Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[NH2:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][O:24][C:25]2=[O:28])=[CH:21][CH:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[O:28]=[C:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([NH:18][C:13]3[N:12]=[C:11]([C:7]4[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=4)[CH:16]=[N:15][CH:14]=3)[CH:27]=2)[CH2:23][O:24]1
Reactant: Nc1ccc2c(c1)C(=O)OC2
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3ccc4c(c3)C(=O)OC4)n2)c1
Yield: 26.2 %

Procedure:
Using Method L, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 6-amino-1,3-dihydroisobenzofuran-1-one (52.2 mg, 0.35 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 85° C. for 16 hours. The same workup as for Method L was followed by washing of the resulting solid with dichloromethane (30 mL) and filtration. The insoluble solid was then washed with acetone (60 mL). The acetone was evaporated under vacuo and the resulting solid was crystallised in cold dimethylformamide: dichloromethane mixtures to give 22.7 mg of title compound. Yield: 26.2%. 1 H NMR (250 MHz, DMSO-d6) δ 2.09 (s, 3 H), 5.39 (s, 2 H), 7.45 (t, 1 H, 8.0 Hz), 7.62-7.69 (m, 2 H), 7.76 (d, 1 H, 7.9 Hz), 8.23 (s, 1 H), 8.24-8.29 (m, 2 H), 8.39 (bs, 1 H), 8.50 (s, 1 H), 9.99 (s, 1 H), 10.06 (s, 1 H); 13C NMR (62.9 MHZ, DMSO-d6) δ 24.05, 69.78, 112.78, 117.31, 120.16, 121.13, 123.36, 124.58, 125.59, 129.29, 130.73, 133.63, 136.83, 139.71, 139.94, 141.47, 147.88, 151.05, 168.47, 170.75; m/z 361.2 [(M+H)+, calcd for C20H16N4O3 360.1].
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[I:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27].CCN=C=NCCCN(C)C>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:21])[NH:27][C:26]3[CH:28]=[CH:29][C:30]([CH3:31])=[C:24]([I:23])[CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:6])([CH3:5])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: Cc1ccc(N)cc1I
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1I
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-Boc-4-(4-carboxyphenyl)piperidine (200 mg, 0.66 mmol) and 3-iodo-4-methyl aniline (153 mg, 0.72 mmol) in DCM (10 mL) was treated with EDCI (380 mg, 1.98 mmol) at rt. After stirring for 48 hr at rt the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was collected, concentrated and the residue was chromatographed on a silica gel column with a 0-30% EtOAc in hexanes to afford the corresponding intermediate 4-[4-(3-Iodo-4-methyl-phenylcarbamoyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester. This intermediate was then dissolved in a 30% TFA in CH2Cl2 mixture (10 mL). Upon consumption of the starting material, as judged by TLC, the solution was partitioned between EtOAc and water. The water layer was basified to pH 12 with solid NaOH. The organic layer was then collected, dried over Na2SO4, filtered and concentrated to a residue that without further delay was dissolved in DMSO (5 mL). The mixture was then treated with 4-fluoro ethyl benzoate (550 mg, 3.28 mmol), diisopropyl ethyl amine (3 mL) and a catalytic amount of DMAP and heated at 120° C. in a sealed tube for 4 days. The reaction mixture was then cooled, partitioned between EtOAc and water. The EtOAc layer was collected dried over Na2SO4 filtered and concentrated to a solid that after suspension in CH2Cl2 and filtration afforded the product (100 mg, Yield: 53%). HRMS m/z calcd for C28H29N2O3I [M+H]+: 569.1296. Found: 569.1294.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([OH:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:18]>O1CCCC1>[CH3:18][O:14][C@H:12]1[CH2:13][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11]1
Reactant: CI
Reactant: O[C@H]1C[C@@H](COCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@H](COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of cis-3-benzyloxymethylcyclobutanol (Albany Molecular Research Institute, 1.0 g, 5.2 mmol) in 10 mL of tetrahydrofuran at 0° C. was added NaH (0.62 g, 15.6 mmol). The mixture stirred for 15 minutes then iodomethane (0.49 mL, 7.8 mmol) was added and the mixture was allowed to warm to ambient temperature and stir for 16 hours. Some starting material remained by TLC so additional NaH (0.21, 5.2 mmol) and iodomethane (0.32 mL, 5.2 mmol) were added and the mixture stirred for an additional 2 hours. The mixture was quenched with 10 mL of NH4Cl and diluted with 10 mL of ethyl acetate. The layers were separated and the aqueous layer was extracted 2×5 mL of ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 75% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 207 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[OH-].[Na+].Br[CH2:12][CH2:13][CH2:14][Cl:15]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][N:6]1[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]1
Reactant: COC1CCNCC1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC1CCN(CCCCl)CC1
Yield: 60.2 %

Procedure:
4-Methoxy-piperidine (1.5 g, 13 mmol), acetone (30 ml, 20 vol), 5M NaOH solution (3.13 ml) and 1-bromo-3-chloropropane (6.14 g, 39 mmol, 3 eq.) were reacted together according to general procedure A to give the title compound (1.5 g, 60%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[O:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]([NH2:18])[C:11]3=[CH:10][C:9]=2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:4]([Cl:28])[CH:3]=1.CCN(CC)CC.[Br:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:36][CH2:37][CH2:38][CH2:39][C:40]([NH:18][CH:17]1[C:11]2[C:12](=[N:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[Cl:28])=[C:9]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[CH:10]=2)[O:14][C:15]([CH3:20])([CH3:19])[CH2:16]1)=[O:41]
Reactant: CC1(C)CC(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Br)cc3Cl)nc2O1
Reactant: O=C(Cl)CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(NC(=O)CCCBr)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Br)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 7-(4-bromo-2-chlorophenyl)-6-(4-chloro-phenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine (303 mg, 0.63 mmol) and NEt3 (221 μL, 1.6 mmol) in 10 mL of CH2Cl2 was added 4-bromobutyryl chloride (110 μL, 0.95 mmol). After stirring at rt for 16 h, the reaction mixture was combined with saturated aq NaHCO3 (20 mL). The aq layer was separated and extracted with CH2Cl2 (3×20 mL). The organic layers were combined, dried over MgSO4, and concentrated to afford the product.
Reaction SMILES: [ClH:1].F[C:3]1[CH:8]=[C:7]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=2)[CH:22]=1)=[O:17].Cl.[Cl:34]C1C=C(NC(=O)C2C=CN=C(OCC)C=2)C=CC=1[C@H]1OCCNC1>>[ClH:34].[Cl:1][C:8]1[CH:3]=[C:4]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]([C:23]3[CH:28]=[N:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=3)[CH:22]=2)=[O:17])[CH:5]=[CH:6][C:7]=1[C@@H:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: O=C(Nc1ccc([C@H]2CNCCO2)cc1F)c1cnn(-c2cncc(C(F)(F)F)n2)c1
Reactant: CCOc1cc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)ccn1
Agent: Cl
Product: O=C(Nc1ccc([C@H]2CNCCO2)c(Cl)c1)c1cnn(-c2cncc(C(F)(F)F)n2)c1

Procedure:
In analogy to example 83, step a) using 1-(6-Trifluoromethyl-pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid (prepared as described in example 125) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-2-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 91) instead of (+)—(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][OH:30]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][CH2:29][OH:30])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCCO)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 3-bromo-1-propanol (0.07 ml, 0.7 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (4% methanol/chloroform) to give the subject compound (64 mg, yield 39%).
Reaction SMILES: [CH:1]([NH2:3])=[O:2].C(OC(=O)[CH2:8][C:9]1[C:10]([Cl:23])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH2:19][N:20]([CH3:22])[CH3:21])[CH:15]=[CH:14]2)C.C[O-].[Na+]>CN(C)C=O.O>[Cl:23][C:10]1[C:9]([CH2:8][C:1]([NH2:3])=[O:2])=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH3:21])[CH3:22])=[N:17]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(CN(C)C)nc12
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)Cc1ccc2ccc(Cl)c(CC(N)=O)c2n1
Temperature: 105 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Formamide (118 mg, 2.62 mmol, 3.35 equiv) was added to a solution of (7-chloro-2-dimethylaminomethyl-quinolin-8-yl)-acetic acid ethyl ester (240 mg, 0.78 mmol) in N,N-dimethylformamide (1.0 ml). The solution was heated to 105° C., and then sodium methoxide (5.4 M in MeOH, 0.14 ml, 0.78 mmol, 1.0 equiv) was added dropwise over 20 minutes. After 1 hour, the reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc and CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatrography (gradient of CH2Cl2/MeOH 96:4 to 60:40) afforded the title compound (161 mg, 74%) as a white solid. 1H NMR (400 MHz, d6-DMSO): δ=8.35 (d, J=8.9 Hz, 1H), 7.89 (d, J=9.2 Hz, 1H), 7.63 (d, J=9.2 Hz, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.41 (br s, 1H), 6.88 (br s, 1H), 4.26 (s, 2H), 3.69 (s, 2H), 2.21 (s, 6H). MS (ES+): 278.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH2:7]([CH2:22][C:23](Cl)=[O:24])[CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH3:15])[CH3:10].[OH-].[Na+]>CCOCC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:23](=[O:24])[CH2:22][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH3:15])[CH3:10]
Reactant: CN(C)CCN
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(=O)NCCN(C)C
Yield: 88 %

Procedure:
A solution of 12.3 g of N,N-dimethylethylenediamine in 50 cc of ether was placed in a three-necked flask equipped with a stirrer, a dropping funnel and a thermometer. Then 37 g of the above-mentioned farnesylacetyl chloride was added dropwise at 5° to 10° C. After completion of the dropping, the reaction was continued at room temperature for an hour. After the reaction, 70 g of a 10% aqueous solution of sodium hydroxide was added, the aqueous layer was separated from the ether layer and extracted with ether, and the ether extract was combined with the ether layer. The ether was distilled off from the ether solution. The residue was subjected to preparative liquid chromatography (Waters Associates, Prep LC/System 500), which gave 38.5 g of N,N-dimethyl-N'-farnesylacetylethylenediamine (1). The structure was identified by proton NMR and mass spectrometry (M.S.). The NMR data are shown below.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2c1ccc(OCc1ccccc1)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-(benzyloxy)-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.123 g, 0.217 mmol) in methylene chloride (10 mL) was added with a 4 N solution of hydrogen chloride in 1,4-dioxane (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate (20 mL), and the precipitated solid was collected by filtration. The resulting solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-(benzyloxy)-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0720 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([NH:21][CH3:22])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([O:20][CH3:25])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([NH:21][CH3:22])[N:11]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CNc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Solvent: CO
Solvent: ClCCl
Product: CNc1nc(C(=O)NCc2ccc(F)cc2)c(OC)c2ncccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of N-(4-fluorobenzyl)-8-hydroxy-5-(methylamino)-1,6-naphthyridine-7-carboxamide (2.65 g, 8.12 mmol) in methanol (50 mL) and CH2Cl2 (20 mL) was added trimethylsilyldiazomethane (12.1 ml of a 2M solution in hexanes, 24.4 mmol) and the mixture was stirred for 16 hr at rt. Additional trimethylsilyldiazomethane (24.0 ml of a 2M solution in hexanes, 48 mmol) was added and the reaction was stirred for 16 hr. The reaction was quenched by the addition of acetic acid (2 mL) and the solvent was evaporated in vacuo. The residue was purified by flash chromatography eluting with MeOH/CH2Cl2 (5-15% gradient elution), to afford the title compound.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24]Cl)[CH:16]=1)[CH:11]=2.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:19]([CH:20]=2)=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24][N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)[CH:16]=2)[CH:11]=3)[CH2:29][CH2:28]1
Reactant: CN1CCNCC1
Reactant: ClCCCOc1ccc2cc3ccc(OCCCCl)cc3nc2c1
Agent: Cl
Product: CN1CCN(CCCOc2ccc3cc4ccc(OCCCN5CCN(C)CC5)cc4nc3c2)CC1

Procedure:
The compound is prepared from 3,6-bis(3-chloropropoxy)acridine hydrochloride and N-methylpiperazine as described in Example 44.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:34])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.[OH-].[Li+]>O1CCCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH:18]([F:19])[F:20])[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:24][CH:23]=1)=[C:8]2[CH3:34]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cc2ccc(C(=O)C(C)(C)C)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A solution of {8-chloro-2-difluoromethoxy-3-[4-(2,2-dimethylpropionyl)benzyl]-4-methylquinolin-5-yloxy}acetic acid methyl ester (0.18 g) in tetrahydrofuran (10 mL) and water (1.5 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.71 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, diluted with water and dichloromethane and then acidified by the addition of 0.1 M aqueous hydrochloric acid solution. The aqueous phase was extracted with dichloromethane and the combined organic phases dried over magnesium sulfate. The solvent was removed under reduced pressure to give title compound as a white solid (0.16 g).
Reaction SMILES: [NH:1]([C:3]([C:5]1[S:28][C:8]2[NH:9][N:10]=[C:11]([NH:12][C:13](=[O:27])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:7]=2[CH:6]=1)=[O:4])[NH2:2].C(O)C.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>Cl.O1CCCC1>[CH:32](=[N:2][NH:1][C:3]([C:5]1[S:28][C:8]2[NH:9][N:10]=[C:11]([NH:12][C:13](=[O:27])[C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[C:7]=2[CH:6]=1)=[O:4])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN)cc34)cc2)CC1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN=Cc5ccccc5)cc34)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
N-(5-Hydrazinocarbonyl-1H-thieno[2,3-c]pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)-benzamide (0.150 g, 0.318 mmol, 1 eq.), ethanol (1 mL) and, by syringe, benzaldehyde (0.048 mL, 0.47 mmol, 1.3 eq.) are placed in a dry 5 mL round-bottomed flask under argon. Two drops of 5 N hydrochloric acid are added to the suspension. The reaction mixture is stirred at a temperature in the region of 50° C. for 3 hours, the solvent is then evaporated off and the residue is placed directly on a column of neutralized silica gel. Elution is performed with a methanol/dichloromethane mixture (10/90 by volume). The product obtained is directly added to a mixture of 1 mL of tetrahydrofuran and 0.5 mL of 5 N hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried. N-[5-(Benzylidenehydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide is obtained in the form of a white solid (0.029 g, 16%). MS: ES m/z=488 MH+ base peak. 1H NMR (400 MHz, (CD3)2SO-d6, δ in ppm): 2.53 (partially masked s, 3H); 2.87 (m, 4H); 3.47 (m, 4H); 7.03 (d, J=9.0 Hz, 2H); from 7.39 to 7.49 (m, 3H); 7.79 (d, J=7.5 Hz, 2H); 8.01 (d, J=9.0 Hz, 2H); 8.28 (s, 1H); 8.39 (s, 1H).
Reaction SMILES: Cl.[CH3:2][NH:3][NH:4][C:5](=[NH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]1([CH3:22])[C:14]([C:19](Cl)=O)=[CH:15][CH:16]=[CH:17][CH:18]=1>C(OCC)C>[CH3:2][N:3]1[C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:22])=[N:12][C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:4]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CNNC(=N)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: Cc1ccccc1-c1nc(-c2ccccc2)nn1C
Temperature: 120 °C
Yield: 76 %

Procedure:
A mixture of 0.56 g. of benzimidic acid 2-methylhydrazide hydrochloride and 3.8 g. of o-toluic acid chloride is heated under stirring at about 120° C. After cooling and addition of diethyl ether, the hydrochloride of the triazole is collected on filter and then suspended in a sodium bicarbonate aqueous solution. The free base is extracted with diethyl ether and the organic phase, after drying over sodium sulfate, is evaporated. The crude compound is purified by distillation at 160° C./0.1 mm Hg. Yield 76%.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][NH2:19])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:20]([O-])(O)=[O:21].[Na+].C(Cl)(Cl)=O>C(Cl)Cl.O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]3[O:17][C:20](=[O:21])[NH:19][N:18]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C([O-])O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]nc(OCC2c3ccccc3-c3ccccc32)o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
A suspension of N-[(9H-fluoren-9-ylmethoxy)carbonyl]hydrazine (141) (1.49 g, 5.78 mmol), CH2Cl2 (60 ml) and saturated NaHCO3 solution (60 ml) was stirred vigorously at 0° C. for 5 minutes, and the solution was then left for 5 minutes without stirring. Phosgene (1.89 M in toluene, 7.95 ml, 15.0 mmol) was then carefully added to the lower, organic phase using a syringe, and stirring of the reaction mixture was begun again immediately after the addition. After 10 minutes, water (20 ml) and CH2Cl2 (20 ml) were added to the reaction mixture. The phases were then separated rapidly, the aqueous phase was extracted with CH2Cl2 (50 ml), and the combined organic phases were dried over Na2SO4. Removal of the solvent under reduced pressure and drying gave a colourless solid (1.35 g, 4.82 mmol, 83%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([Cl:18])=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.O.O.O.O.O.O.O.O.O.O.O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[CH:39]1([NH2:42])[CH2:41][CH2:40]1>CC1C=CC=CC=1C.O>[Cl:18][C:12]1[C:11]([NH:10][C:8]([C:7]2[C:2]([NH:42][CH:39]3[CH2:41][CH2:40]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[C:16]([CH3:17])[CH:15]=[CH:14][N:13]=1
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Reactant: NC1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccnc(Cl)c1NC(=O)c1cccnc1NC1CC1
Temperature: 135 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (50 g), trisodium phosphate dodecahydrate (67.37 g), cyclopropylamine (40.43 g) were suspended in o-xylene (150 ml) and heated to 130-140° C. for 6-8 h in autoclave. Then the reaction mass was cooled to 70-75° C., diluted with o-xylene (250 ml) and DM water (150 ml) and stirred for 10 min at 70-80° C. The aqueous layer was separated and washed the organic layer with DM water (150 ml) at 70-80° C. The organic layer was concentrated at 60-65° C. under reduced pressure up to residual weight attained is approximately 200 g. The concentrated mass was cooled to 5-10° C. and stirred for 30 min. Filtered the solid obtained and washed with chilled o-xylene (50 ml, 5-10° C.). Dried the obtained solid at 55-60° C. under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1B(O)O>>[CH3:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: COc1cnccc1B(O)O
Product: COc1cnccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Example 8 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and (3-methoxypyridin-4-yl)boronic acid (Combi-Blocks Inc.). The batch was purified by preparative HPLC: