Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:24]([CH3:26])[CH3:25])[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:4](=[O:37])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:49][C:50]1[C:58]2[C:53](=[CH:54][C:55]([F:59])=[CH:56][CH:57]=2)[N:52]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[N:51]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[F:59][C:55]1[CH:54]=[C:53]2[C:58]([C:50]([CH2:49][CH:3]3[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:24]([CH3:26])[CH3:25])[C:13]4[CH:14]=[CH:15][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:17][CH:18]=4)=[O:11])[C:7]4[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=4[N:5]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:4]3=[O:37])=[N:51][N:52]2[C:60]([O:62][C:63]([CH3:65])([CH3:64])[CH3:66])=[O:61])=[CH:57][CH:56]=1
Reactant: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccc(F)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
To a solution of 250 mg of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-trifluoromethoxy-phenyl) acetamide, prepared as in Part C, in 5 mL of dry DMF at 0° C. is added 1.5 mL of a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene. The reaction mixture is stirred for 30 min at 0° C. and a solution of 170 mg of 3-Bromomethyl-6-fluoro-1-tert-butoxycarbonyl-indazole in 3 mL of dry DMF is added dropwise. The reaction mixture is stirred overnight at RT, poured into water and the product extracted with ethyl acetate (2×15 mL). The solvent is removed in vacuo and the residue is purified by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent to afford 100 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ7.98-6.95 (m,16H) 5.07 (m, 1H), 4.30 (m, 3H), 3.86 (dd, 1H, J=16.5, 6.4), 3.65 (dd, 1H,J=16.5,6.4), 1.69 (s, 9H), 1.13 (d, 6H, J=6.8).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2.CCCCCC.[H-].[Na+].Br[CH2:25][C:26]1[CH:43]=[CH:42][C:29]([C:30]([N:32]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH:33]([CH3:35])[CH3:34])=[O:31])=[CH:28][C:27]=1[O:44][CH3:45]>CC(N(C)C)=O>[CH:36]1([N:32]([CH:33]([CH3:35])[CH3:34])[C:30](=[O:31])[C:29]2[CH:42]=[CH:43][C:26]([CH2:25][N:11]3[CH:12]=[CH:13][CH:14]=[C:9]4[N:8]=[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[N:15]=[C:10]34)=[C:27]([O:44][CH3:45])[CH:28]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1CBr
Reactant: c1ccc(-c2nc3ncccc3[nH]2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCCCCC
Product: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1Cn1cccc2nc(-c3ccccn3)nc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
2-(2-Pyridyl)-1H-imidazo(4,5-b)pyridine (1.1 g, 5.6 mmol) was added portionwise with stirring over 5 minutes to a suspension of hexane-washed NaH (150 mg, 6.16 mmol) in dimethylacetamide (15 ml) under Ar and stirred at room temperature for 1 hour. 4-Bromomethyl-3-methoxy-N-cyclohexyl-N-isopropylbenzamide (2.1 g, 5.6 mmol) was added portionwise over 30 minutes and the mixture was stirred overnight at 25° C. The solvent was removed at <50° C. in vacuo using an oil pump and the residue was chromatographed on silica gel with 95/5/1 CH2Cl2 /MeOH/NH4OH to give the titled product (1.95 g, 67%) as a glass. Anal. Calcd. for C29H33N5O2.H2O: C, 69.44; H, 7.03; N, 13.96. Found: C, 69.70; H, 7.16; N, 13.87.
Reaction SMILES: [I-].[Na+].C(=O)([O-])[O-].[K+].[K+].C1(CN(CC2C=CC=CC=2)[C:17]2[C:26]3[N:27]=[C:28]([CH2:30][CH2:31][CH2:32][CH2:33]Cl)[NH:29][C:25]=3[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=2)C=CC=CC=1.[CH3:42][C:43]([CH3:45])=O>>[C:43]1([CH2:45][N:29]([CH2:25][C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[N:18]=[CH:17][C:26]2[N:27]=[C:28]4[CH2:30][CH2:31][CH2:32][CH2:33][N:29]4[C:25]3=2)[CH:32]=[CH:31][CH:30]=[CH:28][CH:42]=1
Reactant: CC(C)=O
Reactant: ClCCCCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: c1ccc(CN(Cc2ccccc2)c2cccc3c2ncc2nc4n(c23)CCCC4)cc1

Procedure:
Sodium iodide (1 g, 6 mmole) and potassium carbonate (0.8 g, 6 mmole) were added to a solution of N,N-bis(phenylmethyl)-2-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.55 g, 1.2 mmole) in acetone. The reaction mixture was heated at reflux for 4 hours, filtered, and then concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with 10-15% ethyl acetate in hexanes v/v). Nuclear magnetic resonance spectroscopy indicated the possible presence of iodo intermediate; so the residue was taken up in acetone, combined with sodium iodide and potassium carbonate and heated at reflux over night. The reaction was worked up to provide 0.38 g of N,N-bis(phenylmethyl)-8,9,10,11 tetrahydropyrido-[1',2':1,2]imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[O:13][CH3:14])#[N:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34]>ClCCl>[C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[OH:34])=[O:10])=[CH:6][C:5]=1[O:13][CH3:14])#[N:2]
Reactant: COc1cc(C(=O)O)ccc1CC#N
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCCC[C@H]2O)ccc1CC#N
Reaction time: 2 h

Procedure:
The 4-(cyanomethyl)-3-methoxybenzoic acid (0.33 g, 1.7 mmol) was suspended in anhydrous dichloromethane (5 mL) and treated with oxalyl chloride (0.3 mL, 3.5 mmol) followed by few drops of DMF at 22° C. under argon. After 2 h stirring, the resulting solution was concentrated to dryness, dissolved in dichloromethane (5 mL), and added slowly to a solution of trans-2-aminocyclohexanol hydrochloride (0.26 g, 1.7 mmol) and TEA (0.5 mL, 3.5 mmol) in anhydrous dichloromethane (10 mL). After 20 min stirring, filtered off salt, and concentrated to afford 4-(cyanomethyl)-N-[(2R)-2-hydroxycyclohexyl]-3-methoxybenzamide as a yellow solid. MS (ESI) 289 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1.[F:35][C:36]1([F:42])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:35][C:36]1([F:42])[CH2:41][CH2:40][N:39]([C:2]2[CH:34]=[CH:33][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=2)[CH2:38][CH2:37]1
Reactant: FC1(F)CCNCC1
Reactant: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)n1
Product: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CCC(F)(F)CC5)cc4)c3c2)n1

Procedure:
The title compound was prepared from racemic cis-2-(1-(4-bromobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid using analogous conditions to Example 152 using 4,4-difluoropiperidine. MS (ESI): mass calcd. for C31H35F2N5O3, 563.65; m/z found, 564.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.55-7.48 (m, 2H), 7.04 (d, J=8.7, 2H), 6.96 (dd, J=10.0, 5.5, 3H), 6.93-6.88 (m, 1H), 6.27 (d, J=2.2, 1H), 5.43 (d, J=16.7, 1H), 5.38 (d, J=16.7, 1H), 4.99 (s, 2H), 3.83 (s, 3H), 3.61-3.52 (m, 1H), 3.34-3.32 (m, 4H), 2.88-2.79 (m, 1H), 2.43-2.29 (m, 1H), 2.12-1.93 (m, 5H), 1.93-1.66 (m, 4H), 1.57-1.37 (m, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.CS(O[CH:20]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH3:21])(=O)=O.C(O)(=O)C>CN(C)C(=O)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH:20]([CH3:21])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(COc1ccc(Cl)cc1)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: COC(=O)Cc1ccc(OC(C)COc2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
To a suspension of 8.0 g of sodium hydride (60% dispersion in oil) (washed with hexane) in 190 ml of N,N-dimethylacetamide is added dropwise 35.2 g of methyl p-hydroxyphenylacetate in 60 ml of N,N-dimethylacetamide. The mixture is stirred at room temperature for one hour and at 50° C. for 20 minutes. To the mixture is added dropwise 53 g of 3-(p-chlorophenoxy)propan-2-ol O-methanesulfonate in 100 ml of N,N-dimethylacetamide. The mixture is stirred and heated at 100° C. for 18 hours. After pouring into 2 liters of ice-water containing 6 ml of acetic acid and chilling in an ice bath for 2 hours, the mixture is filtered and the solid washed with water. The damp waxy product is dissolved in dichloromethane and the solution dried (MgSO4). The solvent is removed under reduced pressure to give 52.6 g of product as an oil. The oil is crystallized from hexane and recrystallized from methanol to give the product as white crystals, mp 84°- 85° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].C([NH+](CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]2[NH:19][N:18]=[N:17][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1F

Procedure:
2.26 g (10.7 mmol) of the compound from Example IV are boiled under reflux with 3.48 g (53.6 mmol) of sodium azide and 7.37 g (53.6 mmol) of triethylammonium chloride in 30 ml of analytical grade dimethylformamide for 24 hours. After cooling, the mixture is partitioned between ether and 1M sulphuric acid, the organic phase is washed with water and dried over sodium sulphate and the solvent is evaporated off. The crude product is extracted by stirring in toluene and, after filtration with suction, the product is dried in vacuo (1.89 g, 7.2 mmol). The mother liquor is evaporated on a rotary evaporator and the residue is purified again as above (0.43 g, 1.7 mmol).
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Br:1][CH2:2][C@@H:3]([CH3:6])[CH2:4][O:5][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1
Reactant: C1=COCCC1
Reactant: C[C@@H](CO)CBr
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@H](CBr)COC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (S)-3-bromo-2-methylpropan-1-ol (7.30 g, 5 mL, 47.7 mmol) in anhydrous dichloromethane (100 mL) was mixed with 3,4-dihydro-2H-pyrane (4.63 g, 5.02 mL, 55 mmol) and pyridinium tosylate (50 mg) with ice cooling and then stirred for 1 h at room temperature. The reaction mixture was then washed with 5% sodium hydrogencarbonate solution and water (3×30 mL each). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=1)[C:19]#[N:20].[C@H]1(N)CCCC[C@@H]1N.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=1)[C:19]#[N:20])[CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(Cl)ccc21
Reactant: N#Cc1cncc(Br)c1
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Yield: 26.4 %

Procedure:
6-Chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (36 mg, 0.2 mmol), 5-bromo-nicotinonitrile (73 mg, 0.4 mmol), CuI (3.8 mg, 0.02 mmol), (1S,2S)-cyclohexane-1,2-diamine (4.5 mg, 0.04 mmol) and Cs2CO3 (130 mg, 0.4 mmol) were dissolved in dioxane (5 mL). The reaction mixture was subjected to microwave reaction at 150° C. for 2.5 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to yield the title compound (15 mg, 26%) as a white solid. MS: 284.1 (M+H+).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]3[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C=CC2CCC(c3ccc(C#N)cc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(CC[C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)cc1

Procedure:
7.0 g of p-[4-[2-(p-pentylphenyl)vinyl]cyclohexyl]benzonitrile were dissolved in 350 ml of toluene, treated with 1.4 g of palladium/carbon (10%) and hydrogenated at room temperature and normal pressure until the hydrogen uptake came to a standstill. The crude p-[trans-4-[2-(p-pentylphenyl)ethyl]cyclohexyl]benzonitrile obtained after filtering off the catalyst and concentrating the filtrate was recrystallized twice from ethanol. Yield 4.2 g; m.p. (C--N) 61.5° C., cl.p. (N--I) 126° C.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[PH5].[F:29][C:30]1[N:31]([C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:32]=[C:33]([CH:35]=O)[N:34]=1>CS(C)=O>[F:29][C:30]1[N:31]([C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:32]=[C:33]([CH:35]=[CH2:2])[N:34]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
Methyl triphenylphosphonium iodide was treated with potassium t-butoxide in DMSO. After generation of the phosphorane, 2-fluoro-4-formyl-1-triphenylmethylimidazole was added, and the mixture heated 2 hours at 60°. Extractive work-up and chromatography gave 2-fluoro-1-triphenylmethyl-4-vinylimidazole, having the following n.m.r. in CDCl3 : 5.1 (d, 1H); 5.77 (d, 1H); 6.26-6.63 (m, 1H); 6.48 (s, 1H); 7.1-7.5 (m, 15H).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17]3[C:13]([NH:14][C:15](=[O:37])[N:16]3[CH:19]3[CH2:27][CH2:26][CH2:25][C:24]4[N:23](S(C5C=CC=CC=5)(=O)=O)[CH:22]=[CH:21][C:20]3=4)=[CH:12][N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+]>CO>[N:1]1([C:10]2[N:18]=[C:17]3[C:13]([NH:14][C:15](=[O:37])[N:16]3[CH:19]3[CH2:27][CH2:26][CH2:25][C:24]4[NH:23][CH:22]=[CH:21][C:20]3=4)=[CH:12][N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=c1[nH]c2cnc(-n3cnc4ccccc43)nc2n1C1CCCc2c1ccn2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]c2cnc(-n3cnc4ccccc43)nc2n1C1CCCc2[nH]ccc21
Yield: 99.2 %

Procedure:
To a solution of 2-(1H-benzo[d]imidazol-1-yl)-9-(1-(phenylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-yl)-7H-purin-8(9H)-one (50 mg) in MeOH (1 mL) was added 4 N NaOH (1 mL), and the mixture was refluxed overnight and cooled. Volatiles were removed under reduced pressure, and the resultant neutralized with 4 N HCl. The white precipitate was filtered, washed with a small amount of water, and dried in vacuo to afford 36 mg of the title compound. 1H NMR (d6-DMSO) δ 11.6 (s, 1H), 10.7 (s, 1H), 8.86 (s, 1H), 8.27 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.33 (m, 2H), 6.53 (t, J=2.4 Hz, 1H), 5.64 (t, J=2.4 Hz, 1H), 5.54 (m, 1H), 2.72 (m, 2H), 2.30 (m, 1H), 2.07 (m, 2H), 1.84 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>ClCCCl>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10]
Reactant: COCCOCCl
Reactant: Cc1cc(C=O)cc(C)c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCCOCOc1c(C)cc(C=O)cc1C

Procedure:
A mixture of 4-hydroxy-3,5-dimethylbenzaldehyde (5 g), N,N-diisopropylethylamine (6.9 ml), (2-methoxyethoxy)methylchloride (4.26 ml) and 1,2-dichloroethane (65 ml) was refluxed for 5 hours. The reaction mixture was washed with water and dried over magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate (8:2 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give 4-[(2-methoxyethoxy)methoxy]-3,5-dimethylbenzaldehyde (6.54 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:14][C:13]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30][C:31]([O:33]C)=[O:32])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[O:16])=[N:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>CO.CS(C)=O.CC#N.O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:14][C:13]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:25][CH2:26][CH:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][CH2:29]4)=[N:22][CH:23]=3)=[O:16])=[N:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)CC1CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(F)c(F)c4)o3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(O)CC1CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(F)c(F)c4)o3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (1-{5-[({5-[(3,4-difluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]pyridin-2-yl}piperidin-4-yl)acetate (Example 619, 189 mg, 0.40 mmol) in MeOH (10 mL) was added a 2M solution of NaOH (1 mL). The resulting yellow solution was allowed to stir at ambient temperature overnight. The volatile organics were removed by evaporation and residue adjusted to pH ˜1 with 2M HCl and the suspension was filtered and dried to leave a solid which was dissolved in DMSO/MeCN/water(7:2:1) and purified on a reverse phase preparative HPLC column eluting 5-95% MeCN 0.2% TFA. The title compound was isolated as a yellow solid (108 mg, 0.235 mmol; 58.9%); 1H NMR δ 1.16-1.27 (m, 2H), 1.76 (d, 2H), 1.91-1.99 (m, 1H), 2.19 (d, 2H), 2.90 (t, 2H), 4.21 (d, 2H), 7.00 (br d, 1H), 7.34-7.37 (m, 1H), 7.49 (q, 1H), 7.67-7.73 (m, 1H), 7.98 (d, 1H), 8.46 (s, 1H), 11.01 (s, 1H), 11.23 (s, 1H); CO2H not seen; MS m/e MH+ 459.
Reaction SMILES: CC([Si](C)(C)O[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]([OH:30])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:9]=1)(C)C.CN(C=O)C.S(Cl)([Cl:40])=O>C(Cl)Cl>[Cl:40][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]([OH:30])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)(C(C)C)C(C)C)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C(O)(C(C)C)C(C)C)c1
Reaction time: 1.5 h
Yield: 109.6 %

Procedure:
To a stirred solution of 69.19B (0.050 g, 0.1 mmol) in DCM (2.00 mL) at 23° C. was added DMF (0.0008 mL) followed by thionyl chloride (0.01 mL, 0.2 mmol). The reaction was then stirred for 1.5 hours and then concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 69.19C as a colorless oil (0.04 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][N+:10]([O-])=O)=[C:4]([CH3:13])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C=C[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1CCN
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
A solution of 4-chloro-2-methyl-1-(2-nitrovinyl)benzene (1.83 g, 9.26 mmol) in tetrahydrofuran (40 mL) was cooled to 0° C. in an ice bath, and a 1M solution of lithium aluminum hydride in tetrahydrofuran (37 mL, 37 mmol) was added, dropwise over 10 minutes. The resulting mixture was stirred in the ice bath for 2 hours 30 minutes, then quenched in the following manner: water (1.5 mL) was added dropwise, and after stirring for 5 minutes, 1M sodium hydroxide (1.5 mL) was added. After stirring for a further 15 minutes, water (5 mL) was added, and the resulting mixture was stirred at ambient temperature for 15 minutes, then filtered through a medium porosity sintered glass funnel. The collected precipitate was washed with ethyl acetate (60 mL). The combined filtrate and wash was dried over sodium sulfate and concentrated to afford 2-(4-chloro-2-methylphenyl)ethanamine as a brown oil (1.17 g, 75% yield).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][C:13]=1[OH:21].N>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:14][C:13]=1[OH:21]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc(F)c(O)c1
Agent: N
Product: Oc1cc(-c2nc(-c3cccnc3)no2)ccc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 4-fluoro-3-hydroxybenzoic acid (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.45 (dd, J=11.1, 8.7 Hz, 1H), 7.62-7.71 (m, 2H), 7.78 (dd, J=8.3, 2.0 Hz, 1H), 8.43 (dt, J=7.9, 1.8 Hz, 1H), 8.82 (dd, J=5.0, 1.8 Hz, 1H), 9.24 (d, J=2.0 Hz, 1H) ppm; MS (DCl/NH3) m/z 258 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[O:30][CH3:29])=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cccc2cc(C(=O)N[C@@H]3CN4CCC3CC4)sc12
Temperature: 70 °C

Procedure:
0.67 ml of 2 M sodium carbonate solution and 18.3 mg (0.02 mmol) of PdCl2(dppf) are added to a mixture of 200 mg (0.45 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 22A) and 68.1 mg (0.45 mmol) of 2-methoxyphenylboronic acid in 2 ml of DMF. The reaction mixture is heated at 70° C. for 17 h and, after cooling, filtered through kieselguhr and purified by preparative HPLC. The product fractions are concentrated, taken up in a 5:1 mixture of methanol and 1N hydrochloric acid and again concentrated. Drying under high vacuum results in 112 mg (58% of theory) of the title compound.