Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[N:11]([CH3:12])[C:10](=[O:13])[NH:9][C:8](=[O:14])[CH:7]=1.[N:15]([O-])=O.[Na+]>O>[NH2:15][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[N:11]([CH3:12])[C:6]=1[NH2:5]
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(N)c(N)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Glacial acetic acid (4.5 ml, 75 mmol) was added to a suspension of 6-amino-1-methyluracil (5.66 g, 50 mmol) in hot water (100 ml). Sodium nitrite (4.14 g) was added in portions and the reaction mixture was stirred for 1 hour. The precipitate was collected by filtration, washed with water (75 ml) and then suspended in water (100 ml). The mixture was warmed to 50° C. and sodium dithionite (10 g) was added in portions keeping the temperature of the reaction between 50-55° C. The mixture was stirred at 50° C. for 1 hr and then cooled to room temperature and filtered. The solid was washed with water (2×25 ml), acetone (2×25 ml) and dried under vacuum to provide 5,6-diamino-1-methyluracil (5.6 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH2:19])=[N:11][C:10]1=2)(=[O:3])[CH3:2].C1(C)C=CC=CC=1.CCCCCC.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CN(C)C1C=CN=CC=1>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH:19][C:33](=[O:35])[CH3:34])=[N:11][C:10]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(ncn2COCCOC(C)=O)c(=O)[nH]1
Temperature: 120 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
9-(2-Acetoxyethoxy)methylguanine (2 gms, 7.5 mmol) was dissolved in 15 ml of acetic anhydride. The mixture was heated to 120° C. and 0.1 gms (0.8 mmol) of 4-dimethylaminopyridine (DMAP) added. The reaction mixture was kept at 120° C. for 3 hours, then the mixture was cooled to 40° C. and 10 ml of toluene added. Hexane (20 ml) was added slowly to effect crystallization of the product. The solid was collected by filtration and washed with hexane, yielding 1.82 gms of 9-(2-acetoxyethoxy)methyl-N2 -acetylguanine (79%) with a N-9/N-7 isomer ratio of >200:1. Characteristic analytical data are as follows: 1H NMR (DMSO-d6) δ1.85 (3H, singlet, --NHCOCH3), 2.08 (3H, singlet, --O2CCH3) , 3.6 (2H, multiplet, --OCH2 --) , 3.95 (2H, multiplet, --CH2O--), 5.4 (2H, singlet, --NCH2O--) , 8.06 (1H, singlet, --N=CH--N--).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:13])=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[C:1]([C:3]1[C:4]([CH3:13])=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[C:6]([N+:14]([O-:16])=[O:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1cccc(C#N)c1C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1c([N+](=O)[O-])ccc(C#N)c1C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(3-cyano-2-methylphenyl)acetamide (CAS #: 70946-79-1) (1.8 g, 10.33 mmol) in conc. sulfuric acid (20 mL) at −10° C., potassium nitrate (2.08 g, 20.67 mmol) in 5 mL of conc. sulfuric acid was added slowly. After addition, the reaction was stirred at −10° C. for 30 min, then at 0° C. for 3.5 hr. The reaction mixture was poured onto ice, and then the precipitate was collected by filtration. The solid was washed with water and then purified by silica gel flash column chromatography (heptanes/EtOAc=1/0 to 1/1) to give the title compound. MS (ESI−) m/z 218.0 (M−H).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[CH:12][C:11]([OH:15])=[C:10]([CH3:16])[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:2]=[CH2:3]>[Pd].C(OCC)(=O)C>[OH:15][C:11]1[C:10]([CH3:16])=[C:5]([C:4]([CH2:1][CH2:2][CH3:3])=[C:13]([OH:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=CCc1c(O)cc(O)c(C)c1C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)cc(O)c(C)c1C(=O)OC
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A mixture of 4.67 g of methyl 2-allyl-3,5-dihydroxy-6-methylbenzoate and 0.23 g of 5% palladium on charcoal in 40 ml of ethyl acetate was hydrogenated for 2 hours at atmospheric pressure. The mixture was filtered and the filtrate evaporated in vacuo. Crystallization of the residue from ethyl acetate/hexane afforded 4.30 g of methyl 3,5-dihydroxy-2-methyl-6-propylbenzoate, m.p. 88°-91° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:12])[C:5]([F:13])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:12])[C:5]([F:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Cl)ccc(F)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(F)ccc(Cl)c1C(=O)O

Procedure:
Methyl 6-chloro-3-fluoro-2-methylbenzoate 65 (14 g, 69 mmol, 1 eq) and NaOH (13.8 g, 345 mmol, 5 eq) were dissolved in a mixture of 1,4-dioxane (10 mL) and H2O (130 mL), and the resulting mixture was stirred at reflux overnight. The reaction mixture was cooled to RT and neutralized with conc. HCl to adjust the pH value to 1. The mixture was extracted with DCM (3×60 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product 6-chloro-3-fluoro-2-methylbenzoic acid 66. The product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[N:21]1([CH2:27][CH2:28]Cl)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>CC(C)=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:28][CH2:27][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:9][CH:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: ClCCN1CCCCC1
Reactant: Clc1ccc(CN2CCNCC2c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Clc1ccc(CN2CCN(CCN3CCCCC3)CC2c2ccccc2)cc1
Yield: 95 %

Procedure:
31 g. of 1-(4'-chloro benzyl)-2-phenyl piperazine prepared according to Example 2 B), 25 g. of piperidino ethylchloride, 20 g. of triethylamine, and 250 cc. of acetone are boiled under reflux for 18 hours. The filtered reaction solution is freed of its solvent by concentration by evaporation. The residue is dissolved in benzene. The benzene solution is washed with water. After drying and distilling off the solvent, the base is obtained in the form of a viscous, yellow oil on distillation at 210° C./0.06 Torr. The oil crystallizes on trituration with isopropanol. After twice recrystallizing the crystals from n-heptane (41 g. of yellow crystals of the melting point 85°-87° C.) are obtained. The yield is 95 % of the theoretical yield.
Reaction SMILES: [OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:4].[OH-].[K+].[OH:33]OS([O-])=O.[K+].OS([O-])(=O)=O.[K+].C(N(CC([O-])=O)CC([O-])=O)CN(CC([O-])=O)CC([O-])=O.[Na+].[Na+].[Na+].[Na+]>P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.CC(C)=O.CCOCC.C(Cl)Cl>[OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3]1([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:33][CH2:4]1
Reactant: O=S([O-])OO
Reactant: C=C(Oc1ccccc1)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C1(Oc2ccccc2)CO1

Procedure:
17α-hydroxy-20-phenoxypregna-4,9(11),20-trien-3-one (4.04 grams, 10 mmoles) is slurried in pH 8 potassium phosphate buffer (50 ml, 0.02M PO4 57 ), 40 ml methylene chloride, 0.222 grams (1 mmole), of Ansul ether 181 (C10H22O5) and 20 ml acetone and the two phase mixture heated to 25° C. and adjusted to pH 8.5 with 30% potassium hydroxide. 18.4 grams, 30 mmoles of OXONE® (2KHSO5.KHSO4.K2SO4) is dissolved in 90 ml of water and 10 ml of a 5% by weight solution of Na4EDTA and the resulting solution added dropwise at 25° C. with vigorous agitation while maintaining the pH at 8.0-8.5 with 30% potassium hydroxide. When the reaction is complete the phases are separated hot and the aqueous phase extracted twice with 50 ml of methylene chloride. The combined organics are washed twice with 100 ml of aqueous 5% sodium hydroxide and clarified thru a solka flok filter and concentrated on a rotary evaporator to yield 17α-hydroxy-20,21-epoxy-20-phenoxypregna-4,9(11)-diene-3-one.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[O:7][C:6]([CH2:8]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(P([N:56]=[N+:57]=[N-:58])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1.ClCCl>[N:56]([CH2:8][C:6]1[O:7][C:3]([CH:2]([F:10])[F:1])=[CH:4][CH:5]=1)=[N+:57]=[N-:58]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(C(F)F)o1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: [N-]=[N+]=NCc1ccc(C(F)F)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a solution of (5-(difluoromethyl)furan-2-yl)methanol (0.55 g, 3.72 mmol), triphenylphosphine (1.07 g, 4.09 mmol) and diethylazodicarboxylate (0.64 mL, 4.09 mmol) in anhydrous tetrahydrofuran (20 mL) was added diphenylphosphorylazide (0.88 mL, 4.09 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with dichloromethane (40 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/9) to afford 2-(azidomethyl)-5-(difluoromethyl)furan as a yellow oil in 77% yield (0.50 g): 1H NMR (300 MHz, CDCl3) δ 6.61 (d, J=3.3 Hz, 1H), 6.58 (t, J=54.3 Hz, 1H), 6.37 (d, J=3.3 Hz, 1H), 4.30 (s, 2H); MS (ES+) m/z 172.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[C:25]1([C:31]([NH2:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C:31]([NH:39][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:23])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: CC(N)(c1ccccc1)c1ccccc1
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(C)(c4ccccc4)c4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 61 %

Procedure:
The title compound was prepared in a yield of 61% in a similar manner to that described in Example 2 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and 1,1-diphenylethylamine.
Reaction SMILES: N1C=CC=CC=1.Cl.Cl.[O:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][N:20]=[CH:21][NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)[CH2:11][CH2:10]1.Cl.[C:33]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[C:42]([CH2:46][C:47](=[O:49])[NH2:48])=[C:41](O)[CH:40]=[CH:39]2)(=[NH:35])[NH2:34].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)=O>[O:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][N:20]=[CH:21][NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][C:41]3[CH:40]=[CH:39][C:38]4[C:43](=[CH:44][CH:45]=[C:36]([C:33](=[NH:34])[NH2:35])[CH:37]=4)[C:42]=3[CH2:46][C:47](=[O:49])[NH2:48])=[O:28])=[CH:30][CH:31]=2)[CH2:11][CH2:10]1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: O=C(O)c1ccc(NC=NNCCCCN2CCOCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: O=CO
Solvent: CCC(C)=O
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(NC=NNCCCCN4CCOCC4)cc3)ccc2c1
Reaction time: 2 h
Yield: 61.7 %

Procedure:
20 Milliliters of 20% hydrous pyridine was added to 1.05 g of 4-[(4-morpholinobutyl)aminoiminomethylamino]benzoic acid.dihydrochloride, 735.7 mg of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 660 mg of DCC and 32.6 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 48 hours at room temperature. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 5 ml of DMF, and the solution was added dropwise to 400 ml of acetone, followed by stirring for 1 hour under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-formic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 10 ml of methanol and 1.2 ml of concentrated hydrochloric acid, and the solution was added dropwise to 400 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 885.3 mg of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[OH2:15]>CC(C)CCO>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([O:15][CH2:11][CH2:10][CH:9]([CH3:14])[CH3:4])[CH:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: O
Solvent: CC(C)CCO
Product: CC(C)CCOc1cc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
The reaction is carried out under an argon protective-gas atmosphere. A solution of 6.7 g (60.5 mmol) of sodium t-amylate in 50 ml of 3-methylbutanol is added dropwise to a solution, cooled to 0° C., of 12.4 g of 4,6-dichloro-2-phenylpyrimidine in 50 ml of 3-methylbutanol. The reaction mixture is allowed to warm to 25° C. overnight. Thin-layer chromatography shows the absence of starting material. The reaction mixture is poured into 180 ml of water and extracted three times with 80 ml of ethyl acetate. Combined organic phases are washed with water, dried using MgSO4 and filtered. Removal of the solvent gives 14.6 g (96% of theory) of the title compound.
Reaction SMILES: [Mg].BrCCBr.[C:6]([C:10]1[CH:11]=[C:12]2[C:16](=[C:17](Br)[CH:18]=1)[CH2:15][C:14]([CH3:20])=[CH:13]2)([CH3:9])([CH3:8])[CH3:7].[Cl:21][Si:22](Cl)([CH3:24])[CH3:23]>C1COCC1>[C:6]([C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([Si:22]([Cl:21])([CH3:24])[CH3:23])[CH:18]=1)[CH2:15][C:14]([CH3:20])=[CH:13]2)([CH3:9])([CH3:8])[CH3:7]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2cc(C(C)(C)C)cc(Br)c2C1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC1=Cc2cc(C(C)(C)C)cc([Si](C)(C)Cl)c2C1
Reaction time: 0.5 h

Procedure:
To 6.68 g (0.278 mol) of magnesium turnings in 200 mL of dry THF 5.26 g (0.028 mol) of 1,2-dibromoethane was added dropwise for 30 minutes. This mixture was stirred for additional 30 minutes, and then a solution of 66.3 g (0.250 mol) of 5-tert-butyl-2-methyl-7-bromo-1H-indene in 900 mL of THF was added dropwise by vigorous stirring in such rate that the mixture is refluxed. Then, this mixture was additionally refluxed for 30 minutes. Further on, to a solution of 113 g (0.875 mol) of dichlorodimethylsilane in 100 mL of THF the above-obtained solution of the Grignard reagent was added dropwise by vigorous stirring at room temperature using a water bath to cool the reaction mixture. The resulting mixture was additionally stirred for 12 hours at ambient temperature, evaporated to dryness, and then 200 mL of dry ether was added. The obtained suspension was stirred for 20 minutes at room temperature and then filtered through glass frit (G3). The precipitate was additionally washed by 2×100 mL of ether. The combined filtrate was evaporated to dryness, and the residue was rectificated in vacuum, b.p. 147° C.-155° C./1 mm Hg. Yield 50.1 g (72%) of the title product. 1H NMR (CD2Cl2): δ 7.46 (s, 1H, 6-H), 7.43 (s, 1H, 4-H), 6.55 (s, 1H, 3-H), 3.47 (s, 2H, 1,1′-H), 2.22 (s, 3H, 2-Me), 1.41 (s, 9H, tBu), 0.82 (s, 6H, SiMe2). Anal. Calc. for C16H23ClSi: C, 68.91; H, 8.31%. Found: C, 69.13; H, 8.58%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1.O[C:12]1C=CC(CCCO)=CC=1.C1C=CN=CC=1.O=S(=O)=O>CS(C)=O.C(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: O=CCc1ccc(O)cc1
Agent: O=S(=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CC(C=O)c1ccc(O)cc1
Yield: 75 %

Procedure:
4-hydroxyphenylpropionaldehyde was prepared by a synthesis analogous to that for 4-hydroxyphenylacetaldehyde (Heterocycles, 2000, 53, 777-784). 3-(4-Hydroxyphenyl)-1-propanol (1.0 g, 6.6 mmol, Aldrich) was dissolved in dimethylsulfoxide (8 mL, Aldrich). TEA (2.0 mL, 14 mmol, Aldrich) was added slowly with stirring. Pyridine-sulfur trioxide (SO3.py) complex (2.3 g, 15 mmol, Aldrich) was completely dissolved in dimethylsulfoxide (9 mL, Aldrich) and this solution was added drop-wise to the alcohol, with vigorous stirring. After stirring for 1 h at room temperature, the reaction was diluted with CH2Cl2, then washed with ice-cold water. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. Purification using silica gel chromatography with hexane-ethyl acetate as eluent (5:1, then 2:1) yielded 745 mg (75%) of 4-hydroxyphenylpropionaldehyde.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O.C[O-].[Na+]>CO>[Cl:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:2][C:3]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])[CH:39]=[CH:40][CH:41]=1
Reactant: COc1ccc(C(=O)O)c(CBr)c1
Reactant: O=Cc1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COc1ccc(C(=O)O)c(C=Cc2cccc(Cl)c2)c1

Procedure:
For the synthesis of the title compound, 45.6 g (0.186 mol) of 2-bromomethyl-4-methoxybenzoic acid, 48.8 g (0.186 mol) of triphenylphosphine, 26.1 g (0.186 mol) of 3-chlorobenzaldehyde and 84.0 g (0.435 mol) of NaOMe (28%) in 150 ml of methanol are reacted by method I. Purification is carried out by recrystallization from methanol at 4° C.
Reaction SMILES: C([Mg]Cl)(C)C.[Li]CCCC.Br[C:12]1[C:17]([CH3:18])=[CH:16][C:15]([N:19]([CH3:21])[CH3:20])=[CH:14][C:13]=1[F:22].[C:23](=[O:25])=[O:24].[OH-].[Na+]>C1COCC1>[CH3:20][N:19]([CH3:21])[C:15]1[CH:16]=[C:17]([CH3:18])[C:12]([C:23]([OH:25])=[O:24])=[C:13]([F:22])[CH:14]=1
Reactant: O=C=O
Reactant: Cc1cc(N(C)C)cc(F)c1Br
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(N(C)C)cc(F)c1C(=O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
At 0° C., to a solution of iPrMgCl (9.10 mL, 2.0M THF, 1.2 eq.) in THF (14 mL) was added nBuLi (22.3 mL, 1.6 M Hexanes, 2.4 eq.). After 10 min., now yellow, homogeneous solution was cooled to −78° C., and to this was added a solution of (4-Bromo-3-fluoro-5-methyl-phenyl)-dimethyl-amine (3.52 g, 15.2 mmol) in THF (18 mL). Following the disappearance of the yellow color, the TLC after 20 min. showed no starting material. CO2(g) was canula transferred into the reaction mixture, which was warmed to room temperature, after 20 min., and added to 1N NaOH. The aqueous layer was acidified with 1NHCl(aq) and extracted with EtOAc. Organic extracts were dried (MgSO4), filtered, concentrated in vacuo to give a crude solid, which was purified by flash chromatography (SiO2, 40%-100% EtOAc/Hexanes) to give 4-Dimethylamino-2-fluoro-6-methyl-benzoic acid as a white solid (2.91 g, 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]([NH:24][CH2:25][CH:26]=[CH2:27])[CH2:18][C:19](OCC)=[O:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]([NH:24][CH2:25][CH:26]=[CH2:27])[CH2:18][CH2:19][OH:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCNC(CC(=O)OCC)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(CCO)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
To a solution of (R)-3-(1-allylamino-2-ethoxycarbonylethyl)piperidine-1-carboxylic acid benzyl ester (0.427 g, 1.14 mmol) in THF (20 mL) was added a solution of lithium borohydride in THF (2M, 5.7 mL, 11.4 mmol). The mixture was stirred at RT for 10 min then at 40° C. for 22 h. After cooling to RT, water was added with initial caution. The mixture was extracted twice with EtOAc, and the combined organic phases were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% 2M NH3/MeOH in DCM) affording the title compound (0.264 g, 70%) as a colourless gum. LCMS (Method B): RT 2.00 min [M+H]+ 333.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:4]=[N:3]1.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]3[CH:28]=[C:29]([CH2:33]O)[CH:30]=[CH:31][CH:32]=3)=[N:25][CH:26]=2)[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.CN(C=O)C>[CH3:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[N:25][C:24]([C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[CH2:33][N:11]3[C:10](=[O:13])[CH:9]=[CH:8][C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[N:12]3)=[N:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: Cn1cc(-c2ccc(=O)[nH]n2)cn1
Reactant: CN1CCN(c2cnc(-c3cccc(CO)c3)nc2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1CCN(c2cnc(-c3cccc(Cn4nc(-c5cnn(C)c5)ccc4=O)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
71 mg (0.40 mmol) of 6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one and 163 mg (0.40 mmol) of {3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]phenyl}-methanol are suspended in 3 ml of THF and 1 ml of DMF with 200 mg (0.60 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g) and shaken at room temperature for 30 min. 139 mg (0.60 mmol) of di-tert-butyl azodicarboxylate are added. The reaction mixture is shaken at room temperature for 1 h. A further 200 mg (0.6 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g) and 139 mg (0.60 mmol) of di-tert-butyl azodicarboxylate are added, and the reaction mixture is shaken at room temperature for 2 h. The reaction mixture is filtered, the residue is evaporated, and the residue is purified by means of preparative HPLC; yield: 18 mg of “A286”; HPLC: Rt=2.08 min (method C); LC-MS: 443 (M+H).