Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=1)[CH:10]=[C:9]2[C:25]([O:27]C)=[O:26]>O1CCCC1>[C:25]([C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([Cl:5])[CH:7]=2)[N:11]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:10]=1)([OH:27])=[O:26]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(Cl)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccnc3ccccc23)c2ccc(Cl)cc12
Reaction time: 16 h
Yield: 87.9 %

Procedure:
0.42 g (15 mmol) of lithium hydroxide monohydrate and 50 cm3 of water are added to 1.13 g (3.35 mmol) of 5-chloro-3-methoxycarbonyl-1-(quinolin-4-yl)-1H-indole dissolved in 50 cm3 of tetrahydrofuran at a temperature in the region of 20° C. After stirring for 16 hours at the reflux temperature of the solvent, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 10 cm3 of 1N hydrochloric acid, the suspension is then filtered, and the solid residue is dried under atmospheric pressure at a temperature in the region of 60° C., giving 0.95 g of 3-carboxy-5-chloro-1-(quinolin-4-yl)-1H-indole in the form of a cream-colored solid, which is used directly in the following step.
Reaction SMILES: O.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1.[O-:28][C:29]#[N:30].[K+].C(O)C.C(O)(=O)C>O>[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:29]([NH2:30])=[O:28])=[CH:5][CH:6]=4)[C:19]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: NC(=O)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 20 °C

Procedure:
A mixture of 150 mg (0.391 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine hydrate (see Step 77.5), 95 mg (1.17 mmol) of potassium cyanate, 3 ml of ethanol, 3 ml of water and 0.0258 ml (0.451 mmol) of acetic acid is heated under reflux for 1 hour. After cooling to about 20° C., filtration and recrystallization of the filtration residue from methanol/water, 4-(3-chloro-phenylamino)-3-(4-{ureido-methyl}-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. >280° C.; FAB-MS: (M+H)+=409.
Reaction SMILES: C[O:2][C:3]1C=CC2C[C@H]3NCC[C@]45[C@H](C(CC[C@@]34O)=O)O[C:4]=1C=25.[CH3:23][N:24]1[C@@H:41]2[CH2:42][C:29]3[CH:30]=[CH:31][C:32]([O:44][CH3:45])=[C:33]4[O:34][C@H:35]5[C:36]([CH2:38][CH2:39][C@:40]2([OH:43])[C@:27]5([C:28]=34)[CH2:26][CH2:25]1)=[O:37].C(OC(=O)C)(=O)C>>[CH3:4][C:3]([O:43][C@@:40]12[C@H:41]3[CH2:42][C:29]4[CH:30]=[CH:31][C:32]([O:44][CH3:45])=[C:33]5[O:34][C@H:35]([C@@:27]1([C:28]=45)[CH2:26][CH2:25][N:24]3[CH3:23])[C:36](=[O:37])[CH2:38][CH2:39]2)=[O:2]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)NCC[C@]314
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@]4(OC(C)=O)[C@@H](C2)N(C)CC[C@]314

Procedure:
The noroxycodone used as starting material for Method II is prepared from oxycodone by the following steps: ##STR13## Oxycodone is refluxed with acetic anhydride to yield 14-acetyloxycodone. This product is reacted with cyanogen bromide to yield 14-acetyloxy-17-cyano-7,8-dihydronorcodone which is in turn converted to noroxycodone by reaction with hydrogen chloride. The oxycodone starting material is prepared according to M. Freund and E. Speyer, J. fur Praktische Chemie, 94, 135-137 (1916), the disclosure of which is hereby incorporated by reference.
Reaction SMILES: O[CH2:2][CH:3]1[C:20]2[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH:19]=2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C@@H:9]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[O:24])[CH2:8][CH2:7]3)[CH2:4]1>Cl.O1CCOCC1>[CH2:2]=[C:3]1[C:20]2[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH:19]=2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C@@H:9]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:28][CH:27]=2)=[O:24])[CH2:8][CH2:7]3)[CH2:4]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC(CO)C4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C=C1C[C@H]2[C@@H]3CC[C@H](C(=O)Nc4ccc(C(F)(F)F)cc4)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (17β)-6-(hydroxymethyl)-3-oxo-N-[4-(trifluoromethyl)phenyl]androst-4-ene-17-carboxamide (3-2 and 3-3) (0.57 g, 1.2 mmol) was dissolved in 15 mL 0.6N HCl in dioxane and stirred at rt. After 3 hr, it was diluted with a large excess of dioxane and stirred overnight. After removal of the solvent, the residue was dissolved in CHCl3 and washed with water, saturated NaHCO3 solution, and brine, then dried with MgSO4 and concentrated. The residue was purified by flash silica gel chromatography (0 to 50% EtOAc/hexane) to afford 3-4 as the desired product.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[BH4-].[Na+]>CO>[C:1]([NH:8][C@H:9]([CH2:14][OH:15])[CH2:10][CH:11]([CH3:12])[CH3:13])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
To a solution of BOC-leucinal (168 mg, 0.780 mmol) in methanol (2 ml) cooled to 0° C., was added sodium borohydride (30 mg, 0.780 mmol). After stirring 15 min, the reaction was complete by TLC. The methanol was removed in vacuo and the resulting residue slurried with water and extracted with ether (3×). The combined ethereal extracts were washed with saturated NaCl (aq) (2×), dried over MgSO4, and filtered. The filtrate was stripped to dryness in vacuo to give 130 mg of BOC-leucinol as a colorless oil with properties identical to those described above in Example 1, Step A.
Reaction SMILES: [OH:1][C:2]([C:7]1[NH:11][N:10]=[C:9]([C:12]2[N:13]=[CH:14][C:15]([O:27][CH3:28])=[C:16]3[C:20]([C:21](=[O:26])[C:22]([O:24]C)=[O:23])=[CH:19][NH:18][C:17]=23)[CH:8]=1)([CH2:5][CH3:6])[CH2:3][CH3:4].CO.C(=O)([O-])[O-].[K+].[K+].Cl>O>[OH:1][C:2]([C:7]1[NH:11][N:10]=[C:9]([C:12]2[N:13]=[CH:14][C:15]([O:27][CH3:28])=[C:16]3[C:20]([C:21](=[O:26])[C:22]([OH:24])=[O:23])=[CH:19][NH:18][C:17]=23)[CH:8]=1)([CH2:3][CH3:4])[CH2:5][CH3:6]
Reactant: CCC(O)(CC)c1cc(-c2ncc(OC)c3c(C(=O)C(=O)OC)c[nH]c23)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCC(O)(CC)c1cc(-c2ncc(OC)c3c(C(=O)C(=O)O)c[nH]c23)n[nH]1
Reaction time: 1 h

Procedure:
To a flask containing methyl 2-(7-(5-(3-hydroxypentan-3-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (0.066 g, 0.171 mmol) was added MeOH (1 mL) and Water (1 mL). To the mixture was added potassium carbonate (0.118 g, 0.854 mmol). After 1 h, the mixture was made acidic (pH=1) by adding 1N HCl. No precipitate formed, so the solvent was removed under reduced pressure. The crude mixture containing 2-(7-(5-(3-hydroxypentan-3-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid was carried forward to the next step with no further purification. LCMS: m/e 373.22 (M+H)+, ret time 1.723 min (method 4).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([O:18]C)=[N:5][C:6]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)=[N:7][CH:8]=1.[OH-].[Na+]>>[F:2][C:3]1[C:4]([OH:18])=[N:5][C:6]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)=[N:7][CH:8]=1
Reactant: COc1nc(-c2cnn3ccncc23)ncc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1nc(-c2cnn3ccncc23)ncc1F
Temperature: 25 °C
Yield: 72 %

Procedure:
Aqueous hydrogen chloride (13 mL of a 6N solution, 78 mmol) was added to 3-(5-fluoro-4-methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 17a, 0.38 g, 1 mmol) in a microwave vessel. The resulting mixture was subjected to microwave irradiation for 1 hour at 120° C. After cooling to room temperature, 8N aqueous sodium hydroxide solution was added until a basic pH was reached. The solid formed was filtered and dried to yield the title compound (72%), which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CO>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:22]=[CH:23][C:18]([C:17]#[C:16][C:4]3[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[C:2]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:3]=3)=[N:19][CH:20]=2)=[CH:25][CH:26]=1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)c(Br)c3)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)c(-c4ccccn4)c3)nc2)cc1

Procedure:
30 mg (0.24 mmol) pyridine-3-boric acid are added to a solution of 115 mg (0.24 mmol) 2-[3-bromo-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine (see Example 3.7), 0.5 mL (1.00 mmol) of a 2 M Na2CO3 solution and 15 mg (0.24 mmol) tetrakis-triphenylphosphane-palladium in 1 mL 1,4-dioxane and 0.3 mL methanol. The reaction mixture is refluxed for 6 h. After filtration the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH/NH3 1:1:0.1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:35])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[C:14]([O:33][CH3:34])[CH:13]=2)[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:35])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[C:14]([O:33][CH3:34])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCC(N2CCCCC2)CC1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCC(N2CCCCC2)CC1

Procedure:
Using 0.2 g of N-(trans-4-methylcyclohexyl)-4-[2-(4-piperidinopiperidino)ethoxy]-3-methoxycinnamamide (Example 162), 0.01 g of 10% palladium-carbon, and 30 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. As a result, 0.12 g of N-(trans-4-methylcyclohexyl)-3-{4-[2-(4-piperidinopiperidino)ethoxy]-3-methoxyphenyl}propionamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: C([Li])CCC.C(NC1CCCCC1)(C)C.C(=NC1CCCCC1)C.[CH:25]1([C:28](=[C:31]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)C=O)[CH2:27][CH2:26]1.[O:46]1C[CH2:49][CH2:48][CH2:47]1>>[CH:25]1([C:28](=[C:31]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)[CH:49]=[CH:48][CH:47]=[O:46])[CH2:26][CH2:27]1
Reactant: O=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CC1
Reactant: C1CCOC1
Agent: CC(C)NC1CCCCC1
Agent: CC=NC1CCCCC1
Agent: [Li]CCCC
Product: O=CC=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CC1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
Butyl lithium (2.9 mL of 1M solution, 6 mmol) was added to a solution of N-isopropylcyclohexylamine (0.85 g, 6 mmol) in 10 mL of tetrahydrofuran at -20° C. After stirring for 30 minutes and further cooling to -50° C., N-ethylidenecyclohexanamine (3 mL of 2M solution, 6 mmol) was added. After stirring for an additional 30 minutes and continued cooling to -70° C., 2-cyclopropyl-3,3-bis(4-fluorophenyl)-2-propenal (0.85 g, 2 mmol) was added. The mixture was stirred for 4 hours at -70° C. and quenched with saturated ammonium chloride. The mixture was extracted with diethyl ether. The diethyl ether was dried with magnesium sulfate and concentrated in vacuo. The residue was stirred for 16 hours with a mixture of 50 mL of benzene, 15 mL of acetic acid and 35 mL of water. The mixture was diluted to 250 mL with water and extracted with diethyl ether. The extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 0.38 g of the title compound; m.p. =139°-140° C.
Reaction SMILES: C(=[N:8][CH2:9][C:10]#[C:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)C1C=CC=CC=1.Cl>O>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:11]#[C:10][CH2:9][NH2:8]
Reactant: C(#Cc1cccs1)CN=Cc1ccccc1
Agent: Cl
Solvent: O
Product: NCC#Cc1cccs1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 6.8 %

Procedure:
To 17.7 g of this toluene solution, 36% hydrochloric acid (1.27 g, 12.5 mol) was added dropwise at 60° C. over 10 minutes, followed by stirring at 60° C. for 1.5 hours. Then, 4 g of water was added and the mixed solution was separated to obtain the aqueous phase and organic phase. The organic phase was extracted once with 2.5 g of water and the resulting aqueous phase was combined with the above aqueous phase. To this aqueous phase, 15 g of toluene was added and an aqueous 27% sodium hydroxide solution was added dropwise at 23° C. over 15 minutes, followed by stirring at 23° C. for 0.5 hours. After separating at the same temperature, the resulting organic phase was washed with 5 g of an aqueous saturated sodium chloride solution, concentrated and dried to obtain 3-(2-thienyl)-2-propynylamine (0.73 g, purity: 87%, yield: 77%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>O1CCCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)o2)cc1
Yield: 92.5 %

Procedure:
A mixture of methyl 4-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (0.800 g), 1 M aqueous sodium hydroxide solution (4.6 ml) and tetrahydrofuran (5 ml) was heated under reflux for 1.5 hrs. After cooling, 1 M hydrochloric acid was added to acidify the mixture. The crystals were collected by filtration to give 4-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]benzoic acid (0.71 g, yield 92%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: >300° C.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]2[C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)(C)(C)C.C(OCC)(=O)C>O1CCOCC1>[CH3:17][C:13]1[N:12]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=3)=[C:9]([NH2:8])[N:10]=[C:11]2[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc2nc(NC(=O)OC(C)(C)C)c(-c3cccc(C(F)(F)F)c3)n12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cccc2nc(N)c(-c3cccc(C(F)(F)F)c3)n12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4 M of Hydrogen chloride in 1,4-dioxane (0.8 mL) was added to [5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-yl]-carbamic acid tert-butyl ester (compound r, 0.14 g, 0.00036 mol). The mixture was stirred at room temperature for 2 hours. Solvent evaporated to give 0.1 g as a yellow oil. Rf 0.42, 100% ethyl acetate; MS m/z 292 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][C:24]([I:26])=[CH:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][C:24]([I:26])=[CH:25][C:16]=12
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: N#Cc1cnc2sc(I)cc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3sc(I)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (1.1 g, 5.7 mmol) and 60% sodium hydride (285 mg, 9.9 mmol) in 30 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 4-chloro-2-iodothieno[2,3-b]pyridine-5-carbonitrile (1.0 g, 3.12 mmol) is added. The reaction mixture is heated at reflux for 5 hours then allowed to stir at room temperature overnight. The resultant dark solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 0.5: 9.5 methanol:dichloromethane to provide 0.28 g of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-b]pyridine-5-carbonitrile as an off white solid, mp 231–233° C. An additional 0.09 g is obtained by chromatography of a mixture of unreacted starting material and product using a gradient of 9:1 to 1:1 hexane:ethyl acetate. 1H NMR (DMSO-d6) δ 3.87 (s, 3H), 7.36 (s, 1H), 7.76 (s, 1H), 8.11 (s, 1H), 8.39 (s, 1H), 9.76 (s, 1H); MS 473.8 (M−H)−.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:22][C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(CO)cc1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(COc2ccn(-c3ccc4nc(C5CC5)n(C)c4c3)c(=O)c2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 21.5 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (170 mg), (4-methylphenyl)methanol (148 mg) and tributylphosphine (454 μl) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (458 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (50 mg) as an off-white solid.
Reaction SMILES: [N:1]([C:4]1[N:8]([C@@H:9]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[CH2:10]2)[C:7]2[CH:17]=[C:18]([Cl:22])[C:19]([Cl:21])=[CH:20][C:6]=2[N:5]=1)=[N+]=[N-]>CCO>[NH2:1][C:4]1[N:8]([C@@H:9]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[CH2:10]2)[C:7]2[CH:17]=[C:18]([Cl:22])[C:19]([Cl:21])=[CH:20][C:6]=2[N:5]=1
Reactant: [N-]=[N+]=Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: CCO
Product: Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
A mixture of 110b (1.032 g, 3 mmol) and Ra-Nl (0.24 g, wet) in 30 mL of EtOH was hydrogenated (50 psi of H2) at room temperature for 6 hr. The reaction mixture was filtered and the filtrate was evaporated. The residue was suspended in 20 mL of MeCN and the suspension was filtered to give 0.856 g (90%, 2 crops) of 113 as a white solid. Analytical sample (as white needles) was obtained by recrystallization from MeOH/MeCN. MP: 216°-221° C. (dec.). MS: (El) m/e 317.0340 (37% M+ =317.0334). 1H NMR (DMSO-d6): d 7.71 (s, 1, 7-H), 7.29 (s, 1, 4-H), 6.93 (br s, 2, 2-NH2), 6.23 (dd, 1, 1 '-H, J1'-2' =8.5 Hz, J1'-2' =6.0 Hz), 5.40 (t, 1, 5'-OH, J5'-5'OH =4.5 Hz), 5.34 (d, 1, 3'-OH, J3'-3'OH=4.0 Hz), 4.40 (m, 1, 3'-H, J3'-2' =7.0 Hz, J3'-2" =2.0 Hz, J3'-4' =2.5 Hz), 3.82 (m, 1, 4'-H, J4'-5' =2.5 Hz), 3.68 (m, 2, 5'-H), 2.40 (m, 1, 2'-H, J2'-2' =13.0 Hz), 2.05 (m, 1, 2"-H). 13C NMR (DMSO-d6): d 155.65 (C2), 143.16 (C3a), 132.40 (C7a), 122.94, 119.77 (C5 and C6), 115.35 (C4), 110.69 (C7), 86.91 (C4'), 83.87 (C1'), 70.20 (C3'), 60.74 (C2'). Anal. Calcd. for C12 H13Cl2N3O3 : C, 45.30; H, 4.12; N, 13.21. Found: C, 45.44; H, 4.10; N, 13.28.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[CH2:12]([S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Sc1cccc(Br)c1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Brc1cccc(SCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-bromobenzenethiol (5 g, 26.44 mmol) was added to a solution of sodium methoxide (1.43 g, 26.48 mmol) in 20 ml of anhydrous methanol. The mixture was stirred for 30 min at room temperature and a solution of benzyl bromide (4.53 g, 26.48 mmol) in 20 ml anhydrous methanol was then added. The reaction mixture was stirred overnight at room temperature, poured into 2M o aqueous NaOH solution (40 ml) and extracted three times with ether (60 ml×3). The combined organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of solvent, the product was purified by distillation at 161° C., 0.3 mmHg and isolated in 85.5% (6.31 g) yield. 1H NMR (CDCl3, 500 MHz) δ ppm: 4.12 (s, 2H, CH2), 7.0-7.5 (m, 4H, Ar—H)GC-MS (relative intensity %): 278, 280 (1:1, 30.8, M+), 91(100, PhCH2+).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([I:16])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:35]([C:36]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1.C[O-].[Li+]>O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:16])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Agent: C[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(I)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 54.1 %

Procedure:
A mixture of 5.00 g of 2-butyl-6-iodo-4(1H)-quinazolinone, 16.98 g of 5-[4'-(bromomethyl)[1,1'-bi-phenyl]-2-yl]-1-(triphenylmethyl) -1H-tetrazole and 0.695 g of lithium methoxide in 60 ml of tetrahydrofuran is heated at reflux for 40 hours. The reaction mixture is cooled, filtered and concentrated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 1:9 ethyl acetate-hexanes to 1:5 ethyl acetate-hexanes to give 6.638 g of the desired product as a solid. FAB MASS SPEC 805 (M+H)
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([CH:7]([CH3:9])[CH3:8])=[N:4][C:3]=1[CH3:10].[O:11]1CCC(C=O)[CH2:12]1>>[I:1][C:2]1[NH:6][C:5]([CH:7]2[CH2:9][CH2:12][O:11][CH2:8]2)=[N:4][C:3]=1[CH3:10]
Reactant: Cc1nc(C(C)C)[nH]c1I
Reactant: O=CC1CCOC1
Product: Cc1nc(C2CCOC2)[nH]c1I

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 159.2, except tetrahydrofuran-3-carbaldehyde was used in place of isobutyraldehyde.