Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.S([O:22][CH2:23][CH:24]1[NH:32][CH:31]=[N:30][C:29]2[N:28]([C@@H:33]3[O:45][C@H:44]([CH2:46][O:47]C(=O)C)[C@@H:39]([O:40]C(=O)C)[C@H:34]3[O:35]C(=O)C)[CH:27]=[N:26][C:25]1=2)(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[CH2:24]1[C:25]2[N:26]=[CH:27][N:28]([C@@H:33]3[O:45][C@H:44]([CH2:46][OH:47])[C@@H:39]([OH:40])[C@H:34]3[OH:35])[C:29]=2[NH:30][CH:31]=[N:32][CH:23]1[OH:22]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c2N=CNC3COS(=O)(=O)c2ccc(C)cc2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Product: OC[C@H]1O[C@@H](n2cnc3c2NC=NC(O)C3)[C@H](O)[C@@H]1O
Reaction time: 4 h
Yield: 20 %

Procedure:
The tosylate (I, 211 mg) obtained in Example 2 was dissolved in acetonitrile (10 ml) and 0.5 N Ba(OH)2 (10 ml) was added. The homogeneous brown solution was then stirred for 4 hr, when no tosylate (I) was detected on thin-layer chromatogram. After treating the reaction mixture as in Example 2, isocoformycin (21 mg, 20%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:42]1[CH:61]=[N:60][C:45]2[NH:46][C:47](=[O:59])[N:48]([CH2:50][CH2:51][N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]3)[CH2:49][C:44]=2[CH:43]=1>C(#N)CC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:58][N:55]1[CH2:56][CH2:57][N:52]([CH2:51][CH2:50][N:48]2[CH2:49][C:44]3[CH:43]=[C:42](/[CH:3]=[CH:2]/[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:61]=[N:60][C:45]=3[NH:46][C:47]2=[O:59])[CH2:53][CH2:54]1
Reactant: CN1CCN(CCN2Cc3cc(Br)cnc3NC2=O)CC1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCC#N
Product: CN1CCN(CCN2Cc3cc(/C=C/C(=O)OC(C)(C)C)cnc3NC2=O)CC1

Procedure:
tert-Butyl acrylate (830 μL, 5.64 mmol), diisopropylethylamine (500 □L, 2.82 mmol) and P(o-tolyl)3 (86 mg, 0.28 mmol) were successively added to a suspension of 6-bromo-3-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (500 mg, 1.41 mmol) in propionitrile (6 mL) and dimethylformamide (2 mL). The resulting mixture was purged with argon prior to the addition of palladium acetate (32 mg, 0.14 mmol). The mixture was then purged a second time with argon and refluxed overnight. The reaction mixture was filtered on Celite® and washed with ethyl acetate (100 mL) and dichloromethane (100 mL). The filtrate was concentrated to dryness and the residue was solubilized in dichloromethane (100 mL). The resulting solution was washed with a saturated solution of sodium chloride (3×100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol/ammoniac (1:0:0.1 to 98:2:0.1) as eluent. The title product was obtained as a brown solid (83 mg, 15%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[Li].O>O.CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(C(=O)O)cc4)C3)nc3scnc23)cc1OC
Reaction time: 0.15 h
Yield: 64.8 %

Procedure:
A solution of methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)benzoate (190 mg, 0.255 mmol) and LiOH.H2O (149 mg, 3.55 mmol) in 2 mL of water, 10 mL of methanol and 15 mL of THF was stirred at room temperature for 2 hours. The solvent was evaporated after the solution was acidified by 2N HCl to pH=2 and the residue was dissolved in 50 mL of THF, filtered to remove the salts. The filtrate was evaporated and the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 25% acetonitrile/75% water (0.1% TFA V/V) initially, and then proceed to 45% acetonitrile/55% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)benzoic acid (86 mg, 46.5%) as a solid. 1H NMR (300 MHz, DMSO): δ 9.63 (s, 1H), 8.36-8.79 (m, 2H), 8.02-7.88 (m, 5H), 7.60-7.50 (m, 1H), 6.93 (d, 1H, J=8.7 Hz), 4.61-4.59 (m, 1H), 3.95-3.66 (m, 10H), 2.28-2.10 (m, 2H). LC-MS: 521 [M+H]+; 518.8 [M−H]−, tR=1.36 min. HPLC: 99.85% at 214 nm, 99.84% at 254 nm, tR=4.67 min.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23]C)=[O:22])=[N:19][CH:20]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[OH:35].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN1C(=O)CCC1.CO>[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[O:35][C:2]1[C:3]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[N:19][CH:20]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc(NC(=O)c2nc3ccccc3nc2Cl)cn1
Reactant: COc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1ccc(Oc2nc3ccccc3nc2C(=O)Nc2ccc(C(=O)O)nc2)c(OC)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
To methyl 5-[(3-chloroquinoxaline-2-carbonyl)amino]pyridine-2-carboxylate (51.41 mg, 0.15 mmol) in NMP (1 mL) was added 2,4-dimethoxyphenol (23.12 mg, 0.15 mmol) and potassium carbonate (62.19 mg, 0.45 mmol) and the reaction was heated at 100° C. for 1.5 hours. To the reaction were added 150 μL of MeOH and 150 μL of 3M sodium hydroxide and the reaction was stirred at 50° C. for 1.5 hours. The reaction was cooled to 25° C., filtered and purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HCl as a modifier to yield 5-(3-(2,4-dimethoxyphenoxy)quinoxaline-2-carboxamido)picolinic acid (26) (26.63 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.05 (d, J=2.5 Hz, 1H), 8.45 (dd, J=8.6, 2.5 Hz, 1H), 8.18 (dd, J=8.4, 1.6 Hz, 1H), 8.14 (d, J=8.6 Hz, 1H), 7.90-7.71 (m, 3H), 7.22 (d, J=8.7 Hz, 1H), 6.76 (d, J=2.8 Hz, 1H), 6.60 (dd, J=8.8, 2.8 Hz, 1H), 3.81 (s, 3H), 3.68 (s, 3H). ESI-MS m/z calc. 346.12, found 347.2 (M+1)+; Retention time: 1.30 minutes (3 minutes run).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[O-:22][CH2:23][CH3:24].[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)C.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:14][OH:15])[CH2:18][OH:17])=[C:4]([O:22][CH2:23][CH3:24])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reactant: CC[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1nc(N)nc2c1ncn2CCC(CO)CO
Reaction time: 1 h
Yield: 85 %

Procedure:
To a suspension of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.31 g, 1.0 mmol) in ethanol (1.5 ml) was added sodium ethoxide (1M in ethanol, 1.5 ml) and the mixture was stirred at 60° for 1 hour. The resulting solution was allowed to cool, hydrochloric acid (5M, 0.3 ml) and water (0.7 ml) were added and the solution was stirred for 1 hour at room temperature. The solution was neutralised by addition of aqueous sodium bicarbonate and the solvent was removed. The residue was extracted with chloroform-ethanol (2:1), the solution was filtered and the solvent removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (6:1) to afford 2-amino-6-ethoxy-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (0.24 g, 85%), m.p. 150-152° C.; λmax (H2O) 213 (24,300), 249 (7,360), and 280 (9,270) nm; νmax (KBr) 3330, 3210, 2900, 1650, 1610, 1580 cm−1; δH [(CD3)2SO] 1.3-1.6 (4H, m, 3′-H and CH3), 1.73 (2H, q, J 7 Hz, 2′-H), 3.2-3.6 (4H, AB part of ABX, 2×4′-H), 4.04 (2H, t, J 7 Hz, 1′-H), 4.3-4.55 (4H, m, 2H D2O exchangeable, 2×OH; D2O exchange leaves 2H, q, J 7 Hz, 6-OCH2), 6.30 (2H, s, D2O exchangeable, 2-NH2), and 7.84 (1H, s, 8-H); (Found: C, 50.91; H, 7.00; N, 24.89%; C12H19N5O3 requires C, 51.23; H, 6.81; N, 24.90%).
Reaction SMILES: [NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH2:15][CH2:16][OH:17])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.S(=O)(=O)(O)O.[C:23](O)(=[O:25])[CH3:24]>>[NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH2:15][CH2:16][O:17][C:23](=[O:25])[CH3:24])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1
Reactant: CC(=O)O
Reactant: NN1NC=C(c2ncc([N+](=O)[O-])n2CCO)S1
Agent: O=S(=O)(O)O
Product: CC(=O)OCCn1c([N+](=O)[O-])cnc1C1=CNN(N)S1

Procedure:
The sample (0.1 g.) of 2-amino-5-[1-(2-hydroxyethyl)-5-nitro-2-imidazolyl]thiadiazole is dissolved in 2 ml. of hot glacial acetic acid and a drop of concentrated sulfuric acid is added. The solution is refluxed for 45 minutes, cooled and poured on ice to give a yellow solid. This solid is collected, washed with water and dried; the yield is 0.1 g., melting point 159°-162° C. (turbid). A purified sample of the 2-amino-5-[1-(2-acetoxyethyl)-5-nitro-2-imidazolyl]thiadiazole, melts at 164°- 165.5° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]([O:14][CH2:15][CH3:16])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[CH2:15]([O:14][C:4]1[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]([CH3:13])=[C:2]([N:28]2[CH2:29][CH2:30][N:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)[CH2:26][CH2:27]2)[C:3]=1[CH3:17])[CH3:16]
Reactant: CCOc1c(C)c(Br)c(C)c2c1OC(C)(C)C2
Reactant: Cc1ccc(N2CCNCC2)cc1
Product: CCOc1c(C)c(N2CCN(c3ccc(C)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 22.6 %

Procedure:
By using 5-bromo-7-ethoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran (500 mg, 1.67 mmol) synthesized in Reference example 98 and 1-(4-methylphenyl)piperazine (589 mg, 3.34 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 149 mg (yield 23%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].C(Cl)Cl.[OH:20][C@H:21]([CH3:55])[CH2:22][NH:23][C:24](=[O:54])[CH:25]([NH:38][C:39](=[O:53])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:42][CH:41]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1>O>[O:54]=[C:24]([NH:23][CH2:22][C:21](=[O:20])[CH3:55])[CH:25]([NH:38][C:39](=[O:53])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][C:49]([F:50])([F:51])[F:52])=[CH:42][CH:41]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1
Reactant: C[C@@H](O)CNC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)CNC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
Pyridinium chlorochromate (266 mg, 1.23 mmol) and sodium acetate (20 mg, 0.247 mmol) were added to a methylene chloride (24 mL) solution of N-{2-{[(2R)-2-hydroxypropyl]amino}-2-oxo-1-[4-(trifluoromethoxy)benzyl]ethyl}-4-(3,3,3-trifluoropropoxy)benzamide (322 mg, 0.616 mmol) prepared in Example 74. The mixture was stirred at room temperature for 8 hours, and water (60 mL) was added thereto. The resulting mixture was extracted with methylene chloride (50 mL, three times). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by alumina column chromatography (ethyl acetate:methanol, 9:1, V/V) to give 299 mg of the title compound (white powder, yield: 93%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:26]3[CH2:25][CH2:24][N:23]([C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=4)[CH2:28][CH2:27]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(c3ccc(F)cc3)CC2)nn1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.120 g, 0.532 mmol) in DMF (2.3 mL) was treated with 1-(4-fluorophenyl)piperazine (0.117 g, 0.638 mmol) in the presence of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (0.23 mL, 1.54 mmol) and tetra-n-butylammonium iodide (Bu4NI) (11 mg, 0.0298 mmol). The reaction mixture was heated at 75° C. to 80° C. for 15 hours, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed with water (3×10 mL), brine (3×10 mL), dried over Na2SO4, and then concentrated in vacuo. The crude product was purified by column chromatography to give the title compound as a white powder in 74% yield (0.146 g). 1H NMR (300 MHz, CDCl3) δ 8.05-7.99 (m, 2H), 7.02-6.89 (m, 5H), 3.90 (t, J=5.2 Hz, 4H), 3.55 (m, 2H), 3.23 (t, J=5.2 Hz, 4H), 1.55-1.47 (m, 2H), 0.79-0.72 (m, 1H), 0.49-0.43 (m, 2H), 0.11-0.06 (m, 2H). MS (ES+) m/z 370.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][CH2:17][CH2:16][CH:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH2:15]3)[CH:6]=[CH:7][CH:8]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.CN(C)C=O>C(N(CC)CC)C>[CH:19]1([C:22]([N:12]2[CH2:13][CH2:14][CH2:15][C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:18][CH2:17][CH2:16][CH:10]3[CH2:11]2)=[O:23])[CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cccc(C23CCCNCC2CCC3)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(C23CCCC2CN(C(=O)C2CC2)CCC3)c1

Procedure:
A solution of 1.1 g. of 5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine and 1.3 g. of cyclopropylformyl chloride in 20 ml. of N,N-dimethylformamide containing 1.4 g. of triethylamine was stirred at 25° C. for eight hours. The reaction mixture then was added to 200 ml. of water, and the aqueous solution was extracted several times with diethyl ether. The ethereal extracts were combined, and the solvent was removed therefrom by evaporation under reduced pressure to provide 2-cyclopropylformyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine. The product so formed was dissolved in 70 ml. of tetrahydrofuran containing 1 g. of lithium aluminum hydride, and the reaction mixture was heated at reflux and stirred for three hours. The reaction mixture was then cooled to 25° C. and diluted by the dropwise addition of 30 ml. of ethyl acetate. The tetrahydrofuran solution was decanted, diluted with diethyl ether, washed with water, and dried. Removal of the solvent by evaporation under reduced pressure provided 2-cyclopropylmethyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine as an oil. The oil so formed was dissolved in 50 ml. of diethyl ether through which was bubbled hydrogen chloride gas, thus forming the hydrochloride salt of the above-named compound, which precipitated out of solution. The precipitate was collected by filtration and recrystallized from 25 ml. of diisopropyl ether and 100 ml. of ethyl acetate to afford 0.75 g. of ethyl acetate to afford 0.75 g. of 2-cyclopropylmethyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine hydrochloride. M.P. 154°-156° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([OH:18])[C:15]([Cl:19])=[CH:14][C:13]=2[F:20])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C(=O)([O-])[O-].[K+].[K+].Cl[N:28]1[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[NH:29]1.C(Cl)Cl>CN(C)C=O.CO>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:18][N:28]3[N:29]=[C:30]([O:36][CH3:37])[CH:31]=[C:32]([O:34][CH3:35])[NH:33]3)[C:15]([Cl:19])=[CH:14][C:13]=2[F:20])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: Cn1nc(-c2cc(O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: COC1=CC(OC)=NN(Cl)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COC1=CC(OC)=NN(Oc2cc(-c3nn(C)c(C(F)(F)F)c3Cl)c(F)cc2Cl)N1
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
4-Chloro-3-(4-chloro-2-fluoro-5hydroxyphenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole (prepared according to the procedure as described in U.S. Pat. No. 5,281,571) (0.25 g, 0.76 mMol) was dissolved in N,N-dimethylformamide (5 ml) and potassium carbonate (0.13 g, 0.91 mMol) and 2-chloro-4,6-dimethoxytriazine (0.16 g, 0.91 mMol) were added. The suspension was stirred at 90° C. for 2 hours under a nitrogen atmosphere and processed. The residue was subjected to column chromatography on silica gel eluting with methylene chloride:methanol, 99:1, to give the title compound (0.29 g, 81.6%). 1H NMR (CDCl3, TMS): 4.01 (6H, s), 4.07 (3H, m), 7.35 (1H, d, J=9.1 Hz), 7.45 (1H, d, J=6.6 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH:15]([NH:17][NH2:18])=O>C(O)CCC>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:15]=[N:17][N:18]=3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: NNC=O
Solvent: CCCCO
Product: Clc1ccc(-c2ccc3nncn3n2)cc1

Procedure:
A mixture of 9.0 g. of 3-chloro-6-(p-chlorophenyl)pyridazine (prepared as in Example 16), 5.1 g. of formylhydrazine and 60 ml. of butyl alcohol is heated at reflux temperature for 40 hours. The reaction mixture is cooled, filtered and the solid washed with petroleum ether and with water. The material is then heated with 125 ml. of ethanol and the insoluble material is collected by filtration. The filtrate is cooled and the precipitate is collected and combined with the insoluble material collected above. The combined solids are recrystallized from 130 ml. of ethyl alcohol to provide the product of the example as crystals, m.p. 216°-218° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C@@H:17]1[CH2:22][CH2:21][CH2:20][C:19](=O)[C@H:18]1[CH2:24][CH2:25][CH2:26][OH:27].O.NN.[OH-].[K+].Cl>CCOCC.C(O)CO>[OH:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:24][CH2:25][CH2:26][OH:27]
Reactant: CCCCCCC(C)(C)c1ccc([C@@H]2CCCC(=O)[C@H]2CCCO)c(O)c1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: OCCO
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CCCC[C@H]2CCCO)c(O)c1
Temperature: 60 °C
Yield: 22 %

Procedure:
A mixture of 1.9 g. (5.08 mmoles) of trans-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-2-(3-hydroxypropyl)cyclohexanone and 10.2 ml. of hydrazine hydrate in 20 ml. of ethylene glycol is heated at 100° C. for an hour. The reaction was cooled to 60° C. and 4.05 g. (72.3 mmoles) of solid potassium hydroxide added. The resultant mixture was heated for 2 hours at 200° C., then cooled and added to 500 ml. 1 N hydrochloric acid and 300 ml. ether. The ether extract was washed with 300 ml. saturated sodium chloride, 300 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure (aspirator) to an oil. The crude oil was purified via column chromatography on 100 g. of silica gel eluted with 70% ether-hexane to yield 406 mg. (22%) of the title compound as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].C1C[O:13][CH2:12][CH2:11]1>>[CH2:2]1[CH:12]([OH:13])[CH2:11][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:1]1
Reactant: C1CCOC1
Reactant: CC(=O)c1ccccc1
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
In situ Preparation of the Compound of Formula (II) wherein R1 is ##STR12## Borane methylsulfide complex (neat, ~10M, 1.4 mL, 14 mmol) was added to a solution of cis, exo-3-amino-2-hydroxybornane [J. Chem. Soc. 49, 1970] (169 mg, 1 mmol) in THF (70 mL) at ambient temperature and was stirred for 16 hours. Acetophenone (2.36 g, 24.6 mmol) as a solution in THF (10 mL) was added to the preceding solution over one hour, stirred for fifteen minutes after addition was completed, cooled to 0° C., and quenched with methanol (27 mL). After stirring the quenched reaction for 18 hours, the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (50 mL), washed with pH 4 phosphate buffer (50 mL), water (50 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give the (R) phenethyl alcohol. 2.17 g (92% yield) 88% ee.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:9]2=[O:14])([O-])=O.CO>[Pd].CCOC(C)=O>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:9]2=[O:14]
Reactant: C[C@H](C(N)=O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Into a round bottom flask was combined (R)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (5.0 g, 0.018 mol), palladium on C (0.3 g, 0.003 mol) and methanol (200 mL, 5 mol) (about 80 mL EtOAc was added to dissolve the reactants). The reaction mixture was stirred under hydrogen balloon at room temperature for 40 min. The mixture was filtered over celite, MeOH was removed and a solid was obtained (4.02 g). MS m/z=232.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccncc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCc1ccncc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
3-Fluoro-4-(2-hydroxyethyl)pyridine (4.0 g, 28.3 mmol) and triethylamine (8.3 mL, 60 mmol) were dissolved in CH2Cl2 (40 mL) and cooled to 0° C. To this solution, methanesulfonyl chloride (2.0 mL, 31.2 mmol) was added dropwise. The mixture stirred at 0° C. for 1 h. The mixture was diluted with water, and the layers separated. The water layer was extracted with CH2Cl2. The organic layers were combined, washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum to provide 3-fluoro-4-(2-methanesulfonyloxyethyl)pyridine (5.2 g, 83%) as a pink oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15](O)=[O:16])[N:10]3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>>[C:1]1([C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[N:10]3[CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc2nc(-c3ccccc3)cn12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cccc2nc(-c3ccccc3)cn12
Temperature: 0 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of 3.14 g (11.79 mmol) of ethyl ester of 2-phenylimidazo[1,2-a]pyridine-5-carboxylic acid was added, under ice-cooling, 1.34 g (35.37 mmol) of sodium borohydride. The mixture was stirred for 3 hours under ice-cooling. The reaction mixture was poured into 150 ml of ice-water, which was sufficiently blended. To the mixture was added 12N HCl until the pH reached 2. This solution was stirred for two hours at room temperature, which was neutralized with a 6N aqueous solution of NaOH. The solvent was then completely distilled off under reduced pressure. To the residue was added 200 ml of methanol. The mixture was sufficiently blended, then insolubles were filtered off. The solvent was distilled off under reduced pressure to leave 1.37 g of a crude product (52.0%, white solid). This crude product was used in the subsequent reaction without purification.