Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=O)[CH:5]=[C:6]([I:8])[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.[OH-].[K+].C(OC(C)C)(C)C>ClCCl.C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([CH2:9][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)[C:3]=1[CH3:19]
Reactant: CCc1ccc(C(=O)c2cc(I)cc(Br)c2C)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CCc1ccc(Cc2cc(I)cc(Br)c2C)cc1

Procedure:
A solution of (3-bromo-5-iodo-2-methyl-phenyl)-(4-ethyl-phenyl)-methanone (4.2 g) and triethylsilane (4.7 mL) in dichloromethane (10 mL) and acetonitrile (28 mL) is cooled in an ice-bath. Then, boron trifluoride diethyletherate (1.4 mL) is added dropwise over 3 min. The solution is stirred for 14 h at ambient temperature, before an aqueous 25% solution of KOH and diisopropylether are added. The organic phase is separated and the aqueous phase is extracted three times with diisopropylether. The combined organic phases are washed with 2 M potassium hydroxide solution and brine and then dried (sodium sulphate). After the solvent is evaporated, the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:0->1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:9]=[CH:10][C:4]=2[C:3]=1O.[H-].[Na+].FC(F)(F)S(N(C1C=CC=CC=1)S(C(F)(F)F)(=O)=O)(=O)=O.[N:44]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.[NH4+].[Cl-]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([N:47]2[CH2:46][CH2:45][N:44]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48]2)=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(Cn2ncc3c(O)c(Cl)cnc32)cc1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Cl)cnc32)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A solution of 5-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (450 mg, 1.55 mmol) in DMF (5 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 74.5 mg, 1.86 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at 40° C. for 30 minutes. The resulting solution was cooled to room temperature and treated with 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (666 mg, 1.86 mmol). The reaction mixture was stirred at room temperature for 1 hour. Next, the solid tert-butyl piperazine-1-carboxylate (636 mg, 3.42 mmol) was added in 2 portions, and the mixture was stirred at 80° C. for 1.5 hours. The mixture was then allowed to cool to room temperature for 18 hours. Saturated NH4Cl solution (30 mL) and water (15 mL) were added, and the mixture was extracted with EtOAc (100 mL). The organic layer was washed with half saturated brine (2×20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Biotage Flash 40 S+) eluting with 15-20%) EtOAc/hexane (step gradient) to provide tert-butyl 4-(5-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (433 mg, 0.946 mmol, 60.9% yield) as a solid after drying under high vacuum for 18 hours. LCMS (APCI+) m/z 458.1, 460 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].FC(F)(F)C(O)=O.C([BH3-])#N.[Na+].O>CO>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1cc(/C=N/OCCO)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: O=C(NOCCO)c1cc(CNOCCO)c(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
To a solution of (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyimino)-methyl]-benzamide (3.62 g, 6.70 mmol) obtained in Step B in methanol (100 ml) were added portionwise trifluoroacetic acid (6.5 ml) and sodium cyanoborohydride (3.78 g, 60.2 mmol) over 2 days while monitoring the progression of the reaction by TLC. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH (15:1)), and the resultant crude compound was crystallized from methylene chloride to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamino)-methyl]-benzamide (1.66 g, 46%, as a total of first and second crystals).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:11][S:12](O)(=[O:14])=[O:13].O=S(=O)=O>>[OH:1][C:2]1[N:10]=[CH:9][C:8]([S:12]([OH:14])(=[O:13])=[O:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1cccnc1O
Agent: O=S(=O)=O
Product: O=C(O)c1cc(S(=O)(=O)O)cnc1O
Temperature: 140 °C
Yield: 82.9 %

Procedure:
2-Hydroxynicotinic acid (27 Kg, 194.2 mol) was added portionwise to 30% oleum (58.1 Kg) at 50° C. over 1 hr. This caused an exotherm to 82° C. The reaction mixture was heated further to 140° C. After maintaining this temperature for 12 hrs the reactor contents were cooled to 15C and filtered. The filter cake was then re-slurried with acetone (33 Kg) at room temperature, filtered and dried to afford the title compound (35.3 Kg, 83%) as a white solid. Decomposition pt 273° C. δ (DMSOd6): 7.93 (1H, d), 8.42 (1H, d). m/z (Found:220 [M+H]+, 100%. C6H6NO6S requires 220.17).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[Cl:20])=[CH:7][C:5]([NH2:6])=[C:4]([N+:21]([O-])=O)[CH:3]=1.Cl>C(O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH2:6])=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][C:11]=1[Cl:20]
Reactant: Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: Nc1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2Cl)cc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
To a solution of 2-chloro-4-(trifluoromethyl)phenol (2 g, 10.18 mmol) in DMSO (250 ml) was added potassium carbonate (4.2 g, 30.17 mmol). The resulting solution was stirred overnight at room temperature, then 4,5-dichloro-2-nitroaniline (2.1 g, 10.14 mmol) was added. The resulting solution was stirred for an additional overnight at 90° C. and then quenched with water (1000 ml) and extracted with ethyl acetate (3×300 ml). The combined organic layers were washed with saturated aqueous brine (3×1000 ml), dried by anhydrous sodium sulfate and concentrated under vacuum to give a residue that was purified by a silica gel column, eluting with 1% to 1.5% ethyl acetate in petroleum ether to produce 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitroaniline as a yellow solid (450 mg, crude). Next, to a solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitroaniline (450 mg, crude) in ethanol (10 ml) was added hydrochloric acid (conc) (0.484 ml) and Zn (478 mg, 7.35 mmol) in several batches at room temperature. The resulting solution was stirred for 10 min at room temperature and 2 h at 80° C. The reaction was concentrated under vacuum and dissolved in water (200 ml), pH adjusted to 8 with potassium carbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Prep-HPLC to produce 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]benzene-1,2-diamine as a off-white solid (150 mg, 61%). Finally, a solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]benzene-1,2-diamine (50 mg, 0.15 mmol) in trifluoroacetic acid (5 ml) and conc. HCl (1 ml) was refluxed overnight. The reaction was then quenched with water (100 ml), pH value adjusted to 8 with sodium bicarbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Prep-TLC with 12.5% ethyl acetate in petroleum ether to produce 5-chloro-6-[2-chloro-4-(trifluoromethyl)phenoxy]-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (36.4 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH2:16][O:17][CH3:18])=[N:13][N:12]([CH:19]4[CH2:21][CH2:20]4)[C:11]=3[C:10](=[O:22])[NH:9]2)=[CH:4][CH:3]=1.Br[C:24]1[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH2:16][O:17][CH3:18])=[N:13][N:12]([CH:19]4[CH2:20][CH2:21]4)[C:11]=3[C:10](=[O:22])[N:9]2[C:24]2[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)cn(C)c1=O
Reactant: COCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)NC2=O
Product: COCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared using an analogous procedure to that described in Example but using 4-(4-chlorophenyl)-1-cyclopropyl-3-(methoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 130.4) and 5-bromo-1,3-dimethyl-2-pyridone. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 0.5-3.5%) to provide the title compound (286 mg) as a colorless solid. tR: 0.95 min (LC-MS 2); ESI-MS: 439.1 [M+H]+ (LC-MS 2); Rf=0.48 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.07 (m, 2H) 1.20-1.27 (m, 2H) 1.91 (s, 3H) 3.02 (s, 3H) 3.34 (s, 3H) 3.81-3.89 (m, 1H) 3.97 (d, J=12.51 Hz, 1H) 4.20 (d, J=12.51 Hz, 1H) 6.09 (s, 1H) 7.20-7.28 (m, 2H) 7.31-7.37 (m, 2H) 7.40-7.45 (m, 1H) 7.76 (d, J=2.74 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16](OC=O)(=O)C.CSC>>[CH3:16][NH:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1sc2ccccc2c1N
Reactant: CC(=O)OC=O
Solvent: CSC
Product: CCOC(=O)c1sc2ccccc2c1NC

Procedure:
3-Amino-2-carboethoxy-benzothiophene (1.11 g, 5 mmol) was reacted with formic acetic anhydride followed by reduction by BH3.DMS, using the procedure described by Krishmanurthy in Tetrahedron Lett, 23:33 15-8 (1982), to yield 0.59 g of the title compound as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.39 (t, 3H), 3.41 (d, 3H), 4.33 (q, 2H), 7.28 (t, 1H), 7.41 (t, 1H), 7.53 (br s, 1H) (d, 1H), 8.18 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:29])([F:28])[F:1])[CH:4]=4)[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]([OH:17])([CH3:16])[C:3]#[C:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[OH:6].C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[OH:17][C:2]([CH3:16])([CH3:1])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(C)(O)C#CC(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
To a room temperature solution of 4-methyl-1-(4-nitrophenyl) pent-2-yne-1,4-diol (2 g, 8.51 mmol, 1 eq) in dry DCM (100 mL) was added NaHCO3 (680 mg, 8.51 mmol, 1 eq) followed by Dess Martin Periodinane (9.2 g, 21.27 mmol, 2.5 eq). The reaction mixture was stirred at RT for 16 h. After completion of the reaction (as monitored by TLC), the reaction mixture was quenched with a saturated sodium bisulfite solution and extracted with DCM (2×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 20% EtOAc in hexanes to afford 4-hydroxy-4-methyl-1-(4-nitrophenyl)pent-2-yn-1-one (1.7 g, 86%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:28])=[CH:4][N:3]=1.[CH3:29][N:30]([CH3:39])[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:28][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)=[O:19])[CH2:15][CH2:16]2)=[C:7]2[N:8]=[C:35]([C:34]3[CH:37]=[CH:38][C:31]([N:30]([CH3:39])[CH3:29])=[CH:32][CH:33]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3cccc(Cl)c3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)Nc5cccc(Cl)c5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(3-chlorophenyl)acetamide (0.036 g, 0.08 mmol), ethanol (3.5 ml), and 4-dimethylaminobenzaldehyde (0.017 g, 0.11 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.35 ml, 0.35 mmol). The reaction mixture was heated at 70° C. for 3 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 30% ethyl acetate in dichloromethane and then 1.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.004 g, 7%); 1H-NMR (500 MHz, DMSO-d6) 2.78 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.24 (s, 2H, NCH2CO), 3.76 (br s, 4H, piperazine N(CH2)2), 6.82 (d, J=8.96 Hz, 2H) and 8.01 (d, J=8.91 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.12 (d, J=7.62 Hz, 1H) and 7.60 (d, J=9.25 Hz, 1H) (4-ArH and 6-ArH), 7.34 (t, J=6.85 Hz, 1H, 5-ArH), 7.90 (s, 1H, 2-ArH), 8.03 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.96 (s, 1H, CONH), 13.09 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][C:10]([CH3:13])([CH3:12])[CH:9](OS(C3C=CC(C)=CC=3)(=O)=O)[C:8]2=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[SH:34].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH:1]1([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[CH:9]([S:34][C:28]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=3[Cl:26])[C:8]2=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OC2C(=O)N(C3CCCCC3)CC2(C)C)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC1(C)CN(C2CCCCC2)C(=O)C1Sc1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 5 h
Yield: 28.8 %

Procedure:
Place toluene-4-sulfonic acid 1-cyclohexyl-4,4-dimethyl-2-oxo-pyrrolidin-3-yl ester (0.102 g, 0.28 mmol), 2,4-dichloro-benzenethiol (0.073 ml, 0.56 mmol) and DBU (0.130 ml, 0.84 mmol) in DMF (3 mL). Stir for 5 hours at 50° C. Quench with water and extract with ethyl acetate. Wash the extract brine and dry over magnesium sulfate, filter, and concentrate. Flash chromatography affords 0.030 g (29%) of the title compound: Mass spectrum (apci) m/z=372 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[CH2:13][NH:12][C:8]1[C:6]2[N:7]=[C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4ccc(Cl)c(Cl)c4)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4ccc(Cl)c(Cl)c4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 168 from 2-chloro-8-(3,4-dichlorobenzyl-amino)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 259°-261° C.) and piperazine.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3[C:17]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=5)=[C:21]([Cl:34])[CH:20]=4)=[N:16][CH:15]=[N:14][C:13]=3[S:35][C:8]=2[CH:7]=1)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:34][C:21]1[CH:20]=[C:19]([NH:18][C:17]2[C:12]3[C:9]4[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][OH:3])=[CH:7][C:8]=4[S:35][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCCc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]acetate (858 mg, 1.64 mmol, 1 equiv) in THF (10 mL) was added 1M solution of diisobutylaluminum hydride in hexanes (6.6 mL, 6.57 mmol, 4 equiv) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 1 h. The reaction mixture was quenched with Rochelle's salt followed by extraction with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL) and water (100 mL), dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (40% EtOAc/hexane then 100% EtOAc) to yield a light yellow (845 mg, 48%). 1H-NMR (CD3OD) δ 8.35 (s, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.43-7.34 (m, 3H), 7.27-7.20 (m, 2H), 7.03 (m, 2H), 5.12 (s, 2H), 3.83 (t, 2H), 2.95 (t, 2H); LCMS RT=3.56 min, [M+H]+=480
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:27][CH:28]1[CH2:30][CH2:29]1>CCO.CCO.CCO.CCO.[Ti].[F-].[K+]>[Br:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:27][CH:28]3[CH2:30][CH2:29]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Reactant: OCC1CC1
Agent: [Ti]
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2

Procedure:
8 g (20 mmol) of tert.butyl (S)-8-bromo-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 25 g (300 mmol) of hydroxymethyl-cyclopropane and 1.8 g (8 mmol) of tetraethyl orthotitanate are stirred at 120° overnight, the solution is evaporated to dryness and the residue is taken up in chloroform. The solution obtained is stirred for 0.5 hour with 40 ml of a saturated potassium fluoride solution, the resulting emulsion is filtered through siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By recrystallization from ethanol there is obtained cyclopropylmethyl (S)-8-bromo-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 212°-213°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[CH3:31][N:32]([CH3:47])[CH2:33][CH2:34][O:35][C:36]1[CH:37]=[C:38]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[NH2:39].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>N1C=CC=CC=1>[CH3:31][N:32]([CH3:47])[CH2:33][CH2:34][O:35][C:36]1[CH:37]=[C:38]([NH:39][C:27](=[O:29])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:6]3[CH:7]=[N:8][C:9]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:21][C:22]=2[F:30])[CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Reactant: CN(C)CCOc1cc(N)cc(C(F)(F)F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(OCCN(C)C)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (100 mg, 0.243 mmol) and 3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)aniline (60.3 mg, 0.243 mmol) in pyridine (2 mL) was added T3P® (0.5 mL, 0.243 mmol) at 27° C. under N2. The mixture was stirred at 27° C. for 30 min. LCMS showed the reaction was completed. Then the mixture was put onto ice (10 mg). The precipitate was filtered and redissolved in DCM (5 mL). The solution was washed with water (5 mL×2), and the combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was suspended in PE/EA (2:1, v/v, 8 mL) and stirred for 10 min. The solid was filtered, and washed with PE/EA (2:1, v/v, 10 mL) and dried in vacuo to give an off-white solid of N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (100 mg, 0.156 mmol, 64.1% yield). TLC (PE/EA=1:1, Rf=0.3): 1H NMR (400 MHz, CD3OD) δ 7.97-7.92 (m, 1H), 7.76 (br. s., 1H), 7.48-7.37 (m, 7H), 7.04 (s, 1H), 6.91 (d, J=8.6 Hz, 2H), 5.36 (s, 2H), 4.14 (q, J=7.1 Hz, 4H), 3.86-3.78 (m, 5H), 2.97 (br. s., 8H), 1.42 (t, J=6.9 Hz, 4H). ES-LCMS m/z 642 (M+H).