Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.CC(C)([O-])C.[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CS(C)=O.O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:5]2[CH:6]=[N:7][C:8]3[C:4]2=[N:3][CH:2]=[N:1][C:9]=3[NH2:10])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1ncnc2nc[nH]c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncnc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
In 100 ml of dimethyl sulfoxide, 4.05 g (30.0 mmol) of adenine was dissolved, and 3.5 g (31.0 mmol) of potassium tert-butoxide and 5.0 g (35.0 mmol) of 4-fluoronitrobenzene were added thereto, and the mixture solution was stirred at 80° C. for three hours. The solution was diluted with 200 mL of water and the precipitate formed was collected by filtration, washed with 100 mL of water and 30 mL of methanol in the order named and vacuum dried to obtain 7.2 g (84%) of a target product as a yellow solid.
Reaction SMILES: C(O)(=O)C.C([N:12]1[CH2:17][CH2:16][C@@H:15]([CH3:18])[C@@H:14]([N:19]([CH3:29])[C:20]2[C:21]3[CH:28]=[CH:27][NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:13]1)C1C=CC=CC=1.[H][H].ClCCl>C(O)(C)C.O.[OH-].[OH-].[Pd+2]>[CH3:29][N:19]([C@@H:14]1[C@H:15]([CH3:18])[CH2:16][CH2:17][NH:12][CH2:13]1)[C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ncnc2[nH]ccc12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: C[C@@H]1CCNC[C@@H]1N(C)c1ncnc2[nH]ccc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
Palladium hydroxide on carbon (50 mg), and acetic acid (44 mg, 0.72 mmol, 1.00 equiv.) were added to a solution of N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (250 mg, 0.67 mmol, 1.00 equiv.) in isopropanol/water (10 mL/2 mL). After hydrogen gas was introduced, the resulting mixture was stirred at about 50° C. for about 16 hours. After filtering the mixture, the pH value of the filtrate was adjusted to 8 by adding sodium hydroxide. Standard extractive workup with dichloromethane (3×20 mL) afforded the title product as an off-white solid (140 mg; yield=81%) 1H NMR (300 MHz, CDCl3) δ: 10.60 (br s, 1H), 8.35 (s, 1H), 7.07 (d, J=3.6 Hz, 1H), 6.60 (d, J=3.6 Hz, 1H), 4.88-4.98 (m, 1H), 3.45 (s, 3H), 3.25-3.37 (m, 1H), 2.80-3.10 (m, 3H), 2.45-2.58 (m, 1H), 1.82-2.00 (m, 1H), 1.60-1.80 (m, 2H), 1.11 (d, J=7.2 Hz, 3H). LC-MS: m/z=246 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:27][CH:26]=2)[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(OCC)(=O)C.[H][H]>[Pt]=O.C(O)C>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]([C:19]([F:20])([F:22])[F:21])=[C:10]([N:8]2[C:7](=[O:23])[N:6]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[S:37](=[O:43])(=[O:44])[NH:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[CH:29][CH:30]=3)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9]2)[CH:15]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 99.6 %

Procedure:
A mixture of 200 mg (0.317 mmole) of 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2,4-dihydro-2-[5-nitro-2-(trifluoromethyl)phenyl] -3H-1,2,4-triazol-3-one (from Step C), 15 mg of platinum oxide, 10 mL of ethyl acetate, and 2 mL of ethanol was shaken with hydrogen at approximately 4 atm for a few hours until complete and then centrifuged. The supernatant was decanted off, and the catalyst pellet was extracted 3× with ethanol in the same manner. The combined supernatant fractions were concentrated to give 190 mg (100%) of the title compound as a brown foam, which was suitable for use without further purification; TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 608 (M+Li)+.
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[C:11]([NH:13][NH2:14])=[O:12])([CH3:7])[CH3:6].C(=O)(O)[O-].[Na+].O>O1CCOCC1>[NH2:1][C:2]1[O:12][C:11]([C:10]2[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]([OH:18])=[C:8]([C:5]([CH3:4])([CH3:6])[CH3:7])[CH:9]=2)=[N:13][N:14]=1
Reactant: N#CBr
Reactant: CC(C)(C)c1cc(C(=O)NN)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(-c2nnc(N)o2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
Cyanogen bromide (0.9 g, 0.0083 mole) is added to a solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, hydrazide (2.2 g, 0.0083 mole) and sodium bicarbonate (0.7 g, 0.0083 mole) in dioxane (10 ml)/water (10 ml). The resulting mixture is stirred two hours at room temperature. The solution is concentrated to half volume in vacuo and the residue diluted with water. The resulting solid is filtered and recrystallized from ethyl acetate/hexane to give 1.5 g (2.4 g theor., 58%) of 4-(5-amino-1,3,4-oxadiazol-2-yl)-2,6-bis(1,1-dimethylethyl)-phenol after drying in vacuo at room temperature, mp 244°-245° C.
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:28][NH:29][CH3:30]>C(O)C>[C:17]1([CH:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:27][N:29]([CH3:30])[CH3:28])=[CH:6][CH:7]=3)[O:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)CC(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)COc1ccc2c(c1)OC(C)(C)CC2c1cccc2ccccc12
Reaction time: 48 h

Procedure:
7-(2,3-Epoxypropoxy)-2,2-dimethyl-4-(1-naphthyl)chroman (3.15 g., 0.0088 moles) was dissolved in a solution of dimethylamine in ethanol (20 ml., ~40%) and left to stand at room temperature for 48 hours. Removal of solvent gave the title compound as a dark coloured oil which was converted to the succinate salt. Recrystallization from acetone gave a white solid (1.72g., 49%) m.p. 123°-125° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:5][CH2:4][N:3]1[C:21]([C@@H:23]1[CH2:27][C@H:26]([S:28][C:29]2[C@H:30]([CH3:53])[C@@H:31]3[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]3[C:33]=2[C:34]([O:36]CC2C=CC([N+]([O-])=O)=CC=2)=[O:35])[CH2:25][N:24]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[O:22].[ClH:67]>O1CCCC1.O>[ClH:67].[CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:21]([C@@H:23]1[CH2:27][C@H:26]([S:28][C:29]2[C@H:30]([CH3:53])[C@@H:31]3[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]3[C:33]=2[C:34]([OH:36])=[O:35])[CH2:25][NH:24]1)=[O:22]
Reactant: C[C@@H]1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)[C@@H]1C[C@H](SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CNCCN1C(=O)[C@@H]1C[C@H](SC2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)CN1

Procedure:
132 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(2R)-2-methyl-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] was dissolved in 3 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 160 μl of 1N aqueous hydrochloric acid were added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 150 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 7(b), to give 23 mg of the title compound as a powder.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: FC(F)(F)c1ccccc1C=C1c2ccccc2CCc2ccccc21

Procedure:
Combine 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.5 g, 1.75 mmol) and 2-(trifluoromethyl)phenyl boronic acid (0.33 g, 1.75 mmol) using procedures essentially as described in Example 219, below. Pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product. Analysis for C23H17F3: Calcd: C, 78.84 H, 4.89; Found: C, 78.65 H, 4.96. HPLC (ISO80-10M)) t=16.67 min (99%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:8]=1
Reactant: O=C(O)c1cccc(-c2ccncc2)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a solution of 3-(pyridin-4-yl)benzoic acid (300 mg, 1.5 mmol) in DCM (6 mL) was added EDCI (430 mg, 2.20 mmol), HOBt (296 mg, 2.20 mmol), Et3N (556 mg, 4.50 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (370 mg, 1.80 mmol). The mixture was stirred at room temperature for 16 h, then the reaction mixture was washed with water and extracted with DCM. The organic layer was then dried, concentrated and the residue purified by prep-HPLC to give the title product (230 mg, Yield 40%). 1H NMR (400 MHz, MeOD) δ 8.54 (d, J=4.0 Hz, 2H), 8.16 (s, 1H), 7.85-7.80 (m, 2H), 7.64 (dd J=4.0 Hz, 2H), 7.48 (dd, J=7.6 Hz, 1H), 7.03-6.95 (m, 4H), 4.13 (br.s, 1H), 3.66 (s, 2H), 3.60-3.48 (m, 2H), 2.80-2.77 (m, 4H), 2.63-2.59 (m, 2H). LCMS (m/z): 388.2 (M+1).
Reaction SMILES: O1CCC[CH2:2]1.[Si]([O:13][C:14]([NH:16][CH:17]([CH2:22][CH:23]=[CH2:24])[C:18]([O:20][CH3:21])=[O:19])=[O:15])(C(C)(C)C)(C)C.CI.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:2][O:13][C:14]([NH:16][CH:17]([CH2:22][CH:23]=[CH2:24])[C:18]([O:20][CH3:21])=[O:19])=[O:15]
Reactant: C1CCOC1
Reactant: C=CCC(NC(=O)O[Si](C)(C)C(C)(C)C)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CI
Product: C=CCC(NC(=O)OC)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran solution (3.0 ml) of the compound prepared in Example 3 (170 mg, 0.59 mmol), were successively added dropwise at 0° C. in a nitrogen atmosphere methyl iodide (0.074 ml, 1.18 mmol) and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.59 ml, 0.59 mmol). The mixture was agitated for 1 hour at 0° C., poured into water and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under vacuum. The resulting reaction mixture was subjected to column chromatography and eluted with a 1:4 mixture of ether and hexane to give 93 mg of the titled compound (yield, 84% based on the starting materials used in Example 3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:5]2=[CH:4][CH:3]=1.[C:14]1([C:20]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:21]2[C:25]([C:26]3[C:31]([C:32]4[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=4)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][N:23]=[N:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:38][C:35]3[CH:34]=[CH:33][C:32]([C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:25]4[N:21]([C:20]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:22]=[N:23][N:24]=4)=[CH:37][CH:36]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCCc1nc2nc(N)ccc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCc1nc2ccc(N)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
5-amino-2-propyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine was prepared according to the procedure described in Example 7, Part A from 5-amino-2-propylimidazo[4,5-b]pyridine (130 mg, 0.80 mmol), N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (445 mg, 0.800 mmol), and NaH (2.4 mmol) Yield: 185 mg (as a glass like solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].[Cl:13][C:14]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:15]=1[C:16]([N:18]=[C:19]=[O:20])=[O:17].C(OCC)C>CN1CCCC1=O>[Cl:13][C:14]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:15]=1[C:16]([NH:18][C:19]([NH:5][C:4]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:20])=[O:17]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: COc1ccc([N+](=O)[O-])cc1N
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
4.0 g (23.8 mmol) of 2-methoxy-5-nitroaniline were dissolved in 10 ml of N-methyl-2-pyrrolidinone, and 5.2 g (23.8 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate were added. Slight warming occurred. After 15 minutes at room temperature, diethyl ether was added, and the resulting precipitate was filtered off with suction. 6.6 g (79%) of the desired product were obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[C:3](=[O:8])[CH2:4][C:5]([OH:7])=[O:6]>C1COCC1>[OH:6][C:5]1[CH:4]=[C:3]([CH:2]([CH3:9])[CH3:1])[O:6][C:5](=[O:7])[C:4]=1[C:3](=[O:8])[CH:2]([CH3:9])[CH3:1]
Reactant: CC(C)C(=O)CC(=O)O
Solvent: C1CCOC1
Product: CC(C)C(=O)c1c(O)cc(C(C)C)oc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
4-Methyl-3-oxo-pentanoic acid (16.4 g, 126 mmol) was taken up in THF (200 mL) at room temperature under a nitrogen atmosphere, and 1,1-carbonyldiimidazole (22.4 g, 138 mmol) was added in one portion. The reuslting yellow solution was stirred at room temperature for 16 h, and then concentrated in vacuo and the residue diluted with DCM (200 mL). The solution was washed with 2N HCl (100 mL) and water (100 mL) and the aqueous was re-extracted with DCM (50 mL). The combined organics were dried over sodium sulfate and were then concentrated in vacuo to give the title compound as a yellow oil (11.7 g, 80%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:8]=2[CH:21]=1)([OH:3])=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[C:8]2[CH:21]=[C:4]([C:1](=[O:3])[NH:33][S:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)(=[O:31])=[O:32])[CH:5]=[CH:6][C:7]=2[N:11]=[C:10]1[CH3:12]
Reactant: COc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)NC(=O)c2ccc3nc(C)n(Cc4ccccc4Cl)c3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
N,N′-carbodiimidazole (0.431 g) was added at a time to a solution of 0.400 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 15 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of 0.498 g of 4-methoxybenzenesulfonamide and 0.405 g of diazabicycloundecene in 5 ml of N,N-dimethylformamide was added thereto, and the mixed solution was stirred at 100° C. for 67 hours. The reaction solution was cooled, and the solvent was distilled off under reduced pressure. water and chloroform were added to the residue, and 10% hydrochloric acid was added thereto while being cooled until the aqueous layer was acidified. The resulting mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, and the solvent was distilled off under reduced pressure. The residue was purified through silica-gel column chromatography (eluent: a mixture of chloroform and methanol at a ratio of 100:2 to 100:10). The resulting product was concentrated, and was crystallized from a mixed solution of ethyl acetate and diethyl ether. The crystals were separated through filtration, and were dried to give 0.450 g of 1-(2-chlorobenzyl)-6-(4-methoxybenzenesulfonylcarbamoyl)-2-methylbenzimidazole (217).
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([SH:15])=[N:12][N:11]=2)=[C:6]([NH:16][CH:17]([CH3:19])[CH3:18])[CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[C:6]([NH:16][CH:17]([CH3:19])[CH3:18])[C:7]([C:10]2[O:14][C:13]([S:15][CH3:1])=[N:12][N:11]=2)=[CH:8][N:9]=1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nnc(S)o1
Reactant: CI
Solvent: CO
Product: CSc1nnc(-c2cnc(Cl)cc2NC(C)C)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (22 mmol, 2 equiv.) was added to a solution of 5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-thiol (42) (1.5 g, 5.5 mmol) in MeOH (10 mL). The reaction mixture was stirred overnight at room temperature. The reaction mass was concentrated under reduced pressure. The crude material obtained was purified by column chromatography through silica gel and MeOH: DCM as eluent to furnish the desired compound, 2-chloro-N-isopropyl-5-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyridin-4-amine (43). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.994 min; LCMS (ES-API), m/z 285.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([N:16]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.[N:23]1[NH:24][N:25]=[N:26][C:27]=1[C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>>[N:26]1[NH:25][N:24]=[N:23][C:27]=1[C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]4)=[C:12]([CH:15]=3)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(-c2nn[nH]n2)cc1
Reactant: N#Cc1cc(-c2ccnc(Cl)n2)ccc1N1CCC(O)CC1
Product: N#Cc1cc(-c2ccnc(Nc3ccc(-c4nn[nH]n4)cc3)n2)ccc1N1CCC(O)CC1

Procedure:
5-2-(4-(2H-Tetrazol-5-yl)phenylamino)pyrimidin-4-yl)-2-(4-hydroxypiperidin-1-yl)benzonitrile was obtained by following procedure E using 5-(2-chloropyrimidin-4-yl)-2-(4-hydroxypiperidin-1-yl)benzonitrile and 4-(2H-tetrazol-5-yl)aniline. 1H NMR (DMSO-d6, 400 MHz) δ 10.09 (s, 1H), 8.61 (d, 1H), 8.50 (d, 1H), 8.38 (dd, 1H), 8.06 (d, 2H), 8.00 (d, 2H), 7.55 (d, 1H), 7.32 (d, 1H), 3.72 (m, 1H), 3.61 (m, 2H), 3.13 (m, 2H), 1.89 (m, 2H), 1.59 (m, 2H). MS (ESI) 440.10 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][C:22]=2[CH3:29])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[CH3:29])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20]
Reactant: COc1ccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)c(C)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(O)ccc1-c1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Temperature: 0 °C
Yield: 94.2 %

Procedure:
Charge a flask with 3-(3-chloro-4′-methoxy-2′-methyl-biphenyl-4-ylmethyl)-1-cyclohexyl-pyrrolidin-2-one (Example 95) (475 mg, 1.2 mmol), dissolve in dry methylene chloride (11 mL) and cool to 0° C. under nitrogen. Add BBr3 (0.22 mL, 2.4 mmol) and stir at 0° C. for 20 minutes. Pour into saturated aqueous sodium bicarbonate and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate in vacuo to yield 450 mg (98%) of the title compound. Mass spectrum (apci) m/z=398.3 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=O)[CH2:9][C:8](=[O:13])[CH2:7]1.[NH2:14][CH2:15][CH:16](O)[CH3:17]>O1CCCC1>[CH3:17][C:16]1[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:11][C:10]=2[NH:14][CH:15]=1
Reactant: O=C1CC(=O)CC(c2cccs2)C1
Reactant: CC(O)CN
Solvent: C1CCOC1
Product: Cc1c[nH]c2c1C(=O)CC(c1cccs1)C2
Temperature: 150 °C
Reaction time: 7 h
Yield: 30.2 %

Procedure:
A mixture of 5-thienylcyclohexane-1,3-dione (2.0 g), 3-aminopropan-2-ol (1.0 g), molecular sieves 4A (12 g) and tetrahydrofuran (30 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (40 ml). To the mixture were added 2-bromomesitylene (2.1 g), tetrakistriphenylphosphine palladium (0.30 g) and potassium carbonate (2.8 g), and the mixture was stirred at 150° C. for 7 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydroindol-4-one (0.72 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([F:15])[CH2:12][N:11]([C:16](OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.ClC1[CH:41]=[CH:40][N:39]=[CH:38][C:37]=1[N+:42]([O-:44])=[O:43]>[Pd].CO>[F:15][C@H:13]1[CH2:12][N:11]([C:16]2[CH:41]=[CH:40][N:39]=[CH:38][C:37]=2[N+:42]([O-:44])=[O:43])[CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(C(=O)OCc2ccccc2)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(c2ccncc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of (3S,5R)-benzyl 3-(tert-butoxycarbonylamino)-5-fluoropiperidine-1-carboxylate (1 eq) in 28 methanol was added 10% Pd/C (0.1 eq). The resulting suspension was stirred at H2 atmosphere for 1 hours. The crude solids were filtered through a pad of Celite on a paper lined Buchner funnel, washed with MeOH, then concentrated in vacuo. The residue was dissolved in 33 mL of isopropanol and DIPEA (2.5 eq) and 4-chloro-3-nitropyridine (1.5 eq) were added. The reaction mixture was stirred at 80° C. for 2 hours, at which point the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with 150 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4; filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (5% methanol in EtOAc:hexanes=1:1) to give the titled compound (90%). LC/MS (m/z): 341.1 (MH+). HPLC: Rt: 2.115 min.