Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6]1)=O.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].O>O1CCCC1>[C:14]([O:13][C:12]([NH:11][C@H:8]1[CH2:9][CH2:10][C@H:5](/[CH:3]=[CH:20]/[C:19]([O:22][CH2:23][CH3:24])=[O:21])[CH2:6][CH2:7]1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethyl phosphonoacetate (107 mg) was dissolved in tetrahydrofuran (1 mL), and 60% sodium hydride (19 mg) was added thereto, followed by stirring at room temperature for 30 minutes. A solution of tert-butyl (trans-4-formylcyclohexyl)carbamate (90 mg) in tetrahydrofuran (1 mL) was added dropwise thereto, followed by stirring at room temperature for 2 hours. Ethyl acetate and water were added thereto, followed by extraction with ethyl acetate. The extracts were washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-50:50) to obtain ethyl (2E)-3-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}acrylate (100 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]([CH3:16])([CH2:14][OH:15])[CH2:12][OH:13].C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:11]([CH3:16])([CH2:14][OH:15])[CH2:12][OH:13])=[CH:2][CH:7]=1
Reactant: CC(CO)(CO)c1ccc([N+](=O)[O-])cc1Br
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(CO)(CO)c1ccc(N)cc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
To a refluxing solution of 2-(2-bromo-4-nitrophenyl)-2-methylpropane-1,3-diol (211 mg, 0.73 mmol) in ethanol (15.5 mL) was added ammonium formate (211 mg, 3.35 mmol) followed by the addition of Pd/C (140 mg, 1.32 mmol). The reaction mixture was refluxed for an additional 10 minutes, cooled to room temperature and filtered through a plug of celite. The solvent was evaporated under reduced pressure to give 2-(4-aminophenyl)-2-methylpropane-1,3-diol (112 mg, 85%).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=4Br)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(#N)C>[C:42]([O:41][C@@H:35]([C:12]1[C:13]([CH3:34])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:46])([O:4][CH2:1][CH:2]=[CH:3][C:24]2[CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=[CH:28][C:23]=2[CH2:22][O:21][CH2:20]3)[CH2:10][CH2:9]1)[C:36]([O:38][CH2:39][CH3:40])=[O:37])([CH3:45])([CH3:43])[CH3:44]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(C(F)(F)F)cc4Br)nn23)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=Cc1cc(C(F)(F)F)ccc1COC3
Temperature: 120 °C
Reaction time: 23 h
Yield: 63 %

Procedure:
To a pressure tube flushed with N2 were added (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-bromo-4-(trifluoromethyl)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.200 g, 0.281 mmol), acetonitrile (8 ml) and triethylamine (0.392 ml, 2.81 mmol). Added to this solution were triphenylphosphine (0.022 g, 0.084 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.026 g, 0.028 mmol). The tube was sealed and stirred at 120° C. for 23 h. The mixture was cooled, filtered and concentrated to give a yellow residue that was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV) to give the title compound (0.1115 g, 0.177 mmol, 62.9% yield) as a yellow foam. LCMS (M+H) calcd for C34H44F3N4O4: 631.31. found: 631.3.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[S:22][CH2:23][C:24]([OH:26])=O.FC(F)(F)C([O-])=O.[NH2:34][C@@H:35]1[C:42](=[O:43])[N:41]2[C@@H:36]1[S:37][CH2:38][C:39](/[CH:47]=[C:48]1/[C:49](=[O:71])[N:50]([CH2:53][C:54]3[CH:59]=[CH:58][N+:57]([CH2:60][C:61](=[O:70])[NH:62][C:63]4[CH:68]=[CH:67][C:66]([OH:69])=[CH:65][CH:64]=4)=[CH:56][CH:55]=3)[CH2:51][CH2:52]/1)=[C:40]2[C:44]([OH:46])=[O:45]>CN(C)C(=O)C>[OH:69][C:66]1[CH:65]=[CH:64][C:63]([NH:62][C:61]([CH2:60][N+:57]2[CH:58]=[CH:59][C:54]([CH2:53][N:50]3[CH2:51][CH2:52]/[C:48](=[CH:47]\[C:39]4[CH2:38][S:37][C@H:36]5[N:41]([C:42](=[O:43])[C@H:35]5[NH:34][C:24](=[O:26])[CH2:23][S:22][C:14]5[S:13][C:17]6[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=6[N:15]=5)[C:40]=4[C:44]([O-:46])=[O:45])/[C:49]3=[O:71])=[CH:55][CH:56]=2)=[O:70])=[CH:68][CH:67]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)cc5)cc4)C3=O)CS[C@H]12
Reactant: O=C(O)CSc1nc2ccccc2s1
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5nc6ccccc6s5)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)cc1

Procedure:
With 70.0 mg (0.43 mmol) 1,1′-carbonyldiimidazole, 96.0 mg (0.43 mmol) (benzothiazol-2-ylsulfanyl)-acetic acid and 233.8 mg (0.36 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml N,N-dimethylacetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=[O:13])[CH2:7][CH2:6]2.[Li+].CC([N-]C(C)C)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([O:13][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(O[Si](C)(C)C)C2

Procedure:
6-Methoxy-3,4-dihydronaphthalen-2(1H)-one (25 g) was treated with LDA (110 ml) in dry THF (500 ml) at −78° C. for 5 minutes. Then TMSCl (21.64 g) was added and after 30 minutes the cooling bath was removed. After 1 hour at room temperature the solvent was evaporated in vacuo and the residue was dissolved in heptane and filtered to eliminate the solid particulate. Finally the heptane was evaporated in vacuo.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=4[N:14]=[CH:15][C:10]3=[N:9][CH:8]=2)[CH2:3][CH2:2]1.Cl.[N:28]1([C:33](=N)[NH2:34])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:16]1[C:13]2[N:14]=[CH:15][C:10]3[N:11]([C:7]([CH:4]4[CH2:3][CH2:2][N:1]([C:33](=[NH:28])[NH2:34])[CH2:6][CH2:5]4)=[CH:8][N:9]=3)[C:12]=2[CH:18]=[CH:17]1
Reactant: N=C(N)n1cccn1
Reactant: C[Si](C)(C)CCOCn1ccc2c1ncc1ncc(C3CCNCC3)n12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1ncc(C3CCN(C(=N)N)CC3)n12
Yield: 33.3 %

Procedure:
A solution of 8-(piperidin-4-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.100 g, 0.269 mmol, Preparation #DDDDD.1), 1H-pyrazole-1-carboximidamid, hydrochloride (0.118 g, 0.807 mmol) and DIEA (0.188 mL, 1.08 mmol) in DMF (2 mL) was stirred at rt for about 72 h. The reaction mixture was purified by RP-HPLC (Table 1, Method 1) to give 4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboximidamide (0.037 g, 33%) as a brown oil: LC/MS (Table 1, Method b) Rt=1.82 min; MS m/z: 414 (M+H)+.
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([C:10]1[CH:43]=[CH:42][C:13]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:41]=[CH:40][C:27]([O:28][C@H:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]([OH:32])=[O:31])=[CH:26][CH:25]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][C@H:29]([CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:30]([O-:32])=[O:31])=[CH:40][CH:41]=2)=[CH:42][CH:43]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[Na+:2]
Reactant: Cc1ccc(-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)n1CCCOc1ccc(Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2ccc(O[C@H](Cc3ccccc3)C(=O)[O-])cc2)n1CCCOc1ccc(Cc2ccccc2)cc1
Yield: 87.3 %

Procedure:
Ethanol (5 ml) and a solution of 1N sodium hydroxide in ethanol (0.900 ml) were added to (2R)-2-(4-{1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoic acid (546 mg, 1.00 mmol) and the mixture was concentrated. To the residue was added diisopropylether to give the object compound as a solid. 447 mg (yield: 87.3%)
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[F:21][C:20]([F:22])([F:23])[O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:14][CH:15]=1
Reactant: O=C1NCc2ccccc21
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1c2ccccc2CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.133 g, 1 mmol), 1-bromomethyl-4-trifluoromethoxy-benzene (0.306 g, 1.2 mmol), Cs2CO3 (0.816 g, 2.5 mmol), and 18-crown-6 (0.026 g, 0.1 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.125 g, 81%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.28 (s, 2H), 4.82 (s, 2H), 7.16 (d, 2H), 7.32-7.52 (m, 5H), 7.90 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10]O)[C:6]=2[CH:12]=1.S(Cl)([Cl:15])=O>C(Cl)Cl.CN(C)C=O>[Cl:15][CH2:10][C:7]1[C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][CH:8]=1
Reactant: OCc1coc2ccc(F)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1ccc2occ(CCl)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-fluorobenzofuran-3-ylmethanol (14 g) in methylene chloride (250 mL) was treated successively with 5 drops of dimethylformamide and thionyl chloride (28 mL). After stirring for 16 h at room temperature the reaction was concentrated in vacuo giving 3-chloromethyl-5-fluorobenzofuran as an oil (19.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](OC)=[O:17])=[CH:12][C:11]=1[CH:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH3:25].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[CH:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH3:25]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2CCCC2C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2C2CCCC2C)c1
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
A 200 mL round bottom flask was charged with 66.56G (0.31 g, 0.91 mmol) and THF (10 mL). To the solution was added LAH (1.0 M in THF) (0.91 mL, 0.91 mmol) dropwise at room temperature. The resulting solution was stirred for 15 minutes, quenched with saturated aqueous Rochelle salt, and extracted with ether. The combined organic layers were dried (MgSO4) and concentrated. The initial product was purified by silica gel flash chromatography (0-30% EtOAc/hexane) to afford 66.56H (mixture of diastereomers) (0.27 g, 95% yield) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:17][N:18]=[N+]=[N-])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:17][NH2:18])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCC[C@@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC[C@@H](C)C[C@H](CN)CC(=O)OC(C)(C)C
Yield: 71.3 %

Procedure:
A solution of compound 160 (1.86 g, 6.25 mmol) in THF (50 mL) was shaken over 5% Pd/C under hydrogen and pressure for 8 hours with three purges of hydrogen. The catalyst was filtered off and the filtrate evaporated. The crude material was chromatographed on silica eluting with methanol to give 161 as an oil (1.21 g, 71%). 1H NMR (400 MHz, CDCl3) δ 2.70 (dd, J=12.9, 4.40 Hz, 1H), 2.54 (dd, J=12.7, 6.59 Hz, 1H), 2.26 (dd, J=14.5, 6.96, 1H), 2.12 (dd, J=14.5, 6.47 Hz, 1H), 1.91 (m, 1H), 1.91 (m, 1H), 1.43 (s, 12H), 1.39–1.25 (m, 4H), 1.14–1.07 (m, 1H), 1.03–0.97 (m, 1H), 0.86–0.82 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][C:17]3[CH:19]=[CH:20][C:21]([Cl:22])=[C:15]([Cl:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: Nc1cc2ncnc(Nc3ccc(Cl)c(Cl)c3)c2cn1
Temperature: 165 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (247 mg, 1.29 mmol) and 3,4-dichloroaniline (1.50 g, 9.26 mmol) is stirred at 165° C. for 30 min. The resulting product is chromatographed over silica gel (7-8% MeOH/CH2Cl2) to give 7-amino-4-(3,4-dichloroanilino)pyrido[4,3-d]pyrimidine (252 mg, 64%) as a pale yellow solid. 1H NMR (DMSO) δ 9.97 (1H, brs), 9.34 (1H, s), 8.47 (1H, s), 8.29 (1H, brs), 7.86 (1H, brd, J=8.6 Hz), 7.62 (1H, d, J=8.8 Hz), 6.70 (2H, brs), 6.46 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[O:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1cc(Br)ccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.9 %

Procedure:
A mixture of 4-bromo-2-fluoro-phenylamine (1 g, 5.26 mmol), tetrahydro-4H-pyran-4-one (0.73 ml, 7.89 mmol), and sodium triacetoxyborohydride (1.66 g, 7.89 mmol) in 1,2-dichloroethane (50 ml) was stirred at room temperature for 72 hours. The mixture was filtered through a diatomaceous earth pad. The diatomaceous earth pad was washed with dichloromethane. The combined filtrates were washed with NaHCO3 (aqueous saturated solution), dried over Na2SO4 and evaporated till dryness. The crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM/MeOH(NH3) up to 5%). The desired fractions were collected and evaporated in vacuo to yield intermediate 11 as a yellow oil (1.44 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([C:18](=[O:25])[NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]([F:26])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:27][CH:28]([CH:31]1[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[O:32]1)[CH2:29][NH2:30].C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O>CN(C)C=O>[OH:27][CH:28]([CH:31]1[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[O:32]1)[CH2:29][NH:30][C:11](=[O:12])[C:10]1[CH:14]=[C:15]([F:26])[CH:16]=[C:17]([C:18](=[O:25])[NH:19][CH2:20][C:21]([F:23])([F:24])[F:22])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(C(O)CN)O1
Reactant: O=C(O)c1cc(F)cc(C(=O)NCC(F)(F)F)c1OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CN(C)C=O
Product: CC1(C)OCC(C(O)CNC(=O)c2cc(F)cc(C(=O)NCC(F)(F)F)c2OCc2ccccc2)O1
Temperature: -10 °C
Reaction time: 6 h

Procedure:
4.46 g (12 mmol) of 2-benzyloxy-5-fluoro-3-(2,2,2-trifluoroethylcarbamoyl)-benzoic acid is dissolved in 30 ml of dry N,N-dimethylformamide with exclusion of moisture, 1.85 g (12 mmol) of hydroxybenzotriazolel, 2.43 g (15 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine are added and the solution is cooled to -10° C. 2.68 g (13 mmol) of dicyclohexylcarbodiimide is added by portions to the cooled solution, it is stirred for 1 hour at -10° C. and 6 hours at room temperature. The precipitate of the dicyclohexylurea is then suctioned off, the filtrate is evaporated to dryness in a vacuum and the residue is dissolved in about 100 ml of ethyl acetate. The solution is shaken out with saturated bicarbonate solution and with water, dried on sodium sulfate, filtered and concentrated by evaporation and chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 4.22 g (8.2 mmol)=68.3% of the theoretical yield of the compound is obtained as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13](I)[C:8]2=[C:7]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])[N:6]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH2:36][CH3:37])=[C:30](B(O)O)[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([C:28]3[CH:27]=[C:26]([F:25])[CH:31]=[CH:30][C:29]=3[O:35][CH2:36][CH3:37])[C:8]2=[C:7]([NH:15][CH2:16][C@H:17]([OH:19])[CH3:18])[N:6]=1
Reactant: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(I)c12
Reactant: CCOc1ccc(F)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOc1ccc(F)cc1-c1n[nH]c2nc(Oc3ccc(F)cc3F)nc(NC[C@@H](C)O)c12
Temperature: 180 °C
Yield: 30.6 %

Procedure:
1-[6-(2,4-Difluoro-phenoxy)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (200 mg, 0.447 mmol), 5-fluoro-2-ethoxyphenyl boronic acid (246 mg), K3PO4 (285 mg), and Tetrakis(triphenylphosphine)palladium(0) CH2Cl2 (73 mg) were added to 2 mL dioxane in a microwave vial. The vial was sealed and the reaction mixture was heated to 180° C. for 10 minutes. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was filtered through silica gel using 10% MeOH in methylene chloride, then purified by preparative scale thin layer chromatography using 10% MeOH in methylene chloride, to give 62.9 mg of (R)-1-[6-(2,4-Difluoro-phenoxy)-3-(2-ethoxy-5-fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol. Mass Spec. M+H=460.
Reaction SMILES: Cl[CH:2]([C:11](=O)[CH2:12][CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:30]([NH2:32])=[S:31])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>>[Cl:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH2:3][C:2]1[S:31][C:30]([NH:29][C:19]2[CH:20]=[CH:21][C:22]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:17]([O:16][CH3:15])[CH:18]=2)=[N:32][C:11]=1[CH2:12][CH3:13]
Reactant: CCC(=O)C(Cl)Cc1cccc(Cl)c1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Product: CCc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)sc1Cc1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 76 mg (0.33 mmol) 2-chloro-1-(3-chloro-phenyl)-pentan-3-one and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 62 mg (47%) [5-(4-chloro-benzyl)-4-ethyl-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light brown viscous oil. MS ISP (m/e): 439.2/441.2 (100/40) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.19 (s, 1H), 7.74 (s, 1H), 7.64 (s, 1H), 7.35-7.18 (m, 5H), 7.10 (d, 1H), 7.02 (s, 1H), 4.02 (s, 2H), 3.79 (s, 3H), 2.56 (q, 2H), 2.14 (s, 3H), 1.20 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:30][C:29](=O)[O:28][C:26](=[O:27])[CH2:25]2)=[CH:20][CH:19]=1.Cl>O1CCOCC1>[ClH:17].[C:5]([C:4]1[CH:13]=[CH:14][C:15]2[N:16]=[C:29]([CH2:30][CH:24]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)[CH2:25][C:26]([OH:28])=[O:27])[NH:1][C:2]=2[CH:3]=1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CC(Cc1nc2ccc(C(=O)c3ccccc3)cc2[nH]1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 140.3 %

Procedure:
The solution of commercial 3,4-diaminobenzophenone (0.43 g) and 3-(4-chlorophenyl)glutaric anhydride (0.45 g) in 1,4-dioxane (3 ml) was stirred under reflux for 0.5 h. 4M HCl in 1,4-dioxane (3 ml) was added and the solution is further heated to reflux for 2.5 h. After cooling to rt the precipitate is collected by suction filtration and washed with 1,4-dioxane and diethyl ether. The crude is recrystallised from acetic acid to give 4-(5-benzoyl-2-benzimidazolyl)-3-(4-chlorophenyl)butanoic acid HCl (0.64 g) as light brown solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[S:25])[S-:24])[CH:19]=[CH:20][CH:21]=1.C([NH+](CC)CC)C.O>C(#N)C.CCOCC>[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[C:3]([C:5]3[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=3)([OH:4])[CH2:2][S:25][C:23]2=[S:24])[CH:19]=[CH:20][CH:21]=1
Reactant: S=C([S-])Nc1cccc(Cl)c1
Reactant: NS(=O)(=O)c1ccc(C(=O)CBr)cc1
Agent: CC[NH+](CC)CC
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccc(C2(O)CSC(=S)N2c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5 g of the product of Example 5 and 5.5 g of the product of Example 6 are dissolved in 60 ml of acetonitrile, and the mixture is stirred for 5 h at ambient temperature. It is then poured into 500 ml of water, extracted with dichloromethane, the dichloromethane phase is then washed with water, then dried over magnesium sulphate and evaporated off. The solid obtained is taken up in ether and filtered.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C@H:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:7]21[CH3:18])[CH3:2].F[B-](F)(F)F.[O:24]=[N+:25]=[O:26]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([N+:25]([O-:26])=[O:24])[CH:12]=1)[N:9]([CH3:13])[C@H:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:7]21[CH3:18])[CH3:2]
Reactant: O=[N+]=O
Reactant: CCOc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOc1cc([N+](=O)[O-])c2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Reaction time: 0.33 h

Procedure:
A degassed solution, under nitrogen, of 3.70 g of (3aS-cis)-5-ethoxy-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole in 50 ml of dry chloroform was treated with 2.00 g of nitronium tetrafluoroborate at a reaction temperature of +10°. After 20 minutes, the reaction was quenched by the addition of ice and saturated sodium bicarbonate solution with vigorous stirring. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to an oil. This was purified by chromatography over silica gel using ethyl acetate as the eluent. The fractions containing the product were combined and concentrated to an oil which crystallized from hexane to afford crystals of pure (3aS-cis)-5-ethoxy-1,2,3,3a,8,8a-hexahydro-7-nitro-1,3a,8-trimethylpyrrolo[2,3-b]indole, mp 106°-108° C.