Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].O=C1C2C(=CC=CC=2)C(=O)[N:5]1[CH2:14][CH2:15][S:16][CH2:17][C:18]1[O:22][C:21]([C:23](OC)=[O:24])=[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:19]=1.C[O-].[Na+].[ClH:36]>CO>[ClH:36].[NH2:5][CH2:14][CH2:15][S:16][CH2:17][C:18]1[O:22][C:21]([C:23]([NH:2][CH3:1])=[O:24])=[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:19]=1
Reactant: COC(=O)c1oc(CSCCN2C(=O)c3ccccc3C2=O)cc1-c1ccccc1
Reactant: CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(=O)c1oc(CSCCN)cc1-c1ccccc1

Procedure:
Gaseous methylamine was passed into a solution of 5-[[2-(1,3-dioxo-2H-isoindol-2-yl)ethyl]thio]methyl-3-phenyl-2-furancarboxylic acid, methyl ester (4 g) and sodium methoxide (0.01 g) in dry methanol (50 ml). After 4 hours 2 M hydrochloric acid (100 ml) was added and the solution was extracted with diethyl ether (200 ml). The aqueous fraction was basified with 5 M sodium hydroxide (40 ml) and extracted with chloroform (200 ml). The chloroform extract was mixed with 2 M hydrochloric acid (100 ml) and the resulting solid was collected by filtration affording the title compound (1.6 g) as yellow needles. m.p. 189°-190°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29][CH2:28]4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2cccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(Cc2cccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
21A (52 mg, 0.089 mmoL) was dissolved in a mixture of TFA/DCM (2 ml/2 ml) and stirred at rt for 10 min, then concentrated. The residue was purified by prep HPLC to give 21B (38 mg, 88%). It has an analytical HPLC retention time=1.93 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=482+.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[C:5]([O:9][C:10](=[O:18])[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6]>C(N(CC)CC)C.C(O)C>[C:5]([O:9][C:10](=[O:18])[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:3][CH2:2][C:1]#[N:4])[CH2:14][CH2:13]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: C=CC#N
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Acrylonitrile (3.6 ml, 55.0 mmol) and triethylamine (2 drops) were added sequentially to a solution of piperidin-4-yl-carbamic acid tert-butyl ester (10 g, 50.0 mmol) in ethanol (100 ml) at 25° C. The reaction mixture was stirred at 25° C. for 3.5 h, then was concentrated under reduced pressure to afford crude [1-(2-cyano-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a white solid. TLC: 5% CH3OH in CH2Cl2, Rf=0.56; 1H NMR (400 MHz, CDCl3) δ 4.42 (s, 1H), 3.45 (s, 1H), 2.82 (d, J=11.8 Hz, 2H), 2.67 (t, J=7.0 Hz, 2H), 2.49 (t, J=7.0 Hz, 2H), 2.18 (td, J=11.5, 2.3 Hz, 2H), 1.94 (d, J=12.1 Hz, 3H), 1.51-1.36 (m, 1H), 1.44 (s, 9H). This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][C:34]1([C:38]([F:41])([F:40])[F:39])[CH2:37][CH2:36][CH2:35]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([C:38]([F:41])([F:40])[F:39])[CH2:37][CH2:36][CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: O=S(=O)(OCC1(C(F)(F)F)CCC1)C(F)(F)F
Product: COc1cn(C(CC2(C(F)(F)F)CCC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
383 mg (1.02 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.23 ml (1.23 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 780 mg (purity 60%, 1.64 mmol, 1.6 eq.) of [1-(trifluoromethyl)cyclobutyl]methyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 119 mg (purity 91%, 21% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.[H][H]>CCO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reaction time: 2 h
Yield: 98.9 %

Procedure:
250 g of 2-nitro-4-trifluoromethylbenzoic acid (1.06 mol) were dissolved in 1 l of EtOH and 7.5 g of Pd/C (5%) were added. The mixture was hydrogenated under 1-2.5 bar of hydrogen pressure. During the hydrogen uptake, the temperature rose temporarily from 10° C. to 104° C. After 2 h, the hydrogen uptake was complete. Subsequently, the catalyst was filtered off and the solvent was removed under reduced pressure to obtain 215 g (99%) of a pale yellow solid, mp 174-176° C.
Reaction SMILES: Br[C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:18])[N:15]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[C:7]([N:6]1[C:2]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[C:3]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:18])[N:15]=2)[CH:4]=[N:5]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc(Cl)cc1
Yield: 38 %

Procedure:
A mixed solution of 2-[2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl]-N-[(tetrahydro-2H-pyran-4-yl)methyl]acetamide (44.1 mg, 100 μmol), 4-chlorophenylboronic acid (15.6 mg, 100 μmol), potassium carbonate (27.6 mg, 200 μmol) and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (7.08 mg, 10.00 μmol) in 1,2-dimethoxyethane (0.5 mL) and water (0.5 mL) was stirred at 150° C. for 30 min under ultrasonic irradiation. To the reaction solution was added water (1 mL), the mixture was extracted with ethyl acetate (2 mL), and the organic layer was concentrated. The residue was purified by preparative HPLC to give the title compound (17.9 mg, 0.038 mmol, 38%).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5](S(C(F)(F)F)(=O)=O)[CH:4]=1)#[N:2].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl-].[Li+].[C:36]1([C:42]#[C:43][Sn](CCCC)(CCCC)CCCC)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN1C(=O)CCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([C:43]#[C:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(C=O)c(C#Cc2ccccc2)c1

Procedure:
A mixture of 4-cyano-2-trifluoromethylsulphonyl-benzaldehyde (1.75 g, 6.3 mmol), tris(dibenzylidenacetone)dipalladium(o) (116 mg, 0.13 mmol), tris(2-furyl)phosphine (234 mg, 1.0 mmol) and anhydrous lithium chloride (0.8 g, 18.9 mmol) in dry N-methyl pyrrolidinone (18 ml) were reacted with (phenylethynyl)tri-n-butyltin (2.91 g, 7.4 mmol) for 3 hours at 50° C. and worked up following the procedure described in Example 15 (i). The crude oil was chromatographed on flash silica eluting with hexane-diethyl ether (4:1) to give 4-cyano-2-(2-phenylethynyl)benzaldehyde as a yellow solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28](O)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CCCCC(=O)O
Agent: Cl
Product: CCCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (91 mg, 88%), MS (ISP) m/z=415.5 [(M+H)+], mp 168° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and pentanoic acid.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH:17]=[CH:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.C(O)(=O)C>[Pd].C(O)C>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([NH:25][C@H:26]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:24])=[CH:39][CH:40]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=Cc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A suspension of diethyl N-(4-(2-(1.2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)vinyl)benzoyl)-L-glutamate (0.16 g, 0.29 mmol) and palladium on carbon (0.10 g) in ethanol (100 ml) was shaken under hydrogen (40 psi) overnight. Ethanol (80 ml) and acetic acid (20 ml) were added and the mixture was hydrogenated (40 psi) for 1 day. The solution was filtered, concentrated in vacuo, and the residue and catalyst were recombined in acetic acid (40 ml) and hydrogenated over the weekend. The solution was filtered, concentrated in vacuo and the product twice filtered from a small volume of methanol to give diethyl N-(4-(2-(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)ethyl)benzoyl)-L-glutamate (0.10 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.16 (t, J=7 Hz, 3H, ester CH3), 1.19 (t, J=7 Hz, 3H, ester CH3), 1.90-2.18 (m, 2H, gluCH2), 2.43 (s, 3H, C3 -CH3), 2.44 (t, J=7.5 Hz, 2H, gluCH2), 3.03-3.22 (m, 4H, ArCH2 's), 4.04 (q, J=7 Hz, 2H, ester CH2), 4.10 (q, J=7 Hz, 2H, ester CH2), 4.37-4.47 (m, 1H, gluCH), 7.40 (d, J=8 Hz, 2H, Ar), 7.54 (dd, J=8, 1.5 Hz, 1H, Ar), 7.57 (d, J=8.5 Hz, 1H, Ar), 7.80 (d, J=8 Hz, 2H, Ar), 7.95 (d, J=8 Hz, 1H, Ar), 8.20 (d, J=9 Hz, 1H, Ar), 8.65 (d, J=7.5 Hz, 1H, gluNH), 9.72 (s, 1H, Ar), 12.51 (br s, 1H, N2H). Mass spectrum (CI-CH4): 544 (M+1, 4.2%). Anal. Calculated for C31H33N3O6.1/10 H2O: C, 68.27; H, 614; N, 7.70. Found: C, 68.34; H, 6.10; N, 7.68.
Reaction SMILES: O[C:2]([C:15]1[C:16](=[O:52])[NH:17][C:18](=[O:51])[N:19]([CH:50]=1)[C@@H:20]1[O:49][C@H:39]([CH2:40][O:41][Si](C(C)(C)C)(C)C)[C@@H:30]([O:31][Si](C(C)(C)C)(C)C)[C@H:21]1[O:22][Si](C(C)(C)C)(C)C)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl.C([SiH](CC)CC)C>[C:9]1([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:15]2[C:16](=[O:52])[NH:17][C:18](=[O:51])[N:19]([CH:50]=2)[C@@H:20]2[O:49][C@H:39]([CH2:40][OH:41])[C@@H:30]([OH:31])[C@H:21]2[OH:22])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(O)(c3ccccc3)c3ccccc3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1C(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 84.2 %

Procedure:
The product of step (i) (8.9 g) was dissolved in dichloromethane (100 ml) and triethylsilane (2 ml). Trifluoroacetic acid (8.9 ml) was added dropwise over 5 minutes and the mixture was stirred for a further 20 minutes. The volatiles were removed under reduced pressure and any residual traces were removed by addition of toluene (50 ml) and evaporation under reduced pressure (three times). The residual gum was treated with tetra-n-butylammonium fluoride (35 ml of a 1M solution in tetrahydrofuran) for 1 hour at room temperature. The volatiles were removed under reduced pressure and the gummy residue purified by silica-gel chromatography eluting with chloroform-methanol mixtures to give 5-diphenylmethyluridine as a white solid (4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[O:16])[O:10][C:9]2=[O:23])=[CH:4][CH:3]=1.[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].C(N(CC)CC)C>O1CCCC1>[Cl:22][C:19]1[S:18][C:17]([C:15]([NH:14][CH2:13][C@@H:11]2[O:10][C:9](=[O:23])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][Cl:24])=[CH:3][CH:4]=3)[CH2:12]2)=[O:16])=[CH:21][CH:20]=1
Reactant: O=C(Cl)CCCCCl
Reactant: Nc1ccc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCCCl)Nc1ccc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc1

Procedure:
0.5 g (1.29 mmol) of N-{[(5S)-3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxamide (from Example 149) is dissolved in 27 ml of tetrahydrofuran and admixed with 0.2 g (1.29 mmol) of 5-chlorovaleryl chloride and 0.395 ml (2.83 mmol) of triethylamine. The mixture is concentrated under reduced pressure and chromatographed over silica gel using a toluene/ethyl acetate=1:1-> ethyl acetate gradient. This gives 315 mg (52% of theory) of a solid.
Reaction SMILES: [OH-].[K+].O.[C:4]([OH:13])(=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[SH:7].I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.C1C=CC=CC=1>[C:15]1([S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:4]([OH:13])=[O:12])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1S
Reactant: Ic1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)c1ccccc1Sc1ccccc1
Reaction time: 18 h
Yield: 82.5 %

Procedure:
5.6 g (0.10 mol) potassium hydroxide, 7 ml water, 30 ml benzene and 7.7 g (0.05 mol) thiosalicyclic acid were combined and heated at reflux under a Dean Stark trap. After the water had been collected, 50 ml of dimethylformamide was added and the mixture slowly heated to 140°-150° C. to remove the benzene. An additional 10 ml of dimethylformamide and 0.25 g (1.75 mmol) of cuprous oxide were then added. 5.8 ml (0.051 mol) of iodobenzene was slowly added over a period of 20 minutes while the temperature was maintained at 140°-150° C. The reaction mixture gradually became a solution and gentle reflux was continued for 18 hours. The mixture was then cooled and poured over ice. The pH was adjusted to 10.0 and precipitated solids removed by filtration. The filtrate was washed with two portions of ethyl acetate (the organics were discarded) and adjusted to pH 2.5 with 1N HCl. A precipitate formed which was collected by filtration and then recrystallized from aqueous isopropanol to yield 9.5 g (83%) of the title compound.
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:3].C=[O:20]>>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:2]([OH:20])=[O:3])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=O
Reactant: O=C(Cl)CCCCCC(=O)OCc1ccccc1
Product: O=C(O)CCCCCC(=O)OCc1ccccc1
Temperature: 120 °C

Procedure:
Pimelic acid monobenzyl ester was prepared according to an adaptation of the method of Hassner et al, Tetrahedron Letters No. 46, 4475 (1970); it boils at 205° C. (1.5 torr). This material was converted to benzyl 6-chloroformylcaproate according to the above methods and 5.25 g of the latter compound was stirred with 0.59 g of paraformaldehyde and several mg of fused zinc chloride and heated to 120° C. in an oil bath. After the paraformaldehyde was consumed (about 11/2 hrs), the mixture was cooled, giving 5.73 g of multi-component product. Purification of 3.85 g of this crude product was achieved on a 180 g (2.9×61 cm) column of Silica Gel 60, prepared in a solvent of toluene/chloroform 9:1. The column was run at the flow rate of 1.8 ml/min. and 20 ml fractions were collected. The column was eluted first with 3 liters of toluene/chloroform 9:1, secondly with 3 liters of a 8.5:1.5 mixture of these solvents and finally with 1 liter of toluene containing 15% of chloroform and 7.5% of ethyl acetate. The various fractions were analyzed and combined where appropriate to produce 1.00 g of an oil identified as benzyl chloromethyl pimelate; ir 1765 and 1735 cm-1 ; pmr δ 7.34, 5.68, 5.11, 2.25-2.50 and 1.1-1.9 ppm.
Reaction SMILES: C([OH:3])C.[OH-].[Na+:5].[OH:6][C:7]1[N:12]2[N:13]=[CH:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:23])=[C:18]([O:30][CH3:31])[CH:17]=3)=[C:11]2[N:10]=[CH:9][N:8]=1>O>[OH2:3].[OH2:6].[CH3:31][O:30][C:18]1[CH:17]=[C:16]([C:15]2[CH:14]=[N:13][N:12]3[C:7]([O-:6])=[N:8][CH:9]=[N:10][C:11]=23)[CH:21]=[CH:20][C:19]=1[S:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:23].[Na+:5]
Reactant: CCO
Reactant: COc1cc(-c2cnn3c(O)ncnc23)ccc1S(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(-c2cnn3c([O-])ncnc23)ccc1S(=O)c1ccccc1

Procedure:
In a mixed solution prepared from 50 ml of ethanol, 10 ml of water and 145 mg of sodium hydroxide were dissolved 1.3 g of (-)-4-hydroxy-8-(3-methoxy-4-phenylsulfinylphenyl)pyrazolo[1,5-a]-1,3,5-triazine with stirring and the solvent was then distilled off under reduced pressure. After addition of 100 ml of ethyl acetate, the mixture was refluxed for 30 minutes. After cooling, the crystals were recovered by filtration and dried to give sodium (-)-8-(3-methoxy-4-phenylsulfinylphenyl)pyrazolo[1,5-a]-1,3,5-triazine-4-olate dihydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=S)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][C:13]([CH2:16][CH3:17])([CH3:14])[CH3:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC(C)(C)NC(=S)Nc1cc(Cl)cc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(C)(C)N=C=Nc1cc(Cl)cc(Cl)c1
Reaction time: 3 h

Procedure:
To a solution of 3.0 g of N-(3,5-dichlorophenyl)-N'-t-pentylthiourea produced in Example A-2 in 25 ml of THF were added 2.44 g of DCC and 0.36 g of triethylamine. The mixture was relfuxed for 3 hours and evaporated in vacuo. The residue was extracted with petroleum ether. The extract was evaporated in vacuo to give N-(3,5-dichlorophenyl)-N'-t-pentylcarbodiimide as an oil. To a solution of this oil in 30 ml of THF were added 1.0 g of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was refluxed for 40 hours and evaporated in vacuo. The residue was recrytallized from diisopropyl ether-ethyl acetate mixture to give 1.9 g of the title compound as colorless needles melting at 151.0°-153.0° C.
Reaction SMILES: CNC.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[C:12]([N:14]3[CH2:19]COC[CH2:15]3)[N:13]=2)[CH:10]=1>>[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[C:12]([N:14]([CH3:19])[CH3:15])[N:13]=2)[CH:10]=1
Reactant: Brc1ccc2nc(N3CCOCC3)nn2c1
Agent: CNC
Product: CN(C)c1nc2ccc(Br)cn2n1

Procedure:
Using dimethylamine, this compound was prepared following the same method as for the synthesis of 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridine White solid (0.65 g, 75%). MS: m/z=242 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:27]([O:13][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[C:3]([C:1]#[N:2])[CH:12]=2)[NH:7][C:8](=[O:15])[C:9]1=[O:14])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2OC(=O)c1ccccc1
Yield: 97.2 %

Procedure:
A solution of 0.4 g (1.48 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in 50 ml dry tetrahydrofuran was added 0.2 ml (1.45 mmol) dry triethylamine and 0.175 ml (1.50 mmol) benzoyl chloride. The mixture was refluxed for 30 min., and then evaporated in vacuo. The residue was stirred with water to give 0.54 g (98%) of 1-benzoyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione. M.p. 186° C. 1H-NMR (DMSO-d6): 8.47 (1H, s), 8.2 (2H, m), 7.8 (4H, m).
Reaction SMILES: C[S:2]([C:4]1[CH:9]=[C:8]([C:10]2[S:14][C:13](CCC)=[CH:12][CH:11]=2)[C:7]([S:18](C)=O)=[CH:6][C:5]=1[C:21]1[S:25][C:24](CCC)=[CH:23][CH:22]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.FC(F)(F)S(O)(=O)=O>>[S:14]1[C:10]2[C:8]3[CH:9]=[C:4]4[S:2][C:22]5[CH:23]=[CH:24][S:25][C:21]=5[C:5]4=[CH:6][C:7]=3[S:18][C:11]=2[CH:12]=[CH:13]1
Reactant: CCCc1ccc(-c2cc(S(C)=O)c(-c3ccc(CCC)s3)cc2S(C)=O)s1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)C(F)(F)F
Product: c1cc2sc3cc4c(cc3c2s1)sc1ccsc14
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A round bottomed flask was filled with 5,5′-(2,5-bis(methylsulfinyl)-1,4-phenylene)bis(2-propylthiophene) (2c) (1.0 g, 2.2 mmol), phosphorus pentoxide (0.1 g, 0.703 mmol) and trifluoromethanesulfonic acid (20 ml). The mixture was stirred for 72 h at room temperature to give a dark brown solution, which was then poured into ice-water (120 ml). The yellow precipitate was collected by suction filtration and dried under vacuum. The structure of this compound, which was insoluble in apolar organic solvents, was assumed to be the sulfonium salt. Demethylation of the solid was achieved by refluxing it in pyridine (167 ml) for 12 h. When the suspension was cooled to room temperature, a large volume of CH2Cl2 was added to extract the product. Dithieno[2,3-d:2′,3′-d′]benzo[1,2-b:4,5-b′]dithiophene (1c) was thus obtained as off-white powder by hexane as an eluent and recrystalised in dichloromethane (370 mg, 43%).