Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C(O[CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)(=O)C>C1(C)C=CC=CC=1>[CH:8]1([N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH:15]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[O:22][C:23]4[C:28]3=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: NC1CCN(C2CC2)CC1
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Oc1ccccc1C2NC1CCN(C2CC2)CC1

Procedure:
Refluxing 4-amino-1-cyclopropylpiperidine and 9-acetoxyxanthene in dry toluene for 24 hours, then working up as in Example 1 gives N-(N-cyclopropyl-4-piperidinyl)-9-xanthenylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[O:5][CH2:6][CH2:7]Br.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>O>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH2:7][CH2:6][O:5][C:4]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:25][CH:24]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Clc1ccc(OCCBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1ccc(CNCCOc2ccc(Cl)c(Cl)c2)cc1

Procedure:
2.70 Grams (10.0 mmol) of 2-(3,4dichlorophenoxy)ethyl bromide was dissolvedin 30 ml of ethanol, followed by the addition of 1.06 g (10.0 mmol) of anhydrous sodium carbonate and 4.25 g (30.0 mmol) of 4-chlorobenzylamine. The mixture was heated and refluxed on an oil bath for 7 hours. After cooling, the reaction mixture was poured into 100 ml of water and was extracted with chloroform (20 ml×3).
Reaction SMILES: C([S:4][C@@H:5]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:6]([NH:8][CH:9]1[CH2:19][CH2:18][CH2:17][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[N:11]([CH2:20][C:21]([O:23]CC)=[O:22])[C:10]1=[O:26])=[O:7])(=O)C.[OH-].[Na+]>CO>[SH:4][C@@H:5]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:6]([NH:8][CH:9]1[CH2:19][CH2:18][CH2:17][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[N:11]([CH2:20][C:21]([OH:23])=[O:22])[C:10]1=[O:26])=[O:7]
Reactant: CCOC(=O)CN1C(=O)C(NC(=O)[C@H](Cc2ccccc2)SC(C)=O)CCCC12CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1C(=O)C(NC(=O)[C@@H](S)Cc2ccccc2)CCCC12CCCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of the product from part (1) (232 mg., 0.43 mmol.) in methanol (5 ml., deoxygenated via nitrogen bubbling) was cooled to 0° C. and treated with 1N sodium hydroxide (5 ml., deoxygenated via nitrogen bubbling). After stirring for one hour at 0° C. while purging continuously with nitrogen, the reaction was warmed to room temperature. After a total of three hours, the reaction was acidified to pH 1 with 5% potassium bisulfate and extracted with ethyl acetate. The organic layers were combined, washed with water (50 ml.), brine, dried (sodium sulfate), filtered, concentrated in vacuo, and reevaporated from hexanes to give 204 mg. of title product as a white foam. HPLC indicates the product to be a 47:53 mixture of diastereomers. TLC (2:3 ethyl acetate:hexanes) Rf =0.22.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[CH2:9][C:8]([CH3:30])([CH3:29])[C:5]2=[N:6][CH:7]=1.[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH3:36].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([N:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([N:35]([CH2:34][CH2:33][O:32][CH3:31])[CH3:36])[CH:3]=4)[C:8]([CH3:29])([CH3:30])[CH2:9]3)=[C:12]([CH3:28])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Reactant: CNCCOC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: COCCN(C)c1cnc2c(c1)N(c1c(C)c(-c3ccccn3)nc3cc(F)ccc13)CC2(C)C
Temperature: 120 °C

Procedure:
Prepared according to procedure N using 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (80 mg, 0.17 mmol), Pd2dba3 (15.8 mg, 0.017 mmol), N-(2-methoxyethyl)methylamine (15.4 mg, 0.17 mmol), sodium tert-butoxide (33.2 mg, 0.34 mmol) and XPhos (16.5 mg, 0.035 mmol) and heating in the microwave for 2 h at 120° C. After purification 1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-N-(2-methoxyethyl)-N,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-amine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.69-8.79 (1H, m), 7.75-7.98 (4H, m), 7.45 (1H, dd, J=2.1, 1.7 Hz), 7.37-7.43 (1H, m, J=7.4, 4.8, 1.5, 1.5 Hz), 7.28-7.33 (1H, m), 5.62-5.75 (1H, m), 3.73-3.87 (2H, m), 3.38-3.45 (2H, m), 3.29-3.35 (2H, m), 3.24 (3H, d, J=1.4 Hz), 2.84 (3H, d, J=1.4 Hz), 2.38 (3H, s), 1.61 (3H, s), 1.55 (3H, s). Mass Spectrum (ESI) m/e=472 (M+1).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[O:17]1[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][C:18]1=[O:24]>C1COCC1>[N:1]1([CH:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][C:18]([OH:24])=[O:17])=[CH:14][CH:15]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)C(c1ccc(N)cc1)n1ccnc1
Reactant: O=C1CCCC(=O)O1
Solvent: C1CCOC1
Product: CC(C)C(c1ccc(NC(=O)CCCC(=O)O)cc1)n1ccnc1
Yield: 99 %

Procedure:
A mixture of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.023 mol) and dihydro-2H-pyran-2,6(3H)-dione (0.03 mol) in THF (200 ml) was stirred and refluxed for 12 hours. When the reaction was complete, the solvent was evaporated, yielding 7.5 g (±)-5-[[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]amino]-5-oxopentanoic acid (compound 218).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:33]1[NH2+:34][C:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)=[CH:36][N:37]=1)[NH:17]C(=O)CC1C2C(=CC=C(OC)C=2)NC=1C)([OH:10])=[O:9].CCN(C(C)C)C(C)C.[CH3:57][N:58]([CH3:63])[S:59](Cl)(=[O:61])=[O:60]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:33]1[NH:34][C:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)=[CH:36][NH+:37]=1)[NH:17][S:59]([N:58]([CH3:63])[CH3:57])(=[O:61])=[O:60])([OH:10])=[O:9]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1ccc2[nH]c(C)c(CC(=O)N[C@@H](CCCCCC(=O)O)C3=NC=C(c4ccc5ccccc5c4)[NH2+]3)c2c1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)N[C@@H](CCCCCC(=O)O)c1[nH]c(-c2ccc3ccccc3c2)c[nH+]1

Procedure:
A solution of Example 107, 15 (1 eq.), DIPEA (2 eq.) and dimethylsulfamoyl chloride (2 eq.) in DMF was stirred overnight at RT. The crude was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18) and the desired fractions were lyophilized to afford the titled compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 12.04 (1H, bs), 8.33 (1H, s), 8.12 (1H, bs), 8.09-8.00 (2H, m), 7.99-7.87 (3H, m), 7.63-7.52 (2H, m), 4.62-4.51 (1H, m), 2.63 (6H, s), 2.19 (2H, t, J=7.2 Hz), 2.02-1.84 (2H, m), 1.55-1.44 (2H, m), 1.44-1.35 (1H, m), 1.35-1.16 (3H, m). MS (ES) C22H28N4O4S requires: 444, found: 445 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:17][CH:16]=1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].Cl>C1COCC1.O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH:22]([CH3:23])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:17][CH:16]=1
Reactant: COC(=O)CBr
Reactant: CCC(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(C)C(=O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (5.1 ml) in anhydrous THF (90 ml) at 0° C. is treated under N2 atmosphere with n-butyllithium (1.6 M, 22 ml) for 20 minutes. The mixture was cooled to -78° C., and a solution of 1(4-methoxyphenyl)-1-oxopropane (5 g) in anhydrous THF (40 ml) is added. The mixture was stirred 30 minutes at -78° C., then methyl bromoacetate (3.05 ml) was added dropwise and then mixture was warmed to ambient temperature over 2 hours. After stirring 18 hours at room temperature the mixture was Poured onto ice, water and conc. HCl (3 ml) was added and the solution was extracted with dichloromethane. The organic extracts were washed with brine, dried over N2SO4 and concentrated to an oil which was purified by chromatography on silica gel to provide the title compound as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[N:14][S:15][CH:16]=2)=[CH:8][CH:7]=1.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:18]1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(OCC)(=O)C.CC(CC(C)C)=O>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]4[N:13]=[N:14][S:15][CH:16]=4)=[CH:8][CH:7]=3)[CH2:30][CH2:31]2)=[N:18]1
Reactant: ClCCCCc1ccc(-c2csnn2)cc1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Solvent: CCOC(C)=O
Product: c1ccc2c(N3CCN(CCCCc4ccc(-c5csnn5)cc4)CC3)nsc2c1

Procedure:
To a 65 ml round-bottom flask equipped with condenser and N2 inlet were added 1.43 g (5.66 mmol) 4-(4-(4-chlorobutyl)phenyl)-1,2,3-thiadiazole, 0.90 g (4.11 mmol) N-benzisothiazolylpiperazine, 1.43 ml (8.22 mmol)diisopropylethyl amine, 0.87 g (8.22 mmol) sodium carbonate, 2 mg sodium iodide, and 30 ml methylisobutyl ketone. The reaction was refluxed for 24 hours, cooled, filtered, and the filtrate evaporated. The residue was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent to give an oil, which was taken up in ethyl acetate and precipitated by addition of ethyl acetate saturated with HCl. The solid was filtered, washed with ethyl acetate, and dried to afford 1.70 g (87.6%), m.p. 246°-247° C., white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:30]([OH:32])=[O:31])[C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][N:15](C4CCCCO4)[C:13]=3[N:14]=2)=[CH:5][C:4]=1[C:33]([O:35][CH3:36])=[O:34].O>O1CCOCC1.C(Cl)Cl>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:30]([OH:32])=[O:31])[C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][NH:15][C:13]=3[N:14]=2)=[CH:5][C:4]=1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)c1cc(-c2cc(C(=O)O)c3c(-c4ccccc4)nn(C4CCCCO4)c3n2)ccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(-c2cc(C(=O)O)c3c(-c4ccccc4)n[nH]c3n2)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
10 mL of a solution of anhydrous hydrogen chloride in dioxane (4 M) are added to a solution of 6-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2.0 g/4.20 mmol) in 35 mL of DCM. The solution is stirred at ambient temperature for 15 minutes and then run into water and extracted with EtOAc. The organic phase is washed with water and then with a saturated aqueous solution of NaCl, dried over sodium sulphate and concentrated to dryness to give 1.4 g of a pale yellow powder (yield: 86%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.O=C1CCC(=O)N1[O:41][C:42](=O)[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][NH:69][C:70](=[O:80])[CH2:71][CH2:72][N:73]1[C:77](=[O:78])[CH:76]=[CH:75][C:74]1=[O:79].CCN(C(C)C)C(C)C>>[Cl:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:32])[C:25]=1[C:24]([NH:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@H:12]([NH:11][C:9]([C:4]2([CH2:3][CH2:2][NH:1][C:42](=[O:41])[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][NH:69][C:70](=[O:80])[CH2:71][CH2:72][N:73]3[C:77](=[O:78])[CH:76]=[CH:75][C:74]3=[O:79])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:10])[C:13]([OH:15])=[O:14])=[CH:22][CH:21]=1)=[O:33]
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Reactant: NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[[1-(2-aminoethyl)cyclopentanecarbonyl]amino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid (607 mg, 1.0 mmol), 3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)propionylamino]- ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (689 mg, 1.0 mmol), and DIPEA (388 mg, 522 uL, 3.0 mmol), and after HPLC purification, resulted in a light yellow solid (788 mg, 74%). ES(+)-HRMS m/e calcd. for C50H69Cl2N5O16 (M+H)+ 1066.4189, obsd. 1066.4182.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C@H:48]1[C:56]2[C:51](=[CH:52][CH:53]=[C:54]([C:57]([O:59][CH3:60])=[O:58])[CH:55]=2)[CH2:50][CH2:49]1>ClCCl>[C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:47][C@H:48]1[C:56]2[C:51](=[CH:52][CH:53]=[C:54]([C:57]([O:59][CH3:60])=[O:58])[CH:55]=2)[CH2:50][CH2:49]1)=[O:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: CC(C)(C)c1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1C(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 57 %

Procedure:
2-tert-Butylbenzoic acid (0.75 g, 4.2 mmol, 1 eq) was dissolved in dichloromethane (40 ml), and at 0° C. HATU (1.5 g, 4.2 mmol, 1 eq) and DIPEA (1.7 ml, 10.52 mmol, 2.5 eq) were added and stirring was carried out for 30 min. Then (R)-methyl 3-amino-2,3-dihydro-1H-indene-5-carboxylate (A-07) (804 mg, 4.2 mmol, 1 eq) dissolved in dichloromethane (20 ml) was added and stirring was carried out for 16 h at RT. After monitoring by thin-layer chromatography, the reaction solution was diluted with dichloromethane (250 ml), washed with sat. sodium hydrogen carbonate solution (50 ml), sat. ammonium chloride solution (50 ml), water (50 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 8-10% ethyl acetate in hexane). Yield: 57% (1.6 g, 4.56 mmol).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Br)C1C=CC=CC=1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>CCOCC>[C:1]1([CH:18]2[CH2:19][CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: c1ccc2ncccc2c1
Agent: Br[Mg]Cc1ccccc1
Solvent: CCOCC
Product: c1ccc(C2CCc3ccccc3N2)cc1

Procedure:
By the 3-step method of Preparation E, substituting 1M phenyllithium in ether for the benzylmagnesium bromide solution, quinoline (25 g, 0.194 mol) was converted to present title product, 22.4 g, as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28].IC.[C:31]([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]([CH3:31])[C:17]3=[O:25])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(N2CCN(C(=O)Cn3c(=O)[nH]c4ccccc43)CC2)ccc1Cl
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CI
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)n(C)c4ccccc43)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (19) (10 mg, 0.025 mmol, 1.0 equiv), 5 μL of iodomethane (0.081 mmol, 3.26 equiv), 25 mg Cs2CO3 (0.075 mmol, 3.00 equiv) and 150 μL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-1,3-dihydro-benzoimidazol-2-one (20): HPLC retention time, 2.14 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 414.9, found, 415.5.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[CH:21]=[C:20]([OH:22])[C:19]2[C:18](=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[OH:24])[C:11](=[O:25])[C:10]=2[CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[C:34]([O:36][CH3:37])=[O:35]>O1CCCC1>[CH2:1]([O:5][C:6]([C:8]1[CH:21]=[C:20]([O:22][C:34]([O:36][CH3:37])=[O:35])[C:19]2[C:18](=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:24][C:6]([O:5][CH3:1])=[O:7])[C:11](=[O:25])[C:10]=2[CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1cc(O)c2c(c1)C(=O)c1cccc(O)c1C2=O
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)c1cc(OC(=O)OC)c2c(c1)C(=O)c1cccc(OC(=O)OC)c1C2=O
Reaction time: 3 h

Procedure:
2.7 g (8 mmoles) of the product of Example 15 are dissolved in 100 ml of anhydrous tetrahydrofuran; the resulting solution is added first with 2.42 g (24 mmoles) of anhydrous triethylamine, then, after cooling to 0°-5° C., with 1.6 g (17 mmoles) of methyl chloroformate. The reaction is complete within 3 hours, keeping room temperature. After that, solvent is evaporated off under reduced pressure and the residue is washed with acidulated water, the product is filtered, washed and crystallized from ethyl ether. M.p. 200°-202° C.
Reaction SMILES: NN[C:3](N)=[S:4].[C:6]1([NH:12][C:13](=[S:16])[NH:14][NH2:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([NH:12][C:13]2[S:16][C:3]([SH:4])=[N:15][N:14]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NNC(=S)Nc1ccccc1
Reactant: NNC(N)=S
Product: Sc1nnc(Nc2ccccc2)s1
Yield: 80 %

Procedure:
The procedure was as described in Example 2, but instead of thiosemicarbazide there were present 83.5 grams of 4-phenylthiosemicarbazide 83.5 grams of 4-phenylthiosemicarbazide. After the cooling and filtering with suction there were isolated 83.6 grams (=80% yield) of 2-phenylamino-5-mercapto-1,3,4-thiadiazole having a melting point of 208° to 210° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[C:4]([N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38](Cl)=[O:39])=[CH:34][CH:33]=1>O1CCOCC1.CO.O1CCOCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[C:4]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:38](=[O:39])[CH2:37][O:36][C:35]3[CH:41]=[CH:42][C:32]([Cl:31])=[CH:33][CH:34]=3)[CH2:20][CH2:19]2)[N:3]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: Nc1nc(N2CCCNCC2)c2nc(-c3ccc(F)cc3)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(N2CCCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of 2-amino-6-(homopiperazin-1-yl)-8-(4-fluorophenyl)-9H-purine (0.2 mmol) in dioxane/methanol (1:1; 5 ml) was added potassium carbonate (55 mg, 0.4 mmol) and a solution of 4-chlorophenoxyacetyl chloride (60 mg, 0.24 mmol) in dioxane (1 ml). The resulting mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by flash chromatography on silica (methanol/dichloromethane 1:40), yielding the pure title compound (60 mg, 60%).
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].CO[CH:14]=[CH:15][C:16]#[N:17].Cl>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[F:8][C:7]([F:10])([F:9])[C:6](=[O:11])[CH:5]=[CH:4][NH:3][CH:14]=[CH:15][C:16]#[N:17]
Reactant: COC=CC#N
Reactant: NC=CC(=O)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC=CNC=CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 400 mg, 10 mmol) was charged and washed with hexane twice. Into this flask, N,N-dimethylformamide (10 ml) was added and then a solution prepared by dissolving 4-amino-1,1,1-trifluoro-3-buten-2-one (1.4 g, 10 mmol) and 3-methoxyacrylonitrile (830 mg, 10 mmol) in N,N-dimethylformamide (5 ml) was added dropwise under ice-cooling. After stirring the mixture at room temperature for 3 hours, the reaction mixture was poured into water (50 ml). This mixture was acidified with concentrated hydrochloric acid under ice-cooling, and then extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (an eluting solvent: hexane/ethyl acetate=3/1 to 1/1) to obtain 993 mg (yield 52.3%) of title compound (IIa) having a low polarity and 457 mg (yield 24.0%) of title compound (IIb) having a high polarity.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(N(CC)C(C)C)(C)C.[C:20](OC([O-])=O)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>ClCCl.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NCc1cccc(Br)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
26.25 g of 3-Bromobenzylamine hydrochloride was suspended in 250 ml of dichloromethane, and the mixture was cooled to 0° C. 33.5 g of N,N-diisopropylethylamine and 28.3 g of t-butyl dicarbonate were added. After stirring was continued at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off, to give 31.28 g of the title compound.