Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:5](C(C)(C)C)([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:31])[CH2:17][N:18]([C:20]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28](=[NH:30])[NH2:29])[CH2:24][CH2:23]2)=[O:21])[CH3:19])=[CH:12][C:11]=1[O:32][CH2:33][C:34]([O-:36])=[O:35])[C:6]([O-:8])=[O:7])(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[C:28]([C@H:25]1[CH2:26][CH2:27][C@H:22]([C:20]([N:18]([CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:5][C:6]([OH:8])=[O:7])=[C:11]([O:32][CH2:33][C:34]([OH:36])=[O:35])[CH:12]=2)=[O:31])[CH3:19])=[O:21])[CH2:23][CH2:24]1)(=[NH:29])[NH2:30]
Reactant: CN(CC(=O)c1ccc(OC(C(=O)[O-])(C(C)(C)C)C(C)(C)C)c(OCC(=O)[O-])c1)C(=O)[C@H]1CC[C@H](C(=N)N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: CN(CC(=O)c1ccc(OCC(=O)O)c(OCC(=O)O)c1)C(=O)[C@H]1CC[C@H](C(=N)N)CC1
Reaction time: 5 h

Procedure:
To the solution of the compound prepared in (d) (50 mg, 0.089 mmole) in anisole was added trifluoroacetic acid under ice-cooling. The mixture was stirred for 5 hours, during which the temperature of the mixture was left rising up to room temperature. After isopropyl ether was added to the reaction mixture, solids deposited were collected to give 31 mg of the title compound as the colorless solid (yield, 62%).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27][C:15]2=3)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:35]>CCOC(C)=O.O1CCOCC1>[ClH:35].[C:1]1([O:11][CH2:12][CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:15]2=3)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3cccc4c3CCCC4)c3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1cc2c(c(OCCn3c4c(c5ccccc53)CCNCC4)c1)CCCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 73 %

Procedure:
tert-Butyl 6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.100 g, 0.302 mmol) was dissolved in THF (6 mL). 5,6,7,8-Tetrahydronaphthalen-1-ol (0.067 g, 0.454 mmol) was added, and after 25 min di-tert-butyl azodicarboxylate (0.105 g, 0.454 mmol) was added. The reaction mixture was stirred at 40° C. for 5 h. The solvent was removed in vacuo. The crude product was flash chromatographed (9:1 hexane:EtOAt) and tert-butyl 6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate was obtained in 22% yield. tert-Butyl 6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.028 g, 0.061 mmol) was dissolved in EtOAc (5 mL). 4N HCl in dioxane (2 mL) was added. The reaction mixture was stirred at rt under N2 for 20 h. The solvent was removed in vacuo. The crude product was dissolved in EtOAc (2 mL) and Et2O (3 mL) was added dropwise. The precipitate was collected by filtration, wash with Et2O and dried in vacuo at reduced pressure to yield 6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride in 73% yield. 1H NMR (400 MHz, CD3OD) δ 1.66-1.72, 2.35-2.39, 2.65-2.72, 3.20-3.23, 3.36-3.50, 4.23-4.28, 4.61-4.64, 6.51, 6.63, 6.93, 7.10, 7.18, 7.44, 7.50; MS (ESI+) for C24H28N2O m/z 361.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]([C:23]([NH:25][C:26]1[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=1)=[S:24])[NH2:22]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:22][NH:21][C:23]([NH:25][C:26]3[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=3)=[S:24])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC(=S)Nc1ccc(C(=O)O)s1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)s1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O

Procedure:
From 1-[5-(4-t-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (40.0 mg, 0.15 mmol) and 5-hydrazinocabonothioylamino-2-thiophenecarboxylic acid (35.5 mg, 0.15 mmol), the desired product was obtained in the same manner as in Synthetic Example 2 as a yellow solid (57.3 mg, yield 83%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]([C:13]3[N:17]4[N:18]=[C:19]([C:22]5[CH:23]=[N:24][N:25]([CH2:27][CH2:28][O:29]C6CCCCO6)[CH:26]=5)[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.Cl>C(Cl)Cl.CO.O1CCOCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]([C:13]3[N:17]4[N:18]=[C:19]([C:22]5[CH:23]=[N:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=5)[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: CC(c1ccc2ncn(C)c2c1)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CC(c1ccc2ncn(C)c2c1)c1cnc2ccc(-c3cnn(CCO)c3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(rac)-3-[1-(3-Methyl-3H-benzoimidazol-5-yl)-ethyl]-6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazine (Stage 185.1, 600 mg, 1.018 mmol) was dissolved in DCM (10 mL) and MeOH (2.5 mL). HCl in dioxane (4 N, 1.272 mL) was added and the RM was stirred 1 h at rt. The solvent was totally evaporated and the residue taken in water /acetonitrile. It was basified with NaHCO3. the mixture was cooled down with dry ice and sonicated to afford a suspension. It was filtered and collected, and dried under high vacuum overnight to afford the title compound as a white solid (tR 2.04 min (conditions 8), MH+=388, 1H-NMR in DMSO-d6: 8.39 (s, 1H); 8.07 (d, 2H); 8.01 (d, 1H); 7.69 (s, 1H); 7.61 (s, 1H); 7.51 (d, 1H); 7.47 (d, 1H); 7.23 (d, 1H); 4.95 (t, 1H); 4.76 (q, 1H); 4.18 (t, 2H); 3.78 (s, 3H); 3.75 (q, 2H); 1.79 (d, 3H)).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:17][C:16](=[O:18])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[CH:15]=[C:7]3[C:6]=2[CH:19]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:42])=[O:43])[C:37]([C:2]4[CH:3]=[CH:4][C:5]5[O:17][C:16](=[O:18])[N:8]6[C:9]7[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=7[CH:15]=[C:7]6[C:6]=5[CH:19]=4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=c1oc2ccc(Br)cc2c2cc3ccccc3n12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4oc(=O)n5c6ccccc6cc5c4c3)cc12
Temperature: 100 °C
Yield: 4.4 %

Procedure:
A mixture of 2-bromo-6H-benzo[5,6][1,3]oxazino[3,4-a]indol-6-one (47 mg, 0.15 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (51 mg, 0.1 mmol), K3PO43H2O (80 mg, 0.3 mmol) and Pd(dppf)Cl2 (7 mg, 0.01 mmol) in 2 mL of DMF was heated in a microwave reactor at 100° C. for 20 minutes, and then the mixture was purified using prep-HPLC to provide Compound 53 (2.7 mg, yield: 4.4%). 1H-NMR (CDCl3, 400 MHz) δ 8.52 (d, J=7.6 Hz, 1H), 8.07 (s, 1H), 7.92˜7.96 (m, 3H), 7.70 (d, J=7.6 Hz, 1H), 7.62 (s, 1H), 7.41˜7.54 (m, 4H), 7.21˜7.23 (m, 2H), 7.12 (s, 1H), 5.89 (s, 1H), 3.11 (s, 3H), 3.00 (d, J=4.8 Hz, 3H), 2.88 (s, 3H). MS (M+H)+: 610.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)=[O:26]
Reactant: O=C(Cl)CCCCCBr
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCCBr)Nc1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (1.30 mL) and 4-aminobenzotrifluoride (1.21 g) were stirred in dichloromethane (35 mL) at 0° C. under nitrogen and treated with 6-bromohexanoyl chloride (1.15 mL). After 20 minutes, the reaction was allowed to warm to 20° C. and stirred an additional 40 minutes. The reaction was treated with aqueous saturated sodium bicarbonate (40 mL), and extracted with dichloromethane. The extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to a solid. This solid was dissolved ethyl acetate and the title compound was precipitated out as fine white needles by addition of hexanes (2.35 g). M.p. 96°-98° C. Anal. Calc. for C13H15BrF3NO: C, 46.17; H, 4.47; N, 4.14. Found: C, 46.25; H, 4.59; N, 4.12. IR(KBr): 3316, 1670, 1600, 1530, 1410, 1322, 1260, 1170, 1128, 1112, 1066, 842 cm-1. CIMS(CH4): 340 (90%), 338 (100%), 320 (50%), 318 (55%), 258 (60%). 1H NMR (CDCl3): 7.65 (2H, d; J=8.5 Hz), 7.56 (2H, d; J=8.5 Hz), 7.47 (1H, bs), 3.42 (2H, t; J=6.5 Hz), 2.40 (1H, t; J=6.6 Hz), 1.90 (2H, m), 1.75 (2H, m), 1.52 (2H, m) ppm. 13C NMR (CDCl3): 171.21, 140.83, 126.27, 119.32, 37.39, 33.49, 32.34, 27.64, 24.42 ppm. 19F NMR (CDCl3): -62.712 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a stirred solution of N-(4-chloro-2-fluorophenyl)acetamide (180.6 g, 0.96 mol) in concentrated sulfuric acid (1L) was added a mixture of 175 mL of concentrated HNO3 and 175 mL of concentrated sulfuric acid at 0 to 5° C. in 1.5 h. After the addition was finished, the reaction mixture was stirred for another 0.5 h. The solution was poured into 5 L of ice water. After the product precipitated, it was isolated by filtration and then was dissolved in 2.5 L of ethyl acetate. After separation of the water layer, the organic layer was dried over sodium sulfate and then the solvent was evaporated. The crude product was triturated in diisopropyl ether (1.5 L), isolated by filtration, and dried under reduced pressure to afford the title compound of Step A (196.2 g, 87.6%) melting at 145-146° C. 1H NMR (Me2SO-d6) δ 10.3-10.2 (s, 1H), 8.9 (d, 1H), 7.9-7.8 (d, 2.2-2.1 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([S:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:27](Br)[CH3:28]>CN(C)C=O>[C:1]1([N:7]2[C:11]([S:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:27][CH3:28])[C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NCCCSc1nnnn1-c1ccccc1)c1ccccc1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCCSc1nnnn1-c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
1-Phenyl-5-[3-(N-benzoylamino)propylthio]-1,2,3,4-tetrazole (1.7 g) is dissolved in dimethylformamide (30 ml). To the mixture is added with stirring 50% oily sodium hydride (0.3 g) at room temperature. After foaming is finished, the mixture is stirred at 60°-70° C. for one hour. After cooling until room temperature, ethyl bromide (0.8 g) is added dropwise to the resulting mixture, and thereafter, the mixture is stirred at 60°-70° C. for 8 hours. After dimethylformamide is distilled off, the residue is purified by column chromatography (Wakogel C-200), followed by eluting with chloroform to give 1-phenyl-5[3-(N-ethyl-N-benzoylamino)propylthio]-1,2,3,4-tetrazole (1.2 g), as a colorless liquid, nD24 =1.5898.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8](C(C)=C)[C:7]1=[O:18].[Cl:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:25](=[O:27])[NH:26][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[OH2:18].[Cl:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[NH:8][C:7]4=[O:18])[CH2:32][CH2:33]3)[C:25](=[O:27])[NH:26][C:22]=2[CH:21]=1.[Cl:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[NH:8][C:7]4=[O:18])[CH2:32][CH2:33]3)[C:25](=[O:27])[NH:26][C:22]=2[CH:21]=1
Reactant: C=C(C)n1c(=O)n(CCCCCl)c2ccccc21
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Yield: 46 %

Procedure:
A mixture of 9.25 parts of 1-(4-chlorobutyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 7.55 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 10.6 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 18 hours. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is dissolved in 40 parts of ethanol and the solution is acidified with 30 parts of a concentrated hydrochloric acid solution. The whole is stirred for 30 minutes and the solvent is evaporated. The residue is suspended in water and the suspension is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of N,N-dimethylformamide and water. The product is filtered off and dried, yielding 6.5 parts (46%) of 5-chloro-1-{1-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)butyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one hemihydrate; mp. 258° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:23]([CH:20]2[CH2:22][CH2:21]2)=[O:24])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(N)c1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc(NC(=O)C2CC2)c1

Procedure:
N-(3-Acetylphenyl)cyclopropanecarboxamide was prepared by the reaction of m-aminoacetophenone, diisopropylethylamine and cyclopropanecarboxylic acid chloride in dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:13][CH:14]=1.[ClH:28]>O1CCOCC1>[ClH:28].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Sc3ccccc3F)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccccc1Sc1cnc(N2CCNCC2)nc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of tert-butyl 4-(5-(2-fluorophenylthio)pyrimidin-2-yl)piperazine-1-carboxylate (5 g, 12.8 mmol) in dioxane (150 mL) was added HCl in dioxane (4 M, ca. 30 mL), and the mixture was stirred at 40° C. overnight. LCMS showed the reaction was completed. The reaction mixture was concentrated to afford 5-(2-fluorophenylthio)-2-(piperazin-1-yl)pyrimidine HCl salt (3.6 g, 88%) as a solid. MS (ES+) C14H15FN4S requires: 290. found: 291 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17](F)=[CH:18][N:19]=1)[C:5]([C:7](=[CH:13][N:14]([CH3:16])C)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:21]1(N)[CH2:26][CH2:25]C[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][N:19]=1)[N:14]([CH:16]1[CH2:25][CH2:26][CH2:21][CH2:22][CH2:23]1)[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2=[O:6]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)ncc1F
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2cnc(Br)cc2c1=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a solution of ethyl 2-(2-bromo-5-fluoroisonicotinoyl)-3-(dimethylamino)acrylate (Intermediate 66, 1.14 g, 3.29 mmol, 1 equiv.) in DMF (6.5 mL) was added cyclohexanamine (592 mg, 3.29 mmol, 1 equiv.). This reaction mixture was stirred at 70° C. for 30 min. Potassium carbonate (1.36 g, 9.86 mmol, 3 equiv.) was added and stirred at 70° C. for 2 h. The reaction mixture was cooled to room temperature and quenched with water (2 mL). 1 N HCl was added until pH 4-5 was reached. The precipitate was washed with water and hexanes and dried to provide ethyl 6-bromo-1-cyclohexyl-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate (1.15 g, 92%).
Reaction SMILES: [C:1]([C:4]1[C:5]2[C:10]([CH:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:3])[CH3:2].[CH2:18]([N:26]=[C:27]=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C([N-]C(C)C)(C)C.[Li+]>>[CH2:18]([NH:26][C:27](=[O:28])[CH2:2][C:1](=[O:3])[C:4]1[C:17]2[C:12]([CH:11]=[C:10]3[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]3)=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCN=C=O
Reactant: CC(=O)c1c2ccccc2cc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCNC(=O)CC(=O)c1c2ccccc2cc2ccccc12

Procedure:
The title compound, mp 70°-72° C., was prepared from 9-acetylanthracene (5.0 g, 0.022 mol), octyl isocyanate (3.52 g, 0.022 mol), and lithium diisopropylamide (0.032 mol) using the procedure described in Example 1. Purification by flash chromatography (silica gel, 5% EtOAc/hexane) yielded 3.84 g (0.010 mol, 45.2%) of the desired product.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:4]=3[CH2:3][CH:2]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[C:8]=2[CH:9]=1
Reactant: O=C1OCCN1CCN1CCNCC1
Reactant: Cc1ccc2c(c1)Sc1ccc(F)cc1C(Cl)C2
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)Sc1ccc(F)cc1C(N1CCN(CCN3CCOC3=O)CC1)C2

Procedure:
10.6 g. of 10-chloro-8-fluoro-10,11-dihydro-3-methyldibenzo[b,f]thiepin are heated at reflux together with 200 ml. of chloroform and 22.8 g. of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone for 30 hours. Thereafter, the mixture is evaporated under reduced pressure, and the residue is worked up as described in Example 5. The insoluble base is recrystallized from ethanol, whereby there is obtained 3-{2-[4-(8-fluoro-10,11-dihydro-3-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone which melts at 173°-175°C. The maleate crystallizes from acetone/ether and has a melting point of 147°-149°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>O1CCCC1>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][C:19](=[O:22])[CH:20]=[CH2:21])[CH:7]=[CH:8][CH:9]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1cccc2cccnc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cccc2cccnc12

Procedure:
A solution of 8-aminoquinoline (14.4 g, 0.1 mole) and triethylamine (15 ml, 0.11 mole) in dry tetrahydrofuran (50 ml) was treated dropwise at 0° (under a nitrogen atmosphere) with a solution of acryloyl chloride (8.5 ml, 0.1 mole) in tetrahydrofuran (25 ml). The reaction was filtered and the filtrate was partitioned between methylene chloride and water. The organic phase was separated, dried over sodium sulphate and concentrated to an oil. The oil was dissolved in ethyl acetate, treated with charcoal, filtered and again concentrated by vacuum distillation to an oil. Seed crystals were added and the oil cooled to -18°. The solid mass was stirred with petroleum ether and filtered affording 15.7 g of crude product of sufficient purity for further synthetic steps. Recrystallization from acetone/pentane afforded N-(8-quinolyl)-2-propenamide of analytical purity (m.p. 76.5°-78.5°).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[NH:24][C:23](=[O:25])[C@H:22]([CH:26]([CH3:28])[CH3:27])[NH:21][C:20](=[O:29])[C@@H:19]([NH2:30])[CH2:18][C:17]2=[CH:31][CH:32]=[C:14]([CH:15]=[CH:16]2)[O:13][CH2:12][CH2:11][CH2:10][CH2:9][S:8][CH2:7]1)=[O:5].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].CCN(C(C)C)C(C)C.CCOC(C)=O.C(Cl)Cl>CN(C=O)C>[CH3:2][O:3][C:4]([C@H:6]1[NH:24][C:23](=[O:25])[C@H:22]([CH:26]([CH3:28])[CH3:27])[NH:21][C:20](=[O:29])[C@@H:19]([NH:30][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:18][C:17]2=[CH:31][CH:32]=[C:14]([CH:15]=[CH:16]2)[O:13][CH2:12][CH2:11][CH2:10][CH2:9][S:8][CH2:7]1)=[O:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CSCCCCOc2ccc(cc2)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CSCCCCOc2ccc(cc2)C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Amine 34 (0.200 g, 0.410 mmol) was dissolved in anhydrous DMF (10 mL). Benzyl chloroformate (0.0877 mL, 0.615 mmol) and DIPEA (0.286 mL, 1.64 mmol) were added. The resultant reaction mixture was stirred at rt for 18 h before being partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted twice more with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica using a gradient of EtOAc/DCM to yield an off-white solid, 0.0430 g, 18%. Rf=0.44 (30% EtOAc/DCM).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.C([Al](CC)CC)C.[O-]CCCC.C([Zn+])C.C([Mg]CC)C.[OH-].[Na+].C(O)[CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41]CO.CC(C)([O-])C.[K+]>C(O)CCC.COC=COC>[CH2:2]1[O:3][CH2:1][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41]1
Reactant: C1CO1
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: CC(C)(C)[O-]
Agent: CCCC[O-]
Agent: CC[Al](CC)CC
Solvent: CCCCO
Product: C1COCCOCCOCCOCCOCCO1
Yield: 1.8 %

Procedure:
Preparation of the cyclic tetramer of ethylene oxide by the cyclization of ethylene oxide over an organo-metallic catalyst, for example triethyl aluminum, ethyl zinc butoxide or diethyl magnesium, is taught by Stewart, et al. in British patent Specification No. 785,229. C. J. Pedersen in U.S. Pat. No. 3,687,978 teaches the preparation of macrocyclic polyethers by the reaction of vicinal aromatic diols with α,ω-dihalides of polyoxyalkylene materials and sodium hydroxide in 1-butanol solvent. Pedersen also describes the preparation of the cyclic oxyethylene hexamer by the autoelimination reaction of the α,ω-chlorohydrin of hexaethylene glycol in the presence of potassium t-butoxide in a 1,2-dimethoxy ethylene solvent in U.S. Pat. No. 3,562,295. The ethylene oxide cyclic hexamer is produced in a very low yield of 1.8%. Dale et al. describe a base catalyzed preparation in Chem. Comm. 670 (1971). There, glycols and glycol ditosylates are condensed with potassium t-butoxide in benzene in about 15-35% yields.