Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=2)[CH:12]=[CH:11][C:10]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=1[CH3:44]>CO>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[C:27]2[CH:28]=[CH:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][CH:32]=2)[CH:12]=[CH:11][C:10]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=1[CH3:44]
Reactant: COC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3C)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cl)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2-c2ccc(C(=O)O)cc2)cc1Cl
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.6 mL, 1.8 mmol) was added to a THF (3 mL) and MeOH (1.5 mL) solution of methyl 2′-(((2,4′-dichloro-2′-methyl-[1,1′-biphenyl]-4-yl)amino)methyl)-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate (326 mg, 0.6 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off, dried in vacuo, and purified via HPLC to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][CH2:25][C:26](O)=[O:27].ClC(OCC(C)C)=O.C(N(CC)CC)C.C(O)(=O)C(O)=O.[CH2:51]([O:53][P:54]([CH2:59][CH2:60][NH2:61])(=[O:58])[O:55][CH2:56][CH3:57])[CH3:52]>C1COCC1>[CH2:56]([O:55][P:54]([CH2:59][CH2:60][NH:61][C:26](=[O:27])[CH2:25][CH2:24][C:23]([CH3:29])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1])[CH2:9][O:8][C:7]2=[O:13])(=[O:58])[O:53][CH2:51][CH3:52])[CH3:57]
Reactant: CCOP(=O)(CCN)OCC
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CCC(=O)O)C(=O)OC2
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(CCNC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of 6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid (50 mg, 0.12 mmol) in THF (1 mL) was added isobutyl chloroformate (17 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol) at 0° C. After stirring at 0° C. for 2 hours, diethyl(aminoethyl)phosphonate oxalate (62 mg, 0.26 mmol) was added and stirred at room temperature was continued for one hour. After removal of solvent, the residue was purified by preparative reverse-phase HPLC to afford 37 mg (54%) of the desired product as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 1.15-1.22 (m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 1.85-1.93 (m,2H), 2.18 (s, 3H), 2.30 (m, 4H), 3.41 (d, 2H, J=7 Hz), 3.48-3.54 (m, 2H), 3.77 (s, 3H), 3.77-4.16 (m, 4H), 4.26-4.32 (m,2H), 5.12 (s, 2H), 5.17-5.19 (m, 1H), 6.30 (bs, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 29.91 ppm; MS (m/z) 584 [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[N:6][C:5]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[C:24]3[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[N:4]1>O1CCOCC1.C(Cl)Cl>[CH3:2][N:3]1[C:7]([C@@H:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[N:6][C:5]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[C:24]3[C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)=[N:4]1
Reactant: Cn1nc(-c2ccc3[nH]nc(-c4ccncc4)c3c2)nc1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc3[nH]nc(-c4ccncc4)c3c2)nc1[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
Added 4M HCl in dioxane (2 ml) to a solution of (R)-tert-butyl 3-(1-methyl-3-(3-(pyridin-4-yl)-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate (25 mg, 0.054 mmol) in DCM (5 ml), then stirred 4 hours at room temperature. The solvent was evaporated to yield (R)-5-(1-methyl-5-(piperidin-3-yl)-1H-1,2,4-triazol-3-yl)-3-(pyridin-4-yl)-1H-indazole as a white solid (15 mg).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[N:17][CH:18]=1>C(Cl)Cl>[CH3:12][C:13]1[CH:18]=[N+:17]([O-:9])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)O)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
m-CPBA (CAN 937-14-4, 5.0 g, 29.2 mmol) was added to a solution of 5-methyl-pyridine-2-carboxylic acid (CAN 4434-13-3, 2.0 g, 14.6 mmol) in methylene chloride (50 mL) and the mixture was stirred overnight at room temperature. The solid was filtered off, quenched with a saturated solution of sodium thiosulfate (50 mL), and the mixture was extracted with methylene chloride (3×60 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give yellow solid which was washed with ether (5×20 mL) to give the product (0.9 g, 40.3%); MS (EI): m/e=154.1 [M+H]+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[N-:5]=[N+:6]=[N-:7].[Na+].[N-]=[N+]=[N-].[Al+3].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[C:19]1([CH:25]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:36]4[CH:44]=[CH:45][C:46]([C:48]#[N:49])=[CH:47][C:35]=4[N:34]=3)=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:50]1([CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:36]4[CH:44]=[CH:45][C:46]([C:48]5[NH:49][N:7]=[N:6][N:5]=5)=[CH:47][C:35]=4[N:34]=3)=[CH:29][CH:28]=2)[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: N#Cc1ccc2c(c1)nc(-c1ccc(OC(c3ccccc3)c3ccccc3)cc1)n2C1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: c1ccc(C(Oc2ccc(-c3nc4cc(-c5nnn[nH]5)ccc4n3C3CCCCC3)cc2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 20.6 %

Procedure:
Aluminum trichloride (33 mg, 0.247 mmol) was added to ice cold THF (4 mL). Sodium azide (48 mg, 0.744 mmol) was added and the resulting mixture was stirred under reflux for 30 min to complete the formation of the aluminum azide. Compound 8 (100 mg, 0.206 mmol) was added and the mixture stirred under reflux for 18 h. The reaction mixture was poured into ice cold dilute HCl to precipitate a solid. The solid was dissolved in DMF (2 mL) and the solution applied to a Shimadzu Prep HPLC. The product containing fractions were combined. Removal of the methanol resulted in the precipitation of 9 as a colorless solid (22.3 mg, 20.6% yield). ESI-MS m/e 527 (M=1). 1H NMR (DMSO) δ 8.33 (s, 1H), 8.20 (d, 1H, J=8.6 Hz), 8.0 (1H, d, J=7.41 Hz), 7.63 (d, 2H, J=8.7 Hz), 7.55 (d, 4H, J=7.2 Hz), 7.41-7.37 (m, 4H), 7.34-7.26 (m, 4). 6.72 (s, 1H), 4.34-4.27 (m, 1H), 2.36-2.23 (m, 2H), 1.97-1.83 (m, 4H), 1.66-1.62 (m, 1H), 1.43-1.21 (m. 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Si]([O:15][CH2:16][C:17]([CH3:61])([CH3:60])[CH2:18][N:19]1[CH:28]=[C:27]([S:29]([CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)(=[O:31])=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:45]3[CH:50]=[C:49]([C:51](=[O:56])[NH:52][CH:53]4[CH2:55][CH2:54]4)[CH:48]=[C:47]([F:57])[C:46]=3[CH3:58])[CH:25]=2)[C:20]1=[O:59])(C(C)(C)C)(C)C>C(Cl)Cl>[CH:53]1([NH:52][C:51](=[O:56])[C:49]2[CH:50]=[C:45]([C:24]3[CH:25]=[C:26]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:59])[N:19]([CH2:18][C:17]([CH3:61])([CH3:60])[CH2:16][OH:15])[CH:28]=[C:27]4[S:29]([CH:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]3)(=[O:31])=[O:30])[C:46]([CH3:58])=[C:47]([F:57])[CH:48]=2)[CH2:54][CH2:55]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(S(=O)(=O)C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(S(=O)(=O)C3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
Trifluoroacetic Acid (1 mL) was added to a solution of tert-butyl 4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfonyl)piperidine-1-carboxylate (Example 60a, 0.116 g) in DCM (2 mL), and the reaction was stirred at room temperature for 30 min. The reaction was then azeotroped with toluene (3×10 mL), and the residue dissolved in methanol and purified by preparative HPLC (Phenomenex Gemini column using a 95-5% gradient of 0.2% aqueous NH3 in MeCN). Solvent removal and trituration with diethyl ether gave the title compound (0.026 g).
Reaction SMILES: [NH2:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.[O:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:42]([CH2:43][CH2:44][C:45]([NH:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=[O:46])([OH:47])=[O:41]
Reactant: O=C1CCC(=O)O1
Reactant: C=C(C)[C@@H]1CC[C@]2(CN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNC(=O)CCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aminomethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (20 mg, 0.037 mmol) in DCM (2 ml) was added dihydrofuran-2,5-dione (11.04 mg, 0.110 mmol) followed by DMAP (4.49 mg, 0.037 mmol) and DIPEA (6.42 μl, 0.037 mmol). The mixture was stirred at rt for 18 h. The solvent was removed in vacuo and the resulting residue was purified by prep. HPLC. The product was isolated as a white solid (5 mg, 21.1%). LCMS: m/e 644.5 (MH+), 2.80 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.94 (d, J=8.5 Hz, 2H), 7.16-7.34 (m, 2H), 5.32 (dd, J=6.4, 1.6 Hz, 1H), 4.74 (d, J=2.0 Hz, 1H), 4.62 (s, 1H), 3.54 (d, J=13.6 Hz, 1H), 3.04 (d, J=13.8 Hz, 1H), 2.57-2.71 (m, 2H), 2.44-2.57 (m, 2H), 2.17 (dd, J=17.2, 6.4 Hz, 1H), 2.09 (dd, J=13.1, 1.8 Hz, 1H), 1.85 (dd, J=12.2, 3.4 Hz, 2H), 1.65-1.82 (m, 8H), 1.61 (br. s., 2H), 1.53 (d, J=10.5 Hz, 3H), 1.48 (d, J=2.0 Hz, 1H), 1.35-1.45 (m, 3H), 1.24-1.35 (m, 3H), 1.16-1.24 (m, 4H), 1.02-1.16 (m, 8H), 0.99 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[Cl:17])[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[K].[CH3:21][SH:22].O>O1CCCC1>[Cl:17][C:8]1[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=1[N:6]1[C:2]([S:22][CH3:21])=[C:3]([C:18]#[N:19])[CH:4]=[N:5]1
Reactant: CS
Reactant: N#Cc1cnn(-c2ccc(C(F)(F)F)cc2Cl)c1Br
Agent: [K]
Solvent: C1CCOC1
Solvent: O
Product: CSc1c(C#N)cnn1-c1ccc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A solution of 3.5 g (0.01 mol) of 5-bromo-1-(2-chloro-4-trifluoromethyl-phenyl)-4-cyano-pyrazole is added dropwise at 20°-25° C. to a suspension of 0.011 mol of potassium methylmercaptide, prepared by passing 0.6 g (0.011 mol) of methyl mercaptan into a solution of 1.4 g (0.012 mol) of potassium t-butylate in 50 ml of tetrahydrofuran. The mixture is stirred overnight, poured into water, and extracted by shaking three times with 100 ml of methylene chloride in each case. After drying the combined phases over sodium sulphate, the solution is concentrated in vacuo. An oily residue remains which crystallizes after standing overnight. 3.1 g (98% of theory) of 1-(2-chloro-4-trifluoromethyl-phenyl)-4-cyano-5-methylthio-pyrazole of melting point 59°-62° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[N:3]=1.N1C(C)=CC=CC=1C.[CH:20]1([CH2:25][C@H:26]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[C:27](Cl)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([CH2:25][C@H:26]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[C:27]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])[N:3]=2)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
In a round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 56 mg, 0.36 mmol), 2,6-lutidine (57 μL, 0.49 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride in methylene chloride (˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 45% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (102 mg, 74%) as a white foam: [α]30589=−13.3° (c=0.12, methylene chloride); ES-HRMS m/e calcd for C21H27N3O2Cl2 (M+H)+ 424.1553, observed 454.1553; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 6H, 2×CH3), 1.09 (m, 2H, CH2), 1.34-1.79 (m, 8H, 4×CH2), 2.03 (m, 1H, CH), 3.80 (m, 1H, ArCHCO), 3.86 (s, 2H, NCH2), 4.65 (s, 1H, OH), 6.45 (s, 1H, Ar), 7.35 (brd, 1H, Ar), 7.51 (s, 1H, Ar), 7.58 (m, 2H, Ar), 10.73 (s, 1H, NH).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[CH2:34][C:35]#[N:36]>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:22]=[CH:21][C:20]=1[CH2:34][C:35]#[N:36]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC1(C)OB(c2ccc(CC#N)c(F)c2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CC#N)c(F)c1
Yield: 99.8 %

Procedure:
Following Step 1 from General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (350 mg, 1.1 mmol) was reacted with 2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetonitrile (440 mg, 1.7 mmol) to afford the desired product (400 mg, >99%) as a brown solid: ESI MS m/z 365 [C20H13FN2O2S+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]=[CH2:13])[S:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])=[O:4].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][O:9][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11]/[CH:12]=[CH:13]/[C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=2)=[CH:22][CH:23]=1)(=[O:4])=[O:5]
Reactant: C=CCN(C)S(=O)(=O)CC(=O)OC
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CS(=O)(=O)N(C)C/C=C/c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of methyl 2-({methyl[allyl]amino}sulfonyl)acetate (300 mg, 1.4 mmol) and 4-bromobiphenyl (370 mg, 1.54 mmol) in acetonitrile (4 ml) was added triethylamine (0.3 ml, 2.1 mmol), palladium(II) acetate (17 mg, 0.07 mmol) and tri-ortho-tolyl phosphine (52 mg, 0.14 mmol) and the solution was heated to reflux under an atmosphere of nitrogen for 3 hours. The mixture was cooled to ambient temperature, the solvent was evaporated and the residue was purified by flash chromatography on silica gel (dichloromethane as eluent) to give the title compound as a pale yellow solid (300 mg).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:5]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)=[CH:6][C:7]2[N:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20]([O:22]C)=[O:21])[CH:14]=3)[NH:9][C:8]=2[CH:24]=1>CO.O>[C:20]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[CH3:19])[O:12][C:10]1[NH:9][C:8]2[CH:24]=[C:4]([F:3])[C:5]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][CH:32]=4)=[CH:27][CH:26]=3)=[CH:6][C:7]=2[N:11]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc(-c5ccc(C(=O)[O-])cc5)cc4)c(F)cc3[nH]2)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(Oc2nc3cc(-c4ccc(-c5ccc(C(=O)O)cc5)cc4)c(F)cc3[nH]2)cc1C(=O)O
Temperature: 70 °C

Procedure:
5 M aqueous NaOH (3 mL) was added to a solution of ethyl, 4′-{6-fluoro-2-[3-(methoxycarbonyl)-4-methylphenoxy]-1H-benzimidazol-5-yl}biphenyl-4-carboxylate (750 mg, 1.43 mmol) in MeOH (30 mL). The solution was diluted with water until cloudy and heated at 70° C. for 20 min. Volatiles were removed and the residue was-dissolved in 20 ml water and acidified with 2 N aqueous HCl. The precipitated white solid was filtered and dried to afford the title compound as a white solid. LC-MS: calculated for C28H19FN2O5 482.46, observed m/e 483.11 (M+H)+ (Rt 1.91/4.0 min). 1H NMR (500 MHz, CD3OD): δ 8.18-7.25 (m, 13H), 2.62 (s, 3H).
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)[N:5]=2.[CH3:24][O-:25].[Na+]>CO>[CH:15]1([CH2:14][CH2:13][O:12][C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([O:25][CH3:24])[N:3]3[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:8]([NH2:11])[N:7]=2)[CH2:17][CH2:16]1
Reactant: C[O-]
Reactant: Nc1nc(OCCC2CC2)nc2c1nc(Br)n2C1CCCCO1
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1C1CCCCO1

Procedure:
A stirring suspension of 8-bromo-2-[(2-cyclopropylethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7.96 g) in methanol (80 ml) was treated with 25 wt % sodium methoxide in methanol (14.29 ml) and refluxed under nitrogen for 3.5 h. After allowing to cool over 16 h the solvent was evaporated and the residue treated with saturated ammonium chloride and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried by passing through a hydrophobic frit and evaporated to give the title compound as a brown solid, yield 6.49 gm.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[CH:15]([NH:18][CH2:19][CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])([CH3:17])[CH3:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][CH:15]([N:18]([CH2:19][CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])[S:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[CH3:17]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)NCCNC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)N(CCNC(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Acetaminobenzene sulfonyl chloride (23.3 g, 0.1 mole) as a slurry in 400 ml methylene chloride was added to N,N'-diisopropyl ethylene diamine (14.46 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in methylene chloride (600 ml). The reaction was stirred overnight at room temperature. The reaction was washed with water, insoluble by-product filtered off, and the filtrate stripped to a brown gum. After filtration through silica gel in 20% MeOH/EtOAc the crude crystalline product was recrystallized from isopropanol to provide the title product as the hydrochloride salt (3.00 g, m.r. 176°-178° C.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([N:14]2[CH2:18][CH2:17][CH2:16]C2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)(=[O:22])C#C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2[NH:14][C:18](=[O:22])[CH:17]=[CH:16][C:12]=2[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(N)=O
Reactant: C1=C(N2CCCC2)CCN(Cc2ccccc2)C1
Solvent: Cc1ccccc1
Product: O=c1ccc2c([nH]1)CCN(Cc1ccccc1)C2
Temperature: 25 °C

Procedure:
To a solution of 1-benzyl-4-pyrrolidin-1-yl-1,2,3,6-tetrahydropyridine (2.58 g, 10.65 mmol) in toluene (30 mL) is added propiolamide (1.47 g, 21.29 mmol) and the mixture is refluxed for 4 hr. The mixture is cooled to rt and the solvent is removed in vacuo. The residue is partitioned between NaHCO3 (30 mL) and DCM (30 mL). The layers are separated and the aqueous layer is extracted with DCM (30 ml). The combined extracts are dried and evaporated and the residue is purified by flash column with 5% MeOH in DCM to give the title compound as a light yellow solid. MS (M+1): 241.1.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1)=[O:5].[N:25]([CH:28]([CH3:30])C)=[C:26]=[O:27]>C(N(CC)CC)C>[C:26]([N:25]1[CH2:28][CH2:30][CH:4]([NH:6][S:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=3[Cl:1])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:27])[CH2:8][CH2:7][CH3:16]
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1Cl
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3Cl)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2-chloro-benzoylamino)-naphthalene-1-sulfonyl chloride, and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 10.86 (s, 1H), 8.68 (d, 1H), 8.35 (d, 1H), {tilde over (□)}□□(d, 1H), 8.13 (d, 1H), 8.0 (m, 1H), 7.74 (m, 3H), 7.64 (m, 3H), 4.00 (d, 1H), 3.60 (d, 1H), 3.26 (m, 1H), 2.93 (t, 1H), 2.59 (m, 2H), 2.17 (t, 2H), 1.46 (m, 2H), 1.43 (q, 2H), 1.17 (m, 1H), 0.82 (t, 3H); LC/MS m/z 512 (M−H)−, 514 (M+H)+.