Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=[O:21])=[CH:11][CH:10]=1)C1C=CC=CC=1.FC1C=CC=CC=1C1(C2C=CC(O)=CC=2)CCCCCC1=O>>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:15]1([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21]
Reactant: O=C1CCCCC1(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Agent: O=C1CCCCCC1(c1ccc(O)cc1)c1ccccc1F
Product: O=C1CCCCC1(c1ccc(O)cc1)c1ccccc1F

Procedure:
The title compound 21 was synthesized from compound 19 (5 mg) using the procedure described for the synthesis of compound 20. Yield: 3 mg. 1H-NMR (400 MHz, CDCl3): δ ppm 7.16-7.06 (m, 3H), 6.97 (ddd, J=11.76, 8.14, 1.28 Hz, 1H), 6.90-6.73 (m, 3H), 6.31 (dt, J=7.87, 7.86, 1.74 Hz, 1H), 4.92 (s, 1H), 2.69-2.40 (m, 2H), 2.41-2.23 (m, 2H), 1.95-1.82 (m, 2H), 1.83-1.69 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:10][CH:9]=[CH:8][C:7]=1[OH:25].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][O:25][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:26])[CH3:35]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Product: CCOC(=O)CCCOc1cccc(C#CCCCCOC2CCCCO2)c1/C=C/C(=O)OC

Procedure:
Using the procedure of example 122, rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester (example 121), was alkylated with ethyl 4-bromobutyrate giving the title compound as a pale-yellow oil, in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][C:6]#[N:7].Br[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[Cl:23].[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([C:13]2[C:14]([Cl:23])=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[CH:17][C:18]=2[Cl:19])[C:6]#[N:7])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: O=[N+]([O-])c1cc(Cl)c(Br)c(Cl)c1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Reaction time: 1 h
Yield: 67 %

Procedure:
To 150 ml of 20% hydrous DMSO were added 6.15 g of 3,4-dichlorobenzyl cyanide, 8.13 g of 4-bromo-3,5-dichloronitrobenzene and 1.50 g of sodium hydroxide. The reaction was allowed to proceed for one hour at temperatures ranging from 60 to 70° C. After completion of the reaction, DMSO was removed, and the residue was dissolved in 50 ml of toluene. The solution was washed with water, dried and concentrated. To the concentrate was added ethyl alcohol to cause crystallization to afford the titled compound in a yield of 67%, m.p.171-172° C.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:23]=[C:22]([N:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:4]=1[C:5]([C:7]1[C:15]([Cl:16])=[C:14]([Cl:17])[C:13]([Cl:18])=[C:12]([Cl:19])[C:8]=1[C:9](O)=[O:10])=[O:6].[CH3:28][N:29]([CH3:39])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH3:38])[CH3:37])[CH:31]=1.C(OC(=O)C)(=O)C>CCCCCC>[CH3:37][N:36]([CH3:38])[C:32]1[CH:31]=[C:30]([N:29]([CH3:39])[CH3:28])[CH:35]=[CH:34][C:33]=1[C:5]1([C:4]2[CH:20]=[CH:21][C:22]([N:24]([CH3:26])[CH3:25])=[CH:23][C:3]=2[N:2]([CH3:27])[CH3:1])[C:7]2[C:8](=[C:12]([Cl:19])[C:13]([Cl:18])=[C:14]([Cl:17])[C:15]=2[Cl:16])[C:9](=[O:10])[O:6]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(N(C)C)c1
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(C)C)c1

Procedure:
A mixture of most of the 2-(2,4-bis(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid from part A of this example, N,N,N',N'-tetramethyl-m-phenylenediamine (0.82 g. plus 0.4 g.) and acetic anhydride was heated under reflux. Concentration of a toluene extract of the resulting product gave a tar, which was slurried in hexane, affording 3,3-bis(2,4-bis(dimethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X = Y2 = Y4 = (CH3)2N, Z4 = Z5 = Z6 = Z7 = Cl) (m.p. 195°-197° C.).
Reaction SMILES: C[CH2:2][N:3](C(C)C)[CH:4](C)C.Cl.CNC.[NH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][C:16]=1[Cl:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CCOC(C)=O>[NH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([N:3]([CH3:4])[CH3:2])=[O:20])=[CH:17][C:16]=1[Cl:24]
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
DIPEA (116 mL, 699.5 mmol) was added into a suspension of dimethylamine hydrochloride (28.51 g, 349.6 mmol) in THF (600 mL). The mixture was stirred at room temperature for 0.5 h. Then 4-amino-3-chlorobenzoic acid (30.00 g, 174.8 mmol) and HATU (86.41 g, 227.2 mmol) were added into the above suspension separately. The reaction mixture was continued to be stirred for 1.5 h. Then it was concentrated and the residue was partitioned between EtOAc (300 mL) and water (150 mL). The separated organic phase was washed with water, dried over Na2SO4 and evaporated in vacuum. The crude product was purified by silica gel chromatography, eluted with Hexanes: EtOAc=1:1 to afford 4-amino-3-chloro-N,N-dimethylbenzamide (34.72 g, yield: 89%). ESI-MS: 199.06. 1H NMR (CDCl3, 400 MHz): δ7.39 (s, 1H, ArH), 7.19 (d, J=8.4 Hz, 1H, ArH), 6.74 (d, J=8.4 Hz, 1H, ArH), 4.24 (br, 2H, NH2), 3.05 (s, 6H, 2CH3).
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=2)[NH2:35])[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:35][C:34]4[CH:36]=[CH:37][CH:38]=[C:32]([N:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)[CH:33]=4)[N:24]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(NCc5cccnc5N(C)S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-[3-({2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-pyridin-2-yl]-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 3-(4-methylpiperazin-1-yl)aniline (44.0 mg, 0.230 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.037 g, 35%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=4.6, 1.6 Hz, 1H), 7.86-7.81 (m, 2H), 7.29-7.25 (m, 1H), 7.24-7.19 (m, 2H), 7.06 (dd, J=8.1, 1.6 Hz, 1H), 6.71 (s, 1H), 6.65 (t, J=7.5 Hz, 1H), 6.57 (dd, J=8.0, 1.7 Hz, 1H), 6.30 (d, J=7.7 Hz, 1H), 5.29 (t, J=6.3 Hz, 1H), 4.76 (d, J=6.2 Hz, 2H), 3.32 (s, 3H), 3.29-3.24 (m, 4H), 3.09 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=522 (MH)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCc1ccccc1
Reactant: BrCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: BrCCCCCCOCCCc1ccccc1
Yield: 81.2 %

Procedure:
3-Phenylpropanol (3.00 g) and 1,6-dibromohexane (16.10 g, 10.2 ml) were stirred rapidly at RT with tetra-n-butylammonium hydrogen sulphate (0.5 g) and 12.5 M aqueous NaOH (16 ml) for 30 h. The mixture was diluted with H2O (80 ml), extracted with ER (3×100 ml), and the combined organic extracts were washed consecutively with H2O (80 ml) and BR (80 ml). The dried extracts were evaporated and the residual oil purified by [FCS], eluting with CK (one columnful), followed by EA-CX (1:20) to give the title compound (5.35 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:9]CCC)=[O:8])[CH2:2][CH3:3].CC(C)([O-])C.[K+].CCCCCC.C(OCC)(=O)C.Cl>CS(C)=O>[CH2:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([OH:9])=[O:8])[CH2:2][CH3:3]
Reactant: CCCOC(=O)c1ccccc1OCCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCOc1ccccc1C(=O)O
Temperature: 70 °C
Yield: 17.6 %

Procedure:
To a stirred solution of Propyl 2-propoxy-benzoate (10 g, 240 mmol) in dimethyl sulfoxide (40 mL) was added potassium tert-butoxide (10 g, 890 mmol) in portions. The solution was heated to 70° C. on a water bath for 2 h, and the progress of the reaction was monitored by TLC using a hexane-ethyl acetate (8:2) solvent system. The reaction mass was cooled to 10° C., poured into ice water, and then acidified with 5% dilute hydrochloric acid. The precipitated solid was filtered and washed thoroughly with distilled water, and the crude mass was recrystallized in hexane (50 mL) to yield an off-white solid of 2-Propoxy-benzoic Acid (7.6 g, 80%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:8][CH:9]=O.[NH:17]1[C:25]2[C:20](=[C:21]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.ClCCCl.C(O)(=O)C>[NH:17]1[C:25]2[C:20](=[C:21]([N:26]3[CH2:31][CH2:30][N:29]([CH2:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:28][CH2:27]3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: O=CCC(c1ccccn1)c1ccccn1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: c1ccc(C(CCN2CCN(c3cccc4[nH]ccc34)CC2)c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 13 %

Procedure:
A mixture of 1.15 g of Compound 16B, 1.2 g of 1-(4-indolyl)piperazine (prepared as described in EP 138,280), 1.24 mL of acetic acid, 1.71 g of sodium triacetoxyborohydride and 85 mL of 1,2-dichloroethane was stirred at room temperature for 24 h. Afterwards it was diluted with water and alkalinized with sodium carbonate. The organic layer was dried on sodium sulphate and evaporated to dryness affording 1.53 g of crude, which was purified by flash chromatography (ethyl acetate-2.2 N methanolic ammonia, gradient from 9.4:0.6 to 9.2:0.8) affording 0.28 g (13%) of the title product as an oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[C:12]=3[O:14][CH:15]([F:17])[F:16])[C:7](=[O:25])[C:6]([C:26]([O:28]CC)=O)=[C:5]2[SH:31])[CH2:3][CH2:2]1.[CH:32]1([N:35]2C3C(=CC(F)=C(F)C=3OC)C(=O)C3C(O)=C(C#N)SC2=3)C[CH2:33]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[C:12]=3[O:14][CH:15]([F:17])[F:16])[C:7](=[O:25])[C:6]3[C:26]([OH:28])=[C:33]([C:32]#[N:35])[S:31][C:5]2=3)[CH2:2][CH2:3]1
Reactant: COc1c(F)c(F)cc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12
Reactant: CCOC(=O)c1c(S)n(C2CC2)c2c(OC(F)F)c(N3CCNCC3)c(F)cc2c1=O
Product: N#Cc1sc2c(c1O)c(=O)c1cc(F)c(N3CCNCC3)c(OC(F)F)c1n2C1CC1

Procedure:
The title compound is prepared from ethyl 1-cyclopropyl-8-(difluoromethoxy)-6-fluoro-2-mercapto-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylate using the method described above for the preparation of 9-cyclopropyl-6,7-difluoro-3-hydroxyl-8-methoxy-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carbonitrile.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn]([C:46]#[N:47])(CCCC)CCCC)CCC>O1CCOCC1.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>[F:32][C:5]1[CH:4]=[N:3][C:2]([C:46]#[N:47])=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:18][CH2:19]3)[C:6]=12
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 100 °C
Yield: 31.4 %

Procedure:
To a sealable flask containing 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.10 g, 0.20 mmol) in 1,4-dioxane (5 mL) was added tributyltin cyanide (0.07 g, 0.22 mmol) followed by Pd(PPh3)4 (0.07 g, 0.06 mmol). The mixture was flushed with N2, and the tube was sealed and heated to 100° C. After 16h of heating, the mixture was cooled to rt, and the solvent was removed in vacuo. The residue was dissolved in DMF and was filtered through a pad of celite to remove any remaining solids. The DMF solution was purified by prep HPLC to give the title compound as an off-white solid (0.028 g). LCMS: m/e 446.2 (M+H)+, ret time 1.81 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 14.06 (s, 1 H) 8.66 (s, 1 H) 8.50 (d, J=2.14 Hz, 1 H) 7.56-7.70 (m, 5 H) 3.67-3.72 (m, 2 H) 3.33-3.50 (m, 4 H) 3.13-3.17 (m, 2 H).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[N:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[CH:8][C:7]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[Zn]>[NH2:18][C:15]1[N:16]=[CH:17][C:12]([C:9]2[CH:8]=[C:7]([NH2:19])[C:6]([NH:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:11][CH:10]=2)=[CH:13][N:14]=1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1[N+](=O)[O-]
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a round bottom flask are added 5-(4-tert-butylamino-3-nitro-phenyl)-pyrimidin-2-ylamine (6.3 g, 0.02 mol) and ammonium formate (6.9 g, 0.1 mol) in EtOH, (100 mL), followed by the addition of zinc dust (4.3 g, 0.066 mol). The reaction mixture is stirred at 50° C. for 2 hours. The reaction mixture is filtered through a short pad of diatomaceous earth. The filter pad is rinsed with MeOH (50 mL) and the combined filtrate is concentrated. The residue is extracted with H2O (50 mL) and EtOAc (3×50 mL). The combined organic layer is washed with saturated NaHCO3 solution (30 mL), dried (MgSO4) and filtered. The filtrate is concentrated to afford 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine as a dark purple solid (4.5 g, 80%). LCMS (ESMS): m/z 258.20 (M++1)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:40]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH2:34]I)[CH2:21][CH2:22][C@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:9]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:40]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][CH2:22][C@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:9]1
Reactant: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](CI)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
By an alternative proceudre, a mixture of 0.208 g. (0.00025 mole) of [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluoro-21-iodocholest-5-ene, 0.087 g. (0.00030 mole) of tri-n-butytin hydride and 3 ml of tetrahydrofuran were stirred at 25° C. for 18 hr under an argon atmosphere. The mixture was evaporated to dryness and the residue was purified by chromatography on 0.06-0.20 mm silica gel to yield [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-ene.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@H:19]2[C@H:23]([OH:24])[C@H:22]([OH:25])[C@@H:21]([CH2:26][O:27][CH3:28])[O:20]2)=[C:12]([NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:11]=1)(=O)=O>CN(C)C=O>[OH:24][C@@H:23]1[C@H:22]([OH:25])[C@@H:21]([CH2:26][O:27][CH3:28])[O:20][C@H:19]1[N:16]1[CH:15]=[N:14][C:13]2[C:17]1=[N:18][C:10]([CH2:9][C:1]#[N:2])=[N:11][C:12]=2[NH:29][CH2:30][CH:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: [C-]#N
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CC#N)nc32)[C@H](O)[C@@H]1O
Temperature: 70 °C
Yield: 63.6 %

Procedure:
Potassium cyanide (22 mg, 0.33 mmol) was added to a stirred solution of {9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (130 mg, 0.22 mmol) (preparation 25) in N,N-dimethylformamide (3 ml). The reaction mixture was heated to 70° C. for 1.5 hr, allowed to cool to room temperature and then partitioned between diethyl ether and water. The aqueous layer was washed with diethyl ether. The combined organic solutions were washed with brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a residue that was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (97:3). This gave the title compound (70 mg) as a powder. MS: 523 (MNa+).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][O:26][C:27](=[O:37])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:25][O:26][C:27](=[O:37])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=4)=[C:9]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: COC(=O)CCc1ccc(Oc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)cc1

Procedure:
Heat 300 mg (0.891 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, 642 mg (3.65 mmol) of 3-(4-hydroxyphenyl)propanoic acid methyl ester and 435.4 mg (1.34 mmol) of caesium carbonate to 120° C. for 2 h. After cooling, add water and filter off the precipitated crude product. Dissolve the solid in ethyl acetate and wash the solution twice with buffer solution (pH 7), dry over magnesium sulphate and concentrate again. After treating the residue with methanol, a solid precipitates out. Filter it off, wash with a little methanol and dry under reduced pressure. 160 mg (36.3% of theory) of the target compound are obtained as a colourless solid.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][S:3][CH:2]1[C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([CH:12]=1)[OH:11].[C:14]1(O)([CH3:23])[CH2:19][CH2:18][CH:17]([C:20]([CH3:22])=[CH2:21])[CH:16]=[CH:15]1>>[S:1]1[CH2:5][CH2:4][S:3][CH:2]1[C:6]1[CH:7]=[C:8]([OH:13])[C:9]2[CH:18]3[CH2:19][C:14]([CH3:23])=[CH:15][CH2:16][CH:17]3[C:20]([CH3:22])([CH3:21])[O:11][C:10]=2[CH:12]=1
Reactant: C=C(C)C1C=CC(C)(O)CC1
Reactant: Oc1cc(O)cc(C2SCCS2)c1
Product: CC1=CCC2C(C1)c1c(O)cc(C3SCCS3)cc1OC2(C)C

Procedure:
The compounds of formula I in which R is hydrogen can be prepared by reacting a 3,5 -dialkanoyloxybenzaldehyde (III) with 1,2-ethanedithiol to produce a 1,3-dialkanoyloxy-5-(1,3-dithiolan-2-yl)benzene (IV), hydrolyzing the 1,3-dialkanoyloxy ester to produce 5-(1,3-dithiolan-2-yl)resorcinol (V), reacting compound V with p-mentha-2,8-dien-1-ol to produce 3-(1,3-dithiolan-2-yl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (VI) which is then subjected to oxidative cleavage conditions to produce a compound of formula I named 3-formyl-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol. This process can be represented as follows: ##STR9## wherein R5 represents a lower alkanoyl group, such as the acetyl, propionyl and butyryl groups.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24]Br>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: Clc1cc(Cl)cc(CBr)c1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(Cl)cc(Cl)c2)c(=O)[nH]c1=O
Yield: 52.7 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dichlorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (220 mg, yield: 52.7%).