Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36]Cl)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:53]([NH2:55])[CH3:54].[C:56](#N)[CH3:57]>C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:55]([CH2:56][CH3:57])[CH2:53][CH3:54])=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCCl)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc2c(c1)cc(-c1nn(C(=O)OC(C)(C)C)c3ccc(OCc4ccccc4)cc13)n2C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution containing 1.5 g of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(2-chloroethoxy)-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester prepared according to procedure J, 1 g of potassium carbonate, 600 mg of potassium iodide and 761 μl of ethylamine in 75 ml of acetonitrile is heated at 80° C. for 18 hours. After this period of time, 1.5 ml of ethylamine are added and the reaction is continued for a further 18 hours at 80° C. This operation is repeated after a further 18 hours and the reaction mixture is then evaporated under reduced pressure. The brown oil obtained is taken up in a mixture of ethyl acetate (80 ml) and of water (80 ml). After separation by settling out and extraction with ethyl acetate (80 ml), the organic extracts are combined, washed with water (100 ml) and with brine (100 ml), dried over magnesium sulfate and then evaporated under reduced pressure to obtain 1.15 g of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(2-diethylaminoethoxy)-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester, which is used as it is in the subsequent stage.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[CH:27][C:22]2=[C:21]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[N:20]=1)([CH3:3])[CH3:2].Cl.[CH3:42][N:43]([CH3:48])[CH2:44][C:45](Cl)=[O:46].C(N(CC)CC)C>ClCCl>[CH3:42][N:43]([CH3:48])[CH2:44][C:45]([N:14]1[CH2:15][CH2:16][CH:11]([C:9]2[CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:6]([NH:18][C:19]3[N:24]=[C:23]4[NH:25][N:26]=[CH:27][C:22]4=[C:21]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])[N:20]=3)=[CH:7][C:8]=2[CH3:17])[CH2:12][CH2:13]1)=[O:46]
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3cn[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3cn[nH]c3n2)c(OC(C)C)cc1C1CCN(C(=O)CN(C)C)CC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (56 mg) was dissolved in 3 mL of dichloromethane. The solution was cooled to 5° C. and 2-(dimethylamino)acetyl chloride hydrochloride (24 mg) was added to the solution followed by triethylamine (15 mg). The solution was stirred at room temperature for approximately 30 minutes. After Prep-LC-MS, the final product is obtained. MS (ES+): 649.32 (M+1)+.
Reaction SMILES: Cl.Cl.[C:3]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.C([O-])(=O)C.[Na+].C(O)(=O)C.[NH3:25]>CO.C1(C)C=CC=CC=1>[NH2:25][C:3]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[CH:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: N
Reactant: COC(=O)CC(=O)c1cccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C=C(N)c1cccnc1
Temperature: 62.5 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A suspension of methyl nicotinoylacetate dihydrochloride (50.0 g, 0.23 mol, dried) and sodium acetate (19.0 g, 0.23 mol) in glacial acetic acid (1.4 g, 0.02 mol), toluene (50 g), and methanol (50 g) was heated to 60-65° C. Ammonia (14.0 g, 0.82 mol) was bubbled through the suspension. After four hours, no starting material was present by HPLC. Two-thirds of the solvents were removed by distillation. The solution was stirred at 0° C. for one hour, and the precipitate was collected by filtration and dried to yield 83% of methyl 3-amino-3-(3-pyridyl)-2-propenoate. The crude product was used as is without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[C:6](\[NH2:8])/[CH3:7])[CH3:2].N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19].O>C1COCC1>[NH2:8]/[C:6](/[CH3:7])=[C:5](\[C:18](=[O:19])[CH2:17][Cl:16])/[C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)/C(C(=O)CCl)=C(\C)N
Reaction time: 2 h

Procedure:
To a solution of ethyl-3-aminocrotonate (F-1) (64.6 g, 0.5 mol, 1.0 eq) and pyridine (44.5 mL, 0.55 mol, 1.1 eq) in THF (600 mL) at −20° C., 2-chloroacetyl chloride (59.3 g, 0.53 mol, 1.05 eq) is added dropwise within 1 h. The resulting mixture is stirred from −20° C. to RT for an additional 2 h and then it is poured into H2O (1200 mL). The mixture is extracted with ethyl acetate (3×1200 mL). The combined organic layer is washed with H2O (2×500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated in vacuo to reduce the volume to about 200 mL. The residue is slurried in petroether (400 mL) at RT for 30 min. The solid is collected by filtration, rinsed with petroether (200 mL), and dried in vacuo to afford the product, (E)-ethyl 3-amino-2-(2-chloroacetyl)but-2-enoate (F-2).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16](I)[N:15]=2)=[N:6]1.[NH:30]1[CH2:33][CH2:32][CH2:31]1>CN1CCCC1=O>[N:30]1([C:16]2[N:15]=[C:14]([C:7]3[C:8]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]([CH2:4][C:3]4[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=4[F:1])[N:6]=3)[N:22]=[C:21]3[C:17]=2[N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)[CH2:33][CH2:32][CH2:31]1
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: C1CNC1
Solvent: CN1CCCC1=O
Product: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N3CCC3)c21
Temperature: 150 °C
Yield: 5.2 %

Procedure:
200 mg (0.399 mmol) of the compound obtained in example 107 were dissolved in N-methylpyrrolidone (3 ml) and admixed with 1.00 g (17.514 mmol) of azetidine, and then heated in a microwavable flask with septum in a microwave at 150° C. for 5 h. The mixture was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 9 mg of the title compound were obtained (5% of theory).
Reaction SMILES: [C:1]([NH:5][CH:6]([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].S(OCC)(O[CH2:13][CH3:14])(=O)=O.[OH-].[K+]>>[C:1]([N:5]([CH:6]([CH3:8])[CH3:7])[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)(C)C
Reactant: CCOS(=O)(=O)OCC
Agent: [K+]
Agent: [OH-]
Product: CCN(C(C)C)C(C)(C)C

Procedure:
A mixture of tert-butylisopropylamine (11.5 g, 0.1 mol) and diethyl sulfate (15.42 g, 0.1 mol) was refluxed for 2 h. Aqueous 8 M potassium hydroxide (20 ml, 0.16 mol) was added and the organic layer was separated. The aqueous layer was extracted with n-pentane (20 ml). The organic solutions were combined, dried over magnesium sulfate, and the product was isolated by distillation: 7.16 g, (50%), bp 140-142° C.; 1H NMR (CDCl3) δ0.99 (m, J=6.2 Hz, 9H, CH3), 1.10 (s, 9H, CH3), 2.55 (q, J=6.2 Hz, 2H, CH2, 3.35 (septet, J=6.2, 1H, CH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:11][C:10](=O)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)[nH]1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (6.96 g, 25.3 mmol) and phosphoryl chloride (80 mL) according to the general procedure I. Obtained as an off-white solid (7.35 g, 99%). MS (EI) 292.0 [(M)+]; mp 108° C.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:10]=1[CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH3:26].[CH2:32](Br)[CH2:33][CH2:34][CH3:35]>C(OCC)(=O)C.O>[CH2:32]([O:31][C:29]1[CH:28]=[CH:27][C:10]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH3:26])=[C:9]([Cl:8])[CH:30]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCBr
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(O)cc3Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(Cn2c(C)nc3ccc(C(=O)OCC)cc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
N,N-dimethylformamide (5 ml) was added to 60% sodium hydride (0.20 g, oily). Crystals of 1-(2-chloro-4-hydroxybenzyl)-6-(ethoxycarbonyl)-2-methylbenzimidazole (0.80 g) were added gradually thereto at room temperature. After stirring for 1 hour at room temperature, n-butyl bromide (0.28 g, 4.14 mmol) was added to the mixture. After further stirring for 15 hours at room temperature, water and subsequently ethyl acetate were added to the solution to effect extraction. The organic layer was separated, washed twice with water, and concentrated to obtain 0.62 g of oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=O.[CH:5]1[CH:10]=[C:9]([C:11]#[N:12])[C:8]([C:13]#[N:14])=[CH:7][CH:6]=1.Cl[Pd:16]Cl>>[CH:5]1[CH:10]=[C:9]2[C:2]3[N-:4][C:13]([C:8]2=[CH:7][CH:6]=1)=[N:14][C:13]1=[N:12][C:11]([C:9]2[C:8]1=[CH:7][CH:6]=[CH:5][CH:10]=2)=[N:14][C:13]1[N-:12][C:11](=[C:9]2[C:8]=1[CH:7]=[CH:6][CH:5]=[CH:10]2)[N:14]=[C:13]1[C:8]2[C:9]([C:11](=[N:12]1)[N:1]=3)=[CH:10][CH:5]=[CH:6][CH:7]=2.[Pd+2:16]
Reactant: Cl[Pd]Cl
Reactant: NC(N)=O
Reactant: N#Cc1ccccc1C#N
Product: [Pd+2]
Product: c1ccc2c(c1)-c1nc-2nc2[n-]c(nc3nc(nc4[n-]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Temperature: 280 °C

Procedure:
A palladium phthalocyanine was prepared by combining 20 g of urea, 20 g of o-phthalonitrile and 6.8 g of PdCl2 and heating the mixture up to a temperature of 280° C. for 4 hours to give the desired product.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([CH:26]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:27][NH2:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[ClH:19].[ClH:19].[N:20]1([CH:26]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:27][NH:28][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NCC(c1cccnc1)N1CCOCC1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCC(c3cccnc3)N3CCOCC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 55 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-(morpholin-4-yl)-2-(pyridin-3-yl)ethylamine as described in Steps 5 and 6, Example 24 to give the title compound as a white solid (55% yield). LC/MS: RT 2.06 min; m/e 489; 1H NMR (δ, ppm): 11.85 (1H, br), 8.98 (1H, s), 8.86 (1H, d), 8.54 (1H, d), 7.90 (2H, t), 7.58 (1H, t), 7.34 (1H, s), 7.1.7 (1H, d), 4.65 (1H, br), 3.6-4.10 (8H, br), 2.8-3.1 (2H, br), 2.40 (2H, q), 2.33 (3H, s), 1.10 (3H, t).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[S:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[N:3]=[C:2]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:7]([C:8]#[N:9])=[C:6]([N:10]4[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]4)[C:5]=3[C:16]#[N:17])[N:21]=2)=[CH:26][CH:27]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Reactant: NCCC(=O)O
Solvent: CN(C)C=O
Product: N#Cc1c(NCCC(=O)O)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 70 mg (0.14 mmol) of the compound from Example 4A and 27 mg (0.30 mmol) of beta-alanine in 2 ml of DMF is stirred at RT for 8 h. The mixture is then stirred at +90° C. for 2 h. After cooling to RT the reaction mixture is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [C:1](/[C:3](=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:17]([CH2:19][C:20](OCC)=O)#N.C1(C)C=CC(C=O)=CC=1.[N+](C(C)C)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[C:19]1([CH3:20])[CH3:17])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)/C(C#N)=C/c1ccc(C)cc1
Agent: Cc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)[N+](=O)[O-]
Product: CCOC(=O)C1(C#N)C(c2ccc(C)cc2)C1(C)C
Yield: 74 %

Procedure:
A mixture of 576 mg (2.68 mmoles) of (E)-ethyl 2-cyano-3-(p-methylphenyl)-2-propenoate (7) [prepared from ethyl cyanoacetate and p-tolualdehyde (p-methylbenzaldehyde) using the procedure described in Example I for an analogous cyanoester], 0.25 ml (2.78 mmoles) of 2-nitropropane, 398 mg (2.88 mmoles) of anhydrous potassium carbonate, and 2.0 ml of absolute ethanol was heated at reflux for 7 hours. The product was isolated as described in the procedure of Example VIII, affording 511 mg (74% yield) of cyclopropanoid cyanoester 15: bp: 155°-183° C. (bath temperature, 0.15 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1.C(N(CC)CC)C.[C:52](Cl)(=[O:54])[CH3:53]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:52](=[O:54])[CH3:53])[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1
Reactant: CC(=O)Cl
Reactant: CCc1cc(NC(CC)CCCCCCN)nc(Cl)n1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cc(NC(CC)CCCCCCNC(C)=O)nc(Cl)n1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
In 10 ml of chloroform were dissolved 0.55 g of dl-5-chloro-6-ethyl-4-(1-ethyl-7-aminoheptyl)aminopyrimidine and 0.25 g of triethylamine, and under ice cooling, 0.18 g of acetyl chloride was added to the solution and the mixture was stirred for one hour. After completion of the reaction, the reaction mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; ethyl acetate) to give 0.20 g of the title compound as pale yellow oily product. nD22.4 1.5296.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]4[CH:21]=[C:22]([CH:29]=[CH:30][C:31]=4[CH3:32])[C:23]([NH:25][CH:26]4[CH2:28][CH2:27]4)=[O:24])[CH:16]=3)[C:11]2=[O:33])=[CH:7][CH:6]=1.[CH3:36][NH:37][CH3:38]>>[CH:26]1([NH:25][C:23](=[O:24])[C:22]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:20]([C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[C:11](=[O:33])[N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:37]([CH3:38])[CH3:36])=[CH:35][CH:34]=3)[CH:19]=[CH:18]4)[CH:21]=2)[CH2:27][CH2:28]1
Reactant: CNC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(OCCCl)cc3)ccc2c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(OCCN(C)C)cc3)ccc2c1

Procedure:
A solution of the product of step ii) (95 mg) in dimethylamine (5M in ethanol, 1.5 mL) was heated using microwave irradiation at 100° C. for 90 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([C:31](=[O:32])[CH2:30][Cl:29])[C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1CC[C@H](NCCNC(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](N(CCNC(=O)OC(C)(C)C)C(=O)CCl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl trans-4-({2-[(t-butoxycarbonyl)amino]ethyl}amino)-cyclohexanecarboxylate (785 mg) obtained in Reference Example 71 (1) is dissolved in chloroform (8 ml), and thereto are added triethylamine (1.82 ml) and chloroacetyl chloride (249 μl) under ice-cooling. The mixture is then stirred at room temperature for 2 hours. The reaction solution is cooled with ice again, and chloroacetyl chloride (62 μl) is supplied thereto. The mixture is stirred at room temperature for 1 hour. To the reaction solution, saturated aqueous sodium hydrogen carbonate solution is poured and the mixture is extracted with chloroform. The organic layer is washed with water and saturated brine successively, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1, followed by 1/1) to give methyl trans-4-[{2-[(t-butoxycarbonyl)amino]ethyl}-(chloroacetyl)amino]cyclohexanecarboxylate (568 mg).
Reaction SMILES: Cl.Cl.[CH3:3][C@@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][S:5]1.[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([F:39])[CH:33]=1)[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C@@H:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])[C:28]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@@H:4]([CH3:3])[S:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:29])=[CH:33][C:34]=1[F:39]
Reactant: C[C@H]1SCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)c(F)c1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1SCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)c(F)c4)NC(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of (R)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (30 mg, 0.097 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)propanoic acid (31 mg, 0.097 mmol) in CH2Cl2 (5 mL) and triethylamine (1 mL) was added HBTU (37 mg, 0.097 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was dissolved in ethyl acetate (100 mL) and washed with water (5×50 mL). The organic phase was dried and concentrated. The residue was subject to silica gel chromatography, eluting with CH2Cl2/MeOH (50:1) to give tert-butyl (R)-3-(4-chloro-3-fluorophenyl)-1-(4-((R)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (44 mg, 85%). MS (APCI+) [M+H]+ 536.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]([O-:16])([O-])[O:13][CH3:14].[NH:17]1[CH2:22]C(=O)[CH2:20][CH2:19][C:18]1=[O:24].C(N(CC)CC)C>CO>[CH3:1][O:16][C:12]1([O:13][CH3:14])[CH2:22][NH:17][C:18](=[O:24])[CH2:19][CH2:20]1
Reactant: O=C1CCC(=O)NC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC([O-])[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC1(OC)CCC(=O)NC1

Procedure:
About 5 mg of p-toluenesulfonic acid was added to a solution of methyl orthoformate (5 ml), and the resulting mixture was then added to a solution of 2,5-piperidinedione (1.8 g, 16 mmol) in methanol (20 ml). The mixture was heated under reflux for 12 hours. After cooling, triethylamine (1 ml) was added to the mixture, and then the mixture was concentrated by using a rotary evaporator. The residue was purified by silica gel column chromatography (CHCl3 :MeOH=15:1), and then recrystallized from ethyl acetate/ether to obtain 5,5-dimethoxy-2-piperidone as the desired compound (1.85 g, 81%). m.p. 89-90° C.; 1H-NMR (CDCl3, 300 MHz) δ: 2.01 (t, 2H, J=7.0 Hz, NCOCH2 --), 2.43 (t, 2H, J=7.0 Hz, NCOCH2CH2 --), 3.25 (s, 6H, OMe), 3.36 (d, 2H, J=2.5 Hz, NCH2C(OMe)2), 5.89 (bs, 1H, NH). P-SIMS (Glycerin matrix) 182 (M+ +1.8%), 160 (100%), 128 (34%), 101 (5%).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([S:14][C:15]#N)=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].[CH2:17](Br)C.[I-].[K+]>CO>[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH3:17])=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCBr
Reactant: COC(=O)c1cc(SC#N)ccc1N
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCSc1ccc(N)c(C(=O)O)c1
Temperature: 10 °C
Reaction time: 2.5 h
Yield: 31.7 %

Procedure:
To a 500 ml flask fitted with a magnetic stirrer, dropping funnel and thermometer, and containing a solution of 12.7 g (0.192 mol) of 85% potassium hydroxide in 300 ml of methanol was added in portions 10.0 g (0.0481 mol) of methyl 2-amino-5-thiocyanatobenzoate. The solution was cooled to 10° C. and a solution of 6.29 g (0.058 mol) ethylbromide in 50 ml of methanol was added over 10 minutes. This was followed by the addition of 8.0 g (0.048 mol) potassium iodide. After 2.5 hours, the reaction mixture was evaporated to a semi-solid under reduced pressure and treated with 300 ml of water. The aqueous solution was extracted with chloroform, and the organic layer dried over magnesium sulfate. The solution was filtered and evaporated to give 7.5 g (79%) of crude product. This material was recrystallized from hexane to give 3.01 g (32%) of the title compound, m.p. 97°-100° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][C:14]([C:17]([NH:19][C@@H:20]4[CH:25]5[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]5)[CH2:21]4)=[O:18])=[CH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:28]([Cl:31])(=[O:30])[CH3:29].C(N(CC)CC)C>C1COCC1>[ClH:31].[C:28]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][C:14]([C:17]([NH:19][C@@H:20]4[CH:25]5[CH2:24][CH2:23][N:22]([CH2:27][CH2:26]5)[CH2:21]4)=[O:18])=[CH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:30])[CH3:29]
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Product: Cl

Procedure:
75 mg (0.16 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 114), 18 μl (0.24 mmol) of acetyl chloride and 68 μl (0.49 mmol) of triethylamine are stirred in 2 ml of THF at RT overnight. The solvent is removed under reduced pressure. Purification takes place by preparative HPLC. The product is dissolved in methanol, and an excess of 1N hydrochloric acid is added. Removal of the solvent under reduced pressure and drying under high vacuum results in 51 mg (72% of theory) of the title compound.