Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:22][CH2:23][C:24]([OH:26])=[O:25].[OH-].[Na+].Cl>CC(C)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5]
Reactant: NCC(=O)O
Reactant: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)Cl)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)NCC(=O)O)c2)C1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2-Chloro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoyl chloride (2.4 g.) and glycine (525 mg.) are dissolved in 30 ml. of water, 30 ml. of acetone and 14 ml. of 1 N sodium hydroxide. After stirring at room temperature for about 25 minutes, the reaction mixture is acidified with concentrated hydrochloric acid. The precipitated material is recrystallized from acetone (25 ml.)-hexane (40 ml.) to yield the product, m.p. 189.5°-191.5° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)(=O)C.[CH2:15](N)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOC(C)=O>[Cl:1][CH2:2][C:3](=[O:10])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NCc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CC1CCCCC1)C(=O)CCl
Reaction time: 24 h

Procedure:
A mixture of ethyl 4-chloro-3-oxo-butanoate (57.3 ml) , cyclohexylaldehyde (53.65 ml ) , acetic acid (2.75 ml) and benzylamine (4.38 ml) is kept for 24 hours at room temperature, then it is diluted with 150 ml of AcOEt and washed with 100 ml of water, then with a NaH2PO4 saturated solution. Solvent is evaporated off to obtain 108.43 g of 4-chloro-3-oxo-2-ethoxycarbonyl-1-cyclohexylbut-1-ene.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10](I)=[N:9]1)=O)(C)(C)C.[C:26]1(/[CH:32]=[CH:33]/B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][N:9]=[C:10]2/[CH:33]=[CH:32]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(OCc3ccccc3)ccc21
Reactant: OB(O)/C=C/c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(=C/c1n[nH]c2ccc(OCc3ccccc3)cc12)\c1ccccc1
Yield: 69 %

Procedure:
The compound, 5-benzyloxy-3-((E)-styryl)-1H-indazole is prepared according to procedure C, step Ib, using 300 mg of 5-benzyloxy-3-iodoindazole-1-carboxylic acid tert-butyl ester, 197 mg of E-phenylethenyl boronic acid, 192 mg of palladium tetrakistriphenylphosphine in suspension in 12 ml of dimethylformamide and 0.61 ml of a saturated sodium bicarbonate solution. The resulting crude product is treated as described hereinabove to obtain 150 mg of 5-benzyloxy-3-((E)-styryl)-1H-indazole.
Reaction SMILES: C([Li])CCC.[C:6]([NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([CH3:9])([CH3:8])[CH3:7].[C:20]([N:39]1[CH:43]=[C:42]([CH2:44][CH2:45][CH:46]=[O:47])[N:41]=[CH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.O1CCCC1>[C:6]([NH:10][C:11]([C:12]1[CH:17]=[CH:16][C:15]([CH:46]([OH:47])[CH2:45][CH2:44][C:42]2[N:41]=[CH:40][N:39]([C:20]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:43]=2)=[CH:14][CH:13]=1)=[O:19])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Reactant: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(C(O)CCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 25 mmoles of n-butyllithium in 10 ml of hexane is added dropwise to a solution of 3.19 g of N-tert-butyl 4-bromobenzamide in 250 ml of tetrahydrofuran at -70° under argon. After 30 min, a solution of 3.74 g of 3-(1-tritylimidazol-4-yl)propionaldehyde in 100 ml of tetrahydrofuran is added slowly. The reaction mixture is stirred at -70° for 30 min, allowed to warm to 25°, stirred at 25° for 2.5 h and quenched with excess saturated ammonium chloride solution. The aqueous layer is separated and extracted with methylene chloride (2×100 ml). The combined organic extracts are dried over sodium sulfate and evaporated. The residue is chromatographed on 220 g of silica with 5:1 ether:ethyl acetate to yield 4-[3-(4-tert-butylaminocarbonylphenyl)-3-hydroxyprop-1-yl]-1-tritylimidazole as an oil. IR (CH2Cl2): 1660 cm-1.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]([NH2:10])=[O:9].[CH3:11][O:12][C:13]([CH3:17])([CH3:16])[CH:14]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH3:11][O:12][C:13]([CH3:17])([CH3:16])[CH2:14][NH:2][C:3]1[N:7]=[CH:6][NH:5][C:4]=1[C:8]([NH2:10])=[O:9]
Reactant: NC(=O)c1nc[nH]c1N
Reactant: COC(C)(C)C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(C)(C)CNc1nc[nH]c1C(N)=O
Reaction time: 0.5 h
Yield: 73 %

Procedure:
5-Amino-4-imidazolecarboxamide hydrochloride (0.162 g, 1.0 mmol) and 2-methoxy-2-methylpropanal, which was obtained from Example 3(a) (0.204 g, 2.0 mmol) were mixed in methanol (3 mL) at r.t. Acetic acid (141 μL, 2.46 mmol) mL) was then added and the mixture was allowed to stir for 30 min followed by addition of NaCNBH3 (0.063 g, 1.0 mmol). After 3 h, additional 2-methoxy-2-methylpropanal (0.060 g, 0.59 mmol) was added. The reaction mixture was stirred at r.t. for 17 h and was then concentrated and purified by flash silica gel chromatography (CHCl3:MeOH=5:1). The title compound was obtained as an oil in 73% yield (0.155 g). MS (ESI) m/z 213 (M+1).
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35].C([N:39](C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:39])=[O:28])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
To a mixture of 0.05 g (0.10 mmole) of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-281), 0.07 mL (0.4 mmole) of ethyldiisopropyl amine and 0.011 g (0.20 mmole) of ammonium chloride in 2.0 mL of dimethylformamide was added 0.048 g (0.11 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.011 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzamide (I-283) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]2[CH:22]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:24]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:30](=[O:31])[CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[CH:17][N:16]2[CH:22]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(N)ccc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(NC(=O)Cc3cccnc3)ccc2n1
Yield: 42 %

Procedure:
As described for Example 56, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-6-ylamine (96 mg, 0.33 mmol) was converted, using 3-pyridylacetic acid instead of cyclopropylacetic acid, to the title compound (26 mg, 42%) which was obtained as a light brown solid. MS: m/e=410.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:21]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[O:28])[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Reactant: O=C(O)c1cccnc1
Product: CC(C)(C)c1ccc(Cn2cnc(NC(=O)c3cccnc3)c2C(N)=O)cc1
Yield: 70 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 1.50 g (5.51 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 57 and nicotinic acid instead of cyclopentyl acetic acid to obtain 1.45 g of 1-(4-t-butylbenzyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 70%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][N:2]2[CH2:8][CH2:9][O:10][C:11]1[CH:43]=[CH:42][C:14]([C:15]([C:17]2[C:18]3[CH:36]=[CH:35][C:34]([O:37]S(C)(=O)=O)=[CH:33][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28]S(C)(=O)=O)=[CH:24][CH:23]=2)=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][N:2]2[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([C:17]2[C:18]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[O:16])=[CH:42][CH:43]=1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CC4CCC3C4)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(c1ccc(OCCN2CC3CCC2C3)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12

Procedure:
A solution of the product from Step 5 (111 mg, 0.17 mmol) and potassium carbonate (7.5 equiv.) in 10 mL of methanol was heated at 50° C. for 48 hrs. The mixture was concentrated to a solid. This solid was chromatographed on silica gel using 1% MeOH/methylene chloride to 20% MeOH/methylene chloride as the gradient eluant to yield the desired product which was then made into the its hydrochloride salt with hydrogen chloride in dioxane.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][C:6]#[C:7][OH:8])([CH3:4])[CH3:3].CCN(CC)CC.[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>CCOCC>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][CH2:7][O:8][C:16](=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)Cl
Reactant: C[Si](C)(C)CC#CO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C)C(=O)OCC#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of trimethylsilyl propyn-1-ol (1 g, 7.8 mmol) and Et3N (1.4 mL, 10 mmol) in Et2O (10 mL) is cooled to −20° C. and a solution of methacryloyl chloride (0.9 mL, 9.3 mmol) in Et2O (5 mL) is added dropwise over 1 h. The mixture is stirred at this temperature for 30 min, and then allowed to warm to ambient temperature overnight. Any precipitated ammonium salts can be removed by filtration, and volatile components can be removed under reduced pressure. The crude product is then purified by flash chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([CH2:16][NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:10]2)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([CH2:16][NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:10]2)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
387 mg (1.00 mmol) of ethyl-trans-3-[2-[(4chlorophenyl)sulfonylaminomethyl]indan-5-yl]acrylate was dissolved in 10 ml of ethanol, to which was added 24 mg (0.1 mmol)of nickel chloride·6H2O. Under ice-cooling, to this solution was added 76 mg (2.00 mmol) of sodium borohydride, followed by stirring at room temperature overnight. The ethanol was distilled off, the residue was added with 10 ml of water, and the obtained product was extracted with ethyl acetate, followed by washing and drying then condensing. The obtained crystals were recrystallized from a solvent mixture of hexane and ether to obtain 241 mg colorless crystals. Yield: 62%
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11]([NH:12][C:13](=[O:21])[CH2:14][CH2:15]1)=[CH:10][C:9]3=[O:22].C([N-]C(C)C)(C)C.[Li+].[CH3:31][Si:32](Cl)([CH3:34])[CH3:33]>C1COCC1>[CH3:31][Si:32]([CH3:34])([CH3:33])[O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11]([N:12]([Si:32]([CH3:34])([CH3:33])[CH3:31])[C:13](=[O:21])[CH2:14][CH2:15]1)=[CH:10][C:9]3=[O:22]
Reactant: C[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H]3[C@@H](C(=O)C=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](C(=O)C=C4N([Si](C)(C)C)C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
17β-Hydroxy-4-aza-androst-5-ene-3,7-dione (40.000 g, 131.84 mmol) prepared in Example 18A or otherwise obtained is prepared in solution at −78° C. in dry THF (300 mL). Lithium diisopropylamide solution (2.0 M in heptane/THF/ethylbenzene; 135.0 mL, 270.0 mmol) is added under an inert atmosphere and the deprotonation reaction occurs while stirring at −78° C. over 60 minutes. Trimethylsilyl chloride (35.00 mL, 275.8 mmol) is added, and stirring is continued for an additional 15 minutes and then the solution is allowed to warm to room temperature. After stirring an additional 2 hours, the reaction mixture is filtered through Celite® and the filtrate is evaporated to dryness. The residue is redissolved in ether (500 mL) and the resultant slurry is filtered again through Celite®. The solvent is evaporated to give the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:18][S@](C(C)(C)C)=O)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1)(C(C)(C)C)(C)C.[ClH:25]>CO.O>[ClH:25].[ClH:25].[NH2:18][C@@H:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1)[CH2:9][OH:8]
Reactant: CC(C)(C)[S@](=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)cn1
Agent: Cl
Solvent: CO
Solvent: O
Product: N[C@H](CO)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (S)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (16 g, 43 mmol) in methanol (300 mL) was added hydrogen chloride (53 mL, 210 mmol) (4M in dioxanes) and the reaction stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and the material taken up in water (200 mL) and washed with dichloromethane (200 mL) to give (S)-2-amino-2-(5-fluoropyridin-2-yl)ethanol bis-hydrochloride (9.8 g, 43 mmol) as a solution in water. The solution was used crude in the next reaction.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH:39]=2)[C:34]([O:36][CH2:37][CH3:38])=[O:35])O1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:12]([NH:11][C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:39]=2)=[C:3]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=2)[CH:4]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCNC(=O)Nc1cc(-c2cncc(F)c2)c(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCNC(=O)Nc1cc(-c2cncc(F)c2)c(-c2cncc(C(=O)OCC)c2)cn1
Temperature: 100 °C
Yield: 46.4 %

Procedure:
N-(5′-bromo-5-fluoro-3,4′-bipyridin-2′-yl)-N′-ethylurea (Intermediate 30, 0.34 g, 1.00 mmol), ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (Oakwood Products, Inc., Cat. #021607) (0.306 g, 1.10 mmol), tetrakis triphenyl phosphine palladium (0.058 g, 0.05 mmol), and cesium carbonate (0.359 g, 1.10 mmol) were added to a microwave vial and degassed with nitrogen. A solution of 1,4-dioxane:water (4:1, 10 mL) was added to the solution and the reaction mixture was heated to 100° C. for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate solution, water, and brine, then dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel chromatography, eluting with (0-100% EtOAc/hexanes) to give the title compound as a white solid (190 mg). MS (ESP): 410 (MH+) for C21H20FN5O3;
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:11][C:12]#[N:13]>>[C:1]1([N:7]2[C:12]([NH2:13])=[CH:11][C:10]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCC(=O)c1cccs1
Reactant: NNc1ccccc1
Product: Nc1cc(-c2cccs2)nn1-c1ccccc1

Procedure:
Phenyl hydrazine and 3-oxo-3-(thiophen-2-yl)propanenitrile were combined according to literature procedures to yield 1-phenyl-3-(thiophen-2-yl)-1H-pyrazol-5-amine. See WO 2006/071940.
Reaction SMILES: [NH2:1][C:2]1[C:9](C)=[CH:8][C:7]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].[CH3:19]O>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:19]
Reactant: Cc1cn(-c2cc(C)c(N)c(C=O)c2)cn1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cn(-c2ccc(N)c(C(C)O)c2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
2-amino-3-methyl-5-(4-methylimidazol-1-yl)benzaldehyde (57 mg) was dissolved in methanol (1 ml) and sodiumborohydride (40 mg) was added thereto at 0° C. The mixture was stirred at room temperature for 6 hours and was distilled under reduced pressure to remove solvent. To the residue was added water. The mixture was extracted with chloroform. The extract was dried with Na2SO4 and distilled to give 34 mg (59%) of the title compound.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[H-].[Na+].Br[CH2:14][C:15]1[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C:17](=[O:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25]>CN(C=O)C>[NH2:10][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[N:7]=[CH:6][N:5]2[CH2:14][C:15]1[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C:17](=[O:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25]
Reactant: Nc1ncnc2[nH]cnc12
Reactant: Cc1ccccc1-n1c(CBr)cc2cccc(C)c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1c(Cn2cnc3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
9H-Purin-6-amine (1901) (540 mg, 4.0 mmol) was dissolved in anhydrous DMF (20 mL). NaH (60% in mineral oil, 160 mg, 4.0 mmol) was added and the resulting mixture was stirred at RT for 30 min. 3-(Bromomethyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1607) (1.37 g, 4.0 mmol) was added. The reaction mixture was stirred at RT for 30 min, poured into ice-water (30 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (25 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (2-20% MeOH/DCM) to afford the desired product, 3-((6-amino-9H-purin-9-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1902) (1.1 g, 70% yield) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:19]C(=O)OC(C)(C)C)[S:9][C:10]=1[C:11]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12]>FC(F)(F)C(O)=O>[NH2:19][C:8]1[S:9][C:10]([C:11]([CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[O:12])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
tert-Butyl N-[4-(2-furyl)-5-(tetrahydropyran-4-ylcarbonyl)thiazole-2-yl]carbamate (350 mg, 0.93 mmol) obtained in Step 2 was dissolved in trifluoroacetic acid (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and saturated sodium bicarbonate aqueous solution were added thereto, then the mixture was extracted. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to give a title compound (212 mg, 72%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[NH:17][C:18](=[S:21])[NH:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]([S:21][CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2c[nH]c(=S)[nH]2)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Sc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c[nH]1
Yield: 39.7 %

Procedure:
By following the same procedure as in Example 10 using 1.8 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thioxo-4-imidazoline, 30 ml of dry acetone, 0.99 g of potassium carbonate, and 1.3 g of ethyl α-bromopropionate and recrystallizing the product from a mixture of toluene and cyclohexane, 0.95 g of ethyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-imidazolylthio]propionate was obtained.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]([CH3:21])=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)C=C(C)c1cc(F)c2cc(OC)ccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)c1cc(F)c2cc(OC)ccc2c1

Procedure:
Ethyl 3-(4-fluoro-6-methoxy-2-naphthyl)-but-2-enoate (12 g) was dissolved in ethyl acetate (100 ml) and 5% palladium on charcoal (1.5 g) was added. The mixture was shaken under a hydrogen atmosphere until uptake of hydrogen ceased (ca. 1 hour). The catalyst was removed by filtration through a celite bed and the solvent was removed under reduced pressure to give ethyl 3-(4-fluoro-6-methoxy-2-naphthyl)-butanoate as an oil (11.9 g., 98%).