Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]2[CH:17]=[CH:18][N:19]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:4]=2[C:3]1=[O:30].Br[C:32]1[CH:33]=[C:34]([NH:47][S:48]([CH2:51][CH3:52])(=[O:50])=[O:49])[CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=1[F:46].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].CC12CC3(C)P(C4C=CC=CC=4)C(C)(CC(C)(O3)O1)O2>[F:46][C:40]1[CH:41]=[C:42]([F:45])[CH:43]=[CH:44][C:39]=1[O:38][C:37]1[CH:32]=[CH:33][C:34]([NH:47][S:48]([CH2:51][CH3:52])(=[O:49])=[O:50])=[CH:35][C:36]=1[C:6]1[C:5]2[CH:17]=[CH:18][N:19]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:4]=2[C:3](=[O:30])[N:2]([CH3:1])[CH:7]=1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Agent: [Pd]
Agent: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1)O2
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A mixture of 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (6.00 g, 14.0 mmol), N-(3-bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (5.77 g, 14.7 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.205 g, 0.700 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.321 g, 0.350 mmol) and potassium phosphate (2.97 g, 14.0 mmol) was combined and sparged with argon for 30 minutes. A mixture of dioxane (60 mL) and water (15 mL) was sparged with nitrogen for 30 minutes and transferred by syringe into the reaction vessel under argon. The reaction mixture was stirred at 60° C. for 2 hours, cooled to ambient temperature, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (anhydrous sodium sulfate), treated with silica gel (2-4 g) for 45 minutes, filtered and concentrated to afford N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (8 g, 13.04 mmol, 93% yield).
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:28][CH2:27][CH2:26][C@H:11]2[C:12]([NH:14][C@H:15]([C:23]([OH:25])=O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][NH:38][C:23](=[O:25])[C@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:14][C:12](=[O:13])[C@@H:11]1[CH2:26][CH2:27][CH2:28][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:29])=[CH:6][CH:5]=1)(=[O:9])=[O:8])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: NOCc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)NOCc2ccccc2)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-prolyl-L-phenylalanine was coupled to O-benzylhydroxylamine using the procedure described in Method 3 to give the title compound as a white solid, mp=127-130° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([OH:10])[C:8]#[CH:9]>C(#N)C.[Cu]I>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:9]#[C:8][CH2:7][OH:10]
Reactant: Brc1nccs1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CC#N
Product: OCC#Cc1nccs1
Reaction time: 80 h
Yield: 16.3 %

Procedure:
Copper (I) iodide (28.5 mg) was added to a stirred solution of 2-bromothiazole (5 g), propargyl alcohol (1.68 g), BTPC (210 mg) and DEA (2.41 g) in acetonitrile (88 ml). The mixture was stirred under nitrogen for 80 h, concentrated and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was dried and concentrated to yield the crude product which was purified by FCC eluting with toluene/ethyl acetate (5:2) to give the title product as a brown oil (0.68 g), t.l.c. (toluene/ethyl acetate 2:1) Rf 0.27.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([C:32]1[O:36][C:35]([C:37](O)=[O:38])=[CH:34][CH:33]=1)#[N:31].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:37]([C:35]3[O:36][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)=[O:38])=[C:16]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(C(=O)O)o1
Reactant: CC1CCN(c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 88.3 %

Procedure:
The procedure of Example 4, step (c) was followed using 145 mg (0.358 mmol) of 4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (as prepared in the previous step), 70 mg of 10% palladium on carbon (50% by weight water), 49.1 mg (358 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 62.4 μL (0.716 mmol) of oxalyl chloride, and 93.6 μL (0.537 mmol) of DIEA. Chromatography on a 20-g silica SPE column with 20-40% EtOAc-dichloromethane followed by recrystallization from EtOAc-hexane afforded 156 mg (88%) of the title compound as a light yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.60 (br s, 1H), 8.32 (d, 1H, J=8.9 Hz), 7.22, 7.24 (AB q, 2H, J=3.7 Hz), 6.79 (d, 1H, J=2.6 Hz), 6.72 (dd, 1H, J=8.9, 2.6 Hz), 3.58-3.60 (m, 4H), 3.10 (br s, 4H), 2.97-3.00 (m, 2H), 2.70-2.75 (m, 2H), 1.82-1.85 (m, 2H), 1.55-1.65 (m, 1H), 1.49 (s, 9H), 1.45-1.55 (m, 2H, partially obscured by t-Bu peak) and 1.07 (d, 3H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C28H37N5O4, 494.3 (M+H), found 494.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[C:7](=[NH:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25]>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:24](=[O:25])[C:23]2[CH:27]=[C:19]([Cl:18])[CH:20]=[CH:21][C:22]=2[O:28][CH3:29])/[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CC(C)(C)c1ccn(C[C@H]2CCCO2)c(=N)c1
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\cc(C(C)(C)C)ccn1C[C@H]1CCCO1
Temperature: 60 °C
Reaction time: 14 h
Yield: 8.8 %

Procedure:
To a solution of the crude product of Example 61A (0.8 g, 1.7 mmol) in tetrahydrofuran (10 mL) were added 5-chloro-2-methoxybenzoyl chloride (0.4 g, 1.9 mmol) and triethylamime (0.7 mL, 5.1 mmol). After stirring at 60° C. for 14 h, the reaction mixture was cooled and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-5% methanol in dichloromethane) to provide 60 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.26 (s, 9H), 1.50-1.69 (m, 1H), 1.69-2.09 (m, 3H), 3.57-3.70 (m, 1H), 3.75 (s, 3H), 3.76-3.86 (m, 1H), 4.00 (dd, J=12.9, 8.5 Hz, 1H), 4.30 (dd, 1H), 4.57 (dd, J=12.7, 3.2 Hz, 1H), 6.87 (dd, J=7.0, 2.2 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.34 (dd, J=8.8, 2.7 Hz, 1H), 7.53 (d, J=2.7 Hz, 1H), 7.95 (d, J=7.1 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H) MS (ESI+) m/z 403 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]([C:11](Cl)=[O:12])[C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.[CH3:15][S:16][C:17](=[NH:23])[NH:18][N:19]=[C:20]([CH3:22])[CH3:21]>C(N(CC)CC)C>[CH:1]1([N:7]2[C:11](=[O:12])[NH:23][CH:17]([S:16][CH3:15])[N:18]([N:19]=[C:20]([CH3:22])[CH3:21])[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSC(=N)NN=C(C)C
Reactant: O=C(Cl)N(C(=O)Cl)C1CCCCC1
Agent: I
Solvent: CCN(CC)CC
Product: CSC1NC(=O)N(C2CCCCC2)C(=O)N1N=C(C)C

Procedure:
Analogously to Example 1, N-cyclohexyl-bis-(chloro-carbonyl)-amine (prepared analogously to Snythesis 1970, pages 542-543; boiling point 80°-82° C/0.3 mm Hg) and acetone-S-methylisothiosemicarbazone hydroiodide, with addition of triethylamine, yielded 1-cyclohexyl-3-isopropylideneamino-4-methylmercaptotetrahydro- 1,3,5-triazine-2,6-dione as a pale yellow powder of melting point 111°-112° C.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:13][C:5]2[NH:6][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:8][C:4]=2[C:3]1=O.C([SiH](CC)CC)C.CO.C(Cl)Cl>C(O)(C(F)(F)F)=O>[F:15][C:2]1([F:1])[CH2:13][C:5]2[NH:6][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:8][C:4]=2[CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CC(F)(F)C2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc2c([nH]1)CC(F)(F)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.7 %

Procedure:
To a solution of methyl 5,5-difluoro-4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (111.2 mg, 0.517 mmol) in TFA (1 mL) under nitrogen at 25° C. was added triethylsilane (0.25 mL, 1.55 mmol) and the reaction mixture was stirred for 18 h at 25° C. TLC analysis (10% MeOH/DCM) indicated that all starting material had been consumed. The solvent was removed using a nitrogen stream and the residue was taken up in MeCN and purified by reverse-phase chromatography (MeCN/H2O, 0.05% TFA) to afford 3.9 mg of methyl 5,5-difluoro-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate in 3.8% yield. 1H NMR (400 MHz, ACETONE-d6) δ ppm 3.15 (t, 2H), 3.31 (t, 2H), 3.76 (s, 3H), 6.64 (d, 1H), 10.83 (bs, 1H); 19F NMR (400 MHz, Acetone-d6) δ ppm −86.73; LCMS-MS (ESI+) 202.0 (M+H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1.[Br:12]N1C(=O)CCC1=O.C(OCCCC)(=O)C>C(#N)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH2:11][C:1]1[CH:2]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Solvent: CCCCOC(C)=O
Product: O=C(O)Cc1cccc(CBr)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
m-Tolylacetic acid (4.0 g, 26.64 mmol) and AIBN (α,α′-azobisisobutyronitrile) (0.044 g, 0.266 mmol) were dissolved in acetonitrile (11.9 g) and the solution was raised to 80° C. To this solution was dropped a solution of N-bromosuccinimide (4.98 g, 27.97 mmol) and AIBN (α,α′-azobisisobutyronitrile) (0.044 g, 0.266 mmol) in acetonitrile (32 g) for 1.5 hours. After stirring for 30 minutes the mixture was cooled to 50° C. and thereto was added butyl acetate (38.7 g). The mixture was concentrated to remove only acetonitrile. The resulting succinimide (crystal) was removed and the residue was washed three times with water. After concentrating to a desired concentration, thereto was added at 45° C. n-heptane (45.6 g) to produce a crystal. After cooling to 5° C., the crystal was filtered to give the sub-subject compound (3.76 g) as a white crystal. Yield: 62%
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[C:11]([NH2:14])[C:10]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]([CH:27]=O)=O>CO>[CH2:1]([N:8]1[C:12]2=[N:13][CH:25]=[CH:27][N:14]=[C:11]2[C:10]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC=O
Reactant: Nc1c(-c2ccc3ccccc3c2)nn(Cc2ccccc2)c1N
Solvent: CO
Product: c1ccc(Cn2nc(-c3ccc4ccccc4c3)c3nccnc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
190 mg of 2-benzyl-5-(naphthalen-2-yl)-2H-pyrazole-3,4-diamine was dissolved in 10 mL of methanol, added with 100 μl of 40% glyoxal aqueous solution, and stirred at room temperature for 5 hours. The reaction solution was partitioned between water and ethyl acetate, and the organic layer was extracted and washed with water. The organic layer was dried over magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5), to afford 180 mg of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[O:25])=[CH:23][C:17]=4[N:16]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[O:25])=[CH:23][C:17]=4[N:16]=3)=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(C(O)c4ccc(Cl)cc4)cc3)nc2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc2[nH]c(-c3ccc(Cc4ccc(Cl)cc4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a solution of 2-{4-[(4-chloro-phenyl)-hydroxy-methyl]-phenyl}-1-H-benzoimidazole-5-carboxylic acid amide (Example 20, 50 mg, 0.13 mmol) in TFA (5.0 mL) was added sodium borohydride (211 mg, 4.2 equiv), and the reaction mixture was stirred at RT for 16 h. Water (5.0 mL) was added to the mixture, which was then adjusted to pH 9 with 1 N NaOH. The precipitate was collected by filtration and washed with H2O (20 mL). Purification by chromatography (silica gel, 1% methanol saturated with ammonia/9% methanol/CH2Cl2) afforded 39 mg (81%) of the title compound. HPLC (Method A): Rt=7.64. MS (ESI+): mass calculated for C21H16ClN3O, 361.1; m/z found, 362.2 [M+H]+. 1H NMR (500 MHz, CD3OD): δ 8.23 (d, J=1.4 Hz, 1H), 8.06 (d, J=8.2 Hz, 2H), 7.94-7.92 (dd, J=8.5, 1.6 Hz, 1H), 7-0.74 (d, J=8.5 Hz, 1H), 7.48 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 4.09 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4]N(C)C)[CH3:3].P(=O)(O)(O)O.[OH-].[Na+].[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[CH-:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.[Fe+2:25]>C(O)(=O)C.O>[CH3:1][N:2]([C:4]1[C-:19]([CH3:18])[CH:15]=[CH:16][CH:17]=1)[CH3:3].[CH-:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.[Fe+2:25]
Reactant: CN(C)CN(C)C
Agent: [Fe+2]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C[c-]1cccc1N(C)C
Temperature: 25 °C
Yield: 83.9 %

Procedure:
173 g (1.69 moles) of bis-dimethylaminomethane were added, while cooling, to a solution of 173 g of phosphoric acid in 1,600 ml of glacial acetic acid, 185.6 g (1.0 mole) of ferrocene were then added and the mixture was warmed for 5 hours under a nitrogen atmosphere on a waterbath. The reaction mixture was then cooled to room temperature and diluted with 2,200 ml of water and unconverted ferrocene was removed by extraction with ether. The remaining reaction mixture was rendered alkaline by adding 480 g of sodium hydroxide, diluted with a further 800 ml of water and then extracted three times with ether. The organic phase was separated off, washed with water and, after drying over sodium sulfate, concentrated. 204 g (89% of theory) of N,N-dimethylamino-methylferrocene remained and were taken up in 215 ml of methanol. 215 ml (500 g) of methyl iodide were added to the resulting solution and the mixture was heated for 5 minutes on a boiling waterbath and, after cooling to room temperature, poured into 3,200 ml of ether. The product, which was initially obtained as an oil, crystallised on trituration. In this way, 323 g (83.9% of theory) of N,N-dimethylamino-methylferrocene methoiodide with a melting point of 213° C (decomposition) were obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH3:29])=[CH:26][C:27]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CCc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(CC)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-5-ethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c14) the title compound is obtained as pale yellow solid.
Reaction SMILES: [CH3:1][CH2:2]N(CC)CC.Br[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:23][C:22]([CH3:24])=[N:21][C:20]=2[Cl:25])=[O:18])=[C:11]([F:26])[C:10]=1[O:27][C:28]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[C:30]([Cl:36])[CH:29]=1.C([B-](F)(F)F)=C.[K+]>C(O)CC>[Cl:25][C:20]1[N:21]=[C:22]([CH3:24])[NH:23][C:19]=1[C:17]([NH:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH:1]=[CH2:2])=[C:10]([O:27][C:28]2[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[C:30]([Cl:36])[CH:29]=2)[C:11]=1[F:26])=[O:18]
Reactant: Cc1nc(Cl)c(C(=O)NCc2ccc(Br)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Reactant: CCN(CC)CC
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCCO
Product: C=Cc1ccc(CNC(=O)c2[nH]c(C)nc2Cl)c(F)c1Oc1cc(Cl)cc(C#N)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
Et3N (0.351 ml, 2.52 mmol) was added to a mixture of N-({4-bromo-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-chloro-2-methyl-1H-imidazole-5-carboxamide (251 mg, 0.504 mmol), potassium vinyltrifluoroborate (101 mg, 0.756 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloride dichloromethane complex (41.1 mg, 0.050 mmol) in n-propanol (5 ml) under N2. The mixture was heated to 100° C. and stirred for 4 h. Cooled down to RT and the reaction mixture was filtered through a pad of celite and concentrated to dryness. The residue was dissolved in EtOAC, washed with Sat. NaHCO3, dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on silica gel eluted with 0-5% 2M NH3 solution of MeOH in CH2Cl2 to give the title compound as a light-yellow solid (154 mg, 69%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.33 (1H, br. s.) 7.40 (1H, d, J=8.2 Hz) 7.31 (1H, s) 7.26-7.29 (1H, m) 7.12 (2H, br. s.) 6.98 (1H, s) 6.69 (1H, dd, J=17.6, 11.2 Hz) 5.81 (1H, d, J=17.6 Hz) 5.37 (1H, d, J=11.1 Hz) 4.70 (2H, d, J=5.9 Hz) 2.39 (3H, s). LCMS: m/z 445 (M+1).
Reaction SMILES: [H-].[K+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.FC(F)(F)S(O[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])(=O)=O>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2CCN(C)CC2)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 173.3 %

Procedure:
To a 10° C. slurry of potassium hydride (1.6 g, 14.3 mmol, 35% in mineral oil) in tetrahydrofuran (40 mL) was added neat 5-bromo-3-(1-methyl-4-piperidinyl)indole (2.8 g, 9.5 mmol) portionwise over 30 minutes. The resulting reaction mixture was stirred at 0° C. for 1 hour. Triisopropylsilyl trifluoromethanesulfonate (3.1 mL, 11.4 mmol) was added dropwise over 20 minutes and a slight exotherm was observed. After stirring 2 hours at 0° C., the reaction was quenched with ice chips then diluted with water and methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride. The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 7.4 g of a clear colorless oil. Purification by chromatography (florisil, 50:50 methylene chloride:hexanes, then 100% methylene chloride, then 95:5 methylene chloride:methanol) provided 3.6 g (84.1%) of the title compound. MS(FD) 448, 450 (M+).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH2:9][C:8]([C:23]#[N:24])([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH:11]=2)[CH2:7][CH2:6][C:5]=1[O:25]COC)=[O:3]>C(O)(=O)C>[NH2:1][C:2]([CH:4]1[CH2:9][C:8]([C:23]#[N:24])([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH:20]3[CH2:21][CH2:22]3)[CH:11]=2)[CH2:7][CH2:6][C:5]1=[O:25])=[O:3]
Reactant: COCOC1=C(C(N)=O)CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CC1
Solvent: CC(=O)O
Product: COc1ccc(C2(C#N)CCC(=O)C(C(N)=O)C2)cc1OCC1CC1
Yield: 35.9 %

Procedure:
A solution of 2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene (0.22 g, 0.57 mmol) in 50% aqueous acetic acid (12 mL, containing 9 drops concentrated sulfuric acid per 30 mL) was heated at 75° C. under an argon atmosphere for 2 h. The mixture was cooled, was partitioned between methylene chloride and water, was extracted twice, the organic layer was dried (potassium carbonate)and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 5% methanol/chloroform, followed by crystallization from ether/methylene chloride, provided a white powder (0.07 g, 51%): m.p. 154°-155° C.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2].[H-].[Na+].[I-].[CH3:15][C:16](C)=C[SH2+]>C1COCC1>[O:2]1[CH:15]2[CH2:16][N:4]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=4[CH:11]=[C:3]3[CH:1]12
Reactant: CC(C)=C[SH2+]
Reactant: O=Cc1cc2ccccc2[nH]1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)cc1n2CC2OC12
Reaction time: 15 h

Procedure:
In a 100-mL round-bottom flask, a total of 626 mg (4.31 mmol) of 2-formylindole and 259 mg (8.63 mmol) of NaH (80% dispersion in mineral oil) was stirred in 50 mL of dry THF under N2 at 0° C. ice bath). A total of 935 mg (4.31 mmol) of dimethylvinylsulfonium iodide was added after 20 minutes and the reaction mixture was stirred overnight (about 15 hours). The mixture was then evaporated under reduced pressure and the residue was washed with pentane or hexane. The filtrate was evaporated under reduced pressure. The resulting solid was analyzed by GC-MS and had a purity of 99%. Yield: 665 mg (72%). 1H NMR (CDCl3): δ4.09 (dd, 1H, J1 =12), 4.33 (d, 1H, J=12), 4.40 (d, 1H, J=2.5), 4.50 (t, 1H, J=2.5), 6.59 (s, 1H), 0.0-7.3 (m, 3H), 7.60 (d, 1H, J=7.5), 13C NMR (CDCl3 : δ45.94, 51.35, 60.83, 97.62, 109.23, 119.64, 121.68, 122.34, 131.44, 133.90, 139.12, MS (EI): m/z 171 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[C:16]#[N:17])[C:10]2[CH:33]=[C:34]([CH2:41][CH3:42])[C:35]([C:37]([F:40])([F:39])[F:38])=[CH:36][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:43]([Sn](CCCC)(CCCC)CCCC)=[N+:44]=[N-:45]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:18][C:19]2[CH:20]=[C:21]([C:29]([F:31])([F:32])[F:30])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=2)[C:16]2[N:43]=[N:44][NH:45][N:17]=2)[C:10]2[CH:33]=[C:34]([CH2:41][CH3:42])[C:35]([C:37]([F:40])([F:38])[F:39])=[CH:36][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Yield: 79.1 %

Procedure:
Heat a mixture of (S)-5-[(3,5-bistrifluoromethylbenzyl)cyanoamino]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid tert-butyl ester (0.510 g, 0.837 mmol), azidotributyltin (0.344 mL, 1.26 mmol) in anhydrous toluene (20 mL) at 100° C. under nitrogen for 16 h. Dilute the cooled mixture with ethyl acetate (50 mL) and wash with aqueous NaF (50 mL) and brine (50 mL). Dry over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0-60%), to provide the title compound (0.432 g, 79%), MS (ES+): 653 (M+H).