Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[CH2:17][CH2:16]2)[C:12]([O:28][CH3:29])=[CH:11][C:10]=1[C:30]([OH:33])([CH3:32])[CH3:31])C1C=CC=CC=1>CCO>[OH:33][C:30]([C:10]1[CH:11]=[C:12]([O:28][CH3:29])[C:13]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:14][C:9]=1[OH:8])([CH3:31])[CH3:32]
Reactant: COc1cc(C(C)(C)O)c(OCc2ccccc2)cc1N1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: COc1cc(C(C)(C)O)c(O)cc1N1CCNCC1
Reaction time: 12 h
Yield: 91.8 %

Procedure:
A mixture of 2-[2-Benzyloxy-4-(4-benzyl-piperazin-1-yl)-5-methoxy-phenyl]-propan-2-ol (2.01 g, 4.5 mmol) 10% Pd/C (0.28 g) in EtOH (60 mL) was hydrogenated at 50 psi at room temperature for 12 hours. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated uner reduced pressure to yield 1.1 g (92% ) of 2-(1-Hydroxy-1-methyl-ethyl)-4-methoxy-5-piperazin-1-yl-phenol.
Reaction SMILES: O=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(Br)(Br)([Br:24])=O>CC#N>[Br:24][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: O=P(Br)(Br)Br
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(=O)[nH]c2c1
Solvent: CC#N
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Yield: 77.7 %

Procedure:
A solution of methyl 3-oxo-2-phenyl-3,4-dihydroquinoxaline-6-carboxylate (2.1 g, 7.50 mmol, 1.00 equiv) and POBr3 (21.5 g, 74.91 mmol, 10.00 equiv) in CH3CN (120 mL) in a 1000-mL round-bottom flask was heated under reflux overnight in an oil bath. The resulting mixture was concentrated under vacuum; the pH value was adjusted to 7-8 with aqueous sodium bicarbonate (saturated), and the solution extracted with 4×100 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum, giving 2 g (78%) of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate as a white solid. LC-MS (ES, m/z): 343 [M+H]+. 1H-NMR (300 MHz, DMSO-d6) 8.620-8.615 (d, J=1.5 Hz, 1H), 8.38-8.35 (q, J=3.3 Hz, 1H), 8.28-8.25 (d, J=8.7 Hz, 1H), 7.85-7.82 (q, J=6 Hz, 2H), 7.60-7.58 (t, J=2.4 Hz, 3H), 3.99 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][CH:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:15][CH:16]=3)=[CH:8][CH:7]=2)[CH2:3]1.[N:29]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31](O)=[O:32].CC(C)N=C=NC(C)C>ClCCl>[C:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:14]1[NH:15][CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH:4]3[CH2:3][CH:2]([NH:1][C:31]([C@@H:30]4[CH2:34][CH2:35][CH2:36][N:29]4[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:32])[CH2:5]3)=[CH:7][CH:8]=2)[N:13]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CC(N)C3)cc2)c[nH]1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1CC(c2ccc(-c3c[nH]c([C@@H]4CCCN4C(=O)OC(C)(C)C)n3)cc2)C1
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of (S)-tert-butyl 2-(4-(4-(3-aminocyclobutyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (A9) (330 mg, 0.86 mmol) in dichloromethane (60 mL), N-Boc-L-Pro-OH (204 mg, 0.95 mmol), and DIC (0.2 mL) were added at rt. After stirring overnight, the reaction mixture was diluted with methylene chloride (50 mL), and washed with saturated aqueous NaHCO3, dried with Na2SO4. After removal of the solvent, the crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate=2:1) to afford the product (S)-tert-butyl 2-(3-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)cyclobutylcarbamoyl)pyrrolidine-1-carboxylate (A10) (294 mg, 59% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24])=[CH:15]2.[OH-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])=[CH:15]2
Reactant: CCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 720.9 %

Procedure:
To a solution of methyl 2-({5-[3-(2-pyridylamino)propoxy]indolyl }methyl)pentanoate (0.015 g, 0.004 mmol), as prepared in the preceding step, in methanol (2.0 mL) was added a solution of NaOH (0.1 g, 2.5 mmol) in H2O (0.3 mL), and the reaction was stirred at ambient temperature overnight. After evaporating the solvent in vacuo, the residue is taken up in H2O (5 mL) and acidified to pH 4–5 with 10% HCl, and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (4% methanol in methylene chloride) to give the title compound as an oil (0.011 g, 85%). 1H-NMR (400 MHz, CDCl3) δ 8.28 (br s, 1H), 7.72 (d, J=4.5 Hz, 1H), 7.49 (m, 1H), 7.26 (d, J=8.9 Hz, 1H), 7.06 (d, J=3.0 Hz, 1H), 6.99 (d, J=2.3 Hz, 1H), 6.78 (dd, J=8.9, 2.4 Hz, 1H), 6.5 (m, 2H), 6.27 (d, J=2.8 Hz, 1H), 4.25 (dd, J=14.1, 8.4 Hz, 1H), 3.97 (m, 3H), 3.33 (t, J=6.6 Hz, 2H), 2.87 (br s, 1H), 1.96 (m, 2H), 1.67 (m, 1H), 1.45 (m, 3H), 0.90 (t, J=6.8 Hz, 3H). Mass spectrum (LCMS, ESI pos.) Calcd. for C22H27N3O3 382.5 (M+H); Found: 382.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](CC(=O)C)=[CH:3][CH:2]=1.F[C:12]1[CH:13]=C(C=[CH:18][C:19]=1[O:20]C)C=O.N1CCCCC1>C1(C)C=CC=CC=1>[N:1]1[CH:2]=[CH:3][CH:4]=[C:5]([CH2:18][C:19](=[O:20])[CH:12]=[CH2:13])[CH:6]=1
Reactant: COc1ccc(C=O)cc1F
Reactant: CC(=O)Cc1ccncc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C=CC(=O)Cc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.9 %

Procedure:
A solution of 4-pyridylacetone (1.0 g, 7.4 mmol), 3-fluoro-p-anisaldehyde (1.25 g, 8.1 mmol), and piperidine (0.13 g, 1.5 mmol) in toluene (50 ml) was heated to reflux. After 18 hours, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The crude product (3.0 g) was purified by column chromatography (silica gel, 65:35 ethyl acetate/hexane) to give 4-(3-fluoro-4-methoxy]phenyl)-3-pyridyl-3-butene-2-one as a pale yellow solid (1.60 g, 80%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([CH2:15]O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1.N1C=CC=CC=1>C1C=CC=CC=1>[CH:5]1([CH2:15][Cl:3])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1
Reactant: OCC1OCCc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: ClCC1OCCc2ccccc21
Yield: 97.8 %

Procedure:
8.4 g (70.6 mmol) of thionyl chloride was dropwise added to a solution of 10 g (61 mmol) of (isochroman-1-yl)methanol [J. Med. Chem., 28, 1026 (1985)] and 5 g (63 mmol) of anhydrous pyridine in dried benzene, and the resulting mixture was heated under reflux for 2 hours. Excessive amounts of thionyl chloride and benzene were evaporated, and the residue was dissolved in ether. The ethereal solution was washed with water and dried, and the solvent was then evaporated. The residue was distilled under reduced pressure (140° C./20 mmHg) to give 10.9 g (98%) of the desired compound as an oily.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=1.[C:17]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)[C:24](O)=[O:25])([CH3:20])([CH3:19])[CH3:18].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[C:30]([C:28]1[CH:27]=[C:23]([CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:29]=1)[C:24]([NH:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=1)=[O:25])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Reactant: CCN(CC)CCSc1nnc(N)s1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCSc1nnc(NC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.1 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole (2.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 3,5-Di-tert-butylbenzoic acid (2.3 g) and carbonyldiimidazole (1.8 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 1.5 g of the aimed compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([NH2:20])=[O:19]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([NH2:20])=[O:19])=[O:11])=[CH:6][CH:7]=1
Reactant: NC(=O)c1sccc1N
Reactant: O=C(O)Cc1ccc(I)cc1
Product: NC(=O)c1sccc1NC(=O)Cc1ccc(I)cc1

Procedure:
This compound was prepared from 2-(4-iodophenyl)acetic acid and 3-aminothiophene-2-carboxamide using protocol B. Method[1], MS (ESI) 387.0, Retention time=1.777 min.
Reaction SMILES: OS(O)(=O)=O.[OH:6]O.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([O:26][C:27]1[CH:34]=[CH:33][C:30](C=O)=[CH:29][CH:28]=1)=[C:21]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[CH:20]=[CH:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(Cl)Cl>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:6])=[CH:33][CH:34]=1)=[C:21]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[CH:20]=[CH:19]2)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OO
Reactant: O=Cc1ccc(Oc2c(-c3ccc(F)cc3)ccc3cc(OCc4ccccc4)ccc23)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Oc2c(-c3ccc(F)cc3)ccc3cc(OCc4ccccc4)ccc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
Add 18M H2SO4 (1 mL, 16.8 mmol) dropwise into a solution of H2O2 (1 mL, 9.7 mmol) and 4-[6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yloxy]-benzaldehyde at 0° C. and stir at room temperature for 12 hours. Add H2O (20 mL) and CH2Cl2 (100 mL). Separate layers and extract the aqueous layer with CH2Cl2 (2×50 mL). Combine the organic layers, dry with magnesium sulfate and concentrate in vacuo to obtain 1.88 g (73%) of the title compound: mass spectrum (ion spray) m/z=435.1 (M−H).
Reaction SMILES: C([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=O.[NH2:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1>N1C=CC=CC=1>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[NH:16][S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:3][CH2:4][CH2:5]2)(=[O:13])=[O:14]
Reactant: O=CN1CCc2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CCN2
Temperature: 60 °C
Yield: 53.3 %

Procedure:
A mixture of N-formyl-5-(chlorosulfonyl)indoline (60 g, 0.26 mol) and 2-amino thiazole (25 g, 0.26 mol) in pyridine (250 mL) was heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature and poured into ice/water. The solid was filtered, co-evaporated with toluene until completely dry and used in the next step without further purification. The crude material was brought to reflux in EtOH/KOH (600 mL, 15-20% KOH). After 2 hours a part of the ethanol was removed in vacuo and the light brown precipitate was filtered and crystallized from ethanol. The sulfonamide (39 g, 62% yield) was isolated with a purity of 90% according to HPLC-MS. 1H-NMR (DMSO-d6) δ 7.33-7.30 (m, 2H), 6.87 (d, J=3.8 Hz, 1H), 6.36-6.34 (m, 2H), 5.80 (s, 1H), 3.42 (dt, J=12.0, 4.3 Hz, 2H), 2.88 (t, J=8.5 Hz, 2H).
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.Cl.[N:29]1([C:34](=N)[NH2:35])C=CC=N1>CN(C=O)C>[F:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:34](=[NH:29])[NH2:35])[CH2:17][CH2:18]2)=[CH:11][CH:12]=1
Reactant: FCCOCc1ccc(N2CCNCC2)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N1CCN(c2ccc(COCCF)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
To a solution of 1-(4((2-fluoroethoxy)methyl)-phenyl)piperazine hydrochloride (50 mg, 0.12 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in DMF (1 mL) was added 1H-pyrazole-1-carboximidamide hydrochloride (29 mg, 0.20 mmol). The reaction stirred at room temperature for 24 h. The next day, the reaction mixture was concentrated to yield a crude oil, which was purified via HPLC using a Phenomenex Luna C-18 (2) column (10μ, 250×21.2 mm, gradient method 15-55% B over 20 min., where B=90% ACN in water using 0.1% formic acid as a modifier and A=water using 0.1% formic acid as a modifier) with a flow rate of 20 mL/min afforded 4-(4-((2-fluoroethoxy)methyl)phenyl)piperazine-1-carboximidamide as a white solid (20 mg, 41% yield based on recovered starting material). 1H NMR (300 MHz, DMSO-d6): δ 7.58 (br s, 4H), 7.211 (d, 2H, J=8.5 Hz), 6.96 (d, 2H, J=8.6 Hz), 4.61 (m, 1H), 4.45 (m, 1H), 4.41 (s, 2H), 3.67 (m, 1H), 3.58 (dd, 4H, J=4.2, 3.9 Hz), 3.22 (m, 5H); 19F NMR (282.4 MHz, DMSO-d6): δ−221.39 (m, 1F); 13C NMR (75.5 MHz, DMSO-d6): δ 156.1, 149.8, 128.9, 115.4, 84.1 (81.9), 71.8, 68.6 (68.4), 47.5, 44.7; HRMS calcd for C14H21FN4O: 281.177216 found 281.17720.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[CH:13][C:12]=2[Cl:19])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=2[Cl:19])[CH2:17][NH:18][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)n1nc(-c2cc(CN)ccc2Cl)[nH]c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(C(C)(C)C)c(=O)[nH]2)c1

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 2-tert-butyl-5-(5-(aminomethyl)-2-chlorophenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-75, 0.250 g), pivaloyl chloride (1.0 mL), DIPEA (2.0 mL), and dry THF (5 mL) to afford 0.180 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 1.08 (s, 9H), 1.49 (s, 9H), 4.24 (d, J=4.5 Hz, 2H), 7.32 (dd, J=4.5 Hz, 3.6 Hz, 2H), 7.43 (s, 1H), 7.50 (s, 1H), 8.14 (d, J=4.5 Hz, 1H); MS (m/z): 365.20 (M+H)+.
Reaction SMILES: P(Cl)(Cl)Cl.[CH2:5]([N:12]1[C:22](=[O:23])[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:15]2[S:16](=O)[CH2:17][CH:18]=[CH:19][N:14]2[C:13]1=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C=O)C>[CH2:5]([N:12]1[C:22](=[O:23])[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:15]2[S:16][CH2:17][CH:18]=[CH:19][N:14]2[C:13]1=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=c1c(-c2ccccc2)c2n(c(=O)n1Cc1ccccc1)C=CCS2=O
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)c2n(c(=O)n1Cc1ccccc1)C=CCS2
Temperature: -10 °C
Yield: 81.1 %

Procedure:
Phosphorus trichloride (0.2 ml) was added dropwise to a solution of 7-benzyl-1-oxo-9-phenyl-2H,6H-pyrimido[6,1-b]-[1,3]thiazine-6,8(7H)-dione (0.4 g) in DMF (8 ml) under stirring at -10° C. The mixture was stirred at the same temperature for 30 minutes and the resulting solution was poured to ice-water to give crystals and the crystals were collected by filtration. The resulting crude crystals were washed and recrystalized from methylene chloride-methanol to give colorless needles (0.31 g, 81%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(OC([O-])=O)([O:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O)=O>O1CCCC1>[N:1]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCSCC1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
Thiomorpholine (5.0 ml, 53 mol) was dissolved in tetrahydrofuran (200 ml); triethylamine (8.1 ml, 58 ml) was added thereto; and the reaction mixture was stirred at room temperature. tert-Butoxycarbonyl dicarbonate (13.3 ml, 58 mmol) was added thereto and the reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure; and the residue was purified by silica gel column (eluent; hexane:ethyl acetate=from 80:20, 75:25 to 70:30) to yield the title compound as colorless crystals (10.4 g, 51 mmol).
Reaction SMILES: [Si:1]([O:18][C:19]1[C:24]2[CH2:25][CH2:26][CH2:27][CH:28]([CH2:30][OH:31])[CH2:29][C:23]=2[CH:22]=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([N:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>N1C=CC=CC=1>[C:32]1([N:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39](=[O:40])[O:31][CH2:30][CH:28]2[CH2:27][CH2:26][CH2:25][C:24]3[C:19]([O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:29]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC(CO)C2)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](Oc1cccc2c1CCCC(COC(=O)N(c1ccccc1)c1ccccc1)C2)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 90.4 %

Procedure:
A mixture of [1-(tert-butyldiphenylsilyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]methanol (200 mg) and diphenylcarbamoyl chloride (324 mg) in pyridine (5 ml) was stirred at 100° C. for 48 hours. After cooling, the reaction mixture was poured into 6N-hydrochloric acid (13 ml) under ice-cooling and extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogencarbonate solution, water, and then brine. It was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 15:1 to 10:1) to give [1-(tert-butyldiphenylsilyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]methyl N,N-diphenylcarbamate (262.7 mg) as an amorphous solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH2:16][CH3:17])[N:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([CH2:36][O:37][CH3:38])[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=1)[C:8]2=[O:39].[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>N1C=CC=CC=1>[C:40]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH2:16][CH3:17])[N:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([CH2:36][O:37][CH3:38])[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=1)[C:8]2=[O:39])(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCc1nc2ccc(OCCO)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Solvent: c1ccncc1
Product: CCCc1nc2ccc(OCCOC(=O)c3ccccc3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
To a solution of 6-(2-hydroxyethyloxy)-3-[[2'-(N-methoxymethyltetrazol-5-yl)biphenyl-4-yl]methyl]-2-propyl-4(3H)-quinazolinone (0.09 g) in pyridine (2 ml) was added benzoyl chloride (0.08 ml) and the reaction solution was stirred at room temperature for 4 hours. The mixture was extracted with ethyl acetate-water and the organic layer was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give a colorless oil (0.1 g, 93%).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([O:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.[Br:16]Br>>[CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[CH:4][C:5]([Br:16])=[CH:6]3)[CH:2]=1)=[O:12]
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: BrBr
Product: O=C1OC(=O)c2cc(Br)cc3cccc1c23
Temperature: 50 °C
Reaction time: 4 h
Yield: 22.7 %

Procedure:
1,8-Naphthalic anhydride (compound 73, 100 g, 505 mmol) was slurried in c-nitric acid (70%, 2.0 L) and heated to 50° C. Bromine (19.4 mL, 379 mmol) was added evenly over 10 min, and the resulting solution was held at 50° C. for 4 h before cooling to 0° C. The resulting solid was isolated by filtration and dried in vacuo to yield the title compound (23.8 g, 17%) as a white solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=2)=[CH:31][CH:30]=1)=O)(C)(C)C.CO.Cl>C1COCC1>[NH2:8][C@@H:9]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:10][C@H:11]([OH:15])[C@@H:12]([NH:13][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=2)=[CH:33][CH:34]=1
Reactant: Cc1cccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@@H](N)Cc3ccccc3)cc2)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 68B (0.07 g, 0.108 mmol) in a mixture of THF (0.5 mL), methanol (0.3 mL), and aqueous HCl (0.5 mL, 1 N) was stirred at 50° C. for 16 hours. The solvent was removed under reduced pressure to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[CH:12][N:13]=[C:7]2[CH:6]=1)=O)[NH2:2].[CH3:29][N:30]=[C:31]=[S:32]>CCO>[SH:32][C:31]1[N:30]([CH3:29])[C:3]([C:5]2[CH:10]=[CH:9][N:8]3[C:11]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=4)=[CH:12][N:13]=[C:7]3[CH:6]=2)=[N:1][N:2]=1
Reactant: CN=C=S
Reactant: NNC(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Solvent: CCO
Product: Cn1c(S)nnc1-c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Temperature: 70 °C
Yield: 31.6 %

Procedure:
To a solution of 1-[3-(7-Hydrazinocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (200 mg, 0.51 mmol) and methyl isothiocyanate (37 mg, 0.57 mmol) were dissolved in EtOH (6 ml) and heated at 70° C. overnight. The reaction mixture was allowed to cool, placed in an ice bath upon which a precipitate was formed. The solid was filtered off, washed with EtOAc and Et2O, then dried to afford the title compound (72 mg). MS: [M+H]+=448.