3]=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][N:20]4[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]4)=[CH:30][CH:29]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cnc(Cl)nc1-c1cccc(Cl)c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1cccc(Cl)c1
Yield: 77 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chlorophenyl)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 77% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.31 (s, 1H), 7.61 (s, 1H), 7.56 (d, 2H, J=8.2 Hz), 7.48 (m, 1H), 7.40 (m, 2H), 7.25 (d, 2H, J: not calculated due to overlapping peaks), 3.45 (s, 2H), 2.45 (bs, 8H), 2.27 (s, 3H), 2.24 (s, 3H); MS (ESI): 408.4 [M+H]+, 204.7 [M+2H]2+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Cl.[Cl:15]([O-])(=O)=O.[Na+].[N+](N([N+]([O-])=O)C1C=CC=CC=1)([O-])=O.Cl([O-])(=O)=O.ClCl>O>[Cl:15][C:7]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[NH2:6]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [O-][Cl+2]([O-])[O-]
Agent: Cl
Agent: ClCl
Agent: O=[N+]([O-])N(c1ccccc1)[N+](=O)[O-]
Solvent: O
Product: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 94 %

Procedure:
183 parts of 2,4-dinitroaniline and 0.15 part of lignosulfonate are suspended in 220 parts of water and the suspension is ground. 800 parts of 32 % hydrochloric acid are charged to a reactor. Then 145 parts of a 33 % solution of sodium chlorate and the aqueous suspension of dinitroaniline obtained by wet grinding are added simultaneously in separate streams at 25° C. to the hydrochloric acid. The chlorate solution is added over 260 minutes and the suspension of dinitroaniline simultaneously over a somewhat shorter time of 240 minutes. The mixture is then allowed to react for 30 minutes. Excess chlorine is expelled and any chlorine residues remaining in the mixture are destroyed by adding a solution of sodium bisulfite. The product is then isolated by filtration, washed until neutral and dried, affording 204 parts of 2-chloro-4,6-dinitroaniline (yield: 94 %). Melting point: 157.5° C. (lit.: 157°-159° C.)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>CO.C(OCC)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Fc1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 113.5 %

Procedure:
To the product from step 1 (271 mg, 0.699 mmol) in methanol (3 mL) was added 1M HCl in diethyl ether (15 mL) and the resulting mixture was stirred at rt for 7 h. The solvent was removed in vacuo to obtain the product as a solid (228 mg, 99%): MS; m/z 288 (M+H): LCMS (UV) 98%. 1H NMR (400 MHz, DMSO-d6) δ 1.70-1.76 (m, 1H), 1.89-1.99 (m, 2H), 2.01-2.14 (m, 1H), 3.18-3.23 (m, 2H), 3.87-3.90 (m, 1H), 4.12-4.16 (dd, 1H J1=8.4 Hz, J2=10.8 Hz), 4.21-4.25 (dd, 1H J1=4 Hz, J2=10.8 Hz), 6.96-6.99 (m, 2H), 7.014-7.016 (m, 4H), 7.17-7.22 (m, 2H), 9.1 (s, 1H), 9.7 (s, 1H)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:12][OH:13])[C:10]#[N:11].[C:16](OCC)(=[O:18])[CH3:17]>CCCCCC>[C:16]([O:13][CH2:12][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:15])[F:1])[C:10]#[N:11])(=[O:18])[CH3:17]
Reactant: CCOC(C)=O
Reactant: N#CC(CO)c1ccccc1C(F)(F)F
Solvent: CCCCCC
Product: CC(=O)OCC(C#N)c1ccccc1C(F)(F)F

Procedure:
This ester was prepared using the procedure described in Example 5, except 2-(2-(trifluoromethyl)phenyl)-3-hydroxypropanenitrile was used in place of 2-(2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 2-(2-(trifluoromethyl)phenyl)-3-hydroxypropanenitrile is described in Example 9. The recovered ester product was a colorless oil (95% yield), Rf 0.35 (silica gel, ethyl acetate:hexane=1:4).
Reaction SMILES: [Br:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1>[C:37]([NH:30][S:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:8]([CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:34][CH:33]=2)[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[CH:28][CH:27]=1)(=[O:32])=[O:31])(=[O:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC(N(CCc2ccc(Br)cc2)Cc2ccc(S(N)(=O)=O)cc2)CC1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccc(CN(CCc2ccc(Br)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
tert-Butyl 4-((4-bromophenethyl)(4-sulfamoylbenzyl)amino)piperidine-1-carboxylate (see Example 15, step 1) was dissolved in anhydrous THF (5 mL/mmol) under atmosphere of argon and the solution was cooled to 0° C. Sodium hydride (2 equiv) was then added in one portion and after 10 minutes acetyl chloride (2 equiv) was added dropwise by syringe over 10 minutes. The cooling batch was removed and the reaction mixture was allowed to stir for two days after which time the starting material could no longer be detected. The reaction mixture was then diluted with EtOAc (12 mL/mmol of starting material), washed with 1 M NaOH (2×), water (2×) and brine (2×) and dried over anhydrous MgSO4. After filtration of the drying agent the solvent was stripped off and the crude product was purified by column chromatography (yield 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12](Cl)(=[O:14])[CH3:13].C(OCC)(=O)C>O1CCCC1>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:12](=[O:14])[CH3:13])[CH:3]=2)[NH:7]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
A stirred solution of 5-amino-1,3-dihydro-indol-2-one (3.5 g, 23.6 mmol, prepared according to U.S. Pat. No. 6,114,371) in 20 ml of tetrahydrofuran was added with tirethylamine (1.3 ml, 9 mmol). The solution was cooled down to −30° C. in an acetone-dry ice bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. Upon the completion of the addition, the resulting mixture was stirred for 20 minutes at room temperature and added with ethyl acetate (20 ml) until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (4 g, 88.9%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O>CO>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[CH:15]/[C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[Br:12])=[CH:6][CH:5]=1
Reactant: O=Cc1ccccc1Br
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CO
Product: COC(=O)c1ccc(/N=C/c2ccccc2Br)cc1
Reaction time: 8 h

Procedure:
4-aminobenzoic acid methyl ester (1.51 g, 10 mmol) and 2-bromobenzaldehyde (1.45 mL, 12.5 mmol) were dissolved in 15 mL of methanol. The mixture was let stand overnight. A white precipitate formed and the crystals were filtered off, washed with cold methanol (2×) and dried.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([OH:26])([CH3:25])[CH3:24])[N:18]=3)[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].Br[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH3:36])[CH:35]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCCC>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([OH:26])([CH3:24])[CH3:25])[N:18]=3)[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH3:36])[CH:35]=1
Reactant: Cc1cnc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)cc(O)c(Cl)c1=O
Reactant: Cc1cncc(CBr)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: Cc1cncc(COc2cc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ncc3C)c(=O)c2Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
To the intermediate at Step F, a solution of 3-chloro-4-hydroxy-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (386 mg, 1.0 mmol) in N,N-dimethylformamide (1.7 mL) was added 3-(bromomethyl)-5-methylpyridine (205 mg, 1.1 mmol), potassium carbonate (0.35 g, 2.52 mmol) and 18-crown-6 (7 mg). The slurry was stirred at ambient temperature for 18 hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was concentrated in vacuo to provide a brown oil. Normal phase chromatography (ethyl acetate/heptane) provided 351 mg of the alkylated product MS (M+H) 493.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(O[CH:13](O)[CH:14]([F:16])[F:15])C.[OH-].[Na+].[BH4-].[Na+]>C1(C)C=CC=CC=1.CO.CO.C(Cl)Cl>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][NH:1][CH2:13][CH:14]([F:16])[F:15])[CH3:6]
Reactant: CCOC(CN)OCC
Reactant: CCOC(O)C(F)F
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(CNCC(F)F)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A solution of 3 g (22.5 mmol) of 1-amino-2,2-diethoxyethane, 3.1 g (24.8 mmol) of difluoroacetaldehyde ethyl hemiacetal and 1 pellet of solid NaOH in 44 ml of toluene was heated at 120° C. with a Dean-Stark trap for 1.5 hours. The mixture was left to stand until it had cooled to room temperature and was concentrated in vacuo. The residue was diluted with 80 ml of methanol, and 3.4 g (90 mmol) of sodium borohydride were added in small quantities. The reaction mixture was then stirred overnight, concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase was isolated, dried (MgSO4) and concentrated in vacuo. 3.7 g of crude substance were obtained as a colorless oil. The residue was subjected to a flash chromatography on 40 g of SiO2 (elution with DCM/MeOH, gradient 1-8%). 3.1 g of the desired amine were obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1F.[CH2:13]([SH:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:15][CH2:13][CH3:14]
Reactant: CCS
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cc(C(F)(F)F)ccc1Br
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1.5 g of 4-bromo-3-fluorobenzotrifluoride, 0.46 ml of ethanethiol, 851 mg of potassium carbonate and 2 ml of DMF was stirred at 75° C. for 2.5 hours. Water was poured to the cooled reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 1.15 g of 4-bromo-3-ethylsulfanylbenzotrifluoride.