Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18](O)[CH3:19])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18]([N:44]3[C:40](=[O:50])[C:41]4[C:42](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:43]3=[O:45])[CH3:19])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1cc2ncccc2nc1-c1cccc(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1cc2ncccc2nc1-c1cccc(F)c1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 1-(2-(3-fluorophenyl)-1,5-naphthyridin-3-yl)ethanol (0.0260 g, 0.0969 mmol), triphenylphosphine (0.0508 g, 0.194 mmol), phthalimide (0.0285 g, 0.194 mmol), and tetrahydrofuran (1.29 mL, 0.0969 mmol) was stirred at room temperature for 5 min to dissolve all reactants. The mixture was then cooled to 0° C. and to the cooled homogenous mixture was added dropwise diisopropyl azodicarboxylate (0.0382 mL, 0.194 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1.5 h. After 1.5 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 12 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 11 min and 100% isocratic of EtOAc for 25 min as eluent to give 2-(1-(2-(3-fluorophenyl)-1,5-naphthyridin-3-yl)ethyl)-1H-isoindole-1,3(2H)-dione as a white solid: LC-MS (ESI) m/z 397.9 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:16][CH2:17][C:18]([NH:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: CC[C@H](C)[C@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CO)NC(=O)CCl
Temperature: -20 °C

Procedure:
To a stirred solution of L-isoleucinol (20 g, 0.17 mol) and triethylamine (28.56 ml, 0.204 mol) in CH2Cl2 (500 ml) at -78° C. was added chloroacetyl chloride (16.3 ml, 0.204 mol) over 5 minutes. The cooling bath was removed and the solution allowed to warm to -20° C. The mixture was diluted with EtOAc and washed sequentially with 1M HCl, and brine and dried (Na2SO4). Evaporation in vacuo afforded the title compound Rf=0.3 CH2Cl2 :MeOH (95:5);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][NH:16][C:18](=[O:19])[O:20][CH2:21][CH3:22])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: NCCC1CCN(c2ccc(Br)cn2)CC1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NCCC1CCN(c2ccc(Br)cn2)CC1

Procedure:
The process is performed according to the method described in Example 1 (step 1.5.). Starting with 4.52 g (15.90 mmol) of 2-(5′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-ethylamine, prepared in step 10.2., 1.89 g (17.49 mmol) of ethyl chloroformate, 5.13 g (39.76 mmol) of N,N-diisopropylethylamine and 0.19 g (1.59 mmol) of N,N-dimethylaminopyridine, and after purifying on a column of silica gel, eluting with a 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia, 3.87 g of expected product are obtained in the form of a powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=3)(=[O:24])=[O:23])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(-c3ccc(C#N)n3C)cc2)cc1

Procedure:
The title compound was prepared according to general procedure for sulfonylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using p-toluenesulfonyl chloride (105 mg, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-4-methyl benzenesulfonamide (0.036 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:26]4[NH:20][C:21](=[O:22])[NH:23][C:24]4=[O:25])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 80 °C

Procedure:
To 5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.184 mmol) in 1 mL EtOH was added hydantoin (54 mg, 0.552 mmol) and piperidine (54 μL, 0.552 mmol). The mixture was heated in microwave for 60 minutes at 80° C. The solid formed was isolated by filtration and air dried to give 5-((5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=355)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].C(N(CC)CC)C.C(OC1C=CC2C=C(C)SC=2C=1)(=O)C>>[C:12]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1)(=[O:14])[CH3:13]
Reactant: Cc1cc2ccc(O)cc2o1
Reactant: CC(=O)Cl
Agent: CC(=O)Oc1ccc2cc(C)sc2c1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2cc(C)oc2c1
Yield: 101.3 %

Procedure:
This material was prepared from 6-hydroxy-2-methylbenzofuran (654 mg, 4.41 mmole) by treatment with acetyl chloride (0.41 ml, 5.74 mmole) and triethylamine (0.74 ml, 5.30 mmole) in a manner as previously described for 8b to give the desired product as an oil (850 mg, ˜quant). 1H NMR (CDCl3) δ7.41 (1H, d, J=8.3 Hz), 7.13 (1H, s), 6.88 (1H, dd, J=8.3, 1.9 Hz), 6.32 (1H, s), 2.42 (3H, s), 2.30 (3H, s).
Reaction SMILES: [ClH:1].Cl.O1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[CH:17]=1.[Cl:30]C1[S:32]C2C=CC=CC=2N=1>>[ClH:30].[ClH:1].[S:32]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[CH:17]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2o1
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2s1

Procedure:
The procedure for 3-benzoxazol-2-yl-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine dihydrochloride except using 2-chlorobenzothiazole in place of 2-chlorobenzoxazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.22 (m, 2H), 2.27 (d, J=13.5 Hz, 2H), 3.07-3.18 (m, 2H), 3.43 (d, J=13.2 Hz, 2H), 4.47-4.57 (m, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.55-7.61 (m, 1H), 8.02 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 8.16 (d, J=7.7 Hz, 1H), 8.21 (br. s., 1H), 8.33 (s, 1H), 8.50 (d, J=2.2 Hz, 1H). MS (ES+): m/z=376.80 [MH+]. HPLC: tR=2.02 min (ZQ2, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:21]([N:23]([CH2:33][CH3:34])[S:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Cl)(=[O:26])=[O:25])[CH3:22]>C(N(C(C)C)C(C)C)C>[CH2:33]([N:23]([CH2:21][CH3:22])[S:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:25])=[O:26])[CH3:34]
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCN(CC)S(=O)(=O)CCCCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)S(=O)(=O)CCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 92 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N,N-diethyl-5-chloropentanesulfonamide (531.9 mg, 2.20 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (50:1), to give N,N-diethyl-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pentanesulfonamide (905.2 mg) as a yellow oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 92.0%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[CH2:12]([C:14]1([CH2:32][CH3:33])[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:17]2[CH:27]=[CH:28][C:29]([NH2:31])=[CH:30][C:16]=2[O:15]1)[CH3:13]>C(Cl)(Cl)Cl>[CH2:32]([C:14]1([CH2:12][CH3:13])[N:19]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:17]2[CH:27]=[CH:28][C:29]([NH:31][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:30][C:16]=2[O:15]1)[CH3:33]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1(CC)N=C(c2ccc(F)cc2)c2ccc(N)cc2O1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCC1(CC)N=C(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (63 μL) and pyridine (131 μL) were added dropwise to a solution of 2,2-diethyl-4-(4-fluorophenyl)-2H-1,3-benzoxazin-7-amine (a compound of Reference Example 4, 81 mg) in chloroform (5 mL), and the mixture was stirred at 40° C. overnight. The reaction mixture was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, Solvent: chloroform/methanol=100/0 to 90/10), and the resultant powder was suspended in diisopropyl ether. The resultant precipitates were collected by filtration and washed with hexane-diisopropyl ether to give the titled compound (69 mg) as a colorless powder.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=CC(CN4CCOCC4)=C[CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.[C:62]([O:66][C:67]([N:69]1CCC[CH:71](C=O)[CH2:70]1)=[O:68])([CH3:65])([CH3:64])[CH3:63]>>[C:62]([O:66][C:67]([N:69]1[CH2:70][CH2:71][CH2:19][CH:18]([C:16]2[NH:15][C:12]3=[N:13][CH:14]=[C:9]([Cl:8])[C:10]([NH:31][C@H:32]4[C@@H:33]([C:39](=[O:40])[NH2:41])[C@H:34]5[CH2:38][C@@H:37]4[CH:36]=[CH:35]5)=[C:11]3[N:17]=2)[CH2:23]1)=[O:68])([CH3:65])([CH3:64])[CH3:63]
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCCC(c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)C1
Yield: 65 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-formyl-piperidine-1-carboxylic acid tert-butyl ester were reacted to produce the title compound (65%). 1H NMR (d-chloroform): 15.20 (br s, 1H), 8.42 (m, 1H), 7.83 (s, 1H), 6.45 (m, 1H), 6.38 (m, 1H), 5.90 (m, 1H), 5.64 (s, 1H), 5.25 (m, 1H), 4.03 (m, 1H), 2.80-3.25 (m, 5H), 2.62 (t, J=8 Hz, 1H), 2.39 (d, J=10 Hz, 2H), 1.32-2.00 (m, 14H). MS: 488.07 (M+H). HPLC retention time: 2.67 minutes (G Method).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[CH2:5][CH2:6][C:7]1[C:12](=[O:13])[NH:11][C:10]([NH2:14])=[N:9][C:8]=1[NH2:15])[CH3:2].C(O[C:23](=[O:25])[CH3:24])(=O)C>N1C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[CH2:5][CH2:6][C:7]1[C:12](=[O:13])[NH:11][C:10]([NH:14][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[N:15]([C:23](=[O:25])[CH3:24])[C:12](=[O:13])[CH3:7])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(CCc1c(N)nc(N)[nH]c1=O)OCC
Solvent: c1ccncc1
Product: CCOC(CCc1c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c1=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 7.20 g (28.1 mmol) of 3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propionaldehyde diethyl acetal, 30 ml of dry pyridine and 30 ml of freshly distilled acetic anhydride was heated on an oil bath at 90° for 6 hours and then stirred at ambient temperature overnight. Solution occurred within 15 minutes as a mixture of diacetyl and triacetyl pyrimidinone formed; extended reaction was required to obtain only the title compound. The solution was spin evaporated in vacuo to give an oil. Ethyl acetate was added and spin evaporated several times until a solid was obtained. The solid was dispersed in cyclohexane and collected; yield, 8.88 g (82%), mp 126°-137° (one spot on TLC). Recrystallization of a portion from cyclohexane-ethylacetate gave the analytical sample, mp 138°-139° ; TLC (C6H6 :EtOH/5:1); NMR (DMSO-d6)δ1.08 (t, 6H, 2CH2CH3), 1.63 (m, 2H, CH2CH 2CH), 2.13 (s, 3H, Ac), 2.27 (s, 6H, 2Ac), 2.2 (2H, CH2CH, superimposed on the acetyl singlets), 3.2-3.7 (m, 4H, 2 x OCH2), 4.42 (t, 1H, CH), 11.87 (br s, 2H, AcNH and HNC(0)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.O>CN(C)C=O>[OH:16][CH:15]([CH2:17][N:38]1[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC(O)CN1CCN(C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (39 mg) and 4-methylpiperazine (27 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (40 mg, yield 84%).
Reaction SMILES: Cl[C:2]1[C:3](F)=[CH:4][C:5](F)=[C:6]([CH:14]=1)[C:7](NS(C)(=O)=O)=[O:8].[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.C1(CO)CCCCC1>>[Cl:17][C:18]1[C:19]([O:8][CH2:7][CH:6]2[CH2:14][CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Agent: OCC1CCCCC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with cyclohexylmethanol, the title compound was obtained as a colorless solid (0.11 g, 28%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.23 (d, J=12.4 Hz, 1H), 3.96 (d, J=5.8 Hz, 2H), 2.87 (s, 6H), 1.84-1.62 (m, 6H), 1.30-1.04 (m, 5H); MS (ES−) m/z 391.1, 393.1 (M−1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].Cl.[CH3:16][N:17]1[C:21](=[O:22])[C:20]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[O:14]=[C:6]1[N:5]([CH2:4][CH2:3][CH2:2][N:25]2[CH2:26][CH2:27][C:20]3([N:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:18][N:17]([CH3:16])[C:21]3=[O:22])[CH2:23][CH2:24]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7]1
Reactant: CN1CN(c2ccccc2)C2(CCNCC2)C1=O
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Yield: 50 %

Procedure:
A mixture of 4.8 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5.6 parts of 3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one hydrochloride, 7.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 4-methyl-2-pentanone. The solid product is filtered off and dried, yielding 4.1 parts (50%) of 8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 186° C.
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([N:17]=[C:18]=[S:19])[CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([N:17]2[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:18]2=[S:19])[CH:16]=1
Reactant: CCOC(=O)CNC
Reactant: Cc1ccc(Cl)cc1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)cc1N1C(=O)CN(C)C1=S
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), 5 -chloro-2-methylphenyl-isothiocyanate (9.18 g), triethyl amine (12 g) and chloroform (200 mL) was heated at reflux for 5 hours. The mixture was cooled to ambient temperature, washed with 1N HCl(2×200 ), then with water (200 mL) The organic phase was evaporated to dryness. The residue was crystallized from ethanol to give the tide compound (9.2 g) as a tan solid, m.p. 132°-134° C. Anal. Calcd. for C11H11 Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.79; H, 4.12; N, 10.73. Mass spectrum (EI, M.+) m/z 254/256.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH2:28][CH2:29][CH3:30])=[C:7]([CH:22]=[CH:23][C:24]=1[C:25](=[O:27])[CH3:26])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[Br:21])(=[O:3])[CH3:2].C(O)(=[O:33])C.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[C:1]([O:4][C:5]1[C:6]([CH2:28][CH2:29][CH3:30])=[C:7]([CH:22]=[CH:23][C:24]=1[C:25](=[O:27])[CH3:26])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([OH:33])=[O:18])=[CH:15][C:14]=1[Br:21])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CCCc1c(OCCCOc2ccc(C=O)cc2Br)ccc(C(C)=O)c1OC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Br)ccc(C(C)=O)c1OC(C)=O

Procedure:
To a solution of 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]3-bromobenzaldehyde (2.39 g) in acetone (50 ml) was added acetic acid (50 ml). To the well stirred mixture was added pulverized potassium permanganate (1.58 g) by portions at room temperature. The reaction was allowed to proceed while stirring for one hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was subjected to extraction with chloroform. Insoluble materials were filtered off, and the filtrate was washed with a dilute aqueous solution of hydrogen peroxide, then with water. The resulting solution was dried and concentrated to give colorless and clear syrup. Crystallization from aqueous alcohol gave 4-[3-(3-acetoxy-4-acetyl-2 propylphenoxy)propoxy]-3-bromobenzoic acid (2.0 g), m.p. 155°-156° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[CH:20]=O)[CH:13]=[CH:12][CH:11]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[N:10]=[CH:11][CH:12]=[CH:13]2)[CH3:2]
Reactant: O=Cc1cccc2cccnc12
Reactant: CCOC(CN)OCC
Product: CCOC(CNCc1cccc2cccnc12)OCC
Reaction time: 8 h
Yield: 91.1 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2 with the modification that the reaction was carried out overnight, 2,2-diethoxyethanamine (2.18 ml, 15 mmol) was reacted with 8-quinolinecarboxaldehyde (1.89 g, 12 mmol) to obtain the title compound (3.0 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[CH2:37][C:38]([OH:40])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>ClCCl>[O:40]=[C:38]([NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:37][C:20]1[N:21]=[C:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]3[N:33]=[CH:34][CH:35]=[CH:36][C:24]=3[N:23]2[C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:11][CH2:12]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CC(=O)O)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CC(=O)Nc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.3 %

Procedure:
To a solution of 2-(3-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetic acid (0.04 g, 1 eq.) in dichloromethane (2 mL) was added successively aniline (0.027 g, 4 eq.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (0.029 g, 2 eq.) and diisopropylethylamine (70 μL, 5 eq.). The reaction was stirred at room temperature for 20 hours. The reaction mixture was diluted with dichloromethane (10 mL), washed with water (2×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative HPLC (YMC PACK ODS-AM; AM12S05-1020WT; 100×20 mm ID; CAN/0.1% TFA, 30 mL/min) gave tert-butyl (1-(4-(2-(2-oxo-2-(phenylamino)ethyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.022 g, 48%). LCMS: 613 [M+H].