Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]1[CH2:8][CH2:7]1)=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C1C=CC=CC=1>CO>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][CH2:8][CH2:7][N:23]1[CH2:22][CH2:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)([OH:26])[CH2:25][CH2:24]1)=[O:5]
Reactant: O=C(c1ccccc1Br)N1CC1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CO
Solvent: c1ccccc1
Product: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccccc1Br

Procedure:
A mixture of 2.26 parts of 1-(2-bromobenzoyl)aziridine, 2.12 parts of 4-(4-chlorophenyl)-4-piperidinol, 10.8 parts of benzene and 0.8 parts of methanol is stirred and refluxed for 2 hours. The reaction mixture is cooled and evaporated. The residue is crystallized from ethyl acetate. The product is filtered off and dried, yielding 2.5 parts of 2-bromo-N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl}benzamide; mp. 120.6° C.
Reaction SMILES: [CH:1]1([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3Cl)[S:5][C@H:4]([CH2:6][OH:7])[CH2:3][CH2:2]1.[CH3:18][NH2:19]>O>[CH3:18][NH:19][C:13]1[C:14]2[N:15]=[CH:16][N:8]([C:9]=2[N:10]=[CH:11][N:12]=1)[C@@H:1]1[S:5][C@H:4]([CH2:6][OH:7])[CH2:3][CH2:2]1
Reactant: OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1
Reactant: CN
Solvent: O
Product: CNc1ncnc2c1ncn2[C@H]1CC[C@@H](CO)S1
Yield: 77 %

Procedure:
The anomeric mixture of 20 (0.132 g, 0.49 mmol) in a steel bomb was stirred with 20 mL 40% methylamine in water at 80° C. overnight. After solvent removal in vacuo, the residue was purified by preparative TLC with 9:1 chloroform/methanol to give 100 mg (77%) of the anomeric mixture. The anomers were partially separated by a Dowex 1×4 (-OH) column with 10% aqueous methanol to give 37 mg of impure β anomer which was recrystallized from hexane-ethyl acetate to afford 22.5 mg of pure β anomer by HPLC; mp. 131°-134° C.; FAB MS 266 (M+H)+ ; 1H NMR (DMSO-d6) δ 8.4 (s, 1, H-2), 8.2 (s, 1, H-8), 7.7 (brs, 1, NH), 6.2 (m, 1, 1'-H), 5.15 (m, 1, 5'-OH), 3.75 (m, 1, 5 '-H), 3.6 (m, 2, 4'-H, 5'-H), 2.95 (s, 3, CH3), 2.4 (m, 2, 4'-H's), 2.15 (m, 1, 3'-H), 2.0 (m, 1, 3'-H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:2]1.C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[C:25]([N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:2]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)CCc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Yield: 100.8 %

Procedure:
A solution of 6.0 g of methyl 3-(1H-imidazol-4-yl)propionate and 11 ml of triethylamine in 31 ml of dimethylformamide is treated with a solution of 9.65 g of triphenylmethyl chloride in 110 ml of dimethylformamide for 2 h at room temperature under nitrogen. The reaction mixture is poured onto 700 g of ice, and the resulting solid is collected by filtration and recrystallized from ether to yield 13.83 g of methyl 3-(1-tritylimidazol-4-yl)propionate, NMR (CDCl3) δ=2.75 (m, 4H), 3.05 (s, 3H), 6.5-7.5 (m, 17H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[OH:14].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:12])([F:13])[F:11])[CH:5]=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(OCC(F)(F)F)cc1Br
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(OCC(F)(F)F)cc1Br

Procedure:
To a solution of 2-bromo-4-(2,2,2-trifluoroethoxy)phenol (Description 20, 0.6 g) in acetone was added added K2CO3 (1 g) and methyl iodide (1 ml). The solution was heated to reflux for 1 h. and then evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the organic phase washed further with water and saturated brine. After drying (MgSO4) the solvent was removed in vacuo to give the title compound as a yellow oil. 1H NMR (250 MHz, CDCl3) δ3.87 (3H, s) 4.30 (2H, q, J 8 Hz), 6.82-6.92 (2H, m), and 7.20 (1H, d, J 3 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12].O1CCCC1>>[CH3:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[NH:14][CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: Cc1ccc(Cl)c(C)c1
Reactant: CC(C)CN
Solvent: C1CCOC1
Product: Cc1ccc(NCC(C)C)c(C)c1
Temperature: 70 °C
Yield: 96.3 %

Procedure:
A mixture of 1-chloro-2,4-dimethylbenzene (1687 mg, 12 mmol), isobutylamine (1755 mg, 24.00 mmol), and Caddick catalyst (140 mg, 0.238 mmol) was treated with lithium hexamethyl disilizide in tetrahydrofuran (1 M LHMDS in THF, 15 mL, 15.00 mmol) under nitrogen. The reaction mixture was heated to 70° C. for 45 minutes in a septum-sealed vessel. The cooled mixture was concentrated in vacuo and the residue was partitioned between aqueous citric acid (50 mL) and tert butyl methyl ether (TBME) (2×50 mL). The organic phase was treated with dried MgSO4, the solid removed by filtration and the organic phase was concentrated in vacuo to give (2,4-dimethylphenyl)(2-methylpropyl)amine (2.05 g, 11.56 mmol) as an orange oil. LCMS [LCMS1] Rt 1.03 min, m/z (ES+) 178 (M+H).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[Se:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.BrBr.O.[Br-].[Br:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:24][C:25]3[C:30]([SeH+]C=2C=1)=[CH:29][C:28](Br)=CC=3>C(O)(=O)C>[Br-:19].[CH2:12]([N:13]([C:3]1[CH:2]=[CH:1][C:14]2[NH:13][C:12]3[C:7]([SeH+:6][C:5]=2[CH:4]=1)=[CH:8][C:9]([N:24]([CH2:23][CH2:22][CH2:21][CH3:20])[CH2:25][CH2:30][CH2:29][CH3:28])=[CH:10][CH:11]=3)[CH2:14][CH2:5][CH2:4][CH3:3])[CH2:11][CH2:10][CH3:9]
Reactant: Brc1ccc2c(c1)[SeH+]c1cc(Br)ccc1N2
Reactant: c1ccc2c(c1)Nc1ccccc1[Se]2
Agent: BrBr
Agent: [Br-]
Solvent: O
Solvent: CC(=O)O
Product: CCCCN(CCCC)c1ccc2c(c1)[SeH+]c1cc(N(CCCC)CCCC)ccc1N2
Reaction time: 18 h
Yield: 17 %

Procedure:
To a stirred solution of phenoselenazine (1.00 g) in glacial acetic acid (170 cm3), under nitrogen and cooled in an ice-bath was added a solution of bromine (10 cm3) in glacial acetic acid (10 cm3). After 10 minutes the reaction mixture was poured into rapidly stirred water (400 cm3). The resultant 3,7-dibromo-phenoselenazin-5-ylium bromide was deposited as a dark solid and was collected by filtration, washed with diethyl ether and dried. A portion of the product (1.24 g) was added to a vigorously stirred solution of dibutylamine (5.00 g) in dichloromethane (200 cm3) under an atmosphere of nitrogen. The reaction mixture was stirred for 18 hours and then washed successively with water, dilute aqueous hydrobromic acid (5% w/w) and finally water. The organic phase was dried (MgSO4) and the solvent removed by rotary evaporation. Flash column chromatography over silica gel 60 A was performed on the crude material using a mobile phase of chloroform with increasing methanol content to a maximum of 2%. 3,7-Bis-(N,N-dibutylamino)-phenoselenazin-5-ylium bromide was isolated as a dark blue solid in 17% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:22])=[O:21]
Reactant: COc1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CCOS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
To a flask under argon was added 10.1 g (0.0661 mole) 3-methoxyphenethyl alcohol, 150 mL methylene chloride and 9.2 ml (0.0661 mole) triethylamine. The solution was cooled to 0° C. and 5.1 ml (0.0661 mole) methanesulfonyl chloride was added slowly. The reaction mixture was warmed to room temperature. After 24 hr, the reaction was washed with water and brine, and dried with MgSO4. The solvent was evaporated in vacuo to give 15.0 g of the product as a clear oil.
Reaction SMILES: [Br:1][CH:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][N:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6]3)[C:3]1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[C:11]([Cl:18])[N:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH:3]=1
Reactant: O=C1c2c(ncc3ccccc23)C=CC1Br
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccc(Br)cc2c2ccccc12
Temperature: 93 °C
Yield: 75.7 %

Procedure:
36.7 g (139 mmol) 2-bromophenanthridinone and 30.7 g (147 mmol) PCl5 were added to a 1 L multi-neck flask (equipped with stir arm, condenser, and base trap) along with 350 mL POCl3 and heated at 93° C. for 16 hours (note: evolution of HCl gas was predominant—destroyed by base trap). Afterwards, the mixture was assayed to determine complete consumption of 2-bromophenanthridinone. A dean stark trap was connected to the flask to remove the solvent by ½ volume. Subsequently, equal volumes of toluene were added and distilled off to remove majority of POCl3. After the third addition of toluene, the volume was reduced to 300 mL's and the remainder of the solvent removed via rotary evaporation. The solids were then recrystallized from toluene and dried to give 30.8 g (78.6% yield, 98% assay) 2-bromo-6-chlorophenanthridine as off white solids (GC-MS confirmed).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[S:3]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].S(O)(O)(=O)=O.Cl[C:27]1[NH:28][CH2:29][CH2:30][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH3:20][N:2]([CH3:1])[S:3]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:27]3[NH:31][CH2:30][CH2:29][N:28]=3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: ClC1=NCCN1
Reactant: CN(C)S(=O)(=O)c1ccc(Cc2ccc(N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(C)O
Product: CN(C)S(=O)(=O)c1ccc(Cc2ccc(NC3=NCCN3)cc2)cc1
Yield: 164.4 %

Procedure:
A mixture of 4-(4-dimethylaminosulfonylbenzyl)-phenylamine (288 mg) and 2-chloro-imidazoline sulfate (110 mg) in 2-propanol was heated under reflux for 1 hours. A dilute solution of potassium carbonate was poured into the mixture and extracted with dichloromethane (4×15 mL). Solvents were evaporated to give 2-[4-(4-dimethylaminosulfonylbenzyl)-phenyl]amino-imidazoline as a solid (320 mg).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[O:21][CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1.C=O.O.[C:30]([BH3-])#N.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:9][CH2:10][N:11]3[CH2:12][CH2:13][N:14]([CH3:30])[CH2:15][CH2:16]3)[C:4]=2[C:3]=1[O:21][CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1
Reactant: [BH3-]C#N
Reactant: Cn1c(=O)n(CCN2CCNCC2)c2c(OCC3CCC3)c(Br)ccc21
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(CCn2c(=O)n(C)c3ccc(Br)c(OCC4CCC4)c32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
A solution of 5-bromo-4-(cyclobutylmethoxy)-1-methyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one (40.0 mg, 0.0945 mmol) in tetrahydrofuran (2.0 mL) was treated with a 1.23M solution of formaldehyde in water (384 μL, 0.474 mmol). The resultant reaction mixture was stirred at RT for 30 min, followed by the addition of sodium cyanoborohydride (17.8 mg, 0.284 mmol). After stirring at RT for 2 h, the reaction mixture was quenched with acetic acid (0.5 mL) and concentrated in vacuo to give the crude product. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (38 mg, 92%). LCMS calculated for C20H30BrN4O2 (M+H)+: m/z=437.2, 439.2. found: 437.1, 439.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH:12]=[CH:11][C:10]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccco1
Reactant: C=CC(=O)OC
Product: COC(=O)C=Cc1ccc(C(=O)OC)o1
Yield: 28 %

Procedure:
The reaction was carried out in the same manner as described in Example 21 except that 25 ml of 2-(methoxycarbonyl)furan and 0.939 g of methyl acrylate were used. Unreacted 2-(methoxycarbonyl)furan was removed from the obtained reaction solution by distillation under reduced pressure. Recrystallization of the solid residue gave 0.65 g of methyl β-(5-methoxycarbonyl-2-furyl)acrylate (4) (the yield was 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH2:16][CH2:17][CH2:18]O)[C:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.S(Cl)([Cl:24])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH2:16][CH2:17][CH2:18][Cl:24])[C:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: OCCCn1c(Cc2ccccc2)nc2cc(Cl)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCCCn1c(Cc2ccccc2)nc2cc(Cl)ccc21
Reaction time: 6 h

Procedure:
To a stirred mixture of 45 parts of 5-chloro-2-(phenylmethyl)-1H-benzimidazole-1-propanol and 225 parts of trichloromethane are added dropwise 29.75 parts of sulfinyl chloride. Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated and the residue is taken up in water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The reisude is purified by columnchromatography over silica gel using a mixture of trichloromethane and methanol (98:2) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5-chloro-1-(3-chloropropyl)-2-(phenylmethyl)-1H-benzimidazole as a solid residue.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[O:15]([C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[CH:25]=[CH:26][C:27](O)=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:27](/[CH:26]=[CH:25]/[C:24]3[CH:30]=[CH:31][CH:32]=[C:22]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:23]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cccc(Oc2ccccc2)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(Oc4ccccc4)c3)nc2n(CC)c1=O
Yield: 62.9 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 4.00 g (16.7 mmol) of 3-phenoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.82 g (yield 63%) of Compound 182 as pale yellow needles.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.N1CCOCC1.C(N1C[CH2:45][N:44]2[CH2:47][CH2:48][N:49]([CH2:50][CH2:51]CC)P1N(CCCC)CC2)CCC.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([N:49]5[CH2:48][CH2:47][N:44]([CH3:45])[CH2:51][CH2:50]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CCCCN1CCN2CCN(CCCC)P1N(CCCC)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: C1COCCN1
Product: CN1CCN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (49 mg, 0.3 mmol), morpholine (130 mg, 1.44 mmol), 2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3]undecane (99 mg, 0.29 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 1 h under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 115 mg of 110 (yield=31%). 1H NMR (CDCl3, 400 MHz): δ8.12-8.10 (m, 1H), 7.58-7.52 (m, 1H), 7.15-7.05 (m, 4H), 6.55 (d, J=9.2 Hz, 1H), 4.25-4.23 (m, 2H), 3.75-3.63 (m, 5H), 3.12-3.10 (m, 2H), 2.93-2.91 (m, 4H), 2.62-2.57 (m, 3H). LC-MS (ESI): m/z=480 [M+H]+
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([OH:20])=O)=[CH:10][CH:9]=1)(=[O:7])[CH3:6]>C1(C)C=CC=CC=1>[C:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([Cl:3])=[O:20])=[CH:10][CH:9]=1)(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)c1ccc(C(=O)O)c2ccccc12
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C(=O)Cl)c2ccccc12
Temperature: 90 °C
Yield: 98.7 %

Procedure:
Thionyl chloride (35.00 g, 0.29 mol) was added to 4-acetyl-1-naphthalenecarboxylic acid (51.70 g, 0.24 mol) in toluene (350 mL). The mixture was warmed to 90° C. for 8.5 h. After cooling to 25° C., the solvent was removed under reduced pressure to give the title product as an off-white solid (55.1 g, 98.7% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:13]([F:16])([F:15])[F:14].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][N:20]=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH:12][C:23]([C:22]3[CH:21]=[N:20][C:19]([C:18]([F:29])([F:17])[F:28])=[CH:27][CH:26]=3)=[O:24])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:13]([F:14])([F:15])[F:16]
Reactant: Cn1c(C(F)(F)F)cc2cc(CN)ccc21
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc2cc(CNC(=O)c3ccc(C(F)(F)F)nc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
[(1-Methyl-2-trifluoromethylindol-5-yl)methyl]amine (Intermediate 11, 150 mg, 0.657 mmol) was dissolved in DCM (10 mL) and 6-(trifluoromethyl)nicotinoyl chloride (ABCR; 165 mg, 0.789 mmol) was added. Et3N (0.183 mL, 1.315 mmol) was added and the reaction mixture was left to stir at room temperature for 2 hrs. The reaction mixture was quenched with methanol (10 mL) and evaporated to dryness. The resulting residues were partitioned between ethyl acetate and a 1M solution of citric acid. The organic layer was collected, dried (MgSO4), filtered and the solvent removed. The resulting residues were then purified by MDAP and evaporated to dryness to give the title compound (100 mg);
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3Cl)[CH:11]=2)=[O:9])[CH2:4]1.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([NH2:30])=[CH:25][CH:24]=2>>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[NH:30][C:26]3[CH:27]=[C:28]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH3:20])=[CH:29]4)[CH:11]=2)=[O:9])[CH2:4]1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: COC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Product: COC1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)C1

Procedure:
The title compound was prepared from (3-methoxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 407 (MH+); HPLC Rf: 4.22 min.; HPLC purity 96%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[NH2:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][NH:22]2)=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>CO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:15][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[N:21][NH:22]3)=[CH:18][CH:17]=2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1Nc1ccc2cn[nH]c2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To the solution of 4-chloro-2-methylthio-5-pyrimidine carboxylic acid ethyl ester (5 g) and 6-aminoindazole (3.15 g) in methanol (70 ml) was added N,N-diisopropylethylamine (4.2 ml), and then the solution was reacted at 30-35° C. for 4 hr. The reaction mixture was cooled, and then stirred at 20° C. for 1 hr. The reaction mixture was filtered, washed with methanol (20 ml) and dried at 40-50° C. in vacuo to obtain the desired compound (5.8 g, 82%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][SH:9])[NH2:7])[CH3:3].C([O-])(=O)C.[K+].CC(C)=O.O.[CH3:21][N:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:25](=[O:32])[N:24]([C:33]2[CH:34]=[CH:35][C:36]3[S:40][N:39]=[C:38]([CH:41]=O)[C:37]=3[CH:43]=2)[C:23]1=[O:44]>CC(C)=O>[CH3:21][N:22]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][C:25](=[O:32])[N:24]([C:33]2[CH:34]=[CH:35][C:36]3[S:40][N:39]=[C:38]([C@@H:41]4[NH:7][CH:6]([C:5]([O:4][CH2:2][CH3:3])=[O:10])[CH2:8][S:9]4)[C:37]=3[CH:43]=2)[C:23]1=[O:44]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1CS[C@H](c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)N1
Reaction time: 8 h
Yield: 43.9 %

Procedure:
To a mixture of L-cysteine ethyl ester hydrochloride (0.580 g, 3.12 mmol), potassium acetate (0.300 g, 3.06 mmol) and 50% acetone-water is added dropwise a solution 5-[3,6-Dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (1.00 g, 2.81 mmol) in acetone. The resultant mixture is stirred four days at room temperature and treated with additional L-cysteine ethyl ester hydrochloride (0.580 g, 3.12 mmol) and, potassium acetate (0.300 g, 3.06 mmol). The resultant mixture is warmed to 35° C. and stirred overnight. The mixture is concentrated in vacuo and the residue is extracted with methylene chloride. The organic layer is washed with water, treated with charcoal, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with methylene chloride-ethyl acetate to afford the title compound as an off-white solid (0.600 g, 43.9%, mp 97-98° C.) which is identified by NMR spectral analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:22][CH3:23])[C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11].C([Li])CCC.[CH:29](N1CCOCC1)=[O:30].Cl>C1COCC1.C(OCC)(=O)C>[CH3:23][O:22][C:4]1[CH:3]=[C:2]([CH:19]=[C:6]([CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[C:5]=1[O:20][CH3:21])[CH:29]=[O:30]
Reactant: O=CN1CCOCC1
Reactant: COc1cc(Br)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C=O)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Reaction time: 0.25 h

Procedure:
To a solution of the 3.616 g of (5-bromo-2,3-dimethoxybenzyloxy)triisopropylsilane in 60 ml of THF there was added dropwise 3.6 ml of n-butyllithium (2.66 M, hexane solution) at −78° C. under a nitrogen atmosphere. After stirring for 15 minutes, 2 ml of N-formylmorpholine was added and the mixture was stirred at room temperature for 20 minutes. Next, 1N hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (2.605 g) as an oil.