Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[C:3]([O:7][C:8]([C@H:10]1[N:14]([C:15](=[O:38])[CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][C:28]([O:30]CC3C=CC=CC=3)=[O:29])[CH:22]=2)=[O:19])[C@@H:13]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:12]([C:45]([OH:47])=[O:46])[S:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C([O-])=O.[NH4+]>[OH-].[Na+].[Pd]>[C:3]([O:7][C:8]([C@H:10]1[N:14]([C:15](=[O:38])[CH2:16][NH:17][C:18](=[O:19])[NH:20][C:21]2[CH:22]=[C:23]([CH2:27][C:28]([OH:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[C@@H:13]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:12]([C:45]([OH:47])=[O:46])[S:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)[C@@H]1S[C@@H](C(=O)O)[C@H](c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1S[C@@H](C(=O)O)[C@H](c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
10 ml of methanol are added slowly, under an inert atmosphere, to a round-bottomed flask containing 0.3 g of (2S,4S,5R)-2-tert-butoxycarbonyl-3-{2-[3-(3-benzyloxycarbonylmethylphenyl)ureido]-acetyl}-4-phenyl-5-thiazolidinecarboxylic acid, 0.18 g of ammonium formate and 0.3 g of 10% palladium-on-charcoal. The reaction medium is heated at reflux for 1 hour and then cooled to a temperature in the region of 25° C. The catalyst is separated out by filtration and the filtrate is concentrated to dryness under reduced pressure at 40° C. The residue obtained is dissolved in 9.4 ml of aqueous 0.1N sodium hydroxide solution. The aqueous solution obtained is filtered and brought to pH 2 by addition of aqueous 0.1N hydrochloric acid solution. The precipitated product is isolated by filtration, washed with twice 5 ml of water and air-dried. 0.19 g of 3-{3-[2-((2S,4S,5R)-2-tert-butoxycarbonyl-5-carboxy-4-phenyl-3-thiazolidinyl)-2-oxoethyl]ureido}phenylacetic acid is thus obtained in the form of a white solid melting at 130° C., [α]D25 =-3.9°±1.0 (c=0.407; MeOH); 1H NMR (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 373 K, δ in ppm): 1.49 (s, 9H: CH3 of the tert-butyl); 3.49 (s, 2H: ArCH2COO); 3.65 and 4.03 (broad d and d respectively, J=17 Hz, 1H each: COCH2N); 4.19 (d, J=3.5 Hz, 1H: H at C5 of the ring); 5.70 (s, 1H: H at C2 of the ring); 5.76 (d, J=3.5 Hz, 1H: H at C4 of the ring); 6.83 (broad d, J=7.5 Hz, 1H: aromatic H (H ortho to the CH2)); 7.14 (t, J=7.5 Hz, 1H: aromatic H (H meta to the CH2); from 7.20 to 7.50 (mt, 5H: aromatic H); 7.72 (broad d, J=7.5 Hz, 2H: H ortho to the phenyl).
Reaction SMILES: C([Li])CCC.I[C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14][OH:15].B(OC)(OC)OC.C(=O)([O-])[O-].[Na+].[Na+].[C:29]([O:33][C:34](=[O:55])[NH:35][C:36]([C:38]1[S:39][C:40]([S:53][CH3:54])=[C:41]([S:43]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48](Br)[CH:47]=2)(=[O:45])=[O:44])[CH:42]=1)=[NH:37])([CH3:32])([CH3:31])[CH3:30]>CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:29]([O:33][C:34](=[O:55])[NH:35][C:36]([C:38]1[S:39][C:40]([S:53][CH3:54])=[C:41]([S:43]([C:46]2[CH:47]=[C:48]([C:7]3[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:14][OH:15])[CH:49]=[CH:50][CH:51]=2)(=[O:45])=[O:44])[CH:42]=1)=[NH:37])([CH3:32])([CH3:31])[CH3:30]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: Cc1cccc(CO)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
n-Butyllithium (2.5M) [4.03 mL] was added to a solution of (2-iodo-3-methyl-phenyl)-methanol (1.00 g, 4.04 mL) [example 213, step a] in ether [20 mL] at −78° C. and stirred for 0.5 hours. Trimethyl borate [1.13 mL, 10.1 mmol) was added and the solution was stirred for 2 hours at room temperature, followed by evaporation. The crude residue was dissolved in ethanol/toluene (1/2) [30 mL] and 2M sodium carbonate [16.2 mL] followed by addition of {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.49 g, 1.01 mmol) [example 27, step c]. The solution was bubbled with argon and then tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.15 mmol) was added. The reaction was refluxed for 3 hours and then cooled to room temperature. Ethyl acetate was added and the crude reaction was washed with brine, dried over magnesium sulfate and evaporated. Column chromatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.40 g, 74%) as a solid. ESI-MS (m/z): Calcd. for C25H28N2O5S3: 532.12; found: 532.7.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].CS(OC[CH:20]([CH2:26][CH:27]=[CH2:28])[CH2:21][CH2:22][CH2:23][C:24]#[N:25])(=O)=O.[Cl-].[Li+]>O1CCCC1.CN(C)C=O.O.C(O)(=O)C>[C:24]([CH2:23][CH2:22][CH2:21][CH:20]([CH2:26][CH:27]=[CH2:28])[CH2:3][CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8])#[N:25]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCC(CCCC#N)COS(C)(=O)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CCC(CCCC#N)CCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5410 g of diethyl malonate in 2000 ml of tetrahydrofuran is added to a mixture of 1351 g of 60% sodium hydride in mineral oil in 36 ml of tetrahydrofuran over a period of 4 h, keeping the temperature below 26°, and the mixture is stirred for 0.5 h. A solution of 3705 g of 6-methylsulfonyloxy-5-(2-propenyl)-hexanenitrile in 200 ml tetrahydrofuran is added rapidly and the mixture is heated under reflux for 24 h and allowed to cool overnight. The mixture is neutralized to pH 7 with glacial acetic acid (about 1 l) and evaporated to dryness. A solution of the residue in 30 l of ether is washed consecutively with water, saturated sodium bicarbonate solution, water and brine, and evaporated to dryness. The mineral oil is separated in a separatory funnel and the remaining product is washed three times with heptane, concentrated at 80°/0.01 mm Hg (=0.013 mbar), and distilled at 150° to remove diethyl malonate and obtain crude diethyl [5-cyano-2-(2-propenyl)-pentyl]-malonate. The above malonate ester (2169 g) is added to a solution of 622.9 g of lithium chloride in a mixture of 10845 ml dimethylformamide and 1085 ml of water. The mixture is heated at reflux for 27 h and is allowed to cool to room temperature overnight. The solution is poured into 22 l of ice/water, extracted with ether, and the extract is then washed with saturated sodium bicarbonate, water and brine, dried over sodium sulfate and evaporated to dryness. The residue is distilled to yield ethyl 4-(3-cyanopropyl)-6-heptenoate, b.p. 136-138/0.2 mm Hg (=0.27 mbar).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1.C(O)C>O>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Solvent: O
Solvent: CCO
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 94 °C
Yield: 72 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (5 g, 0.02 mol), N-methylpiperazine (12.5 mL, 2.5 vol) and ethanol (15 mL, 3 vol) were charged into a three-necked round bottom flask equipped with a reflux condenser, overhead stirrer, and thermometer. The reaction mixture was slowly heated to reflux (94° C.) under a nitrogen atmosphere and kept at this temperature overnight. The reaction mixture was cooled to below 50° C. and water (10 mL, 2 vol) was added to precipitate out the solid, which was isolated by filtration. The light yellow solid was washed twice with water (5 mL) and dried to furnish pure olanzapine in 72% yield (4.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:23][CH:24]([CH3:26])[O-:25].[Na+]>C(O)(C)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:25][CH:24]([CH3:26])[CH3:23])[N:3]=1
Reactant: CC(C)[O-]
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and sodium isopropoxide in isopropanol. ES-MS m/e (%): 299 (M+H+, 100).
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[CH2:23]([C@@H:30]1[CH2:35][C@@H:34]([N:36]([CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[CH:46][CH:45]=2)[C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])[CH2:33][CH2:32][NH:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[F:54][C:55]([F:70])([F:69])[C:56]1[CH:57]=[C:58]([CH:62]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:64]=1)[C:59](O)=[O:60]>C(Cl)Cl>[CH2:23]([C@@H:30]1[CH2:35][C@@H:34]([N:36]([CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[CH:46][CH:45]=2)[C:37](=[O:42])[C:38]([F:40])([F:41])[F:39])[CH2:33][CH2:32][N:31]1[C:59](=[O:60])[C:58]1[CH:62]=[C:63]([C:65]([F:66])([F:67])[F:68])[CH:64]=[C:56]([C:55]([F:54])([F:69])[F:70])[CH:57]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
143 mg (561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine are added to a solution of 200 mg (467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 113 mg (561 mmol) of 3,5-bis-(trifluoromethyl)-benzoic acid in 3 ml of methylene chloride, and the reaction mixture is left to stir at room temperature for 16 hours. It is then diluted with methylene chloride, and the organic phase is washed once each with 10% strength citric acid, 1N sodium bicarbonate solution and with brine, dried over magnesium sulfate and evaporated to dryness. The yellowish foam is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (1000:50:1). The title compound is obtained as yellow oil. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.34, FD-MS: M+ =667.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C1(C(C2C=CC=CC=2)=[NH:29])C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C>[NH2:29][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C1CCN(c2c(F)cncc2Br)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C1CCN(c2c(N)cncc2F)CC1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
Tert-butyl 1-(3-bromo-5-fluoropyridin-4-yl)piperidine-4-carboxylate 26 (800 g, 2.23 mol) was dissolved in 1,4-dioxane (7.5 L). Diphenylmethanimine (484 g, 2.67 mol) was added in one portion followed by cesium carbonate (1.45 Kg, 4.45 mol), xantphos (129 g, 223 mmol) and Pd2(dba)3 (102 g, 111 mmol). Additional 1,4-dioxane (2.9 L) was added and the mixture heated to 95° C. under nitrogen until the reaction was complete (determined by HPLC analysis). The mixture was cooled to 20° C. and ethyl acetate (8 L) and water (4 L) were added. The organic phase was isolated and washed with water (4 L) and brine (3.5 L) and dried over magnesium soleplate and filtered. The filtrate was concentrated to a brown oil (1.3 Kg). The oil was dissolved in 2-methyltetrahydrofuran (7.2 L) and 2M HCl was added at 20° C. and the mixture stirred for 30 minutes. The aqueous layer was isolated and the organic layer extracted with 2M HCl (1.2 L). The combined aqueous was neutralised with 2M NaOH (5.4 L, pH 8-9). The product was extracted into 2-methyltetrahydrofuran (14 L then 2×5 L). The combined extracts were washed with water (1.6 L) and the organic solution concentrated. The residue was slurried in acetonitrile (2 L), filtered and dried. This gave the product 27 as a white solid (568.7 g, 86.5%); 1H NMR (500 MHz, DMSO-d6) δ 7.82 (d, 1H), 7.63 (d, 1H), 5.22 (s, 2H), 3.11-3.00 (m, 2H), 2.91 (tt, 2H), 2.36 (tt, 1H), 1.88-1.83 (m, 2H), 1.79-1.71 (m, 2H), 1.43 (s, 9H); 19F NMR (500 MHz, DMSO-d6) δ −140.0; MS (ES+) 297.1.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]2[N:17]=[C:16]([O:18][C@H:19]3[CH2:23][CH2:22][O:21][CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][N:34]([CH3:49])[CH2:35][CH2:36][NH:37][C:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)=[O:39]>CN(C=O)C.O>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]2[N:17]=[C:16]([O:18][C@H:19]3[CH2:23][CH2:22][O:21][CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:43]4[CH:44]=[CH:45][C:40]([C:38]([NH:37][CH2:36][CH2:35][N:34]([CH3:33])[CH3:49])=[O:39])=[CH:41][CH:42]=4)[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CNc2nc(O[C@H]3CCOC3)c3cc(Br)ccc3n2)cc1
Reactant: CN(C)CCNC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1ccc(-c2ccc3nc(NCc4ccc(F)cc4)nc(O[C@H]4CCOC4)c3c2)cc1
Yield: 64.5 %

Procedure:
(S)—N-(4-fluorobenzyl)-6-bromo-4-(tetrahydrofuran-3-yloxy)quinazolin-2-amine (50 mg, 0.12 mmol), potassium carbonate (33 mg, 0.24 mmol), tetrakis(triphenyl-phosphine)palladium (8 mg, 0.007 mmol) and 4-((2-(dimethylamino)ethyl)-carbamoyl)phenylboronic acid (36 mg, 0.132 mmol) in DMF (1.0 mL) and water (0.3 mL) was heated to 150° C. for 10 minutes under microwave irradiation. Solvents were concentrated in vacuo and the residue was purified by RP HPLC, using a C18 column with a gradient of 0.1% H2O, 0.1% TFA-acetonitrile, to provide the desired product (41 mg) which was characterized by its mass spectrum as follows: MS (m/z): 530 ([M+H]+, 100); HPLC Rt=1.26 minutes (Method B).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][OH:7].C(O[CH:17](OCC)[CH2:18][CH2:19][Cl:20])C.Cl>O>[Cl:20][CH2:19][CH2:18][CH:17]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6][O:7]1
Reactant: CCOC(CCCl)OCC
Reactant: COc1cccc(CCO)c1OC
Agent: Cl
Solvent: O
Product: COc1ccc2c(c1OC)CCOC2CCCl
Reaction time: 0.42 h
Yield: 85.2 %

Procedure:
To a mixture of 20 g of 2,3-dimethoxyphenethyl alcohol and 22 g of β-chloropropionaldehyde diethyl acetal was added 30 ml of concentrated hydrochloric acid, followed by heating at 60°-85° C with stirring for 25 minutes. After cooling, the reaction mixture was diluted with 100 ml of water and extracted with ethyl acetate. The extract was rinsed with water, dehydrated, treated with activated carbon and concentrated under reduced pressure. By the above procedure was obtained 24 g of 1-(2-chloroethyl)-5,6-dimethoxyisochroman as a colorless oil. Together with 15 ml of piperidine, 3 of this oil was heated under reflux for 2 hours, with constant stirring. After cooling, the reaction mixture was concentrated and the residue was diluted with 100 ml of water and extracted with ethyl acetate. The extract was rinsed with water, dried and concentrated under reduced pressure. The oily residue was chromatographed on a column of silica gel, elution being carried out with a 9:1 mixture of chloroform and methanol. By this procedure was obtained 2.7 g of 5,6-dimethoxy-1-(2-piperidinoethyl)isochroman as an oil. This oil was dissolved in 10 ml of alcoholic hydrochloric acid, followed by addition of ethyl ether. The mixture was left standing, whereby 1.5 g of 5,6-dimethoxy-1-(2-piperidinoethyl)-isochroman hydrochloride was obtained as colorless crystals, melting point: 178°-180° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(O[K])(C)(C)C.F[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].CCOC(C)=O>CS(C)=O>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: c1c[nH]cn1
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of imidazole (0.997 g, 14.65 mmol) and tert-BuOK (1.722 g, 15.35 mmol) was put under Ar in a 100 mL and dissolved in dry DMSO (15 mL) to give a colorless solution. After 5 min, 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (2.04 mL, 14.58 mmol) was added within 30 s, immediately leading to a darkening of the rm to black. A temperature rise was also noted. The black solution was stirred at RT for 20 min. Ice water (60 mL) and EtOAc (50 mL) were added, the organic layer was isolated, and the aqueous phase was extracted twice with 20 mL EtOAc. The organic layer was washed with H2O (2×30 mL), brine, dried, filtered and evaporated to give the title compound as an orange oil. Yield: 3.66 g (97%).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14]([NH2:16])=[N:13][CH:12]=[N:11][C:10]=3[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]CC4C=CC=CC=4)[CH:18]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C1COCC1>[C:1]1([C:7]2[C:15]3[C:14]([NH2:16])=[N:13][CH:12]=[N:11][C:10]=3[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Nc1ncnc2c1c(-c1ccccc1)cn2-c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccccc1)cn2-c1cccc(O)c1
Temperature: 25 °C

Procedure:
2.61 g of 5-phenyl-7-(3-benzyloxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine (Ex. 11) and 1.0 g of palladium on carbon 10% are stirred at 40° C. for 30 h in 100 ml of THF until the amount of hydrogen theoretically required has been consumed. After cooling to RT, the mixture is filtered and the filtrate is concentrated in an RE. The residue is slurried with ether and the crystals are filtered off. Recrystallization from methylene chloride/ethanol and from chloroform does not give a pure product. After chromatography on silica gel (methylene chloride/methanol containing NH3 (4N) 92:8), the product-containing fractions are concentrated. The residue is dissolved in hot chloroform, the solution is cooled to 0° C. and the crystals are filtered off. After filtration and drying under HV, pure 5-phenyl-7-(3-hydroxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine having a melting point of 227°-228° C. is obtained. 1H--NMR (d6 -DMSO): delta (ppm)=6.2 (br. s, 2H), 6.8 (br. d, 1H), 7.2-7.4 (m, 4H), 7.5-7.6 (m, 4H), 7.7 (s, 1H), 8.2 (s, 1H), 9.8 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[C:1]1([CH:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][CH:8]2[CH2:16][C:17]([OH:19])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CC1OC2=CC=CC2=CC1c1ccccc1

Procedure:
3-Phenyl-7-benzofuranacetic acid (2.5 g., 0.01 mole) is reduced with hydrogen gas using palladium on charcoal as catalyst and ethanol as solvent in a Brown hydrogenator. After the absorption of hydrogen stops, the reaction mixture is filtered, then the filtrate is evaporated in vacuo to a white solid. Recrystallization from a benzene-hexane mixture gives white crystals of 2,3-dihydro-3-phenyl-7-benzofuranacetic acid, m.p. 110.5°-111.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][C:5]2[O:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:3]1=[O:23].[H][H]>[Pd].C(O)C>[NH:15]=[C:16]([C:4]1[C:3](=[O:23])[N:2]([CH3:1])[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][C:5]=1[OH:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cn1c(-c2ccccn2)cc2onc(-c3ccccc3)c2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cn1c(-c2ccccn2)cc(O)c(C(=N)c2ccccc2)c1=O

Procedure:
A mixture of 16.5 g. (0.0545 mole) of 5-methyl-3-phenyl-6-(2-pyridyl)-isoxazolo[4,5-c]pyridin-4(5H)-one, 330 ml. ethanol and 1.65 g. 10% palladium on carbon is hydrogenated at 50 psi and room temperature. The hydrogenation is ceased after one equivalent of hydrogen is absorbed (ca. 2.5 hours). The mixture is treated with methylene chloride and the catalyst is removed by filtration. The solvents are removed in vacuo to a volume of ca. 50 ml. and then ether is added, to precipitate solids which are removed by filtration to give 3-(α-iminobenzyl)-4-hydroxy-6-(2-pyridyl)-1-methyl-2(1H)-pyridone; m.p. 242° to 245° C. In order to obtain the sodium salt of the aforementioned compound, for example, the compound is dissolved in methanol and treated with sodium hydroxide solution to yield after evaporation the sodium salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Br:26])[C:5]2[N:10]=[C:9]([C:11]3[N:12]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:13]=[C:14]([Br:16])[CH:15]=3)[O:8][C:7](=[O:24])[C:6]=2[CH:25]=1.O.[NH2:28][NH2:29].O1CCCC1>O>[Br:16][C:14]1[CH:15]=[C:11]([C:9]([NH:10][C:5]2[C:4]([Br:26])=[CH:3][C:2]([Br:1])=[CH:25][C:6]=2[C:7]([NH:28][NH2:29])=[O:24])=[O:8])[N:12]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:13]=1
Reactant: O=c1oc(-c2cc(Br)cn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: NNC(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
Under ice-cooling, 0.569 g of 6,8-dibromo-2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one, 0.20 g of hydrazine monohydrate and 2 ml of tetrahydrofuran were mixed, and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain 0.53 g of 4-bromo-N-[4,6-dibromo-2-(hydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][C:9]([C:13]([OH:15])=O)=[CH:8]2.P(C#N)(OCC)(OCC)=O.[CH2:26]([N:28](CC)[CH2:29]C)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][C:9]([C:13]([N:28]([CH3:29])[CH3:26])=[O:15])=[CH:8]2
Reactant: COc1cccc2c1OCC(C(=O)O)=C2
Reactant: CCN(CC)CC
Agent: CCOP(=O)(C#N)OCC
Product: COc1cccc2c1OCC(C(=O)N(C)C)=C2

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 4 using 8-methoxy-2H-chromene-3-carboxylic acid (8.0 g), triethylamine (14.0 ml) and diethyl cyanophosphate (8.2 ml), the title compound (3.2 g) was obtained as a brown oil.