Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[C:22]([NH:30][C:31]2[N:40]=[CH:39][C:38]3[N:37]([CH3:41])[C:36](=[O:42])[CH2:35][N:34]([CH:43]([CH3:45])[CH3:44])[C:33]=3[N:32]=2)[CH:23]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:25]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10](=[O:12])[NH:19][C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:23]=[C:22]([NH:30][C:31]2[N:40]=[CH:39][C:38]3[N:37]([CH3:41])[C:36](=[O:42])[CH2:35][N:34]([CH:43]([CH3:45])[CH3:44])[C:33]=3[N:32]=2)[CH:21]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CCCCC1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)[C@H](NC(=O)OC(C)(C)C)C4CCCCC4)cc(S(C)(=O)=O)c3)nc21
Yield: 17.5 %

Procedure:
Starting from (R)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (31.6 mg; 0.123 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (40 mg; 0.102), 11.3 mg (0.018 mmol; 17.5% yield) of the desired compound were obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C.[C:41]([O:45][CH2:46][CH3:47])(=[O:44])[CH:42]=[CH2:43]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Br:1][C:2]1[N:3]=[CH:4][C:5](/[CH:43]=[CH:42]/[C:41]([O:45][CH2:46][CH3:47])=[O:44])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(I)cnc1Br
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(Br)c(C)c1
Temperature: 90 °C

Procedure:
To a solution of 2-bromo-5-iodo-3-methylpyridine (1.5 g) in DMF (15 mL) was added palladium(II) acetate (56.5 mg) and tri-o-tolylphosphine (230 mg) and diisopropylethylamine (3.5 mL), and ethyl acrylate (1.09 mL). The mixture was heated at 90° C. for 1 hour. Resulting mixture was poured into water and extracted with AcOEt. The organic layer was washed with water and brine, and dried over Na2SO4, and the solvent was removed in vacuo. Residual brown oil was purified by silica gel column chromatography eluted with AcOEt and hexane (1:4-1:2) to give ethyl (2E)-3-(6-bromo-5-methyl-3-pyridyl)acrylate (1.00 g) as pale yellow powder.
Reaction SMILES: [Na].[OH:2][CH:3]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[CH2:9])[C:4]([O:6][CH3:7])=[O:5].C(O)(=O)C>CO>[CH3:9][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[C:3](=[O:2])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C(c1ccc(-c2ccc(F)cc2)cc1)C(O)C(=O)OC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(=O)C(C)c1ccc(-c2ccc(F)cc2)cc1
Yield: 75.4 %

Procedure:
To a solution of 0.55 g of metallic sodium in 50 ml of anhydrous methanol was added a solution of 6.1 g of methyl 2-hydroxy-3-(4'-fluoro-4-biphenylyl)-3-butenoate in 20 ml of anhydrous methanol. The resulting mixture was refluxed for 20 minutes and then cooled, and the reaction liquid was charged with 5 ml of glacial acetic acid. The mixture was distilled at a low temperature and under reduced pressure to remove the methanol therefrom. To the residue were added ethyl acetate and water, thereby effecting ethyl acetate extraction. The ethyl acetate layer was successively washed with water, aqueous sodium bicarbonate solution and water. The ethyl acetate was removed by distillation under reduced pressure to obtain crude crystals. 5.4 Grams of the crude crystals was recrystallized from ethanol to obtain 4.6 g of methyl 3-methyl-3-(4'-fluoro-4-biphenylyl)-pyruvate, m.p. 100.0°-101.6° C. The yield was 75%.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N+:16]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:8]1(=[O:9])[N:4]([CH2:3][CH:2]([OH:1])[CH2:15][N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[N+:16]([O-:18])=[O:17])[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]12
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(O)Cn1ccnc1[N+](=O)[O-]

Procedure:
To a solution of N-(2,3-epoxypropyl)phthalimide (commercially available, 20.3 g, 0.1 mol) in ethanol (200 mL), 2-nitroimidazole (11.3 g, 0.1 mol) and potassium carbonate (1.2 g) were added and the reaction mixture was refluxed for 6 hrs. The reaction mixture was cooled and poured into water (700 ml) and the yellow solid formed was filtered and dried. Yield 28.2 g (89%). It was recrystallized from methanol. mp. 213°-214° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:26][C:23]([F:24])([F:25])[C:19]1[N:18]=[C:17]([NH:16][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Reactant: Nc1cccc(C(F)(F)F)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn2ccc(Nc3cccc(C(F)(F)F)n3)nc12
Temperature: 140 °C
Yield: 17.3 %

Procedure:
A 20-mL microwave vial was charged with ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.28 g, 5.67 mmol, 1 equiv), 2-amino-6-(trifluoromethyl)pyridine (1.10 g, 6.81 mmol, 1.2 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (132 mg, 0.22 mmol, 4 mol %), tris(dibenzylideneacetone) dipalladium(0) (104 mg, 0.11 mmol, 2 mol %), sodium tert-butoxide (652 mg, 6.81 mmol, 1.2 equiv) and toluene (12 mL). The vial was sealed and the contents degassed, purged with argon and then heated in a microwave reactor at 140° C. for 20 minutes. After cooling, the mixture was diluted with ethyl acetate and filtered through a pad of Celite®. The filtrate was washed with water and saturated aqueous sodium chloride solution, dried over anydrous sodium sulphate, filtered, and concentrated under vacuum. The resultant residue was purified by flash column chromatography on silica gel (gradient: 0 to 20% ethyl acetate in dichloromethane) to give 344 mg (17%) of ethyl 5-(6-(trifluoromethyl)pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate as an orange solid. LCMS (ESI) m+H=352.1; 1H NMR (300 MHz, DMSO-d6) δ: 11.06 (s, 1H), 9.16 (d, 1H), 8.94 (d, 1H), 8.39 (s, 1H), 8.10 (t, 1H), 7.57 (d, 1H), 7.05 (d, 1H), 4.31 (q, 2H), 1.40 (t, 3H).
Reaction SMILES: C(N(CC)CC)C.Cl[CH:9]([C:35](=[O:48])[NH:36][C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[Cl:47])[C:10]([O:12][C:13]1[CH:34]=[CH:33][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:15][CH:14]=1)=[O:11].[S:49]([C:59]1[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=1)([C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)(=[O:51])=[O:50]>CN(C=O)C>[Cl:47][C:38]1[CH:39]=[CH:40][C:41]([C:43]([F:46])([F:45])[F:44])=[CH:42][C:37]=1[NH:36][C:35]([CH:9]([O:58][C:55]1[CH:54]=[CH:53][C:52]([S:49]([C:59]2[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=2)(=[O:51])=[O:50])=[CH:57][CH:56]=1)[C:10]([O:12][C:13]1[CH:34]=[CH:33][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:15][CH:14]=1)=[O:11])=[O:48]
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)C(Cl)C(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)C(Oc2ccc(S(=O)(=O)c3ccc(O)cc3)cc2)C(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1
Reaction time: 1 h
Yield: 41 %

Procedure:
Triethylamine (12.12 g, 120 mmol) was added to a solution of the chloro-coupler (24.5 g, 40.5 mmol) from (e) and 4,4'-sulfonyldiphenol (40.5 g, 162 mmol) in dry DMF (130 ml) which has been degassed with nitrogen. After stirring at 45°-50° C. under nitrogen for 1 h, the suspension was cooled and poured slowly into cold water (300 ml) and conc. hydrochloric acid (10 ml), with rapid stirring. The whole mixture was extracted with ethyl acetate (500 ml) and the organic solution washed with 3N sodium carbonate (2×400 ml), 3N hydrochloric acid (300 ml), dried over MgSO4 and evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (gradient elution from 20% ethyl acetate in petrol (b.p. 60°-80° C.) to 60% ethyl acetate in petrol (b.p. 60°-80° C.) followed by recrystallization from methanol to give a white solid (13.5 g, 41%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C(N(C(C)C)C(C)C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl>[CH3:21][O:22][CH2:23][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: COCCl
Reactant: O=C1CCc2c(O)cccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc2c1CCC2=O
Reaction time: 8 h

Procedure:
To a solution of 4.12 g of 4-hydroxy-1-indanone and 7.3 ml of N-ethyldiisopropylamine in 30 m of dichloromethane, 2.3 ml of chloromethyl methyl ether was added dropwise while stirring under ice cooling. An ice bath was removed and the mixture was continuously stirred overnight. The reaction solution was diluted with diethyl ether, washed with water, an aqueous 10% citric acid solution and an aqueous 5% sodium hydroxide solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4.23 g of the desired compound as a pale orange crystal having a melting point of 51 to 54° C.
Reaction SMILES: [CH:1]1([C@H:4]([NH2:6])[CH3:5])[CH2:3][CH2:2]1.C([O:9][C:10]([C:12]1[N:13]([CH2:25][CH2:26]Br)[N:14]=[C:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)=O)C.[I-].[K+]>C(#N)C>[CH:1]1([C@H:4]([N:6]2[CH2:26][CH2:25][N:13]3[N:14]=[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[C:12]3[C:10]2=[O:9])[CH3:5])[CH2:3][CH2:2]1
Reactant: C[C@@H](N)C1CC1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CCBr
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](C1CC1)N1CCn2nc(COc3ccccc3)cc2C1=O
Temperature: 90 °C
Reaction time: 20 h

Procedure:
(R)-1-Cyclopropylethylamine (0.3 mL, 2.82 mmol) was added to a suspension of 2-(2-bromo-ethyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (100 mg, 0.128 mmol) and potassium iodide (9.36 mg, 0.056 mmol) in ACN (1 mL). The mixture was stirred at 90° C. for 20 hours. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield (R)-5-(1-cyclopropyl-ethyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one as a orange oil. 1H NMR (500 MHz, CDCl3) δ ppm 0.29-0.37 (m, 1H), 0.38-0.49 (m, 2H), 0.60-0.70 (m, 1H), 0.86-0.97 (m, 1H), 1.28 (d, J=6.9 Hz, 3H), 3.75 (ddd, J=12.9, 7.6, 4.9 Hz, 1H), 3.87 (ddd, J=12.9, 7.4, 5.2 Hz, 1H), 4.07 (dq, J=9.2, 6.9 Hz, 1H), 4.32-4.44 (m, 2H), 5.09 (s, 2H), 6.92 (s, 1H), 6.96 (t, J=7.4 Hz, 1H), 6.98-7.03 (m, 2H), 7.27-7.32 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:11]=3[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccncc23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(-c2n[nH]c3ccncc23)c1
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
To a solution of 12 mg of 3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine in 2 mL of dichloromethane was added 1 mL of trifluoroacetic acid at room temperature and stirred at this temperature for 10 minutes. The reaction solution was poured into aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10-1:3), to afford 4 mg of the title compound as colorless crystals.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[O:15]1[CH2:19][C:18](=[O:20])[CH2:17][C:16]21[CH2:25][CH2:24][C@H:23]1[C@H:26]3[C@H:36]([CH2:37][CH2:38][C@:21]21[CH3:22])[C@:34]1([CH3:35])[C:29](=[CH:30][C:31](=[O:39])[CH:32]=[CH:33]1)[CH2:28][CH2:27]3.N.[Li]>O1CCOCC1.O1CCCC1>[O:15]1[CH2:19][C:18](=[O:20])[CH2:17][C:16]21[CH2:25][CH2:24][C@H:23]1[C@H:26]3[C@H:36]([CH2:37][CH2:38][C@:21]21[CH3:22])[C@:34]1([CH3:35])[C:29](=[CH:30][C:31](=[O:39])[CH2:32][CH2:33]1)[CH2:28][CH2:27]3
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21CC(=O)CO1
Agent: N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21CC(=O)CO1

Procedure:
The compounds of this invention defined by the introductory formula when R therein represents methyl can be prepared as follows: 21-(Hydroxymethyl)-5α,17α-pregn-20-ene-3β,17-diol, upon prolonged contact with p-toluenesulfonyl chloride in pyridine, affords spiro[5α-androstane-17,2' (5'H)-furan]-3β-ol, from which, upon consecutive contact in cold tetrahydrofuran under nitrogen with borane and sodium peroxide (formed in situ), 4',5'-dihydrospiro[5α-androstane-17,2'(3'H)-furan] -3β,4'-diol is obtained. The hydroxyls therein are oxidized to oxos with Jones' reagent (prepared by dissolving 10 parts of chromium trioxide in 20 parts of water and consecutively adding to the resultant solution 15 parts of concentrated sulfuric acid and 20 parts of water) in acetone. The 4',5'-dihydrospiro[5α-androstane-17,2'(3'H)-furan]-3,4'-dione thus obtained, upon heating in dioxane under nitrogen with dichlorodicyanobenzoquinone, affords a mixture of 4',5'-dihydrospiro[5α-androst-1-ene-17,2'(3'H)-furan]-3,4'-dione and 4',5'-dihydrospiro[androsta-1,4-diene-17,2'(3'H)-furan]-3,4'-dione, separable by chromatography. The Δ1,4 product, consecutively contacted in tetrahydrofuran with liquid ammonia and lithium, affords 4',5'-dihydrospiro[androst-4-ene-17,2'(3'H)-furan]-3,4'-dione.
Reaction SMILES: C1C2C(=CC=CC=2)C=NN=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[CH3:22][N:23]([CH3:25])[NH2:24]>>[CH3:22][N:23]([CH3:25])[N:24]1[C:14](=[O:15])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:16]
Reactant: CN(C)N
Reactant: O=C1OC(=O)c2ccccc21
Agent: c1ccc2cnncc2c1
Product: CN(C)N1C(=O)c2ccccc2C1=O

Procedure:
Phthalazine derivatives of formula IA were prepared as described in FIG. 8 and as further detailed in Example 4. The commercially available phthalic anhydride was reacted with N,N-dimethyl hydrazine to give 2-(dimethylamino)isoindoline-1,3-dione 16 in good yield [Hanefeld W et al. J Heterocyclic Chem. 1996;33:1443]. Then, 16 was reacted with phenylmagnesium bromide, to lead to the intermediate 17 in good yield [Deniau E et al. Tetrahedron: Asym. 2003;14:2253], which in turn was quantitatively converted by reaction with hydrazine to 4-phenylphthalazin-1(2H)-one 18 [Saito Y et al. Synthesis 2001;2:221]. Finally, the N-amidation product 19 (Compound I) was the major product obtained in good yield whatever the experimental conditions. Two different carbamoyl chlorides were used (R1=CH3—compound 19a; and i-Pr—compound 19b) for the preparation of phthalazine derivatives. (FIG. 8).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8](=[C:14]([F:16])[F:15])[CH2:9][CH2:10][C:11](O)=[O:12].O>C(OCC)C>[F:7][C:8](=[C:14]([F:16])[F:15])[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: O=C(O)CCC(F)=C(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCCC(F)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a stirred suspension of 0.4 gram (0.01 mole) of lithium aluminum hydride in 20 ml of diethyl ether was added dropwise a solution of 1.5 grams (0.01 mole) of 4,5,5-trifluoro-4-pentenoic acid in 30 ml of diethyl ether. Upon completion of addition the reaction mixture was stirred at ambient temperature for one hour, then 20 ml of water was added carefully. The mixture was filtered and the filtrate concentrated under reduced pressure to give 0.8 gram of 4,5,5-trifluoro-4-penten-1-ol as an oil. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[C:21]([C:22](OCC)=[O:23])=[C:12]2[C:13]3[CH:19]=[C:18]([CH3:20])[O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:7]([C:9]1[C:21]([CH2:22][OH:23])=[C:12]2[C:13]3[CH:19]=[C:18]([CH3:20])[O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8]
Reactant: CCOC(=O)c1c(CC)nn2ccc3oc(C)cc3c12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nn2ccc3oc(C)cc3c2c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.1 %

Procedure:
To a suspension of 80% lithium aluminum hydride (293 mg, 7.91 mmol) in tetrahydrofuran (16 mL) was added a solution of ethyl 2-ethyl-8-methylfuro[3,2-c]pyrazolo[1,5-a]pyridine-1-carboxylate (430 mg, 1.26 mmol) in tetrahydrofuran (16 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Sodium sulfate decahydrate (4.3 g) was added under ice-cooling, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give the title compound (360 mg, yield 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@@H:7]1[C:12]([OH:14])=O)=[O:5])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1>>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@@H:7]1[C:12](=[O:14])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)=[O:5])[CH3:2]
Reactant: C=C1C[C@H](C(=O)O)[C@@H](C(=O)OCC)C1
Reactant: Nc1ccc(Cl)cn1
Product: C=C1C[C@H](C(=O)Nc2ccc(Cl)cn2)[C@@H](C(=O)OCC)C1
Yield: 48 %

Procedure:
Starting from 41b, the title compound was prepared in 48% yield according to the procedure for example 1 and 2, step 2 using 2-amino-5-chloropyridine. MS: 309.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=O)[C:5]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[N:6][CH:7]=1.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[N:15]([OH:17])[C:9]([C:10]([F:13])([F:12])[F:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(Nc1ncc(Cl)cc1[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: On1c(C(F)(F)F)nc2ncc(Cl)cc21

Procedure:
5-Chloro-3-nitro-2-(trifluoroacetamido)pyridine (2.0 grams) was hydrogenated with two moles of hydrogen in ethanol containing 0.5 gram of 5 percent palladium on carbon. The resulting reaction mixture was filtered and evaporated to separate the desired 6-chloro-1-hydroxy-2-(trifluoromethyl)-1H-imidazo-(4,5-b)pyridine compound which, after recrystallization from benzene melted at 268°-70°C.
Reaction SMILES: [F:1][C:2]1([F:14])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][C:3]1([F:13])[F:12].C([Li])CCC.[Br:20]C(F)(F)C(F)(F)Br.[Cl-].[Na+]>O1CCCC1.O>[Br:20][C:11]1[C:5]2[O:4][C:3]([F:12])([F:13])[C:2]([F:1])([F:14])[O:7][C:6]=2[CH:8]=[CH:9][CH:10]=1
Reactant: FC1(F)Oc2ccccc2OC1(F)F
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC1(F)Oc2cccc(Br)c2OC1(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin (5.00 g, 24.0 mmol) in dry tetrahydrofuran (150 mL) is cooled to -78° C. under a nitrogen atmosphere. A solution of n-butyllithium (10.6 mL, 26.4 mmol of a 2.5M solution in hexanes) is added dropwise while maintaining the reaction temperature below -65° C. The reaction mixture is stirred at -78° C. for 30 min and then 1,2-dibromotetrafluoroethane (3.16 mL, 26.4 mmol) is added dropwise. After this addition is complete, the reaction mixture is allowed to come to room temperature. A small mount of water is slowly added to the mixture which is then poured into water. The aqueous mixture is saturated with sodium chloride and is extracted with diethyl ether. The combined organic extracts are dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound of Step A.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.CCN=C=NCCCN(C)C.[C:31]12([C:41](O)=[O:42])[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2>C(Cl)Cl>[C:31]12([C:41]([N:12]3[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]3)=[O:42])[CH2:38][CH:37]3[CH2:36][CH:35]([CH2:34][CH:33]([CH2:39]3)[CH2:32]1)[CH2:40]2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)C13CC4CC(CC(C4)C1)C3)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 0.096 ml was added in a methylene chloride 5 ml solution of (IS)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 100 mg, and stirred at 0° C. for 30 min. WSC 0.13 g and 1-adamantanecarboxylic acid 0.11 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 15 hours. The reaction mixture was washed with saturated sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(1-adamantyl carbonyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 10 ml solution of lithium aluminum hydride 24.0 mg and refluxed under heating for 1.5 hour. The reaction mixture was cooled, then added water, and removed the insoluble material by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform) to obtain the product.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1.Cl>C(O)(C)C>[ClH:1].[Br:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[C:26]([F:31])[CH:25]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C)CC1
Yield: 95.8 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (200 mg, 0.62 mmol) and 4-bromo-2-fluoroaniline (142 mg, 0.74 mmol) in isopropanol (3 ml) containing 6N hydrogen chloride in isopropanol (110 μl, 0.68 ml) was heated at reflux for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol followed by ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride (304 mg, 90%).