Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C:5](=[O:14])[CH2:4]1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+].O>C(OCC)C>[CH3:1][N:2]([CH3:15])[CH:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:14])[CH2:4]1
Reactant: [Li]c1ccccc1
Reactant: CN(C)C1CCc2ccccc2C(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CN(C)C1CCc2ccccc2C(O)(c2ccccc2)C1
Reaction time: 2 h

Procedure:
A solution of 24.46 g of 7-dimethylamino-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene in 488 ml of ethyl ether was added over 75 minutes under a nitrogen atmosphee at 0° to 5° C to a solution of 1.2 M of phenyl lithium in ethyl ether and the mixture was stirred for 2 hours at 0° to 5° C. 120 ml of an aqueous saturated ammonium chloride solution and then 100 ml of water were slowly added thereto at 0° to 15° C and the mixture was decanted. The ether phase was washed with water and dried to obtain 29.4 g of raw 7-dimethylamino-5ξ-phenyl-5ξ-hydroxy6,7,8,9-tetrahydro [5H] benzocycloheptene which was used as is for the next step. The product was a mixture of the 2 isomers with substitution in the 5-position.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]([NH2:10])([CH3:9])[CH3:8].[C:11]([Si:15]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]I)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])([CH3:13])[CH3:12].O>C1COCC1>[Si:15]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:10][CH:7]([CH3:9])[CH3:8])([C:11]([CH3:12])([CH3:13])[CH3:14])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OCCCCCI)(c1ccccc1)c1ccccc1
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 12 h
Yield: 84.9 %

Procedure:
K2CO3 (1.50 g, 11.05 mmol), isopropylamine (0.65 mL, 11.05 mmol) and iodide 3 (2.50 g, 5.83 mmol) in dry THF (15 mL) were heated at 66° C. in a sealed tube under an argon atmosphere. After 12 h, water (5 mL) was added to the reaction mixture which was then extracted with EtOAc (3×50 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to afford 4 as a colorless liquid (1.90 g, 92%) sufficiently pure it was used without further purification. TLC:MeOH/CH2Cl2 (1:4), Rf˜0.30; 1H NMR (400 MHz) δ 7.65-7.67 (m, 4H), 7.30-7.40 (m, 6H), 3.65 (t, J=6.4 Hz, 2H), 2.70-2.82 (m, 1H), 2.55 (t, J=7.3 Hz, 2H), 1.50-1.64 (m, 2H), 1.32-1.50 (m, 4H), 1.05 (d, J=5.8 Hz, 3H), 1.04 (s, 9H); 13C NMR (100 MHz) δ 135.68, 134.21, 129.63, 127.70, 63.95, 48.81, 47.64, 32.60, 30.27, 27.0, 23.76, 23.15, 19.34.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:34](O)=[O:35])=[N:11][C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:71][CH2:72][C:73]1[CH:83]=[CH:82][C:81]([F:84])=[CH:80][C:74]=1[C:75]([O:77][CH2:78][CH3:79])=[O:76]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:34]([NH:71][CH2:72][C:73]2[CH:83]=[CH:82][C:81]([F:84])=[CH:80][C:74]=2[C:75]([O:77][CH2:78][CH3:79])=[O:76])=[O:35])=[N:11][C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(F)ccc1CN
Reactant: CC(C)(C)OC(=O)NCCCCCCNc1nc(C(=O)O)c(OCc2ccccc2)c2ncccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)ccc1CNC(=O)c1nc(NCCCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8-(Benzyloxy)-5-(6-(tert-butoxycarbonylamino)hexylamino)-1,6-naphthyridine-7-carboxylic acid (Example 1.2; 0.42 g; 0.85 mmol) was dissolved in dichloro methane (9 ml). DIPEA (0.58 ml; 3.42 mmol) and HBTU (0.39 g; 1.03 mmol) were added. The reaction mixture was stirred at room temperature during 5 min. Ethyl 2-(aminomethyl)-5-fluorobenzoate hydrochloride (Example 4; 0.24 g; 1.03 mmol) was added portionwise at room temperature. The mixture was stirred overnight at room temperature. The mixture was diluted with CH2Cl2 and washed with a saturated aqueous Na2CO3 solution (2×) and H2O. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromategraphy over silica gel (eluent: hexane/EtOAc 10:1 up to 1:1). The fractions were collected and the solvent evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)([OH:14])[CH2:9][NH:10][CH2:11][CH2:12]O)=[CH:4][CH:3]=1.OS(O)(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[O:14][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCCNCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1ccc(C2(c3ccc(I)cc3)CNCCO2)cc1
Reaction time: 20 h
Yield: 43.2 %

Procedure:
A solution of 1-(4-chloro-phenyl)-2-(2-hydroxy-ethylamino)-1-(4-iodo-phenyl)-ethanol (701 mg, 1.68 mmol) in DCM (10 mL) was treated with concentrated H2SO4 (0.1 mL, 1.9 mmol). After 20 hours, another portion of H2SO4 (1.0 mL, 19 mmol) was added and the mixture stirred for a further 2 hours. The mixture was diluted with ethyl acetate and washed with saturated potassium carbonate and brine then dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (SiO2), eluting with 0.5% triethylamine in ethyl acetate to afford the title compound (290 mg, 43%); LCMS (PS-A2) Rt 2.40 min [M+H]+400.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.C[Sn](C)(C)[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][C:28]([O:34][CH3:35])=[C:27]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:26]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:37]([O:36][C:27]1[C:28]([O:34][CH3:35])=[CH:29][C:30]([N+:31]([O-:33])=[O:32])=[C:25]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11]3)[CH:26]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1cc([N+](=O)[O-])c([Sn](C)(C)C)cc1OCc1ccccc1
Reactant: COc1cc2ccc(OS(=O)(=O)C(F)(F)F)cc2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2ccc(-c3cc(OCc4ccccc4)c(OC)cc3[N+](=O)[O-])cc2cc1OC
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (200 mg) and cuprous bromide (20 mg) were added to a solution of 6,7-dimethoxy-2-trifluoromethanesulfonyloxy-naphthalene 10 (500 mg, 1.49 mmol) and trimethylnitroarylstannane 38 (950 mg, 2.25 mmol) in THF (40 mL) at room temperature and stirred for 0.5 h. The mixture was then refluxed under N2 for 2 days. After cooling, THF was evaporated and ethyl acetate (30 mL) was added to the residue. The solution was washed with water. The organic layer was separated and passed through a Celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na2SO4), and evaporated in vacuo. The residue was chromatographed using a 70:30 mixture of hexanes:ethyl acetate to give 39 (230 mg) in 35% yield; mp 151-153° C.; IR (KBr) 2962, 1608, 1573, 1508, 1416, 1330, 1275, 1254 cm−1; 1H NMR (CDCl3) δ3.98 (3H, s), 3.99 (3H, s), 4.01 (3H, s), 5.20 (2H. s), 6.94 (1H, s), 7.10 (1H, s), 7.14 (1H, s), 7.18 (1H, dd, J1=8.4, J2=1.8), 7.36-7.43 (5H, m), 7.54 (1H, d, J=1.5), 7.56 (1H, s), 7.68 (1H, d, J=8.3); 13C NMR δ56.37, 56.95, 71.69, 106.69, 106.99, 108.67, 116.35, 124.91, 125.78, 127.00, 128.00, 128.87, 129.00, 129.23, 129.53, 131.81, 134.49, 136.15, 141.89, 148.95, 150.41, 151.85; HRMS (EI) calcd for C26H23NO6 m/z: 445.1525; found: 445.1355.
Reaction SMILES: [OH:1][CH2:2][CH:3]([OH:6])[CH:4]=[CH2:5]>ClCCl>[CH2:5]([CH:3]([OH:6])[CH2:2][OH:1])[CH2:4][CH:3]([OH:6])[CH2:2][OH:1]
Reactant: C=CC(O)CO
Solvent: ClCCl
Product: OCC(O)CCC(O)CO
Yield: 8.2 %

Procedure:
Self-metathesis of 1,2-dihydroxy-3-butene. 1,2-Dihydroxy-3-butene (158 mg, 1.8 mmol) and (PCy3)2Cl2Ru═CHPh (30 mg, 0.036 mmol, 2.0 mol %) were dissolved in dry dichloromethane (5 ml). The solution was degassed then heated to reflux. Gradually, the solution's purple color changed to red-brown and a white solid formed. After 21 h heating was stopped and the white solid was filtered and dried in vacuo to give 11 mg, (0.074 mmol, 8.2% yield) of 3,4-dideoxyhexitol. 1H NMR (D2O) δ 5.80 (s, 1H), 4.25 (br s, 1H), 3.62 (m, 1H), 3.52 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C:13]2[CH:16]=[CH:17][C:18]([F:21])=[C:19]([Br:20])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:16]=[CH:17][C:18]([F:21])=[C:19]([Br:20])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccc(F)c(Br)c2OCCN1Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Fc1ccc2c(c1Br)OCCN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a solution of 4-benzyl-9-bromo-8-fluoro-3,4-dihydro-1,4-benzoxazepine-5 (2H)-one (3.23 g, 9.22 mmol) in tetrahydrofuran (10 ml) was added under ice-cooling 1M borane-tetrahydrofuran solution (46 ml, 46.1 mmol), and the mixture was refluxed for 2 hr. Under ice-cooling, methanol was added, and the solvent was evaporated under reduced pressure. 6N hydrochloric acid (46 ml) was added, and the mixture was stirred at 100° C. for 1 hr. The solution was basified with 8N sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (2.94 g, 94.8%) as an oil.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].[Cl:10][C:11]1[C:16](O)=[C:15]([Cl:18])[C:14]([Cl:19])=[C:13]([Cl:20])[C:12]=1[Cl:21].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:10][C:11]1[C:16]([O:8][C:7](=[O:9])[C@@H:2]2[CH2:3][CH2:4][C:5](=[O:6])[NH:1]2)=[C:15]([Cl:18])[C:14]([Cl:19])=[C:13]([Cl:20])[C:12]=1[Cl:21]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C1CC[C@@H](C(=O)Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2Cl)N1
Temperature: 0 °C
Reaction time: 5 h
Yield: 46.4 %

Procedure:
129 g (1mol) of L-pyroglutamic acid were finely ground in a mortar and suspended in 2 l of tetrahydrofurane. 319 g (1.2 mol) of pentachlorophenol and, at 0° C., 220 g (1.06 mol) of dicyclohexylcarbodiimide dissolved in 300 ml of tetrahydrofurane were added. The mixture was stirred for 1 hour at 0° C. and for 5 hours at room temperature. The dicyclohexyl urea was filtered off, and extracted with a small amount of warm tetrahydrofurane. The solvent was distilled off in vacuum. The residue was boiled with isopropanol and filtered off after cooling. After drying under vacuum over P2O5 and KOH, 175 g product were obtained which melted at 198° C., [α]D20 = + 18.6° (c=1, dimethyl formamide)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3ccnc(C(F)(F)F)c3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K38) (274 mg, 0.75 mmol) in xylene (15 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light red solid (290 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.98 g, 0.015 mole) and 1,1'-carbonyldiimidazole (2.59 g, 0.016 mole) in 120 ml of tetrahydrofuran was stirred at room temperature for 4 hrs. The di-n-propylamine (3.04 g, 0.03 mole) was added and the reaction mixture was heated at reflux for (65° C.) for 8-9 hrs. The reaction mixture was filtered and the filtrate was evaporated to an oil, which was placed under high vacuum for 3 hrs. The solid residue was treated with water, collected by filtration, washed with water, and dried under high vacuum. The solid was recrystallized from isopropyl alcohol-water, collected by filtration, washed with water, and dried under high vacuum to give 3.2 g (52%), mp 125°-27° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[Cl:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)=[CH:25][C:26]([NH:30][CH3:31])=[C:27]([CH:29]=1)[NH2:28].CC(C)N=C=NC(C)C>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[N:30]([CH3:31])[C:26]2[CH:25]=[C:24]([N:32]3[CH2:37][CH2:36][N:35]([C:38]4[CH:39]=[CH:40][C:41]([C:44]([F:45])([F:47])[F:46])=[CH:42][CH:43]=4)[CH2:34][CH2:33]3)[C:23]([Cl:22])=[CH:29][C:27]=2[N:28]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1cc(N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c(Cl)cc1N
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(Cl)c(N3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-Chloro-3-isothiocyanatobenzyl)-1-trifluoromethyl-cyclopropane carboxamide (161 mg, 0.48 mmol) was added to the THF solution from step (a) above and the mixture was concentrated. DMF (2 mL) was added to the residue, the mixture was stirred at rt for 1 h and DIC (67 mg, 0.53 mmol) was added. The mixture was stirred at rt overnight, another portion of DIC (17 mg, 0.13 mmol) was added and the mixture was stirred at rt overnight. The mixture was concentrated and the residue was purified by column chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17][CH2:18][CH2:19][CH3:20])=[C:15]([C:21]([O:23]C(C)(C)C)=[O:22])[CH:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([S:17][CH2:18][CH2:19][CH3:20])=[C:15]([C:21]([OH:23])=[O:22])[CH:14]=[N:13]2)=[CH:10][CH:11]=1)=[O:4]
Reactant: CCCSc1c(C(=O)OC(C)(C)C)cnn1-c1ccc(CC(=O)OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCSc1c(C(=O)O)cnn1-c1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-butyl 1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylate (Intermediate#36) was dissolved in DCM (10 mL). TFA (2 mL) was added and the mixture was stirred at ambient temperature for 5 h. Volatiles were then evaporated under reduced pressure and the residue dried under vacuum to afford 1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylic acid as a light brown oil. (440 mg, 98%)
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:9][NH:10][C:11]([S-:13])=[S:12])=O)(=[O:3])[CH3:2].[K+].S(=O)(=O)(O)O.[OH-].[Na+]>>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[S:12][C:11]([SH:13])=[N:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC(=O)NNC(=S)[S-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: CC(=O)NCCc1nnc(S)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
Potassium 3-(N-acetyl-β-alanyl)dithiocarbazate (8.15 g) was added bit by bit to concd. sulfuric acid (50 ml) at 5° to 10° C. The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was poured into ice-water (c.a. 300 ml) and adjusted to pH around 6 with 20% sodium hydroxide, and then extracted seven times with ethyl acetate (each 300 ml). The extract was dried and the solvent was distilled off under reduced pressure to give 5-(2-acetamidoethyl)-1,3,4-thiadiazole-2-thiol (5.03 g). having m.p. 157° to 160° C.
Reaction SMILES: S=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1.[F:13][C:14]([F:20])([F:19])[C:15]([NH:17][NH2:18])=O>C1COCC1.[Hg](OC(C)=O)OC(C)=O>[F:13][C:14]([F:20])([F:19])[C:15]1[N:3]2[CH2:4][CH2:5][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][C:2]2=[N:18][N:17]=1
Reactant: CCOC(=O)C1CCNC(=S)C1
Reactant: NNC(=O)C(F)(F)F
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCn2c(nnc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of ethyl 2-thioxopiperidine-4-carboxylate (5.7 g, 14.95 mmol) in THF (203 mL) was added 2,2,2-trifluoroacetohydrazide (7.8 g, 60.88 mmol) and Hg(OAc)2 (10.71 g, 33.48 mmol) at ice-water. The mixture was stirred at room temperature for 2 hours and heated at 60° C. for overnight, then filtered. Removed the solvent under reduced pressure and the filtrate was concentrated and purified by silica gel column chromatography (PE/EA=3/1) to afford ethyl 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (3.5 g, yield 43.8%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10-1.32 (m, 3H) 2.16 (br. s., 1H) 2.36 (br. s., 1H) 2.93 (br. s., 1H) 3.02-3.39 (m, 2H) 3.90-4.30 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:23])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12](=[O:22])[N:13]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14])=[CH:7]2.C([O:26][CH:27]=[C:28]([C:34](OCC)=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:32]([O:31][C:29]([CH:28]1[C:27](=[O:26])[C:3]2[C:2](=[C:11]3[C:6](=[CH:5][C:4]=2[F:23])[CH:7]=[C:8]([C:12](=[O:22])[N:13]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:14])[CH:9]=[N:10]3)[N:1]=[CH:34]1)=[O:30])[CH3:33]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CN(Cc1ccccc1)C(=O)c1cnc2c(N)cc(F)cc2c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C1C=Nc2c(c(F)cc3cc(C(=O)N(C)Cc4ccccc4)cnc23)C1=O
Yield: 70 %

Procedure:
Using an analogous procedure to that described in Example 2, in the section relating to the preparation of starting materials, 8-amino-3-[N-benzyl-N-methylcarbamoyl]-6-fluoroquinoline was reacted with diethyl ethoxymethylenemalonate, and then refluxed in diphenyl ether. The product so obtained was recrystallised from a mixture of ethyl acetate and hexane to give 3-ethoxycarbonyl-8-(N-benzyl-N-methylcarbamoyl)-5-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline in 70% yield, mp 201-203° C.
Reaction SMILES: Br[CH:2]([F:9])[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[F:9][CH:2]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C(=O)C(F)Br
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)C(=O)C(F)n1cncn1
Reaction time: 18 h
Yield: 84.4 %

Procedure:
63.0 g of 1-bromo-1-fluoro-3,3-dimethyl-2-butanone are added slowly to a mixture of 23.0 g of 1,2,4-triazole and 44.2 g of potassium carbonate in 280 ml of ethyl methyl ketone. The reaction mixture is stirred for 18 hours at 45°-50° C. and is then filtered and evaporated. The residue is taken up in methylene chloride and washed with water. Drying and evaporating the organic phase gives 50.0 g of 1-fluoro-1-(1H-1,2,4-triazol-1-yl)-3,3-dimethyl-2-butanone, melting point 54°-55° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O>CN(C)C=O>[N:16]1[CH:17]=[CH:18][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[CH:14][CH:15]=1
Reactant: Nc1ccncc1
Reactant: CN1CC(=O)NC1=NC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccncc1

Procedure:
A mixture of 4.0 g (17 mM) of the phenyl ester of tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene carbamic acid 8 and 1.6 g (17 mM) of 4-aminopyridine in 25 ml of anhydrous dimethylformamide (DMF) was heated at 55° for 5 hrs. (hours), cooled, and poured with stirring into 250 ml of water. The precipitated solid was collected, washed with ethanol and ether, and air dried. Recrystallization from methanol gave 2.0 g of the above urea as a pale yellow solid, m.p. 218°-220° C. (dec.).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]4[CH2:25][CH2:24][S:23][CH2:22][CH2:21]4)[CH:15]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:44])C=1>ClCCl>[CH3:1][C:2]([CH3:35])([CH3:34])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]4[CH2:25][CH2:24][S:23](=[O:44])[CH2:22][CH2:21]4)[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(N4CCSCC4)c3)nc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCS(=O)CC4)c3)nc12
Yield: 61 %

Procedure:
To a flask was added 2,2-Dimethyl-1-[2-(3-thiomorpholin-4-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (prepared using general procedures described in these Examples) 0.030 gm (0.059 mM), 3-chloroperbenzoic acid (77%) 0.015 gm (0.067 mM), dichloromethane, stirred over night, rinsed with saturated aqueous sodium bicarbonate and purified on preparative TLC plate (3:1 ethyl acetate/hexane) tog give 0.019 gm (0.036 mM, 61% yield) of the sulfoxide. The SEM protecting group was removed following general procedures as described in these Examples to give 2,2-Dimethyl-1-{2-[3-(1-oxo-1lambda*4*-thiomorpholin-4-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-propan-1-one, 0.0025 gm, (0.006 mM) M+1 397.