Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17](Br)=[CH:18][CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCNCC1)CC2=O>>[CH3:30][O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:17]1[CH:16]=[C:15]2[C:20]([C:21](=[O:23])[CH2:22][C:11]3([O:14]2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccc(Br)cc1O2
Reactant: C=CC(=O)OC
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)CC2=O

Procedure:
7-Bromo-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylic acid tert-butyl ester (9.1 g, 23 mmol) was treated with methyl acrylate according to the procedure for preparation of Intermediate 1, Step B, giving (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-7-yl}-acrylic acid methyl ester (7.07 g) as a yellow solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.O.CO[CH:35](OC)[N:36]([CH3:38])[CH3:37]>>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])/[CH:17]=[CH:35]/[N:36]([CH3:38])[CH3:37])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)cccc12
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)cccc12
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (3.1 g, 9.2 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) was heated to reflux for 6 days. The mixture was cooled to room temperature, ethyl acetate was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (ethyl acetate) provided (2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (3.6 g, 99%) as a tinted oil: 1H NMR (CDCl3): δ 7.73–7.61 (m, 4H), 7.32 (t, 1H), 7.14 (t, 2H), 6.03 (d, 1H), 5.96 (d, 1H), 5.05 (d, 1H), 3.99 (m, 1H), 5.15–2.42 (broad, 6H), 2.19–2.08 (m, 2H), 1.86–1.62 (m, 6H); 19F NMR (CDCl3) δ −113.75; MS m/z 393 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](Cl)=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:19]([C:15]3[C:16]4[C:11](=[CH:10][C:9]([O:8][C:4]5[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=5)=[CH:18][CH:17]=4)[CH:12]=[CH:13][CH:14]=3)=[O:20])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=C(Cl)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2ccc(NC(=O)c3cccc4cc(Oc5cc(Cl)ncn5)ccc34)cc2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 2.2 mMol 6-(6-chloropyrimidin-4-yloxy)-naphthalene-1-carbonyl chloride (Step 19.3) in 15 ml CH2Cl2 is added to a stirred solution of 410 mg (2.0 mMol) 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine and 680 μl (4.0 mMol) diisopropylethylamine in 15 ml CH2Cl2. After 30 min, the reaction mixture is poured into a mixture of NaHCO3 and CH2Cl2. The aq. phase is separated off and extracted with CH2Cl2. The combined organic layers are washed with water and brine, dried (Na2SO4) and concentrated to give the crude product which is purified by column chromatography (SiO2; CH2Cl2/EtOH/NH3 95:4.5:0.5) to afford the title compound as a yellow powder.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.C([Mg]Br)C.CN[C:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[CH3:39].[Cl-:41].[NH4+]>ClCCl.C(OCC)C>[ClH:41].[ClH:41].[CH3:39][C:34]1[C:33]([CH2:32][C:2]2[N:3]=[CH:4][NH:5][CH:6]=2)=[CH:38][CH:37]=[CH:36][N:35]=1
Reactant: CNC(=O)c1cccnc1C
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: [Cl-]
Agent: CC[Mg]Br
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ncccc1Cc1c[nH]cn1
Product: Cl
Reaction time: 2.5 h

Procedure:
To a solution of 4-iodo-1-tritylimidazole (6.88 g, 15.8 mmol) in 65 mL anhydrous dichloromethane was added 6.3 mL of a solution of ethyl magnesium bromide (3.0 M, 18.9 mmol) in diethyl ether under argon. The reaction mixture was stirred for 2.5 h, and then a solution of N-methoxy, N-methyl-2-methylnicotinamide (2.84 g, 15.8 mmol) was added. After 5 days of stirring, the reaction mixture was poured into saturated aqueous ammonium chloride solution (125 mL). The layers were separated, and the aqueous layer was extracted twice with dichloromethane (50 mL). The organic extracts were combined, dried (Na2SO4), and concentrated to provide a red-orange foam which was purified on flash silica gel (1% methanol-chloroform to 2% methanol-chloroform) to provide the desired product as 5.56 g (82%) of a golden-brown foam. MS (PB-NH3), m/z 430 (MH+). 1H NMR (CDCl3) δ 2.63 (s, 3H), 7.02-7.16 (m, 7H), 7.19 (dd, J=7.8, 5.1 Hz, 1H), 7.28-7.41 (m, 8H), 7.49 (d, J=0.9 Hz, 1H), 7.70 (d, J=0.9 Hz, 1H), 7.96 (dd, J=7.9, 1.2 Hz, 1H), 8.57 (dd, J=7.9, 4.9 Hz, 1H.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[CH:16][C:17]([F:27])=[C:18]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>O1CCCC1.C(OCC)(=O)C>[C:11]([C:10]1[C:4]2[S:3][C:2]([NH:1][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:38])=[N:6][C:5]=2[CH:7]=[CH:8][C:9]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([F:27])=[C:18]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:23])[F:24])[CH:19]=1)#[N:12]
Reactant: O=C(Cl)C1CC1
Reactant: N#Cc1c(Oc2ccc(F)c(NC(=O)C(F)(F)F)c2)ccc2nc(N)sc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)C(F)(F)F)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of N-{5-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]-2-fluorophenyl}-2,2,2-trifluoroacetamide (1.0 g, 2.52 mmol) in tetrahydrofuran (10 mL) were added pyridine (1.0 mL, 12.5 mmol) and cyclopropanecarbonyl chloride (395 μL, 4.35 mmol), and the mixture was stirred at room temperature for 10% hr. Pyridine (4.0 mL, 50 mmol) and cyclopropanecarbonyl chloride (100 μL, 1.10 mmol) were added, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed successively with 1N hydrochloric acid (20 mL×2), 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (410 mg, 38%) as a white powder.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1[OH:24].C([O-])(=O)C.[K+]>C(O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1[OH:24]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@H]1C/C=C\CCCC(=O)O
Reaction time: 144 h

Procedure:
A solution of 1.00 g. of racemic PGE2 and 5 g. of potassium acetate in 100 ml. of 95% ethanol is allowed to stand at room temperature under nitrogen for 6 days; then is concentrated by evaporation under reduced pressure to about one third volume. The concentrated mixture is diluted with 75 ml. of cold water and dilute hydrochloric acid is added until the mixture reaches pH 3. The acidified mixture is extracted twice with ethyl acetate, then is saturateed with sodium chloride and extracted once more with ethyl acetate. The ethyl acetate extracts are combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated under reduced pressure, then dried under a stream of nitrogen to remove acetic acid from the residue. Thin layer chromatographic analysis shows that the residue comprises a mixture of racemic PGE2 and racemic 8-iso PGE2. The residue is chromatographed on 200 g. of Silicar CC4, eluting with 500 ml. 40%, 500 ml. 50%, 250 ml. 60%, and 250 ml. 100% ethyl acetate in cyclohexane, collecting 50-ml. fractions. Fractions 23-25 are combined and evaporated to give racemic 8-iso-PGE2. Fractions 27-30 are combined to give racemic PGE2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.[Si](C#N)(C)(C)C.[N:28]1([C:33](N2C=CN=C2)=[O:34])C=CN=[CH:29]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:15]([C:14]4[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:12]([F:11])[CH:13]=4)[CH2:29][NH:28][C:33]3=[O:34])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(C=O)cc1F
Agent: C[Si](C)(C)C#N
Product: COc1ccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)cc1F

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 3-fluoro-4-methoxybenzaldehyde (0.617 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (0.524 mL, 3.76 mmol), di-(imidazol-1-yl)methanone (0.333 g, 2.05 mmol) as described in method 2. The product was purified by means of FPLC.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][NH:18]C(OC(C)(C)C)=O)=[N:16][C:12]=2[CH:11]=1)=[O:9].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][NH2:18])=[N:16][C:12]=2[CH:11]=1)=[O:9].[F:36][C:37]([F:42])([F:41])[C:38]([O-:40])=[O:39]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNC(=O)OC(C)(C)C)n2C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN)n2C)c1ccccn1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4.81 g (0.10 mol) of 1-methyl-2-(N-tert.butoxycarbonyl-aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide were dissolved in 25 ml of methylene chloride, mixed with 5 ml of trifluoroacetic acid and stirred for 5 hours at ambient temperature. Then the solvent was evaporated off and the residue was stirred with ether. The crystals thus formed were filtered off, washed with ether and dried. Yield: 3.15 g (68% of theory), C20H23N5O3 (381.4) Rf value: 0.18 (silica gel; methylene chloride/ethanol=9:1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[CH:5]2.[C:16](=O)([O-])[O-].[K+].[K+].BrCC(OC)=O>CN(C)C=O>[CH3:16][O:13][C:12](=[O:14])[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[CH3:15]
Reactant: Cc1cc2cc(Cl)ccc2n1CC(=O)O
Reactant: O=C([O-])[O-]
Agent: COC(=O)CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(C)cc2cc(Cl)ccc21
Temperature: 60 °C
Reaction time: 48 h
Yield: 101.6 %

Procedure:
A mixture of (5-chloro-2-methylindol-1-yl)acetic acid (25 g), potassium carbonate (100 g) and N,N-dimethylformamide (220 mL) was treated dropwise with methyl bromoacetate (37 g), and the resulting mixture was stirred at 60° C. for 2 days. The mixture was cooled to room temperature and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic solution was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and pentane (1:10 to 1:0 by volume) to afford the title compound as a white solid (27 g).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[C@@H:31]([CH2:34]Cl)[CH2:32][CH2:33][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[C@@H:31]([CH2:34][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH2:32][CH2:33][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](CCl)N2C[C@H]1Cc1c[nH]c2ccccc12
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](CN3CCOCC3)N2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 120 °C

Procedure:
To a solution of (3,5-bis(trifluoromethyl)phenyl)-[(3R,6R,8aR)-6-chloromethyl-3-(1H-indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-methanone (1.06 g) in dimethylformamide (15 mL) was added morpholine (5 mL). The resulting mixture was heated at 120° C. for 6 hours. After cooling to room temperature, ethyl acetate and 5% aqueous sodiumbicarbonate were added and the layers were separated. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, MTBE/MeOH/NH4OH 95:4.5:0.5) to afford 3,5-bis(trifluoromethyl)phenyl-[(3R,6R,8aR)-3-(1H-indol-3-ylmethyl)-6-(morpholin-4-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-methanone (407 mg). Rf 0.46 (MTBE/MeOH/NH4OH 95:4.5:0.5) (compound 2).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][CH3:20]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][CH3:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 84.2 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) in N,N-dimethylformamide (1.6 mL) was added cesium carbonate (798 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromopropane (301 mg), and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (161 mg) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[C:8]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCCCCBr
Reactant: OCCCCCc1ccccc1
Product: BrCCCCCOCCCCCc1ccccc1

Procedure:
(3.2 g), b.p. 185°-195°/0.3 torr, from 1,5-dibromopentane (8.5 g) and benzenepentanol (2 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][OH:30])[CH:23]=2)[C:9]1=[O:31].COC1C=CC(C[NH2:39])=CC=1>>[NH2:39][C:13]1[N:12]=[C:11]2[N:10]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][OH:30])[CH:23]=3)[C:9](=[O:31])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[CH2:17][C:16]2=[CH:15][N:14]=1
Reactant: COc1ccc(CN)cc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CCO)c1)C(=O)N(c1ccccc1Br)C2
Product: Nc1ncc2c(n1)N(c1cccc(CCO)c1)C(=O)N(c1ccccc1Br)C2
Temperature: 100 °C
Yield: 40 %

Procedure:
A mixture of 300 mg (0.6 mmol) of 3-(2-bromophenyl)-7-methanesulfonyl -3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one and 1.5 ml of 4-methoxybenzylamine was heated at 100° C. for 1 hour. The mixture was cooled and partitioned between 30 ml of dichloromethane and 30 ml of 2M aqueous hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 10 ml of trifluoroacetic acid and then heated at reflux for 3 hours. The mixture was cooled and evaporated and the residue was partitioned between 25 ml of ethyl acetate and 25 ml of saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated and the residue was subjected to column chromatography on silica gel using ethyl acetate for the elution. Product-containing fractions were combined and evaporated to give 105 mg (40%) of 7-amino-3-(2-bromophenyl)-3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 154° C.
Reaction SMILES: [S:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][CH:5]=1)C#N.C(S)[C@@H](O)[C@@H](O)CS.[CH2:18]([O:20][C:21](=[O:26])[C:22](Br)([CH3:24])[CH3:23])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O.O>[CH2:18]([O:20][C:21](=[O:26])[C:22]([S:1][C:4]1[S:8][C:7]([NH2:9])=[N:6][CH:5]=1)([CH3:24])[CH3:23])[CH3:19]
Reactant: N#CSc1cnc(N)s1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: O[C@H](CS)[C@@H](O)CS
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
In a nitrogen atmosphere 5-thiocyanato-thiazol-2-ylamine (10 g, 64 mmol) dissolved in MeOH (300 mL) was added 2,3-dihydroxy-1,4-dithiolbutane (DTT, 9.8 g, 64 mmol) and stirred at room temperature for 1½ h. Then 2-bromo-2-methyl-propionic acid ethyl ester (13.6 g, 70 mmol) and K2CO3 (10.5 g, 76 mmol) was added and the reaction mixture was stirred for further 13 hs. The reaction mixture was divided between water (500 mL) and EtOAc (500 mL). The aqueous phase was extracted with EtOAc (2×300 mL). The combined organic phases were washed with water (500 mL) and brine (2×400 mL) and dried (MgSO4), filtered and evaporated. The crude product was dissolved in a small amount of DCM and purified by flash chromathography (heptane/EtOAc 2:1->1:2). Fractions containing the product were pooled and evaporated to a product containing impurities of DDT. This product was dissolved in diethyl ether (100 mL) and washed with water several times. The ether phase was dried (MgSO4), filtered and evaporated to give 8.45 g (54%) of 95% pure 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester as light brown crystals.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH2:21][CH2:22][NH2:23])[CH:14]=[CH:15][C:16]=3[O:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[O:24](C(C(F)(F)F)=O)[C:25]([C:27]([F:30])([F:29])[F:28])=O>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=3[O:17][CH:18]([CH3:19])[CH3:20])[CH2:21][CH2:22][NH:23][C:25](=[O:24])[C:27]([F:30])([F:29])[F:28])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(C)Oc1ccc(CCN)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)Oc1ccc(CCNC(=O)C(F)(F)F)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a stirred solution of 2-(3-(1-Admantyl)-4-isopropoxyphenyl)ethanamine (0.28 g, 0.86 mmol) in a mixture of solvents (CH2Cl2:Et3N: 10:0.5 ml) (CF3CO)2O (0.157 ml) was added at 0° C. under N2. The reaction mixture was stirred for 2 h at room temperature, then the solvent was evaporated to dryness. The residue was diluted to 50 ml with EtOAc and washed with 1M HCl. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title product (0.29 g, 82.4%). 1H-NMR (CDCl3) 1.37 (d, 6H, J=6 Hz); 1.67-1.75 (m, 6H); 2.04-2.23 (m, 9H); 2.78 (tr, 2H, J=6.84 Hz); 3.53-3.59 (m, 2H); 4.57-4.63 (m, 1H); 6.77 (d, 1H, J=8.32 Hz); 6.92 (dd, 1H, J=2.21, 8.27 Hz); 6.98 (d, 1H, J=2.21 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[C:12](OC)[CH2:13][O:14][CH3:15])[C:5](=[O:11])[CH2:6][C:7](OC)=[O:8].[NH4+:19].[OH-]>CCO.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5]([OH:11])=[CH:6][C:7]([OH:8])=[N:19][C:12]=1[CH2:13][O:14][CH3:15]
Reactant: COCC(OC)=C(C(=O)CC(=O)OC)C(=O)OC
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCc1nc(O)cc(O)c1C(=O)OC
Temperature: 60 °C

Procedure:
2-(1,2-Dimethoxy-ethylidene)-3-oxo-pentanedioic acid dimethyl ester (29.8 g, 115 mmol) is dissolved in a solution of EtOH (250 mL), water (250 mL) and concentrated NH4OH(aq) (30 mL). The mixture is heated to 60° C. for 5 hours. The reaction mixture is cooled to room temperature and the EtOH removed under reduced pressure. The remaining aqueous solution is cooled in an ice bath and acidified with concentrated hydrochloric acid, at which time a white precipitate appeared. The precipitate is collected and dried in a vacuum oven to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:21]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23].[K].C1(C)C=CC=CC=1>O>[CH2:21]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:7]([S:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)c2cccnc2Cl)cc1
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Agent: [K]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(-c2ncccc2S(=O)(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 55.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(b) (0.076 g) was added to a deoxygenated mixture of 4-nitrophenyl 2-chloropyridine-3-sulphonate (0.69 g), 4-isobutylphenylboronic acid (0.47 g), potassium fluorsde (0.38 g), toluene (15 ml) and water (2.5 ml) and the mixture was stirred and heated under reflux for 24 hours. Water (50 ml) was added and the mixture was extracted with ethyl acetate (2×80 ml). The organic extracts were washed with saturated sodium chloride solution and then combined and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with dichoromethane/hexane (1:1-1:0 v/v) then dichloromethane/hexane/ethyl acetate (10:9:1 v/v) through a silica gel Mega Bond Elut column followed by recrystallisation from ethyl acetate/hexane to give 4-nitrophenyl 2-(4-isobutylphenyl)pyridine-3-sulphonate (0.50 g), m.p. 123-124° C.; 1H NMR (d6 -DMSO): 0.9 (d, 6H), 1.9 (m, 1H), 2.55 (d, 2H), 7.2-7.3 (m, 4H), 7.5 (d, 2H), 7.7 (dd, 1H), 8.2 (d, 2H), 8.4 (dd, 1H), 9.0 (dd, 1H); mass spectrum (+ve FAB, NBA/DMSO): 413 (M+H)+.