Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55](O)=[O:56])=[O:40])([CH3:37])([CH3:36])[CH3:35].[Cl:58][C:59]1[N:63]([CH3:64])[N:62]=[CH:61][C:60]=1[NH2:65].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:58][C:59]1[N:63]([CH3:64])[N:62]=[CH:61][C:60]=1[NH:65][C:55]([C:43]1[N:44]=[C:45]([C:47]2[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=2[F:53])[S:46][C:42]=1[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:56]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A solution of PyBOP (4.08 g, 7.84 mmol) and 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (2.20 g, 6.16 mmol) in DCM (50 mL) was stirred at room temperature for 30 min. A solution of 5-chloro-1-methyl-1H-pyrazol-4-amine (737 mg, 5.60 mmol) and DIPEA (1.6 mL, 9.0 mmol) in DCM (50 mL) was then added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM (50 mL) and washed with water (3×50 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-100% EtOAc/isohexane) followed by trituration with MeCN gave tert-butyl 4-(5-chloro-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate as an off-white solid (1.71 g, 65%). 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 8.73 (s, 1H), 8.06 (s, 1H), 7.42-7.33 (m, 1H), 7.09-7.01 (m, 2H), 3.87 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: C(O[C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)=O.[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:16]1([S:13]([N:6]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[C:4]([N:25]3[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]3)=[CH:5]2)(=[O:15])=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=COc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Into a 150 mL sealed tube was placed 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl formate (1.5 g, 4.97 mmol). To this was added tert-butyl piperazine-1-carboxylate (9.24 g, 49.68 mmol). Addition of p-toluenesulfonic acid (171 mg, 0.99 mmol) was next. To the mixture was added toluene (70 mL). After nitrogen bubbled, the resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 120° C. in a bath of oil. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The residue was dissolved in 300 mL of ethyl acetate. The resulting mixture was washed 2 times with 150 mL of brine. The mixture was dried over Na2SO4. The residue was purified by eluting through a column with a 1:2 ethyl acetate/petroleum ether solvent system. This resulted in 420 mg (18%) of tert-butyl 4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16]C2C=CC=CC=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:54][OH:55])CO)C1C=CC=CC=1.F[C:57](F)(F)[C:58](O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:58]2[CH:57]=[CH:54][CH:10]=[CH:9][CH:14]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:11][C@@:10]1([CH2:54][OH:55])[CH2:32][O:31]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Reaction time: 4 h
Yield: 104.3 %

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 3m (1.0 g, 1.29 mmol) was dissolved in 10 mL dichloromethane, followed by addition of trifluoroacetic acid (0.19 mL, 2.58 mmol). The reaction mixture was stirred for 4 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 3n (500 mg, yellow grease), yield: 52.1%. MS m/z (ESI): 760.3 [M+18]. 1H NMR (400 MHz, CD3OD): δ 7.37-7.30 (m, 13H), 7.23-7.18 (m, 3H), 6.91-6.89 (m, 2H), 6.68 (dd, 1H), 6.55 (dd, 1H), 4.93-4.90 (m, 2H), 4.79-4.56 (m, 4H), 4.30-4.28 (m, 2H), 4.18-4.05 (m, 4H), 3.83-3.49 (m, 5H), 1.33 (t, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[O:24][C:23]2[CH:25]=[C:26]([F:37])[C:27]([C:29]([N:31]3[CH2:36][CH2:35][S:34][CH2:33][CH2:32]3)=[O:30])=[CH:28][C:22]=2[O:21]1>ClCCl>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[O:24][C:23]2[CH:25]=[C:26]([F:37])[C:27]([C:29]([N:31]3[CH2:36][CH2:35][S:34](=[O:9])[CH2:33][CH2:32]3)=[O:30])=[CH:28][C:22]=2[O:21]1
Reactant: O=C(c1cc2c(cc1F)OC(c1ccc(F)cc1)(c1ccc(Cl)cc1Cl)O2)N1CCSCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(c1cc2c(cc1F)OC(c1ccc(F)cc1)(c1ccc(Cl)cc1Cl)O2)N1CCS(=O)CC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A solution of m-chloroperbenzoic acid (74 mg, 0.3 mmol) in dichloromethane (1.2 mL) was added to a cooled (−20° C.) solution of [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone (Example 136) (153 mg, 0.3 mmol) in dichloromethane (1.7 mL). The reaction mixture was stirred at −20° C. for 3 h, quenched with 5% aqueous sodium thiosulfate solution. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 10% sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and the volatiles were removed under vacuo. Purification by flash chromatography afforded the title product as a white foam (141 mg, 89%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[C:32]2[CH:33]=[C:34]([NH2:37])[CH:35]=[CH:36][C:31]=2[N:30]=[CH:29]1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:37][C:34]4[CH:35]=[CH:36][C:31]5[N:30]=[CH:29][N:28]([CH3:27])[C:32]=5[CH:33]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cnc2ccc(N)cc21
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Product: Cn1cnc2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)cc21

Procedure:
Following the synthetic and purification procedures described in Example 1293d, N-tert-butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (103 mg, 0.262 mmol) was coupled with 3-methyl-3H-benzimidazol-5-ylamine (66 mg, 0.45 mmol) at 105° C. for 120 h to afford the title compound. Yield of TFA salt: 78 mg (50%) of brown powder; LC/MS: 476 (M+H); HPLC: 97% pure, RT=2.64 min; 1H NMR: (DMSO, δ) 10.04 (s, 1H), 9.38 (s, 1H), 9.12 (s, 1H), 8.49 (s, 1H), 8.41 (d, J=8.0, 1H), 8.31 (s, 1H), 7.87 (d, J=8.0, 1H), 7.79 (m, 3H), 7.61 (s, 1H), 7.24 (d, J=4.9, 1H), 7.07 (d, J=4.9, 1H), 3.81 (s, 3H), 1.08 (s, 9H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([O:18][CH3:19])[C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:11]=2[Cl:13])[CH:6]=[CH:5]1)(=[O:3])[CH3:2].C(O)(=O)C>[Pt].CO>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([O:18][CH3:19])[C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:11]=2[Cl:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)c2c(ccn2C(C)=O)c1OC
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Cl)c2c(c1OC)CCN2C(C)=O
Reaction time: 48 h

Procedure:
The mixture of the indole of step 8 above (0.9 g) and Pt-C (0.2 g), acetic acid and MeOH (100 ml) is stirred under H2 at 1 atm. pressure for 48 hours. The catalyst is filtered (celite), the filtered material is washed (MeOH) and the reaction mixture and methanol washings are evaporated. The residue is diluted with CH2Cl2, washed with saturated NaHCO3, dried (MgSO4) and evaporated affording a colorless, semicrystalline material which is determined to be the desired compound by NMR. M.P. 107°-109° C.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:41])=[C:11]([CH3:40])[C:12]=1[C:13]([C:15]1[CH:34]=[CH:33][C:18]([O:19][S:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([OH:32])[CH:24]=2)(=[O:22])=[O:21])=[C:17]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Mg+2].[I-].[C:45](OC(=O)C)(=[O:47])[CH3:46]>CCOCC>[C:45]([O:32][C:25]1[CH:24]=[C:23]([S:20]([O:19][C:18]2[CH:33]=[CH:34][C:15]([C:13]([C:12]3[C:11]([CH3:40])=[C:10]([CH3:41])[S:9][C:8]=3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:14])=[CH:16][C:17]=2[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:22])=[O:21])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])(=[O:47])[CH3:46]
Reactant: Cc1sc(Cc2ccccc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Reactant: CC(=O)OC(C)=O
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(C(=O)c3c(Cc4ccccc4)sc(C)c3C)cc2C2CCCC2)ccc1C(=O)O
Yield: 51 %

Procedure:
The title compound was prepared according to the procedure in Example 22 using 4-[4-(2-benzyl-4,5-dimethyl-thiophene-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoic acid (0.233 g, 0.394 mmol), magnesium iodide (0.110 g, 0.394 mmol) and acetic anhydride (3.3 mL) in ether. Purification on 2% H3PO4 /MeOH treated silica gel, eluting with 18% EtOAc/pet ether followed by a second chromatography on 2% H3PO4 /MeOH treated silica gel, eluting with 5% CH3CN/CH2Cl2 gave 0.128 g (51%) of the title compound as a white solid, mp 94-96° C. 1H NMR (DMSO-d6) δ 1.24-1.33 (m, 2 H), 1.52-1.57 (m, 2 H), 1.61-1.76 (m, 4 H), 1.79 (s, 3 H), 2.23 (s, 3 H), 2.26 (s, 3 H), 2.94 (quintet, 1 H), 3.85 (s, 2 H), 6.99-7.01 (m, 2 H), 7.13 (m, 4 H), 7.52 (dd, 1 H), 7.59 (d, 1 H), 7.84 (d, 1 H), 7.90 (dd, 1 H), 8.14 (d, 1 H), 13.8 (br s, 1 H). mass spectrum (-ESI) m/z 631 (M-H). Anal. Calcd. for C34H32O8S2.0.2H2O: C, 64.17; H, 5.13; N, 0.00. Found: C, 64.06; H, 4.98; N, 0.04.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:15]=[C:14]([N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:12]=1)C(=O)OC(C)(C)C.C(OCC)(=O)C.[ClH:36]>C(OCC)(=O)C.CO>[ClH:36].[CH3:23][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]1[N:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:12]=[C:11]([CH2:10][NH:2][CH3:1])[CH:15]=1
Reactant: CN(Cc1cc(N(C)c2ccccc2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCc1cc(N(C)c2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
tert-Butyl methyl({5-[methyl(phenyl)amino]-1-phenyl-1H-pyrazol-3-yl}methyl)carbamate (67 mg) was dissolved in ethyl acetate (1 mL) and methanol (0.5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from a mixed solvent of ethyl acetate and hexane, and recrystallized from a mixed solvent of ethyl acetate and ethanol to give the title compound as colorless crystals (yield 25 mg, yield 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.[Cl:16][C:17]1([Cl:23])[CH2:19][CH:18]1[C:20](Cl)=[O:21]>O1CCCC1>[Cl:16][C:17]1([Cl:23])[CH2:19][CH:18]1[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:6][CH:7]=1)=[O:21]
Reactant: O=C(Cl)C1CC1(Cl)Cl
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Solvent: C1CCOC1
Product: O=C1NN=C(c2ccc(NC(=O)C3CC3(Cl)Cl)cc2)C2CC12
Yield: 48.9 %

Procedure:
5.0 g (24.8 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one, 5.2 g (30.0 millimoles) of 2,2-dichlorocyclopropanecarboxylic acid chloride and 100 ml of absolute tetrahydrofuran are refluxed for 6 hours. The product is filtered off at 10° C., washed with water and recrystallized from a dimethylformamide/water mixture. 4.1 g (49% of theory) of 2-[p-(2,2-dichlorocyclopropylcarbonylamino)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as colorless crystals, of melting point 264°-265° C.
Reaction SMILES: [C:1]1([C:11]2[NH:12][C:13]3[C:18]([N:19]=2)=[C:17]([O:20][C@H:21]2[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22]2)[N:16]=[CH:15][N:14]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[S:29]([NH2:32])(=[O:31])=[O:30]>CC(N(C)C)=O.CC#N>[S:29](=[O:31])(=[O:30])([O:27][CH2:26][C@H:23]1[CH2:24][CH2:25][C@H:21]([O:20][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[C:18]=2[N:19]=[C:11]([C:1]2[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=2)[NH:12]3)[CH2:22]1)[NH2:32]
Reactant: OC[C@H]1CC[C@H](Oc2ncnc3[nH]c(-c4cccc5ccccc45)nc23)C1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)OC[C@H]1CC[C@H](Oc2ncnc3[nH]c(-c4cccc5ccccc45)nc23)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of ((1S,3S)-3-{[8-(1-naphthyl)-9H-purin-6-yl]oxy}cyclopentyl)-methanol (66.1 mg, 0.000183 mol) in DMA (8.12 mL) at 0° C. was added chlorosulfonamide (106 mg, 0.000917 mol) in CH3CN (2.0 mL). The reaction was stirred at 0° C. for 10 mins, then 23° C. for 3 hours. The reaction was quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (2×), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (0 to 6% MeOH/CH2Cl2) to obtain 56.3 mg (70%) of the title compound as a white solid. 1H NMR (CD3OD, 400 MHz) δ: 8.52-8.48 (m, 2H), 8.10-8.07 (m, 1H), 8.01-7.98 (m, 1H), 7.90-7.87 (m, 1H), 7.65-7.57 (m, 3H), 5.89-5.85 (m, 1H), 4.12-4.07 (m, 2H), 2.75-2.66 (m, 1H), 2.30-2.21 (m, 2H), 2.16-2.01 (m, 2H), 1.93-1.85 (m, 1H), 1.62-1.53 (m, 1H) ppm. LC/MS: Rt=1.38 min, ES+ 442 (FA standard).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:7]=[C:6]2[NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:7]=[C:6]2[NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23]
Reactant: COc1ccc2nc(-c3cccnc3)nc(Nc3ccccc3C(N)=O)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a suspension of 2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (synthesized as described in Scheme 1 and 4, substituting 5-methoxy-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid) (371 mg, 1.0 mmol) in CH2Cl2 (4.5 mL) was slowly added boron tribromide, 1M solution in dichloromethane (4.5 ml, 4.5 mmol) at 0° C. The reaction mixture was stirred overnight at room temperature after which it was carefully poured into a vigorously stirring mixture of ice and saturated solution of aqueous NaHCO3. The resultant solid was collected by filtration, dried and then stirred in a saturated solution of aqueous NH4Cl for 1 h after which the suspension was filtered to give the desired product as a yellowish tan solid (262 mg, 73%). LCMS m/z=357.9 (M+1) (Method C) (retention time=1.68 min), 1H NMR (300 MHz, DMSO) δ 12.80 (s, 1H), 10.50 (s, 1H), 9.57 (s, 1H), 9.15 (d, J=8.5 Hz, 1H), 8.70 (t, J=7.3 Hz, 2H), 8.50 (s, 1H), 8.08-7.79 (m, 3H), 7.73 (t, J=7.5 Hz, 1H), 7.57 (dd, J=7.6, 4.8 Hz, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[NH:5][CH:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)[CH3:2].[H-].[Na+].[CH3:23]N(C=O)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[N:5]([CH3:23])[CH:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)NC1CCC=C(C#Cc2ccccc2)C1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(C)C1CCC=C(C#Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
22 mg (0.082 mmol) (3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl ester are dissolved in 2 ml DMF and 1 mL THF. 8 mg (0.165 mmol) of a 60% dispersion of NaH in oil is added and the mixture stirred under argon for 90 minutes at room temperature. The reaction mixture is cooled to 0°, and 16 microliters Mel in 0.5 ml THF are added dropwise. After stirring one hour at room tenmperature, the reaction mixture is cooled to 0° again, ice is added and the crude product extracted with ethyl acetate, washed with water and saline, dried with sodium sulfate and column chromatographed using a 4:1 mixture of petroleum ether and ethyl acetate. Yield: 43% .
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:10]([Cl:11])[C:4]=2[N:3]=1.[F:16][C:17]([F:31])([F:30])[C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1>>[Cl:11][C:10]1[C:4]2[N:3]=[C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:19]4[C:18]([C:17]([F:31])([F:16])[F:30])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:25][CH2:26]3)[NH:6][C:5]=2[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: FC(F)(F)c1cc(Cl)c2nc(Cl)[nH]c2c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: FC(F)(F)c1cc(Cl)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The benzoimidazole from step (b) above (69.3 mg, 0.3 mmol) reacted with 1-(3-trifluoromethylpyridin-2-yl)piperazine (128 mg, 0.5 mmol, Fluorochem) under the conditions of Example 1d to give the title compound as a white solid. M.p. 204° C. MS (ESI, pos. ion) m/z: 450 (M+1).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([CH3:15])[N:4]=1)[NH2:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH3:24])=[CH:19][CH:18]=1>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[N:2][NH:1][C:3]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]=[C:5]([CH3:15])[N:4]=2)[CH3:24])=[CH:19][CH:18]=1
Reactant: Cc1nc(NN)cc(-c2ccccc2)n1
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: CCO
Product: CC(=NNc1cc(-c2ccccc2)nc(C)n1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from 4-hydrazino-2-methyl-6-phenylpyrimidine (300 mg, 1.5 mmol) and 1-(4-Chloro-phenyl)-ethanone (136 μL, 1.05 mmol) in 8.0 mL of ethanol by a procedure similar to example 1, step 4 yielding 190 mg (38%) of an off-white solid. HPLC Purity: 98%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.Cl.O[NH2:18].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)#[N:18]
Reactant: NO
Reactant: Cc1ccc(-c2ccccc2C=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
A mixture of 4'-methyl-2-biphenylcarbaldehyde (2.0 g) and hydroxyamine hydrochloride (1.0 g) in pyridine (10 ml) was stirred at room temperature for 15 min., followed by addition of acetic anhydride (4.1 g). The reaction mixture was stirred at 90°-100° C. for 1 hr. and concentrated to dryness. After addition of water to the residue, the precipitated crystals were collected by filtration. Recrystallization from hexane gave colorless needles (1.5 g, 79%).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[F:22][C:23]1[CH:45]=[CH:44][C:26]([C:27]([C:29]2[C:38](O)=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:34]3)=[O:28])=[CH:25][CH:24]=1.S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[C:38]([O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([S:40]([NH2:43])(=[O:41])=[O:42])=[CH:34]3)=[O:28])=[CH:44][CH:45]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: NS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(O)ccc2c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
Pyridine (4.25 ml, 52.1 mmol) and trifluoromethanesulfonic anhydride (4.4 ml, 26.1 mmol) were added to a solution of 5-(4-fluorobenzoyl)-6-hydroxy-2-naphthalenesulfonamide (3.0 g, 8.7 mmol), [prepared as described in step 1 above], in methylene chloride (50 ml) at 0° C. After 0.5 h, 1N sodium bisulfate was added and the stirring was continued for an additional 30 minutes. The organic layer was separated, washed with brine, and dried over sodium sulfate. The solvent was removed in vacuo to give 3.1 g of 5-(4-fluorobenzoyl)-6-trifluoromethylsulfonyloxy-2-naphthalenesulfonamide as an oil (75% yield).