Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:32])[CH2:14][C@H:13]1[C:33]([O:35][CH3:36])=[O:34])=O)C1C=CC=CC=1.N[C@@H]1CCN(CCN2C3C(=C(F)C=C(F)C=3)C=CC2=O)C[C@@H]1C(OC)=O>>[NH2:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:32])[CH2:14][C@H:13]1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC(=O)OCc1ccccc1
Agent: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Product: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N

Procedure:
Methyl(3R,4R)-4-{[(benzyloxy)carbonyl]amino}-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 39) (535 mg, 1.07 mmol) was hydrogenated as described for Intermediate 34 to give 391 mg (quantitative) of the product as a colorless hard foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[C:3]1=[CH:4][C:5]1[N:9]=[C:8]([SH:10])[NH:7][C:6]=1[CH:11]=2.[OH-].[Na+].Cl.Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>O>[CH3:1][C:2]1([CH3:18])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[C:3]1=[CH:4][C:5]1[N:9]=[C:8]([S:10][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[NH:7][C:6]=1[CH:11]=2
Reactant: ClCc1ccccn1
Reactant: CC1(C)CCC(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc3[nH]c(SCc4ccccn4)nc3cc21
Yield: 57.6 %

Procedure:
9.0 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1H-naphth(2,3-d)imidazole-2-thiol were suspended in 60 ml of alcohol in a 250 ml sulfonation flask equipped with stirrer, thermometer, dropping funnel and reflux condenser. A solution of 3.24 g of sodium hydroxide in 20 ml of water was added dropwise thereto while stirring well and the mixture was stirred at room temperature for an additional 30 minutes. After adding 6.0 g of 2-chloromethyl-pyridine hydrochloride, the mixture was boiled at reflux overnight and subsequently evaporated. The residue was taken up in 1 l of ethyl acetate, washed neutral three times with 250 ml of water, dried over sodium sulfate and, after evaporation in vacuo, recrystallized from acetonitrile. There were obtained 7.0 g (57.3% of theory) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-[(2-pyridylmethyl)thio]-1H-naphth(2,3-d)-imidazole of melting point 199°-200° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[F:29][C:30]1[CH:44]=[CH:43][C:33]([C:34]([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)=[O:35])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:44]=[CH:43][C:33]([C:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:15][CH2:14][CH2:13][C:11]3[N:10]=[CH:9][NH:8][CH:12]=3)=[CH:38][CH:37]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Product: O=C(c1ccc(F)cc1)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of 4-fluoro-4′-hydroxybenzophenone are treated as described in Example 76.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9](=[O:47])[CH2:10][CH:11]([OH:46])[CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]1[C@@H:20](/[CH:21]=[CH:22]/[C@@H:23]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:24]([CH3:30])([CH3:29])[CH2:25][CH2:26][CH2:27][CH3:28])[C@H:19]([O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH2:18][C:17]1=[O:45].S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH3:7][O:8][C:9](=[O:47])[CH2:10][C:11](=[O:46])[CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]1[C@@H:20](/[CH:21]=[CH:22]/[C@@H:23]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:24]([CH3:29])([CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28])[C@H:19]([O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH2:18][C:17]1=[O:45]
Reactant: CCCCC(C)(C)[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCC(O)CC(=O)OC)OC1CCCCO1
Agent: [Cr+6]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(C)(C)[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCC(=O)CC(=O)OC)OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
Under an atmosphere of nitrogen, 100 mg of chromium trioxide and 0.5 g of infusorial earth were added to 0.162 ml of pyridine in 3 ml of methylene chloride, and the mixture was stirred for 15 minutes at room temperature. 55 mg of the 3-hydroxy compound (prepared as described in Example 1) in 1 ml of methylene chloride were added thereto at 0° C., and the mixture was stirred for 20 minutes at the same temperature. To the reaction solution obtained was added 1 g of sodium bisulphate and, after stirring for 20 minutes at 0° C., the mixture was filtered through a magnesium sulphate layer. The filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (6:1) as eluent to obtain 42 mg of the title compound having the following physical characteristics:
Reaction SMILES: [SH:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[C:3]([OH:5])=[O:4].N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CCOCC>[CH2:28]([O:27][C:25]([S:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[C:3]([OH:5])=[O:4])=[O:26])[CH3:29]
Reactant: COc1ccc2cc(C(S)C(=O)O)ccc2c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)SC(C(=O)O)c1ccc2cc(OC)ccc2c1
Reaction time: 2 h

Procedure:
A solution of α-mercapto-6-methoxy-2-naphthylacetic acid (0.02 moles) in 25 ml. of pyridine is cooled in an ice bath. To this is added dropwise 2.1 mol (0.022 moles) of ethyl chloroformate. The mixture is then stirred for 2 hours, diluted with ether and filtered. The mixture is basified with 10% sodium bicarbonate solution. The alkaline mixture is worked with ether, then acidified with 10% hydrochloric acid, washed with ether, dried and filtered. The solvent is removed and the residue is triturated with hexane to obtain α-ethoxycarbonylthio-6-methoxy-2-naphthylacetic acid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Mg].Br[C:17]1[S:21][C:20]([C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:25]([C:37]3[S:38][C:39](Br)=[CH:40][CH:41]=3)=[CH:24][C:23]=2[O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:19][CH:18]=1>C1COCC1.C(OCC)(=O)C>[CH2:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:17]1[S:21][C:20]([C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:25]([C:37]3[S:38][C:39]([C:2]4[S:3][CH:4]=[CH:5][C:6]=4[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:40][CH:41]=3)=[CH:24][C:23]=2[O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCc1ccsc1Br
Reactant: CCCCCCCCOc1cc(-c2ccc(Br)s2)c(OCCCCCCCC)cc1-c1ccc(Br)s1
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCOc1cc(-c2ccc(-c3sccc3CCCCCCCC)s2)c(OCCCCCCCC)cc1-c1ccc(-c2sccc2CCCCCCCC)s1
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 2-bromo-3-octylthiophene (1.800 grams, 6.533 mmol) in 7 milliliters of anhydrous THF was added slowly over a period of 20 minutes to a mechanically stirred suspension of magnesium turnings (0.238 grams, 9.79 mmol) in 3 milliliters of THF in a 250 milliliter round-bottomed flask under an inert argon atmosphere. The resultant mixture was stirred at 60° C. for 4 hours, and then cooled down to room temperature. The resultant mixture was then added via a cannula to a mixture of 1,4-bis(5-bromo-2-thienyl)-2,5-dioctyloxybenzene (1.650 grams, 2.513 mmol) and [1,3-bis(diphenylphosphinopropane]dichloronickel (II) (0.057 gram, 0.105 mmol) in 20 milliliters of anhydrous THF in a 250 milliliter round-bottomed flask under an inert atmosphere, and refluxed for 48 hours. Subsequently, the reaction mixture was diluted with 200 milliliters of ethyl acetate, was washed twice with water and dried with anhydrous magnesium sulfate. A brown solid, obtained after evaporation of the solvent, was purified by column chromotography on silica gel and recrystallized yielding 1,4-bis[5-(3-octyl-2-thienyl)-2-thienyl]-2,5-dioctyloxybenzene as a yellow crystalline product in 30 percent yield.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1>CN(C=O)C.O>[O:7]([CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CBr)nc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(COc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenol (489 mg, 5.21 mmol) and K2CO3 (1.44 g, 10.4 mmol) in DMF (15 mL) was added methyl 6-(bromomethyl)nicotinate (1.1a) (1.20 g, 5.21 mmol). The reaction was stirred at room temperature for 30 min and then diluted with water to give 1.2a after isolation by vacuum filtration and further drying in vacuo (810 mg): 1H-NMR (400 MHz, CDCl3) δ 9.21 (d, J=2.0 Hz, 1H), 8.34 (dd, J=8.0, 2.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.37-7.26 (m, 2H), 7.05-6.96 (m, 3H), 5.34 (s, 2H), 3.99 (s, 3H); LC-MS (220 nm) >98%, 244.2 [M+H].
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:35](C(OCC)=O)[CH3:36])[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:42])(=[O:6])=[O:5])([CH3:3])[CH3:2].Cl.[OH-:44].[Na+]>C(O)C.O>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH2:35][CH2:36][C:27]([O:28][CH2:29][CH3:30])=[O:44])[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:20]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:42])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)c1nc(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)c(-c2ccccc2)n1COCC[Si](C)(C)C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCc1nc(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)c(-c2ccccc2)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
To a solution of 1-isopropylsulfonyl-2-amino-6-(1-(trimethylsilylethoxymethyl)-2-(1-(ethoxycarbonyl)ethyl)-5-(phenyl)-imidazol-4-yl)-benzimidazole (91 mg, 0.14 mmol) in ethanol (3 mL) add HCl (37%, 3 mL) and stir at room temperature for 24 hours. Then, dilute the mixture with water (10 mL) and add a solution of NaOH (15%) until pH=6-7. Extract the mixture with EtOAc (3×30 mL) and dry (MgSO4) the combined organic layers and concentrate int vacuo. Purify the residue by HPLC to give 1-isopropylsulfonyl-2-amino-6-(1-(trimethylsilylethoxymethyl)-2-(ethoxycarbonylethyl)-5-(phenyl)-imidazol-4-yl)-benzimidazole as a white solid, 11 mg, 16% yield. FIA MS(ES+): m/z=482 (M+H)+. 1-Isopropylsulfonyl-6-(2-(2-carboxyethyl)-5-(phenyl)-imidazol-4-yl)-benzimidazole as a white solid is also obtained, 3 mg, 5% yield. MS (ES+): m/z=454 (M+H)+
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][CH:25]1[CH2:29][NH:28][CH2:27][CH:26]1[C:30]([OH:32])=[O:31].C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl-].[Na+].O.CO.O.C(Cl)Cl>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:28]2[CH2:29][CH:25]([CH3:24])[CH:26]([C:30]([OH:32])=[O:31])[CH2:27]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: CC1CNCC1C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC1CN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1C(=O)O
Temperature: 25 °C

Procedure:
A solution of 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (140 mg, 0.46 mmol) and 4-methylpyrrolidine-3-carboxylic acid (60.1 mg, 0.465 mmol) in Ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 h. The yellow solution was cooled to rt and Sodium cyanoborohydride (35.1 mg, 0.558 mmol) was added and was heated to reflux for 1 h. After cooled down to rt, DCM, water and citric acid were added along with some brine to clear up the layers. Concentration of the cloudy organic layer gave a precipitate that was dissolved in methanol and filtered before purification by preparative HPLC. 1H NMR (400 MHz, DMSO-d6) □ 7.81-7.98 (m, 3H), 7.53 (d, J=7.28 Hz, 1H), 7.42 (d, J=2.26 Hz, 1H), 7.17-7.25 (m, J=2.38, 8.91 Hz, 1H), 4.34-4.55 (m, 3H), 3.61 (br. s., 2H), 3.05 (br. s., 1H), 2.94 (d, J=5.52 Hz, 1H), 2.63-2.80 (m, 1H), 2.21 (d, J=10.54 Hz, 2H), 1.83 (d, J=12.05 Hz, 2H), 1.29-1.43 (m, 2H), 1.19-1.28 (m, 2H), 1.02-1.18 (m, 5H), 0.88 (s, 9H) [M+1] 424.30.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:23]([Cl:24])=[CH:22][C:10]3[NH:11][C:12]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[O:31]1CCOCC1>O=[Mn]=O>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:23]([Cl:24])=[CH:22][C:10]3[NH:11][C:12]([C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=4)=[O:31])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: Clc1cc2[nH]c(Cc3cccc(Br)c3)nc2cc1-c1ccc(-c2ccccc2)cc1
Reactant: C1COCCO1
Agent: O=[Mn]=O
Product: O=C(c1cccc(Br)c1)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
To a solution of compound 14-1 (270 mg, 0.57 mmol) in dioxane was added MnO2 (100 mg, 1.1 mmol). The reaction was allowed to stir at 70° C. for 48 h. The reaction mixture was filtered over a bed of Celite™ and washed with copious amounts of EtOAc. The product was concentrated in vacuo, and then purified on ISCO (EtOAc/Hexanes=1/1) to give the title compound 14-2 as a pale yellow solid.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH2:13]([NH2:16])[CH:14]=[CH2:15]>C(O)C>[CH2:13]([NH:16][C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])[CH:14]=[CH2:15]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: C=CCN
Solvent: CCO
Product: C=CCNc1c(OCC)c(=O)c1=O
Yield: 99.7 %

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.2 g, 31 mmol) in ethanol (80 mL) was treated at room temperature with allylamine (2.3 mL, 31 mmol), which was dissolved in ethanol (40 mL), over a 2 hour period. The reaction mixture was concentrated in vacuo to afford crude 1-(2-propenylamino)-2-ethoxy-3,4-dioxo-1-cyclobutene as a light yellow solid (5.6 g). The crude intermediate was dissolved in anhydrous dimethylformamide (50 mL) and added dropwise to a suspension of 60% sodium hydride (1.5 g, 37 mmol) in anhydrous dimethylformamide (50 mL) under nitrogen. The anion was quenched with t-butyl bromoacetate (6.0 mL, 37 mmol) and the reaction mixture was stirred for 1.5 hours, poured into water (500 mL), extracted with ethyl acetate (2×200 mL), and dried (MgSO4) to yield N-(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)-N-(2-propenyl)glycine 1,1-dimethylethyl ester. Purification was achieved by flash chromatography (10 cm diameter, elution with 20% ethyl acetate in petroleum ether) affording a yellow oil (4.56 g, 50%); 1H NMR (CDCl3, 300 MHz); δ 5.88-5.72 (m, 1H), 5.35-5.22 (m, 2H), 4.80-4.68 (m, 2H), 4.35, 4.08 (d, J=7 Hz, 2H), 4.28, 3.95 (s, 2H), 1.48 (s, 9H), 1.45 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:27]([C:21]1[CH:22]=[CH:23][C:24]([C:10](=[O:12])[CH2:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:25][CH:26]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: N#Cc1cccc(CC(=O)O)c1
Reactant: CCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCc1ccc(C(=O)Cc2cccc(C#N)c2)cc1
Temperature: 0 °C
Yield: 29.7 %

Procedure:
A mixture of 3-cyanophenylacetic acid (13 g, 0.08 mole) and thionyl chloride (100 ml) is heated under reflux for 90 minutes. The excess thionyl chloride is removed by evaporation under reduced pressure. The residue is dissolved in methylene chloride (20 ml) and the resulting solution added to aluminum chloride (16.2 g, 0.12 mole) in methylene chloride (200 ml) with vigorous stirring. A solution of 1-phenylheptane (14.3 g, 0.12 mole) in methylene chloride (50 ml) is then added over 20 minutes. The reaction mixture is heated under reflux (1 hour) and then poured into ice water (1 liter) with vigorous stirring. The mixture is extracted twice with ether (600 ml and 100 ml). The extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel (hexane/ether) to give 3-(4-n-heptylphenacyl)benzonitrile (7.6 g) as a White crystalline solid, m.p. 68° C. Then, 3-(4-n-heptylphenacyl)benzonitrile (1.5 g, 4.7 mole) is heated under reflux (1 hour) in a mixture of 75% aqueous sulfuric acid (12 g) and acetic acid (12 g). The reaction mixture is diluted with water (100 ml) and extracted with ether (2×75 ml). The ether extract is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting yellow solid is chromatographed on silica gel (hexane:ether:acetic acid; 60:40:1) and recrystallized from heptane to give 3-(4-n-heptylphenacyl)benzoic acid (1 g) as a pale yellow crystalline solid, 128°-133°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[NH:18][C:17](=[O:19])[O:16][N:15]=3)[CH:11]=[C:10]3[N:20]=[C:21]([CH:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[F:39])[OH:32])[N:22]([CH2:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]4)[C:9]=23)[CH:5]=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:22]([CH2:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]4)[C:21]([C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[F:39])=[O:32])=[N:20][C:10]=3[CH:11]=[C:12]([C:14]3[NH:18][C:17](=[O:19])[O:16][N:15]=3)[N:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(C(O)c3ccccc3F)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CC[C@H](Cn2c(C(=O)c3ccccc3F)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a room temperature slurry of 3-{4-(5-chloropyridin-3-yl)-2-[(2-fluorophenyl)(hydroxy)methyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-d]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (Example 7.4 in Table 7, 150 mg, 0.273 mmol) in dichloromethane (4 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (127 mg, 0.301 mmol). The mixture was stirred at room temperature for 1 hour during which time it became a homogeneous solution. Saturated aqueous sodium thiosulfate was added, and the resulting mixture was extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification via mass guided reverse phase HPLC (acetonitrile/water+0.1% TFA modifier) afforded 3-{4-(5-chloropyridin-3-yl)-2-[(2-fluorophenyl)carbonyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (TFA salt) as a white solid. MS ESI calcd. for C28H24ClFN6O3 [M+H]+ 547. found 547. 1H NMR (500 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.96 (s, 1H), 8.89 (s, 1H), 8.51 (s, 1H), 8.45 (s, 1H), 7.85-7.87 (m, 2H), 7.45-7.41 (m, 2H), 4.25 (d, J=6.5 Hz, 2H), 1.43-1.40 (m, 2H), 1.15-1.02 (m, 2H), 0.86-0.80 (m, 2H), 0.73-0.65 (m, 5H), 0.55-0.50 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:1][C:2]1[C:7]([NH:8][CH:19]2[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17][CH2:18]2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Nc1cncnc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cncnc2N)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4,5-diaminopyrimidine (1.0 g, 9.1 mmol), N-(t-butoxycarbonyl)-4-piperidone (3.0 g, 15 mmol) and sodium triacetoxyborohydride (1.2 g, 5.6 mmol) in dichloroethane (60 mL) was stirred at room temperature for 3 d. The reaction was partitioned between chloroform (200 mL) and 3N sodium hydroxide (30 mL). After drying over magnesium sulfate, the organic phase was concentrated to give the title compound as a tan gum. MS 294 (M+1).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([NH2:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH:5]1([N:15]=[C:1]=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: NC1CCCc2ccccc21
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: O=C=NC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a stirred solution of 242.4 grams (2.46 moles) of phosgene in 200 ml of toluene and 600 ml of benzene is slowly added a solution of 119.9 grams (0.814 mole) of 1,2,3,4-tetrahydro-1-naphthylamine, while maintaining the reaction temperature at 10°C. to 15°C. The mixture is stirred overnight at room temperature and then heated to reflux under a nitrogen atmosphere. After 4 hours reflux, most of the solvent is distilled from the reaction at atmospheric pressure. The residual solvent is evaporated at reduced pressure. The crude product is distilled to give 121.4 grams of product with boiling point 90°C. to 96°C. (0.3 mm).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[C:26]4[CH:34]=[C:33](Cl)[N:32]=[CH:31][C:27]=4[N:28]=[CH:29][N:30]=3)=[CH:21][CH:22]=2)[CH:17]=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CS(C)=O>[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[C:26]4[CH:34]=[C:33]([N:1]5[CH:5]=[CH:4][N:3]=[CH:2]5)[N:32]=[CH:31][C:27]=4[N:28]=[CH:29][N:30]=3)=[CH:21][CH:22]=2)[CH:17]=[N:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: Clc1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5cnc(-n6ccnc6)cc45)ccc32)cc1
Temperature: 120 °C
Reaction time: 168 h

Procedure:
Imidazole (0.8 g) in dry DMSO was treated with sodium hydride (60%, 0.47 g) and (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine in a reacti-vial and heated at 120° C. After 7 days, the mixture was poured onto water and extracted with ethyl acetate. Purification using a Bond Elute™ cartridge gave the title compound as a brown solid after trituration from water; δH [2H6]DMSO 10.28(1H,s), 9.25(1H,s), 8.90(1H,s), 8.78(1H,s), 8.67(1H,s), 8.40(1H,s), 8.30(1H,s), 8.10(1H,s), 7.88(2H,m), 7.40(5H,m), 5.70(2H,s); m/z (M+) 419.