Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13](C(C)=O)C.C([O-])([O-])=O.[K+].[K+].CI>O>[CH3:13][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:11])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: CCC(C)=O
Reactant: O=C1CCc2cc(O)c(I)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1cc2c(cc1I)C(=O)CC2

Procedure:
The product of Example 60 was added to methyl ethyl ketone (50 ml), K2CO3 (5 g) and methyl iodide (5 ml) then heated at reflux for 41/2 hrs. The reaction was cooled, H2O added, followed by an EtOAc extraction. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and evaporated. Trituration of the residue afforded the desired compound after filtration, m.p. 129°-30° C.
Reaction SMILES: [N+](C1C=CC(C[C:9]2[S:15][CH:14]3[N:11]([C:12](=[O:38])[C:13]3([CH:17](OC(=O)C)[C:18]3[S:26][C:25]4[CH2:24][CH2:23][N:22]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:21][C:20]=4[CH:19]=3)Br)[C:10]=2[C:39]([O-:41])=[O:40])=CC=1)([O-])=O.P([O-])([O-])([O-])=O>C1COCC1.C(#N)C.[Zn]>[CH2:27]([N:22]1[CH2:23][CH2:24][C:25]2[S:26][C:18](/[CH:17]=[C:13]3\[C@@H:14]4[N:11]([C:12]\3=[O:38])[C:10]([C:39]([OH:41])=[O:40])=[CH:9][S:15]4)=[CH:19][C:20]=2[CH2:21]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(=O)OC(c1cc2c(s1)CCN(Cc1ccccc1)C2)C1(Br)C(=O)N2C(C(=O)[O-])=C(Cc3ccc([N+](=O)[O-])cc3)SC21
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3cc4c(s3)CCN(Cc3ccccc3)C4)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Nitrobenzy-6-[(acetyloxy)(5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(450 mg, 0.65 mmol) was dissolved in THF (20 mL) and acetonitrile (10 mL). Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 mL). The reaction vessel was covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 hours at room temperature. The reaction mixture was filtered, cooled to 3° C., and 0.1 M NaOH was added to adjust pH to 8.5. The filtrate was washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 lits) and latter with 10% CAN: Water. The fractions containing the product were collected and concentrated at reduced pressure at room temperature. The yellow solid was washed with acetone and filtered. Dried. Yield: 50 mg, 18%; as yellow crystals; mp. 198° C.; (M+H) 411.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][N:54]1[NH:58][CH:57]=[CH:56][S:55]1>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:53][N:54]2[NH:58][CH:57]=[CH:56][S:55]2)=[O:7])=[CH:4][C:3]=1[B:11]1[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[O:15]1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: NN1NC=CS1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (2.0 g, 7.63 mmol), DIPEA (4 ml, 22.89 mmol) and HATU (3.05 g, 8.02 mmol) were dissolved in DMF (20 ml) and stirred at room temperature for 15 mins. 2-Aminothiadiazole (810 mg, 8.01 mmol) was added and the reaction stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250 ml) and hydrochloric acid (2N, 150 ml). The aqueous was extracted with ethylacetate (2×250 ml). The combined organic extracts were dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane/ethyl acetate (4:1 then 1:1). The solvent was evaporated from the product fractions under vacuum to 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (0.95 g). LCMS: retention time 3.34 min, MH− 346. NMR: δH [2H6]-DMSO 13.08, (1H, b), 9.22, (1H, s), 8.35, (1H, d), 8.11, (1H, dd), 7.38, (1H, d), 2.55, (3H, s), 1.34, (12H, s).
Reaction SMILES: [OH:1][C:2](=[C:5]1[C:10](=[O:11])[O:9][C:8]([CH3:13])([CH3:12])OC1=O)[CH2:3][CH3:4].[CH3:15]C(O)(C)C>C1C=CC=CC=1>[O:1]=[C:2]([CH2:3][CH3:4])[CH2:5][C:10]([O:9][C:8]([CH3:12])([CH3:13])[CH3:15])=[O:11]
Reactant: CC(C)(C)O
Reactant: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Solvent: c1ccccc1
Product: CCC(=O)CC(=O)OC(C)(C)C

Procedure:
A solution of 5-(1-hydroxypropylidene)-2,2 dimethyl-1,3-dioxane-4,6-dione (18.2 g, 69.4 mmol), tBuOH (19.9 ml, 208 mmol) and benzene (400 ml) was heated at reflux for 6 hours. Concentration in vacuo gave a red liquid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[N:38]O)[NH2:37])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:38]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:37]=2)=[CH:32][CH:31]=1
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccc(F)cc3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 34 mg (0.22 mmol, 1.1 eq.) of 4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 55 mg (53% of theory)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.FC(F)(F)S(O[Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])(=O)=O>C(OCC)C>[CH:18]([Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[C:2]1[O:1][CH:5]=[CH:4][N:3]=1)([CH3:20])[CH3:19]
Reactant: c1cocn1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)[Si](c1ncco1)(C(C)C)C(C)C
Temperature: -78 °C

Procedure:
Oxazole (10 g, 144.797 mmol) is dissolved in 400 mL abs. diethylether under argon. The solution is cooled to −78° C. and n-butyllithium (1.6 M solution in hexane, 100 mL, 160 mmol) is added slowly at that temperature. After stirring for 1 h triisopropylsilyl trifluoromethanesulfonate (40.265 mL, 144.797 mmol) in 100 mL abs. diethylether is added slowly. The mixture is warmed to r.t. within 12 h, and the solvent is evaporated in vacuo. The residue is treated with cyclohexane, filtered over silica gel, washed with cylcohexane/ethyl acetate 8:1, and the solvent is evaporated in vacuo. Yield: 33 g; ESI mass spectrum: [M+H]+=226; retention time HPLC: 1.428 min (HPLC method Z001_002).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[C:8](=[O:18])[NH:7]1.[H-].[Na+].I[CH3:26]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[C:8](=[O:18])[N:7]1[CH3:26]
Reactant: O=c1[nH]n(Cc2ccc(F)c(F)c2)c2ccc([N+](=O)[O-])cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a solution of 1-(3,4-difluoro-benzyl)-5-nitro-1,2-dihydro-indazol-3-one (prepared in analogy to example 80 using 3,4-difluorobenzylbromide (step A)) (0.2 g) in DMF was added NaH (0.019 g) and the solution was stirred for 1 hour. Iodomethane (0.14 g) was then added and the mixture was stirred overnight. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to afford a crude orange residue. Flash column chromatography of the crude residue over silica gel afforded the desired 1-(3,4-difluoro-benzyl)-2-methyl-5-nitro-1,2-dihydro-indazol-3-one (0.11 g) as a yellow solid. MS (ESI−): 318.1 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[H-].[Na+].Br[C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:15]=1>C1COCC1>[C:16]1([C:13]2[S:12][C:11]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)=[N:15][CH:14]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccncn1
Reactant: Brc1ncc(-c2ccccc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(-c2cnc(Nc3ccncn3)s2)cc1

Procedure:
4-aminopyrimidine (30 mg, 0.32 mmol) was dissolved in 1 mL anhydrous THF in a flame dried flask under Ar. Sodium hydride (6 mg, 60% dispersion, 0.2 mmol) was then added to the flask at room temperature. When the bubbling stopped, 2-bromo-5-phenylthiazole (50 mg, 0.21 mmol) was added and the reaction was heated to reflux overnight. The solvent was removed under reduced pressure, water was added, and the resulting precipitate filtered. The compound was then dissolved in DMSO, purified by reverse phase preparative HPLC (C18), free-based with NaHCO3 (aq.), extracted with 3×DCM, and concentrated. 1H-NMR (300 MHz, DMSO-d6) 8.87 (1H, s), 8.47 (1H, d, J=5.6), 7.88 (1H, s), 7.63 (2H, d, J=7.1), 7.42 (2H, t, J=7.8), 7.29 (1H, t, J=7.6), 7.07 (1H, d, J=6.1). MS M+1=255.3. MP>250° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20](Cl)=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][Al](C)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([CH3:35])=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Al](C)C
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)nc(Cl)nc32)CC1
Solvent: C1CCOC1
Product: Cc1nc(Oc2ccc(S(C)(=O)=O)cc2)c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Yield: 42.4 %

Procedure:
A mixture of 4-[6-chloro-4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 172; 230 mg, 0.45 mmol), trimethylaluminum (2 M in toluene; 0.5 mL, 1 mmol), and tetrakis(triphenyl-phosphine)palladium(0) (58 mg, 0.05 mmol) in tetrahydrofuran (5 mL) was heated at reflux for 2 h. The solvent was evaporated and the residue was purified by column chromatography to give 4-[4-(4-methanesulfonyl-phenoxy)-6-methyl-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (93 mg, 42%) as a white foam/solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18](N)=[O:19].Cl.C(O)(=[O:31])C>>[Cl:16][C:4]1[CH:5]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:7]=[C:2]([Cl:1])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18]([OH:31])=[O:19]
Reactant: NC(=O)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Yield: 27.8 %

Procedure:
A mixture of 13.2 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetamide, 648 parts of concentrated hydrochloric acid and 200 parts of acetic acid was stirred and refluxed for 224 hours. The resulting product was filtered off, washed with water and taken up to 100 parts of water. After treatment with a sodium hydroxide solution, the resulting solution was acidified with concentrated hydrochloric acid. The product was filtered off and purified by column chromatography over silica gel using a mixture of methylbenzene, tetrahydrofuran and acetic acid (70:30:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.8 parts (27.8%) of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetic acid; mp. 219.5° C. (intermediate 29).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][C:16]([Br:26])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.C1COCC1.[OH-].[Na+]>O>[Br:26][C:16]1[CH:17]=[C:18]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=1
Reactant: O=C(NC(=S)Nc1ncc(Br)cc1Oc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A 2 L flask was charged with 1-benzoyl-3-(5-bromo-3-phenoxypyridin-2-yl)thiourea (94.3 g, 220 mmol) and THF (900 mL). 2M NaOH (330 mL, 660 mmol) was added and the reaction was heated at reflux overnight. The reaction was cooled to ambient temperature and 300 mL water was added slowly and then the THF was removed in vacuo to afford an aqueous slurry which was filtered, washed with water and dried to give 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea (66.35 g, 93% yield) as a light tan solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][C:10](=[CH2:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4]>C(O)C.[Pd]>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4]
Reactant: C=C1CN(C(=O)C(F)(F)F)C(C)Cc2cc(OC)ccc21
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)CC(C)N(C(=O)C(F)(F)F)CC2C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-4-methyl-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine (1.39 g, 4.64 mmol) in ethanol (40 mL) was treated with 10% Pd/C (0.49 g, 0.46 mmol) and stirred overnight under an atmosphere of hydrogen. The product mixture was filtered through a pad of celite and silica and then concentrated. Flash chromatography (20% EtOAc in hexane, silica) resulted in 0.77 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.06 (m, 1H), 6.71 (m, 1H), 6.63 (m, 1H), 4.38 (bm, 1H), 3.8 (s, 3H), 3.6 (m, 1H), 3.25 (m, 1H), 3.18 (bm, 2H), 2.72 (m, 1H), 1.34 (m, 3H) 1.22 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(c2cc(Br)cc(C(C)(C)C)c2OC)CC1
Yield: 75 %

Procedure:
1-[5-Bromo-3-(tert-butyl)-2-methoxyphenyl]piperazine (750 mg), potassium carbonate (411 mg) and ethyl bromoacetate (0.27 ml) were stirred in dimethylformamide (4 ml) at room temperature for one day. The reaction mixture was diluted with ethyl acetate, the insoluble portion was filtered off and then the concentrated residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (715 mg) as a light red oil (75%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:13]=[CH:14][C:8]2[S:7][C:6]([N:5]=[C:1]=[O:2])=[N:10][C:9]=2[CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nc2cc(C(F)(F)F)ccc2s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2cc(C(F)(F)F)ccc2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-5-trifluoromethylbenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about one hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 5-trifluoromethylbenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: [C:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13](I)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8](I)[CH:9]=2)(=[O:3])[CH3:2].[C:19]1([SiH:25]([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>CN1CCCC1=O>[C:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([Si:25]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([Si:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:9]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)n1c2ccc(I)cc2c2cc(I)ccc21
Reactant: c1ccc([SiH](c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: CC(=O)n1c2ccc([Si](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c2cc([Si](c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 12.5 %

Procedure:
9-Acetyl-3,6-diiodocarbazole (10.0 g) and triphenylsilane (12.4 g) were dry N-methylpyrrolidone (200 mL), followed by bubbling with argon gas for 30 min. Tripotassium phosphate (27.6 g) and bis(tri-t-butylphosphine)palladium (0.111 g) were added thereto, and the mixture was stirred at room temperature for 19 hours. The obtained reaction mixture was filtrated, and the filtrate was extracted with methylene chloride. The separated organic layer was washed with brine and dried, and the methylene chloride was evaporated. The residue was treated through silica gel column chromatography (eluent: toluene), to thereby obtain 1.97 g of 9-acetyl-3,6-bis(triphenylsilyl)carbazole as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:68])([F:67])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[CH2:65][NH2:66]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:66][CH2:65][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=3[C:58]([F:57])([F:67])[F:68])=[O:20])=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)O
Reactant: NCc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)NCc1ccccc1C(F)(F)F
Yield: 17.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoic acid (Intermediate-15, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropyl ethyl amine (1.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[2-(trifluoromethyl)phenyl]methanamine (0.072 g, 0.410 mmol) to afford 0.025 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.96 (s, 3H), 4.70 (d, J=4.8 Hz, 2H), 7.45-7.50 (m, 3H), 7.57 (t, J=8.4 Hz, 2H), 7.67 (t, J=8.7 Hz, 2H), 7.71 (d, J=9.3 Hz, 2H), 7.92 (d, J=8.4 Hz, 1H), 8.80 (t, 1H), 12.77 (br s, 1H); MS (m/z): 519.43 (M−H)−.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:8]=1[NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].[C:21](=[O:23])=[O:22].[OH-].[Na+]>CCCCCC.O1CCCC1>[C:16]([C:15]1[O:20][C:9]2[C:10]([C:21]([OH:23])=[O:22])=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=2[N:14]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1nc2c(Cl)ccc(C(=O)O)c2o1
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
n-Butyl lithium (101.6 ml of a 2.5M solution in hexane) was added during 30 minutes to a stirred solution of 2,5-dichloro-1-(trimethylacetylamino)benzene (25.0 g) in dry tetrahydrofuran at -40° C. and the solution stirred at -20° C. for 1.5 hours and poured onto solid carbon dioxide in dry tetrahydrofuran. The mixture was allowed to reach room temperature, 2M sodium hydroxide solution added and extracted with ethylacetate. The aqueous solution was acidified (concentrated hydrochloric acid) and the precipitated solid collected and dried to give 2-t-butyl-4-chlorobenzoxazole-7-carboxylic acid (1 1.7 g) m.p. 209°-210° C.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4]([C:10]([OH:12])=O)=[N:3][CH:2]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:10]([C:4]2[C:5]3[S:9][CH:8]=[CH:7][C:6]=3[N:1]=[CH:2][N:3]=2)=[O:12])=[CH:22][CH:23]=1)([O-:15])=[O:14]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ncnc2ccsc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc([N+](=O)[O-])cc1)c1ncnc2ccsc12

Procedure:
To a solution of compound 7.2 (1.0 mmol) and 4-nitrobenzyl amine (1.0 mmol) in dichloromethane (5.0 mL) is added TEA (3.0 equivalents) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (“HATU”; 1.1 equivalents). After completion of the reaction, the reaction is partitioned between EtOAc and water. The organic layer is separated, washed with 0.5 N HCl, saturated sodium bicarbonate, brine and dried. Purification by flash column chromatography on silica gel provides thieno[3,2-d]pyrimidine-4-carboxylic acid 4-nitro-benzylamide (compound 7.3).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][N:17]([CH3:32])[CH2:18][CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][C:22]=1[CH:30]=O>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:30][C:22]1[NH:23][C:24]2[C:29]([C:21]=1[CH2:20][CH2:19][CH2:18][N:17]([CH3:32])[CH3:16])=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CN(C)CCCc1c(C=O)[nH]c2ccccc12
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]c3ccccc3c1CCCN(C)C)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (98 mg, 0.43 mmol) was condensed with 3-(3-dimethylamino-propyl)-1H-indole-2-carbaldehyde (100 mg) to give the title compound as an orange solid.