Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[Cl:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)=[CH:25][C:26]([NH:30][CH3:31])=[C:27]([CH:29]=1)[NH2:28].CC(C)N=C=NC(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[N:30]([CH3:31])[C:26]2[CH:25]=[C:24]([N:32]3[CH2:37][CH2:36][CH:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:34][CH2:33]3)[C:23]([Cl:22])=[CH:29][C:27]=2[N:28]=1
Reactant: CNc1cc(N2CCC(c3ccccc3)CC2)c(Cl)cc1N
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(Cl)c(N3CCC(c4ccccc4)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (200 mg; 0.60 mmol) and 5-chloro-2-methylamino-4-(4-phenyl-piperidin-1-yl)aniline (190 mg; 0.60 mmol) in DMF (4 mL) was stirred overnight at rt. DIC (76 mg; 0.60 mmol) was added and the mixture was heated at 90° C. for 1.5 h. The mixture was poured in water, extracted with EtOAc and the combined organic layer was dried over Na2SO4, filtered and concentrated and the residue was purified by column chromatography.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:3]1=[CH:15]N(C)C.C(O)(=O)C.[C:23]([NH2:26])(=[NH:25])[CH3:24]>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C:2]2[N:25]=[C:23]([CH3:24])[N:26]=[CH:15][C:3]=2[CH2:4]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CC(=N)N
Solvent: CC(=O)O
Product: Cc1ncc2c(n1)CCN(C(=O)OC(C)(C)C)C2

Procedure:
Reaction of tert-butyl 4-oxo-3-(dimethylaminomethylidene)-1-piperidinecarboxylate (1.15 g) from Intermediate 28, Step A with acetamidine acetate (0.54 g) according to the procedure described for Intermediate 28, Step B, and purification by flash chromatography (silica gel; 2% methanol/dichloromethane as eluant) afforded the title compound as a viscous orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:22]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1)(=[O:24])[CH3:23]
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(N)ccn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccnc(N2CCN(C(=O)OCC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,2-Dimethylpropyl 4-(4-aminopyridin-2-yl)-1-piperazinecarboxylate (105 mg) obtained in Example 20 was dissolved in pyridine (2 mL), acetic anhydride (0.1 mL) was added thereto, and stirred at room temperature for 3 hours, and the reaction liquid was diluted with chloroform, washed with saturated sodium hydrogencarbonate and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (chloroform/methanol=19/1) to obtain 52 mg of the entitled compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].[I:20]I.Cl>O.C1COCC1>[OH:13][C:9]1[C:10]([I:20])=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:12]2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc2ccc(O)cc2c1
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2ccc(O)c(I)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of 7-cyano-2-naphthol (22.3 g, 131.8 mmol), sodium carbonate (29.3 g, 277 mmol) and I2 (31.8 g, 125.2 mmol) in water (500 mL) and THF (80 mL) at 0 ° C was stirred at room temperature for 3 h, acidified with 1M HCl and extracted with ethyl acetate. The extracts were washed with saturated Na2S2O3 and brine, dried (Na2SO4) and concentrated. The product was recrystallized from ethyl acetate to yield 33 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([CH3:20])[CH:16]=[CH:15]3)=[C:6]([Cl:21])[CH:5]=[CH:4][C:3]=1[N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH:28][C:29](=[O:43])/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][C:35]([C:38]([O:40]CC)=[O:39])=[CH:36][CH:37]=1.[OH-].[Na+]>C(O)C>[C:38]([C:35]1[N:34]=[CH:33][C:32](/[CH:31]=[CH:30]/[C:29]([NH:28][CH2:27][C:23]2[N:22]([C:3]3[CH:4]=[CH:5][C:6]([Cl:21])=[C:7]([CH2:8][O:9][C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[C:19]=4[N:18]=[C:17]([CH3:20])[CH:16]=[CH:15]5)[C:2]=3[Cl:1])[CH:26]=[CH:25][CH:24]=2)=[O:43])=[CH:37][CH:36]=1)([OH:40])=[O:39]
Reactant: CCOC(=O)c1ccc(/C=C/C(=O)NCc2cccn2-c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(-n4cccc4CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a suspension of 1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-2-[(E)-3-(6-ethoxycarbonylpyridin-3-yl)acryloylaminomethyl]pyrrole (116 mg) in ethanol was added 1N sodium hydroxide solution (0.3 ml) at ambient temperatures, and the mixture was stirred at 50° C. for 2 hours. The solvent was removed in vacuo, and the residue was dissolved in water. The aqueous solution was washed with diethyl ether and adjusted to pH 5 with 1N hydrochloric acid. The resulting precipitates were collected by filtration and washed with water and diethyl ether to give 2-[(E)-3-(6-carboxypyridin-3-yl)acryloylaminomethyl]-1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]pyrrole (77 mg) as amorphous powder.
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.Cl.[CH3:14][NH:15][CH:16]1[CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH:16]1([N:15]([CH3:14])[CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CNC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C1CC1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
Combined a solution of tert-butyl 3-oxoazetidine-1-carboxylate (175 mg, 1.022 mmol) and N-methylcyclopropanamine hydrochloride (121 mg, 1.124 mmol) in methylene chloride (5 mL) and added sodium triacetoxyborohydride (325 mg, 1.533 mmol) and the solution stirred at 20° C. for 30 min. The solution was concentrated in vacuo to give white solid which was taken up in ethyl acetate (50 mL), washed with saturated sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate and concentrated in vacuo, and then purified on a 40 g silica gel column eluted with 0 to 50% ethyl acetate in hexanes to give the title compound (128 mg, 0.566 mmol, 55.3%) as a clear, colorless oil. MS: 227 (M+H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.41-0.47 (m, 2H) 0.48-0.56 (m, 2H) 1.43 (s, 9H) 1.64 (tt, J=6.7, 3.9 Hz, 1H) 2.28 (s, 3H) 3.50 (tt, J=7.5, 5.7 Hz, 1H) 3.84-4.01 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:5][CH:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)#[N:2].N>CO.[Ni]>[NH2:2][CH2:1][C:3]1[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:5][CH:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)nc2C#N)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)nc2CN)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(3-cyano-5-(thiophen-2-yl)pyrazin-2-yl)piperazine-1-carboxylate (0.75 g, 2.01 mmol), Raney Ni (200 mg) and 2 M solution of NH3 in MeOH (50 mL). The resulting mixture was stirred at room temperature overnight under H2 atmosphere. Work-up: the reaction mixture was filtered. The filtrated was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with 5% MeOH in CH2Cl2, to afford 680 mg (89%) of the product.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[Cl:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)s1
Product: O=C(Cl)c1ccc(Cl)s1

Procedure:
8.2 g (50.4 mmol) 5-chloro-thiophene-2-carboxylic acid were suspended in 26 ml (7 equiv.) thionyl chloride and the resulting mixture was refluxed for 1 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was co-distilled three times with 150 ml toluene to give crude 9.64 g 5-chloro-thiophene-2-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18][NH:19]C)[C:12]=2[F:21])[CH:9]=1)[C:5]#[N:6].[Cl:22][C:23]1[N:24]=[C:25]([CH2:31][CH3:32])[NH:26][C:27]=1[C:28]([OH:30])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:23]1[N:24]=[C:25]([CH2:31][CH3:32])[NH:26][C:27]=1[C:28]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:12]=1[F:21])=[O:30]
Reactant: CNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: CCc1nc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 58.1 %

Procedure:
4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-ethyl-1H-imidazole-5-carboxamide was prepared in a similar manner as described herein from 3-chloro-5-({6-chloro-2-fluoro-3-[(methylamino)methyl]phenyl}oxy)benzonitrile (0.713 g, 2.29 mmol), 4-chloro-2-ethyl-1H-imidazole-5-carboxylic acid (0.400 g, 2.29 mmol), HATU (1.133 g, 2.98 mmol), DIPEA (0.520 mL, 2.98 mmol) and DMF (12 mL). Purification was accomplished by silica gel chromatography (0-5% MeOH (2M NH3) in CH2Cl2) to afford the title compound (0.622 g, 58%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.09 (br. s., 1H), 7.81-7.84 (m, 1H), 7.48-7.53 (m, 2H), 7.45-7.47 (m, 1H), 7.33-7.40 (m, 1H), 4.54 (d, 2H), 2.60 (q, 2H), 1.18 (t, 3H). ES-LCMS: m/z 467.0, 469.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[F:10][CH:11]([F:14])[CH2:12][NH2:13].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:13][CH2:12][CH:11]([F:14])[F:10])=[CH:6][CH:7]=1
Reactant: NCC(F)F
Reactant: ClCc1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)CNCc1ccc(Cl)nc1
Yield: 53.9 %

Procedure:
41.57 g (256.6 mmol) of 2-chloro-5-chloromethylpyridine, 20.80 g (256.6 mmol) of 2,2-difluoroethane-1-amine and 35.8 ml (256.6 mmol) of triethylamine in 500 ml of acetonitrile are stirred at 45° C. for 21 hours. The reaction mixture is concentrated under reduced pressure and the residue is then taken up in 1 N aqueous hydrochloric acid and the mixture is washed with ethyl acetate. The aqueous phase is made alkaline using 2.5 N aqueous sodium hydroxide solution and extracted repeatedly with ethyl acetate. Concentration of the organic phase under reduced pressure gives 28.6 g (53% of theory) of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethane-1-amine.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])C.[Br:17]C[C@H](O)CO.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:17][CH2:16][C@H:15]1[CH2:1][O:3][C@H:4]([CH2:5][P:6]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:7])[O:14]1
Reactant: OC[C@@H](O)CBr
Reactant: CCOC(CP(=O)(OCC)OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(C[C@H]1OC[C@H](CBr)O1)OCC
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a solution of diethylphosphonoacetaldehyde diethylacetal (4.20 g, 16.5 mmol) and (2R)-3-bromo-1,2-propanediol (example 90) (3.00 g, 19.4 mmol, 1.2 eq.) in toluene (30 mL) was added pTSA (few crystals). The mixture was stirred at reflux for 50 hr. After, the solution was cooled to room temperature, and a saturated solution of sodium bicarbonate was added, and the aqueous phase was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude material was pure by TLC and NMR, and gave 5.06 g of the compound in a 97% yield.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.CCN(CC)CC.S(Cl)(Cl)=O.[F:21][C:22]1[CH:29]=[CH:28][C:25]([NH:26][CH3:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([N:26]([CH3:27])[C:4]([C:1]2([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)=[O:5])=[CH:24][CH:23]=1
Reactant: CNc1ccc(F)cc1
Reactant: O=C(O)C1(C(=O)O)CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C(=O)C1(C(=O)O)CC1)c1ccc(F)cc1
Yield: 80.6 %

Procedure:
Using a procedure analogous to Example B1, 1,1-cyclopropanedicarboxylic acid (2 g, 15.37 mmol), Et3N (2.14 mL, 15.4 mmol), thionyl chloride (1.12 mL, 15.4 mmol), and 4-fluoro-N-methylaniline (1.83 g, 14.6 mmol) were combined to provide 1-((4-fluorophenyl)(methyl)carbamoyl)cyclopropanecarboxylic acid (2.79 g, 72% yield). MS (ESI) m/z: 260.0 (M+Na+).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]1=[O:11]>>[CH3:3][N:4]1[CH:9]=[C:8]([Br:1])[C:7]([CH3:10])=[N:6][C:5]1=[O:11]
Reactant: BrBr
Reactant: Cc1ccn(C)c(=O)n1
Product: Cc1nc(=O)n(C)cc1Br
Reaction time: 3 h
Yield: 40 %

Procedure:
Bromine (0.012 mol) was added to an aqueous solution (100 ml) of 1,4-dimethylpyrimid-2-one (0.008 mole) and the reaction mixture left at room temperature for 3 hr before freeze-drying. The residual material was triturated with acetone and recrystallised from water; yield 40%, m.p. 170° C. (decomp.). (Found: C, 25.5; H, 2.9. Calc. for C6H7BrN2O HBr: C, 24.4; H, 2.8).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[O-]CC.[Na+].[CH2:20](Br)[CH:21]=[CH2:22].[I-].[Na+]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:22][CH:21]=[CH2:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: CCOC(=O)CC(=O)c1ccc(C)cc1
Agent: CC[O-]
Agent: [I-]
Agent: [Na+]
Product: C=CCC(C(=O)OCC)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Ethyl 3-(4-methylphenyl)-3-oxopropanoate (prepared as described in W. Wierenga and H. I. Skulnick, J. Org. Chem. (1979), 44, 310) (63.66 g, 309 mmol, 1 eq) was added to a freshly prepared sodium ethoxide solution (Na, 7.43 g, 323 mmol, 1.05 eq; EtOH, 250 mL). The ethanol was removed in vacuo and the residue was dissolved in DMF (250 mL). Allyl bromide (29.3 mL, 338 mmol, 1.1 eq) followed by sodium iodide (4.56 g, 304 mmol, 1 eq) were then added and the contents stirred overnight at room temperature. The DMF was removed in vacuo, water (250 mL) was added and the aqueous layer extracted with ethyl acetate (3×200 mL). The organic layers were dried (MgSO4) and the solvent removed in vacuo to yield 74.21 g of an amber oil. NMR (200 MHz, CDCl3) δ 7.81 (d, 2H, J=10 Hz); 7.30 (d, 2H, J=10 Hz); 5.96-5.72 (m, 1H); 5.21-5.00 (m, 2H); 4.41 (t, 1H, J=7 Hz); 4.16 (q, 2H, J=7 Hz); 2.78 (t, 2H, J=7 Hz); 2.42 (s, 3H); 1.18 (t, 3H, J=7 Hz). Anal. Calcd. for C15H18O3 : C, 73.15; H, 7.37. Found: C, 73.10; H, 7.38.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:10][CH:9]=1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CCl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(Cn2cncn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To 1,2,4-triazole (2.0 g, 29 mmol) in THF (80 mL) at 0° C. was added 4-methoxybenzyl chloride (4.0 mL, 29 mmol) and DBU (5.20 mL, 34.7 mmol). The reaction mixture was warmed to room temperature and allowed to stir overnight. The solution was filtered and the filtrate was concentrated. The resulting residue was purified by column chromatography (EtOAc/MeOH, 1:9) to give 3.12 g (57%) of 1-(4-methoxybenzyl)-1H-1,2,4-triazole as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH2:18][CH:19]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:20][O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=O.B.[CH2:32]1COCC1.CO.[ClH:39]>C1COCC1.CCOCC>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH2:10][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH2:18][CH:19]([CH2:20][O:21][CH2:22][C:23]([CH3:32])([CH3:25])[CH3:24])[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCOC1
Reactant: CC(C)COCC(CN(C(=O)c1ccncc1)c1c(Cl)cccc1Cl)N1CCCC1
Agent: B
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)COCC(CN(Cc1ccncc1)c1c(Cl)cccc1Cl)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 6 g (0.017 m) of N-(2,6-dichlorophenyl)-beta[(2,2-dimethylpropoxy)methyl]-1-pyrrolidineethanamine (the compound of Example 4b.), 4.2 g (0.042 m) of triethylamine, 3.28 g (0.018 m) of 4-picolinoylchloride in 100 ml of dry toluene was stirred at gentle reflux for 2.5 hrs then for 18 hrs at 25° C. Ether (50 ml), then ice and water were added followed by 3N NaOH. The aqueous layer was separated and extracted twice with EtOAc. The combined organic solution was washed with water then brine, dried (Na2SO4 and charcoal) and evaporated to yield a dark oil 7.4 g. This sample was combined with 5.3 g from another run and dissolved in 25 ml of CH2Cl2 and this solution was applied to a silica flash column (2"×71/4") containing 360 ml of silica gel and eluted with acetone:hexane 1:4. A 200 ml second fraction yielded 6 g of pure oily N-(2,6-dichlorophenyl)-N-[3-(2-methylpropoxy)-2-(pyrrolidinyl)propyl]-4-pyridinecarboxamide. A 4 g (0.0086 m) sample of the above 4-pyridinecarboxamide in 20 ml of THF was cooled in an ice bath and 26 ml of 1M (0.026 m) BH3.THF in THF was added over 15 mins. The reaction was stirred for 3 hrs at 25° C. and one hr at reflux. Reaction was cooled to 10° C. and an additional 10 ml of 1M BH3.THF was added. Reaction stirred at reflux for an additional 6 hrs and cooled. After addition of ice, 2 ml of methanol and 3 ml of 3N HCl was added and the solution stirred for 30 min. After making basic with 50% then 3N NaOH, the solution was extracted three times with CH2Cl2 ; extracted aqueous three times with EtOAc and combined all organic extracts (dried Na2SO4) and evaporated solvents off the give 3.35 of oil. Added ether to warm isopropanolic-ethereal HCl solution of the 3.35 g of oil. After cooling 3.1 g of crystalline HCl salt was collected. Recrystallizations from acetonitrile-ether then acetonitrile gave white plates (1.3 g) of title compound m.p. 227° C. (softens), melt 230°-23° C. (dec.)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II.[CH3:10][C:11]([CH3:13])=O>>[NH:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[CH:11][CH2:13]1
Reactant: Nc1ccccc1
Reactant: CC(C)=O
Agent: II
Product: C1=Cc2ccccc2NC1
Yield: 18 %

Procedure:
1,2-dihydroquinolines are key intermediates in the preparation of a number of steroid receptor modulating compounds, and are prepared by a multi-step route culminating in the treatment of an aniline with acetone and iodine at elevated temperatures in a process known as the Skraup reaction, as shown below. See R. H. F. Manske et al., Organic Reactions 7: 59-98 (1953), and W. R Vaughan, Org. Synth. Coll. Vol III, 329-332 (1955). ##STR1## Many 1,2-dihydroquinolines are themselves steroid receptor modulating compounds. See, for example, PCT Int'l Publ. No. WO 96/19458; U.S. Pat. No. 5,693,647. Application of the traditional Skraup reaction to the synthesis of many of these 1,2-dihydroquinolines is problematic in that large quantities of a number of tarry by-products are formed that must be removed prior to use in further synthetic transformations, and the yields are generally low (15-50%). For example, as shown in U.S. Pat. No. 5,693,647, treatment of a polycyclic aniline, such as the amino-chloro-benzocoumarin shown below, with acetone and iodine at 130-135° C. affords only an 18% yield of the corresponding 1,2-dihydroquinoline. Furthermore, purification is very difficult due to the aforementioned by-product formation. ##STR2##
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1N.O>CO>[CH2:1]([C:8]1[NH:9][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: N#CCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: c1ccc(Cc2nc3ccccc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1 M solution of benzyl cyanide in anhydrous methanol was treated with hydrogen chloride gas at 0° C. for about thirty minutes. The mixture was stirred for two hours at 0° C. and then a 1 M solution of diaminobenzene was added and the resulting solution was stirred at 0° C. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then poured into water. The unreacted nitrile was extracted with ethyl acetate. The aqueous layer was neutralized with 1 N sodium hydroxide. The organic fraction was extracted with ethyl acetate and condensed. The desired title product was recrystallized from methanol/water.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: C1COCCN1
Solvent: CCO
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCOCC1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
2-Chloro-5-nitrobenzonitrile (16.7 g) and morpholine (16 g) were added to ethanol (300 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give 5-nitro-2-morpholinobenzonitrile (19.7 g), melting point: 138–140° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)O1>>[NH:30]1[C:31]2[C:27](=[C:26]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[CH:7][N:8]4[CH3:11])=[C:4]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[N:3]=3)[CH:34]=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: Cn1cnc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
4-(2-Chloro-9-methyl-9H-purin-6-yl)morpholine (20 mg) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via General Procedure A and purified via reverse phase HPLC to give 13.8 mg of 129 as a white solid. MS (Q1) 336.2 (M)+