Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=4)=[CH:20][C:15]=3[O:14][N:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:31][NH2:32]>C1COCC1.O.CCOC(C)=O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:32][CH3:31])[N:23]=4)=[CH:20][C:15]=3[O:14][N:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1noc2cc(Oc3ccnc(Cl)n3)ccc12
Reactant: CN
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CNc1nccc(Oc2ccc3c(C(=O)Nc4cccc(C(F)(F)F)c4)noc3c2)n1
Reaction time: 20 h

Procedure:
50 mg (0.115 mMol) 6-(2-chloro-pyrimidin-4-yloxy)-benzo[d]isoxazole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide are dissolved in 5 ml THF. Then 250 μl methylamine (2 M in THF; 0.50 mMol) are added and the solution is stirred in a sealed tube for 20 h. The mixture is diluted with water and EtOAc, the aq. layer separated off and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (reversed phase; Gilson) gives the title compound: MS: [M+1]+=430; HPLC: tRet=14.0.
Reaction SMILES: C1[C@H](N)[C@@H]([O:8][C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2N)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)[C@@H](O)[C@@H]1N.FC(F)(F)C([O-])=O.[CH:39]1([N:45]=[C:46]=[N:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2N)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)[C@@H](O)[C@@H]1N.C(O)(=O)C>O1CCCC1.CN(C)C=O>[C:46]([NH:45][CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)([NH:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)=[O:8]
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)[C@@H](O)[C@H](N)C[C@@H]2N)[C@H](N)[C@@H](O)[C@@H]1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
2 g of the ribostamycin trifluoroacetate prepared in the same manner as in Example 1 was taken and dissolved in 35 ml of a liquid mixture of tetrahydrofuran and dimethylformamide (10:1 by volume). This solution was admixed with a solution of 1.74 g of (S)-α-hydroxy-δ-N-phthalimido-n-valeric acid in 16 ml of tetrahydrofuran. A solution of 3.62 g of dicyclohexylcarbodiimide in 16 ml of tetrahydrofuran was added thereto under ice-cooling. The mixture was agitated for 30 minutes under ice-cooling and agitated at ambient temperature for 1 hour 25 minutes to effect the esterification of the hydroxyl groups of the ribostamycin with the substituted valeric acid. The reaction mixture was admixed with 0.8 ml of glacial acetic acid and allowed to stand at ambient temperature overnight to decompose the excess of dicyclohexylcarbodiimide. The dicylcohexylurea by-produced which precipitated was removed by filtration. The filtrate was concentrated to give a solid comprising mixed trifluoroacetic acid salts of O-((S)-α-hydroxy-δ-N-phthalimido-n-valeryl)-ribostamycins.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[O:24]=[C:25]1[CH2:29][S:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=[O:37])[CH2:32][CH2:31]2)=[N:26]1>>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:29]4[S:28][C:27]([N:30]5[CH2:31][CH2:32][CH:33]([C:36]([OH:38])=[O:37])[CH2:34][CH2:35]5)=[N:26][C:25]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:21])([F:23])[F:22])[CH:3]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(F)cc2C(F)(F)F)c1
Reactant: O=C1CSC(N2CCC(C(=O)O)CC2)=N1
Product: O=C1N=C(N2CCC(C(=O)O)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(F)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic acid was prepared from 1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and 1-(4-Oxo-4,5-dihydro-thiazol-2-yl)piperidine-4-carboxylic acid following General Procedure E.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]2)=[N:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([F:32])[CH:25]=1.[C:33]([CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)#[CH:34].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CC#N.CC#N.Cl[Pd]Cl>[C:19]([O:18][C:17](=[O:23])[NH:16][CH:13]1[CH2:14][CH2:15][N:10]([C:5]2[N:6]([CH3:9])[C:7](=[O:8])[C:2]([C:34]#[C:33][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:3]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([F:32])[CH:25]=3)[N:4]=2)[CH2:11][CH2:12]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: C#CC1CCCC1
Reactant: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(Cl)c1=O
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(C#CC2CCCC2)c1=O
Temperature: 95 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A mixture of tert-butyl 1-(5-chloro-4-(3-fluoro-4-cyanophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-ylcarbamate (200 mg, 0.43 mmol), ethynyl-cyclopentane (82 mg, 0.87 mmol), Pd(MeCN)2Cl2 (4.5 mg, 0.017 mmol), X-Phos (10 mg, 0.022 mmol) and K2CO3 (120 mg, 0.87 mmol) in ACN (15 mL) was stirred overnight at 95° C. in a sealed tube. The reaction mixture was cooled to RT and the solvent was concentrated in vacuo. The residue was purified by silica chromatography (1:2, EA:PE) to give 100 mg (45%) of the title compound. [M+H] Calc'd for C29H34FN5O3, 519. Found, 519.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[CH3:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=4)[N:22]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Cc1cccc(N2CCNCC2)c1
Agent: Cl
Product: Cc1cccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
A mixture of 1-(3-methylphenyl)piperazine dihydrochloride and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 4. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(3-methylphenyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])=[CH:3]1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@:4]3([O:30][C@H:5]3[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1
Reactant: C[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Reaction time: 0.5 h
Yield: 47115.7 %

Procedure:
To a stirred solution of 3β-hydroxyandrost-4-en-17-one (0.81 g) in CH2Cl2 (7.4 mL) cooled at 0° C., a solution of mCPBA (0.77 mg) in CH2Cl2 (13.6 mL) was added dropwise. After 0.5 h at 0° C. and 0.5 h at room temperature, a 10% aqueous solution of Na2SO3 was added. The mixture was neutralized by addition of 5% NaHCO3 solution and extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with H2O, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 60/20/20) to give 3β-hydroxy-5α,6α-epoxyandrostane-17-one (0.64 g, 75%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.62 (1H, d), 3.52 (1H, m), 2.87 (1H, d), 2.44-0.56 (19H, m), 1.00 (3H, s), 0.72 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]CC)=[O:12])=[CH:7]2.[OH-].[K+].Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2c(OC)ccc(F)c2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c2[nH]c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.3 %

Procedure:
To a solution of ethyl 7-fluoro-4-methoxy-1H-indole-2-carboxylate (1.00 g, 4.22 mmol) in ethanol was added KOH (473 mg, 8.43 mmol). The reaction was stirred at room temperature for 12 hours, cooled to 0° C. and acidified with 1 N HCl. The mixture was extracted with EtOAc and CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford the title compound (550 mg, 62%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C:5](=[O:7])[CH2:4][C@@H:3]1[CH2:8][C:9]([CH3:18])([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[C:5]([CH2:4][C@H:3]1[C:2]([CH3:19])([CH3:1])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[C:9]([CH3:18])([CH3:10])[CH2:8]1)([OH:6])=[O:7]
Reactant: Cc1ccc(C(C)(C)C[C@H]2CC(=O)OC2(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(C)(C)[C@H](CC(=O)O)CC2(C)C
Yield: 95 %

Procedure:
To a solution of (S)-5,5-dimethyl-4-(2-methyl-2-p-tolylpropyl)-tetrahydro-2-furanone (100 mg) in toluene (10 ml), anhydrous aluminum chloride (130 mg) was added, and the resultant mixture was stirred at 70° C. for 30 minutes. The reaction mixture was washed with dilute hydrochloric acid, dried and concentrated to give (S)-3-carboxymethyl-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (95 mg).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCCCC1.C(OCC)C.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(OCC)C>O>[C:1]1([C:27]2[N:26]=[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: c1ccc(-c2ccccn2)nc1
Solvent: CCOCC
Solvent: O
Solvent: C1CCCCC1
Product: c1ccc(-c2cccc(-c3ccccn3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A solution of phenyllithium.cyclohexane/diethyl ether (40.9 ml, 38.4 mmol) was dropwise added to a mixture of 2,2′-bipyridine (5.0 g, 32.0 mmol) and diethyl ether (50 ml) at 5° C. while 15 minutes. This reaction mixture was stirred at room temperature for 2 hours, then the mixture was poured into water, an organic layer was separated from the mixture, furthermore an aqueous layer was extracted with dichloromethane. The organic layer was combined, and the solvent was distilled off, and the residue was diluted with acetone (50 ml), then saturated potassium permanganate acetone solution (120 ml) was added thereto, the mixture was stirred at room temperature for 1 hour. The obtained reaction mixture was filtered by Celite, the solvent of the filtrate was distilled off, and the residue was purified by silica gel column chromatography and recrystallization, thereby obtaining 4.2 g of 6-phenyl-2,2′-bipyridine as white crystal. Yield: 55.4%.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[N:12][C:11]=2[Cl:17])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][O:27][CH2:28][C:29](O)=[O:30].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:17][C:11]1[N:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:9]([NH:8][C@H:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:29](=[O:30])[CH2:28][O:27][CH3:26])[CH2:3][CH2:4]1)=[O:18]
Reactant: N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Cl)CC1
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
N-(cis-4-Aminocyclohexyl)-2-chloro-5-fluoronicotinamide (837 mg, 2.72 mmol) and triethylamine (1.14 ml, 8.15 mmol) were dissolved in dimethylformamide (20 ml) and 2-methoxy acetic acid (208 μl, 2.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (573 mg, 2.99 mmol) and 1-hydroxybenzotriazole (404 mg, 2.99 mmol) were added. The reaction was stirred under nitrogen at room temperature for 18 h then partitioned between water and ethyl acetate. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting using dichloromethane:methanol (96:4 to 91:9) as eluant to give 2-chloro-5-fluoro-N-{cis-4-[(methoxyacetyl)amino]cyclohexyl}nicotinamide (550 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:30])=[C:25](B(O)O)[CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=[CH:25][C:24]=3[CH3:30])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ccc(C)c(B(O)O)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)ccc3C)cccc2c1N
Yield: 73.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 5-methoxy-2-methyl-phenylboronic acid (125 mg, 1.000 mmol) were reacted to afford the title compound (125 mg, 73% yield). 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.88 (m, 1H), 7.76-7.64 (m, 2H), 7.21 (m, 1H), 6.92-6.81 (m, 2H), 3.79 (s, 3H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.97 (s, 3H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=351 (M+H). HPLC 1.77 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[CH3:18])[CH2:13][CH3:14]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCCC1(C(=O)OCC)CCCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1(C(=O)OCC)CCCC1OC(=O)c1ccccc1C
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-n-propyl-cyclopentane carboxylate (6.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.66 ml) was slowly added, then 2-methyl-benzoyl chloride (5.95 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 9.61 g of yellow liquid. MS: m/e 319(M+′+1), 318(M+′), 273, 259, 199, 183, 153, 119(base), 91, 77.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[CH:11][C:12]([OH:14])=[O:13]>CC(O)=O.[Zn]>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)C=C1Cc2ccccc2C1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(O)CC1Cc2ccccc2C1=O
Yield: 83.2 %

Procedure:
To a solution of 1.9 g (0.031 mol) of zinc dust suspended in 10 mL of HOAc was added 2.3 g (0.012 mol) of the product from Step A. The reaction mixture was refluxed for 1 hour, cooled, filtered and rinsed with acetic acid. The acetic acid solution was poured into 200 mL of H2O and extracted with ethyl acetate (3×50 mL), washed with H2O (2×50 mL), dried over anhydrous magensium sulfate, filtered and concentrated under vacuum to afford 1.9 g of a yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:16])[NH:6][CH:7]=[N:8]2>CO.[Pt]=O>[NH2:13][C:12]1[C:3]([NH:2][CH3:1])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:16]
Reactant: CNc1c([N+](=O)[O-])ccc2nc[nH]c(=O)c12
Agent: O=[Pt]
Solvent: CO
Product: CNc1c(N)ccc2nc[nH]c(=O)c12

Procedure:
The above amine (350 mg, 1.6 mmol) was hydrogenated over platinum oxide (30 mg) in MeOH (200 mL) at 60 psi for 4 h. The mixture was filtered through diatomaceous earth and the solvent evaporated, to give 6-amino-5-methylaminoquinazolin-4-one, which was immediately suspended in EtOAc (20 mL) and THF (10 mL). A solution of 2,6-dichlorophenylisothiocyanate (340 mg, 1.67 mmol) in EtOAc (5 mL) was added, and the mixture stirred for 16 h. The reaction mixture was concentrated to half the volume, filtered, and the solid washed with EtOAc to yield the thiourea (400 mg, 64% over 2 steps.)
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([C:21]([OH:26])=[CH:22][C:23]=2[O:24][CH3:25])[CH:19]=[O:20])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:27]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([C:21]([O:26][CH3:27])=[CH:22][C:23]=2[O:24][CH3:25])[CH:19]=[O:20])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: COc1cc(O)c(C=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)c(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.1 %

Procedure:
To a solution of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehyde (1.04 g, 2.95 mmol) in acetone (20 mL) was added dimethylsulfate (0.37 mL, 3.84 mmol) and potassium carbonate (490 mg, 3.55 mmol). The reaction mixture was stirred at room temperature for 15 hours and extracted with ethyl acetate (2×50 mL). The organic extracts were successively washed with water (100 mL) and a saturated aqueous solution of NaCl (100 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzaldehyde (1.05 g, 97%).
Reaction SMILES: C(C1C=CC(C[S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=CC=1)C.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1>>[F:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[F:33])[CH2:26][S:8][C:9]1[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=1
Reactant: Fc1ccc(CCl)cc1F
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Product: COCOc1cc(SCc2ccc(F)c(F)c2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 1-(chloromethyl)-3,4-difluorobenzene instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14]([C@@H:16]2[C@@H:20]([OH:21])[CH2:19][CH2:18][NH:17]2)=[O:15])=[CH:5][CH:4]=1)#[N:2].[CH:22](=O)[C:23]([CH3:26])([CH3:25])[CH3:24].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1.CCCCC>[C:23]([C@@H:26]1[N:17]2[CH2:18][CH2:19][C@H:20]([OH:21])[C@H:16]2[C:14](=[O:15])[N:13]1[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:25])([CH3:24])[CH3:22]
Reactant: CC(C)(C)C=O
Reactant: N#Cc1ccc(NC(=O)[C@H]2NCC[C@@H]2O)c2ccccc12
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Solvent: CCCCC
Product: CC(C)(C)[C@H]1N(c2ccc(C#N)c3ccccc23)C(=O)[C@@H]2[C@@H](O)CCN21
Yield: 81.8 %

Procedure:
A suspension of 30D (40 mg, 0.14 mmol) and pivalaldehyde (30 μl, 0.27 mmol) in a mixture of dry benzene (0.5 ml) and dry pentane (5.0 ml) was refluxed for 20 hr with a Dean-Starke receiver, after which additional pivalaldehyde (30 μl, 0.27 mmol), dry benzene (0.5 ml) and catalytic toluenesulfonic acid was added (Ref: Org. Lett. 2 (18) 2781-2783, (2000)). The reaction mixture was refluxed for another 25 hr, evaporated to dryness and dried in vacuo. Purification using automated flash chromatography (10 g silica gel column, EtOAc/hexane gradient) gave the title compound (single diastereoisomer) as a white foam (40 mg, 81.8%). MS (ES): m/z 350 [M+1]+.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([N:22](CCO)[CH2:23][CH2:24][NH:25][C:26](=O)OC(C)(C)C)[CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[O:36]1CCOC[CH2:37]1>Cl>[ClH:21].[ClH:21].[C:1]12([CH2:11][NH:12][C:13](=[O:14])[C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([NH:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:37][OH:36])[CH:16]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)NCCN(CCO)c1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Reactant: C1COCCO1
Agent: Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCNCCO)ncc1Cl
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-[(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)(2-hydroxyethyl)amino]ethylcarbamate (Example 13(i)) (0.013 g) was dissolved in anhydrous hydrogen chloride in 1,4-dioxane (4M, 2 ml) and the resulting mixture was allowed to stand at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to afford the titled product (0.020 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.[F-].[Cs+]>O1CCOCC1.O.CCOC(C)=O.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]>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[C:3]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:19]4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]3[CH3:14])[N:7]=2)=[CH:38][N:39]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)c2c(n1)N(C1CN(C(=O)OC(C)(C)C)C1)CC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N(C1CN(C(=O)OC(C)(C)C)C1)CC2
Yield: 100 %

Procedure:
To a stirred mixture of tert-butyl 3-{4-chloro-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}azetidine-1-carboxylate (8.33 g, 20.32 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (9.88 g, 44.7 mmol) and CsF (9.26 g, 61 mmol) in 1,4-dioxane (250 mL) and water (50 mL) was added Pd(dppf)2Cl2 (2.23 g, 3.05 mmol) under nitrogen. The mixture was heated under reflux for 18 h. The mixture was diluted with EtOAc (300 mL) and washed with water (300 mL), brine (300 mL×2), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of petroleum ether/EtOAc (from 1:1 to 0:1) to give 9.52 g (100%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 2 H), 6.97 (s, 2 H), 4.75-4.67 (m, 1 H), 4.63-4.56 (m, 1 H), 4.26-4.13 (m, 3 H), 4.08-4.00 (m, 2 H), 3.90-3.84 (m, 1 H), 3.71-3.64 (m, 3 H), 3.56 (dd, J=11.3, 3.0 Hz, 1 H), 3.40 (dt, J=11.7, 2.7 Hz, 1H), 3.17-3.02 (m, 3 H), 1.39 (s, 9 H), 1.15 (d, J=6.7 Hz, 3 H).