Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=C)=[N-].[CH3:4]N(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+].[O:20]=[C:21]1[C:34]2[C:33]([C:35]([OH:37])=[O:36])=[CH:32][CH:31]=[CH:30][C:29]=2[O:28][C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2>CO>[CH3:4][O:36][C:35]([C:33]1[C:34]2[C:21](=[O:20])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:28][C:29]=2[CH:30]=[CH:31][CH:32]=1)=[O:37]
Reactant: O=C(O)c1cccc2oc3ccccc3c(=O)c12
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cccc2oc3ccccc3c(=O)c12
Yield: 100 %

Procedure:
Esterification of acid can be achieved by several conventional methods by those skilled in the art. These procedures include utilizing diazomethane or methyl alcohol catalyzed by mineral acids. For example, ethereal diazomethane solution can be prepared from N-methyl-N-nitrosotoluene-p-sulphonamide and potassium hydroxide from a water bath. 9-Oxoxanthene-1-carboxylic acid (1.29 g, 5 mmol) in absolute methanol is added to this ethereal diazomethane solution at 0° C. until a pale yellow color formed. Removal of the solvent provides the desired ester solid in 100% yield. Thus the final products, Examples 5-9, can be prepared by condensation hydrazine with the ketonester 11 as described in General procedure C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[C:14]([O:18][C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)([CH3:17])([CH3:16])[CH3:15].N1C=CC=CC=1>C(Cl)Cl.CCOCC.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:14]([O:18][C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)=[CH:25][CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reaction time: 0.17 h
Yield: 29.5 %

Procedure:
4 Å molecular sieves were added to a stirred solution of 3-(trifluoromethyl)phenylboronic acid (2.4 g, 12.643 mmol, 2 eq) and [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.5 g, 6.321 mmol, 1 eq) in dry DCM (68.7 ml) at ambient temperature in a dark flask flushed with dry air. The reaction mixture was stirred for 10 min with a drying tube attached. Copper (II) acetate (1.16 g, 6.385 mmol, 1.01 eq), TEA (4.4 ml, 31.609 mmol, 5 eq) and pyridine (2.55 ml, 31.609 mmol, 5 eq) were added and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with 50 ml of Et2O, filtered through celite and washed with 0.5 M HCl. Organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give a crude product. Crude product was purified via Biotage SP-1 Snap Si 50 g; 40 mil/min; in the gradient of EtOAc in Cy: 3% for 1.5 CV, 3-25% for 12 CV; 25-40% for 8 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product {2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (710 mg, yield=22.4%, purity=76%). [M+H]+=382.40 1H NMR (300 MHz; CDCl3) δ/ppm 1.43 (s, 9H), 2.77 (t, J=7.0 Hz, 2H), 3.37 (q, J=6.5 Hz, 2H), 4.58 (br. s., 1H), 6.92-6.97 (m, 1H), 7.06-7.22 (m, 5H), 7.28-7.33 (m, 1H), 7.34-7.45 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH2:29][CH3:30])[CH3:28])[CH:21]=2)=[N:7][CH:6]=1.[Se](=O)=[O:33].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([C:19](=[O:33])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH2:29][CH3:30])[CH3:28])[CH:21]=2)=[N:7][CH:6]=1
Reactant: O=[Se]=O
Reactant: CCC(C)Oc1cccc(Cc2ncc(CC(=O)OC)c3cc(OC)c(OC)cc23)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(C)Oc1cccc(C(=O)c2ncc(CC(=O)OC)c3cc(OC)c(OC)cc23)c1
Temperature: 85 °C
Yield: 82.7 %

Procedure:
To a stirred solution of [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid methyl ester (200 mg, 0.47 mmol) in ethyl acetate (4 mL) was added selenium dioxide (65 mg, 0.59 mmol). The reaction mixture was heated at 85° C. for 1 hr. The solvent was evaporated and afford a crude product. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded [1-(3-sec-butoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid methyl ester as a light brown oil (170 mg, 83% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12](C(O)=O)[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Cu].C1(C2C=CC=CN=2)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc2c(OCc3ccccc3)c(F)ccc2[nH]1
Agent: [Cu]
Agent: c1ccc(-c2ccccn2)cc1
Product: Fc1ccc2[nH]ccc2c1OCc1ccccc1
Temperature: 235 °C
Yield: 62 %

Procedure:
Compound 1-4a (6.28 g, 0.022 mol), copper powder (7.05 g, 0.11 mol) and 2-phenylpyridine (50 mL) were heated at reflux (230-240° C.) under a stream of nitrogen for 10 min, by which time TLC analysis showed complete reaction. The reaction mixture was cooled, filtered through Celite, and the filter cake was washed with EtOAc. The filtrate and EtOAc washings were combined, diluted with water, and extracted three times with EtOAc. The organic extract was washed with 1 N HCl, H2O and brine, dried with NaSO4, and concentrated. The resulting residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes to give the product as a greenish solid (1-5a) in 62% yield, 3.32 g. 1H NMR (300 MHz, CDCl3-d) δ (ppm) 5.31 (s, 2H), 6.62-6.64 (m, 1H), 6.93-7.03 (m, 2H), 7.15 (dd, 1H, J=3.0, 2.5), 7.31-7.40 (m, 3H), 7.49-7.52 (m, 2H), 8.12 (br, 1H). APCI [M+1]: 242.1.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH:13]=[CH:14][CH:15]=[N:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>[Pd].C1COCC1>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][NH:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3cccnc3nc2-c2ccccc2)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Reaction time: 61 h

Procedure:
A suspension of 2,3-diphenylpyrido[3,2-b]pyrazine (Intermediate D) (49.1 g, 143 mmol), triethylamine (20 ml, 143 mmol) and 10% palladium on carbon (19.5 g) in dry THF (410 ml) was placed under an atmosphere of hydrogen (100 mbar) at room temperature for 61 h. After 24 h and 48 h additional palladium catalyst was added (2×4.9 g). The reaction mixture was filtered and the catalyst was washed with THF. The filtrate was concentrated in vacuo and the crude product was dissolved in warm EtOAc (1500 ml) and washed with sat. Na2CO3 solution (400 ml). The aqueous portion was extracted with EtOAc (200 ml) and the combined organic extracts were washed with water (150 ml), brine (300 ml), dried over sodium sulfate and concentrated in vacuo. This crude product was purified by chromatography on silica eluting with neat DCM followed by DCM (1% MeOH) to afford the title product;
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:41]([NH:48][C:7]([C:3]1[O:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:9])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Cc1ccoc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccoc1C(=O)NCc1ccccc1
Reaction time: 16 h
Yield: 42.2 %

Procedure:
To a mixture of 3-methylfuran-2-carboxylic acid (0.79 g, 6.28 mmol), 1-hydroxybenzotriazole (1.27 g, 9.42 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.81 g, 9.42 mmol) in N,N-dimethylformamide (6 mL) was added N,N-diisopropylethylamine (3.30 mL, 18.94 mmol) and benzylamine (0.69 mL, 6.28 mmol). The reaction mixture was stirred for 16 hours, and then diluted with ethyl acetate (75 mL). The organic layer was washed with 10% aqueous hydrochloric acid (2×25 mL), saturated aqueous sodium bicarbonate (2×25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford N-benzyl-3-methylfuran-2-carboxamide as a light brown solid (0.57 g, 80%): 1H NMR (300 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 7.27 (d, J=1.5 Hz, 1H), 6.61 (br s, 1H), 6.34 (d, J=1.5 Hz, 1H), 4.59 (d, J=5.9 Hz, 2H), 2.42 (s, 3H); MS (ES+) m/z 216.2 (M+1).
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:13][CH2:12]1)C1C=CC=CC=1>[Pd].CO>[NH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][OH:8])[CH2:12][CH2:13]1
Reactant: NCCCCC1CCN(CCOCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: NCCCCC1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A suspension of 5a (0.3 g, 1.03 mmol) and catalyst (10% palladium on carbon, 0.8 g, 50% wet) in methanol (25 mL) was placed in a Parr shaker bottle. The system was vacuumed and flushed with nitrogen. The procedure was repeated three times. The mixture was then shaken at room temperature overnight under 40 psi hydrogen atmosphere. The system was then vacuumed again and flushed with nitrogen. The procedure was repeated three times. The catalyst was filtered under vacuum and washed with methanol (2×10 mL). The filtrate and washings were combined and concentrated under reduced pressure to provide 6a (186 mg, 90%). The crude product was used directly without purification. m/z (ESI): 201 [C11H24N2O+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NCCN1CCCCC1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.018 mole), 1,1'-carbondiimidazole (2.9 g, 0.018 mole) and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 3 hours. The nitrogen flow was stopped and a solution of 1-(2-aminoethyl)piperdine (2.3 g, 0.018 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue triturated in potassium bicarbonate solution (100 ml) and filtered. The filter cake was washed with water and recrystallized from isopropyl alcohol-isopropyl ether to give 5.8 g (73%) of off-white needles, mp 178°-179° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][N:6]1[C:10]2[N:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[OH:16])[CH3:2].[Cl:19]([O-])(=O)=O.[K+].[OH-].[Na+]>Cl>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:10]2[N:11]=[C:12]([Cl:15])[C:13]([Cl:19])=[CH:14][C:9]=2[N:8]=[C:7]1[OH:16])[CH3:18]
Reactant: CCN(CC)CCn1c(O)nc2ccc(Cl)nc21
Reactant: [O-][Cl+2]([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Product: CCN(CC)CCn1c(O)nc2cc(Cl)c(Cl)nc21
Temperature: 33 °C

Procedure:
15 grams of 1-(2-diethylaminoethyl)-2-hydroxy-6-chloro-7-aza-benzimidazole were dissolved in 200 ml of concentrated hydrochloric acid and there were added in portions with stirring 24.5 grams of potassium chlorate at room temperature. The temperature increased temporarily to 33° C. The mixture was stirred for another hour, made alkaline with sodium hydroxide, the mixture extracted with shaking with n-butanol, the extract evaporated in a vacuum and the residue chromatographed over silica gel. The reaction product was recrystallized from ethyl acetate. M.P. 137°-139° C.; Yield: 3 grams.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=4[Cl:25])[CH2:13][C@H:12]3[CH3:26])=[N:10][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH:31]1([CH:37]=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([CH2:37][N:1]([CH2:27][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:2][CH2:3]2)[C:2]2[C:7]3[NH:8][C:9]([N:11]4[CH2:16][CH2:15][N:14]([C:17]5[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=5[Cl:25])[CH2:13][C@H:12]4[CH3:26])=[N:10][C:6]=3[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(N)c2[nH]1
Reactant: O=CC1CCCCC1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(N(CC3CCCCC3)CC3CCCCC3)c2[nH]1

Procedure:
{6-[(3R)-4-(7-Amino-5-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-methanol (221 mg, 0.5 mmol, Example 175b) and cyclohexanecarbaldehyde (62 mg, 0.55 mmol, Aldrich) reacted under the conditions of Example 59 to give the title compound as a light-yellow solid. MS (ESI, pos. ion) m/e: 633 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:12])=[CH:5][C:6]=1[CH2:7][CH2:8][C:9]([OH:11])=O.[Li][CH3:14]>CCOCC>[Cl:1][C:2]1[S:3][C:4]([Cl:12])=[CH:5][C:6]=1[CH2:7][CH2:8][C:9](=[O:11])[CH3:14]
Reactant: O=C(O)CCc1cc(Cl)sc1Cl
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)CCc1cc(Cl)sc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-(2,5-dichloro-3-thienyl)propanoic acid (0.225 g) in Et2O (5 mL) was added 1.05M MeLi in Et2O (2.0 mL) at 0° C. under nitrogen. After stirring at 0° C. for 30 minutes, the mixture was warmed to room temperature and stirred for 1 hour. The reaction was quenched by the addition of phosphate buffer solution (pH=7), and the resulting mixture was extracted with Et2O (30 mL). The organic layer was washed with water, brine, dried over MgSO4, and concentrated in vacuo. Chromatographic purification of the residue eluting with hexane-ethyl acetate (4:1) to give the title compound (0.173 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:26][CH2:25][C@@H:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][N:13](C4CCCCO4)[C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1.Cl>C(Cl)Cl.CO.O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:26][CH2:25][C@@H:24]([NH2:27])[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)n4)nn(C4CCCCO4)c3cn2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(-c2cc3c(-c4cccc(N5CC[C@@H](N)C5)n4)n[nH]c3cn2)cn1
Temperature: 60 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a stirred solution of tert-butyl (3R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate (60.0 mg, 0.12 mmol) in anhydrous DCM (5.0 mL) and methanol (2.5 mL) was added 4M HCl in 1,4-Dioxane (4.0 mL). The reaction mixture was stirred at 60° C. under N2 for 18 h. Volatile solvent was evaporated in vacuo. The crude was redissolved in DMSO (1 mL) and was purified by reverse phase HPLC to give 189 as a white solid (25.5 mg, 58.4%). 1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.71 (s, 1H), 8.13 (s, 1H), 7.87 (s, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 3.81-3.64 (m, 4H), 3.63-3.52 (m, 2H), 2.17 (dt, J=12.3, 6.5 Hz, 2H), 1.88-1.75 (m, 2H). LC/MS: m/z 361.1 [M+1]
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([CH:31]2[CH2:32][CH2:33][CH:34]([N:1]3[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=5)[NH:11][N:10]=4)[CH2:4]3)[CH2:35][CH2:36]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(C2CCC(=O)CC2)cn1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: COc1ccc(C2CCC(N3CC(NC(=O)CNc4n[nH]c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-(6-methoxy-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][N:2]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:5]=1.[CH:21]1([O:26][C:27](Cl)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([O:26][C:27]([N:18]2[CH2:19][CH2:20][CH:15]([N:2]([CH3:1])[CH2:3][C:4]3[O:8][N:7]=[C:6]([C:9]4[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=4)[N:5]=3)[CH2:16][CH2:17]2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: CN(Cc1nc(-c2ccncc2)no1)C1CCNCC1
Product: CN(Cc1nc(-c2ccncc2)no1)C1CCN(C(=O)OC2CCCC2)CC1

Procedure:
The tert-butoxycarbonyl group of 4-[methyl(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylic acid tert-butyl ester (Example 119) was removed using the procedure described in Example 51 to afford methylpiperidin-4-yl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine: RT=0.65 min; m/z (ES+)=274.0 [M+H]+. Derivatisation of methylpiperidin-4-yl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine with cyclopentylchloroformate, using the procedure described for Example 52, afforded the title compound: RT=3.02 min; m/z (ES+)=386.0 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:44]=[C:43]([S:45](=[O:65])(=[O:64])[N:46](CC2C=CC(OC)=CC=2OC)[C:47]2[CH:52]=[CH:51][N:50]=[CH:49][N:48]=2)[C:42]([F:66])=[CH:41][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][C:7]=1[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)[CH:23]=1>O1CCOCC1.CO>[ClH:2].[Cl:2][C:3]1[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[CH:23]=2)=[CH:41][C:42]([F:66])=[C:43]([S:45]([NH:46][C:47]2[CH:52]=[CH:51][N:50]=[CH:49][N:48]=2)(=[O:65])=[O:64])[CH:44]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnc(N3CCNCC3)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 163.6 %

Procedure:
A 4M solution of hydrogen chloride in 1,4-dioxane (10 mL) was added to a solution of tert-butyl 4-(4-(4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(pyrimidin-4-yl)sulfamoyl)-5-fluorophenoxy)-4′-(trifluoromethyl)biphenyl-3-yl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 109, 310 mg, 0.332 mmol) in methanol (2 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile/water with 0.1% formic acid) to afford the title compound (196 mg, 82%) as a white solid.
Reaction SMILES: B(Br)(Br)Br.[SH:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=2)[C:9]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[N:8][N:7]=1>C(Cl)Cl>[SH:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:9]([CH2:20][N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[N:8][N:7]=1
Reactant: COc1cccc(Cn2c(S)nnc2CN2CCN(C)CC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CCN(Cc2nnc(S)n2Cc2cccc(O)c2)CC1

Procedure:
Reaction according to standard procedures of boron tribromide (40% BBr3 in methylene chloride) with 3-mercapto-4-(3-methoxybenzyl)-5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-triazole in methylene chloride yields 3-mercapto-4-(3-hydroxybenzyl)-5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-triazole.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6][C:7]1[NH:11][C:10]2[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[N:8]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6]([C:7]1[NH:8][C:9]2[CH2:15][CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=1)=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)c1ccccc1CSc1nc2c([nH]1)CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccccc1CS(=O)c1nc2c([nH]1)CCCC2
Temperature: 0 °C
Yield: 35 %

Procedure:
To a solution of 0.70 g (2.4 mmol) of 2-(2-dimethylaminobenzylthio)-4,5,6,7-tetrahydro-1H-benzimidazole in 7 ml of chloroform was added under chilling with ice 0.53 g (2.4 mmol) of 80% m-chloroperbenzoic acid for 10 min. To the resulting mixture were added chloroform and aqueous NaHCO3. The chloroform portion was taken out, and then subjected to extraction using six portions of 1N aqueous NaOH. To the aqueous NaOH portion was added an excess amount of aqueous NH4Cl to separate an oil out of the solution. The oil was then extracted with chloroform and dried over anhydrous sodium sulfate. Chloroform was distilled off, and the residue was crystallized from diethyl ether/hexane. The obtained crystalline products were collected by filtration and dried under reduced pressure to give 0.26 g of the desired compound as a white crystalline product, yield 35%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Na].C(N(CC)CC)C.[SH:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1COCC1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])([O-:3])=[O:2]
Reactant: CCOC(=O)CS
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
Into a 100 ml round-bottomed flask were placed 14.8 g (10 ml, 79.6 mmol) 2,4-dinitrofluorobenzene, THF (20 ml, freshly distilled from sodium benzophenone) and triethylamine (11.1 ml, 79.6 mmol). The reaction was cooled in an ice bath while 9.55 g (8.73 ml, 79.6 mmol) ethyl 2-mercaptoacetate dissolved in THF (10 ml) was added dropwise. The resulting nearly black solution was allowed to warm slowly to room temperature and stirred 18 hours. The reaction mixture was poured onto 150 ml ice and the resulting layers were separated. The aqueous phase was extracted with EtOAc (2×125 ml). The organic layers were combined and washed with water (100 ml), dried over MgSO4 and concentrated to dryness in vacuo to yield 16.9 g of red-brown solid (74.1% yield).