Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:27]([O:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]([NH:34][NH2:35])=O)[CH3:28]>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[CH2:27]([O:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]1[O:12][C:10]([C:8]2[S:9][C:5]([C:3](=[O:4])[C:2]([F:1])([F:14])[F:13])=[CH:6][CH:7]=2)=[N:35][N:34]=1)[CH3:28]
Reactant: O=C(O)c1ccc(C(=O)C(F)(F)F)s1
Reactant: CCOc1ccccc1C(=O)NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccccc1-c1nnc(-c2ccc(C(=O)C(F)(F)F)s2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the carboxylic acid (A1) in DCM was added to PS-CDI (1.7 eq., loading 1.30 mmol/g), and the suspension stirred at RT for 30 min. 2-Ethoxybenzohydrazide (1.3 eq.) dissolved in DCM/DMF was added, and the resulting suspension was stirred at RT overnight. The suspension was filtered and the filtrate evaporated. The crude N′-(2-ethoxybenzoyl)-5-(trifluoroacetyl)thiophene-2-carbohydrazide (MS (ES) C16H13F3N2O4S requires: 386, found: 427 (M+H20+Na)+ and 385 (M−H+e)−) was used as such, without any purification. It was dissolved in excess thionyl chloride and the solution was heated in a microwave oven (sealed tube, 100° C., 5 min) and the thionyl chloride was evaporated. The desired product was isolated by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents (column: C18). The pooled product fractions were evaporated to afford the title compound. 1H NMR (300 MHz, CD3CN): 8.1-8.08 (1H, m), 8.06-8.01 (1H, m), 7.95-7.90 (1H, m), 7.63-7.56 (1H, m), 7.23-7.17 (1H, m), 7.16-7.09 (1H, m), 4.23 (2H, q, J=7 Hz), 1.48 (3H, t, J=7 Hz). 19F NMR (282 MHz, CD3CN); δ −74.25 (keto form), −86.14 (hydrate form). MS (ES) C16H11F3N2O3S requires: 368, found: 369 (M+H)+ and 387 (M+H2O+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][N:14]=[C:13]2[N:23]([CH2:32][C:33](O)=[O:34])[N:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]=12.Cl.[CH3:37][N:38]([CH3:47])[CH2:39][CH2:40][CH2:41][N:42]=[C:43]=NCC.OC1C=CC=C[N+]=1[O-]>C(Cl)Cl>[Cl:10][C:11]1[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:15][N:14]=[C:13]2[N:23]([CH2:32][C:33]([N:42]3[CH2:41][CH2:40][CH:39]([N:38]([CH3:47])[CH3:37])[CH2:43]3)=[O:34])[N:24]=[C:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:12]=12
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.9 %

Procedure:
A solution of diisopropylethylamine (DIPEA) (120 μL, 0.67 mmol) and N,N-dimethylpyrrolidine (34 mg, 0.3 mmol) in CH2Cl2 (1 mL) was added to a mixture of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (60 mg, 0.3 mmol) and 2-hydroxypyridine-N-oxide (HOPO) (30 mg, 0.27 mmol). The solution obtained was stirred at room temperature for 18 h then N′-dimethylpyrrolidine (10 mg, 0.09 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (30 mg, 0.15 mmol) were added. After a further 3.5 h the reaction was purified using chromatography (silica gel, gradient 0 to 5% triethylamine/acetone) followed by preparative HPLC yielding Compound 67 as a white solid (27.3 mg).
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH2:20][CH2:21][CH3:22])[C:11]2[CH:17]=[C:16]([CH2:18]O)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]1(=[O:55])[NH:49][C:48](=[O:50])[C:47]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]12.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH2:20][CH2:21][CH3:22])[C:11]2[CH:17]=[C:16]([CH2:18][N:49]3[C:45](=[O:55])[C:46]4[C:47](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:48]3=[O:50])[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:24][CH3:25]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCN(CCC)CCCCc1nc2ccc(CO)cc2n1CCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCN(CCC)CCCCc1nc2ccc(CN3C(=O)c4ccccc4C3=O)cc2n1CCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
The compound (302 mg) obtained in Example 3-4 was dissolved in toluene (6.0 ml) and added with triphenylphosphine (275 mg) and phthalimide (193 mg) and the whole was cooled to 0° C. In this solution, a 40% diethyl azodicarboxylate/toluene solution (452 mg) was dropped and the whole was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with water. Then, the resultant was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (174 mg) as a pale-yellow solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH3:7])[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>O1CCCC1>[C:3]([C@H:2]([O:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:6][CH3:7])(=[O:4])[NH2:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@@H](O)C(N)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@@H](OS(C)(=O)=O)C(N)=O
Temperature: 20 °C

Procedure:
To a mixture of (R)-2-hydroxybutyramide (4.2 g, 40.7 mmol) and triethylamine (6.2 ml, 44.8 mmol, 1.1 equiv.) in tetrahydrofuran (50 ml) is added drop wise at −40° C. methanesulfonic acid chloride (3.5 ml, 44.8 mmol, 1.1 equiv.). The mixture is allowed to warm to 20° C. and is filtered over magnesium sulfate (8 g). The cake is rinsed twice with tetrahydrofuran (2×20 ml) and combined filtrates are concentrated to dryness under reduced pressure to afford methanesulfonic acid (R)-1-carbamoyl-propyl ester (IIi) as a solid. (7.9 g, 106%, triethylamine hydrochloride salts are present).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:29]([O:31][C:32](=[O:41])[C@H:33]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH2:34])[CH3:30].ON1C2C=CC=CC=2N=N1.CCN(CC)CC.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[NH:38]1[CH:37]=[C:36]([CH2:35][C@H:33]([NH:34][C:13](=[O:14])[CH:12]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:32]([O:31][CH2:29][CH3:30])=[O:41])[N:40]=[CH:39]1
Reactant: O=C(O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
A solution of 0.5 g (1.5 mmol) of bis-(1-naphthylmethyl)-acetic acid, 0.77 g (3.0 mmol) of histidine ethyl ester dihydrochloride (His-OEt·2 HCl), and 0.22 g (1.6 mmol) of 1-hydroxybenzotriazole (HOBt) in 20 mL of THF was treated with 0.85 mL (6.0 mmol) of Et3N followed by 0.33 g (1.6 mmol) of N,N'-dicyclo hexylcarbodiimide (DCC) and the solution allowed to stir at room temperature overnight. The mixture was filtered and the solvent removed under reduced pressure. The residue was taken up in EtOAc and washed with a saturated solution of NaHCO3, then with a saturated solution of NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave the crude product. Chromatography on silica gel, eluting with a gradient of methylene chloride (CH2Cl2) to CH2Cl2 /MeOH (96/4) gave 0.15 g of the product as a white foam. The structure was confirmed by NMR and mass spectroscopy; (m+H)+ =506.
Reaction SMILES: [CH3:1][C:2]1[NH:6][NH:5][C:4](=[O:7])[C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]2[CH2:18][CH2:17]2)=[CH:11][CH:10]=1.[CH3:19][C:20]([O:22][CH2:23][C@H:24]1[O:29][C@H:28](Br)[C@H:27]([O:31][C:32]([CH3:34])=[O:33])[C@@H:26]([O:35][C:36]([CH3:38])=[O:37])[C@@H:25]1[O:39][C:40]([CH3:42])=[O:41])=[O:21]>O1CCCC1.C(=O)([O-])[O-].[Ag+2]>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([O:7][C@@H:28]2[O:29][C@H:24]([CH2:23][O:22][C:20](=[O:21])[CH3:19])[C@@H:25]([O:39][C:40](=[O:41])[CH3:42])[C@H:26]([O:35][C:36](=[O:37])[CH3:38])[C@H:27]2[O:31][C:32](=[O:33])[CH3:34])[C:3]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[C:16]2[CH2:18][CH2:17]2)=[CH:13][CH:14]=1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1[nH][nH]c(=O)c1Cc1ccc(C=C2CC2)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(C=C3CC3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
To a suspension of 5-methyl-4-{[4-(cyclopropylidenemethyl)phenyl]methyl}-1,2-dihydro-3H-pyrazol-3-one (0.026 g) and acetobromo-α-D-glucose (0.049 g) in tetrahydrofuran was added silver carbonate (0.036 g), and the mixture was stirred at 60° C. overnight under light shielding. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran) and successively by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3) to give 5-methyl-4-{[4-(cyclopropylidenemethyl)phenyl]methyl}-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.010 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[S:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[O:8][CH2:7][C@H:6]1[OH:18].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[ClH:1].[ClH:1].[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:9]2[O:8][CH2:7][C@@H:6]([OH:18])[C@H:5]([CH2:4][CH2:3][CH2:2][N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[S:11][C:10]=2[CH:12]=1
Reactant: COc1ccc2c(c1)S[C@@H](CCCCl)[C@H](O)CO2
Reactant: c1ccc(N2CCNCC2)cc1
Product: COc1ccc2c(c1)S[C@@H](CCCN1CCN(c3ccccc3)CC1)[C@H](O)CO2
Product: Cl
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of trans-4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol(0.1 g) and N-phenylpiperazine (0.2 g) is stirred at 90° C. for 2 hours. The reaction mixture is purified by silica gel column chromatography eluting with n-hexane-ethyl acetate methanol (10:10:1) and treated, with ethanolic hydrogen chloride to give trans-7-methoxy-4-[3-(4-phenylpiperazine-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol dihydrochloride as an amorphous powder.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:30][CH:31]=4)=[O:37])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(OC(F)(F)F)cc4)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.50 g, 1.40 mmol) and 4-(trifluoromethoxy)phenylisocyanate (0.20 mL, 1.40 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.38 mL, 2.7 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration and washed with water (30 mL). The crude solids were slurried in EtOAc (15 mL) for 4 h then filtered, washed with EtOAc (15 mL) and dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-trifluoromethoxy-phenyl)-urea as an off-white solid (0.43 g, 67% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 8.87 min (98.89%); mp: 269-271° C.; 1H NMR (DMSO-d6) δ 1.85-2.13 (m, 1H, CHH), 2.25-2.47 (m, 1H, CHH), 2.60 (d, J=17.2 Hz, 1H, CHH), 2.79-3.08 (m, 1H, CHH), 4.22-4.38 (d, J=17.4 Hz, 1H, CHH), 4.38-4.57 (m, 3H, CHH, CH2), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CH), 6.81 (t, J=5.9 Hz, 1H, NH), 7.23 (d, J=8.7 Hz, 2H, Ar), 7.45 (d, J=7.9 Hz, 1H, Ar), 7.48-7.60 (m, 3H, Ar), 7.70 (d, J=7.7 Hz, 1H, Ar), 8.87 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.18, 42.79, 47.12, 51.56, 120.08 (q, M03), 118.80, 120.08 (q, J=250 Hz), 121.56, 121.86, 122.93, 126.88, 130.30, 139.71, 142.07, 142.38, 144.69, 155.10, 167.93, 170.99, 172.85; LCMS: MH=477; Anal Calcd for C22H19N4O5F3: C, 55.47; H, 4.02; N, 11.76; F, 11.96. Found: C, 55.27; H, 3.88; N, 11.73; F, 11.99.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[F:25])[CH3:2].[C:26](#N)C.O>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24][CH3:26])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[F:25])[CH3:2]
Reactant: CC#N
Reactant: CCc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)cc1F
Solvent: O
Product: CCc1ccc(COc2ccnn2-c2cc(C(=O)OC)ccn2)cc1F

Procedure:
The title compound was prepared from 2-[5-[(4-ethyl-3-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid (EXAMPLE 96) according to the procedure for the preparation of Example 62. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.6 Hz), 2.67 (2H, q, J=7.6 Hz), 3.97 (3H, s), 5.20 (2H, s), 5.75 (1H, d, J=1.6 Hz), 7.12-7.23 (3H, m), 7.58 (1H, d, J=2.0 Hz), 7.78 (1H, dd, J=1.6, 5.2 Hz), 8.34 (1H, s), 8.71 (1H, d, J=5.2 Hz). LCMS (mobile phase: 30%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=3.783 min. [M+H] Calc'd for C19H18FN3O3, 356. Found, 356.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:15]([CH2:30][CH2:31][CH2:32][OH:33])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:32]([CH2:31][CH2:30][C:15]1[CH:14]=[C:13]([O:12][CH3:11])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1[O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)=[O:33]
Reactant: COc1cc(CCCO)c(OC2CCCCO2)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(CCC=O)c(OC2CCCCO2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
An oven-dried 25 ml 2-necked (14/20) round bottom flask, equipped with magnetic stirring bar nitrogen inlet and serum cap, is charged with a solution of oxalyl chloride (61 μl) in 2 ml methylene chloride. This solution is placed under a nitrogen atmosphere and cooled to -60° C. to -50° C. Dimethylsulfoxide (99 μl) is added (neat) dropwise to give a colorless solution. After 2.3 min a solution of 3-[4-methoxy-1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-naphthalenyl]-1-propanol (0.19 g) in 1 ml methylene chloride is added dropwise. The resulting mixture is stirred at -60° C. to -50° C. for 15 min and then treated with triethylamine (0.44 ml). This gives rise to a yellow colored milky suspension. The cooling bath is removed and the stirred mixture is allowed to warm to room temperature at which time the mixture is diluted with water and extracted with ether. The organic phase is washed three times with water (after adjusting the pH to 7 with 10% aqueous sodium bisulfate), dried with magnesium sulfate, filtered and concentrated to give 0.18 g of the crude title compound as an orange colored oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[CH:8]=[CH:7][CH:6]=[CH:5]2.[CH2:11]=[C:12]1[N:13]=[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:15][C:16](=[O:25])/[C:17]/1=[CH:18]/[C:19](=[CH:23]\[CH3:24])/[C:20](Cl)=[O:21]>C1COCC1.C(OCC)(=O)C>[CH2:11]=[C:12]1[N:13]=[C:14]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:15][C:16](=[O:25])/[C:17]/1=[CH:18]/[C:19](/[C:20]([C:10]1[N:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[CH:3][C:2]=1[CH3:1])=[O:21])=[CH:23]\[CH3:24]
Reactant: Cc1cc2ccccn2c1
Reactant: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)c1c(C)cc2ccccn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
A solution of 2-methylindolizine (11.5 g; 87.7 mmol) in 35 mL of THF is added dropwise to a suspension of (2E)-2-[(E)-(4-methylidene-6-oxo-2-phenyl-4H-1,3-oxazin-5(6H)-ylidene)methyl]but-2-enoyl chloride (25 g; 87.7 mmol) in 140 mL of THF at 0° C. under nitrogen. After 18 h of stirring at ambient temperature, the reaction medium is diluted in ethyl acetate, and the solution is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulphate and concentrated to dryness. The residue obtained is purified by flash chromatography on silica (DCM) to give 22.75 g (69%) of a yellow powder.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9]Br)=O)=[CH:5][CH:4]=[C:3]([Br:11])[CH:2]=1.[C:12]([NH2:15])(=[S:14])[CH3:13].[OH-].[Na+]>O1CCOCC1>[Br:11][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[N:15]=[C:12]([CH3:13])[S:14][CH:9]=2)=[CH:1][CH:2]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(Br)cc2)cs1
Temperature: 25 °C
Yield: 103.4 %

Procedure:
To a stirred solution of 2,4-dibromoacetophenone (5 g, 18 mmol) in dioxane (180 ml) was added thioacetamide (6.76 g, 90 mmol), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 2N NaOH aqueous solution. The whole was extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (4.73 g, 99% yield).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C:11]2[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:12]=2[F:21])=[O:9])=[CH:6][CH:5]=1.[C:24](Cl)([Cl:26])=[S:25]>O.C(Cl)(Cl)Cl>[Cl:26][C:24]([O:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C:11]2[C:12]([F:21])=[C:13]([F:20])[C:14]([F:19])=[C:15]([F:18])[C:16]=2[F:17])=[O:9])=[CH:6][CH:5]=1)=[S:25]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(O)cc1
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(OC(=S)Cl)cc1
Temperature: 5 °C

Procedure:
A solution of 1.34 g of sodium hydroxide in water was added dropwise over 15 minutes with vigorous stirring to a solution of 8.45 g of pentafluorophenyl 4-hydroxybenzoate and 3.2 ml of thiophosgene in 100 ml of chloroform at -20° C. The mixture was stirred at 5° C. until the reaction was complete and the organic layer separated, dried over calcium chloride and the solvent evaporated. Chromatography of the residue on silica gel eluting with hexane/ethyl acetate mixtures afforded 5.9 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[C:5]([SH:8])=[CH:6][CH:7]=1.[OH-:10].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O>[ClH:12].[ClH:12].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:4]([S:9][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:10][CH2:18][CH2:17]2)[CH:3]=1
Reactant: [OH-]
Reactant: Cc1ccc(S)c(S)c1
Reactant: ClCCCN1CCOCC1
Agent: [Na+]
Solvent: O
Product: Cc1ccc(SCCCN2CCOCC2)c(SCCCN2CCOCC2)c1
Product: Cl
Reaction time: 0.5 h

Procedure:
To a warm (60° C.) solution of 10.0 g (0.0640 mole) of 4-methyl-o-benzenedithiol, 5.12 g (0.128 mole) of sodium hydroxide in 70 ml of water was added 21.0 g (0.128 mole) of 4-(3-chloropropyl)morpholine. The reaction mixture was stirred at 60° to 65° C. for 30 minutes, cooled and extracted with methylene chloride. After the extract was dried over anhydrous magnesium sulfate and filtered, ethanolic hydrogen chloride was added, and the solvent and excess hydrogen chloride were removed by evaporation in vacuo. The oily residue was crystallized from propanol-2. Recrystallization from methanol-propanol-2 (1.4:1) gave the product, 4,4'-((4-methyl-1,2-phenylene)bis(thio-3,1-propanediyl))bismorpholine dihydrochloride as white crystals, m.p. 233-234° C.
Reaction SMILES: Br[C:2]1[C:15]([F:16])=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=2)=[C:4]([O:17][CH3:18])[CH:3]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+].[CH:28](B1OC(C)(C)C(C)(C)O1)=[CH2:29]>O.C(#N)C>[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:14]=[C:15]([F:16])[C:2]([CH:28]=[CH2:29])=[CH:3][C:4]=2[O:17][CH3:18])[N:8]=1
Reactant: COc1cc(Br)c(F)cc1Oc1cccc(F)n1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: C=Cc1cc(OC)c(Oc2cccc(F)n2)cc1F
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To 2-(4-bromo-5-fluoro-2-methoxyphenoxy)-6-fluoropyridine (227 mg, 0.71 mmol) were added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (58.9 mg, 0.07 mmol) and potassium carbonate (597 mg, 4.26 mmol). To the mixture were added acetonitrile (4 mL), water (1.3 mL) and vinyl boronic acid pinacol ester (180 μL, 1.07 mmol). The reaction was flushed with argon, and left to stir for 3 days at 60° C. The reaction mixture was then filtered on celite, rinsed with dichloromethane and concentrated. After purification by preparative TLC (cyclohexane/ethyl acetate: 70/30), the title product was isolated as an orange oil (166 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1([C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH3:23])[C:9]=3[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.Cl.[C:31]([O:34][CH2:35][CH3:36])(=[O:33])C>O1CCCC1>[CH2:17]([N:12]1[C:13](=[O:16])[C:14]2[NH:15][C:7]([C:2]3([NH:1][C:31]([O:34][CH2:35][CH3:36])=[O:33])[CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:8][C:9]=2[N:10]([CH2:21][CH2:22][CH3:23])[C:11]1=[O:20])[CH2:18][CH3:19]
Reactant: CCOC(C)=O
Reactant: CCCn1c(=O)c2[nH]c(C3(N)CCCC3)nc2n(CCC)c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCn1c(=O)c2[nH]c(C3(NC(=O)OCC)CCCC3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.5 g of 8-(1-aminocyclopentyl)-1,3-dipropylxanthine in 45 ml of anhydrous tetrahydrofurane 1.83 ml of pyridine and 1.97 ml of ethyl chloroformiate are added. The mixture is stirred for 2 hours at room temperature, followed by the addition of 1N HCl and extraction with ethyl acetate. The organic phase is washed with water, dried and evaporated to obtain 4.2 g of raw product, which is finally crystallized from ethanol/water.