Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)=[O:22])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[N+:34]([C:37]1[CH:42]=CC(O)=[CH:39][CH:38]=1)([O-:36])=[O:35].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([C:23]1[NH:27][CH:26]=[CH:25][N:24]=1)=[O:22])([O:6][C:7]1[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:42][CH:8]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOP(=O)(CCCCCCCCCCCOC(=O)c1ncc[nH]1)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCCCCCCCCOC(=O)c1ncc[nH]1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 16 (1.2 g, 3.0 mmol) dissolved in 25 mL of CH2Cl2 was added oxalyl chloride (0.65 n-flL, 7.5 mmol) dropwise at 0° C. The reaction mixture was allowed to slowly warm to room temperature. After stirring for 8 h, the mixture was concentrated to remove excess oxalyl chloride. The crude residue was redissolved in 20 mL of CH2Cl2, followed by the addition of 4-nitrophenol (414 mg, 3.0 mmol) and Et3N (0.80 mL, 6.0 mmol). After stirring at room temperature for 10 h, the reaction mixture was concentrated. The residue was purified by flash chromatography (hexane/EA=1:1) to give 601 mg (41%) of pure 17. 1H NMR (CDCl3, 500 MHz) δ 8.16 (d, J=9.0 Hz, 2H), 8.10 (s, 1H), 7.37 (s, 1H), 7.32 (d, J=9.0 Hz, 2H), 7.01 (s, 1H), 4.35 (t, J=6.5 Hz, 2H), 4.11 (m, 2H), 1.87 (m, 2H), 1.72 (m, 2H), 1.62 (m, 2H), 1.38-1.17 (br m, 20H). 31P NMR (CDCl3, 500 MHz) δ 30.49.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][C:11]=1[CH3:18].[CH3:19][C:20]1(C)[O:25]C(=O)CC(=O)[O:21]1.Cl>C(=O)([O-])[O-].[K+].[K+].O.C(O)=O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:19][C:20]([OH:25])=[O:21])=[CH:12][C:11]=1[CH3:18]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(C=O)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1C
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
Formic acid, 40.3 grams (0.88 mole), was stirred and cooled to below 5° C., to which was added 36.9 grams (0.37 mole) of triethylamine at a rate to maintain the reaction mixture temperature below 20° C. Upon completion of addition, 22.0 grams (0.15 mole) of (4-methoxy-3-methylphenyl)formaldehyde was added to the reaction mixture, followed by 22.2 grams (0.15 mole) of 2,2-dimethyl-1,3-dioxane-4,6-dione. Upon completion of addition, the reaction mixture was warmed to 60° C. where it stirred for about 15 minutes. The source of heat was removed, during a period when an exothermic reaction with evolution of gas took place within the reaction vessel. The heat source was returned once the exothermic reaction subsided, and heating of the reaction mixture was resumed for about two hours at 75° C. to 95° C. After this time the reaction mixture was cooled in an ice and water bath, and 200 mL of water, followed by 100 mL of aqueous 4N hydrochloric acid were added. The mixture was then extracted with two portions of diethyl ether. The combined extracts were washed with two portions of an aqueous dilute sodium chloride solution, with one portion of an aqueous saturated sodium chloride solution, and then dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding a residual solid. The solid was dissolved in an aqueous solution of 1N potassium carbonate and washed with two portions of diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid, and then it was extracted with two portions of diethyl ether. The combined ether extracts were washed with one portion of an aqueous dilute sodium chloride solution, and then dried with sodium sulfate. The mixture was filtered and concentrated under reduced pressure, yielding 26.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:12][CH2:11][C:10]2[C:9]([C:13]([NH2:15])=[O:14])=[C:8]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:7]=[CH:6][C:5]=2[C@H:4]1[OH:24].[CH2:25]([CH2:32][C:33](=O)[CH3:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([BH3-])#N.[Na+]>CO.O>[ClH:1].[CH2:17]([O:16][C:8]1[CH:7]=[CH:6][C:5]2[C@@H:4]([OH:24])[C@H:3]([NH:2][CH:33]([CH3:34])[CH2:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:12][CH2:11][C:10]=2[C:9]=1[C:13]([NH2:15])=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: NC(=O)c1c(OCc2ccccc2)ccc2c1CC[C@@H](N)[C@@H]2O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(CCc1ccccc1)N[C@@H]1CCc2c(ccc(OCc3ccccc3)c2C(N)=O)[C@H]1O
Reaction time: 8 h
Yield: 60.9 %

Procedure:
In 30 ml of methanol was dissolved 1 g of trans-6-amino-2-benzyloxy-5-hydroxy-5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydrochloride, followed by addition of 5 g of benzylacetone. Then, under ice-cooling, 1 g of sodium cyanoborohydride was added and the mixture was allowed to stand at room temperature overnight. The reaction mixture was diluted with 300 ml of water and extracted 3 times with 30 ml of CHCl3. The CHCl3 layers were combined, washed with water, dried and concentrated under reduced pressure. The residue was dissolved in 50 ml of ethyl ether, followed by addition of 5 ml of 20% ethanolic hydrochloric acid, whereby 0.84 g of trans-2-benzyloxy-5-hydroxy-6-(1-methyl-3-phenylpropylamino)-5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydrochloride was obtained as colorless crystals, m.p. 215°-218° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[C:18]1([S:24]([CH:27]=[CH2:28])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[BrH:1].[C:18]1([S:24]([CH:27]=[CH:28][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Br
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CS(=O)(=O)c3ccccc3)cc12
Yield: 61 %

Procedure:
A mixture of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (0.25 g), phenylvinylsulphone (0.19 g), tri-o-tolylphosphine (0.075 g), palladium (II) acetate (0.0125 g), triethylamine (0.25 mL) and acetonitrile (2.5 mL) was heated under reflux for 42 hours in an atmosphere of nitrogen. The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/methanol/concentrated aqueous ammonia (90:10:1) gave the title compound as a foam (0.24 g): Anal. Calcd for C22H24N2O2S. HBr. 1/3 CH2Cl2 : C,54.77; H,5.29; N,5.72. Found: C,55.00; H,4.85; N,5.58.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[N+]([NH:22][C:23](N)=[O:24])([O-])=O.O>C(O)C>[NH2:22][C:23]([N:8]1[CH2:9][CH2:10][CH:5]([O:4][C:3]2[C:11]([F:18])=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:2]=2[F:1])[CH2:6][CH2:7]1)=[O:24]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: NC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 65 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
A solution of 4.0 g 4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 100 ml of 95% ethanol was treated with 1.73 g of nitrourea and then stirred at 65° C. for five hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Filtration, followed by evaporation of the solvents afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane). The resultant solid was recrystallized from hot isopropanol to yield 3.41 g (73.3%) of 1-aminocarbonyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 170°-172° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.[CH3:16][O:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:27][CH2:26][O:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]([O:17][CH3:16])=[O:29])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: COC(=O)c1ccccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1

Procedure:
10 g (0.05 mol) of 4-(3-indolyl)-piperidine, 16.1 g (0.075 mol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester both prepared in Example 1 (parts A and B), 31.1 g (0.225 mol) of potassium carbonate and 1.33 g (0.008 mol) of potassium iodide were suspended in 90 ml of methyl isobutyl ketone. This mixture was refluxed for 24 h. Once the reaction was completed, the inorganic salts were filtered and the liquid phase evaporated to dryness. The remaining material was redissolved in dichloromethane and water and worked-up as usual. The crude mixture was purified by flash-chromatography over silica gel affording 9.58 g (51% of yield) of methyl 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoate.
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([CH2:9][OH:10])[CH:5]=1)([CH3:3])[CH3:2].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([O:10][CH2:9][C:6]2[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[O:8][N:7]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1cc(CO)no1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCc2cc(C(C)C)on2)cc1
Reaction time: 5 h
Yield: 20.5 %

Procedure:
4.24 g of (5-i-propyl-isoxazol-3-yl)methanol was dissolved in 10 ml of pyridine, and 6.67 g of 4-toluenesulfonyl chloride was then added under ice-cooling. The mixture was stirred for 5 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.82 g of (5-i-propyl-isoxazol-3-yl)methyl 4-toluenesulfonate.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5](CC2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[CH3:35][O:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH:39]=O>>[CH3:35][O:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][N:5]1[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[CH:23]=[N:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:19]=3[N:20]=2)[CH2:4]1
Reactant: COc1ccccc1C=O
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccccc1CN1C[C@@H](C)[C@H](c2nc3c(cnn3C3CCOCC3)c(=O)[nH]2)C1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyano borohydride and 2-methoxybenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.00 (s, 1H), 7.29-7.22 (m, 2H), 6.92-6.88 (m, 2H), 4.83-4.75 (m, 1H), 4.14-4.08 (m, 2H), 3.93 (s, 3H), 3.76-3.69 (m, 2H), 3.62-3.54 (m, 2H), 3.34 (t, J=8.7 Hz, 1H), 3.01 (d, J=9.5 Hz, 1H), 2.78 (m, 1H), 2.56 (m, 1H), 2.41-2.27 (m, 3H), 1.92-1.82 (m, 3H), 1.18 (d, J=7.1 Hz, 3H). MS: (M+H m/z 424.1).
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[C:16](=[O:18])[NH:15]C(N)=NC=2[N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH:22]1([CH2:25]Br)C[CH2:23]1.[CH3:27][N:28]([CH3:31])[CH:29]=[O:30]>O.CO>[CH2:2]([N:9]1[C:17]2[C:16](=[O:18])[NH:15][C:29](=[O:30])[N:28]([CH2:31][CH:22]3[CH2:25][CH2:23]3)[C:27]=2[N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Reactant: BrCC1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1[nH]c(=O)n(CC2CC2)c2ncn(Cc3ccccc3)c12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 7 g (29.0 mmol) of 7-benzylxanthine from Example 6 b) in 200 ml of dimethylformamide was heated to 50° C. and treated in portions with 0.69 g (29.0) mmol of sodium hydride and stirred at 50° C. for one hour. 2.76 ml (29.0 mmol) of cyclopropylmethyl bromide were added to this suspension and the temperature was increased to 80° C. After 7 hours at 80° C., 1 ml (11.0 mmol) of cyclopropylmethyl bromide was added again. After a further 6 hours, 24 ml of water and 10 ml of methanol were added, and the mixture was allowed to stand overnight, treated again with 120 ml of water and extracted three times using 300 ml of methyl tert-butyl ether each time. The organic phases were washed with water, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane/methanol (99/1).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([CH2:26][C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=3)[C:30]([O:32]C)=[O:31])[C:15](=[O:25])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[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.[OH-].[Li+]>O1CCCC1.CO.O>[NH:1]([C:8]1[N:13]=[C:12]2[N:14]([CH2:26][C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=3)[C:30]([OH:32])=[O:31])[C:15](=[O:25])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(CN2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(CN2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Temperature: 60 °C
Yield: 33.3 %

Procedure:
A solution of 90 mg (0.17 mmol) of methyl 3-[[7-anilino-3-(2-bromophenyl)-1,2,3,4-tetrahydro-2-oxopyrimido[4,5-d]pyrimidin-1-yl]methyl]benzoate in tetrahydrofuran/methanol/water (6 ml:6 ml:1.5 ml) was treated with 27 mg (1.125 mmol) of lithium hydroxide monohydrate then heated at 60° C. for 3 hours under a nitrogen atmosphere. The solvent was evaporated and the residue partitioned between ethyl acetate (10 ml) and 2M hydrochloric acid (10 ml). The ethyl acetate layer was separated, washed with saturated aqueous sodium bicarbonate (10 ml), dried over magnesium sulfate, filtered and evaporated to give 30 mg (35%) of 3-[[7-anilino-3-(2-bromophenyl)-1,2,3,4-tetrahydro-2-oxopyrimido[4,5-d]pyrimidin-1-yl]methyl]benzoic acid as a pale yellow solid of melting point 180-183° C. [Mass spectrum (ESI) MH+ =530].
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].[N+](C1C=C[C:20]([O:23]C(Cl)=O)=CC=1)([O-])=O.CCN(CC)CC.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([CH2:53][C:54]2([C:60]([OH:62])=[O:61])[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[CH2:49][CH2:48]1>C(Cl)Cl>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:20]([NH:45][CH2:46][CH:47]2[CH2:52][CH2:51][N:50]([CH2:53][C:54]3([C:60]([OH:62])=[O:61])[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)[CH2:49][CH2:48]2)=[O:23])[C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: NCC1CCN(CC2(C(=O)O)CCOCC2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC3(C(=O)O)CCOCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
A mixture of 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (1.0 g, 5.7 mmol) and chloroformic acid 4-nitrophenyl ester (1.14 g, 5.7 mmol) in CH2Cl2 (20 mL) was stirred at room temperature for 5 min under N2. To this mixture, Et3N (1.7 mL, 12.5 mmol) was added slowly and this generated mixture was added to a mixture of 4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid 4-methylbenzenesulfonate (2.4 g, 5.7 mmol, Step 12) in CH2Cl2 (15 mL) at rt. The resulting mixture was stirred at room temperature for 2 hrs. This mixture was washed with 0.5 N HCl aq (100 mL) and the organic layer was washed with saturated NaHCO3 aq (75 ml) then the organic layer was concentrated. The residue was diluted with EtOAc (75 mL) and it was concentrated until ca 15 mL. After seeding of the product, this mixture was stirred at room temperature for 30 min. During this procedure, the solid was formed and this mixture was filtered: Obtained solid was washed with EtOAc (10 mL), dried at 50° C. under vacuum to give 1.9 g (73%) of the titled compound as white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:26][C:27]1[CH:35]=[C:34]([C:36]#[C:37][CH2:38][O:39][CH3:40])[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH2:41].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[C:34]([C:36]#[C:37][CH2:38][O:39][CH3:40])[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH:41][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)CC4=O)c(OC)cc23)c2c1OCO2
Yield: 75.9 %

Procedure:
This was prepared by the method described in example 4 using 1-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}-4-methylpiperazin-2-one (200 mg, 0.55 mmol), 5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (145 mg, 0.60 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 1.15 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using ethyl acetate as eluent. There was thus obtained the title compound (237 mg, 76%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 2.05 (quintet, 2H), 2.20 (s, 3H), 2.58 (t, 2H), 2.92 (s, 2H), 3.33 (t, 2H), 3.36 (s, 3H), 3.48 (t, 2H), 3.94 (s, 3H), 4.13 (t, 2H), 4.37 (s, 2H), 6.15 (s, 2H), 7.15 (s, 2H), 7.82 (s, 1H), 8.34 (s, 1H), 9.51 (s, 1H); Mass Spectrum: M+H+ 568/570.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:18][C:19]#[N:20].C(O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:18][C:19]#[N:20])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1c1ccc(Cl)cc1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: N#CCC1(c2ccc(Cl)cc2)CCCCC1=O
Temperature: 22.5 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-(4-chlorophenyl)-cyclohexanone (100 g, 0.48 mol) in N,N-dimethylformamide (0.5 L) was added slowly to a mixture of sodium hydride (13.8 g, 0.78 mol) in N,N-dimethylformamide (0.2 L), the temperature being kept below 40° C. The reaction mixture was stirred at 20-25° C. for 1.5 h when a precipitate was formed. The mixture was diluted with N,N-dimethylformamide (0.2 L), and thereafter, a solution of chloroacetonitrile (43.0 g, 0.57 mol) in N,N-dimethylformamide (0.1 L) was slowly added with cooling over 0.5 h, the temperature being kept below 25° C. The mixture was stirred for 18 h, and then, ethanol (50 mL) was slowly added. The mixture was stirred for 0.5 h and then poured onto ice-water.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(C)(C)C.C(N(CC)C(C)C)(C)C.[CH3:44][O:45][CH2:46][CH2:47][NH:48][CH2:49][CH2:50][O:51][CH3:52]>C(Cl)Cl.C(N(CC)CC)C>[CH3:44][O:45][CH2:46][CH2:47][N:48]([CH2:49][CH2:50][O:51][CH3:52])[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[CH:27][CH:26]=1)=[O:24]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: COCCNCCOC
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CCOC)C(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid (1.5 g) was dissolved in methylene chloride (45 ml) and then, triethylamine (0.7 ml) was added and cooled. Pivaloyl chloride (0.58 ml) was added slowly to the solution at 0~5° C. and the mixture was stirred at 5° C. for 2 hours. N,N-Diisopropylethylamine (0.8 ml) and bis(2-methoxyethyl)amine (0.6 g) were added in order, the solution was stirred at 0~5° C. for 2 hours and heated slowly to 20~25° C. and stirred for 30 minutes. The reaction mixture was washed with water twice and with aqueous 5% sodium bicarbonate. Then, the solvent was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with ether and further recrystallized using ethyl acetate and ether. The recrystallized product was filtered and dried to give 1.65 g (yield: 84%) of the desired compound. m.p.: 82~83° C.; 1H-NMR(CDCl3), ppm: δ 1.21(d, 6H), 3.08(m, 4H), 3.25(s, 3H), 3.36(m, 5H), 3.52(m, 5H), 3.64(m, 2H), 3.74(m, 2H), 3.90(m, 2H), 4.15(m, 1H), 6.82(m, 1H), 6.91(m, 1H), 7.44(m, 4H), 7.66(m, 1H)
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:9]([CH2:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)[C:8]2[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:18][C:7]=2[C:6](=[O:25])[N:5]1[CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.[CH3:39][O:40][CH2:41]Cl>C1COCC1.CN(C=O)C>[CH3:39][O:40][CH2:41][N:13]1[N:14]=[N:15][C:11]([CH2:10][N:9]2[C:8]3[CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:18][C:7]=3[C:6](=[O:25])[N:5]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)[C:4]2=[O:3])=[N:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)c3sc(-c4ccccc4)cc3n(Cc3nnn[nH]3)c2=O)CC1
Reactant: COCCl
Agent: CC(C)(C)OC(=O)N1CCC(n2c(=O)c3sc(-c4ccccc4)cc3n(Cc3nn[nH]n3)c2=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of sodium hydride (206 mg, 60% dispersion in mineral oil) in 7 ml absolute THF in a sealed tube is added a solution of a tautomeric mixture of tert-butyl 4-[2,4-dioxo-6-phenyl-1-(1H-tetrazol-5-ylmethyl)-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate and 4-[2,4-dioxo-6-phenyl-1-(2H-tetrazol-5-ylmethyl)-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl-]-piperidine-1-carboxylic acid tert-butyl ester (1.74 g; compound 14b) in absolute THF (7 ml) and absolute DMF (7 ml) at 0° C. After stirring for 40 min at 40° C. chloromethyl methyl ether (452 mg) dissolved in absolute DMF (3.5 ml) is added. The reaction mixture is stirred for 3 h at 50° C. and for 16 h at RT. The reaction is quenched by addition of a saturated aqueous solution of sodium bicarbonate and extracted with diethyl ether (two times). The combined organic phases are dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure. The resulting residue is purified by flash chromatography [silica gel, eluent: cyclohexane/diethyl ether, 1/1 (v/v)] to give the separated title compounds as solids.