Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25].CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)C.C1(C)C=CC=CC=1>[F:21][C:22]1[CH:23]=[C:24]([NH:25][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Nc1ccc(F)c(F)c1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(Nc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a 300-mL three-neck flask were placed 200 mL of toluene, 0.21 g (0.96 mmol) of palladium acetate, and an ellipsoidal stirring chip. The two outer necks were closed with septum caps and the center neck was provided with a reflux coiled condenser. To the top of the condenser was attached a three-way stopcock, to which is attached a balloon filled with nitrogen gas. The atmosphere in the flask was replaced three times by nitrogen gas supplied from the balloon with the help of a vacuum pump. Into the flask was injected 3.8 g (18.9 mmol) of tris-t-butylphosphine by means of a syringe, followed by stirring for five to ten minutes at room temperature. The flask was further charged with 10 g (63.7 mmol) of 4-bromobenzene, 4.11 g (31.8 mmol) of 3,4-difluoroaniline, and 6.1 g (63.7 mmol) of sodium t-butoxide. With the flask placed on an oil bath, the solution therein was gradually heated to 120° C. with stirring. After 20 hours, the flask was dismounted from the oil bath so as to terminate reaction, and the solution was allowed to cool to room temperature in an atmosphere of nitrogen. The reaction solution was transferred to a separatory funnel and was given 70 mL of diethyl ether. It was washed several times with 100 mL of saturated aqueous solution of sodium chloride. The organic layer was separated and dried with anhydrous magnesium sulfate. With the anhydrous magnesium sulfate filtered out, the organic layer was freed of solvent by means of an evaporator. Thus there was obtained a crude product, which was subsequently purified by means of a silica gel column (hexane:chloroform=2:1) (Yields: 92%).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].N1C=CC=CC=1.[C:13]12([NH:23][C:22](=[O:24])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[O:19]1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2.O>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([N:23]1[C:13]2([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[O:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]1=[O:24])=[O:4]
Reactant: CC(Br)C(=O)Br
Reactant: O=C1NC2(CCCCC2)Oc2ccccc21
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(Br)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 89.1 ml of 2-bromopropionyl bromide in 95 ml of methylene chloride and a solution of 61.13 g of pyridine in 95 ml of methylene chloride are added dropwise to a suspension of 140 g of spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one in 190 ml of methylene chloride under nitrogen atmosphere at -5° C. during about 45 minutes. Then the mixture is stirred at a room temperature for 6 hours. The reaction mixture is poured into 500 ml of water and the mixture is extracted with methylene chloride. The extract is washed, dried and evaporated to remove the solvent and the residue obtained is crystallized from methanol and the crystals are collected by filtration to obtain 197.3 g of 3-(2-bromopropionyl)-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.C(Br)C.[Mg].[CH3:12][C@H:13]1[CH2:18][C:17](=[O:19])[CH2:16][CH2:15][O:14]1.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Br:1][C:2]1[S:3][C:4]([C@@:17]2([OH:19])[CH2:16][CH2:15][O:14][C@@H:13]([CH3:12])[CH2:18]2)=[CH:5][CH:6]=1
Reactant: Brc1ccc(Br)s1
Reactant: C[C@H]1CC(=O)CCO1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H]1C[C@@](O)(c2ccc(Br)s2)CCO1
Temperature: 40 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A solution of a mixture of 2,5-dibromothiophene (1.9 g) and ethyl bromide (2.56 g) in THF (6 ml) was added dropwise to a stirred suspension of magnesium (0.29 g) in diethyl ether (3 ml) and the mixture was warmed gently to promote the formation of a Grignard Reagent. The mixture was heated to 40° C. for 1 hour. The mixture was cooled in an ice-bath and a solution of (2S)-2-methyltetrahydropyran-4-one [European Patent Application No. 0385662 (Example 20 thereof); 0.61 g] in THF (5 ml) was added dropwise. The mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using initially methylene chloride and then increasingly polar mixtures of methylene chloride and diethyl ether as eluent. There was thus obtained, as a less polar isomer, (2S,4R)-4-(5-bromothien-2-yl)-4-hydroxy-2-methyltetrahydropyran (0.248 g, 19%) as an oil, having the 2-methyl and 4-hydroxy groups in a trans-relationship.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1[CH:8]=[CH:9][C:10]2[C:16](C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)[O:15][C:13](=O)[C:11]=2[CH:12]=1.C(OCC)(=O)C.Cl>O1CCCC1.O>[CH2:13]1[O:15][CH2:16][C:10]2[C:11]1=[CH:12][CH:7]=[CH:8][CH:9]=2
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)COC2
Reaction time: 6 h

Procedure:
Lithium aluminum hydride (3.0 g) and 100 ml of dry tetrahydrofuran wereplaced in a 3-neck flask equipped with a mechanical stirrer, condenser witha nitrogen inlet and addition funnel. Phenolphthalein (6.4 g) dissolved in 300 ml of dry tetrahydrofuran was added dropwise to the stirred lithium aluminum hydride suspension at a rate to maintain a gentle reflux. When addition was complete, the reaction mixture was stirred for six hours at reflux by heating with an oil bath and then allowed to stand overnight. Tothe stirred solution was added excess ethyl acetate followed by 500 ml of water. The pH was adjusted to approximately 2 with conc. HCl and the solution extracted with two 500 ml portions of ether. The ether layer was washed six times with 10% aqueous potassium carbonate (each time the base layer was magenta), and then evaporated to dryness to leave an off-white solid (4.5 g crude yield). The solid was crystallized from 440 ml of 20% ethanol and dried in vacuo at 60° C. to give the corresponding phthalan as very light yellow crystals (yield 3.3 g; melting range 195°-197.5° C.). TLC using ether-silica gel gave one spot. Nmr did not show methine H and was more consistent with the cyclic ether (phenolphthalan) than the open form (phenolphthalol).
Reaction SMILES: [CH2:1]([S:3]([C@@H:6]1[N:9]([C:10](=[O:12])[CH3:11])[C:8](=[O:13])[C@H:7]1[CH2:14][CH2:15][CH2:16][N:17](C(OCC1C=CC=CC=1)=O)[C:18]([NH:20]C(OCC1C=CC=CC=1)=O)=[NH:19])(=[O:5])=[O:4])[CH3:2].[ClH:41]>[Pd].CO.C(OCC)(=O)C>[ClH:41].[CH2:1]([S:3]([C@@H:6]1[N:9]([C:10](=[O:12])[CH3:11])[C:8](=[O:13])[C@H:7]1[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH2:20])=[NH:19])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)[C@H]1[C@H](CCCN(C(=N)NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)C(=O)N1C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)[C@H]1[C@H](CCCNC(=N)N)C(=O)N1C(C)=O
Yield: 62 %

Procedure:
A methanol/ethyl acetate (2.5 mL/2.5 mL) solution of compound 22 (380 mg, 0.66 mmol) and 1N HCl (0.66 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere until TLC indicated the disappearance of the starting material. The suspension was filtered through a pad of Celite, and the solution was concentrated to afford 140 mg (62%) of the product as a yellow foam.
Reaction SMILES: [C:1]([CH:4]1[C:8](=[O:9])[CH:7]([CH3:10])[CH2:6][S:5]1)(=[O:3])[CH3:2].S(Cl)(Cl)(=O)=O.S(Cl)(Cl)(=O)=O.C(Cl)Cl.Cl>C(Cl)Cl.O>[C:1]([C:4]1[S:5][CH:6]=[C:7]([CH3:10])[C:8]=1[OH:9])(=[O:3])[CH3:2]
Reactant: CC(=O)C1SCC(C)C1=O
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1scc(C)c1O
Reaction time: 0.5 h

Procedure:
36.0 g (0.227 mol) of 2-acetyl-3-keto-4-methyl-4,5-dihydrothiophene are initially introduced into 260 ml of methylene chloride 21.9 ml of sulphuryl chloride in 260 ml of methylene chloride are then added dropwise at 0° C. While the sulphuryl chloride/methylene chloride mixture is added dropwise, a stream of nitrogen is passed into the solution to expel the HCl gas which is formed. When the addition is complete, stirring is continued for 30 minutes at 10°-15° C. The mixture is then introduced into 600 ml of water, and the organic phase is extracted with a 5% strength NaHCO3 solution, dried and concentrated in vacuo.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[O:29]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[O:32][CH2:31][CH2:30]1>>[O:29]1[C:33]2([CH2:38][CH2:37][N:36]([C@H:2]3[CH2:19][C@@:18]4([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]5[C@@H:17]4[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@H:9]5[CH2:10][C@H:11]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)[C@@H:12]4[OH:21])[CH2:4][C@@H:3]3[OH:1])[CH2:35][CH2:34]2)[O:32][CH2:31][CH2:30]1
Reactant: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@@H]6O[C@@H]6C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1
Reactant: C1CC2(CCN1)OCCO2
Product: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](N6CCC7(CC6)OCCO7)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1
Yield: 72.34 %

Procedure:
2α,3α-Epoxy-17β-hydroxy-16β-(4-methyl-1-piperazinyl)-5α-androstane is reacted with 1,4-dioxa-8-azaspiro[4.5]decane as described in Example 3 to give the title compound in a yield of 72.34%, m.p.: 185°-187° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=13)[N:8]=[CH:7][N:6]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]1[OH:29])[C:5]2=[O:30].[Cl-].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][Zn+])=[CH:35][N:34]=1>ClCCl>[Cl:32][C:33]1[N:34]=[CH:35][C:36]([CH2:39][C:2]2[CH:3]=[C:4]3[C:9](=[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=24)[N:8]=[CH:7][N:6]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH:17]2[OH:29])[C:5]3=[O:30])=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc3c(cc(Br)c4ccccc43)c2=O)C(O)C1
Reactant: Clc1ccc(C[Zn+])cn1
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cnc3c(cc(Cc4ccc(Cl)nc4)c4ccccc43)c2=O)C(O)C1
Temperature: 90 °C

Procedure:
To a dry 25 mL round bottom flask containing tert-butyl rac-(3R,4R)-4-(6-bromo-4-oxobenzo[h]quinazolin-3(4H)-yl)-3-hydroxypiperidine-1-carboxylate (0.163 g, 0.344 mmol) under N2(g) was added (2-chloro-5-pyridyl)methylzinc chloride (0.5 M in THF, 2.06 mL, 1.03 mmol) and tetrakis (triphenylphosphine)palladium (0) (10 mol %). The reaction was heated to reflux at 90° C. for 20 h, cooled to room temperature, and diluted with dichloromethane. Hexanes were added to the solution and the resultant beige precipitate was collected via filtration, washed with dichloromethane and hexanes, and dried on high vac to provide crude tert-butyl rac-(3R,4R)-4-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]-3-hydroxypiperidine-1-carboxylate that gave a mass ion (ES+) of 520.9 for M+H+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>CN(C)C=O>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
To a solution of 4-fluoronitrobenzene (25 g; ~0.18 mol) in 250 ml N,N-dimethylformamide was added imidazole (50 g; ~0.74 mol). The reaction mixture was stirred at 140° C. for 2 h, and then poured into ice-water to give the title compound as a precipitate. Yield: 32 g (~94%). M.p. 199°-202° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:17]([CH:18]=[CH:19][C:20](=[O:26])[CH2:21][O:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH2:15][C:10]21[O:14][CH2:13][CH2:12][O:11]2.S(=O)(=O)(O)[OH:28].C(OCC)C.O>CN(C)C=O.[O-2].[O-2].[O-2].[Cr+6]>[O:26]=[C:20]([CH2:21][O:22][CH2:23][CH2:24][CH3:25])[CH:19]=[CH:18][CH:17]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:28])=[O:1]
Reactant: O=S(=O)(O)O
Reactant: CCCOCC(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCC(=O)C=CC1CCC2(OCCO2)C1CCCCCCC(=O)O
Reaction time: 1 h

Procedure:
Chromium trioxide (9.8 g.) (dried over phosphorus pentoxide) was added portionwise with stirring to a solution of 6-(7-hydroxyhepty)-7-(3-oxo-4-propoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane (8.6 g.) in dry dimethylformamide (130 ml.) at a temperature lower than 0° C. Concentrated sulphuric acid (3.5 ml.) in dimethylformamide (130 ml.) was added and the mixture stirred at below 10° C. for 1 hour. Diethyl ether was added followed by a minimum quantity of water to produce two readily separable layers. The ether layer was separated and stirred with aqueous 2 N sodium carbonate solution. The aqueous layer was separated, washed with diethyl ether and then covered with a layer of diethyl ether and acidified to pH 5 by the addition of 20% aqueous sodium dihydrogen phosphate solution. The ethereal layer was separated and the aqueous layer again extracted with diethyl ether. The combined ethereal layers were dried over sodium sulphate and evaporated to give 7-{7-(3-oxo-4-propoxybut-1-enyl)-1,4-dioxaspiro[ 4,4]-non-6-yl}heptanoic acid (2.1 g.),
Reaction SMILES: CO[Na].[CH2:4]([N:11]1[C:15](=[O:16])/[C:14](=[C:17](\[NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)/[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)/[C:13]([CH2:35][C:36]([O:38]C)=O)=[N:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH2:4]([N:11]1[C:15](=[O:16])[C:14]2=[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:36](=[O:38])[CH:35]=[C:13]2[NH:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)CC1=NN(Cc2ccccc2)C(=O)/C1=C(/Cc1cccc(OC)c1)NCc1ccccn1
Agent: CO[Na]
Solvent: CO
Product: COc1cccc(Cc2c3c(=O)n(Cc4ccccc4)[nH]c3cc(=O)n2Cc2ccccn2)c1
Yield: 43 %

Procedure:
The above obtained methyl [(4Z)-1-benzyl-4-{2-(3-methoxyphenyl)-1-[(pyridin-2-ylmethyl)amino]ethylidene}-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VIII) was treated with freshly prepared MeONa in MeOH (2M, 20 ml). The solution was stirred at room temperature until disappearance of the starting enamine (t=0.5-2 h). The reaction mixture was concentrated in vacuum to eliminate MeOH and the crude was dissolved in ethyl acetate (80 ml), extracted with water (30 ml*3). Then the combined inorganic layer was acidified to pH=6, extracted with ethyl acetate (30 ml*3), the combined organic layer was dried over Na2SO4, purified by TLC yielding the final product 2-benzyl-4-(3-methoxybenzyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione as yellow oil (65 mg, yield: 43%). 1HNMR (400 MHz, DMSO-d6): 3.635 (s, 3H); 4.702 (s, 2H); 4.860 (s, 2H); 5.274 (s, 2H), 5.696 (s, 1H); 6.646-6.716 (m, 3H), 7.104-7.144 (m, 2H); 7.277-7.416 (m, 6H); 7.823-7.859 (t, 1H); 8.492-8.501 (d, 1H). MS (ESI+): 453.2; MS (ESI): 451.2.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.Br[CH2:30][CH:31]=[CH2:32]>>[CH2:32]([O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[CH:31]=[CH2:30]
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C=CCBr
Product: C=CCOCCCc1c[nH]cn1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of 3-bromo-1-propene are treated as described in Example 5. The title compound is crystallized in the form of the hydrogen oxalate from ethanol and diethyl ether.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.CN(C)C=O>O>[Si:12]([O:1][CH2:2][C:3]1[NH:4][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1nc2cncnc2[nH]1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1nc2cncnc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A mixture of 1.81 g of 2-hydroxymethyl-3H-imidazo-[5,4-d]pyrimidine (prepared as described in Preparation 48), 2.71 g of t-butyldimethylsilyl chloride, 2.45 g of imidazole and 100 ml of dimethylformamide was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue thus obtained was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 1.89 g of the title compound, melting at 104-107° C.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:10]=[C:9]2[C:18](O)=[O:19].C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C)C=O>[F:1][CH:2]([F:21])[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:10]=[C:9]2[C:18]([Cl:25])=[O:19]
Reactant: O=C(O)c1cc(C(F)(F)F)nc2c(OC(F)F)cccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(F)(F)F)nc2c(OC(F)F)cccc12
Reaction time: 8 h

Procedure:
A solution of 8-difluoromethoxy-2-trifluoromethylquinoline-4-carboxylic acid (0.50 g) in dichloromethane (30 ml) was stirred at room temperature under an atmosphere of nitrogen. Oxalyl chloride (0.28 ml) was added followed by N,N-dimethylformamide (1 drop) and stirring continued overnight. The solvent was removed in vacuo to give 8-difluoromethoxy-2-trifluoromethylquinoline-4-carbonyl chloride (650 mg) as an off white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(CCO)cc1
Product: COc1ccc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-5-methoxynitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: C(O[C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[CH:24]=3)[C:19]=2[CH:32]=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:34]([OH:37])(=O)[CH3:35]>[Zn]>[CH3:29][O:28][C:23]1[C:22]([O:30][CH3:31])=[CH:21][C:20]2[C:19]3[CH:32]=[N:15][C:13]4[CH:14]=[CH:9][C:10]([O:37][CH2:34][C:35]5[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=5)=[CH:11][C:12]=4[C:18]=3[CH:27]=[CH:26][C:25]=2[CH:24]=1
Reactant: COc1cc2ccc(-c3ccc(OCc4ccccc4)cc3[N+](=O)[O-])c(C=O)c2cc1OC
Reactant: CC(=O)O
Agent: [Zn]
Product: COc1cc2ccc3c4cc(OCc5ccccc5)ccc4ncc3c2cc1OC
Yield: 56 %

Procedure:
2-( 4-Benzyloxy-6-nitrophenyl)-6,7-dimethoxy-1-naphthaldehyde (100 mg, 0.23 mmol) was dissolved in glacial acetic acid (15 mL) and heated to reflux with zinc dust (163 mg, 2.5 mmol) for 3.5 h. Acetic acid was evaporated in vacuo and the residue was dissolved in chloroform. The solution was filtered through a celite bed and the filtrate was washed successively with saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was chromatographed over 50 g of silica gel using 1:2 mixture respectively of hexanes and ethyl acetate to give the title compound as a white solid in 56% yield; 1H NMR(CDCl3) δ4.08(3H, s), 4.18(3H, s), 5.29(2H, s), 7.33(1H, s), 7.42(5H, m), 7.52(1H, d, J=8.9), 7.72(1H, d, J=2.6), 8.02(1H, d, J=8.9), 8.17(1H, s), 8.39(1H, d, J=8.9), 8.52(1H, d, J=8.9), 10.04(1H, s); 13C NMR(CDCl3) δ56.5, 56.6,70.8, 102.3, 108.6, 110.9, 112.8, 118.4, 119.6, 120.7, 124.2, 125.8, 127.7, 128.2, 128.6, 129.2, 131.4, 131.7, 137.1, 146.8, 148.6, 150.1, 151.2, 159.5; HRMS calcd for C26H24N3: 395.1521 , found: 395.1522.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl.O>[CH3:18][S:19]([O:10][CH2:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:21])=[O:20]
Reactant: COc1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COS(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
A solution of (6-methoxypyridin-3-yl)methanol (2.9 g, 20.93 mmol) and triethylamine (4.35 mL) in dichloromethane (20 mL) was treated with methanesulfonyl chloride (2.9 g, 25.1 mmol) dropwise and the reaction mixture stirred at rt overnight. After this time, the reaction was diluted with water and extracted with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford the title compound (1.4 g, 49%) as a yellow oil. MW=217.24. 1H NMR (CDCl3, 300 MHz) δ 8.16-8.14 (m, 1H), 7.68-7.59 (m, 1H), 6.76 (d, J=8.6 Hz, 1H), 4.55 (s, 2H), 3.94 (s, 3H), 3.19 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:18]1([CH2:17][S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10]2)(=[O:16])=[O:15])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)Cc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccn(S(=O)(=O)Cc2ccccc2)c1

Procedure:
Starting materials: (E)-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-acrylic acid tert-butylester (compound C2) (1.45 g), CH2Cl2 (80 ml), TFA (8 ml). Reaction conditions: room temperature, 2 hours.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:31]1([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccccc1
Yield: 56 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and phenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (56% yield); 1H-NMR (d6-DMSO) 1.04 (9H, s), 3.68 (2H, m), 4.09 (2H, m), 6.38 (1H, s), 7.18-7.20 (3H, m), 7.27-7.29 (2H, m); 13C-NMR (CDCl3) 27.7, 41.5, 66.8, 125.0, 126.3, 128.0, 132.2; MS ES(+) 206.0 (M+-tBu); HRMS m/z calcd for C15H19NO3+H+ 262.1443 [M+H+]. Found 262.1447. IR λmax=3441, 1701, 1367, 1355, 1163 cm−1.