Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]([OH:12])[CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:19]([O:12][CH:11]1[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH:9]=[CH:10]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: OC1C=CCC1(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC1C=CCC1(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 5,5-diphenyl-2-cyclopenten-1-ol (0.70 g) in pyridine (5 ml) were added acetic anhydride (0.84 ml) and catalytic amount of 4-dimethylaminopyridine at room temperature. After being stirred for 30 minutes, the pH of the reaction mixture was adjusted to 1.0 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 5,5-diphenyl-2-cyclopentenyl acetate (0.82 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[S:13]([NH:16][C:17]1[N:22]=[C:21](Cl)[C:20]([S:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:19][N:18]=1)(=[O:15])=[O:14].CCOCC>C1COCC1>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[S:13]([NH:16][C:17]1[N:22]=[C:21]([NH:4][CH2:1][CH2:2][CH3:3])[C:20]([S:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:19][N:18]=1)(=[O:14])=[O:15]
Reactant: CCCN
Reactant: O=S(=O)(Nc1ncc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)c(Cl)n1)c1ccc(Cl)cc1Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCNc1nc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
n-Propylamine (25 mg, 0.42 mmol) was added to a solution of 11 (50 mg, 0.08 mmol) in THF (5 mL) and the mixture was stirred at 50° C. for 2 hours. The solution was cooled to room temperature, filtered and the precipitate was washed with THF. The filtrate was concentrated under reduced pressure to afford a yellow oil. Trituration with ether gave a solid which was purified by flash column chromatography (2% MeOH in DCM) to afford 12 as a white solid (28 mg). 1H NMR (DMSO): δ 0.54 (t, 3H), 1.22 (q, 2H), 1.33-1.34 (m, 2H), 1.51 (quin, 4H), 2.80-2.84 (m, 6H), 7.32 (d, 2H), 7.56 (d, 1H), 7.58 (d, 2H), 7.70 (s, 1H), 7.97 (br s, 1H), 8.07 (d, 1H), 8.15, (s, 1H) ppm. Mass Spectrum m/e=618.0 (M+1)
Reaction SMILES: C1(COC([N:11]2[CH2:16][CH2:15][N:14]3[C:17](=[O:22])[O:18][C:19]([CH3:21])([CH3:20])[CH:13]3[CH2:12]2)=O)C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:20][C:19]1([CH3:21])[CH:13]2[CH2:12][NH:11][CH2:16][CH2:15][N:14]2[C:17](=[O:22])[O:18]1
Reactant: CC1(C)OC(=O)N2CCN(C(=O)OCc3ccccc3)CC21
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC(=O)N2CCNCC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
(Phenylmethyl)tetrahydro-3-oxo-1,1-dimethyl-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (0.97 g, 3.2 mmol) was dissolved in ethanol (50 mL). 10% Palladium carbon (0.10 g) was added thereto, and the resulting mixture was stirred under hydrogen atmosphere at room temperature one whole day and night. The reaction solution was filtered through a Celite, and the Celite was washed with ethanol. The filtrate was concentrated under reduced pressure and left to stand at room temperature overnight. The resulting crystals were collected by filtration and washed with diethyl ether to obtain the title compound (0.39 g, yield 73%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[NH:11][CH2:10]1.Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:10]1
Reactant: CCOC(=O)CCCBr
Reactant: O=C1NCC(COc2cccc(Cl)c2)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CC(COc2cccc(Cl)c2)OC1=O
Yield: 50 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.52 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 30 ml of anhydrous dimethylformamide, 2.00 g of 5-(3-chlorophenoxymethyl)oxazolidin-2-one and 2.34 g of ethyl 4-bromobutyrate were used, to give 1.50 g of the title compound having an Rf value of 0.39 (on silica gel thin layer chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:9]1([CH2:15][N:16]2[CH2:24][C:23]3[C:18](=[C:19]([CH3:32])[CH:20]=[C:21]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:22]=3)[C:17]2=[O:33])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>O>[CH:9]1([CH2:15][N:16]2[CH2:24][C:23]3[C:18](=[C:19]([CH3:32])[CH:20]=[C:21]([CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([CH2:2][C:3]5[N:8]=[CH:7][CH:6]=[CH:5][N:4]=5)[CH2:30][CH2:31]4)[CH:22]=3)[C:17]2=[O:33])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cc(CC2CCNCC2)cc2c1C(=O)N(CC1CCCCC1)C2
Reactant: ClCc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(CC2CCN(Cc3ncccn3)CC2)cc2c1C(=O)N(CC1CCCCC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a mixture of 2-Chloromethylpyrimidine (32 mg, 0.247 mmol), 2-Cyclohexylmethyl-7-methyl-5-piperidin-4-ylmethyl-2,3-dihydro-isoindol-1-one (56 mg, 0.164 mmol) and cesium carbonate (160 mg, 0.492 mmol) was added acetonitrile (3.0 mL). The mixture was allowed to stir at room temperature overnight. Water (2.0 mL) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Column chromatography provided the title compound as a yellow oil (48 mg, 69%). 1H NMR (300 Adz, CDCl3): δ 8.76-8.72 (d, 2H), 7.18 (t, 1H), 6.99 (s, 1H), 6.95 (s, 1H), 4.30 (s, 2H), 3.78 (s, 2H), 3.40-3.37 (d, 2H), 2.97-2.93 (d, 2H), 2.70 (s, 3H), 2.58-2.56 (d, 2H), 2.10-2.05 (t, 2H), 1.71-1.42 (m, 10H), 1.26-1.13 (m, 4H), 1.09-0.98 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:10]2[CH:5]([CH:6]([OH:11])[CH2:7][CH2:8][CH2:9]2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14].[CH2:16]([O:18][CH2:19]OCC)[CH3:17]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH:10]2[CH:5]([CH:6]([O:11][CH2:19][O:18][CH2:16][CH3:17])[CH2:7][CH2:8][CH2:9]2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14]
Reactant: CCOCOCC
Reactant: CC1C(C)(C)C2CCCC(O)C2C1(C)C
Solvent: Cc1ccccc1
Product: CCOCOC1CCCC2C1C(C)(C)C(C)C2(C)C
Temperature: 100 °C
Yield: 68.1 %

Procedure:
A reaction flask was charged with 300 g (1.4 mole) 1,1,2,3,3-pentamethyl-hexahydro-4-indanol, 258 g (2.5 mole) diethoxymethane, 0.25 liter toluene, and 5 g boron trifluoride etherate complex. The reaction mass was heated to 100° C. and methanol and lite organics were collected in a Dean Stark trap (190 g recovered). After aging the reaction for 2 hrs the reaction was cooled to 25° C. and acid catalyst was quenched with 100 g of 10% aqueous sodium carbonate. The mass was transferred to a separatory funnel and water washed. The organic layer was separated and purified by fractional distillation. The procedure afforded a 68% yield (256 g) of 1,1,2,3,3-pentamethyl-octahydro-4-(ethoxymethoxy)-1H-indene.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:13]=[C:12]([NH:14]C(=O)C(C)C)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:20]2[CH2:24][C@H:23]([CH2:25][OH:26])[CH:22]=[CH:21]2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)(C)C>[CH:8]1[N:9]([C@H:20]2[CH:21]=[CH:22][C@@H:23]([CH2:25][OH:26])[CH2:24]2)[C:10]2[N:11]=[C:12]([NH2:14])[N:13]=[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)[C:6]=2[N:7]=1
Reactant: CC(C)C(=O)Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Yield: 46.8 %

Procedure:
N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide (1.25 g, 3.51 mmol) was slurried in a mixture of isopropanol (2.5 ml) and 10% solution of NaOH (1.37 ml, 3.51 mmol). The mixture was refluxed for 1 h and concentrated to dryness. The residue was crystallized in acetone. Abacavir (0.47 g, 47%) was obtained as a white powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Br:22]Br>C(O)(=O)C.C(Cl)Cl.C(=O)([O-])O>[Br:22][C:3]1[C:4]2[CH:9]=[C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: BrBr
Reactant: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2sccc2c1
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2scc(Br)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a solution of (1S,2R,3S,4R)-3-(1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide (30 mg, 0.1 mmol) in acetic acid (2 mL) was added bromine (5.5 μL, 0.1 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with methylene chloride (5 mL) and neutralised by careful addition of a saturated hydrogen carbonate solution. The layers were separated and the aqueous was extracted with methylene chloride (2×5 mL). The organic extracts were washed with water, dried over magnesium sulfate and evaporated in vacuo to give (1S,2R,3S,4R)-3-(3-bromo-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide as a glass (37 mg, 97%). M/e 378/380 (MH+).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+]>CCOC(C)=O>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCCCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1nc(C(=O)NCCCCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), 5-aminovaleric acid (525 mg, 4.5 mmol) and NaOMe solution (6.7 mL, 3.36 mmol, 0.5 M in MeOH) was refluxed for 48 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (20-100% EtOAc/hexanes+2% AcOH) to give a crude solid. The solid was dissolved in EtOAc and washed several times with 1 M HCl. The organic layer was dried over MgSO4 and concentrated. The residue was taken up in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 1 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 18 mg of the title compound as an off-white solid. MS: (−) m/z 418.94 (M−1).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:35]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]1[CH3:48])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:45]4[CH2:46][CH2:47][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:43]([CH3:48])[CH2:44]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(=O)OC(C)(C)C)[C@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (80.0 mg, 0.155 mmol) and (R)-1-boc-2-methylpiperazine (93.1 mg, 0.465 mmol) in 1,4-dioxane (2 mL) was added triethylamine (156.8 mg, 0.19 mL, 1.549 mmol). The reaction mixture was stirred at 40° C. for 4 h, at room temperature overnight, then at 40° C. for an additional 7 h. The reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C35H43ClN5O5S (M+H+): 680.3; Found: 680.0 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([O:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:5]([N:12]1[CH2:13][CH2:14][CH:15]([O:18][CH2:19][C:20]([O:3][CH2:1][CH3:2])=[O:21])[CH2:16][CH2:17]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)Cl
Reactant: OCCOC1CCN(Cc2ccccc2)CC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)COC1CCN(Cc2ccccc2)CC1
Reaction time: 48 h
Yield: 65.8 %

Procedure:
15.6 g (0.2 mole) of acetyl chloride were added dropwise while cooling at 20° C with an ice bath to a solution of 47 g (0.2 mole) of 2-(1-benzyl-4-piperidyloxy)-ethanol, prepared according to the step B of Example I, and 20.2 g (0.2 mole) of triethylamine in 300 ml of benzene and after standing for 48 hours at room temperature, the precipitate was removed by vacuum filtration. The benzene filtrate was washed with aqueous sodium bicarbonate solution, then water, dried and the benzene distilled off. The residue was distilled to obtain 36.5 g (66% yield) of ethyl 2-(1-benzyl-4-piperidyloxy)-acetate as a clear oil boiling at 160°-170° C at 0.1 mm Hg and having a refractive index nD20 = 1.512.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH:3]=[N:2]1.[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][NH:1]2
Reactant: Oc1cccc2[nH]ncc12
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cccc3[nH]ncc23)c(F)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
100 mg (0.75 mmol) of 1H-indazol-4-ol (from example XXIV), 94 mg (0.64 mmol) of 3,4-difluoronitrobenzene and 103 mg (0.75 mmol) of potassium carbonate are suspended in 2 ml of anhydrous dimethylformamide, and the mixture is stirred at 50° C. for 5 hours. The reaction solution is then diluted with water and extracted 2× with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure. The crude product is purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14]C)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Mg].[Cl-].[NH4+].C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1Cc2ccc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.4 %

Procedure:
To a stirred suspension-solution of ethyl 6-chloroindole-2-carboxylate (20.0 g, 89.4 mmol) in methanol (350 mL) under Ar was added magnesium turnings (21.7 g, 0.89 mol). After 10 min, the internal temperature had risen to 24° C. and effervescence was apparent. The mixture was to 10-15° C. and was maintained for 1.5 h. After this time, the reaction mixture was allowed to warm to ambient temperature, and was stirred for 1 h. The mixture was poured onto saturated aqueous ammonium chloride solution (1 L), and ethyl acetate (300 mL) was added. After 1.5 h sting, the layers were separated, and the aqueous layer was extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine (200 mL), dried (magnesium sulfate) and concentrated in vacuo to give a brown oil. Purification by flash column chromatography [SiO2; ethyl acetate-heptane (1:3)] afforded the title compound (12.0 g, 63%) as an orange oil which crystallised on standing: IR νmax (film)/cm−1 3375, 2953, 2851, 1737, 1610, 1486, 1438, 1321, 1287, 1204, 1161, 1069, 1011, 948, 906, 846, 796, 794, 594 and 548; NMR δH (400 MHz; CDCl3) 3.27 (1H, dd, J 16.0, 5.0 Hz), 3.34 (1H, ddd, J 16.0, 10.5, 1.0 Hz), 3.76 (3H, s), 4.40 (1H, dd, J 10.5, 5.0 Hz), 4.47 (1H, br s), 6.68 (1H, br d, J 2 Hz), 6.69 (1H, dd, J 7.5, 2.0 Hz) and 6.96 (1H, d, J 7.5 Hz); hplc [Chiralcel OD; hexane-isopropanol (90:10); 1 mL/min; 260 nm] 50% (10.04 min) and 5% (11.61 min).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[N:5][CH:6]=[CH:7][CH:8]=1.[C:17](Cl)(Cl)=[O:18]>O>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:9]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:3]2[NH:2][C:17]1=[O:18]
Reactant: O=C(Cl)Cl
Reactant: Nc1cccnc1Nc1ccccc1F
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cccnc2n1-c1ccccc1F

Procedure:
The product from step B (1.5 g.) was dissolved in 40 ml. of water and treated with phosgene as described in Example 1, Step C, to provide 3-(2-fluorophenyl)-1,3-dihydroimidazo[ 4,5-b] pyridin-2-one, m.p. 199°-200° C.
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[O:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[CH2:25][CH2:24]2)=[CH:8][CH:7]=1>O1CCCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[NH:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][N:31]([C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[C:2]([NH:1][CH3:4])=[O:3])[CH2:27][CH2:28]2)=[CH:10][CH:11]=1
Reactant: CN=C=O
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNc4nccs4)CC3)nc3ccccc32)cc1
Solvent: C1CCOC1
Product: CNC(=O)N(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1nccs1
Yield: 59 %

Procedure:
A mixture of 1.1 parts of isocyanatomethane, 6.76 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[2-thiazolylamino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine and 90 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was crystallized from acetonitrile, yielding 4.5 parts (59%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N'-methyl-N-(2-thiazolyl)urea; mp. 171.9° C. (compound 103).
Reaction SMILES: [CH3:1]I.[OH:3][CH:4]1[C:13]2[C:8]3=[C:9]([CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:7]3[CH2:6][CH2:5]1)[C:10]([CH3:14])=[CH:11][CH:12]=2.[H-].[Na+]>O1CCCC1>[CH3:14][C:10]1[C:9]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:7]3[C:8]=2[C:13]([CH:4]([O:3][CH3:1])[CH2:5][CH2:6]3)=[CH:12][CH:11]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3OC
Temperature: 25 °C
Yield: 58.8 %

Procedure:
Methyl iodide (0.55 g, 3.86 mmol) was added dropwise to a mixture of ethyl 5,6-dihydro-6-hydroxy-9-methyl-4H-pyrrolo [3,2,1-ij]quinoline-2-carboxylate (0.50 g, 1.93 mmol), 60% sodium hydride (0.08 g, 1.93 mmol) and tetrahydrofuran (20 ml) with stirring at room temperature, and the resulting mixture was stirred at room temperature for another 2 hours. The reaction mixture was poured into ice water and extracted three times with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane= 5/95) to obtain 0.31 g of ethyl 5,6-dihydro-9-methyl-6-methoxy-4H-pyrrolo [3,2,1-ij]quinoline-2-carboxylate.
Reaction SMILES: [F:1][C:2]1([F:21])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13]/[C:12]/3=[N:17]\C(=O)C)=[CH:10][C:4]=2[O:3]1.Cl>C(O)C.O>[F:21][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([CH3:16])[S:13][C:12]3=[NH:17])=[CH:10][C:4]=2[O:3]1
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(C)=O)S1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)O3)c(=N)s1

Procedure:
A mixture of Example 5 (1.8 g, 5.76 mmol) and hydrochloric acid (38%, 4.76 mL) in 40 mL of ethanol-water (1:1) was refluxed for 15 hours. Then the solvent was removed under reduced pressure, and the residue was carried on to the next step. 1H NMR (CD3OD) δ ppm 2.28 (3H), 7.15 (1H), 7.40-7.65 (3H); MS (ESI) 271(M+H).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:35]4C(=O)C5=CC=CC=C5C4=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO>[NH2:35][CH2:34][CH2:33][C:29]1[CH:28]=[C:27]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])[C:15]2=[O:26])[CH:32]=[CH:31][CH:30]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cccc(N2C(=O)N(c3cc(Cl)ccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: NN
Solvent: O
Solvent: CO
Product: NCCc1cccc(N2C(=O)N(c3cc(Cl)ccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 52.3 %

Procedure:
A solution of 90 mg (0.14 mmol) of 7-anilino-3-(2,5-dichlorophenyl)-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.07 ml of hydrazine hydrate in 15 ml of methanol was stirred at room temperature under an atmosphere of nitrogen for 18 hours. The reaction was evaporated and the residue purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol/acetic acid/water (240:24:3:2). Product containing fractions were combined and evaporated and the residue re-evaporated with toluene. The residue was then dissolved in 20 ml of dichloromethane, washed with 20 ml of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to give 37 mg (52%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3-(2,5-dichlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 120-123° C. [Mass spectrum (ESI) MH+ =505].
Reaction SMILES: [CH3:1]I.[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:21]=[C:20]2[C:16](=[N:17][C:18]([SH:22])=[N:19]2)[C:15](=[O:23])[N:14]=1)[CH2:4][CH3:5].[OH-].[Na+].Cl>>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:21]=[C:20]2[C:16](=[N:17][C:18]([S:22][CH3:1])=[N:19]2)[C:15](=[O:23])[N:14]=1)[CH2:4][CH3:5]
Reactant: CI
Reactant: CCCOc1ccccc1C1=NC(=O)C2=NC(S)=NC2=N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1ccccc1C1=NC(=O)C2=NC(SC)=NC2=N1

Procedure:
Methyl iodide (0.5 g) was added to a stirred solution of 2-(2-propoxyphenyl)-8-mercaptopurin-6-one (1.0 g) in 1 Normal sodium hydroxide solution (8 ml). After 2.5 hours at room temperature the solution was neutralised with dilute hydrochloric acid to give the crude product which was recrystallised three times from aqueous ethanol to give the title compound, 0.32 g, m.p. 245-247° C.