Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: COc1ccc2oc(=O)cc(O)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1cc(O)c2cc(O)ccc2o1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
4-Hydroxy-6-methoxy-chromen-2-one (500 mg, 2.588 mmol) was suspended in CH2Cl2 (10 mL) and cooled to −78° C. under nitrogen. BBr3 (1 M solution in CH2Cl2, 13 mL, 13 mmol) was added to this suspension dropwise. Following completion of the addition, the resulting suspension was stirred at 25° C. for 1 h before being quenched by the slow addition of H2O. The product was extracted with EtOAc and the combined organic layers dried over Na2SO4 and concentrated to give 350 mg (75%) of the title compound as a tan solid. MS (ESI(+)Q1MS) m/z 179 (M+H)+; 1H NMR (300 MHz, DMSO) δ ppm 9.71 (bs, 1H), 7.01-7.23 (m, 3H), 5.57 (s, 1H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([N:21]([CH3:34])[CH2:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:33][N:25]([CH2:24][CH2:23][CH2:22][N:21]([CH3:34])[C:14]1[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=[C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:13]=1)[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29]
Reactant: CN(CCCN(C)c1cc(N)cc2ccoc12)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CCCN(C)c1cc(NS(=O)(=O)c2ccccc2)cc2ccoc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
Benzenesulfonyl chloride (115 μL, 0.9 mmol) was added to a mixture of tert-butyl 3-[(5-amino-1-benzofuran-7-yl)(methyl)amino]propyl(methyl)carbamate (Intermediate 2; 250 mg, 0.75 mmol) in DCM (2 mL) followed by addition of pyridine (1 mL). The reaction mixture was stirred at room temperature for 4 h. The volatiles were evaporated in vacuo and the residue obtained was purified using RP-HPLC (Gilson/YMC AQ C18; 150×30 mm) to give the title compound as a beige oil (202 mg, 43% over 4 steps); HPLC 93%, RT: 2.49 min (System A); 95%, RT: 2.27 min (System B); 1H NMR (CDCl3) δ ppm 1.41 (s, 9H), 1.60-1.75 (m, 2H), 2.74 (s, 3H), 2.93 (s, 3H), 3.13-3.25 (m, 2H), 3.42-3.53 (m, 2H), 6.19-6.69 (m, 2H), 6.87-7.06 (m, 1H), 7.33-7.58 (m, 4H), 7.71-7.79 (m, 2H); MS m/z 474 (M+H)+.
Reaction SMILES: C(Cl)Cl.O.C[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](C(F)(F)F)[CH:13]=2)[NH:8][C:7]=1[Si](C)(C)C.CC1NC2C(C=1[Si](C)(C)C)=CC(C(F)(F)F)=CC=2>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C.C(OCC)(=O)C>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: Cc1c([Si](C)(C)C)[nH]c2ccc(C(F)(F)F)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cc1[nH]c2ccc(C(F)(F)F)cc2c1[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: c1ccc2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
[Pd(dppf)Cl2×CH2Cl2]; 327 mg, 0.4 mmol) was then added. The reaction mixture was stirred at 100° C. (oil bath temperature) for 6 h and at room temperature for 18 h. The reaction mixture was then cooled with ice water, water (50 ml) and ethyl acetate (100 ml) were added and the mixture was stirred for 30 min. In order to separate off the catalyst, the dark brown mixture was filtered over Celite. The phases of the filtrate were separated. The aqueous phase was extracted with ethyl acetate (5×35 ml). The combined organic phases were washed with saturated sodium chloride solution (3×35 ml), subsequently dried with sodium sulfate, filtered and concentrated in vacuo. The dark brown oil obtained (1.8 g) which, apart from 3-methyl-5-trifluoromethyl-2-trimethylsilanyl-1H-indole, contained traces of DMF and also the isomer 2-methyl-5-trifluoromethyl-3-trimethylsilanyl-1H-indole, was employed as the crude product for the next stage.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:10])[CH:9]=1)[CH:5]=O.[C:11]([O:17][CH3:18])(=[O:16])[CH2:12]C([O-])=O.N1CCCC1>N1C=CC=CC=1>[CH3:18][O:17][C:11](=[O:16])[CH:12]=[CH:5][C:4]1[CH:7]=[C:8]([I:10])[CH:9]=[C:2]([F:1])[CH:3]=1
Reactant: O=Cc1cc(F)cc(I)c1
Reactant: COC(=O)CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCNC1
Product: COC(=O)C=Cc1cc(F)cc(I)c1

Procedure:
3-Fluoro-5-iodobenzaldehyde, monomethyl malonate, and a catalytic amount of pyrrolidine are heated in pyridine. After cooling, the solvent is distilled off in vacuo. 2N HCl and ethyl acetate are added to the residue, and the phases are separated. The organic layer is washed with brine and dried over Na2SO4. After evaporation, the residue is purified by CC on silica gel with EtOAc/hexane. Evaporation of appropriate fractions yields the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(C1C(O[SiH](C)C)=C(Br)C(OC)=CC=1CC1C(=O)C=CCC1(C)C)(C)(C)C>>[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][CH:9]2[C:2](=[O:1])[CH:3]=[C:4]([CH3:10])[CH2:5][C:6]2([CH3:8])[CH3:7])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: COc1cc(CC2C(=O)C=CCC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Product: CC1=CC(=O)C(Cc2ccc([N+](=O)[O-])cc2)C(C)(C)C1

Procedure:
This compound was prepared from isophorone (2.065 g, 14.94 mmol) and p-nitrobenzyl bromide (4.06 g, 18.80 mmol, 1.25 equiv) in the manner previously described for the synthesis of enone (11), affording 1.891 g (46%), of the nitro-enone as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 0.98 and 1.13 (2s, 2×3H, geminal-CH3 's), 1.92 (s, 3H, 3-CH3), 2.17 and 231 (ABq, 2H, JAB =18.5 Hz, 4-H), 2.38 (dd, 1H, J=9.0, 3.3 Hz, 6-H), 2.75 and 3.05 (d of ABq, 2H, JAB =14.0 Hz, JA =3.2 Hz, JB =8.9 Hz, benzylic-CH2), 5.84 (s, 1H, 2-H), 7.33 and 7.53 ppm (ABq, 2H, JAB =8.2 Hz, Ar--H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([C:12]1[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([C:12]1[C:13]([O:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[N:14][CH:15]=[CH:16][CH:17]=1)[OH:11]
Reactant: O=C(CCc1ccccc1Cl)c1cccnc1Oc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCc1ccccc1Cl)c1cccnc1Oc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
A solution of 76.0 mg (0.214 mmol) 3-(2-Chlorophenyl)-1-[2-(4-fluorophenoxy)-3-pyridinyl]-1-propanone in 5 mL of methanol was cooled to 0° C. and treated with 8.0 mg (0.21 mmol) of NaBH4. The mixture was stirred for 30 min at 0° C. and quenched by the addition of 1 mL of aqueous 1 N hydrochloric acid solution. The mixture was evaporated, and the residue was partitioned between 100 mL of EtOAc and 50 mL of saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with brine, dried (Na2SO4), and evaporated to give 79 mg (100%) of the title compound as an oil. 1H NMR (CDCl3) d 2.10-2.32 (2H, m), 2.35 (1H, d, J=6 Hz), 2.83-3.08 (2H, m), 5.06-5.15 (1H, m), 7.01-7.33 (9H, m), 7.85 (1H, dd, J=2, 7 Hz), 8.05 (1H, dd, J=2, 5 Hz); thermospray MS (m/e) 358 and 360 (M++1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][N:15]=2)=[C:8]([N+:23]([O-])=O)[CH:7]=1.[Sn].Cl.[OH-].[Na+]>C(O)C>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](/[CH:13]=[CH:12]/[C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]=2[NH2:23])=[N:15]1
Reactant: COCCOc1ccc(/C=C/c2n[nH]c3ccccc23)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCOc1ccc(/C=C/c2n[nH]c3ccccc23)c(N)c1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 97 %

Procedure:
(E)-3-{2-[4-(2-methoxyethoxy)-2-nitrophenyl]vinyl}-1H-indazole (0.04 g, 0.12 mmol) obtained in Step 2 was dissolved in ethanol (1.0 mL), and the solution was added with tin (0.03 g, 0.25 mmol) and concentrated hydrochloric acid (1.0 mL) under ice-cooling, followed by stirring at 40° C. for 2.5 hours. To the reaction mixture under ice-cooling, 6 mol/L aqueous sodium hydroxide solution was added to neutralize the mixture. Then the mixture was filtered. The filtrate was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethyl acetate to obtain (E)-2-[2-(1H-indazol-3-yl)vinyl]-5-(2-methoxyethoxy)phenylamine (36 mg, 100%).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][NH:6][CH:7]=1)=[O:2].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(CC)CC)C.CCCCCCC>CN(C)C(=O)C.O>[S:14]([N:6]1[CH:7]=[C:3]([CH:1]=[O:2])[N:4]=[CH:5]1)([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: O=Cc1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cnc(C=O)c2)cc1
Yield: 84.8 %

Procedure:
4-Formylimidazole (20.0 g, 208.14 mmol) and p-toluenesulfonyl chloride (43.7 g, 229.0 mmol) were suspended in N,N-dimethylacetamide (200 mL). To the obtained suspension was added dropwise triethylamine (23.2 g, 229.0 mmol) at 10° C. or below, and the mixture was stirred at 10° C. or below for 1 hr or more. To the reaction mixture was added n-heptane (60 mL) at 30° C. or below. To the obtained solution was added dropwise water (240 mL) at 30° C. or below for crystallization. The mixture was stirred at room temperature for 1 hr or more to give crystals. The obtained crystals were collected by filtration, and washed with water (300 mL) to give wet crystals. The obtained wet crystals were dried under reduced pressure at an outside temperature of 50° C. to give 1-tosyl-4-formyl-1H-imidazole (44.2 g, 176.6 mmol). yield 85%.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([F:15])=[C:11]([N+:12]([O-])=O)[C:6]=2[CH2:5][S:4]1(=[O:17])=[O:16])[CH3:2].Cl[Sn]Cl.O.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH2:1]([N:3]1[C:7]2=[CH:8][CH:9]=[C:10]([F:15])[C:11]([NH2:12])=[C:6]2[CH2:5][S:4]1(=[O:17])=[O:16])[CH3:2]
Reactant: CCN1c2ccc(F)c([N+](=O)[O-])c2CS1(=O)=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1c2ccc(F)c(N)c2CS1(=O)=O
Reaction time: 12 h
Yield: 74.3 %

Procedure:
A mixture of 1-ethyl-5-fluoro-1,3-dihydro-4-nitro-2,1-benzisothiazole 2,2-dioxide (1.0 g, 3.8 mmol) and SnCl2.H2O (4.34 g, 19.2 mmol) in ethyl acetate (50 mL) was heated at reflux for 3 h. After completion of the reaction based on thin layer chromatography, the mixture was diluted with ethyl acetate (100 mL) and solid Na2CO3 (12.5 g) was added. The resulting mixture was vigorously stirred for 12 h and then filtered through a pad of diatomaceous earth (Celite®). The filtrate was then evaporated under reduced pressure, and the residue was subjected to flash chromatography (silica gel, chlorobutane:ether 1:10 v/v) to give 650 mg of the title compound of Step D. 1H NMR (CDCl3, 400 MHz): δ6.94 (m,1H), 6.08 (m,1H), 4.10 (s,2H), 3.80 (br s,2H), 3.62 (q,2H), 1.36 (t,3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1.CCOCC.[O-]S([O-])(=O)=O.[Na+].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[NH:19]1[CH2:18][CH2:17][CH:16]([CH:15]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]3[CH:22]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCc1cccnc1C2C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution 66.27 g (0.21 mole) of 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta(1,2-b]pyridin-11-ylidene)-piperidine (product from Preparative Example 1 Example, step G), in THF (1 L) was added LiAIH4 (24.32 g, 0.64 mole) and the reaction mixture was heated to reflux overnight. The reaction mixture was then cooled to room temperature and ~3 L of Et2O is added followed by dropwise addition of saturated Na2SO4 until a white gray precipitate forms. MgSO4 was then added to the separated organic layer and stirred for 30 minutes. All the volatiles were then removed and the resulting crude mixture was chromatographed on a silica gel column eluting with 10% MeOH saturated with NH4OH in CH2Cl2. The material obtained contained both the desired compound and the des-chloro compound. Separation on HPLC using reverse phase column and eluting with 40% MeOH-water afforded the desired compounds as white solids (Product A's mp=95.2-96.1° C., Product B's mp=145.1-145.7° C.).
Reaction SMILES: [C:1]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]([S:33]CC2C=CC(OC)=CC=2)[CH:10]([CH2:18][C:19]2[CH:20]=[N:21][C:22]([NH:25]C(OC(C)(C)C)=O)=[CH:23][CH:24]=2)[C:11]([O:13]C(C)(C)C)=[O:12])[CH:2]=1>C([SiH](CC)CC)C.FC(F)(F)C(O)=O>[NH2:25][C:22]1[N:21]=[CH:20][C:19]([CH2:18][CH:10]([CH:9]([SH:33])[CH2:8][CH2:7][C:3]2[CH:2]=[C:1]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:6]=[CH:5][CH:4]=2)[C:11]([OH:13])=[O:12])=[CH:24][CH:23]=1
Reactant: COc1ccc(CSC(CCc2cccc(-c3ccccc3)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CC(C(=O)O)C(S)CCc2cccc(-c3ccccc3)c2)cn1
Temperature: 60 °C
Yield: 87.1 %

Procedure:
tert-Butyl 5-(1,1′-biphenyl-3-yl)-2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-[(4-methoxybenzyl)thio]pentanoate (0.669 g, 1.00 mmol) was dissolved in triethylsilane (0.75 mL) and trifluoroacetic acid (6.0 mL). The solution was heated to 60° C. for 3 h and then concentrated. Purification of the residue by reversed-phase HPLC (C-8 column, linear gradient 40%→100% of MeCN in 5% aqueous MeCN containing 0.15% trifluoroacetic acid) gave the title diastereomeric compound as the trifluoroacetic salt (0.342 g, 68%) after freeze-drying.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=3)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[N:10]=2
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)cn1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
Potassium thiocyanate (1.26 g, 13.0 mmol) was suspended in acetic acid (15 mL), and the mixture was stirred at room temperature for 15 min. To the obtained solution was added a solution of N-{3-[(5-aminopyridin-2-yl)oxy]-4-methoxyphenyl}-3-(1-cyano-1-methylethyl)benzamide obtained above in acetic acid (25 mL), and the mixture was further stirred at room temperature for 15 min. A solution of bromine (690 mg, 4.32 mmol) in acetic acid (30 mL) was added dropwise to the obtained solution for 30 min or more. After the completion of the dropwise addition, the mixture was stirred at room temperature for 10 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (100 mL)/tetrahydrofuran (10 mL), and the suspension was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and aqueous ammonium chloride solution (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/80→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (1.00 g, 65%, 3 step yield) as a colorless amorphous substance.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[B-](F)(F)(F)[CH:15]=[CH2:16].[K+].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([CH:15]=[CH2:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)c1c(Br)cccc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cccc(OC)c1C(=O)OC
Temperature: 100 °C
Yield: 95.4 %

Procedure:
To a mixture of methyl 2-bromo-6-methoxybenzoate (30 g, 0.12 mol) and potassium trifluoro(vinyl)borate (18 g, 0.13 mol) in dioxane and H2O (5:1, 360 mL) was added Pd(dppf)Cl2 (2.63 g, 0.0036 mol) and Na2CO3 (25.4 g, 0.24 mol) at RT. The reaction mixture was heated at 100° C. for 12 hours under a nitrogen atmosphere. The mixture was subsequently concentrated in vacuo, diluted with water, and extracted with EtOAc (3×100 mL). The organic layers were combined, washed with brine, dried over anhydrous Na2CO3, filtered, and concentrated. The crude product was purified by column chromatography eluting with a gradient of petroleum ether (1-2%) and EtOAc to give the title compound (22 g, 95%). 1H NMR (400 MHz, CDCl3) δ ppm 7.33 (t, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.67 (dd, J=11.0, 17.4 Hz, 1H), 5.75 (d, J=17.4 Hz, 1H), 5.35 (d, J=11.0 Hz, 1H), 3.93 (s, 3H), 3.84 (s, 3H); ESI-MS m/z [M+H]+ 193.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[NH2:16][CH2:17][CH:18]1[CH2:20][CH2:19]1.Cl>CS(C)=O>[CH:18]1([CH2:17][N:16]2[C:2]3[C:3](=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=3[F:8])[CH2:12][C:13]2=[O:15])[CH2:20][CH2:19]1
Reactant: NCC1CC1
Reactant: O=C(O)Cc1cc([N+](=O)[O-])cc(F)c1F
Agent: Cl
Solvent: CS(C)=O
Product: O=C1Cc2cc([N+](=O)[O-])cc(F)c2N1CC1CC1
Temperature: 45 °C
Reaction time: 20 h

Procedure:
Crude (2,3-difluoro-5-nitrophenyl) acetic acid (2.50 g, 11.5 mmol) and (aminomethyl)cyclopropane (6 eq., 5.98 ml, 0.0691 mol) are mixed in DMSO (10 ml) and stirred at 45° C. for 20 hours. 2N Hydrochloric acid (40 ml) is added in one portion and the mixture stirred at room temperature for 2 hours. The resulting light yellow precipitate is filtered, washed with water and ether, and dried under vacuum to give the title compound as a yellow solid. HPLC r.t. 4.91 min; MS for C12H11FN2O3 m/z 251.2 (M+H)+.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:35]3[C:34]([N:36]4[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]4)=[N:33][CH:32]=[N:31][C:30]=3[S:29][CH:28]=2)=[CH:23][CH:22]=1>CC(O)C.CS(C)=O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:35]3[C:34]([N:36]4[CH2:41][CH2:40][CH:39]([NH:42][CH2:17][CH:15]([OH:16])[CH2:14][O:13][C:10]5[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=5)[CH2:38][CH2:37]4)=[N:33][CH:32]=[N:31][C:30]=3[S:29][CH:28]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Reactant: NC1CCN(c2ncnc3scc(-c4ccc(F)cc4)c23)CC1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Oc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccc(F)cc5)c34)CC2)cc1
Yield: 45 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 10 h), using 200 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) with 45% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) with 74% yield.
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16]N[CH2:14][CH2:13]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=[C:5]3[C:4]=2[CH:3]=1.FC1C(F)=CC2C3C([C:39](=[O:48])N(C4C=CC=CC=4)N=3)=CNC=2C=1.OC1CCNCC1>>[F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][CH:39]([OH:48])[CH2:14][CH2:13]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=[C:5]3[C:4]=2[CH:3]=1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Agent: OC1CCNCC1
Product: O=c1c2c[nH]c3cc(N4CCC(O)CC4)c(F)cc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27a and 4-hydroxypiperidine. 1H-NMR (DMSO-d6) δ (ppm): 1.54 (2H, brm), 1.87 (2H, brm), 2.85 (2H, brm), 3.20 (1H, m), 3.64 (1H, brm), 4.74 (1H, brd, J=3.84 Hz), 7.10 (1H, m), 7.22 (1H, d, J=7.97 Hz), 7.40 (2H, m), 7.76 (1H, d, J=2.90 Hz), 8.20 (2H, m), 8.64 (1H, s). m/z 379.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3COC)[N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2C3C(C)=C(C)SC=3NC(=O)C3(CC3)N=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]3([CH2:25][CH2:24]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Agent: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(CC1)C(=O)N2
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(CC1)c1nnc(C)n1-2

Procedure:
A procedure analogous to that set forth for Compound 202 was followed, with the exception that 5′-(4-chlorophenyl)-6′,7′-dimethylspiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one was used as starting material. LRMS (M+H)+: 369 m/z. 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.57 (m, 4H), 2.60 (s, 3H), 2.39 (s, 3H), 1.67-1.83 (m, 1H), 1.57 (s, 3H), 1.33-1.45 (m, 1H), 0.83 (t, J=8.47 Hz, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([NH:12][C:13]([NH2:15])=[S:14])[CH3:11].[O-]CC.[Na+].[C:20]([CH2:22][C:23](OCC)=[O:24])#[N:21].S(=O)(=O)(O)O>CCO.O>[NH2:21][C:20]1[N:12]([CH:10]([C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH3:11])[C:13](=[S:14])[NH:15][C:23](=[O:24])[CH:22]=1
Reactant: CC(NC(N)=S)c1nc2ccccc2[nH]1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(c1nc2ccccc2[nH]1)n1c(N)cc(=O)[nH]c1=S
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 48.7 %

Procedure:
To a suspension of N-[1-(1H-benzimidazol-2-yl)ethyl]thiourea (0.33 g, 1.5 mmol, obtained from Example 9(a)) in EtOH (2 mL) was added, dropwise, sodium ethoxide (21% w/w, 1.67 mL, 4.5 mmol) and a solution of ethyl cyanoacetate (0.48 mL, 4.47 mmol) in EtOH (1 mL), while heating the reaction to 80° C. during 1 h 20 minutes. The reaction was kept at 80° C. for an additional 2 h 40 minutes. After cooling to r.t., water (50 mL) and 2M sulphuric acid was added. The formed solid was collected by filtration, washed with H2O and dried to give the title compound (0.21 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)[OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1>O=[Mn]=O.ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC(c1cc(F)cc(F)c1)c1cc(F)cc(F)c1
Agent: O=[Mn]=O
Solvent: ClCCCl
Product: O=C(c1cc(F)cc(F)c1)c1cc(F)cc(F)c1
Yield: 95 %

Procedure:
1.56 g bis-(3,5-difluoro-phenyl)-methanol, 1.06 g MnO2 and 36 mL 1,2-dichloroethane were refluxed for 4 hours. The mixture was cooled, filtered and evaporated. Chromatography of the residue afforded 1.47 g of a white solid, m.p.: 79° C.; MS: 254 ([M]+).