Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)(=[O:11])=[O:10]
Reactant: Fc1cccc(CBr)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2)Cc2cccc(F)c2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) (500 mg, 1.49 mmol), 3-fluorobenzyl bromide (280 mg, 2.98 mmol), and cesium carbonate (971 mg, 2.98 mmol) were placed in DMF (12 mL) and stirred at 90° C. for 4 hours. The solution was cooled to ambient temperature, diluted with H2O (200 mL) and extracted with ethyl acetate (3×, 100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (10-20% ethyl acetate in hexane) to afford methyl 4-(N-(3-fluorobenzyl)-N-(4-methoxybenzyl) sulfamoyl)benzoate (528 mg, 80%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][CH:17]3[CH:12]([CH2:13][CH:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[NH:16]3)[CH2:11]2)=[CH:5][CH:4]=1.[BH4-].[Li+]>C1COCC1>[OH:22][CH2:21][CH:14]1[CH2:13][CH:12]2[CH:17]([CH2:18][CH2:19][CH:10]([CH2:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:11]2)[NH:16][C:15]1=[O:20]
Reactant: CCOC(=O)C1CC2CC(Cc3ccc(OC)cc3)CCC2NC1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CC2CCC3NC(=O)C(CO)CC3C2)cc1
Yield: 10.5 %

Procedure:
Ethyl 3,4,4a,5,6,7,8,8a-octahydro-6-(4-methoxyphenyl)methyl-quinolin-2[1H]-one-3-carboxylate (1 g) (prepared according to Example 6) was mixed with 2M lithium borohydride solution in THF (15 ml) and heated at reflux. After 4 hours the reaction mixture was quenched by addition of water. The reaction mixture was partitioned between water and dichloromethane and the organic layer was washed with 2M HCl, then with saturated sodium carbonate solution, dried (MgSO4) and evaporated. The residue was recrystallised from methanol to give the title compound (0.092 g) mp 193°-200° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:32])[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH3:23])[CH:17]=2)=O)=[CH:8][CH:7]=1.Cl.[NH2:34][OH:35].C([O-])(O)=O.[Na+]>>[OH:1][CH2:2][CH2:3][N:4]([CH3:32])[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:13]/[C:14](=[N:34]\[OH:35])/[C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH3:23])[CH:17]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N(C)CCO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N(C)CCO)cc1

Procedure:
In analogy to example 151, step 3, N-(2-hydroxy-ethyl)-N-methyl-4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=448.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([C:22]([S:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:23][N:24]=1)[C:16](N(OC)C)=[O:17])(=[O:11])=[O:10].[CH2:41]([Mg]Cl)[CH2:42][CH3:43]>C1COCC1>[C:16]([C:15]1[C:22]([S:25][C:26]2[CH:27]=[CH:28][C:29]([S:32]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)(=[O:33])=[O:34])=[CH:30][CH:31]=2)=[CH:23][N:24]=[C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:11])[CH:14]=1)(=[O:17])[CH2:41][CH2:42][CH3:43]
Reactant: CON(C)C(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Reaction time: 8 h
Yield: 6.8 %

Procedure:
2-(2,4-Dichloro-benzenesulfonylamino)-N-methoxy-N-methyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-isonicotinamide (150 mg, 0.233 mmol) was stirred in THF (30 ml) under nitrogen at room temperature. 2M Propylmagnesium chloride (1.2 ml, 2.33 mmol) was added and the reaction stirred overnight. The reaction was quenched using 1N HCl solution partitioned between a mixture of NaHCO3 solution (30 ml) and ethyl acetate (30 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate 2/3 hexane as eluent to give N-{4-butyryl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-2,4-dichloro -benzenesulfonamide as an off-white solid (10 mg, 6%). 1H NMR (CDCl3): 8.21 (1H, s, Ar); 8.06 (1H, d, Ar); 7.60 (2H, d, Ar); 7.47 (1H, s, Ar); 7.38 (1H, d, Ar); 7.26 (3H, m, py and Ar); 2.89 (4H, m, 2×CH2N pip); 2.70 (2H, t, COCH2); 1.56 (6H, m, 2×CH2 pip, COCH2CH2); 1.47 (2H, m, CH2 pip); 0.90 (3H, t, COCH2CH2CH3). HPLC (Luna 2, Gradient 1): rt=6.92 minutes. LCMS: rt=7.61 minutes, 629 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17](=[O:20])[NH:18][CH3:19])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:25]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]4)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:18][CH3:19])=[O:20])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(C3CCN(C(=O)OC(C)(C)C)C3)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1c2cc(C3CC3)c(N(C3CCNC3)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 43.5 %

Procedure:
To a solution of tert-butyl 3-{[2-(4-bromophenyl)-5-cyclopropyl-3-(methylcarbamoyl)-2H-indazol-6-yl](methylsulfonyl)amino}pyrrolidine-1-carboxylate (12 mg, 0.019 mmol) in DCM (0.5 mL) was added trifluoroacetic acid (50 μL) and the mixture was stirred at 40° C. for 40 min. The mixture was cooled to RT, washed with saturated aqueous sodium bicarbonate (0.5 mL), dried (MgSO4) and concentrated to dryness. The residue was purified by preparative LCMS (5-100% ACN in 0.1% aqueous formic acid) to afford 2-(4-bromophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)(pyrrolidin-3-yl)amino]-2H-indazole-3-carboxamide as a white solid (4.4 mg, 44%).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28](S(C)(=O)=O)[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH:36]1([CH2:39][N:28]2[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:33])([F:1])[CH2:3][CH2:4]2)=[O:9])[CH2:38][CH2:37]1
Reactant: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC1CC1
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-{1-methanesulfonyl-5-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 20), sodium hydride and cyclopropylmethyl bromide, to give the desired product as a light yellow oil (53%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CO.[Pd]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:14])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][NH:54][C:55](=[O:61])[O:56][C:57]([CH3:59])([CH3:58])[CH3:60])=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(C#CCOCCOCCOCCOCCOCCOCCNC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(CCCOCCOCCOCCOCCOCCOCCNC(=O)OC(C)(C)C)cc1
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 88.9 %

Procedure:
A mixture of alkyne 59 (100 mg, 0.11 mmol) and 10% Pd/C (50 mg, 0.04 mmol) in MeOH (15 mL) was stirred at 20° C. under H2 (60 psi) for 2.5 h. The mixture was filtered through Celite®, washed with MeOH (100 mL), the solvent was evaporated and the residue was dried to give the carbamate 60 (85 mg, 85%) as a white gum, which was used in the next step without further purification: 1H NMR δ 9.22 (t, J=5.8 Hz, 1H, CONH), 8.57 (d, J=1.8 Hz, 1H, H-2′), 8.46 (dd, J=4.7, 1.6 Hz, 1H, H-6′), 7.99 (br d, J=8.6 Hz, 2H, H-2, H-6), 7.89 (br d, J=8.6 Hz, 2H, H-3, H-5), 7.73 (dt, J=7.9 1.9 Hz, 1H, H-4′), 7.68 (br d, J=8.3 Hz, 2H, H-2″, H-6″), 7.44 (br d, J=8.3 Hz, 2H, H-3″, H-5″), 7.36 (ddd, J=7.9, 4.8, 0.6 Hz, 1H, H-5′), 6.73 (t, J=5.5 Hz, 1H, NHCO2), 4.64 (s, 2H, CH2SO2), 4.51 (d, J=5.8 Hz, 2H, CH2NH), 3.43-3.50 (m, 20H, CH2O), 3.36 (br t, J=6.3 Hz, 4H, H-3′″, H-20′″), 3.05 (br q, J=5.9 Hz, 2H, H-21′″), 2.71 (br t, J=7.6 Hz, 2H, H-r), 2.12 (s, 3H, CH3), 1.79 (br q, J=7.1 Hz, 2H, H-2′″), 1.36 [s, 9H, (CH3)3].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)(=[O:21])=[O:20])[C:13]=1[OH:34])=[O:10]>Cl.O1CCOCC1>[ClH:18].[NH2:26][CH2:25][CH2:24][CH2:23][NH:22][S:19]([C:14]1[C:13]([OH:34])=[C:12]([NH:11][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[O:10])[CH:17]=[CH:16][C:15]=1[Cl:18])(=[O:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Agent: Cl
Solvent: C1COCCO1
Product: NCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Yield: 171.6 %

Procedure:
A solution of N-(2-bromophenyl)-N′-[3-[N″-[3-(tert-butoxycarbonylamino)-propyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl] urea (59 mg, 0.102 mmol) in 1 mL of 4.0 M HCl in 1,4-dioxane was stirred at room temperature for 10 min. The solvent was concentrated. Recrystallization from acetone and hexane produced desired product (45 mg, 85%). LC-MS 477.0 (M+).
Reaction SMILES: F[B-](F)(F)F.[Br:6][C:7]1[C:8]([Cl:17])=[C:9]([N+]#N)[CH:10]=[C:11]([F:14])[C:12]=1[F:13].[C-:18]#[N:19].[K+].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>O>[Br:6][C:7]1[C:8]([Cl:17])=[C:9]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[C:18]#[N:19]
Reactant: N#[N+]c1cc(F)c(F)c(Br)c1Cl
Reactant: [C-]#N
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1cc(F)c(F)c(Br)c1Cl
Temperature: 25 °C
Yield: 41.4 %

Procedure:
3-Bromo-2-chloro-4,5-difluorobenzenediazonium tetrafluoroborate (35.6 g) was added portionwise during 40 minutes to a solution of cuprous cyanide (18.67 g), potassium cyanide (27.14 g) and sodium carbonate (5.52 g) in water (200 ml) with stirring vigorously at room temperature. After the mixture was stirred for 4.5 hours, benzene (250 ml) was added to the suspension and then the mixture was stirred for 25 minutes. The insoluble materials were collected by filtration, and washed with benzene. The filtrate and washings were combined and washed with water, dried over anhydrous sodium sulfate and then concentrated. The resulting residue was purified by silica gel chromatography eluting with dichloromethane-n-hexane (1:3) and further recrystallized from n-hexane-dichloromethane to give the title compound (10.9 g) as light yellow needles, mp 71°-72.5° C.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7](O)=[O:8].[Cl-].[NH4+].O.[N:20]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[CH:3]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([NH2:20])=[O:8])=[O:2]
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(C(=O)O)cc1C(OC)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(C(N)=O)cc1C=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 71.9 %

Procedure:
3-Dimethoxymethyl-4-methoxybenzoic acid (1.81 g) obtained in step B, 0.65 g of ammonium chloride, 1.48 g of benzotriazol-1-ol monohydrate, and 1.85 g of (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride were dissolved in 50 mL of N,N-dimethylformamide, and 4.20 mL of N,N-diisopropylethylamine was added to the solution. The resulting solution was stirred for 13 hours at room temperature, and then 1M hydrochloric acid was added little by little until the mixture reached nearly pH 2. This mixture was extracted with ethyl acetate twice, whereafter the organic layer combined was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The residue was washed with ethanol, and then dried under reduced pressure to obtain 1.03 g (71%) of 3-formyl-4-methoxybenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][C:17]([O-:19])=[O:18])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CO.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(N2CCCC2CC(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)cc(N2CCCC2CC(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 53.6 g. (0.192 mole) methyl dl-2-[1-(3,5-dimethoxyphenyl)pyrrolidin-2-yl]acetate and 250 ml. methanol was warmed to obtain a solution and 22.8 g. (0.57 mole) sodium hydroxide in 200 ml. water was added. The resulting mixture was stirred at room temperature for 2.5 hours, the methanol evaporated and the aqueous residue cooled in ice. To this was added dropwise 48 ml. concentrated hydrochloric acid, the mixture extracted with 4x 150 ml. methylene chloride, the extract washed with water, dried (MgSO4) and the solvent evaporated to afford 48.9 g. (96%) of product. 1H-NMR (CDCl3) ppm (delta): 3.80 (s, 6H, OCH3), 4.10 (m, 1H, N--CH), 5.82 (s, 3H, aromatic), 11.0 (s, 1H, COOH). Mass spectrum (m/e): 206 (base peak), 265 (m+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].C(=O)([O-])[O-].[K+].[K+]>Br.O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: COc1cccc(Cl)c1-c1ccccc1C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccccc1-c1c(O)cccc1Cl
Temperature: 25 °C
Yield: 77.3 %

Procedure:
2-Chloro-6-methoxy-2′-methylbiphenyl (15.0 g, 64.5 mmol) was heated in hydrogen bromide (33% in acetic acid, 60 mL) at 65° C. overnight. The resulting mixture was cooled to room temperature, poured in water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue oil was further treated with potassium carbonate (10.5 g, 75.6 mmol) in methanol (100 mL) at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and the organic layer was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by ISCO using a solvent gradient of 10 to 40% ethyl acetate in hexanes produced 10.9 g (77%) of 6-chloro-2′-methyl-biphenyl-2-ol as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1.[C:19]1([CH2:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:29]([NH:28][C:26](=[O:27])[CH2:25][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[S:30])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1
Reactant: Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
A mixture of 268 (20 mg, 0.08 mmol) and 2-phenylacetyl isothiocyanate (16 μL, 0.08 mmol) in THF (1 mL) was stirred at room temperature for 2 hours and concentrated. The residue was purified by flash column chromatography (eluent EtOAc) followed by preparative HPLC (column Aqusil C18, gradient elution with 60-95% MeOH in water, 45 min) to afford the title compound 269a (13 mg, 40% yield) as an off-white solid. 1H NMR (CD3OD) δ (ppm): 8.41(s, 1H), 8.16(d. 1H, J=5.6 Hz), 8.02(dd, 1H, J1=2.3 Hz, J2=12.2 Hz), 7.62(d, 1H, J=3.3 Hz), 7.44(m, 1H), 7.37-7.33(m, 4H) 7.31-7.26(m, 1H), 6.65(d, 1H, J=3.1 Hz), 6.52(d, 1H, J=5.7 Hz), 3.76(s, 2H), MS (m/z): 421.1(M+H) (found).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33](Br)[N:32]=3)=[C:20]([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:39]1NC(C=O)CC[CH2:40]1.C[Si](C#C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(OCC)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH2:39][CH3:40])[N:32]=3)=[C:20]([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CCCC(Br)N1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3cccc(Br)n3)[nH]2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1cccc(-c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 3 %

Procedure:
To a solution of 4-[4-benzo[1,3]dioxol-5-yl-5-(6-bromo-pyridin-2-yl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (prepared in accordance with Scheme 1b with 6-bromo-piperidine-2-carbaldehyde as the starting material; 100 mg, 0.18 mmol) in DMF (1 mL) and triethylamine (2 mL) under nitrogen, was added PdCl2(PPh3)2 (2 mg, 0.005 mmol) and CuI (2 mg, 0.01 mmol), then followed with trimethylsilylacetylene (30 uL, 0.20 mmol). The mixture was stirred at room temperature for 4 hours until LC-MS showed complete coupling. Diethyl ether (30 mL) was added and the precipitate was filtered off. The clear solution was washed with saturated aqueous NH4Cl, then 0.5M EDTA solution, and water, and then dried (MgSO4). Concentration gave a yellow syrup that was dissolved in THF (20 mL). The solution was cooled to 0° C. and tetrabutylammonium fluoride (2 mL, 1 M in THF) was added. The mixture was stirred at room temperature for 30 minutes until LC-MS indicated complete removal of the silyl group. The reaction mixture was then concentrated in vacuum and passed through a short silica gel column with ethyl acetate/dichloromethane (1:1). The purified material was dissolved in ethanol (20 mL) and PtO2 (50 mg) was added. The mixture was stirred under hydrogen (1 atm) at room temperature for 3 days until LC-MS showed major conversion of the alkyne to the correponding alkane. The solids were filtered off and the filtrates were concentrated and purified on preparative HPLC to give the title compound (3 mg, 3%) as a TFA salt. MS (EPS+: 511.3 (MH+)). 1H NMR (400 MHz, MeOH-d4) δ 7.60 (t, 1H), 7.39-7.29 (m, 5H), 7.23 (d, 1H), 7.13 (d, 1H), 6.93 (dd, 1H), 6.91 (dd, 1H), 6.81 (d, 1H), 5.95 (s, 2H), 5.14 (s, 2H), 4.28 (d(br), 2H), 3.04 (m, 1H), 3.02 (br, 2H), 2.79 (q, 2H), 2.00 (d(br), 2H), 1.85 (ddd, 2H), 1.28 (t, 3H)
Reaction SMILES: C(OC([NH:11][C@H:12]([C@@H:20]([OH:29])[C:21]([F:28])([F:27])[C@H:22]([OH:26])[CH:23]([CH3:25])[CH3:24])[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]([C@@H:20]([OH:29])[C:21]([F:27])([F:28])[C@H:22]([OH:26])[CH:23]([CH3:25])[CH3:24])[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)[C@@H](O)C(F)(F)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H](O)C(F)(F)[C@H](O)[C@@H](N)CC1CCCCC1
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A solution of 700 mg of the product from Example 177 in 10 ml of methanol was stirred vigorously under a hydrogen atmosphere using 10% Pd/C as catalyst. After 30 min, the catalyst was filtered off and the solution concentrated to give 470 mg the desired product. Mass spectrum: M+ =279.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][OH:12])[CH2:6]1)=[O:4].[F:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1>>[F:14][C:2]([F:1])([F:13])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][O:12][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][C:19]3[CH:29]=[CH:30][C:16]([F:15])=[CH:17][CH:18]=3)=[CH:22][CH:23]=2)[CH2:6]1)=[O:4]
Reactant: Fc1ccc(Oc2ccc(CCl)cc2)cc1
Reactant: O=C(N1CCCC(CO)C1)C(F)(F)F
Product: O=C(N1CCCC(COCc2ccc(Oc3ccc(F)cc3)cc2)C1)C(F)(F)F
Yield: 13.4 %

Procedure:
Using 1-trifluoroacetylpiperidin-3-yl methanol (422 mg, 2.00 mmol) and 4-(4-fluorophenoxy)benzylchloride (473 mg, 2.00 mmol), the same procedure was followed as in Step 5a of Example 5 to give 110 mg (13%) of the desired compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:22]=[O:23])[C:9]=1I.[Cu][C:26]#[N:27]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:22]=[O:23])[C:9]=1[C:26]#[N:27]
Reactant: N#C[Cu]
Reactant: O=Cc1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2F)c1I
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1c(C=O)cn(S(=O)(=O)c2cccnc2)c1-c1ccccc1F
Yield: 99.8 %

Procedure:
5-(2-Fluorophenyl)-4-iodo-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (489 mg), copper (I) cyanide (480 mg), tris(dibenzylideneacetone)dipalladium (0) (49 mg) and 1,1′-bis(diphenylphosphino)ferrocene (89 mg) were mixed in 1,4-dioxane (20 mL), and the mixture was heated under reflux for 3 hr. The reaction mixture was allowed to cool, diluted with ethyl acetate, and filtered. The obtained filtrate was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:3→3:7) to give the title compound as a colorless oil (yield 380 mg, about 100%).