Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:36][CH2:37][CH2:38][C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=1>>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13](=[O:15])[N:14]1[CH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]#[N:44])=[CH:45][CH:46]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Reactant: N#Cc1ccc(CCCBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCc1ccc(C#N)cc1)Cc1ccccc1
Yield: 69.4 %

Procedure:
Analogous to the procedure described for Example 1A, Step D, the anion derived from 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one (262.8 mg, 0.756 mmol) and NaHMDS (0.83 mL, 0.83 mmol) was reacted with 4-(3-bromo-propyl)-benzonitrile (186 mg, 0.832 mmol) at 70° C. for 24 h. Purification by medium pressure chromatography (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzonitrile (257.6 mg). 1H NMR (CDCl3) δ7.56 (m, 2H), 7.26 (m, 5H), 7.13 (m, 2H), 3.85 (m, 1H), 3.62 (m, 1H), 3.48 (m, 1H), 2.93 (m, 1H), 2.82-2.60 (m, 4H), 2.29 (m, 2H), 1.88-1.25 (m, 7H); MS 491.5 (M+1).
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]([NH:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]([NH2:18])=[O:17])=[CH:13][CH:12]=[C:11]([C:19]1[O:20][C:21]([CH:24]=O)=[CH:22][CH:23]=1)[CH:10]=2)=[O:5].[BH4-].[Na+]>CO>[NH2:3][C:4]([NH:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]([NH2:18])=[O:17])=[CH:13][CH:12]=[C:11]([C:19]1[O:20][C:21]([CH2:24][NH:2][CH3:1])=[CH:22][CH:23]=1)[CH:10]=2)=[O:5]
Reactant: NC(=O)Nc1[nH]c2cc(-c3ccc(C=O)o3)ccc2c1C(N)=O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(-c2ccc3c(C(N)=O)c(NC(N)=O)[nH]c3c2)o1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A solution of 40% methylamine in methanol (49 μL, 0.48 mmol) was added to a solution of 2-aminocarbonylamino-6-(5-formylfuran-2-yl)indole-3-carboxamide (Compound 4-74, 0.10 g, 0.32 mmol) in anhydrous methanol (2 mL), and the mixture was stirred at 60° C. for 6 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a solution mixture of methanol and tetrahydrofuran (methanol/tetrahydrofuran=1/2, 3 mL). Sodium borohydride (0.024 g, 0.64 mmol) was added to the solution mixture under ice-cooling, and the mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the precipitated solid was washed with H2O (5 mL) and dried under reduced pressure to give the title compound (0.077 g) as a slightly brown solid (yield 74%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]([N:28]1[CH2:32][CH2:31][CH:30]([CH2:33][NH:34][CH3:35])[CH2:29]1)([CH3:27])[CH3:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:34]([CH2:33][CH:30]4[CH2:31][CH2:32][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29]4)[CH3:35])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CNCC1CCN(C(C)C)C1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)CC3CCN(C(C)C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(1-isopropylpyrrolidin-3-yl)-N-methylmethanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (br. s., 5H) 2.09 (br. s., 1H) 2.42 (s, 3H) 2.60-2.78 (m, 1H) 2.90-3.09 (m, 4H) 3.09-3.44 (m, 5H) 7.44 (d, J=8.49 Hz, 1H) 7.47 (s, 1H) 7.76-7.80 (m, 1H) 7.85 (d, J=7.33 Hz, 1H) 8.30 (d, J=8.34 Hz, 1H) 8.45 (br. s., 1H) 8.55 (d, J=8.59 Hz, 1H); ESI-MS m/z [M+H]+ 459.2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(N)(N)=[O:13].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.COC(C1C(C)=[N+]([O-])C=CN=1)=O>C(Cl)Cl>[CH3:11][O:10][C:8]([C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N+:4]=1[O-:13])=[O:9]
Reactant: NC(N)=O
Reactant: COC(=O)c1nccnc1C
Agent: COC(=O)c1ncc[n+]([O-])c1C
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(C)ncc[n+]1[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a solution of methyl 3-methylpyrazine-2-carboxylate (9.1 g, 59.8 mmol) in DCM (100 mL) at 0° C., was added urea hydrogen peroxide adduct, 97% (7.81 g, 83 mmol) and trifluoroacetic acid anhydride (10.8 ml, 78 mmol) dropwise. The resulting mixture was stirred at 0° C. for 1 h, and at room temperature for 18 h. The reaction was diluted with DCM and quenched with saturated Na2SO3 solution; the aqueous layer was back-extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude mixture was purified with ISCO (20% to 80% EtOAc/Hexanes) to afford a mixture of products: 2-(methoxycarbonyl)-3-methylpyrazine 1-oxide (5.2 g, 51.7% yield) and 3-(methoxycarbonyl)-2-methylpyrazine 1-oxide. The mixture was taken to next step without further purification.
Reaction SMILES: ClC1C=CC(S(Cl)(=O)=O)=CC=1[N+]([O-])=O.COC1C=CC=CC=1N.Cl[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])(=[O:33])=[O:32])=[CH:27][C:26]=1[N+:43]([O-:45])=[O:44].[NH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>N1C=CC=CC=1>[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[NH:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[C:26]([N+:43]([O-:45])=[O:44])[CH:27]=1)(=[O:33])=[O:32]
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C1CNCCN1
Agent: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: COc1ccccc1N
Solvent: c1ccncc1
Product: COc1ccccc1NS(=O)(=O)c1ccc(N2CCNCC2)c([N+](=O)[O-])c1

Procedure:
The compound was prepared from 4-chloro-3-nitrobenzenesulfonyl chloride (1 g, 3.9 mmol), 2-methoxyaniline (0.53 mL, 4.7 mmol) and pyridine (1.6 mL) in CH2CL2 (2 mL). 4-Chloro-N-(2-methoxyphenyl)-3-nitrobenzenesulfonamide (0.345 g) was reacted with piperazine (0.111 g) to afford N-(2-methoxyphenyl)-4-(piperazinyl)-3-nitrobenzenesulfonamide. This was then treated with Raney-Ni and hydrazine monohydrate. The final product was isolated as its HCl salt. 1H NMR (DMSO-d6) δ 7.18-7.20 (m, 1H), 7.08-7.10 (m, 2H), 6.93-6.96 (m, 1H), 6.91-6.93 (m, 2H); 6.84 (dt, 1H), 3.56 (s, 3H), 3.22-3.27 (m, 4H), 3.00-3.02 (m, 4H); MS (posESI) m/z=362.1 (M+H+).
Reaction SMILES: C(Cl)CCl.[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][NH2:13])=[N:10][CH:11]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]([NH:13][NH:12][C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][N:10]=2)=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNc2ccc(F)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
EDC (543 mg, 2.83 mmol) was added portionwise to a stirred solution of 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 0.30 g, 2.36 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (Aldrich, 649 mg, 2.83 mmol) and HOBt (32 mg, 0.24 mmol) in dry DCM (20 mL). The mixture was stirred at RT for 18 h. The solution was washed with water (2×20 mL), dried (Na2SO4) and evaporated. The residue was triturated (diethyl ether) to give the title compound as an off-white solid (713 mg, 82%). LCMS (Method 1): Rt 2.76 min, m/z 339 [MH+].
Reaction SMILES: [SH-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18](=[N:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1OC)[O-:19].[CH3:29]S(C)=O>>[CH3:29][O:19][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH3:10])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccccc1N=[N+]([O-])c1ccccc1OC
Reactant: CS(C)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [SH-]
Product: COc1ccccc1N(Nc1ccccc1)OC
Temperature: 75 °C
Yield: 88 %

Procedure:
85 Parts of an aqueous solution of 36 percent technical sodium hydrosulphide, containing 1 percent sodium thiosulphate, were added to a mixture comprising 51.6 parts of 2,2'-dimethoxy azoxybenzene in 100 parts dimethyl sulfoxide at 60° within one hour. Subsequently, the temperature of the reaction mixture was raised to 75° C and maintained at 70° C-75° C for 2 1/2 hours. The pH of the reaction mixture was maintained between 9.5 and 10.0. After this period the starting material was shown to be entirely reduced. Then the reaction mixture was cooled down to 0° C, the separated product was filtered off and washed with water until alkali-free. After drying below 70° C, 43.0 parts of high quality 2,2'-dimethoxyhydrazobenzene of a melting point of 100° C to 102° C were obtained, this repesenting a yield of 88 percent of the theory.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[N:35][CH:36]=1>CN(C=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([O:1][C:31]2[CH:36]=[N:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)[CH:3]=[C:4]([CH3:23])[C:5]=1[C:9]1[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])nc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 50 °C
Yield: 66.6 %

Procedure:
A solution of 5-3 (1.92 g, 5.91 mmol) in DMF (15 mL) was added with cesium carbonate (2.41 g, 7.39 mmol). The reaction mixture was heated at 50° C. for 60 min and added with 5-bromo-2-nitropyridine (24-1, 1.80 g). The reaction mixture was heated at 50° C. for 4.0 h. The solution was quenched with water (40 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=3/1-1/3) to give 24 (1.76 g) in 67% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.78 (d, 2 H), 8.42 (d, 1 H), 8.33 (d, 1 H), 7.96 (d, 2 H), 7.63 (m, 1 H), 7.21 (s, 1 H), 7.01 (s, 2 H), 2.08 (s, 6 H), ESI-MS=m/z 447.5 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:25])=[O:24])=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:38]1[C:42]([NH2:43])=[N:41][CH:40]=[N:39]1.C1COCC1.CC([O-])(C)C.[Li+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23]([NH:43][C:42]1[S:38][N:39]=[CH:40][N:41]=1)(=[O:25])=[O:24])=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncns1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3Cc3ccccc3)cccc2c1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ncns1)c1ccc2c(C3CCCN3Cc3ccccc3)cccc2c1
Reaction time: 1 h
Yield: 60.9 %

Procedure:
A flask was charged with perfluorophenyl 5-(1-benzylpyrrolidin-2-yl)naphthalene-2-sulfonate (INTERMEDIATE LL) (24.8 mg, 0.046 mmol), 1,2,4-thiadiazol-5-amine (5.64 mg, 0.056 mmol), and THF (465 μl) to give a clear, colorless solution. The flask was cooled in an ice-bath for 5 min, then lithium 2-methylpropan-2-olate (1M in hexane) (102 μl, 0.102 mmol) was added dropwise. After 1 h, the mixture was loaded directly onto a 5-g silica gel loading column with the aid of DCM. The column was dried under vacuum, then eluted onto a prequilibrated 12-g silica gel column with 0 to 10% MeOH/DCM to give 5-(1-benzylpyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (12.69 mg, 0.028 mmol, 60.6% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.46-8.33 (m, 2H), 8.07 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.97 (d, J=7.1 Hz, 1H), 7.83 (dd, J=1.9, 8.9 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.34-7.21 (m, 5H), 4.62 (br. s., 1H), 3.91 (d, J=13.0 Hz, 1H), 3.24 (br. s., 4H), 1.97 (d, J=14.1 Hz, 2H), 1.86-1.72 (m, 1H); m/z (ESI) 451.4 (M+H)+.
Reaction SMILES: [C:1]1([PH+:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC[C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:29]([C:36]2[CH:41]=[CH:40][C:39](CBr)=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1.[C:50]1([P:56]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C1(C)C=CC=CC=1>CN(C=O)C>[C:25]1([C:28]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:24]=[CH:23][CH:22]=[CH:27][CH:26]=1.[C:14]1([PH+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:63]1([PH+:56]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1
Reactant: BrCc1ccc(C(=C(c2ccccc2)c2ccc(CBr)cc2)c2ccccc2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc(C(=C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reaction time: 24 h
Yield: 80 %

Procedure:
Triphenylphosphonium salt, TPE-TPP, was prepared from 3 (0.5 g, 1.0 mmol) and triphenylphosphine (1.0 g, 4.0 mmol) in DMF at 100° C. After stirring for 24 h, the solution was poured into large amount of toluene. The white precipitate was collected in 80% yield. 1H NMR (400 MHz, DMSO-d6), δ (TMS, ppm): 7.90-7.55 (m, 30H), 7.16-6.66 (m, 18H), 5.039 (d, 4H). 13C NMR (100 MHz, DMSO-d6), δ (TMS, ppm): 143.4, 142.5 140.1, 135.2, 134.0, 131.1, 130.6, 130.3, 130.1, 128.0, 127.0, 126.1, 118.1, 17.2, 40.21. m/z (MALDI-TOF) 882.49 [M−2Br)+]; calc. 882.35. Anal. Calcd. C64H52Br2P2: C, 73.7; H, 5.0. Found: C, 73.7; H, 4.9.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:26]=1[C:27](O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(S(C)(=O)=O)ccc2Cl)n1
Temperature: 150 °C
Yield: 26.1 %

Procedure:
A solution was prepared using 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol), 2-chloro-5-(methylsulfonyl)benzoic acid (0.108 g, 0.463 mmol), HATU (0.176 g, 0.463 mmol), triethylamine (0.047 g, 0.463 mmol) and anhydrous DMF (10 mL). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.042 g (26% yield) of pure product: MS (ES) m/z 522 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:11]=1[C:12](Cl)=[O:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:12](=[O:13])[C:11]2[C:10]([F:9])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1ccc(Br)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)nc1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a (0° C.) cooled and stirred solution of 2-bromo-5-aminopyridine (2.0 g, 11.56 mmol, 1.0 eq) in DCM (25 mL) was added sequentially 2,6-difluorobenzoyl chloride (1.44 mL, 11.56 mmol, 1.0 eq) and pyridine (1.19 mL, 13.87 mmol, 1.2 eq). The resulting mixture was allowed to warm to room temperature and then stirred at the same temperature for 30 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[CH:63]=[CH:62][C:61]([S:64](Cl)(=[O:66])=[O:65])=[C:60]([CH3:68])[CH:59]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:64]([C:61]1[CH:62]=[CH:63][C:58]([NH:57][C:54](=[O:56])[CH3:55])=[CH:59][C:60]=1[CH3:68])(=[O:66])=[O:65])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)c(C)c1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(NC(C)=O)cc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (20 mg) was reacted with 4-acetylamino-2-methyl-benzenesulfonyl chloride to give (S)-2-({(S)-7-(4-acetylamino-2-methyl-benzenesulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure E. The title compound was prepared by the hydrolysis of (S)-2-({(S)-7-(4-acetylamino-4-methyl-benzenesulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (8 mg) according to General Procedure B. LCMS (m/z): 945.
Reaction SMILES: ClC1C=C(N[C@H](C2CC2)C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)=O)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49](OC(C)(C)C)=O)[CH2:44]2)=[O:41])[CH:34]=[C:35]([Cl:37])[CH:36]=1.[NH2:56][C:57]1[C:62](C#N)=C(Cl)[N:60]=[CH:59][N:58]=1.ClC1N=CN=C(N)C=1>>[NH2:56][C:57]1[N:58]=[CH:59][N:60]=[C:49]([N:45]2[CH2:46][CH2:47][CH2:48][C@@H:43]([NH:42][C:40](=[O:41])[CH2:39][NH:38][C:33]3[CH:34]=[C:35]([Cl:37])[CH:36]=[C:31]([Cl:30])[CH:32]=3)[CH2:44]2)[CH:62]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)CNc2cc(Cl)cc(Cl)c2)C1
Reactant: N#Cc1c(N)ncnc1Cl
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)[C@H](Nc2cc(F)cc(Cl)c2)C2CC2)C1
Agent: Nc1cc(Cl)ncn1
Product: Nc1cc(N2CCC[C@@H](NC(=O)CNc3cc(Cl)cc(Cl)c3)C2)ncn1

Procedure:
The title compound of Example 145 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-tert-butyl 3-(2-(3,5-dichlorophenylamino)acetamido)piperidine-1-carboxylate and the 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 6-chloropyrimidin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.00 (d, J=7.28 Hz, 1H), 7.50 (br. s., 2H), 6.54-6.70 (m, 1H), 6.47 (d, J=1.76 Hz, 3H), 3.98 (br. s., 1H), 3.84 (br. s., 1H), 3.55-3.71 (m, 6H), 3.06 (dd, J=8.91, 12.93 Hz, 2H), 1.76 (br. s., 3H), 1.38-1.60 (m, 3H). EIMS (m/z): calcd. for C17H20Cl2N6O (M+1H) 395. found 395.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[N:11]#[C:12]Br.C(=O)(O)[O-].[Na+]>O>[F:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[NH:10][C:12]([NH2:11])=[N:1][C:2]=2[CH:7]=1
Reactant: N#CBr
Reactant: Nc1cc(F)c(F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
Step 1 The procedure used was similar to that reported in J. Med. Chem. 40:811-818, 1997. A solution of 1,2-diamino-4,5-difluorobenzene (500 mg, 3.47 mmol) in water (5 mL) was cooled to 0° C. and then treated with a solution of cyanogen bromide (0.83 mL, 4.16 mmol, 5 M in acetonitrile) and solid sodium bicarbonate (583 mg, 6.94 mmol). The solution was stirred at rt overnight and was then concentrated in vacuo. The dark residue was suspended in ethanol and heated at reflux for 15 minutes. The hot suspension was filtered, rinsing with hot ethanol, and the filtrate was concentrated in vacuo to afford 5,6-difluoro-1H-benzimidazol-2-amine (580 mg, 59%), which was used in the next step without further purification. LC-MS m/z 170.2 (MH+), ret. time 0.85 min; 1H NMR (300 MHz, DMSO-d6) δ 6.30 (br s, 2H), 7.06 (dd, 2H), 10.79 (br s, 1H).