Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:14])[CH:6]=1)(=O)C.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1O>>[O:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:9]1[C:8]1[CH:12]=[CH:13][C:5]([NH2:4])=[CH:6][C:7]=1[CH3:14]
Reactant: Nc1ccccc1O
Reactant: CC(=O)Nc1ccc(C(=O)O)c(C)c1
Product: Cc1cc(N)ccc1-c1nc2ccccc2o1
Temperature: 200 °C

Procedure:
To a suspension of 4-acetylamino-2-methyl-benzoic acid (2.0 g, 10.3 mmol) in PPA (˜85 g) was added aminophenol (1.2 g, 10.8 mmol). The reaction was heated to 200° C. for 2 h, then carefully quenched in aqueous sodium carbonate (˜50% saturated) at room temperature. Ethyl acetate was added, and the organic layer was washed with water and brine, and dried over sodium sulfate. The crude product was obtained as an orange oil and was subsequently purified by flash column chromatography on silica gel eluting with ethyl acetate in hexanes to afford the desired product, 4-benzooxazol-2-yl-3-methyl-phenylamine as a colorless solid, 290 mg (13%). 1H NMR (300 MHz, DMSO-d6): δ 7.84-7.81 (m, 1H), 7.64-7.62 (m, 2H), 7.32-7.27 (m, 2H), 6.51 (d, J=9.0 Hz, 2H), 5.83 (s, 2H), 2.61 (s, 3H). LC-MS m/z=225 [C14H12N2O+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31]C(=O)C)[CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.Cl>>[CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCNC1CCCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)C1
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCC(NCCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS402 starting from 49 mg (0.23 mmol) of acetic acid 4-[6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-3-ylamino]butyl ester. The product is the hydrochloride.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10])([CH3:5])[CH3:4])#[N:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[N:28]=2)[CH:25]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:15][C:16]1[CH:37]=[CH:36][CH:35]=[C:18]([O:19][C:20]2[CH:21]=[CH:22][C:23]3[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]4[CH2:33][CH2:34]4)=[O:31])[N:28]=3)[CH:25]=2)[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (5.0 mL) was added N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.485 mmol) produced in Example B2(vii), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100), and the obtained oil was triturated with ethyl acetate, toluene and diisopropyl ether to give the title compound (117 mg, 42%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:19])[C:10]([C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[CH:13]=1)=[O:11].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:20]([O:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH3:19])[CH:17]=[CH:16][N:15]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C(=O)c1cc[nH]c(=O)c1)c1ccc(Cl)cc1Cl
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: CC(C(=O)c1ccnc(OCc2ccccc2)c1)c1ccc(Cl)cc1Cl
Temperature: 50 °C
Yield: 59.8 %

Procedure:
This material was re-benzylated as follows: 4-[2-(2,4-Dichloro-phenyl)-propionyl]-1H-pyridin-2-one (100 mg) was dissolved in absolute benzene (6 mL) and silver carbonate (65 mg) and benzyl bromide (70 mg, 0.05 mL) were added. The mixture was stirred at 50° C. over night and was then poured into ice water. The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (20 g silica gel, gradient of ethyl acteate in heptane (0 to 20%)) to give 1-(2-benzyloxy-pyridin-4-yl)-2-(2,4-dichloro-phenyl)-propan-1-one (78 mg) as a colorless oil. MS (m/e)=386.0 [MH+].
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]1[CH3:20])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([CH3:20])=[C:6]2[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c(-c2ccncc2)c2cc(O)ccc2n1C(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccncc1)c(C)n2C(C)C

Procedure:
The above compound was prepared from 1-isopropyl-2-methyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methylpropanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[C:10]21[CH2:12][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.Cl[Si:26]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[O:27][Si:28](Cl)([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH2:1]([O:8][C@H:9]1[C:10]2([CH2:12][CH2:11]2)[C@H:13]2[C@@H:14]([O:17][Si:26]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[O:27][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:30])[CH3:31])[O:19][CH2:18]2)[C@H:15]1[OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H]1[C@@H](O)[C@@H](O)[C@@H](OCc2ccccc2)C12CC2
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si]1(C(C)C)OC[C@@H]2[C@@H](O[Si](C(C)C)(C(C)C)O1)[C@@H](O)[C@@H](OCc1ccccc1)C21CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a stirred mixture of triol 24 (2.9 g, 10.9 mmol) and imidazole (5.2 g, 76.8 mmol) in DMF (80 mL) at 0° C. under argon was added dropwise 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (3.5 mL, 11.0 mmol). After the mixture was stirred at room temperature for 1 h, quenched with MeOH (15 mL) and water (100 mL) was added and the mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (40 mL) dried over Na2SO4. The solvent was removed and the residue was purified by silica gel column chromatography (EtOAc:Hexane 1:30 to 1:5) to give 25 (5.1 g, 92%) as an oil. [α]24D −105.94° (c 0.58, CHC13); 1H NMR (500 MHz, CDCl3) δ 7.41-7.26 (m, 5H), 4.77 (d, J=12 Hz, 1H), 4.62 (d, J=12 Hz, 1H), 4.18-4.14 (m, 3H), 4.05 (dd, J=4.5, 12.0 Hz, 1H), 3.78 (dd, J=8, 12 Hz, 1 H), 2.89 (m, 1 H), 2.78 (d, J=2.0 Hz, 1H, OH) 1.08-0.97 (m, 28H), 0.61 (m, 1H), 0.43 (m, 1H), 0.32 (m, 1H), 0.24 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 154.0,147.3, 138.1, 128.4, 80.2, 74.2, 71.2, 71.1, 64.9, 50.1, 29.24 23.83, 17.6, 17.5, 17.4, 17.3, 17.2, 17.1, 17.0, 16.9, 16.8, 13.4, 12.9, 12.7, 12.5. 7.20; HR-MS Calcd. For (C27H46O5Si2+H)+ 507.2884, found 507.2798.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=O.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28](=[O:30])[CH3:29])[CH2:17][CH2:16]1.[OH-].[K+].[ClH:33]>CCO.O>[ClH:33].[ClH:33].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28](=[O:30])/[CH:29]=[CH:1]/[C:3]2[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=2)[CH2:17][CH2:16]1
Reactant: CC(=O)c1ccccc1CN1CCN(C)CC1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(Cc2ccccc2C(=O)/C=C/c2ccc(/C=C/C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-formylcinnamic acid (189 mg, 1.077 mmol), 1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-ethanone (obtained as described in Preparation 11, 250 mg, 1.077 mmol) and 1.7 M KOH (1.26 ml) in EtOH (5 ml) and H2O (5 ml) was stirred at room temperature overnight and then acidified with 10% HCl. The resulting precipitate was filtered to give 350 mg of (E)-3-(4-{(E)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid bis-hydrochloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14]([C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([C:18]1[N:23]=[C:22]([NH:24][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:21]=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cccc(N)n1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)C)n1
Temperature: 130 °C
Yield: 48.7 %

Procedure:
A mixture of ethyl 4,6-dichloropyridazine-3-carboxylate (0.73 g, 3.3 mmol) and 6-tert-butylpyridin-2-amine (992 mg, 6.61 mmol, available commercially from J&W PharmLab, LLC) was dissolved in acetonitrile (3.00 mL) and heated at 130° C. for 20 h. After cooling to room temperature, the mixture was concentrated and the residue purified by flash chromatography (spherical silica 20-45 μM, 50 g, Versaflash Supelco) eluting with 0 to 20% acetone in dichloromethane over 20 min to give ethyl 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (539 mg, 48.7% yield) as a light brown residue. 1H NMR (CHLOROFORM-d) δ: 10.59 (s, 1H), 9.32 (s, 1H), 7.55 (t, J=7.9 Hz, 1H), 6.98 (d, J=7.2 Hz, 1H), 6.66 (d, J=7.9 Hz, 1H), 4.48 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H), 1.28-1.35 (m, 9H); LC-MS 335.0, 337.0 [M+H]+.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:28][CH2:29][C:30](=O)[CH2:31]Cl>>[Cl:28][CH2:29][C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:31]=1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: O=C(CCl)CCl
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(CCl)cs2)C1

Procedure:
250 mg (about 0.44 mmol) of the compound from Example 53A and 60 mg (0.52 mmol) of 1,3-dichloropropan-2-one were reacted according to the General Method 3. Yield: 150 mg (12% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][Br:31])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCc1cccc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCc1cccc(Br)c1
Reaction time: 12 h
Yield: 37.3 %

Procedure:
Compound 40-2 (2.78 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.72 g) and N-bromosuccinimide (2.53 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.34 g) as a colorless oil.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Br:8][C:9]1[C:10]([O:19][C@H:20]2[CH2:24][N:23](C(OC(C)(C)C)=O)[C@H:22]([C:32]([OH:34])=[O:33])[CH2:21]2)=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2>C(Cl)Cl>[Br:8][C:9]1[C:10]([O:19][C@H:20]2[CH2:24][NH:23][C@H:22]([C:32]([OH:34])=[O:33])[CH2:21]2)=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2nc3ccccc3cc2Br)C[C@H]1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@@H](Oc2nc3ccccc3cc2Br)CN1
Temperature: 25 °C

Procedure:
TFA (5.0 ml, 65 mmol) was added to a solution of (2S,4R)-4-((3-bromoquinolin-2-yl)oxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (300 mg, 0.686 mmol) in DCM (5 mL) and stirred at RT until LCMS analysis indicated complete conversion. The solution was concentrated to afford the product (2S,4R)-4-((3-bromoquinolin-2-yl)oxy)pyrrolidine-2-carboxylic acid, TFA (310 mg) as a sticky oil. Yield was assumed to be 100%. ESI-MS(+) m/z=337 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[N:32]1[O:36][N:35]=[C:34]2[C:37]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:39]=[CH:40][C:33]=12>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:37]4[C:34]5=[N:35][O:36][N:32]=[C:33]5[CH:40]=[CH:39][CH:38]=4)(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1cccc2nonc12
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc5nonc45)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and benzo[1,2,5]oxadiazole-4-sulfonyl chloride. Purity (ELSD, based on MW=603.6)=95%.
Reaction SMILES: O=[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N+:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[C-:19]>>[C:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]3[CH:19]=[N:18][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:2]3[CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1cc(-c2ccccc2)c2ccccc2[nH]1
Reactant: [C-]#[N+]CC(=O)OCC
Product: CCOC(=O)c1ncn2c1cc(-c1ccccc1)c1ccccc12

Procedure:
Ethyl 5-phenyl-imidazo(1,5-a)quinoline-3-carboxylate was prepared from 1,2-dihydro-2-oxo-4-phenyl-quinoline and ethyl isocyanoacetate. M.p. 176°-185° C.
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.[Ni]>[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
Agent: [Ni]
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-Ni (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: (EI) 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 155.85 (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 (C5'), 38.05 (C2'). Anal. Calcd. for C12H13Cl2N3O3 : C, 45.30; H, 4.12; N, 13.21. Found: C, 45.44; H, 4.10; N, 13.28.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Br[CH2:13][C:14]([C:16]1[C:17]([O:24][CH3:25])=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:15]>>[CH3:25][O:24][C:17]1[C:16]([C:14]2[O:15][C:5]3[C:6](=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=3)[CH:13]=2)=[CH:21][CH:20]=[C:19]([O:22][CH3:23])[N:18]=1
Reactant: COc1ccc(C(=O)CBr)c(OC)n1
Reactant: COc1cc(O)cc(OC)c1
Product: COc1ccc(-c2cc3c(O)cc(O)cc3o2)c(OC)n1
Yield: 47 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(2,6-dimethoxypyridin-3-yl)ethanone: Yield 47% following procedures A.2 and A.5; m.p. 97° C. (dec.); IR 3434, 2958, 1587, 1471, 1319, 1265, 1084, 1020 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.77 (s, 1H), 9.30 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.13 (s, 1H), 6.51 (d, J=8.3 Hz, 1H), 6.40 (s, 1H), 6.16 (s, 1H), 4.08 (s, 3H), 3.92 (s, 3H); 13C-NMR (126 MHz, δ ppm, CD3OD) 163.3, 159.7, 157.8, 157.5, 152.3, 149.5, 138.2, 113.3, 107.8, 102.8, 102.6, 98.7, 90.7, 54.1, 54.1.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][C:12]1([CH3:19])[C:16]([CH3:18])([CH3:17])[O:15][BH:14][O:13]1.CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:10][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[B:14]1[O:15][C:16]([CH3:18])([CH3:17])[C:12]([CH3:19])([CH3:11])[O:13]1
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1cc(O)cc(C)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(O)cc(C)c1B1OC(C)(C)C(C)(C)O1
Yield: 180.3 %

Procedure:
Following the procedure described in Example 220, step a, reaction of 4-bromo-3,5-dimethyl-phenol (1.5 gm, 7.6 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.3 mL, 23 mmol, Aldrich Chemical Company), PdCl2(PPh3)2 (530 mg, 0.76 mmol, Strem Chemicals Inc, Newburyport, Mass.), Et3N (634 μL, 46 mmol), and dioxane (30 mL) afforded 3.4 gm of a tan glassy solid after chromatography (50 gm, silica SPE column) which was used without further purification. 1H-NMR (CDCl3; 400 MHz): δ 6.4 (s, 2H), 2.3 (s, 6H), 1.4 (s, 12H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[S:21][C:20]2[C:19]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:19]3[C:20]4[S:21][C:13]([C:6]5[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=5)=[CH:14][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Product: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from p-formylbenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.2 (s, 1H), 9.95 (s, 1H), 8.85 (s, 1H), 7.90 (m, 6H), 7.75 (s, 1H), 7.46 (m, 3H), 7.20 (d, 1H), 6.49 (s, 1H), 2.28 (s, 3H), LC-MS: 371 (MH+); HPLC RT: 4.10 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:31]>O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Solvent: O
Product: CC(C)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3,4-difluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 35 mg, 42%). mp 169-171° C. 1H NMR (300 MHz, DMSO-d6) δ 0.78 (d, 6H), 1.84, (m, 1H), 4.2 (d, 2H), 7.54 (m, 3H), 7.6 (m, 1H), 7.82 (m, 3H), 7.91 (d, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 436 (M+H)+, 453 (M+NH4)+. Anal. calc. for C20H19F2N3O4S.0.25 H2O: C, 55.17; H, 4.40; N, 9.65. Found: C, 54.19; H, 4.25; N, 9.35
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:29])[C:13]1[C:14](=[C:19]([NH:23]CCCCC)[CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]>>[CH3:10][O:11][C:12](=[O:29])[C:13]1[C:14](=[C:19]([NH:23][CH2:2][C:3]2[O:7][C:6]([CH2:8][OH:9])=[CH:5][CH:4]=2)[CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reactant: O=Cc1ccc(CO)o1
Product: COC(=O)c1cccc(NCc2ccc(CO)o2)c1C(=O)OC
Yield: 76 %

Procedure:
5-Hydroxymethyl-furan-2-carbaldehyde (0.95 ml, 7.5 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by chromatography (SiO2, 40/60 ethyl acetate/hexanes) to give 0.97 g (76%) of yellow oil: 1H NMR (CDCl3) δ 7.35–7.27 (m, 1H), 7.05 (bs, 1H), 6.87–6.83 (m, 2H), 6.21 (d, J=3.1 Hz, 1H), 6.17 (d, J=3.2 Hz, 1H), 4.57 (s, 2H), 4.38 (bs, 2H) 3.86 (s, 3H), 3.83 (s, 3H), 1.98 (bs, 1H).
Reaction SMILES: [OH-].[Na+].O.C([O:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C:17]2=[O:27])[CH2:9]1)(=O)C>CO>[OH:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C:17]2=[O:27])[CH2:9]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 98.5 %

Procedure:
A solution of 7.6 parts of sodium hydroxide in 25 parts of water is added to a solution of 42.5 parts of 3β-acetoxy-5β-androstan-17-one in 140 parts of methanol with stirring. The resultant mixture is heated to reflux for 2 hours whereupon distillation is initiated and 109 parts of methanol are removed. The remaining methanol is removed by evaporation and the resulting crystalline solid is diluted with water and stirred. The crystals are collected by filtration, washed with water until the washings are about pH 6 and air-dried to afford, in 98.5% yield, 3β-hydroxy-5β-androstan-17-one. This compound melts at about 152°-155° C. and exhibits infrared absorption maxima in chloroform at 3620, 2940, 1735 cm-1 and is represented by the following structural formula. ##STR5##